VigRx Delay Spray Based on the original sizing your men body program, there are many medical methods that can impact the sizing your men body program, such as suspensory ligament removal, dermal graft augmentation, fat transfers and others. Whilst the results usually vary individually for every person, usually people take advantage of the surgeries and the answers are long lasting. As the operations are painful as well as costly, they are not incredibly well-known in the modern day globe. However, these methods do help in assisting the gap as well as the width of your men body program.
https://www.godiply.com/vigrx-delay-spray-reviews/

Apparently he made a video on some DNP protocol and some people got fucked up from it.

Here he is pleading the 5th. Fuk I wish we could do that in Australia.
https://www.youtube.com/watch?v=48-JC9Va8lM

For those that have any interest in stocks you should at least take a look at the Canadian marijuana sector. It's been going nuts for the last month. Marijuana goes fully legal in 6 weeks and big American alcohol and tobacco companies are buying in big. CGC was $5 just 2 months ago, it's now $52 dollars. That's over a 10x gain and it's not slowing down. You can trade these companies on American stock exchanges under (CGC), (CRON), and (TLRY).

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3 Reasons Big Tobacco and Marijuana Partnerships Are Imminent

https://finance.yahoo.com/news/3-rea...html?.tsrc=rss

The green rush is in full force. Beginning in less than six weeks, recreational marijuana will be completely legal in Canada. Aside from Canada becoming the first developed country in the world, and second overall, to wave the proverbial green flag on adult-use weed, this move could also generate upwards of $5 billion in added annual revenue once the industry is running on all cylinders.

Dealmaking ramps up as legalization inches closer
Legalizing weed in our neighbor to the north has also spurred a lot of dealmaking activity both outside and within the cannabis industry. Within the industry, leading producer Aurora Cannabis, which is expected to yield 570,000 kilograms a year once fully operational, acquired CanniMed Therapeutics and Ontario-based MedReleaf for $852 million and approximately $2.5 billion, respectively.

But what's happening outside the industry is what has investors' full attention. Last month, we witnessed two major partnerships take place between Big Alcohol and the cannabis industry. On Aug. 1, Molson Coors Brewing announced the formation of a 57.5%-42.5% joint venture with HEXO Corp (previously known as Hydropothecary Corp) to develop nonalcoholic, cannabis-infused beverages. Interestingly enough, infused beverages won't be legal come Oct. 17, although Canada's Parliament is expected to discuss, and likely broaden, what forms of consumption are legal next year.

Making even bigger headlines was Constellation Brands' (NYSE:STZ) $3.8 billion equity investment in Canopy Growth Corp (NYSE:CGC) at a 51% premium to its prior-day closing price on Aug. 15. This was actually the third time the maker of the Corona and Modelo beer brands had invested in Canopy Growth. Aside from just product innovation, Constellation should be able to offer its marketing and international expansion expertise to Canopy Growth, while Canopy will be able to offer its insight into the cannabis industry to Constellation Brands.

A Big Tobacco-marijuana marriage appears inevitable
Though most investors have wondered what alcohol company could be next -- rumor has it that Diageo is looking for a cannabis partner -- they might be overlooking the next-most logical entrant into the cannabis space: Big Tobacco.

Here are three reasons a Big Tobacco-marijuana partnership appears inevitable.

1. Key tobacco metrics are declining in developed markets
The biggest impetus for Big Tobacco to seek out a partnership or investment opportunity with the marijuana industry is declining usage and shipment volume in developed markets. Within the U.S., the percentage of U.S. adults smoking cigarettes has declined from around 42% in the mid-1960s to just 15.5% as of 2016. The industry is also facing marketing, advertising, and branding restrictions in key developed markets around the globe.

For example, Altria (NYSE:MO), which is best known for its premium Marlboro brand in the U.S., reported a 6.3% sales decline in smokable products during the second quarter of 2018, as well as a 3.7% decline through the first half of the year. Overall, Altria's smokable domestic shipment volume wound up plunging 10.8%.

Meanwhile, Philip Morris International (NYSE:PM), which operates in more than 180 countries around the world, not including the U.S., saw its total cigarette shipment volume fall by 1.5% in the second quarter, and 3.3% through the first half of the year. In fact, with the exception of its Fortune and Dji Sam Soe brands, every other cigarette brand has delivered a volume decline during the first half of 2018.

2. Big Tobacco has more than enough capital to make a deal happen
Another good reason to believe a deal should happen between Big Tobacco and cannabis is that Big Tobacco has more than enough cash on hand, and operating cash flow, to make it happen.

Despite the fact that volume has been in constant decline for Altria and more recently Philip Morris, both tobacco companies offer incredible pricing power as a result of nicotine's addictive nature. For instance, even though Philip Morris experienced a 3.3% slide in cigarette shipments during the first half of the year, it still managed to grow revenue by 8.3%, if you exclude the benefit of currency movements. Being able to pass along price hikes to consumers has long been a means to higher sales and profitability for tobacco stocks.

But the thing is, Big Tobacco also needs to innovate and find new ways to grow. For as long as this investor can recall, Altria and Philip Morris have paid out enormous dividends to lure in long-term investors. Yet, these companies are still generating a lot of annual operating cash flow. Altria has averaged about $5 billion annually over the past five years, with Philip Morris generating closer to $8.5 billion over the same time frame. That's more than enough to divert some of this cash flow to an investment or joint venture in the cannabis industry.

3. It's a logical product evolution
Finally, Big Tobacco partnering with the marijuana industry would be a logical evolution of where the tobacco industry is already headed.

Earlier this decade, the introduction of electronic cigarettes were all the rage. More recently, heated tobacco units, such as Philip Morris' iQOS device, have been garnering attention. The point being that Big Tobacco has been working on ways to lessen its reliance on traditional dried tobacco for years, and what the cannabis industry is trying to accomplish would be complementary to the tobacco industry's goals.

For example, assuming the Canadian federal government approves new forms of consumption in 2019, beyond just dried cannabis and cannabis oils, vaporized cannabis cartridges could be used in existing devices that consumers have been using for vape products, or perhaps even with heated tobacco units. It would be a relatively seamless transition for both the tobacco and cannabis industries, and should be beneficial to both.

A former Hamden police officer has been sentenced for distributing steroids, according to the office of John H. Durham, United States Attorney for the District of Connecticut.

Madison resident Bryan Kelly, 46, was sentenced to three years of probation, with the first six months in home confinement with location monitoring, for distributing anabolic steroids. He was also ordered to pay a $1,000 fine and perform 100 hours of community service.

In December 2017, the Statewide Narcotics Task Force West searched a Hamden home and seized around 25,000 pills and 530 vials of anabolic steroids. Investigators found that the resident had text messages relating to Kelly’s purchase and dealing of the steroids. At the time, Kelly was a police officer with the Hamden Police Department. He has since retired.

According to court documents, Kelly purchased the steroids and distributed some to friends and colleagues.

Kelly pleaded guilty to one count of possession with intent to distribute anabolic steroids.

https://www.nbcconnecticut.com/news/...492432601.html

7 Most Important Benefits Of Deadlifting:
1) Muscle Growth

This tops the list of benefits for very obvious reasons. Most guys want bigger muscles and there is no better exercise for overall muscle growth. When you deadlift the right way, you use almost every single muscle in your body. You get a rigorous full body workout. And when you combine that with heavy lifting, you naturally release growth hormones that induce muscle development.

2) Strength Gain

If you want fast strength increase on all the exercises that are part of your workout routine, deadlifting is your solution. It increases your grip and core strength like no other exercise can. Want a bigger bench? Stronger squat? Crazy curling strength? Pullup power? Easy fix, just deadlift heavy.

3) More Powerful

Power while sometimes used interchangeably with strength is actually different from it. Power is the ability to exert great force and a short period of time. While strength is the ability to move or support heavy objects sustainably for a longer period of time. Power is useful for athletic performance. A football linebacker tackling a an opponent, a tennis player returning a serve, a basketball player dunking over opponents etc. If you play any sport, deadlifting will make a big difference in your performance.

4) Testosterone increase

What guy doesn’t want more testosterone? It makes you more manly, more attractive to the ladies, more upbeat about life and you just want to get shit done. Resistance training itself can increase your testosterone level, but add heavy deadlifts to the mix and you’ve got a natural test booster with only positive side effects.

5) Better Overall health

Stronger, more testosterone, more positive outlook on life equals better overall health. It’s simple. Doing deadlifts also improves your cardio. And as you know, good cardio is important for overall health. You also build joint strength and your immune system gets stronger. Most Compound exercises will do these things but the one thing that makes the deadlift stand out is that it does this for your entire body. It’s a true full body powerhouse.

6) Positive Effect on other exercises

When you combine the above benefits, what you get is increased strength and flexibility on all other exercises. When you do heavy deadlifts, you are actually doing heavy lifting using all the major muscles in your body, back, chest, legs, arms etc. So when you do isolation movements or other more specific compound movements, you will notice an immediate strength gain.

7) Fat burning

Because of the exertion involved during the deadlift, you recruit more muscle fibers, burn more calories and than you could with other movements. The result is increased fat burning. If you’ve read my other articles, you know that compound movements are the best exercises for fat loss. And the deadlift is the king of compound exercises so you get the idea. Thanks

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2822143/

Abstract
The growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis regulates cardiac growth, stimulates myocardial contractility and influences the vascular system. The GH/IGF-1 axis controls intrinsic cardiac contractility by enhancing the intracellular calcium availability and regulating expression of contractile proteins; stimulates cardiac growth, by increasing protein synthesis; modifies systemic vascular resistance, by activating the nitric oxide system and regulating non-endothelial-dependent actions. The relationship between the GH/IGF-1 axis and the cardiovascular system has been extensively demonstrated in numerous experimental studies and confirmed by the cardiac derangements secondary to both GH excess and deficiency. Several years ago, a clinical non-blinded study showed, in seven patients with idiopathic dilated cardiomyopathy and chronic heart failure (CHF), a significant improvement in cardiac function and structure after three months of treatment with recombinant GH plus standard therapy for heart failure. More recent studies, including a small double-blind placebo-controlled study on GH effects on exercise tolerance and cardiopulmonary performance, have shown that GH benefits patients with CHF secondary to both ischemic and idiopathic dilated cardiomyopathy. However, conflicting results emerge from other placebo-controlled trials. These discordant findings may be explained by the degree of CHF-associated GH resistance. In conclusion, we believe that more clinical and experimental studies are necessary to exactly understand the mechanisms that determine the variable sensitivity to GH and its positive effects in the failing heart.

Keywords: GH/IGF-1 axis, Chronic heart failure, Acromegaly, GH deficiency.
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INTRODUCTION
Growth hormone (GH), a 191 amino acid single-chain peptide, is synthesized and secreted by the somatotroph cells of the anterior pituitary gland [1, 2]. Its secretion is strictly regulated by two hypothalamic neurohormones: GH releasing factor (GHRF) and GH inhibiting factor (somatostatin). The ratio between these two factors represents the mechanism by which neurologic and extra-neurologic influences may functionally affect GH release [2-9]. Furthermore, GH can modulate its own secretion by different feedback loops: indirectly by producing insulin-like growth factor-1 (IGF-1), which inhibits somatotroph cells and stimulates somatostatin release, or directly by inhibiting GHRF messenger RNA (mRNA) and by stimulating somatostatin mRNA synthesis [10].

GH secretion is pulsatile, and is regulated by a number of neurologic, metabolic and hormonal influences: during most of the day, the plasma GH level of adults is 5 ng/ml, with one or two sharp spikes three to four hours after meals. The lowest circulating level is early in the morning and highest about one hour after the onset of deep sleep [11-14]. Secretion is enhanced by α2 agonists, hypoglycemia and daily life stresses, and inhibited by β and α1 agonists, glucocorticoids and aging [12, 14-17].

The biological effects of GH are mediated by the interaction with a specific receptor (GHR), a single chain trans-membrane protein, expressed in almost all cellular types (liver membranes, adipocytes, fibroblasts, lymphocytes, myocytes) [8, 11, 18, 19]. Its dimerization activates the Jak/Stat pathway (Janus Kinase and Signaling Transducer and Activates of Transcription), which induces intracellular signal transduction, thereby altering calcium (Ca2+) trafficking, regulating expression of contractile and cytoskeletal proteins and modifying activation of intrinsic neurohormonal networks [20].

GH exerts its effects either directly or indirectly [2, 21, 22]. Most of the indirect effects are mediated by induction of IGF-1 expression in the liver and in peripheral tissues [23-27]. It is well known that IGF-1 is the principal, but not the only, GH mediator. For instance, GH stimulates induction of c-myc proto-oncogene in various tissues and of platelet-derived growth factor in the heart [28, 29]. But the role of these and other growth factors is still unknown.

IGF-1, a 70 amino acid single chain protein, structurally homologous to pro-insulin, is synthesized in liver and kidney, although the local production in other tissues appears to be important in mediating, by paracrine or autocrine mechanisms, GH anabolic and growth-promoting effects [30-33]. IGF-1 circulates bound to protein carriers (IGFBPs), which serve not only to transport IGF-1 in the circulation but also to prolong its half life, modulate its tissue specificity and strengthen or neutralize its biological actions [31]. The serum concentration of IGFBPs is influenced by circulating GH levels, but does not have a circadian pattern. The intracellular signal pathways involved in IGF-1 transduction implicate insulin receptor substrate (IRS)-1, phosphatidylinositol (PI) 3-kinase, phospholipase C (PLC)-g1, mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) cascade [34].

The diminished age-related amplitude of GH pulses and the increased resistance to GH action contribute to reduce IGF-1 plasma concentration. The mechanisms underlying these age-related modifications include peripheral influences (gonadal steroids, adiposity), changes in hypotalamic neuropeptides and neurotransmitters, and increase in somatostatin secrection. [35]. Although the decline of GH/IGF-1 axis is associated with an increase in GH/IGF-1 receptors on cardiomyocytes, this increase fails to compensate the reduction of GH secretion probably because of the diminished intracellular signal transduction [36, 37]. In fact, in rodents, it has been widely demonstrated that with aging there is a reduction of JAK2 phosphorilation, a decline of MAP kinase activity, a reduction of STAT3 activation and a decrease in nuclear translocation [37-40]. GH/IGF-1 deficiency contributes to physiological age-related cardiovascular modifications, such as decrease in the number of cardiomyocytes [41-43], rarefaction of coronary arterioles [44], increase in fibrosis and collagen deposition [45-48], reduced protein synthesis [49] and alteration of contractile proteins with reduction in myosin-actin bridges [50].

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PHYSIOLOGICAL EFFECTS OF GH
GH alters body’s homeostasis and its effects can generally be described as anabolic. GH directly stimulates chondrocyte division and multiplication; it increases calcium retention, thereby strengthening bone mineralization [51]; promotes lipolysis and protein synthesis, by stimulating amino acid uptake [16, 52-55]; induces hyperglycemia, consequent to insulin resistance and gluconeogenesis [52, 56]; increases muscle mass, through sarcomere hyperplasia, and stimulates the immune system. In addition, GH increases peripheral conversion of thyroid hormone thyroxine (T4) to triiodothyronine, with a consequent decline of thyroid stimulating hormone and T4 levels [57]. It also activates the renin-angiotensin-aldosterone system and decreases atrial natriuretic peptide circulating level [58, 59].

CARDIOVASCULAR EFFECTS
Besides growth promoting and metabolic effects, the GH/IGF-1 axis regulates cardiac growth, stimulates myocardial contractility and influences the vascular system (Fig. ​11).

The myocardium and the endothelium not only express receptors for both GH and IGF-1, but also produce IGF-1 locally. Thus, there is a direct action of GH by endocrine mechanism and/or indirect action by autocrine/paracrine mechanisms of IGF-1 [30-32]. On vascular system, the GH/IGF-1 axis exerts its effects by activating the nitric oxide (NO) system and regulating non-endothelial-dependent actions [60-69]. NO production relaxes arterial smooth muscle cells, thereby reducing vascular tone. Furthermore, NO inhibits proliferation and migration of smooth muscle cells, reduces platelet adhesion, decreases lipoxygenase activity and oxidized LDL-cholesterol [60-69]. Recently, NO has been shown to modulate cardiac cytoskeletal functions by altering calcium myofilament responsiveness [70]. In addition, IGF-1 may cause vasorelaxation both by enhancing Na+/K+ ATPase activity [71] and regulating gene expression of KATP channel in vascular smooth cells [72]. This ATP-sensitive potassium channel consists of two subunits: the sulfonylurea receptor and the inwardly rectifying potassium channel, which could be critical in regulating vascular tone [73, 74].

The GH/IGF-1 axis may also regulate cardiac growth and metabolism, by increasing amino acid uptake, protein synthesis, cardiomyocyte size and muscle-specific gene expression. Specifically IGF-1 promotes cardiac hypertrophy and increases muscle specific gene transcription (namely, troponin I, myosin light chain-2, and α-actin) [75-77]. Moreover, IGF-1 promotes collagen synthesis by fibroblasts, whereas GH increases the collagen deposition rate in the heart [78-81]. Substantial evidence indicates that IGF-1 influences the trophic status of myocardium by reducing apoptosis of cardiomyocytes, thus preventing myocyte loss [76, 82].

The GH/IGF-1 axis can also control intrinsic cardiac contractility through different mechanisms: by enhancing myofilament calcium sensitivity [76, 77, 82, 83], modifying intracellular calcium transient through an increase in L- type calcium channel activity [84, 85] and up-regulating sarcoplasmatic reticulum ATPase (SERCA) levels [86, 87]. SERCA up-regulation may cause an increase in contractility, enhancing calcium contractile reserve in the sarcoplasmatic reticulum and allowing a higher calcium peak level on stimulation.

While IGF-1 positively affects cardiac contractility, GH physiological role, although GHRs are expressed on the heart, probably does not include acute modulation of myocardial contractility, but it needs to mediate some other functions such as protein synthesis or local IGF-1 production [82, 88].

Moreover, GH induces myosin phenoconversion toward the low ATPase activity V3 isoform. The prevalence of V3 isoform increases the number of actin-myosin cross-bridges and their attachment time, enhances protein calcium sensitivity and calcium availability and allows the myocardium to function at lower energy cost [76, 77]. V3 isoform also prevails in pathologic cardiac hypertrophy secondary to hemodynamic overload, to compensate depressed contractility and high wall stress.

Although GH reduces energy output, it favours the conversion of metabolic energy to external work and enhances the intrinsic ability of the myofilament to develop force, resulting in an improvement of LV performance [89]. In conclusion, GH improves myocardial energy metabolism reducing oxygen consumption and energy demand, even in failing heart in which the increment in wall stress increases oxygen demand [90]

The relationship between the GH/IGF-1 axis and the cardiovascular system has been extensively demonstrated in numerous experimental studies and confirmed by the derangements of cardiac structure and function reported in patients with both GH excess (acromegaly) and GH deficiency (GHD).

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CLINICAL EVIDENCE OF GH EXCESS IN HUMANS
Acromegaly is a clinical condition consequent to chronic GH excess that affects the heart. Acromegalic cardiac involvement was first described by Huchard in 1895 [91]. Subsequent reports documented that chronic GH excess leads to cardiac functional and morphological abnormalities [30, 76, 77, 92-97].

Acromegalic cardiomyopathy can be divided into three main stages [22, 89]. The early stage is characterized by functional abnormalities: enhanced myocardial contractility, decreased peripheral vascular resistance and increased cardiac output (hyperkinetic state) [22, 89, 98, 99]. In stage 1, ventricular wall thickening is not associated with cavity dilatation, so that relative wall thickness (left ventricular [LV] wall thickness/LV radius) increases and causes a reduction in wall stress and an increase in cardiac performance, according to the Laplace’s law (wall stress=LV pressure/LV relative wall thickness) [10, 22, 89, 99-106]. In this stage, the reduction of wall stress together with the positive effects of GH/IGF-1 on myocardial contractility and systemic vascular resistance produces an improvement in cardiac function. Initially, this increase in wall thickness and LV mass has no negative impact on diastolic function [22, 99, 105]. The intermediate stage (after about five years of active disease) is characterized by biventricular hypertrophy, diastolic dysfunction and impaired cardiac performance, which are undetected under resting condition, but appear on effort [22, 89, 103, 104, 107-109]. Hypertrophy, which entails proliferation of myocardial fibrous tissue, leads to progressive interstitial remodelling, which causes inexorable deterioration of cardiac performance. Diastolic abnormallities, which usually anticipate systolic dysfunction, include prolonged isovolumic relaxation time, decreased early-to-late mitral and tricuspid velocity ratio, reduced diastolic filling wave and increased reversal flow during atrial contraction. These alterations result in impaired ventricular relaxation and enhanced ventricular stiffness [22, 29, 104, 106]. In a very late stage, acromegalic cardiomyopathy is characterized by systolic and diastolic dysfunction that can lead to congestive heart failure, often resistant to conventional therapies, increased myocardial mass, marked ventricular cavity dilatation and high peripheral vascular resistance [22, 30, 98]. It also includes cardiac valve disease (mitral and aortic valve regurgitation), coronary artery disease and arrhythmias [110]. The prevalence of these complications is likely to depend on the duration of GH excess. Myocardial hypertrophy and interstitial fibrosis, which increase as the disease progresses, are responsible for myocardial ischemia, consequent to reduced capillary density, and arrhythmias, due to the interference of the pulse propagation process in the myocardium [111]. Electrocardiographic recordings have demonstrated a higher frequency of ectopic beats, paroxysmal atrial fibrillation or supraventricular tachycardia, sick sinus syndrome, ventricular tachycardia and bundle branch block in acromegalic patients as compared with the normal population [112-114].

The most relevant histological abnormalities are interstitial fibrosis, reduced capillary density, increased extracellular collagen deposition, myofibrillar derangement, lymphomononuclear infiltration and myocyte death due to necrosis and apoptosis [22, 110, 115, 116].

GH excess seems to exert different and potentially opposite effects on the heart: it enhances cardiac performance in early-stage acromegaly, whereas it causes cardiac dysfunction in the intermediate-late phase. This apparent discrepancy is easily clarified: a physiological GH level or short-term excess exert positive inotropic effect, whereas by causing morphological and functional adaptive changes, long-term exposure to GH excess induces cardiac dysfunction and progression to heart failure [76, 77, 92, 98, 106, 117, 118].

GH/IGF-1 may cause acromegalic morphological and functional changes either directly by affecting myocyte growth and contractility, or indirectly by affecting peripheral vascular resistance, modifying extracellular volume and neurohormonal activity. Subsequently, with the increase of arterial stiffness due to hypertrophy and fibrosis of the arterial muscular tunica, about 20-50% of acromegalic patients become hypertensive [119]. Experimental studies about the role of the neurohormonal system in the development and progression of acromegalic cardiomyopathy, have produced conflicting results [30, 120-128]. In the late 1970s, it was reported that chronic GH excess, by eliciting sympathetic overactivity, induces myocardial hypertrophy [120]. Only two decades later, it was demonstrated that GH exerts no sympatho-excitatory effects [122, 129]. Recently, it has been shown that in acromegalic cardiomyopathy, in contrast with other conditions of cardiac hypertrophy, there are low B-type natriuretic peptide (BNP) circulating levels and that the normalization of GH/IGF-1 serum concentrations is followed by an increase in BNP levels [130].

There is compelling evidence that IGF-1 is involved in the intricate cascade of events leading to cardiac hypertrophy. In fact, in response to pressure or volume overload, IGF-1 expression increases in parallel to hypertrophy [131, 132]. Moreover, numerous trials have shown that GH suppression, associated with IGF-1 normalization, reduces cardiovascular mortality to that of general population, which supports the concept that cardiac alterations in acromegaly are strictly related to GH/IGF-1 excess [104,133-141]. By normalizing serum GH and IGF-1 values, somatostatin analogues improve diastolic filling parameters (ventricular isovolumic relaxation and early diastolic filling velocity), reduce volume overload and pulmonary and wedge pressures, and enhance cardiac performance [137, 142, 143]. Data on the effectiveness of acromegalic treatment are still conflicting as regards the effects on ventricular hypertrophy. Some studies demonstrate that treatment can reduce LV mass to a normal value [105], whereas others show no significant change or only a small improvement in LV mass [144]. Although it is not yet known whether the acromegalic heart can return to normal condition, the experimental data available indicate that cardiac hypertrophy is reversible and that the reversal may be complete if GH activity is restored to normal level for a sufficient amount of time [135-137, 140, 141, 144-146]. However, it should be noted that the cardiac effects of somatostatin analogues seem to be related not only to the strict biochemical control of acromegaly, but also to the patient's age and the disease duration before starting treatment [22].

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GH DEFICIENCY
Growth hormone deficiency produces different clinical features depending on the time of onset and disease severity and duration [2, 22, 106, 147]. GHD negatively affects cardiovascular function by directly acting on the heart and endothelium; it also acts indirectly by causing insulin resistance, abdominal obesity, hypercoagulability, increase in serum lipids, reduction in exercise performance and pulmonary capacity [148, 149]. GHD patients have increased total body fat, atherothrombotic and proinflammatory abnormalities, dyslipidemia and decreased insulin-stimulated glucose uptake by fat and skeletal muscle [150, 151]. In addition to the cardiovascular risk factors mentioned above, GHD patients have increased vessel intima-media thickness, which is the earliest morphological change in the development of atherosclerosis [149, 152-155]. Patients with GHD are also affected by endothelial dysfunction, reduced NO production, high peripheral vascular resistance and enhanced aorta stiffness [152-157]. Furthermore, GHD affects cardiac size and function, thereby leading to a reduction in both myocardial growth rate and cardiac performance [158, 159]. Cardiac function decreases because of reduced ventricular mass and intrinsic myocardial contractility [160].

Childhood-onset GHD is characterized by cardiac atrophy with a significant reduction in LV mass, relative wall thickness and cavity dimensions, compared with age-, sex- and height-matched controls [158-162]. Moreover, patients are affected by a hypokinetic syndrome, namely, they have a low ejection fraction, low cardiac output and high peripheral vascular resistance [158, 160-163]. These alterations are more pronounced during physical exercise and, besides reducing skeletal muscle mass and strength, they reduce exercise capacity, as shown by subjective symptoms, low values of achieved workload and exercise duration [160, 164-166]. Adult-onset GHD does not feature a reduction in cardiac mass, but only impaired cardiac performance and exercise capacity [165, 167, 168].

Evidence that cardiac alterations in GHD are strictly related to the GH deficiency comes from many GH replacement trials, which taken together show an increase in LV mass and improvement in cardiac performance, diastolic filling and systolic function after GH treatment [158-160, 163, 164, 166, 169-172]. Although some studies have failed to demonstrate an improvement in cardiac structure or function [173, 174], a meta-analysis that included all trials on the effects of GH replacement included in Medline, Biosis and EMBASE from the year of their inception to June 2002, showed positive effects on LV mass, wall thickness, LV end-diastolic and end-systolic diameters and cardiac output [169]. All the GH replacement trials showed that cardiac function returns to the pre-treatment setting upon cessation of GH treatment [158-160, 163, 164, 166, 169-172, 175].

The beneficial cardiovascular effects of GH replacement are related not only to cardiac anabolic actions but also to its peripheral effects. Treatment with GH normalizes NO production, thereby reducing peripheral vascular resistance and modulating cardiac cytoskeletal functions by altering calcium myofilament responsiveness [70, 157]. Moreover, GH replacement improves body composition, which is an important factor for reducing cardiovascular risk [176, 177], induces beneficial effects on lipid profile [178, 179] and reduces arterial intima-media thickness [152, 155, 178, 179].

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GH AND HEART FAILURE
The rationale for GH therapy in CHF appears evident when considering the cardiovascular effects of GH and the cardiac morphological and functional features in heart failure. Patients with CHF have reduced myocardial contractility, decreased cardiac output, dilated LV cavity, increased peripheral vascular resistance and enhanced wall stress. Cardiac dilatation, which initially helps to maintain an adequate stroke volume, initiates a vicious cycle whereby dilatation leads to dilatation. GH replacement may be beneficial in all steps of heart failure. By stimulating cardiac growth, GH induces a concentric pattern of remodelling, which reduces wall stress. By decreasing peripheral vascular resistance, GH reduces afterload, attenuates pathologic cardiac remodelling and improves cardiac function. Furthermore, by inducing positive inotropic effects, GH directly counteracts the impaired contractility, which is the primum movens of the vicious cycle responsible for pathologic remodelling.

The pathogenesis and the progression of CHF seem to be related also to an imbalance between pro-inflammatory/anti-inflammatory factors and endothelial dysfunction. Patients with CHF have excessive plasma levels of pro-inflammatory cytokines and impaired vascular reactivity, which consists of attenuated vasodilatation in response to acetylcholine and preserved response to the direct NO donor nitroprusside. By shifting the cytokine balance toward anti-inflammatory predominance and reducing pro-apoptotic factors, GH positively acts on LV remodelling, increasing LV contractile performance and enhancing exercise capacity. In addition, GH is able to improve vascular reactivity, not only by restoring NO production, but also activating non-endothelium-mediated actions, in particular by modifying intracellular calcium concentration and regulating Na+/K+ ATPase activity.

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EXPERIMENTAL STUDIES ON ANIMALS
The first study of the effects of the GH/IGF-1 system in experimental heart failure models dates back to 1992. At that time, Castagnino and colleagues evaluated the effect of GH on the connective tissue, fibroblast growth and proliferation in rats with experimental myocardial infarction, and found a significant decrease in the incidence of ventricular aneurysms [180]. A subsequent study, designed to assess the effects of IGF-1 on cardiac function and structure in rats with a doxorubicin-induced cardiomyopathy, showed that IGF-1 increases cardiac output as well as reduces histologically-detected myocyte damage [181]. In this scenario, Ito and co-workers proved, in cultured neonatal cardiomyocytes, that IGF-1, but not GH, promotes transcription of muscle-specific genes (namely, troponin I, myosin light chain-2, and α-actin), induces protein synthesis and increases myocyte size [75]. Duerr and colleagues demonstrated that IGF-1, administrated in rats early during the onset of experimental post-infarction heart failure, enhances the hypertrophic response of viable myocardium and cardiac performance [182]. Similarly, Cittadini and co-workers, investigating the cardiac effects of GH adminis-tration during the early phase of pathologic remodelling in a rat model of large myocardial infarction, confirmed that GH causes hypertrophy of the non-infarcted myocardium in a concentric pattern and improves LV function [183]. Two subsequent trials showed that GH plus IGF-1, given to rats with LV failure, starting one month after myocardial infarction, and then in the late phase of LV remodelling, improved cardiac function and reduced peripheral vascular resistance and LV dilatation [184, 185]. Other experimental studies confirmed that GH attenuates both the early and the late pathologic LV remodelling, induces hypertrophy of non-infarcted myocardium, improves LV function and increases cardiac output [186, 187].

Cittadini and co-workers administered GH or IGF-1 or GH plus IGF-1 to adult HF rats and found a significant increase in cardiac performance and LV mass, without development of significant fibrosis, and no additional hypertrophy in rats receiving GH plus IGF-1 compared with rats treated singularly with GH or IGF-1 alone. This interesting result suggested that, in vivo, IGF-1 mediates the GH-induced cardiac hypertrophy [188]. Subsequent studies confirmed that GH/IGF-1 modifies cardiac structure, reduces interstitial fibrosis and improves myocardial function [189-191].

More recently, Cittadini and colleagues demonstrated, in a rat model of post-infarction heart failure, that GH improves a broad spectrum of structural abnormalities of the extra-cellular matrix [187]. Specifically, they found a decrease in the collagen volume fraction and in the collagen I/III ratio, and an increase in capillary density. The authors hypothesized that GH attenuates fibrosis, directly by reducing collagen synthesis or increasing its breakdown, and indirectly by reducing accumulation of extracellular matrix proteins in the interstitial space. This latter was explained as due to the GH-induced improvement in hemodynamic and to the decrease in wall stress [187]. Cittadini and colleagues supposed that GH reduces interstitial fibrosis thanks also to its anti-apoptotic properties. Although apoptosis per se does not induce fibrosis, it leaves myocardial defects that are filled with interstitial fluid from myocardial edema, subsequently leading to fibrous tissue accumulation [187]. GH and IGF-1 exert direct beneficial effects on myocyte contractile performance in heart failure models, not solely by stimulating cardiac growth, modifying cardiac structure, reducing interstitial fibrosis or inducing peripheral vasodilatation, but also by changing calcium handling and the inotropic state [82, 88, 192-195]. Kinugawa and colleagues demonstrated that acute IGF-1 administration in isolated cardiomyocytes, in both normal and heart failure conditions, exerts a direct positive inotropic effect, due to calcium transient amplitude and calcium availability to the contractile apparatus [193]. They also showed IGF-1 does not modify the terminal portion of the relaxation phase trajectory, which indicates that calcium sensitivity is not altered by IGF-1 administration [193]. This result was consistent with previous studies in which acute IGF-1 administration increases the contractility of cardiomyocytes and isolated ventricular muscle [82, 88]. In addition, Freestone and colleagues reported that, in isolated rat cardiac muscle, acute IGF-1 administration had a positive inotropic effect, in fact, it increased the peak of cytosolic free calcium concentration, the amplitude of calcium transient and the time to peak [194]. In contrast with these results, Cittadini and co-workers showed that, in isolated isovolumic aequorin-loaded rat whole hearts and ferret papillary muscles, IGF-1 administration produces an acute positive inotropic effect, not associated with an increased intra-cellular calcium availability but to a significant increase of myofilament calcium sensitivity [82]. All these experimental studies, in which GH did not induce acute effects on cardiac function, and IGF-1 positively affected cardiac contractility, provide further insight into the intricate interaction between the GH/IGF-1 axis and cardiovascular system. In fact, although GHRs are expressed on the heart, their physio-logical role probably does not include acute modulation of myocardial contractility, but they serve to mediate such other functions as protein synthesis or local IGF-1 production [82, 88, 193, 194].

Von Lewinski and colleagues were the first to study the functional effects of IGF-1 in isolated human myocardium. They demonstrated that IGF-1: 1) exerts a concentration-dependent positive inotropic effect, which is almost completely prevented by blocking its receptors or phosphoinositide 3-kinase (PI3-kinase); 2) increases L-type calcium currents; 3) activates Na+-H+ and reversed Na+-Ca2+ exchanges [196]. The beneficial effects of GH treatment in heart failure may be also related to the anti-apoptotic proprieties of the GH/IGF-1 system [80, 81, 187, 197]. Although cardiomyocytes were long thought not undergo apoptosis, it is now recognized that cardiomyocyte apoptosis is increased in CHF and it may play a key role in CHF progression. Cardiomyocyte apoptosis occurs in the early stages of myocardial dysfunction; it impairs LV performance by reducing the contractile mass of the heart and by contributing to the progressive loss of myocytes [198, 199]. The anti-apoptotic effects of GH do not appear to be mediated by IGF-1: Gonzalez-Juanatey and co-workers demonstrated, in primary cultures of rat neonatal cardiomyocytes, that GH regulates apoptosis through the inhibition of calcineurin, a calcium-dependent phosphatase [197]. Others showed that the effects exerted by GH on cell survival and proliferation are mediated through two different signalling pathways, involving nuclear factor-kappa B (NF-kB) and PI3-kinase, respectively, which promote high circulating levels of the anti-apoptotic molecules [200-202].

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CLINICAL STUDIES IN HUMANS WITH HEART FAILURE
Several research groups have studied the effects of GH and IGF-1 in patients with impaired cardiac function (Table ​11). The first results were limited to case reports showing that GH administration considerably improved cardiac function [203, 204]. The earliest open clinical trial in CHF was reported by Fazio and co-workers in 1996 [90]. They studied seven patients with idiopathic dilated cardiomyopathy, with moderate to severe heart failure, without GHD. The evaluation was performed at baseline, after three months of recombinant human GH (rhGH) therapy and three months after therapy discontinuation. They assessed cardiac function with Doppler echocardiography, right-heart catheterization and exercise testing. After three months of treatment at a dose of 4 international units every other day, they found improvement in cardiac performance, exercise tolerance, hemodynamic profile and myocardial energetic metabolism. Transthoracic echocardiography revealed a significant increase in relative wall thickness and cardiac mass, a dramatic decrease in wall stress and an improvement in systolic performance indices (ejection fraction, shortening velocity and aortic acceleration). Using right-heart catheterization to evaluate the effects of rhGH on hemodynamic variables, at rest and in response to physical exercise, they found significant decrease in mean pulmonary arterial and capillary wedge pressures, increased cardiac output and reduced systemic vascular resistance. The also demonstrated beneficial changes in myocardial energetic metabolism, particularly during physical exercise, i.e., the heart generated more mechanical work with lower oxygen consumption and energy production. This improvement in energetic metabolism was attributed to wall stress reduction and not to change in metabolic substrates. These encouraging preliminary findings prompted several larger and controlled clinical trials.

Conflicting results emerged from a randomized, double-blind, placebo-controlled rhGH treatment study, which showed, in fifty CHF patients, an increase in LV mass related to serum IGF-1 level but no change in LV wall stress, arterial blood pressure, ejection fraction, clinical status or 6-minute walking distance [205]. Similarly, in another clinical trial, carried out in twenty-two patients with CHF of various etiologies, rhGH treatment did not significantly affect clinical status, exercise duration, ejection fraction, end-diastolic and end-systolic volumes. Furthermore, no significant increases in LV mass and wall thickness were shown [206]. On the contrary, rhGH significantly increased exercise capacity and decreased LV end-systolic and end-diastolic volumes in patients with post-ischemic CHF [207]. The patients also had a 15% increase in posterior wall thickness and 16% increase in cardiac output [207]. rhGH did not affect cardiac structure but greatly improved exercise performance and quality of life in ten post-ischemic CHF patients [208]. Conflicting results were obtained from other numerous experimental trials. For instance, some studies showed that rhGH caused a significant increase in cardiac performance [209-211], whereas others found no changes [212-214].

More recently, Adamopoulos and colleagues investigated the immunomodulatory role of rhGH administration in CHF patients. They found that a three-month course of GH normalizes circulating levels of proinflammatory cytokines, such as tumour necrosis factor α (TNF-α) and interleukin- 6 (IL-6), their soluble receptors, as well as apoptosis mediators, such as soluble Fas (sFas) and soluble Fas ligand (sFasL) [215, 216]. They subsequently reported that GH reduces the soluble adhesion molecules ICAM-1 and VCAM-1, the granulocyte-macrophage colony-stimulating factor (GM-CSF), which generates free radicals and enhances cytokine production, and the macrophage chemoattractant protein-1 (MCP-1), which promotes the migration of mononuclear phagocytes into the injured myocardial tissue and endothelial cells [217]. To evaluate whether these changes are related to modifications in exercise tolerance and echocardiographic markers of cardiac remodelling and performance, they found a significantly correlation between improvement in exercise capacity and restoration to the normal of the inflammatory response, as well as a good correlation between exercise capacity improvement and reduction in adhesion molecules and in soluble apoptosis mediators. They also showed that GH induced a decrease in end systolic wall stress and an increase in contractile reserve and that these changes were correlated with the decrease in the chemotactic protein MCP-1 and pro-inflammatory cytokines [215-217].

In an attempt to gain further insight into the mechanisms by which GH may benefit CHF patients, Fazio and co-workers have recently carried out a double-blind, placebo-controlled study of the effects of GH on physical exercise capacity and cardiopulmonary performance in twenty-two patients with moderate heart failure [218]. Patients underwent spirometry, cardiopulmonary exercise testing and Doppler echocardiography. The baseline clinical status was comparable in the GH patients and in the placebo group. After three months of treatment, at exercise testing, the GH group had an improvement of exercise capacity, cardio-pulmonary performance, and ventilatory efficiency, with a significant increase of VO2max and of chronotropic index (Fig. ​22).

Moreover, at transthoracic echocardiography, the GH group had an increase in LV mass index, relative wall thickness and cardiac performance. The LV ejection fraction and early-to-late mitral peak velocity ratio were significantly.

The conflicting results of the clinical trials of GH treatment analyzed in this review may be related to the small number of patients enrolled, the different dose and duration of GH treatment, the different CHF etiologies, and differences in the patients' demographic, hemodymamic and clinical characteristics. This discrepancy may also reflect the heterogeneity of IGF-1 increase in response to GH. In fact, a recent meta-analysis, which analyzed all randomized controlled trials and open studies on sustained GH treatment in adults with CHF in the absence of GHD, contained in the Medline, Biosis and EMBASE databases from their inception to June 2005, confirms that there is a close relationship between change in IGF-1 concentration and GH effects [219]. When the studies were divided into two groups based on the degree of IGF-1 increment, in trials with an IGF-1 increase >89% versus baseline there was a significant improvement in cardiac performance, echocardiographic parameters and exercise capacity, whereas in trials with an IGF-1 increase <89% there were no beneficial cardiovascular effects. In other words, patients with a blunted IGF-1 response to exogenous GH administration are less likely to benefit from GH treatment. This suggests that some patients may be not “sensitive” to GH. Therefore, “responders” should be identified before starting GH treatment in CHF patients.

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CONCLUSIONS
Although experimental models and preliminary human studies have demonstrated that GH administration may have beneficial cardiovascular effects in CHF, more experimental and clinical studies are necessary to clarify the mechanisms that determine the variable sensitivity to GH and its positive effects in the failing heart.

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ACKNOWLEDGEMENT
We are grateful to Jean Ann Gilder for text editing.

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REFERENCES
1. Duello TM, Halmi NS. Ultrastructural-immunocytochemical localization of growth hormone and prolactin in human pituitaries. J Clin Endocrinol Metab. 1979;49:189–96. [PubMed]
2. Thorner MO, Vance ML, Horvath E, Kovacs K. In: Textbook of Endocrinology. The anterior pituitary. Wilson JD, Foster DW, editors. Philadelphia: WB Saunders Co; 1992. pp. 221–310.
3. Tannenbaum GS, Ling N. The interrelationship of growth hormone (GH)-releasing factor and somatostatin in generation of the ultradian rhythm of GH secretion. Endocrinology. 1984;115:1952–7. [PubMed]
4. Plotsky PM, Vale W. Patterns of growth hormone-releasing factor and somatostatin secretion into the hypophyseal-portal circulation of the rat. Science. 1985;230:461–3. [PubMed]
5. Arce V, Lima L, Lois N, et al. Role of central dopaminergic pathways in the neural control of growth hormone secretion in normal men: studies with metoclopramide. Neuroendocrinology. 1991;53:143–9. [PubMed]
6. Guillemin R, Brazeau P, Bohlen P, Esch F, Ling N, Wehrenberg WB. Growth hormone releasing factor from a human pancreatic tumor that caused acromegaly. Science. 1982;218:585–9. [PubMed]
7. Brazeau P, Vale W, Burgus R, et al. Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone. Science. 1973;179:77–9. [PubMed]
8. Casanueva FF. Physiology of growth hormone secretion and action. Endocrinol Metab Clin North Am. 1992;21:483–515. [PubMed]
9. Laron Z. Growth hormone secretagogues: clinical, experimental and therapeutic potential. Drugs. 1995;50:595–601. [PubMed]
10. Gomberg-Maitland M, Frishman WH. Recombinant growth hormone: a new cardiovascular drug therapy. Am Heart J. 1996;132:1244–62. [PubMed]
11. Strobl JS, Thomas MJ. Human growth hormone. Pharmacol Rev. 1995;46:1–34. [PubMed]
12. Tapanaienen P, Knip M. Evaluation of growth hormone secretion and treatment. Ann Med. 1992;24:237–47. [PubMed]
13. Dronby EC, Amburn K, Powmakn G. Circadian variation of basal growth hormone in man. J Clin Endocrin Metab. 1983;57:524–8. [PubMed]
14. Moller N, Jorgensen JOL, Abildgard N, Orskov L, Schmitz O, Christiansen JS. Effects of growth hormone on glucose metabolism. Horm Res. 1991;36:32–5. [PubMed]
15. Betherat J, Bluet-Pajt MT, Eppelbaun J. Neuroendocrine regulation of growth hormone. Eur J Endocrinol. 1995;132:12–24. [PubMed]
16. Rudman D, Kutner MH, Rogers MC, Lubin MF, Fleming Ga, Bain RP. Impaired growth hormone secretion in the adult population. Relation to age and adiposity. J Clin Invest. 1981;67:1361–9. [PMC free article] [PubMed]
17. Rudman D. Growth hormone, body composition and aging. J Am Geriatr Soc. 1985;33:800–7. [PubMed]
18. Rudd BT. Growth hormone and the somatomedins: a historical perspective and current concepts. Ann Clin Biochem. 1991;28:542–55. [PubMed]
19. Mathews LS, Enberg B, Norstedt G. Regulation of rat growth hormone receptor gene expression. J Biol Chem. 1989;17:9905–10. [PubMed]
20. Sotiropoulos A, Perrot-Applanat M, Dinerstein H, et al. Distinct cytoplasmatic regions of the growth hormone receptor are required for activation of JAK2, mitogen-activated protein kinase, and transcription. Endocrinology. 1994;135:1289–91. [PubMed]
21. Underwood LE, Van Wyk JJ. In: Textbook of Endocrinology. Normal and aberrant growth. Wilson JD, Foster DW, editors. Philadelphia: WB Saunders Co; 1992. pp. 1079–138.
22. Colao A, Vitale G, Pivonello R, Ciccarelli A, Di Somma C, Lombardi G. The heart: an end-organ of GH action. Eur J Endocrinol. 2004;151:93–101. [PubMed]
23. Froesch ER, Schnid C, Schwander J, Zapf J. Action of insulin-like growth factors. Annu Rev Physiol. 1985;47:443–67. [PubMed]
24. Isaksson OG, Lindahl A, Nilsson A, Isgaard J. Action of growth hormone: current views. Acta Paediatr Scand. 1988;343:12–8. [PubMed]
25. Laron Z. Somatomedin, insulin, growth hormone and growth: a review. Isr J Med Sci. 1982;18:823–9. [PubMed]
26. Salmon WD, Daughaday H. A hormonally controlled serum factor which stimulates sulfate incorporation by cartilage in vitro. J Lab Clin Med. 1957;49:825–36. [PubMed]
27. Daughaday WH, Karl IE, Karl MM. A failed assay opened a new door in growth hormone research. Endocrinology. 1992;130:565–6. [PubMed]
28. Murphy LJ, Bell GI, Friesen Hg. Growth hormone stimulates sequential induction of c-myc and insulin-like growth factor I expression in vivo. Endocrinology. 1987;120:1806–12. [PubMed]
29. Murray RD, Kim K, Ren SG, Chelly M, Umehara Y, Melmed S. Central and peripheral actions of somatostatin on the growth hormone-IGF-I axis. J Clin Invest. 2004;114:349–56. [PMC free article] [PubMed]
30. Saccà L, Cittadini A, Fazio S. Growth hormone and the heart. Endocr Rev. 1994;15:555–73. [PubMed]
31. Fazio S, Palmieri EA, Biondi B, Cittadini A, Saccà L. The role of the GH-IGF-1 axis in the regulation of myocardial growth: from experimental model to human evidence. Eur J Endocrinol. 2000;142:211–6. [PubMed]
32. Meyers DE, Cuneo RC. Controversies regarding the effects of growth hormone on the heart. Mayo Clin Proc. 2003;78:1521–6. [PubMed]
33. Svensson J, Tivesten A, Isgaard J. Growth hormone and the cardiovascular function. Minerva Endocrinol. 2005;30:1–13. [PubMed]
34. Foncea R, Andersson M, Ketterman A, et al. Insulin-like growth factor-I rapidly activates multiple signal transduction pathways in cultured rat cardiac myocytes. J Biol Chem. 1997;272:19115–24. [PubMed]
35. Giordano R, Bonelli L, Marinazzo E, Ghigo E, Arvat E. Growth hormone treatment in human aging: benefit and risks. Hormones. 2008;7(2):133–9. [PubMed]
36. Takahashi S, Meites J. GH binding to liver in young and old female rats: relation to somatomedin-C secretion. Proc Soc Exp Biol Med. 1987;186:229–33. [PubMed]
37. Xu X, Bennett SA, Ingram RL, Sonntag WE. Decreases in growth hormone receptor signal transduction contribute to the decline in insulin-like growth factor I gene expression with age. Endocrinology. 1995;136:4551–7. [PubMed]
38. D'Costa AP, Xu X, Ingram RL, Sonntag WE. Insulin-like growth factor-1 stimulation of protein synthesis is attenuated in cerebral cortex of aging rats. Neuroscience. 1995;65:805–13. [PubMed]
39. Carvalho CR, Brenelli SL, Silva AC, et al. Effect of aging on insulin receptor, insulin receptor substrate-1, and phosphatidy-linositol 3-kinase in liver and muscle of rats. Endocrinology. 1996;137:51–9. [PubMed]
40. Xu X, Sonntag WE. Growth hormone-induced nuclear translocation of Stat-3 decreases with age: modulation by caloric restriction. Am J Physiol. 1996;271:E903–9. [PubMed]
41. Roupas P, Herington AC. Postreceptor signaling mechanisms for growth hormone. Trends Endocrinol Metab. 1994;5:154–8. [PubMed]
42. Nitahara JA, Cheng W, Liu Y, et al. Intracellular calcium, DNase activity and myocyte apoptosis in aging Fischer 344 rats. J Mol Cell Cardiol. 1998;30:519–35. [PubMed]
43. Olivetti G, Melissari M, Capasso JM, Anversa P. Cardiomyopathy of the aging human heart. Myocyte loss and reactive cellular hypertrophy. Circ Res. 1991;68:1560–8. [PubMed]
44. Corpas E, Harman SM, Blackman MR. Human growth hormone and human aging. Endocr Rev. 1993;14:20–39. [PubMed]
45. Eghbali M, Robinson TF, Seifter S, Blumenfeld OO. Collagen accumulation in heart ventricles as a function of growth and aging. Cardiovasc Res. 1989;23:723–9. [PubMed]
46. Rudman D, Kutner MH, Rogers CM, et al. Impaired growth hormone secretion in the adult population: relation to age and adiposity. J Clin Invest. 1981;67:1361–9. [PMC free article] [PubMed]
47. Ghigo E, Goffi S, Nicolosi M, et al. Growth hormone (GH) responsiveness to combined administration of arginine and GH-releasing hormone does not vary with age in man. J Clin Endocrinol Metab. 1990;71:1481–5. [PubMed]
48. Bichell DP, Kikuchi K, Rotwein P. Growth hormone rapidly activates insulin-like growth factor I gene transcription in vivo. Mol Endocrinol. 1992;6:1899–908. [PubMed]
49. Parrado J, Bougria M, Ayala A, Castano A, Machado A. Effects of aging on the various steps of protein synthesis: fragmentation of elongation factor 2. Free Radic Biol Med. 1999;26:362–70. [PubMed]
50. Huxley HE. The crossbridge mechanism of muscular contraction and its implications. J Exp Biol. 1985;115:17–30. [PubMed]
51. Bouillon R. Growth hormone and bone. Horm Res. 1991;36:49–55. [PubMed]
52. Davidson MB. Effects of growth hormone on carbohydrate and lipid metabolism. Endocri Rev. 1987;8:115–31. [PubMed]
53. Keller U, Miles JM. Growth hormone and lipids. Horm Res. 1991;36:36–40. [PubMed]
54. Hjalmarson A, Isaksson O, Ahren K. Effects of growth hormone and insulin on amino acid transport in perfused heart rat. Am J Physiol. 1969;217:1795–802. [PubMed]
55. Saloman F, Cuneo R, Sonksen PH. Growth hormone and protein metabolism. Horm Res. 1991;36:41–3. [PubMed]
56. Czernichow P. Growth hormone administration and carbohydrate metabolism. Horm Res. 1993;39:102–3. [PubMed]
57. Grunfeld C, Sherman BM, Cavalieri RR. The acute effects of human growth hormone administration on thyroid function in normal man. J Clin Endocrinol Metab. 1988;67:1111–4. [PubMed]
58. Ho KY, Kelly JJ. Role of growth hormone in fluid homeostasis. Horm Res. 1991;36:44–8. [PubMed]
59. Moller J, Jorgensen JOL, Moller N, Hansen KW, Pedersen EB, Christiansen JS. Expansion of extracellular volume and suppression of atrial natriuretic peptide after growth hormone administration in normal man. J Clin Endocrinol Metab. 1991;72:768–72. [PubMed]
60. Walsh MF, Barazi M, Pete G, Muniyappa R, Dunbar JC, Sowers JR. Insulin-like growth factor I diminishes in vivo and in vitro vascular contractility: role of vascular nitric oxide. Endocrinology. 1996;137:1798–803. [PubMed]
61. Tsukahara H, Gordienko DV, Tonshoff B, Gelato MC, Goligorsky MS. Direct demonstration of insulin-like growth factor-I-induced nitric oxide production by endothelial cells. Kidney Int. 1994;45:598–604. [PubMed]
62. Muniyappa R, Walsh MF, Rangi JS, et al. Insulin like growth factor 1 increases vascular smooth muscle nitric oxide production. Life Sci. 1997;61:925–31. [PubMed]
63. Haylor J, Singh I, Nahas AM. Nitric oxide synthesis inhibitor prevents vasodilatation by insulin-like growth factor I. Kidney Int. 1991;39:333–5. [PubMed]
64. Hasdai D, Rizza RA, Holmes DR Jr, Richardson DM, Cohen P, Lerman A. Insulin and insulin-like growth factor-I cause coronary vasorelaxation in vitro. Hypertension. 1998;32:228–34. [PubMed]
65. Caidahl K, Eden S, Bengtsson BA. Cardiovascular and renal effects of growth hormone. Clin Endocrinol (Oxf) 1994;40:393–400. [PubMed]
66. Fryburg D. NG- monomethyl-L-arginine inhibits the blood flow but not the insulin-like response of forearm muscle to IGF-1. Possible role of nitric oxide in muscle protein synthesis. J Clin Invest. 1996;97:1319–28. [PMC free article] [PubMed]
67. Capaldo B, Guardasole V, Pardo F, et al. Abnormal vascular reactivity in growth hormone deficiency. Circulation. 2001;103:520–4. [PubMed]
68. Napoli R, Guardasole V, Matarazzo M, et al. Growth hormone corrects vascular dysfunction in patients with chronic heart failure. J Am Coll Cardiol. 2002;39:90–5. [PubMed]
69. Joannides R, Haefeli WE, Linder L, et al. Nitric oxide is responsible for flow-dependent dilation of peripheral conduit arterias in vivo. Circulation. 1995;92:1314–9. [PubMed]
70. Badorff C, Dimmeler S. NO balance: regulation of the cytoskeleton in congestive heart failure by nitric oxide. Circulation. 2003;107:1348–9. [PubMed]
71. Standley PR, Zhang F, Zayas RM, et al. IGF-1 regulation of Na(+)-K(+)-ATPase in rat arterial smooth muscle. Am J Physiol. 1997;273:113–21. [PubMed]
72. Tivesten A, Barlind A, Caidahl K, et al. Growth hormone-induced blood pressure decrease is associated with increased mRNA levels of the vascular smooth muscle KATP channel. J Endocrinol. 2004;183:195–202. [PubMed]
73. Fujita A, Kurachi A, Kurachi Y. Molecular aspects of ATP sensitive K+ channels in the cardiovascular system and K+ channel openers. Pharmacol Ther. 2000;85:39–53. [PubMed]
74. Miki T, Suzuki M, Shibasaki T, et al. Mouse model of Prinzmetal angina by disruption of the inward rectifier Kir6.1. Nat Med. 2002;8:466–72. [PubMed]
75. Butt RP, Laurent GJ, Bishop JE. Collagen deposition and replication by cardiac fibroblasts is enhanced in response to diverse classes of growth factors. Eur J Cell Biol. 1995;68:330–5. [PubMed]
76. Bruel A. Oxlund Biosynthetic growth hormone increase the collagen deposition rate in rat aorta and heart. Eur J Endocrinol. 1995;132:195–9. [PubMed]
77. Buerke M, Murohara T, Skurk C, Nuss C, Tomaselli K, Lefer AM. Cardioprotective effect of insulin-like growth factor I in myocardial ischemia followed by reperfusion. Proc Natl Acad Sci USA. 1995;92:8031–35. [PMC free article] [PubMed]
78. Li Q, Li B, Wang X, et al. Overexpression of insulin-like growth factor-I in mice protects from myocyte death after infarction, attenuating ventricular dilation, wall stress and cardiac hypertrophy. J Clin Invest. 1997;100:1991–9. [PMC free article] [PubMed]
79. Timsit J, Riou B, Bertherat J, et al. Effects of chronic growth hormone hypersecretion on intrinsic contractility, energetics, isomyosin pattern, and myosin adenosine triphosphatase activity of rat left ventricle. J Clin Invest. 1990;86:507–15. [PMC free article] [PubMed]
80. Cittadini A, Ishiguro Y, Stromer H, et al. Insulin-like growth factor-1 but not growth hormone augments mammalian myocardial contractility by sensitizing the myofilament to Ca2+ through a wortmannin-sensitive pathway: studies in rat and ferret isolated muscles. Circ Res. 1998;83:50–9. [PubMed]
81. Mayoux E, Ventura-Clapier R, Timsit J, Behar-Cohen F, Hoffmann C, Mercadier JJ. Mechanical properties of rat cardiac skinned fibers are altered by chronic growth hormone hypersecretion. Circ Res. 1993;72:57–64. [PubMed]
82. Ren J. Short-term administration of insulin-like growth factor (IGF-1) does not induce myocardial IGF-1 resistance. Growth Horm IGF Res. 2002;12:162–8. [PubMed]
83. Xu X, Best PM. Decreased transient outward K+ current in ventricular myocytes from acromegalic rats. Am J Physiol. 1991;260:935–42. [PubMed]
84. Solem ML, Thomas AP. Modulation of cardiac Ca2+ channels by IGF-1. Biochem Biophys Res Commun. 1998;252:151–5. [PubMed]
85. Tajima M, Weinberg EO, Batunek J, et al. Treatment with growth hormone enhances contractile reserve and intracellular calcium transients in myocytes from rats with postinfarction heart failure. Circulation. 1999;99:127–34. [PubMed]
86. Houck Wv, Pan LC, Kribbs SB, et al. Effects of growth hormone supplementation on left ventricular morphology and myocyte function with the development of congestive heart failure. Circulation. 1999;100:2003–9. [PubMed]
87. Huchard H. Anatomie pathologique, lesions et trouble cardiovasculaires de l’acomegalie. J Praticiens. 1895;9:249–51.
88. Penney DG, Dunbar Jr JC, Baylerian MS. Cardiomegaly and hemodynamics in rats with a transplantable growth hormone-secreting tumor. Cardiovasc Res. 1985;19:270–7. [PubMed]
89. Rubin SA, Buttrick P, Malhotra A, Melmed S, Fishbein MC. Cardiac physiology, biochemistry and morphology in response to excess growth hormone in the rat. J Mol Cell Cardiol. 1990;22:429–38. [PubMed]
90. Prysor-Jones RA, Jenkins JS. Effect of excessive secretion of growth hormone on tissues of the rat, with particular reference to the heart and skeletal muscle. J Endocrinol. 1980;85:75–82. [PubMed]
91. Gilbert PL, Siegel RJ, Melmed S, Sherman CT, Fishbein MC. Cardiac morphology in rats with growth hormone-producing tumours. J Mol Cell Cardiol. 1985;17:805–11. [PubMed]
92. Evans HM, Simpson HE, Li CH. The gigantism produced in normal rats by injection of pituitary growth hormone. Growth. 1948;12:15–32. [PubMed]
93. Beznak M. The restoration of cardiac hypertrophy and blood pressure in hypophysectomized rats by large doses of lyophilized anterior pituitary and growth hormone. J Physiol (London) 1954;124:64–74. [PubMed]
94. Saccà L, Napoli R, Cittadini A. Growth hormone, acromegaly, and heart failure: an intricate triangulation. Clin Endocrinol. 2003;59:660–71. [PubMed]
95. Thuesen L, Christensen SE, Weeke J, Orskov H, Henningsen D. A hyperkinetic heart in uncomplicated active acromegaly. Explanation of hypertension in acromegalic patients? Acta Med Scand. 1988;223:337–43. [PubMed]
96. Fazio S, Cittadini A, Biondi B, et al. Cardiovascular effects of short-terms growth hormone hypersecretion. J Clin Endocrinol Metab. 2000;85:179–82. [PubMed]
97. Martins JB, Kerber RE, Sherman BM, Marcus ML, Ehrhardt JC. Cardiac function in acromegaly. Circulation. 1977;56:863–9. [PubMed]
98. Mather HM, Boyd MJ, Jenkins JS. Heart size and function in acromegaly. Br Heart J. 1979;41:697–701. [PMC free article] [PubMed]
99. Smallridge RC, Rajfer S, Davia J, Schaaf M. Acromegaly and the heart. An echocardiographic study. Am J Med. 1979;66:22–7. [PubMed]
100. Fazio S, Cittadini A, Sabatini D, et al. Evidence for biventricular involvement in acromegaly: a Doppler echocardiographic study. Eur Heart J. 1993;14:26–33. [PubMed]
101. Colao A, Ferone D, Marzullo P, Lombardi G. Systemic complications of acromegaly epidemiology, pathogenesis and management. Endocr Rev. 2004;25:102–52. [PubMed]
102. Cittadini A, Berggren A, Longobardi S, et al. Supraphysiological doses of GH induce rapid changes in cardiac morphology and function. J Clin Endocrinol Metab. 2002;87:1654–9. [PubMed]
103. Fazio S, Cittadini A, Sabatini D, et al. Growth hormone and heart performance. A novel mechanism of cardiac wall stress regulation in humans. Eur Heart J. 1997;18:340–7. [PubMed]
104. Bertoni PD, Morandi G. Impaired left ventricular diastolic in acromegaly: an echocardiographic study. Acta Cardiol. 1985;42:1–10. [PubMed]
105. Morvan D, Komajda M, Grimaldi A, Turpin G, Grosgogeat Y. Cardiac hypertrophy and function in asymptomatic acromegaly. Eur Heart J. 1991;12:666–72. [PubMed]
106. Fazio S, Cittadini A, Cuocolo A, et al. Impaired cardiac performance is a distinct feature of uncomplicated acromegaly. J Clin Endocrinol Metab. 1994;79:441–6. [PubMed]
107. Lie JT, Grossman SJ. Pathology of the heart in acromegaly: anatomic findings in 27 autopsied patients. Am Heart J. 1980;100:41–52. [PubMed]
108. Kahaly G, Stover C, Beyer J, Mohr-Kahaly S. Relation of endocrine and cardiac findings in acromegalics. J Endocrinol Invest. 1992;15:13–8. [PubMed]
109. Rossi L, Thiene G, Caregaro L, Giordano R, Lauro S. Dysrhythmias and sudden death in acromegalic heart disease. A clinicopathologic study. Chest. 1977;72:495–8. [PubMed]
110. Herrmann BL, Bruch C, Saller B, et al. Occurrence of left ventricular late potentials in patients active acromegaly. Clin Endocrinol. 2001;55:201–7. [PubMed]
111. Colao A. Are patients with acromegaly at risk for dysrhythmias? Clin Endocrinol. 2001;55:305–6. [PubMed]
112. Van den Heuvel PACMB, Elbers HRJ, Plokker HWM, Bruschke VG. Myocardial involvement in acromegaly. Int J Cardiol. 1984;6:550–5. [PubMed]
113. Frustaci A, Chimenti C, Setoguchi M, et al. Cell death in acromegalic cardiomyopathy. Circulation. 1999;99:1426–34. [PubMed]
114. Passa P, Masquet C, Cophignon J, Gourgon R, Bouvrain Y. Le coeur dans l’acromegalie. Etude hemodynamique. Arch Mal Coeur Vaiss. 1973;66:1517–23. [PubMed]
115. Thuesen L, Christiansen JS, Sorensen KE, Jorgensen JOL, Orskov H, Henningsen P. Increased myocardial contractility following growth hormone administration in normal man. Dan Med Bull. 1988;35:193–6. [PubMed]
116. Losa M, von Werder K. In: Growth hormone and the heart. The heart in acromegaly. Manelli F, editor. Boston: Kluwer Academic Publishers; 2001. pp. 33–43.
117. Van Loon GR. Abnormal plasma catecholamine responses in acromegalics. J Clin Endocrinol Metab. 1979;48:784–9. [PubMed]
118. Sverrisdottir YB, Elam M, Herlitz H, Bengtsson BA, Johannsson G. Intense sympathetic nerve activity in adults with hypopituitarism and untreated growth hormone deficiency. J Clin Endocrinol Metab. 1998;83:1881–5. [PubMed]
119. Capaldo B, Lembo G, Rendina V, et al. Sympathetic deactivation by growth hormone in patients with dilated cardiomyopathy. Eur Heart J. 1998;19:623–7. [PubMed]
120. Capaldo B, Lembo G, Rendina V, et al. Muscle sympathetic nerve activity in patients with acromegaly. J Clin Endocrinol Metab. 2000;85:3203–7. [PubMed]
121. Bondanelli M, Ambrosio MR, Franceschetti P, Margutti A, Trasforini G, Degli Uberti EC. Diurnal rhythm of plasma catecholamines in acromegaly. J Clin Endocrinol Metab. 1999;84:2458–67. [PubMed]
122. Moller J, Moller N, Frandsen E, Wolthers T, Jorgensen JO, Christiansen JS. Blockade of the renin-angiotensin-aldosterone system prevents growth hormone induced fluid retention in humans. Am J Physiol. 1997;272:803–8. [PubMed]
123. McCaa RE, Montalvo JM, McCaa CS. Role of growth hormone in the regulation of aldosterone biosynthesis. J Clin Endocrinol Metab. 1978;46:247–53. [PubMed]
124. Kalberg BE, Ottoson AM. Acromegaly and hypertension: role of the renin-angiotensin-aldosterone system. Acta Endocrinol. 1982;100:581–7. [PubMed]
125. Leri A, Liu Y, Wang X, et al. Overexpression of insulin-like growth factor-I attenuates the myocytes renin-angiotensin system in transgenic mice. Circ Res. 1999;84:752–62. [PubMed]
126. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341:709–17. [PubMed]
127. Andreassen M, Faber J, Vestergaard H, Kistorp C, Kristensen LØ. N-terminal pro-B-type natriuretic peptide in patients with growth hormone disturbances. Clin Endocrinol (Oxf) 2007;66:619–25. [PubMed]
128. Hanson MC, Kenneth AF, Alexander RW, De Lafontaine P. Induction of cardiac insulin-like growth factor I gene expression in pressure overload hypertrophy. Am J Med Sci. 1993;306:69–74. [PubMed]
129. Isgaard J, Wahlander H, Adams MA, Friberg P. Increased expression of growth hormone receptor mRNA and insulin-like growth factor-I mRNA in volume-overloaded hearts. Hypertension. 1994;23:884–8. [PubMed]
130. Wright AD, Hill DM, Lowy C, Fraser TR. Mortality in acromegaly. Q J Med. 1971;39:1–16. [PubMed]
131. Swearingen B, Barker FG, Katznelson L, et al. Long-term mortality after transsphenoidal surgery and adjunctive therapy for acromegaly. J Clin Endocrinol Metab. 1998;83:3419–26. [PubMed]
132. Tokgozoglu SL, Erbas T, Aytemir K, Akalin S, Kes S, Oram E. Effects of octreotide on left ventricular mass in acromegaly. Am J Cardiol. 1994;74:1072–4. [PubMed]
133. Pereira J, Rodriguez-Puras MJ, Leal-Cerro A, et al. Acromegalic cardiomyopathy improves after treatment with increasing doses of octreotide. J Endocrinol Invest. 1991;14:17–23. [PubMed]
134. Merola B, Cittadini A, Colao A, et al. Chronic treatment with the somatostatin analog octreotide improves cardiac abnormalities in patients with acromegaly. J Clin Endocrinol Metab. 1993;77:790–3. [PubMed]
135. Colao A, Cuocolo A, Marzullo P, et al. Effects of one-year treatment with octreotide on cardiac performance in patients with acromegaly. J Clin Endocrinol Metab. 1999;84:17–23. [PubMed]
136. Colao A, Cuocolo A, Marzullo P, et al. Is the acromegalic cardiomyopathy reversible? Effect of 5-year normalization of growth hormone and insulin-like growth factor I levels on cardiac performance. J Clin Endocrinol Metab. 2001;86:1551–7. [PubMed]
137. Baldelli R, Ferretti E, Jaffrain-Rea ML, et al. Cardiac effects of slow-release lanreotide, a slow release somatostatin analog, in acromegalic patients. J Clin Endocrin Metab. 1999;84:527–32. [PubMed]
138. Colao A, Marzullo P, Cuocolo A, et al. Reversal of acromegalic cardiomyopathy in young but not in middle-aged patients after 12 months of treatment with the depot long-acting somatostatin analogue octreotide. Clin Endocrinol. 2003;58:169–76. [PubMed]
139. Chanson P, Timsit J, Masquet C, et al. Cardiovascular effects of the somatostatin analog octreotide in acromegaly. Ann Intern Med. 1990;113:921–5. [PubMed]
140. Ludens JH, Back RR, Williamson HE. Characteristics of the antinatriuretic action of growth hormone. Proc Soc Exp Biol Med. 1969;130:1156–8. [PubMed]
141. Iida K, Koide Y, Matsuda M, et al. Follow-up study of the heart in acromegaly: pre- and post-operative evaluation. Jnp J Med. 1990;29:22–6. [PubMed]
142. Lim MS, Barkan AL, Buda AJ. Rapid reduction of left ventricular hypertrophy in acromegaly after suppression of growth hormone hypersecretion. Ann Intern Med. 1992;117:719–26. [PubMed]
143. Colao A, Marzullo P, Ferone D, et al. Cardiovascular effects of depot long-acting somatostatin analog Sandostatin LAR in acromegaly. J Clin Endocrinol Metab. 2000;86:32–40. [PubMed]
144. Shahi M, Beshyah SA, Hackett D, Sharp PS, Johnston DG, Foale RA. Myocardial dysfunction in treated adult hypopituitarism: a possible explanation for increased cardiovascular mortality. Br Heart J. 1992;67:92–6. [PMC free article] [PubMed]
145. Colao A, Marzullo P, Di Somma C, Lombardi G. Growth hormone and the heart. Clin Endocrinol (Oxf) 2001;54:137–54. [PubMed]
146. Beshyah SA, Johnston DG. Cardiovascular disease and risk factors in adults with hypopituitarism. Clin Endocrinol. 1999;50:1–15. [PubMed]
147. Salomon F, Cuneo RC, Hesp R, Sonksen PH. The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency. N Engl J Med. 1989;321:1797–803. [PubMed]
148. Cuneo RC, Salomon F, McGauley GA, Sonksen PH. The growth hormone deficiency syndrome in adults. Clin Endocrinol (Oxf) 1992;37:387–97. [PubMed]
149. Pfeifer M, Verhovec R, Zizek B, Prezelj J, Poredos P, Clayton RN. Growth hormone (GH) treatment reverses early atherosclerotic changes in GH-deficient adults. J Clin Endocrinol Metab. 1999;84:453–7. [PubMed]
150. Markussis V, Beshyah SA, Fisher C, Sharp P, Nicolaides AN, Johnston DG. Detection of premature atherosclerosis by high-resolution ultrasonography in symptom-free hypopituitary adults. Lancet. 1992;340:1188–92. [PubMed]
151. Capaldo B, Patti L, Oliviero U, et al. Increased arterial intima-media thickness in childhood-onset growth hormone deficiency. J Clin Endocrinol Metab. 1997;82:1378–81. [PubMed]
152. Borson-Chazot F, Serusclat A, Kalfallah Y, et al. Decrease in carotid intima-media thickness after 1 year growth hormone (GH) treatment in adults with GH deficiency. J Clin Endocrinol Metab. 1999;84:1329–33. [PubMed]
153. Tsukahara H, Gordienko DV, Tonshoff B, Gelato MC, Goligorsky MS. Direct demonstration of insulin-like growth factor I induced nitric oxide production by endothelial cells. Kidney Int. 1994;45:598–604. [PubMed]
154. Boger RH, Skamira C, Bode-Boger SM, Brabant C, Von Zur Muhlen A, Frolich JC. Nitric oxide may mediate the hemodynamic effects of recombinant growth hormone in patients with acquired growth hormone deficiency: a double blind placebo controlled study. J Clin Invest. 1996;98:2706–13. [PMC free article] [PubMed]
155. Amato G, Carella C, Fazio S, et al. Body composition, bone metabolism, and heart structure and function in growth hormone (GH)-deficient adults before and after GH replacement therapy at low doses. J Clin Endocrinol Metab. 1993;77:1671–7. [PubMed]
156. Merola B, Cittadini A, Colao A, et al. Cardiac structural and functional abnormalities in adult patients with growth hormone deficiency. J Clin Endocrinol Metab. 1993;77:1658–61. [PubMed]
157. Cittadini A, Cuocolo A, Merola B, et al. Impaired cardiac performance in growth hormone deficient adults and its improvement after growth hormone replacement. Am J Physiol. 1994;267:219–25. [PubMed]
158. Longobardi S, Cuocolo A, Merola B, et al. Left ventricular function in young adults with childhood and adulthood onset growth hormone deficiency. Clin Endocrinol. 1998;48:137–43. [PubMed]
159. Thuesen L, Jorgensen JOL, Muller JR, et al. Short and long-term cardiovascular effects of growth hormone deficient adults. Clin Endocrinol. 1994;41:615–50. [PubMed]
160. Valcavi R, Gaddi O, Zini M, Iavicoli M, Mellino U, Portioli I. Cardiac performance and mass in adult with hypopituitarism: effects of one year of growth treatment. J Clin Endocrinol Metab. 1995;80:659–66. [PubMed]
161. Johannsson G, Bengtsson BA, Andersson B, Isgaard J, Caidahl K. Long-term cardiovascular effects of growth hormone treatment in GH-deficient adults: preliminary data in a small group of patients. Clin Endocrinol. 1996;45:305–14. [PubMed]
162. Cuneo RC, Salomon F, Wiles CM, Hesp R, Sonksen PH. Growth hormone treatment in growth hormone deficient adults. I. Effects on muscle mass and strength. J Appl Physiol. 1991;70:688–94. [PubMed]
163. Cuneo RC, Salomon F, Wiles CM, Hesp R, Sonksen PH. Growth hormone treatment in growth hormone deficient adults. II. Effects on exercise performance. J Appl Physiol. 1991;70:695–70. [PubMed]
164. Colao A, Cuocolo A, Di Somma C, et al. Impaired cardiac performance in elderly patients with growth hormone deficiency. J Clin Endocrinol Metab. 1999;85:3950–5. [PubMed]
165. Colao A, Di Somma C, Cuocolo A et al. The severity of GH deficiency (GHD) correlates with the severity of cardiac impairment in 100 adult patients with hypopituitarism: an observational, case-control study. J Clin Endocrinol Metab. 2004;89(12):5998–6004. [PubMed]
166. Maison P, Chanson P. Cardiac effects of growth hormone in adults with growth hormone deficiency. Circulation. 2003;108:2648–52. [PubMed]
167. Cuocolo A, Nicolai E, Colao A, et al. Improved left ventricular function after growth hormone replacement in patients with hypopituitarism assessment with radionuclide angiography. Eur J Nucl Med. 1996;23:390–4. [PubMed]
168. Colao A, Di Somma C, Cuocolo A, et al. Improved cardiovascular risk factors and cardiac performance after 12 months of growth hormone (GH) replacement in young adult patients with GH deficiency. J Clin Endocrinol Metab. 2001;86:1874–81. [PubMed]
169. Johannsson G, Albertsson-Wikland K, Bengtsson BA. Discontinuation of growth hormone (GH) treatment metabolic effects in GH-deficient and GH-sufficient adolescent patients compared with control subjects. J Clin Endocrinol Metab. 1999;84:4516–24. [PubMed]
170. Beshyah SA, Shahi M, Skinner E, Sharp P, Foale R, Johnston DG. Cardiovascular effects of growth hormone replacement therapy in hypopituitary adults. Eur J Endocrinol. 1994;130:451–8. [PubMed]
171. Jorgensen JOL, Pedersen SA, Thuesen L, et al. Beneficial effects of growth hormone treatment in GH-deficient adults. Lancet. 1989;1:1221–5. [PubMed]
172. Colao A, Di Somma C, Salerno M, Spinelli L, Orio F Jr, Lombardi G. The cardiovascular risk of growth hormone-deficient adolescents. J Clin Endocrinol Metab. 2002;87:3650–5. [PubMed]
173. Maison P, Griffin S, Nicoue-Beglah M, Haddad N, Balkau B, Chanson P. Impact of growth hormone (GH) treatment on cardiovascular risk factors in GH-deficient adults: a metaanalysis of blinded, randomized, placebo controlled trials. J Clin Endocrinol Metab. 2004;89:2192–9. [PubMed]
174. Chrisoulidou A, Beshyah SA, Rutherford O, et al. Effects of 7 years of growth hormone replacement therapy in hypopituitary adults. J Clin Endocrinol Metab. 2000;85:3762–9. [PubMed]
175. Colao A, Di Somma C, Rota F, et al. Short-term effects of growth hormone (GH) treatment or deprivation on cardiovascular risk parameters and intima-media thickness at carotid arteries in patients with severe GH deficiency. J Clin Endocrinol Metab. 2005;90:2056–62. [PubMed]
176. Colao A, Di Somma C, Cuocolo A, et al. Does a gender-related effect of growth hormone (GH) replacement exist on cardiovascular risk factors, cardiac morphology, and performance and atherosclerosis? Results of a 2-year open, prospective study in young adult men and women with severe GH deficiency. J Clin Endocrinol Metab. 2005;90:5146–55. [PubMed]
177. Castagnino HE, Toranzos FA, Milei J, et al. Preservation of the myocardial collagen framework by human growth hormone in experimental infarctions and reduction in the incidence of ventricular aneurysms. Int J Cardiol. 1992;35:101–14. [PubMed]
178. Ambler GR, Johnston BM, Maxwell L, Gavin JB, Gluckman PD. Improvement of doxorubicin induced cardiomyopathy in rats treated with insulin-like growth factor I. Cardiovasc Res. 1993;27(7):1368–73. [PubMed]
179. Ito H, Hiroe M, Hirata Y, et al. Insulin-like growth factor-I induces hypertrophy with enhanced expression of muscle specific genes in cultured rat cardiomyocytes. Circulation. 1993;87:1715–21. [PubMed]
180. Duerr RL, Huang S, Miraliakbar HR, Clark R, Chien KR, Ross J Jr. Insulin-like growth factor-1 enhances ventricular hypertrophy and function during the onset of experimental cardiac failure. J Clin Invest. 1995;95(2):619–27. [PMC free article] [PubMed]
181. Cittadini A, Grossman JD, Napoli R, et al. Growth hormone attenuates early left ventricular remodeling and improves cardiac function in rats with large myocardial infarction. J Am Coll Cardiol. 1997;29:1109–16. [PubMed]
182. Jin H, Yang R, Gillett N, Clark RG, Ko A, Paoni NF. Beneficial effects of growth hormone and insulin-like growth factor-1 in experimental heart failure in rats treated with chronic ACE inhibition. J Cardiovasc Pharmacol. 1995;26(3):420–5. [PubMed]
183. Duerr RL, McKirnan MD, Gim RD, Clark RG, Chien KR, Ross J Jr. Cardiovascular effects of insulin-like growth factor-1 and growth hormone in chronic left ventricular failure in the rat. Circulation. 1996;93(12):2188–96. [PubMed]
184. Yang R, Bunting S, Gillet N, Jin H. Growth hormone improves cardiac performance in experimental heart failure. Circulation. 1995;92:262–7. [PubMed]
185. Cittadini A, Isgaard J, Monti MG, et al. Growth hormone prolongs survival in experimental postinfarction heart failure. J Am Coll Cardiol. 2003;41:2154–63. [PubMed]
186. Cittadini A, Strömer H, Katz SE, Clark R, Moses AC, Morgan JP, Douglas PS. Differential cardiac effects of growth hormone and insulin-like growth factor-1 in the rat. A combined in vivo and in vitro evaluation. Circulation. 1996;93(4):800–9. [PubMed]
187. Grimm D, Cameron D, Griese DP, Riegger GAJ, Kromer E. Differential effects of growth hormone on cardiomyocyte and extracellular matrix protein remodeling following experimental myocardial infarction. Cardiovas Res. 1998;40:297–306. [PubMed]
188. Isgaard J, Kujacic V, Jennische E, et al. Growth hormone improves cardiac function in rats with experimental myocardial infarction. Eur J Clin Invest. 1997;27(6):517–25. [PubMed]
189. Ross J Jr, Hongo M. The role of hypertrophy and growth factors in heart failure. J Card Fail. 1996;2(4 Suppl):121–8. [PubMed]
190. Houck WV, Pan LC, Kribbs SB, et al. Effects of growth hormone supplementation on left ventricular morphology and myocyte function with the development of congestive heart failure. Circulation. 1999;100:2003–9. [PubMed]
191. Kinugawa S, Tsutsui H, Ide T, et al. Positive inotropic effect of insulin-like growth factor-1 on normal and failing cardiac myocytes. Cardiovasc Res. 1999;43:157–64. [PubMed]
192. Vetter U, Kupferschmid C, Lang D, Pentz S. Insulin-like growth factors and insulin increase the contractility of neonatal rat cardiocytes in vitro. Basic Res Cardiol. 1988;83:647–54. [PubMed]
193. Freestone NS, Ribaric S, Mason WT. The effect of insulin-like growth factor-1 on adult rat cardiac contractility. Mol Cell Biochem. 1996;163-164:223–9. [PubMed]
194. Stromer H, Cittadini A, Douglas PS, Morgan JP. Exogenously administered growth hormone and insulin-like growth factor-i alter intracellular Ca2+ handling and enhance cardiac performance in vitro evaluation in the isolated isovolumic buffer-perfused rat heart. Circ Res. 1996;79:227–36. [PubMed]
195. Von Lewinski D, Voß K, Hülsmann S, Kögler H, Pieske B. Insulin-like growth factor-1 exerts Ca2+-dependent positive inotropic effects in failing human myocardium. Circ Res. 2003;92:169–76. [PubMed]
196. Gonzalez-Juanatey JR, Pineiro R, Iglesias MJ, et al. GH prevents apoptosis in cardiomyocytes cultured in vitro through a calcineurin-dependent mechanism. J Endocrinol. 2004;180:325–35. [PubMed]
197. Haunstetter A, Izumo S. Apoptosis. Basic mechanisms and implications for cardiovascular disease. Circ Res. 1998;82:1111–29. [PubMed]
198. Kang PM, Izumo S. Apoptosis and heart failure: a critical review of the literature. Circ Res. 2000;86:1107–13. [PubMed]
199. Baixeras E, Jeay S, Kelly PA, Postel-Vinay MC. The proliferative and antiapoptotic actions of growth hormone and insulin-like growth factor-1 are mediated through distinct signaling pathways in the Pro-B Ba/F3 cell line. Endocrinology. 2001;142:2968–77. [PubMed]
200. Jeay S, Sonenshein GE, Postel-Vinay MC, Baixeras E. Growth hormone prevents apoptosis through activation of nuclear factor-kB in interleukin-3-dependent Ba/F3 cell line. Mol Endocrinol. 2000;14:650–61. [PubMed]
201. Jeay S, Sonenshein GE, Kelly PA, Postel-Vinay MC, Baixeras E. Growth hormone exerts antiapoptotic and proliferative effects through two different pathways involving nuclear factor-kB and phosphatidylinositol 3-kinase. Endocrinolgy. 2001;142:147–56. [PubMed]
202. Cuneo RC, Wilmshurst P, Lowy C, McGauley G, Sonksen PH. Cardiac failure responding to growth hormone. Lancet. 1989;1:838–9. [PubMed]
203. Frustaci A, Perrone GA, Gentiloni N, Russo MA. Reversible dilated cardiomyopathy due to growth hormone deficiency. Am J Clin Pathol. 1992;97:503–11. [PubMed]
204. Fazio S, Sabatini D, Capaldo B, et al. A preliminary study of growth hormone in the treatment of dilated cardiomyopathy. N Engl J Med. 1996;334:809–14. [PubMed]
205. Osterziel KJ, Strohm O, Schuler J, et al. Randomised, double-blind, placebo-controlled trial of human recombinant growth hormone in patients with chronic heart failure due to dilated cardiomyopathy. Lancet. 1998;351:1233–7. [PubMed]
206. Isgaard J, Bergh CH, Caidahl K, Lomsky M, Hjalmarson A, Bengtsson BA. A placebo-controlled study of growth hormone in patients with congestive heart failure. Eur Heart J. 1998;19:1704–11. [PubMed]
207. Genth-Zotz S, Zotz R, Geil S, Voigtländer T, Meyer J, Darius H. Recombinant growth hormone therapy in patients with ischemic cardiomyopathy: effects on hemodynamics, left ventricular function, and cardiopulmonary exercise capacity. Circulation. 1999;99:18–21. [PubMed]
208. Spallarossa P, Rossettin P, Minuto F, et al. Evaluation of growth hormone administration in patients with chronic heart failure secondary to coronary artery disease. Am J Cardiol. 1999;84:430–3. [PubMed]
209. Perrot A, Ranke MB, Dietz R, Osterziel KJ. Growth hormone treatment in dilated cardiomyopathy. J Card Surg. 2001;16:127–31. [PubMed]
210. Frustaci A, Gentiloni N, Russo MA. Growth hormone in the treatment of dilated cardiomyopathy. N Engl J Med. 1996;335:672–3. [PubMed]
211. Jose VJ, Zechariah TU, George P, Jonathan V. Growth hormone therapy in patients with dilated cardiomyopathy: preliminary observations of a pilot study. Indian Heart J. 1999;51:183–5. [PubMed]
212. Acevedo M, Corbalan R, Chamorro G, et al. Administration of growth hormone to patients with advanced cardiac heart failure: effects upon left ventricular function, exercise capacity, and neurohormonal status. Int J Cardiol. 2003;87:185–91. [PubMed]
213. Cittadini A, Comi IL, Longobardi S, et al. A preliminary randomized study of growth hormone administration in Becker and Duchenne muscular distrophies. Eur Heart J. 2003;24:664–72. [PubMed]
214. Smit JW, Janssen YJ, Lamb HJ, et al. Six months of recombinant human GH therapy in patients with ischemic cardiac failure does not influence left ventricular function and mass. J Clin Endocrinol Metab. 2001;86:4638–43. [PubMed]
215. Adamopoulos S, Parissis JT, Georgiadis M, et al. Growth hormone administration reduces circulating proinflammatory cytokines and soluble Fas/soluble Fas ligand system in patients with chronic heart failure secondary to idiopathic dilated cardiomyopathy. Am Heart J. 2002;144:359–64. [PubMed]
216. Parissis JT, Adamopoulos S, Karatzas D, Paraskevaidis J, Livanis E, Kremastinos D. Growth hormone-induced reduction of soluble apoptosis mediators is associated with reverse cardiac remodelling and improvement of exercise capacity in patients with idiopathic dilated cardiomyopathy. Eur J Cardiovasc Prev Rehabil. 2005;12:164–8. [PubMed]
217. Adamopoulos S, Parissis JT, Paraskevaidis J, et al. Effects of growth hormone on circulating cytokine network, and left ventricular contractile performance and geometry in patients with idiopathic dilated cardiomyopathy. Eur Heart J. 2003;24:2186–96. [PubMed]
218. Fazio S, Palmieri EA, Affuso F, et al. Effects of growth hormone on exercise capacity and cardiopulmonary performance in patients with chronic heart failure. J Clin Endocrinol Metab. 2007;92:4218–23. [PubMed]
219. Le Corvoisier P, Hittinger L, Chanson P, Montagne O, Macquin-Mavier I, Maison P. Cardiac effects of growth hormone treatment in chronic heart failure: a meta-analysis. J Clin Endocrinol Metab. 2007;92:180–5. [PubMed]

"There were around 20 people chasing him. They started throwing petanque balls at him," Najah said. "Around four or five balls hit him in the head, but they weren't able to stop him."




French police are not characterizing a knife rampage in a popular Paris tourist spot as a terror attack, a French Interior Ministry spokesman told CNN.

Seven people were injured, including two middle-aged British tourists, in Sunday night's assault by a man wielding a knife and an iron bar, according to the spokesman.

"This is not being treated as a terrorist attack," he said.

The attack took place at 10:50 p.m. (4:50 p.m. ET) in the Parc de la Villette by the Ourcq Canal in the 19th arrondissement, a lively neighborhood in northeastern Paris popular with young people and tourists.

A bystander fought off the attacker with balls from a petanque game, a local kind of bowling, until police arrived.

Eyewitness Youssef Najah, 28, told Agence France-Presse he was walking along the canal near a bowling green when he saw a man running and holding a large knife.

"There were around 20 people chasing him. They started throwing petanque balls at him," Najah said. "Around four or five balls hit him in the head, but they weren't able to stop him."

According to the same witness, the attacker then dived into an alleyway, where the man "tried to hide behind two British tourists. We said to them: 'Watch out, he has a knife." But they didn't react."

The pair were then attacked, he said.

Sunday evening's attack was the latest in a stream of knife crimes in France recently.

On August 23, a man stabbed his mother and sister to death and seriously injured another person in a town near Paris before police shot him and killed him.

ISIS claimed responsibility for that attack, but French authorities said the 36-year-old had mental health problems and had been on their terror watch list since 2016.

Ten days earlier an Afghan asylum-seeker was arrested in the southwestern French town of Perigueux after wounding four people in a drunken rampage, AFP reported.

On June 17, two people were hurt in another southern town when a woman shouting "Allahu akbar" attacked them with a knife in a supermarket before being overpowered.

The previous month, a 21-year-old Chechen-born French citizen armed with a knife killed one pedestrian and injured several more near the Palais Garnier, the opera house in Paris, before police shot him dead.

https://www.cnn.com/2018/09/10/europ...ntl/index.html

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2822143/

Abstract
The growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis regulates cardiac growth, stimulates myocardial contractility and influences the vascular system. The GH/IGF-1 axis controls intrinsic cardiac contractility by enhancing the intracellular calcium availability and regulating expression of contractile proteins; stimulates cardiac growth, by increasing protein synthesis; modifies systemic vascular resistance, by activating the nitric oxide system and regulating non-endothelial-dependent actions. The relationship between the GH/IGF-1 axis and the cardiovascular system has been extensively demonstrated in numerous experimental studies and confirmed by the cardiac derangements secondary to both GH excess and deficiency. Several years ago, a clinical non-blinded study showed, in seven patients with idiopathic dilated cardiomyopathy and chronic heart failure (CHF), a significant improvement in cardiac function and structure after three months of treatment with recombinant GH plus standard therapy for heart failure. More recent studies, including a small double-blind placebo-controlled study on GH effects on exercise tolerance and cardiopulmonary performance, have shown that GH benefits patients with CHF secondary to both ischemic and idiopathic dilated cardiomyopathy. However, conflicting results emerge from other placebo-controlled trials. These discordant findings may be explained by the degree of CHF-associated GH resistance. In conclusion, we believe that more clinical and experimental studies are necessary to exactly understand the mechanisms that determine the variable sensitivity to GH and its positive effects in the failing heart.

Keywords: GH/IGF-1 axis, Chronic heart failure, Acromegaly, GH deficiency.
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INTRODUCTION
Growth hormone (GH), a 191 amino acid single-chain peptide, is synthesized and secreted by the somatotroph cells of the anterior pituitary gland [1, 2]. Its secretion is strictly regulated by two hypothalamic neurohormones: GH releasing factor (GHRF) and GH inhibiting factor (somatostatin). The ratio between these two factors represents the mechanism by which neurologic and extra-neurologic influences may functionally affect GH release [2-9]. Furthermore, GH can modulate its own secretion by different feedback loops: indirectly by producing insulin-like growth factor-1 (IGF-1), which inhibits somatotroph cells and stimulates somatostatin release, or directly by inhibiting GHRF messenger RNA (mRNA) and by stimulating somatostatin mRNA synthesis [10].

GH secretion is pulsatile, and is regulated by a number of neurologic, metabolic and hormonal influences: during most of the day, the plasma GH level of adults is 5 ng/ml, with one or two sharp spikes three to four hours after meals. The lowest circulating level is early in the morning and highest about one hour after the onset of deep sleep [11-14]. Secretion is enhanced by α2 agonists, hypoglycemia and daily life stresses, and inhibited by β and α1 agonists, glucocorticoids and aging [12, 14-17].

The biological effects of GH are mediated by the interaction with a specific receptor (GHR), a single chain trans-membrane protein, expressed in almost all cellular types (liver membranes, adipocytes, fibroblasts, lymphocytes, myocytes) [8, 11, 18, 19]. Its dimerization activates the Jak/Stat pathway (Janus Kinase and Signaling Transducer and Activates of Transcription), which induces intracellular signal transduction, thereby altering calcium (Ca2+) trafficking, regulating expression of contractile and cytoskeletal proteins and modifying activation of intrinsic neurohormonal networks [20].

GH exerts its effects either directly or indirectly [2, 21, 22]. Most of the indirect effects are mediated by induction of IGF-1 expression in the liver and in peripheral tissues [23-27]. It is well known that IGF-1 is the principal, but not the only, GH mediator. For instance, GH stimulates induction of c-myc proto-oncogene in various tissues and of platelet-derived growth factor in the heart [28, 29]. But the role of these and other growth factors is still unknown.

IGF-1, a 70 amino acid single chain protein, structurally homologous to pro-insulin, is synthesized in liver and kidney, although the local production in other tissues appears to be important in mediating, by paracrine or autocrine mechanisms, GH anabolic and growth-promoting effects [30-33]. IGF-1 circulates bound to protein carriers (IGFBPs), which serve not only to transport IGF-1 in the circulation but also to prolong its half life, modulate its tissue specificity and strengthen or neutralize its biological actions [31]. The serum concentration of IGFBPs is influenced by circulating GH levels, but does not have a circadian pattern. The intracellular signal pathways involved in IGF-1 transduction implicate insulin receptor substrate (IRS)-1, phosphatidylinositol (PI) 3-kinase, phospholipase C (PLC)-g1, mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) cascade [34].

The diminished age-related amplitude of GH pulses and the increased resistance to GH action contribute to reduce IGF-1 plasma concentration. The mechanisms underlying these age-related modifications include peripheral influences (gonadal steroids, adiposity), changes in hypotalamic neuropeptides and neurotransmitters, and increase in somatostatin secrection. [35]. Although the decline of GH/IGF-1 axis is associated with an increase in GH/IGF-1 receptors on cardiomyocytes, this increase fails to compensate the reduction of GH secretion probably because of the diminished intracellular signal transduction [36, 37]. In fact, in rodents, it has been widely demonstrated that with aging there is a reduction of JAK2 phosphorilation, a decline of MAP kinase activity, a reduction of STAT3 activation and a decrease in nuclear translocation [37-40]. GH/IGF-1 deficiency contributes to physiological age-related cardiovascular modifications, such as decrease in the number of cardiomyocytes [41-43], rarefaction of coronary arterioles [44], increase in fibrosis and collagen deposition [45-48], reduced protein synthesis [49] and alteration of contractile proteins with reduction in myosin-actin bridges [50].

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PHYSIOLOGICAL EFFECTS OF GH
GH alters body’s homeostasis and its effects can generally be described as anabolic. GH directly stimulates chondrocyte division and multiplication; it increases calcium retention, thereby strengthening bone mineralization [51]; promotes lipolysis and protein synthesis, by stimulating amino acid uptake [16, 52-55]; induces hyperglycemia, consequent to insulin resistance and gluconeogenesis [52, 56]; increases muscle mass, through sarcomere hyperplasia, and stimulates the immune system. In addition, GH increases peripheral conversion of thyroid hormone thyroxine (T4) to triiodothyronine, with a consequent decline of thyroid stimulating hormone and T4 levels [57]. It also activates the renin-angiotensin-aldosterone system and decreases atrial natriuretic peptide circulating level [58, 59].

CARDIOVASCULAR EFFECTS
Besides growth promoting and metabolic effects, the GH/IGF-1 axis regulates cardiac growth, stimulates myocardial contractility and influences the vascular system (Fig. ​11).

The myocardium and the endothelium not only express receptors for both GH and IGF-1, but also produce IGF-1 locally. Thus, there is a direct action of GH by endocrine mechanism and/or indirect action by autocrine/paracrine mechanisms of IGF-1 [30-32]. On vascular system, the GH/IGF-1 axis exerts its effects by activating the nitric oxide (NO) system and regulating non-endothelial-dependent actions [60-69]. NO production relaxes arterial smooth muscle cells, thereby reducing vascular tone. Furthermore, NO inhibits proliferation and migration of smooth muscle cells, reduces platelet adhesion, decreases lipoxygenase activity and oxidized LDL-cholesterol [60-69]. Recently, NO has been shown to modulate cardiac cytoskeletal functions by altering calcium myofilament responsiveness [70]. In addition, IGF-1 may cause vasorelaxation both by enhancing Na+/K+ ATPase activity [71] and regulating gene expression of KATP channel in vascular smooth cells [72]. This ATP-sensitive potassium channel consists of two subunits: the sulfonylurea receptor and the inwardly rectifying potassium channel, which could be critical in regulating vascular tone [73, 74].

The GH/IGF-1 axis may also regulate cardiac growth and metabolism, by increasing amino acid uptake, protein synthesis, cardiomyocyte size and muscle-specific gene expression. Specifically IGF-1 promotes cardiac hypertrophy and increases muscle specific gene transcription (namely, troponin I, myosin light chain-2, and α-actin) [75-77]. Moreover, IGF-1 promotes collagen synthesis by fibroblasts, whereas GH increases the collagen deposition rate in the heart [78-81]. Substantial evidence indicates that IGF-1 influences the trophic status of myocardium by reducing apoptosis of cardiomyocytes, thus preventing myocyte loss [76, 82].

The GH/IGF-1 axis can also control intrinsic cardiac contractility through different mechanisms: by enhancing myofilament calcium sensitivity [76, 77, 82, 83], modifying intracellular calcium transient through an increase in L- type calcium channel activity [84, 85] and up-regulating sarcoplasmatic reticulum ATPase (SERCA) levels [86, 87]. SERCA up-regulation may cause an increase in contractility, enhancing calcium contractile reserve in the sarcoplasmatic reticulum and allowing a higher calcium peak level on stimulation.

While IGF-1 positively affects cardiac contractility, GH physiological role, although GHRs are expressed on the heart, probably does not include acute modulation of myocardial contractility, but it needs to mediate some other functions such as protein synthesis or local IGF-1 production [82, 88].

Moreover, GH induces myosin phenoconversion toward the low ATPase activity V3 isoform. The prevalence of V3 isoform increases the number of actin-myosin cross-bridges and their attachment time, enhances protein calcium sensitivity and calcium availability and allows the myocardium to function at lower energy cost [76, 77]. V3 isoform also prevails in pathologic cardiac hypertrophy secondary to hemodynamic overload, to compensate depressed contractility and high wall stress.

Although GH reduces energy output, it favours the conversion of metabolic energy to external work and enhances the intrinsic ability of the myofilament to develop force, resulting in an improvement of LV performance [89]. In conclusion, GH improves myocardial energy metabolism reducing oxygen consumption and energy demand, even in failing heart in which the increment in wall stress increases oxygen demand [90]

The relationship between the GH/IGF-1 axis and the cardiovascular system has been extensively demonstrated in numerous experimental studies and confirmed by the derangements of cardiac structure and function reported in patients with both GH excess (acromegaly) and GH deficiency (GHD).

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CLINICAL EVIDENCE OF GH EXCESS IN HUMANS
Acromegaly is a clinical condition consequent to chronic GH excess that affects the heart. Acromegalic cardiac involvement was first described by Huchard in 1895 [91]. Subsequent reports documented that chronic GH excess leads to cardiac functional and morphological abnormalities [30, 76, 77, 92-97].

Acromegalic cardiomyopathy can be divided into three main stages [22, 89]. The early stage is characterized by functional abnormalities: enhanced myocardial contractility, decreased peripheral vascular resistance and increased cardiac output (hyperkinetic state) [22, 89, 98, 99]. In stage 1, ventricular wall thickening is not associated with cavity dilatation, so that relative wall thickness (left ventricular [LV] wall thickness/LV radius) increases and causes a reduction in wall stress and an increase in cardiac performance, according to the Laplace’s law (wall stress=LV pressure/LV relative wall thickness) [10, 22, 89, 99-106]. In this stage, the reduction of wall stress together with the positive effects of GH/IGF-1 on myocardial contractility and systemic vascular resistance produces an improvement in cardiac function. Initially, this increase in wall thickness and LV mass has no negative impact on diastolic function [22, 99, 105]. The intermediate stage (after about five years of active disease) is characterized by biventricular hypertrophy, diastolic dysfunction and impaired cardiac performance, which are undetected under resting condition, but appear on effort [22, 89, 103, 104, 107-109]. Hypertrophy, which entails proliferation of myocardial fibrous tissue, leads to progressive interstitial remodelling, which causes inexorable deterioration of cardiac performance. Diastolic abnormallities, which usually anticipate systolic dysfunction, include prolonged isovolumic relaxation time, decreased early-to-late mitral and tricuspid velocity ratio, reduced diastolic filling wave and increased reversal flow during atrial contraction. These alterations result in impaired ventricular relaxation and enhanced ventricular stiffness [22, 29, 104, 106]. In a very late stage, acromegalic cardiomyopathy is characterized by systolic and diastolic dysfunction that can lead to congestive heart failure, often resistant to conventional therapies, increased myocardial mass, marked ventricular cavity dilatation and high peripheral vascular resistance [22, 30, 98]. It also includes cardiac valve disease (mitral and aortic valve regurgitation), coronary artery disease and arrhythmias [110]. The prevalence of these complications is likely to depend on the duration of GH excess. Myocardial hypertrophy and interstitial fibrosis, which increase as the disease progresses, are responsible for myocardial ischemia, consequent to reduced capillary density, and arrhythmias, due to the interference of the pulse propagation process in the myocardium [111]. Electrocardiographic recordings have demonstrated a higher frequency of ectopic beats, paroxysmal atrial fibrillation or supraventricular tachycardia, sick sinus syndrome, ventricular tachycardia and bundle branch block in acromegalic patients as compared with the normal population [112-114].

The most relevant histological abnormalities are interstitial fibrosis, reduced capillary density, increased extracellular collagen deposition, myofibrillar derangement, lymphomononuclear infiltration and myocyte death due to necrosis and apoptosis [22, 110, 115, 116].

GH excess seems to exert different and potentially opposite effects on the heart: it enhances cardiac performance in early-stage acromegaly, whereas it causes cardiac dysfunction in the intermediate-late phase. This apparent discrepancy is easily clarified: a physiological GH level or short-term excess exert positive inotropic effect, whereas by causing morphological and functional adaptive changes, long-term exposure to GH excess induces cardiac dysfunction and progression to heart failure [76, 77, 92, 98, 106, 117, 118].

GH/IGF-1 may cause acromegalic morphological and functional changes either directly by affecting myocyte growth and contractility, or indirectly by affecting peripheral vascular resistance, modifying extracellular volume and neurohormonal activity. Subsequently, with the increase of arterial stiffness due to hypertrophy and fibrosis of the arterial muscular tunica, about 20-50% of acromegalic patients become hypertensive [119]. Experimental studies about the role of the neurohormonal system in the development and progression of acromegalic cardiomyopathy, have produced conflicting results [30, 120-128]. In the late 1970s, it was reported that chronic GH excess, by eliciting sympathetic overactivity, induces myocardial hypertrophy [120]. Only two decades later, it was demonstrated that GH exerts no sympatho-excitatory effects [122, 129]. Recently, it has been shown that in acromegalic cardiomyopathy, in contrast with other conditions of cardiac hypertrophy, there are low B-type natriuretic peptide (BNP) circulating levels and that the normalization of GH/IGF-1 serum concentrations is followed by an increase in BNP levels [130].

There is compelling evidence that IGF-1 is involved in the intricate cascade of events leading to cardiac hypertrophy. In fact, in response to pressure or volume overload, IGF-1 expression increases in parallel to hypertrophy [131, 132]. Moreover, numerous trials have shown that GH suppression, associated with IGF-1 normalization, reduces cardiovascular mortality to that of general population, which supports the concept that cardiac alterations in acromegaly are strictly related to GH/IGF-1 excess [104,133-141]. By normalizing serum GH and IGF-1 values, somatostatin analogues improve diastolic filling parameters (ventricular isovolumic relaxation and early diastolic filling velocity), reduce volume overload and pulmonary and wedge pressures, and enhance cardiac performance [137, 142, 143]. Data on the effectiveness of acromegalic treatment are still conflicting as regards the effects on ventricular hypertrophy. Some studies demonstrate that treatment can reduce LV mass to a normal value [105], whereas others show no significant change or only a small improvement in LV mass [144]. Although it is not yet known whether the acromegalic heart can return to normal condition, the experimental data available indicate that cardiac hypertrophy is reversible and that the reversal may be complete if GH activity is restored to normal level for a sufficient amount of time [135-137, 140, 141, 144-146]. However, it should be noted that the cardiac effects of somatostatin analogues seem to be related not only to the strict biochemical control of acromegaly, but also to the patient's age and the disease duration before starting treatment [22].

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GH DEFICIENCY
Growth hormone deficiency produces different clinical features depending on the time of onset and disease severity and duration [2, 22, 106, 147]. GHD negatively affects cardiovascular function by directly acting on the heart and endothelium; it also acts indirectly by causing insulin resistance, abdominal obesity, hypercoagulability, increase in serum lipids, reduction in exercise performance and pulmonary capacity [148, 149]. GHD patients have increased total body fat, atherothrombotic and proinflammatory abnormalities, dyslipidemia and decreased insulin-stimulated glucose uptake by fat and skeletal muscle [150, 151]. In addition to the cardiovascular risk factors mentioned above, GHD patients have increased vessel intima-media thickness, which is the earliest morphological change in the development of atherosclerosis [149, 152-155]. Patients with GHD are also affected by endothelial dysfunction, reduced NO production, high peripheral vascular resistance and enhanced aorta stiffness [152-157]. Furthermore, GHD affects cardiac size and function, thereby leading to a reduction in both myocardial growth rate and cardiac performance [158, 159]. Cardiac function decreases because of reduced ventricular mass and intrinsic myocardial contractility [160].

Childhood-onset GHD is characterized by cardiac atrophy with a significant reduction in LV mass, relative wall thickness and cavity dimensions, compared with age-, sex- and height-matched controls [158-162]. Moreover, patients are affected by a hypokinetic syndrome, namely, they have a low ejection fraction, low cardiac output and high peripheral vascular resistance [158, 160-163]. These alterations are more pronounced during physical exercise and, besides reducing skeletal muscle mass and strength, they reduce exercise capacity, as shown by subjective symptoms, low values of achieved workload and exercise duration [160, 164-166]. Adult-onset GHD does not feature a reduction in cardiac mass, but only impaired cardiac performance and exercise capacity [165, 167, 168].

Evidence that cardiac alterations in GHD are strictly related to the GH deficiency comes from many GH replacement trials, which taken together show an increase in LV mass and improvement in cardiac performance, diastolic filling and systolic function after GH treatment [158-160, 163, 164, 166, 169-172]. Although some studies have failed to demonstrate an improvement in cardiac structure or function [173, 174], a meta-analysis that included all trials on the effects of GH replacement included in Medline, Biosis and EMBASE from the year of their inception to June 2002, showed positive effects on LV mass, wall thickness, LV end-diastolic and end-systolic diameters and cardiac output [169]. All the GH replacement trials showed that cardiac function returns to the pre-treatment setting upon cessation of GH treatment [158-160, 163, 164, 166, 169-172, 175].

The beneficial cardiovascular effects of GH replacement are related not only to cardiac anabolic actions but also to its peripheral effects. Treatment with GH normalizes NO production, thereby reducing peripheral vascular resistance and modulating cardiac cytoskeletal functions by altering calcium myofilament responsiveness [70, 157]. Moreover, GH replacement improves body composition, which is an important factor for reducing cardiovascular risk [176, 177], induces beneficial effects on lipid profile [178, 179] and reduces arterial intima-media thickness [152, 155, 178, 179].

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GH AND HEART FAILURE
The rationale for GH therapy in CHF appears evident when considering the cardiovascular effects of GH and the cardiac morphological and functional features in heart failure. Patients with CHF have reduced myocardial contractility, decreased cardiac output, dilated LV cavity, increased peripheral vascular resistance and enhanced wall stress. Cardiac dilatation, which initially helps to maintain an adequate stroke volume, initiates a vicious cycle whereby dilatation leads to dilatation. GH replacement may be beneficial in all steps of heart failure. By stimulating cardiac growth, GH induces a concentric pattern of remodelling, which reduces wall stress. By decreasing peripheral vascular resistance, GH reduces afterload, attenuates pathologic cardiac remodelling and improves cardiac function. Furthermore, by inducing positive inotropic effects, GH directly counteracts the impaired contractility, which is the primum movens of the vicious cycle responsible for pathologic remodelling.

The pathogenesis and the progression of CHF seem to be related also to an imbalance between pro-inflammatory/anti-inflammatory factors and endothelial dysfunction. Patients with CHF have excessive plasma levels of pro-inflammatory cytokines and impaired vascular reactivity, which consists of attenuated vasodilatation in response to acetylcholine and preserved response to the direct NO donor nitroprusside. By shifting the cytokine balance toward anti-inflammatory predominance and reducing pro-apoptotic factors, GH positively acts on LV remodelling, increasing LV contractile performance and enhancing exercise capacity. In addition, GH is able to improve vascular reactivity, not only by restoring NO production, but also activating non-endothelium-mediated actions, in particular by modifying intracellular calcium concentration and regulating Na+/K+ ATPase activity.

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EXPERIMENTAL STUDIES ON ANIMALS
The first study of the effects of the GH/IGF-1 system in experimental heart failure models dates back to 1992. At that time, Castagnino and colleagues evaluated the effect of GH on the connective tissue, fibroblast growth and proliferation in rats with experimental myocardial infarction, and found a significant decrease in the incidence of ventricular aneurysms [180]. A subsequent study, designed to assess the effects of IGF-1 on cardiac function and structure in rats with a doxorubicin-induced cardiomyopathy, showed that IGF-1 increases cardiac output as well as reduces histologically-detected myocyte damage [181]. In this scenario, Ito and co-workers proved, in cultured neonatal cardiomyocytes, that IGF-1, but not GH, promotes transcription of muscle-specific genes (namely, troponin I, myosin light chain-2, and α-actin), induces protein synthesis and increases myocyte size [75]. Duerr and colleagues demonstrated that IGF-1, administrated in rats early during the onset of experimental post-infarction heart failure, enhances the hypertrophic response of viable myocardium and cardiac performance [182]. Similarly, Cittadini and co-workers, investigating the cardiac effects of GH adminis-tration during the early phase of pathologic remodelling in a rat model of large myocardial infarction, confirmed that GH causes hypertrophy of the non-infarcted myocardium in a concentric pattern and improves LV function [183]. Two subsequent trials showed that GH plus IGF-1, given to rats with LV failure, starting one month after myocardial infarction, and then in the late phase of LV remodelling, improved cardiac function and reduced peripheral vascular resistance and LV dilatation [184, 185]. Other experimental studies confirmed that GH attenuates both the early and the late pathologic LV remodelling, induces hypertrophy of non-infarcted myocardium, improves LV function and increases cardiac output [186, 187].

Cittadini and co-workers administered GH or IGF-1 or GH plus IGF-1 to adult HF rats and found a significant increase in cardiac performance and LV mass, without development of significant fibrosis, and no additional hypertrophy in rats receiving GH plus IGF-1 compared with rats treated singularly with GH or IGF-1 alone. This interesting result suggested that, in vivo, IGF-1 mediates the GH-induced cardiac hypertrophy [188]. Subsequent studies confirmed that GH/IGF-1 modifies cardiac structure, reduces interstitial fibrosis and improves myocardial function [189-191].

More recently, Cittadini and colleagues demonstrated, in a rat model of post-infarction heart failure, that GH improves a broad spectrum of structural abnormalities of the extra-cellular matrix [187]. Specifically, they found a decrease in the collagen volume fraction and in the collagen I/III ratio, and an increase in capillary density. The authors hypothesized that GH attenuates fibrosis, directly by reducing collagen synthesis or increasing its breakdown, and indirectly by reducing accumulation of extracellular matrix proteins in the interstitial space. This latter was explained as due to the GH-induced improvement in hemodynamic and to the decrease in wall stress [187]. Cittadini and colleagues supposed that GH reduces interstitial fibrosis thanks also to its anti-apoptotic properties. Although apoptosis per se does not induce fibrosis, it leaves myocardial defects that are filled with interstitial fluid from myocardial edema, subsequently leading to fibrous tissue accumulation [187]. GH and IGF-1 exert direct beneficial effects on myocyte contractile performance in heart failure models, not solely by stimulating cardiac growth, modifying cardiac structure, reducing interstitial fibrosis or inducing peripheral vasodilatation, but also by changing calcium handling and the inotropic state [82, 88, 192-195]. Kinugawa and colleagues demonstrated that acute IGF-1 administration in isolated cardiomyocytes, in both normal and heart failure conditions, exerts a direct positive inotropic effect, due to calcium transient amplitude and calcium availability to the contractile apparatus [193]. They also showed IGF-1 does not modify the terminal portion of the relaxation phase trajectory, which indicates that calcium sensitivity is not altered by IGF-1 administration [193]. This result was consistent with previous studies in which acute IGF-1 administration increases the contractility of cardiomyocytes and isolated ventricular muscle [82, 88]. In addition, Freestone and colleagues reported that, in isolated rat cardiac muscle, acute IGF-1 administration had a positive inotropic effect, in fact, it increased the peak of cytosolic free calcium concentration, the amplitude of calcium transient and the time to peak [194]. In contrast with these results, Cittadini and co-workers showed that, in isolated isovolumic aequorin-loaded rat whole hearts and ferret papillary muscles, IGF-1 administration produces an acute positive inotropic effect, not associated with an increased intra-cellular calcium availability but to a significant increase of myofilament calcium sensitivity [82]. All these experimental studies, in which GH did not induce acute effects on cardiac function, and IGF-1 positively affected cardiac contractility, provide further insight into the intricate interaction between the GH/IGF-1 axis and cardiovascular system. In fact, although GHRs are expressed on the heart, their physio-logical role probably does not include acute modulation of myocardial contractility, but they serve to mediate such other functions as protein synthesis or local IGF-1 production [82, 88, 193, 194].

Von Lewinski and colleagues were the first to study the functional effects of IGF-1 in isolated human myocardium. They demonstrated that IGF-1: 1) exerts a concentration-dependent positive inotropic effect, which is almost completely prevented by blocking its receptors or phosphoinositide 3-kinase (PI3-kinase); 2) increases L-type calcium currents; 3) activates Na+-H+ and reversed Na+-Ca2+ exchanges [196]. The beneficial effects of GH treatment in heart failure may be also related to the anti-apoptotic proprieties of the GH/IGF-1 system [80, 81, 187, 197]. Although cardiomyocytes were long thought not undergo apoptosis, it is now recognized that cardiomyocyte apoptosis is increased in CHF and it may play a key role in CHF progression. Cardiomyocyte apoptosis occurs in the early stages of myocardial dysfunction; it impairs LV performance by reducing the contractile mass of the heart and by contributing to the progressive loss of myocytes [198, 199]. The anti-apoptotic effects of GH do not appear to be mediated by IGF-1: Gonzalez-Juanatey and co-workers demonstrated, in primary cultures of rat neonatal cardiomyocytes, that GH regulates apoptosis through the inhibition of calcineurin, a calcium-dependent phosphatase [197]. Others showed that the effects exerted by GH on cell survival and proliferation are mediated through two different signalling pathways, involving nuclear factor-kappa B (NF-kB) and PI3-kinase, respectively, which promote high circulating levels of the anti-apoptotic molecules [200-202].

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CLINICAL STUDIES IN HUMANS WITH HEART FAILURE
Several research groups have studied the effects of GH and IGF-1 in patients with impaired cardiac function (Table ​11). The first results were limited to case reports showing that GH administration considerably improved cardiac function [203, 204]. The earliest open clinical trial in CHF was reported by Fazio and co-workers in 1996 [90]. They studied seven patients with idiopathic dilated cardiomyopathy, with moderate to severe heart failure, without GHD. The evaluation was performed at baseline, after three months of recombinant human GH (rhGH) therapy and three months after therapy discontinuation. They assessed cardiac function with Doppler echocardiography, right-heart catheterization and exercise testing. After three months of treatment at a dose of 4 international units every other day, they found improvement in cardiac performance, exercise tolerance, hemodynamic profile and myocardial energetic metabolism. Transthoracic echocardiography revealed a significant increase in relative wall thickness and cardiac mass, a dramatic decrease in wall stress and an improvement in systolic performance indices (ejection fraction, shortening velocity and aortic acceleration). Using right-heart catheterization to evaluate the effects of rhGH on hemodynamic variables, at rest and in response to physical exercise, they found significant decrease in mean pulmonary arterial and capillary wedge pressures, increased cardiac output and reduced systemic vascular resistance. The also demonstrated beneficial changes in myocardial energetic metabolism, particularly during physical exercise, i.e., the heart generated more mechanical work with lower oxygen consumption and energy production. This improvement in energetic metabolism was attributed to wall stress reduction and not to change in metabolic substrates. These encouraging preliminary findings prompted several larger and controlled clinical trials.

Conflicting results emerged from a randomized, double-blind, placebo-controlled rhGH treatment study, which showed, in fifty CHF patients, an increase in LV mass related to serum IGF-1 level but no change in LV wall stress, arterial blood pressure, ejection fraction, clinical status or 6-minute walking distance [205]. Similarly, in another clinical trial, carried out in twenty-two patients with CHF of various etiologies, rhGH treatment did not significantly affect clinical status, exercise duration, ejection fraction, end-diastolic and end-systolic volumes. Furthermore, no significant increases in LV mass and wall thickness were shown [206]. On the contrary, rhGH significantly increased exercise capacity and decreased LV end-systolic and end-diastolic volumes in patients with post-ischemic CHF [207]. The patients also had a 15% increase in posterior wall thickness and 16% increase in cardiac output [207]. rhGH did not affect cardiac structure but greatly improved exercise performance and quality of life in ten post-ischemic CHF patients [208]. Conflicting results were obtained from other numerous experimental trials. For instance, some studies showed that rhGH caused a significant increase in cardiac performance [209-211], whereas others found no changes [212-214].

More recently, Adamopoulos and colleagues investigated the immunomodulatory role of rhGH administration in CHF patients. They found that a three-month course of GH normalizes circulating levels of proinflammatory cytokines, such as tumour necrosis factor α (TNF-α) and interleukin- 6 (IL-6), their soluble receptors, as well as apoptosis mediators, such as soluble Fas (sFas) and soluble Fas ligand (sFasL) [215, 216]. They subsequently reported that GH reduces the soluble adhesion molecules ICAM-1 and VCAM-1, the granulocyte-macrophage colony-stimulating factor (GM-CSF), which generates free radicals and enhances cytokine production, and the macrophage chemoattractant protein-1 (MCP-1), which promotes the migration of mononuclear phagocytes into the injured myocardial tissue and endothelial cells [217]. To evaluate whether these changes are related to modifications in exercise tolerance and echocardiographic markers of cardiac remodelling and performance, they found a significantly correlation between improvement in exercise capacity and restoration to the normal of the inflammatory response, as well as a good correlation between exercise capacity improvement and reduction in adhesion molecules and in soluble apoptosis mediators. They also showed that GH induced a decrease in end systolic wall stress and an increase in contractile reserve and that these changes were correlated with the decrease in the chemotactic protein MCP-1 and pro-inflammatory cytokines [215-217].

In an attempt to gain further insight into the mechanisms by which GH may benefit CHF patients, Fazio and co-workers have recently carried out a double-blind, placebo-controlled study of the effects of GH on physical exercise capacity and cardiopulmonary performance in twenty-two patients with moderate heart failure [218]. Patients underwent spirometry, cardiopulmonary exercise testing and Doppler echocardiography. The baseline clinical status was comparable in the GH patients and in the placebo group. After three months of treatment, at exercise testing, the GH group had an improvement of exercise capacity, cardio-pulmonary performance, and ventilatory efficiency, with a significant increase of VO2max and of chronotropic index (Fig. ​22).

Moreover, at transthoracic echocardiography, the GH group had an increase in LV mass index, relative wall thickness and cardiac performance. The LV ejection fraction and early-to-late mitral peak velocity ratio were significantly.

The conflicting results of the clinical trials of GH treatment analyzed in this review may be related to the small number of patients enrolled, the different dose and duration of GH treatment, the different CHF etiologies, and differences in the patients' demographic, hemodymamic and clinical characteristics. This discrepancy may also reflect the heterogeneity of IGF-1 increase in response to GH. In fact, a recent meta-analysis, which analyzed all randomized controlled trials and open studies on sustained GH treatment in adults with CHF in the absence of GHD, contained in the Medline, Biosis and EMBASE databases from their inception to June 2005, confirms that there is a close relationship between change in IGF-1 concentration and GH effects [219]. When the studies were divided into two groups based on the degree of IGF-1 increment, in trials with an IGF-1 increase >89% versus baseline there was a significant improvement in cardiac performance, echocardiographic parameters and exercise capacity, whereas in trials with an IGF-1 increase <89% there were no beneficial cardiovascular effects. In other words, patients with a blunted IGF-1 response to exogenous GH administration are less likely to benefit from GH treatment. This suggests that some patients may be not “sensitive” to GH. Therefore, “responders” should be identified before starting GH treatment in CHF patients.

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CONCLUSIONS
Although experimental models and preliminary human studies have demonstrated that GH administration may have beneficial cardiovascular effects in CHF, more experimental and clinical studies are necessary to clarify the mechanisms that determine the variable sensitivity to GH and its positive effects in the failing heart.

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ACKNOWLEDGEMENT
We are grateful to Jean Ann Gilder for text editing.

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REFERENCES
1. Duello TM, Halmi NS. Ultrastructural-immunocytochemical localization of growth hormone and prolactin in human pituitaries. J Clin Endocrinol Metab. 1979;49:189–96. [PubMed]
2. Thorner MO, Vance ML, Horvath E, Kovacs K. In: Textbook of Endocrinology. The anterior pituitary. Wilson JD, Foster DW, editors. Philadelphia: WB Saunders Co; 1992. pp. 221–310.
3. Tannenbaum GS, Ling N. The interrelationship of growth hormone (GH)-releasing factor and somatostatin in generation of the ultradian rhythm of GH secretion. Endocrinology. 1984;115:1952–7. [PubMed]
4. Plotsky PM, Vale W. Patterns of growth hormone-releasing factor and somatostatin secretion into the hypophyseal-portal circulation of the rat. Science. 1985;230:461–3. [PubMed]
5. Arce V, Lima L, Lois N, et al. Role of central dopaminergic pathways in the neural control of growth hormone secretion in normal men: studies with metoclopramide. Neuroendocrinology. 1991;53:143–9. [PubMed]
6. Guillemin R, Brazeau P, Bohlen P, Esch F, Ling N, Wehrenberg WB. Growth hormone releasing factor from a human pancreatic tumor that caused acromegaly. Science. 1982;218:585–9. [PubMed]
7. Brazeau P, Vale W, Burgus R, et al. Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone. Science. 1973;179:77–9. [PubMed]
8. Casanueva FF. Physiology of growth hormone secretion and action. Endocrinol Metab Clin North Am. 1992;21:483–515. [PubMed]
9. Laron Z. Growth hormone secretagogues: clinical, experimental and therapeutic potential. Drugs. 1995;50:595–601. [PubMed]
10. Gomberg-Maitland M, Frishman WH. Recombinant growth hormone: a new cardiovascular drug therapy. Am Heart J. 1996;132:1244–62. [PubMed]
11. Strobl JS, Thomas MJ. Human growth hormone. Pharmacol Rev. 1995;46:1–34. [PubMed]
12. Tapanaienen P, Knip M. Evaluation of growth hormone secretion and treatment. Ann Med. 1992;24:237–47. [PubMed]
13. Dronby EC, Amburn K, Powmakn G. Circadian variation of basal growth hormone in man. J Clin Endocrin Metab. 1983;57:524–8. [PubMed]
14. Moller N, Jorgensen JOL, Abildgard N, Orskov L, Schmitz O, Christiansen JS. Effects of growth hormone on glucose metabolism. Horm Res. 1991;36:32–5. [PubMed]
15. Betherat J, Bluet-Pajt MT, Eppelbaun J. Neuroendocrine regulation of growth hormone. Eur J Endocrinol. 1995;132:12–24. [PubMed]
16. Rudman D, Kutner MH, Rogers MC, Lubin MF, Fleming Ga, Bain RP. Impaired growth hormone secretion in the adult population. Relation to age and adiposity. J Clin Invest. 1981;67:1361–9. [PMC free article] [PubMed]
17. Rudman D. Growth hormone, body composition and aging. J Am Geriatr Soc. 1985;33:800–7. [PubMed]
18. Rudd BT. Growth hormone and the somatomedins: a historical perspective and current concepts. Ann Clin Biochem. 1991;28:542–55. [PubMed]
19. Mathews LS, Enberg B, Norstedt G. Regulation of rat growth hormone receptor gene expression. J Biol Chem. 1989;17:9905–10. [PubMed]
20. Sotiropoulos A, Perrot-Applanat M, Dinerstein H, et al. Distinct cytoplasmatic regions of the growth hormone receptor are required for activation of JAK2, mitogen-activated protein kinase, and transcription. Endocrinology. 1994;135:1289–91. [PubMed]
21. Underwood LE, Van Wyk JJ. In: Textbook of Endocrinology. Normal and aberrant growth. Wilson JD, Foster DW, editors. Philadelphia: WB Saunders Co; 1992. pp. 1079–138.
22. Colao A, Vitale G, Pivonello R, Ciccarelli A, Di Somma C, Lombardi G. The heart: an end-organ of GH action. Eur J Endocrinol. 2004;151:93–101. [PubMed]
23. Froesch ER, Schnid C, Schwander J, Zapf J. Action of insulin-like growth factors. Annu Rev Physiol. 1985;47:443–67. [PubMed]
24. Isaksson OG, Lindahl A, Nilsson A, Isgaard J. Action of growth hormone: current views. Acta Paediatr Scand. 1988;343:12–8. [PubMed]
25. Laron Z. Somatomedin, insulin, growth hormone and growth: a review. Isr J Med Sci. 1982;18:823–9. [PubMed]
26. Salmon WD, Daughaday H. A hormonally controlled serum factor which stimulates sulfate incorporation by cartilage in vitro. J Lab Clin Med. 1957;49:825–36. [PubMed]
27. Daughaday WH, Karl IE, Karl MM. A failed assay opened a new door in growth hormone research. Endocrinology. 1992;130:565–6. [PubMed]
28. Murphy LJ, Bell GI, Friesen Hg. Growth hormone stimulates sequential induction of c-myc and insulin-like growth factor I expression in vivo. Endocrinology. 1987;120:1806–12. [PubMed]
29. Murray RD, Kim K, Ren SG, Chelly M, Umehara Y, Melmed S. Central and peripheral actions of somatostatin on the growth hormone-IGF-I axis. J Clin Invest. 2004;114:349–56. [PMC free article] [PubMed]
30. Saccà L, Cittadini A, Fazio S. Growth hormone and the heart. Endocr Rev. 1994;15:555–73. [PubMed]
31. Fazio S, Palmieri EA, Biondi B, Cittadini A, Saccà L. The role of the GH-IGF-1 axis in the regulation of myocardial growth: from experimental model to human evidence. Eur J Endocrinol. 2000;142:211–6. [PubMed]
32. Meyers DE, Cuneo RC. Controversies regarding the effects of growth hormone on the heart. Mayo Clin Proc. 2003;78:1521–6. [PubMed]
33. Svensson J, Tivesten A, Isgaard J. Growth hormone and the cardiovascular function. Minerva Endocrinol. 2005;30:1–13. [PubMed]
34. Foncea R, Andersson M, Ketterman A, et al. Insulin-like growth factor-I rapidly activates multiple signal transduction pathways in cultured rat cardiac myocytes. J Biol Chem. 1997;272:19115–24. [PubMed]
35. Giordano R, Bonelli L, Marinazzo E, Ghigo E, Arvat E. Growth hormone treatment in human aging: benefit and risks. Hormones. 2008;7(2):133–9. [PubMed]
36. Takahashi S, Meites J. GH binding to liver in young and old female rats: relation to somatomedin-C secretion. Proc Soc Exp Biol Med. 1987;186:229–33. [PubMed]
37. Xu X, Bennett SA, Ingram RL, Sonntag WE. Decreases in growth hormone receptor signal transduction contribute to the decline in insulin-like growth factor I gene expression with age. Endocrinology. 1995;136:4551–7. [PubMed]
38. D'Costa AP, Xu X, Ingram RL, Sonntag WE. Insulin-like growth factor-1 stimulation of protein synthesis is attenuated in cerebral cortex of aging rats. Neuroscience. 1995;65:805–13. [PubMed]
39. Carvalho CR, Brenelli SL, Silva AC, et al. Effect of aging on insulin receptor, insulin receptor substrate-1, and phosphatidy-linositol 3-kinase in liver and muscle of rats. Endocrinology. 1996;137:51–9. [PubMed]
40. Xu X, Sonntag WE. Growth hormone-induced nuclear translocation of Stat-3 decreases with age: modulation by caloric restriction. Am J Physiol. 1996;271:E903–9. [PubMed]
41. Roupas P, Herington AC. Postreceptor signaling mechanisms for growth hormone. Trends Endocrinol Metab. 1994;5:154–8. [PubMed]
42. Nitahara JA, Cheng W, Liu Y, et al. Intracellular calcium, DNase activity and myocyte apoptosis in aging Fischer 344 rats. J Mol Cell Cardiol. 1998;30:519–35. [PubMed]
43. Olivetti G, Melissari M, Capasso JM, Anversa P. Cardiomyopathy of the aging human heart. Myocyte loss and reactive cellular hypertrophy. Circ Res. 1991;68:1560–8. [PubMed]
44. Corpas E, Harman SM, Blackman MR. Human growth hormone and human aging. Endocr Rev. 1993;14:20–39. [PubMed]
45. Eghbali M, Robinson TF, Seifter S, Blumenfeld OO. Collagen accumulation in heart ventricles as a function of growth and aging. Cardiovasc Res. 1989;23:723–9. [PubMed]
46. Rudman D, Kutner MH, Rogers CM, et al. Impaired growth hormone secretion in the adult population: relation to age and adiposity. J Clin Invest. 1981;67:1361–9. [PMC free article] [PubMed]
47. Ghigo E, Goffi S, Nicolosi M, et al. Growth hormone (GH) responsiveness to combined administration of arginine and GH-releasing hormone does not vary with age in man. J Clin Endocrinol Metab. 1990;71:1481–5. [PubMed]
48. Bichell DP, Kikuchi K, Rotwein P. Growth hormone rapidly activates insulin-like growth factor I gene transcription in vivo. Mol Endocrinol. 1992;6:1899–908. [PubMed]
49. Parrado J, Bougria M, Ayala A, Castano A, Machado A. Effects of aging on the various steps of protein synthesis: fragmentation of elongation factor 2. Free Radic Biol Med. 1999;26:362–70. [PubMed]
50. Huxley HE. The crossbridge mechanism of muscular contraction and its implications. J Exp Biol. 1985;115:17–30. [PubMed]
51. Bouillon R. Growth hormone and bone. Horm Res. 1991;36:49–55. [PubMed]
52. Davidson MB. Effects of growth hormone on carbohydrate and lipid metabolism. Endocri Rev. 1987;8:115–31. [PubMed]
53. Keller U, Miles JM. Growth hormone and lipids. Horm Res. 1991;36:36–40. [PubMed]
54. Hjalmarson A, Isaksson O, Ahren K. Effects of growth hormone and insulin on amino acid transport in perfused heart rat. Am J Physiol. 1969;217:1795–802. [PubMed]
55. Saloman F, Cuneo R, Sonksen PH. Growth hormone and protein metabolism. Horm Res. 1991;36:41–3. [PubMed]
56. Czernichow P. Growth hormone administration and carbohydrate metabolism. Horm Res. 1993;39:102–3. [PubMed]
57. Grunfeld C, Sherman BM, Cavalieri RR. The acute effects of human growth hormone administration on thyroid function in normal man. J Clin Endocrinol Metab. 1988;67:1111–4. [PubMed]
58. Ho KY, Kelly JJ. Role of growth hormone in fluid homeostasis. Horm Res. 1991;36:44–8. [PubMed]
59. Moller J, Jorgensen JOL, Moller N, Hansen KW, Pedersen EB, Christiansen JS. Expansion of extracellular volume and suppression of atrial natriuretic peptide after growth hormone administration in normal man. J Clin Endocrinol Metab. 1991;72:768–72. [PubMed]
60. Walsh MF, Barazi M, Pete G, Muniyappa R, Dunbar JC, Sowers JR. Insulin-like growth factor I diminishes in vivo and in vitro vascular contractility: role of vascular nitric oxide. Endocrinology. 1996;137:1798–803. [PubMed]
61. Tsukahara H, Gordienko DV, Tonshoff B, Gelato MC, Goligorsky MS. Direct demonstration of insulin-like growth factor-I-induced nitric oxide production by endothelial cells. Kidney Int. 1994;45:598–604. [PubMed]
62. Muniyappa R, Walsh MF, Rangi JS, et al. Insulin like growth factor 1 increases vascular smooth muscle nitric oxide production. Life Sci. 1997;61:925–31. [PubMed]
63. Haylor J, Singh I, Nahas AM. Nitric oxide synthesis inhibitor prevents vasodilatation by insulin-like growth factor I. Kidney Int. 1991;39:333–5. [PubMed]
64. Hasdai D, Rizza RA, Holmes DR Jr, Richardson DM, Cohen P, Lerman A. Insulin and insulin-like growth factor-I cause coronary vasorelaxation in vitro. Hypertension. 1998;32:228–34. [PubMed]
65. Caidahl K, Eden S, Bengtsson BA. Cardiovascular and renal effects of growth hormone. Clin Endocrinol (Oxf) 1994;40:393–400. [PubMed]
66. Fryburg D. NG- monomethyl-L-arginine inhibits the blood flow but not the insulin-like response of forearm muscle to IGF-1. Possible role of nitric oxide in muscle protein synthesis. J Clin Invest. 1996;97:1319–28. [PMC free article] [PubMed]
67. Capaldo B, Guardasole V, Pardo F, et al. Abnormal vascular reactivity in growth hormone deficiency. Circulation. 2001;103:520–4. [PubMed]
68. Napoli R, Guardasole V, Matarazzo M, et al. Growth hormone corrects vascular dysfunction in patients with chronic heart failure. J Am Coll Cardiol. 2002;39:90–5. [PubMed]
69. Joannides R, Haefeli WE, Linder L, et al. Nitric oxide is responsible for flow-dependent dilation of peripheral conduit arterias in vivo. Circulation. 1995;92:1314–9. [PubMed]
70. Badorff C, Dimmeler S. NO balance: regulation of the cytoskeleton in congestive heart failure by nitric oxide. Circulation. 2003;107:1348–9. [PubMed]
71. Standley PR, Zhang F, Zayas RM, et al. IGF-1 regulation of Na(+)-K(+)-ATPase in rat arterial smooth muscle. Am J Physiol. 1997;273:113–21. [PubMed]
72. Tivesten A, Barlind A, Caidahl K, et al. Growth hormone-induced blood pressure decrease is associated with increased mRNA levels of the vascular smooth muscle KATP channel. J Endocrinol. 2004;183:195–202. [PubMed]
73. Fujita A, Kurachi A, Kurachi Y. Molecular aspects of ATP sensitive K+ channels in the cardiovascular system and K+ channel openers. Pharmacol Ther. 2000;85:39–53. [PubMed]
74. Miki T, Suzuki M, Shibasaki T, et al. Mouse model of Prinzmetal angina by disruption of the inward rectifier Kir6.1. Nat Med. 2002;8:466–72. [PubMed]
75. Butt RP, Laurent GJ, Bishop JE. Collagen deposition and replication by cardiac fibroblasts is enhanced in response to diverse classes of growth factors. Eur J Cell Biol. 1995;68:330–5. [PubMed]
76. Bruel A. Oxlund Biosynthetic growth hormone increase the collagen deposition rate in rat aorta and heart. Eur J Endocrinol. 1995;132:195–9. [PubMed]
77. Buerke M, Murohara T, Skurk C, Nuss C, Tomaselli K, Lefer AM. Cardioprotective effect of insulin-like growth factor I in myocardial ischemia followed by reperfusion. Proc Natl Acad Sci USA. 1995;92:8031–35. [PMC free article] [PubMed]
78. Li Q, Li B, Wang X, et al. Overexpression of insulin-like growth factor-I in mice protects from myocyte death after infarction, attenuating ventricular dilation, wall stress and cardiac hypertrophy. J Clin Invest. 1997;100:1991–9. [PMC free article] [PubMed]
79. Timsit J, Riou B, Bertherat J, et al. Effects of chronic growth hormone hypersecretion on intrinsic contractility, energetics, isomyosin pattern, and myosin adenosine triphosphatase activity of rat left ventricle. J Clin Invest. 1990;86:507–15. [PMC free article] [PubMed]
80. Cittadini A, Ishiguro Y, Stromer H, et al. Insulin-like growth factor-1 but not growth hormone augments mammalian myocardial contractility by sensitizing the myofilament to Ca2+ through a wortmannin-sensitive pathway: studies in rat and ferret isolated muscles. Circ Res. 1998;83:50–9. [PubMed]
81. Mayoux E, Ventura-Clapier R, Timsit J, Behar-Cohen F, Hoffmann C, Mercadier JJ. Mechanical properties of rat cardiac skinned fibers are altered by chronic growth hormone hypersecretion. Circ Res. 1993;72:57–64. [PubMed]
82. Ren J. Short-term administration of insulin-like growth factor (IGF-1) does not induce myocardial IGF-1 resistance. Growth Horm IGF Res. 2002;12:162–8. [PubMed]
83. Xu X, Best PM. Decreased transient outward K+ current in ventricular myocytes from acromegalic rats. Am J Physiol. 1991;260:935–42. [PubMed]
84. Solem ML, Thomas AP. Modulation of cardiac Ca2+ channels by IGF-1. Biochem Biophys Res Commun. 1998;252:151–5. [PubMed]
85. Tajima M, Weinberg EO, Batunek J, et al. Treatment with growth hormone enhances contractile reserve and intracellular calcium transients in myocytes from rats with postinfarction heart failure. Circulation. 1999;99:127–34. [PubMed]
86. Houck Wv, Pan LC, Kribbs SB, et al. Effects of growth hormone supplementation on left ventricular morphology and myocyte function with the development of congestive heart failure. Circulation. 1999;100:2003–9. [PubMed]
87. Huchard H. Anatomie pathologique, lesions et trouble cardiovasculaires de l’acomegalie. J Praticiens. 1895;9:249–51.
88. Penney DG, Dunbar Jr JC, Baylerian MS. Cardiomegaly and hemodynamics in rats with a transplantable growth hormone-secreting tumor. Cardiovasc Res. 1985;19:270–7. [PubMed]
89. Rubin SA, Buttrick P, Malhotra A, Melmed S, Fishbein MC. Cardiac physiology, biochemistry and morphology in response to excess growth hormone in the rat. J Mol Cell Cardiol. 1990;22:429–38. [PubMed]
90. Prysor-Jones RA, Jenkins JS. Effect of excessive secretion of growth hormone on tissues of the rat, with particular reference to the heart and skeletal muscle. J Endocrinol. 1980;85:75–82. [PubMed]
91. Gilbert PL, Siegel RJ, Melmed S, Sherman CT, Fishbein MC. Cardiac morphology in rats with growth hormone-producing tumours. J Mol Cell Cardiol. 1985;17:805–11. [PubMed]
92. Evans HM, Simpson HE, Li CH. The gigantism produced in normal rats by injection of pituitary growth hormone. Growth. 1948;12:15–32. [PubMed]
93. Beznak M. The restoration of cardiac hypertrophy and blood pressure in hypophysectomized rats by large doses of lyophilized anterior pituitary and growth hormone. J Physiol (London) 1954;124:64–74. [PubMed]
94. Saccà L, Napoli R, Cittadini A. Growth hormone, acromegaly, and heart failure: an intricate triangulation. Clin Endocrinol. 2003;59:660–71. [PubMed]
95. Thuesen L, Christensen SE, Weeke J, Orskov H, Henningsen D. A hyperkinetic heart in uncomplicated active acromegaly. Explanation of hypertension in acromegalic patients? Acta Med Scand. 1988;223:337–43. [PubMed]
96. Fazio S, Cittadini A, Biondi B, et al. Cardiovascular effects of short-terms growth hormone hypersecretion. J Clin Endocrinol Metab. 2000;85:179–82. [PubMed]
97. Martins JB, Kerber RE, Sherman BM, Marcus ML, Ehrhardt JC. Cardiac function in acromegaly. Circulation. 1977;56:863–9. [PubMed]
98. Mather HM, Boyd MJ, Jenkins JS. Heart size and function in acromegaly. Br Heart J. 1979;41:697–701. [PMC free article] [PubMed]
99. Smallridge RC, Rajfer S, Davia J, Schaaf M. Acromegaly and the heart. An echocardiographic study. Am J Med. 1979;66:22–7. [PubMed]
100. Fazio S, Cittadini A, Sabatini D, et al. Evidence for biventricular involvement in acromegaly: a Doppler echocardiographic study. Eur Heart J. 1993;14:26–33. [PubMed]
101. Colao A, Ferone D, Marzullo P, Lombardi G. Systemic complications of acromegaly epidemiology, pathogenesis and management. Endocr Rev. 2004;25:102–52. [PubMed]
102. Cittadini A, Berggren A, Longobardi S, et al. Supraphysiological doses of GH induce rapid changes in cardiac morphology and function. J Clin Endocrinol Metab. 2002;87:1654–9. [PubMed]
103. Fazio S, Cittadini A, Sabatini D, et al. Growth hormone and heart performance. A novel mechanism of cardiac wall stress regulation in humans. Eur Heart J. 1997;18:340–7. [PubMed]
104. Bertoni PD, Morandi G. Impaired left ventricular diastolic in acromegaly: an echocardiographic study. Acta Cardiol. 1985;42:1–10. [PubMed]
105. Morvan D, Komajda M, Grimaldi A, Turpin G, Grosgogeat Y. Cardiac hypertrophy and function in asymptomatic acromegaly. Eur Heart J. 1991;12:666–72. [PubMed]
106. Fazio S, Cittadini A, Cuocolo A, et al. Impaired cardiac performance is a distinct feature of uncomplicated acromegaly. J Clin Endocrinol Metab. 1994;79:441–6. [PubMed]
107. Lie JT, Grossman SJ. Pathology of the heart in acromegaly: anatomic findings in 27 autopsied patients. Am Heart J. 1980;100:41–52. [PubMed]
108. Kahaly G, Stover C, Beyer J, Mohr-Kahaly S. Relation of endocrine and cardiac findings in acromegalics. J Endocrinol Invest. 1992;15:13–8. [PubMed]
109. Rossi L, Thiene G, Caregaro L, Giordano R, Lauro S. Dysrhythmias and sudden death in acromegalic heart disease. A clinicopathologic study. Chest. 1977;72:495–8. [PubMed]
110. Herrmann BL, Bruch C, Saller B, et al. Occurrence of left ventricular late potentials in patients active acromegaly. Clin Endocrinol. 2001;55:201–7. [PubMed]
111. Colao A. Are patients with acromegaly at risk for dysrhythmias? Clin Endocrinol. 2001;55:305–6. [PubMed]
112. Van den Heuvel PACMB, Elbers HRJ, Plokker HWM, Bruschke VG. Myocardial involvement in acromegaly. Int J Cardiol. 1984;6:550–5. [PubMed]
113. Frustaci A, Chimenti C, Setoguchi M, et al. Cell death in acromegalic cardiomyopathy. Circulation. 1999;99:1426–34. [PubMed]
114. Passa P, Masquet C, Cophignon J, Gourgon R, Bouvrain Y. Le coeur dans l’acromegalie. Etude hemodynamique. Arch Mal Coeur Vaiss. 1973;66:1517–23. [PubMed]
115. Thuesen L, Christiansen JS, Sorensen KE, Jorgensen JOL, Orskov H, Henningsen P. Increased myocardial contractility following growth hormone administration in normal man. Dan Med Bull. 1988;35:193–6. [PubMed]
116. Losa M, von Werder K. In: Growth hormone and the heart. The heart in acromegaly. Manelli F, editor. Boston: Kluwer Academic Publishers; 2001. pp. 33–43.
117. Van Loon GR. Abnormal plasma catecholamine responses in acromegalics. J Clin Endocrinol Metab. 1979;48:784–9. [PubMed]
118. Sverrisdottir YB, Elam M, Herlitz H, Bengtsson BA, Johannsson G. Intense sympathetic nerve activity in adults with hypopituitarism and untreated growth hormone deficiency. J Clin Endocrinol Metab. 1998;83:1881–5. [PubMed]
119. Capaldo B, Lembo G, Rendina V, et al. Sympathetic deactivation by growth hormone in patients with dilated cardiomyopathy. Eur Heart J. 1998;19:623–7. [PubMed]
120. Capaldo B, Lembo G, Rendina V, et al. Muscle sympathetic nerve activity in patients with acromegaly. J Clin Endocrinol Metab. 2000;85:3203–7. [PubMed]
121. Bondanelli M, Ambrosio MR, Franceschetti P, Margutti A, Trasforini G, Degli Uberti EC. Diurnal rhythm of plasma catecholamines in acromegaly. J Clin Endocrinol Metab. 1999;84:2458–67. [PubMed]
122. Moller J, Moller N, Frandsen E, Wolthers T, Jorgensen JO, Christiansen JS. Blockade of the renin-angiotensin-aldosterone system prevents growth hormone induced fluid retention in humans. Am J Physiol. 1997;272:803–8. [PubMed]
123. McCaa RE, Montalvo JM, McCaa CS. Role of growth hormone in the regulation of aldosterone biosynthesis. J Clin Endocrinol Metab. 1978;46:247–53. [PubMed]
124. Kalberg BE, Ottoson AM. Acromegaly and hypertension: role of the renin-angiotensin-aldosterone system. Acta Endocrinol. 1982;100:581–7. [PubMed]
125. Leri A, Liu Y, Wang X, et al. Overexpression of insulin-like growth factor-I attenuates the myocytes renin-angiotensin system in transgenic mice. Circ Res. 1999;84:752–62. [PubMed]
126. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341:709–17. [PubMed]
127. Andreassen M, Faber J, Vestergaard H, Kistorp C, Kristensen LØ. N-terminal pro-B-type natriuretic peptide in patients with growth hormone disturbances. Clin Endocrinol (Oxf) 2007;66:619–25. [PubMed]
128. Hanson MC, Kenneth AF, Alexander RW, De Lafontaine P. Induction of cardiac insulin-like growth factor I gene expression in pressure overload hypertrophy. Am J Med Sci. 1993;306:69–74. [PubMed]
129. Isgaard J, Wahlander H, Adams MA, Friberg P. Increased expression of growth hormone receptor mRNA and insulin-like growth factor-I mRNA in volume-overloaded hearts. Hypertension. 1994;23:884–8. [PubMed]
130. Wright AD, Hill DM, Lowy C, Fraser TR. Mortality in acromegaly. Q J Med. 1971;39:1–16. [PubMed]
131. Swearingen B, Barker FG, Katznelson L, et al. Long-term mortality after transsphenoidal surgery and adjunctive therapy for acromegaly. J Clin Endocrinol Metab. 1998;83:3419–26. [PubMed]
132. Tokgozoglu SL, Erbas T, Aytemir K, Akalin S, Kes S, Oram E. Effects of octreotide on left ventricular mass in acromegaly. Am J Cardiol. 1994;74:1072–4. [PubMed]
133. Pereira J, Rodriguez-Puras MJ, Leal-Cerro A, et al. Acromegalic cardiomyopathy improves after treatment with increasing doses of octreotide. J Endocrinol Invest. 1991;14:17–23. [PubMed]
134. Merola B, Cittadini A, Colao A, et al. Chronic treatment with the somatostatin analog octreotide improves cardiac abnormalities in patients with acromegaly. J Clin Endocrinol Metab. 1993;77:790–3. [PubMed]
135. Colao A, Cuocolo A, Marzullo P, et al. Effects of one-year treatment with octreotide on cardiac performance in patients with acromegaly. J Clin Endocrinol Metab. 1999;84:17–23. [PubMed]
136. Colao A, Cuocolo A, Marzullo P, et al. Is the acromegalic cardiomyopathy reversible? Effect of 5-year normalization of growth hormone and insulin-like growth factor I levels on cardiac performance. J Clin Endocrinol Metab. 2001;86:1551–7. [PubMed]
137. Baldelli R, Ferretti E, Jaffrain-Rea ML, et al. Cardiac effects of slow-release lanreotide, a slow release somatostatin analog, in acromegalic patients. J Clin Endocrin Metab. 1999;84:527–32. [PubMed]
138. Colao A, Marzullo P, Cuocolo A, et al. Reversal of acromegalic cardiomyopathy in young but not in middle-aged patients after 12 months of treatment with the depot long-acting somatostatin analogue octreotide. Clin Endocrinol. 2003;58:169–76. [PubMed]
139. Chanson P, Timsit J, Masquet C, et al. Cardiovascular effects of the somatostatin analog octreotide in acromegaly. Ann Intern Med. 1990;113:921–5. [PubMed]
140. Ludens JH, Back RR, Williamson HE. Characteristics of the antinatriuretic action of growth hormone. Proc Soc Exp Biol Med. 1969;130:1156–8. [PubMed]
141. Iida K, Koide Y, Matsuda M, et al. Follow-up study of the heart in acromegaly: pre- and post-operative evaluation. Jnp J Med. 1990;29:22–6. [PubMed]
142. Lim MS, Barkan AL, Buda AJ. Rapid reduction of left ventricular hypertrophy in acromegaly after suppression of growth hormone hypersecretion. Ann Intern Med. 1992;117:719–26. [PubMed]
143. Colao A, Marzullo P, Ferone D, et al. Cardiovascular effects of depot long-acting somatostatin analog Sandostatin LAR in acromegaly. J Clin Endocrinol Metab. 2000;86:32–40. [PubMed]
144. Shahi M, Beshyah SA, Hackett D, Sharp PS, Johnston DG, Foale RA. Myocardial dysfunction in treated adult hypopituitarism: a possible explanation for increased cardiovascular mortality. Br Heart J. 1992;67:92–6. [PMC free article] [PubMed]
145. Colao A, Marzullo P, Di Somma C, Lombardi G. Growth hormone and the heart. Clin Endocrinol (Oxf) 2001;54:137–54. [PubMed]
146. Beshyah SA, Johnston DG. Cardiovascular disease and risk factors in adults with hypopituitarism. Clin Endocrinol. 1999;50:1–15. [PubMed]
147. Salomon F, Cuneo RC, Hesp R, Sonksen PH. The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency. N Engl J Med. 1989;321:1797–803. [PubMed]
148. Cuneo RC, Salomon F, McGauley GA, Sonksen PH. The growth hormone deficiency syndrome in adults. Clin Endocrinol (Oxf) 1992;37:387–97. [PubMed]
149. Pfeifer M, Verhovec R, Zizek B, Prezelj J, Poredos P, Clayton RN. Growth hormone (GH) treatment reverses early atherosclerotic changes in GH-deficient adults. J Clin Endocrinol Metab. 1999;84:453–7. [PubMed]
150. Markussis V, Beshyah SA, Fisher C, Sharp P, Nicolaides AN, Johnston DG. Detection of premature atherosclerosis by high-resolution ultrasonography in symptom-free hypopituitary adults. Lancet. 1992;340:1188–92. [PubMed]
151. Capaldo B, Patti L, Oliviero U, et al. Increased arterial intima-media thickness in childhood-onset growth hormone deficiency. J Clin Endocrinol Metab. 1997;82:1378–81. [PubMed]
152. Borson-Chazot F, Serusclat A, Kalfallah Y, et al. Decrease in carotid intima-media thickness after 1 year growth hormone (GH) treatment in adults with GH deficiency. J Clin Endocrinol Metab. 1999;84:1329–33. [PubMed]
153. Tsukahara H, Gordienko DV, Tonshoff B, Gelato MC, Goligorsky MS. Direct demonstration of insulin-like growth factor I induced nitric oxide production by endothelial cells. Kidney Int. 1994;45:598–604. [PubMed]
154. Boger RH, Skamira C, Bode-Boger SM, Brabant C, Von Zur Muhlen A, Frolich JC. Nitric oxide may mediate the hemodynamic effects of recombinant growth hormone in patients with acquired growth hormone deficiency: a double blind placebo controlled study. J Clin Invest. 1996;98:2706–13. [PMC free article] [PubMed]
155. Amato G, Carella C, Fazio S, et al. Body composition, bone metabolism, and heart structure and function in growth hormone (GH)-deficient adults before and after GH replacement therapy at low doses. J Clin Endocrinol Metab. 1993;77:1671–7. [PubMed]
156. Merola B, Cittadini A, Colao A, et al. Cardiac structural and functional abnormalities in adult patients with growth hormone deficiency. J Clin Endocrinol Metab. 1993;77:1658–61. [PubMed]
157. Cittadini A, Cuocolo A, Merola B, et al. Impaired cardiac performance in growth hormone deficient adults and its improvement after growth hormone replacement. Am J Physiol. 1994;267:219–25. [PubMed]
158. Longobardi S, Cuocolo A, Merola B, et al. Left ventricular function in young adults with childhood and adulthood onset growth hormone deficiency. Clin Endocrinol. 1998;48:137–43. [PubMed]
159. Thuesen L, Jorgensen JOL, Muller JR, et al. Short and long-term cardiovascular effects of growth hormone deficient adults. Clin Endocrinol. 1994;41:615–50. [PubMed]
160. Valcavi R, Gaddi O, Zini M, Iavicoli M, Mellino U, Portioli I. Cardiac performance and mass in adult with hypopituitarism: effects of one year of growth treatment. J Clin Endocrinol Metab. 1995;80:659–66. [PubMed]
161. Johannsson G, Bengtsson BA, Andersson B, Isgaard J, Caidahl K. Long-term cardiovascular effects of growth hormone treatment in GH-deficient adults: preliminary data in a small group of patients. Clin Endocrinol. 1996;45:305–14. [PubMed]
162. Cuneo RC, Salomon F, Wiles CM, Hesp R, Sonksen PH. Growth hormone treatment in growth hormone deficient adults. I. Effects on muscle mass and strength. J Appl Physiol. 1991;70:688–94. [PubMed]
163. Cuneo RC, Salomon F, Wiles CM, Hesp R, Sonksen PH. Growth hormone treatment in growth hormone deficient adults. II. Effects on exercise performance. J Appl Physiol. 1991;70:695–70. [PubMed]
164. Colao A, Cuocolo A, Di Somma C, et al. Impaired cardiac performance in elderly patients with growth hormone deficiency. J Clin Endocrinol Metab. 1999;85:3950–5. [PubMed]
165. Colao A, Di Somma C, Cuocolo A et al. The severity of GH deficiency (GHD) correlates with the severity of cardiac impairment in 100 adult patients with hypopituitarism: an observational, case-control study. J Clin Endocrinol Metab. 2004;89(12):5998–6004. [PubMed]
166. Maison P, Chanson P. Cardiac effects of growth hormone in adults with growth hormone deficiency. Circulation. 2003;108:2648–52. [PubMed]
167. Cuocolo A, Nicolai E, Colao A, et al. Improved left ventricular function after growth hormone replacement in patients with hypopituitarism assessment with radionuclide angiography. Eur J Nucl Med. 1996;23:390–4. [PubMed]
168. Colao A, Di Somma C, Cuocolo A, et al. Improved cardiovascular risk factors and cardiac performance after 12 months of growth hormone (GH) replacement in young adult patients with GH deficiency. J Clin Endocrinol Metab. 2001;86:1874–81. [PubMed]
169. Johannsson G, Albertsson-Wikland K, Bengtsson BA. Discontinuation of growth hormone (GH) treatment metabolic effects in GH-deficient and GH-sufficient adolescent patients compared with control subjects. J Clin Endocrinol Metab. 1999;84:4516–24. [PubMed]
170. Beshyah SA, Shahi M, Skinner E, Sharp P, Foale R, Johnston DG. Cardiovascular effects of growth hormone replacement therapy in hypopituitary adults. Eur J Endocrinol. 1994;130:451–8. [PubMed]
171. Jorgensen JOL, Pedersen SA, Thuesen L, et al. Beneficial effects of growth hormone treatment in GH-deficient adults. Lancet. 1989;1:1221–5. [PubMed]
172. Colao A, Di Somma C, Salerno M, Spinelli L, Orio F Jr, Lombardi G. The cardiovascular risk of growth hormone-deficient adolescents. J Clin Endocrinol Metab. 2002;87:3650–5. [PubMed]
173. Maison P, Griffin S, Nicoue-Beglah M, Haddad N, Balkau B, Chanson P. Impact of growth hormone (GH) treatment on cardiovascular risk factors in GH-deficient adults: a metaanalysis of blinded, randomized, placebo controlled trials. J Clin Endocrinol Metab. 2004;89:2192–9. [PubMed]
174. Chrisoulidou A, Beshyah SA, Rutherford O, et al. Effects of 7 years of growth hormone replacement therapy in hypopituitary adults. J Clin Endocrinol Metab. 2000;85:3762–9. [PubMed]
175. Colao A, Di Somma C, Rota F, et al. Short-term effects of growth hormone (GH) treatment or deprivation on cardiovascular risk parameters and intima-media thickness at carotid arteries in patients with severe GH deficiency. J Clin Endocrinol Metab. 2005;90:2056–62. [PubMed]
176. Colao A, Di Somma C, Cuocolo A, et al. Does a gender-related effect of growth hormone (GH) replacement exist on cardiovascular risk factors, cardiac morphology, and performance and atherosclerosis? Results of a 2-year open, prospective study in young adult men and women with severe GH deficiency. J Clin Endocrinol Metab. 2005;90:5146–55. [PubMed]
177. Castagnino HE, Toranzos FA, Milei J, et al. Preservation of the myocardial collagen framework by human growth hormone in experimental infarctions and reduction in the incidence of ventricular aneurysms. Int J Cardiol. 1992;35:101–14. [PubMed]
178. Ambler GR, Johnston BM, Maxwell L, Gavin JB, Gluckman PD. Improvement of doxorubicin induced cardiomyopathy in rats treated with insulin-like growth factor I. Cardiovasc Res. 1993;27(7):1368–73. [PubMed]
179. Ito H, Hiroe M, Hirata Y, et al. Insulin-like growth factor-I induces hypertrophy with enhanced expression of muscle specific genes in cultured rat cardiomyocytes. Circulation. 1993;87:1715–21. [PubMed]
180. Duerr RL, Huang S, Miraliakbar HR, Clark R, Chien KR, Ross J Jr. Insulin-like growth factor-1 enhances ventricular hypertrophy and function during the onset of experimental cardiac failure. J Clin Invest. 1995;95(2):619–27. [PMC free article] [PubMed]
181. Cittadini A, Grossman JD, Napoli R, et al. Growth hormone attenuates early left ventricular remodeling and improves cardiac function in rats with large myocardial infarction. J Am Coll Cardiol. 1997;29:1109–16. [PubMed]
182. Jin H, Yang R, Gillett N, Clark RG, Ko A, Paoni NF. Beneficial effects of growth hormone and insulin-like growth factor-1 in experimental heart failure in rats treated with chronic ACE inhibition. J Cardiovasc Pharmacol. 1995;26(3):420–5. [PubMed]
183. Duerr RL, McKirnan MD, Gim RD, Clark RG, Chien KR, Ross J Jr. Cardiovascular effects of insulin-like growth factor-1 and growth hormone in chronic left ventricular failure in the rat. Circulation. 1996;93(12):2188–96. [PubMed]
184. Yang R, Bunting S, Gillet N, Jin H. Growth hormone improves cardiac performance in experimental heart failure. Circulation. 1995;92:262–7. [PubMed]
185. Cittadini A, Isgaard J, Monti MG, et al. Growth hormone prolongs survival in experimental postinfarction heart failure. J Am Coll Cardiol. 2003;41:2154–63. [PubMed]
186. Cittadini A, Strömer H, Katz SE, Clark R, Moses AC, Morgan JP, Douglas PS. Differential cardiac effects of growth hormone and insulin-like growth factor-1 in the rat. A combined in vivo and in vitro evaluation. Circulation. 1996;93(4):800–9. [PubMed]
187. Grimm D, Cameron D, Griese DP, Riegger GAJ, Kromer E. Differential effects of growth hormone on cardiomyocyte and extracellular matrix protein remodeling following experimental myocardial infarction. Cardiovas Res. 1998;40:297–306. [PubMed]
188. Isgaard J, Kujacic V, Jennische E, et al. Growth hormone improves cardiac function in rats with experimental myocardial infarction. Eur J Clin Invest. 1997;27(6):517–25. [PubMed]
189. Ross J Jr, Hongo M. The role of hypertrophy and growth factors in heart failure. J Card Fail. 1996;2(4 Suppl):121–8. [PubMed]
190. Houck WV, Pan LC, Kribbs SB, et al. Effects of growth hormone supplementation on left ventricular morphology and myocyte function with the development of congestive heart failure. Circulation. 1999;100:2003–9. [PubMed]
191. Kinugawa S, Tsutsui H, Ide T, et al. Positive inotropic effect of insulin-like growth factor-1 on normal and failing cardiac myocytes. Cardiovasc Res. 1999;43:157–64. [PubMed]
192. Vetter U, Kupferschmid C, Lang D, Pentz S. Insulin-like growth factors and insulin increase the contractility of neonatal rat cardiocytes in vitro. Basic Res Cardiol. 1988;83:647–54. [PubMed]
193. Freestone NS, Ribaric S, Mason WT. The effect of insulin-like growth factor-1 on adult rat cardiac contractility. Mol Cell Biochem. 1996;163-164:223–9. [PubMed]
194. Stromer H, Cittadini A, Douglas PS, Morgan JP. Exogenously administered growth hormone and insulin-like growth factor-i alter intracellular Ca2+ handling and enhance cardiac performance in vitro evaluation in the isolated isovolumic buffer-perfused rat heart. Circ Res. 1996;79:227–36. [PubMed]
195. Von Lewinski D, Voß K, Hülsmann S, Kögler H, Pieske B. Insulin-like growth factor-1 exerts Ca2+-dependent positive inotropic effects in failing human myocardium. Circ Res. 2003;92:169–76. [PubMed]
196. Gonzalez-Juanatey JR, Pineiro R, Iglesias MJ, et al. GH prevents apoptosis in cardiomyocytes cultured in vitro through a calcineurin-dependent mechanism. J Endocrinol. 2004;180:325–35. [PubMed]
197. Haunstetter A, Izumo S. Apoptosis. Basic mechanisms and implications for cardiovascular disease. Circ Res. 1998;82:1111–29. [PubMed]
198. Kang PM, Izumo S. Apoptosis and heart failure: a critical review of the literature. Circ Res. 2000;86:1107–13. [PubMed]
199. Baixeras E, Jeay S, Kelly PA, Postel-Vinay MC. The proliferative and antiapoptotic actions of growth hormone and insulin-like growth factor-1 are mediated through distinct signaling pathways in the Pro-B Ba/F3 cell line. Endocrinology. 2001;142:2968–77. [PubMed]
200. Jeay S, Sonenshein GE, Postel-Vinay MC, Baixeras E. Growth hormone prevents apoptosis through activation of nuclear factor-kB in interleukin-3-dependent Ba/F3 cell line. Mol Endocrinol. 2000;14:650–61. [PubMed]
201. Jeay S, Sonenshein GE, Kelly PA, Postel-Vinay MC, Baixeras E. Growth hormone exerts antiapoptotic and proliferative effects through two different pathways involving nuclear factor-kB and phosphatidylinositol 3-kinase. Endocrinolgy. 2001;142:147–56. [PubMed]
202. Cuneo RC, Wilmshurst P, Lowy C, McGauley G, Sonksen PH. Cardiac failure responding to growth hormone. Lancet. 1989;1:838–9. [PubMed]
203. Frustaci A, Perrone GA, Gentiloni N, Russo MA. Reversible dilated cardiomyopathy due to growth hormone deficiency. Am J Clin Pathol. 1992;97:503–11. [PubMed]
204. Fazio S, Sabatini D, Capaldo B, et al. A preliminary study of growth hormone in the treatment of dilated cardiomyopathy. N Engl J Med. 1996;334:809–14. [PubMed]
205. Osterziel KJ, Strohm O, Schuler J, et al. Randomised, double-blind, placebo-controlled trial of human recombinant growth hormone in patients with chronic heart failure due to dilated cardiomyopathy. Lancet. 1998;351:1233–7. [PubMed]
206. Isgaard J, Bergh CH, Caidahl K, Lomsky M, Hjalmarson A, Bengtsson BA. A placebo-controlled study of growth hormone in patients with congestive heart failure. Eur Heart J. 1998;19:1704–11. [PubMed]
207. Genth-Zotz S, Zotz R, Geil S, Voigtländer T, Meyer J, Darius H. Recombinant growth hormone therapy in patients with ischemic cardiomyopathy: effects on hemodynamics, left ventricular function, and cardiopulmonary exercise capacity. Circulation. 1999;99:18–21. [PubMed]
208. Spallarossa P, Rossettin P, Minuto F, et al. Evaluation of growth hormone administration in patients with chronic heart failure secondary to coronary artery disease. Am J Cardiol. 1999;84:430–3. [PubMed]
209. Perrot A, Ranke MB, Dietz R, Osterziel KJ. Growth hormone treatment in dilated cardiomyopathy. J Card Surg. 2001;16:127–31. [PubMed]
210. Frustaci A, Gentiloni N, Russo MA. Growth hormone in the treatment of dilated cardiomyopathy. N Engl J Med. 1996;335:672–3. [PubMed]
211. Jose VJ, Zechariah TU, George P, Jonathan V. Growth hormone therapy in patients with dilated cardiomyopathy: preliminary observations of a pilot study. Indian Heart J. 1999;51:183–5. [PubMed]
212. Acevedo M, Corbalan R, Chamorro G, et al. Administration of growth hormone to patients with advanced cardiac heart failure: effects upon left ventricular function, exercise capacity, and neurohormonal status. Int J Cardiol. 2003;87:185–91. [PubMed]
213. Cittadini A, Comi IL, Longobardi S, et al. A preliminary randomized study of growth hormone administration in Becker and Duchenne muscular distrophies. Eur Heart J. 2003;24:664–72. [PubMed]
214. Smit JW, Janssen YJ, Lamb HJ, et al. Six months of recombinant human GH therapy in patients with ischemic cardiac failure does not influence left ventricular function and mass. J Clin Endocrinol Metab. 2001;86:4638–43. [PubMed]
215. Adamopoulos S, Parissis JT, Georgiadis M, et al. Growth hormone administration reduces circulating proinflammatory cytokines and soluble Fas/soluble Fas ligand system in patients with chronic heart failure secondary to idiopathic dilated cardiomyopathy. Am Heart J. 2002;144:359–64. [PubMed]
216. Parissis JT, Adamopoulos S, Karatzas D, Paraskevaidis J, Livanis E, Kremastinos D. Growth hormone-induced reduction of soluble apoptosis mediators is associated with reverse cardiac remodelling and improvement of exercise capacity in patients with idiopathic dilated cardiomyopathy. Eur J Cardiovasc Prev Rehabil. 2005;12:164–8. [PubMed]
217. Adamopoulos S, Parissis JT, Paraskevaidis J, et al. Effects of growth hormone on circulating cytokine network, and left ventricular contractile performance and geometry in patients with idiopathic dilated cardiomyopathy. Eur Heart J. 2003;24:2186–96. [PubMed]
218. Fazio S, Palmieri EA, Affuso F, et al. Effects of growth hormone on exercise capacity and cardiopulmonary performance in patients with chronic heart failure. J Clin Endocrinol Metab. 2007;92:4218–23. [PubMed]
219. Le Corvoisier P, Hittinger L, Chanson P, Montagne O, Macquin-Mavier I, Maison P. Cardiac effects of growth hormone treatment in chronic heart failure: a meta-analysis. J Clin Endocrinol Metab. 2007;92:180–5. [PubMed]

Cottage Cheese
Dairy products tend to be high in protein.
One of the best ones is cottage cheese, which — calorie for calorie — is mostly protein with very few carbs and little fat.
Eating cottage cheese is a great way to boost your protein intake. It’s also very satiating, making you feel full with a relatively low number of calories.

Avocados
Avocados are a unique fruit.
While most fruits are high in carbs, avocados are loaded with healthy fats.
They’re particularly high in monounsaturated oleic acid, the same type of fat found in olive oil.
Despite being mostly fat, avocados also contain a lot of water and fiber, making them less energy-dense than you may think. tham khảo thêm chế độ ăn low-carb để giảm béo nhé

Apple Cider Vinegar
Apple cider vinegar is incredibly popular in the natural health community.
It’s often used in condiments like dressings or vinaigrettes, and some people even dilute it in water and drink it.
Several human-based studies suggest that apple cider vinegar can be useful for weight loss.
Taking vinegar at the same time as a high-carb meal can increase feelings of fullness and make people eat 200–275 fewer calories for the rest of the day

Nuts
Despite being high in fat, nuts are not as fattening as you would expect.
They're an excellent snack, containing balanced amounts of protein, fiber and healthy fats.
Studies have shown that eating nuts can improve metabolic health and even promote weight loss

Whole Grains
Though cereal grains have received a bad reputation in recent years, some types are definitely healthy.
This includes some whole grains that are loaded with fiber and contain a decent amount of protein.
Notable examples include oats, brown rice and quinoa.

Oats are loaded with beta-glucans, soluble fibers that have been shown to increase satiety and improve metabolic health

There’s a pungent cloud of hype and hope around probiotics—and researchers have long tried to clear the air about what the bowel-blasting products can ( and mostly can’t) do. Now, a new set of studies offers a gut-check on funky claims, ripping current probiotics as likely ineffective at boosting health and potentially even causing harm.

In the two studies, both published this week in the journal Cell, Israeli researchers report that bacteria taken in supplements, aka probiotics, often have little impact on healthy people’s innards and, at worst, can elbow out native populations of microbes.

In the first study, the researchers found that healthy microbial populations in people’s plumbing tends to flush out the newcomers. Thus, the microbial interlopers from supplements have little impact on resident microbiomes—and, by extension, consumers’ health—and are largely just pooped out.

But probiotic strains can more easily take root in the gut if a person takes a strong dose of antibiotics that beats back their beneficial bacteria, the researchers found in the second study. This finding might suggest that the living supplements could help rejuvenate the intestinal inhabitants after an antibiotic onslaught—as probiotic makers would surely like to claim. But in fact, probiotics made it harder for the healthy, native community of gut bugs to recover, the researchers found. People who took probiotic supplements to rally their microbiome after antibiotics didn’t regain their healthy communities for as long as five months afterward. People who didn’t take anything after their antibiotics did.

The stinky findings are not shocking given past disappointing and inconclusive data on probiotics. A 2016 review of randomized controlled studies concluded that probiotics had almost no effect on the overall mix of microbes in people’s poop. While other studies have pushed out evidence of microbial changes from probiotics, there’s still little data on what those changes might mean in terms of health and what our microbiomes are actually doing for us. And previous studies looking specifically at probiotic use after antibiotics also found the supplements were ineffective. For instance, probiotics couldn’t stop up antibiotic-induced diarrhea or thwart the more serious antibiotic-associated gut invader, Clostridium difficile.

So far, such findings haven’t deterred consumers from plopping down money for probiotics in the hopes of better bowel health. Probiotics are an ever-growing market, with 3.9 million adults in the US using either probiotics or prebiotics. They’re among the most commonly used dietary supplements.

And the idea behind probiotics still isn’t a foolish one. The communities of microbes thriving in our intestines do all sorts of useful things: they can alter our immune response, influence our hormones, protect us from infectious germs, help us digest and process foods, and keep things, well, regular. Optimizing and stabilizing such communities could have a lot of perks and help thwart disease. The trouble is, we don’t know enough about our complex, highly variable microbiomes to manipulate them effectively yet—despite what probiotic makers will try to tell you.

Some good news is that the new set of studies has some helpful hints for moving forward.

Flushed out
For the first study, researchers at the Weizmann Institute of Science in Israel turned to a commercially available probiotics product that included 11 strains of bacteria. Those bugs are commonly used in products and believed by marketers and some consumers to improve health. They inventory includes: Lactobacillus acidophilus, L. casei, L. casei sbsp. paracasei, L. plantarum, L. rhamnosus, Bifidobacterium longum, B. bifidum, B. breve, B. longum sbsp. infantis, Lactococcus lactis, and Streptococcus thermophilus. The researchers independently confirmed that those bacteria were alive and kicking in the probiotic mix.

Fifteen healthy adults agreed to have their guts and stool probed for preexisting microbes before entering the trial. They did colonoscopies (for sampling the microbes in lower gastrointestinal tract) and endoscopies (for sampling the microbes in the upper GI tract). Then 10 volunteers took a course of probiotics twice a day for four weeks, and the remaining five got a placebo. They all had their feces sampled throughout and had colonoscopies and endoscopies again three weeks after the treatments.

The researchers found a lot of microbial variability among individuals before and after the treatments. But for the most part, the probiotics seemed to have little effect. Those that took probiotics clearly pooped them out while they were taking them. The five that got the placebo didn’t—as was expected.

Six of the 10 people in the probiotic group were dubbed “permissive” because some of the probiotic strains seemed to stick with them in their lower GI tracts at low levels after the four-week treatment. The remaining four were dubbed “resistant” because the probiotic strains seemed to flush out completely. Importantly, these designations were based solely on the direct intestinal probing—not what the researchers could see in the stool samples. Those deposits were nearly useless for figuring out which probiotics were colonizing the gut.

When the researchers looked even more closely at the intestinal data, they noted that the permissive people tended to have lower levels of probiotic strains in their guts before the treatment than the resistant crowd. Thus, the probiotic strains may have had an easier time finding a niche in the permissive group due to less competition from the resident microbes.

Overall, the researchers took two main takeaways from the study. The first is that poop samples aren’t that useful for gleaning information about whether probiotic bacteria are blooming in the bowels. This is rather notable, because many microbiome studies rely on fecal samples as a proxy for microbiome residents. The second takeaway is that the microbes already present in our innards seem to dictate which probiotic strains have a chance of colonizing. Thus, successful probiotics may have to be custom designed for individual microbiomes.

Microbial mayhem
Of course, this study was all in healthy people. Many consumers turn to probiotics when they’re not healthy. In the second study, the researchers aimed to look at the effects of probiotics on microbiomes that were known to be out of whack.

For this, they had 21 healthy adults take a seven-day course of antibiotics that knocked back their microbiomes. This kills off resident microbes indiscriminately and causes “dysbiosis,” which is essentially the collapse of microbial community structure.

Eight of the 21 participants then took the 11-strain probiotic mix twice a day for four weeks, while seven took nothing—the control group. The remaining six participants got fecal transplants of their own poop collected prior to the antibiotic treatment (this is a so-called autologous Fecal Microbiome Transplant, or aFMT.) The researchers again used stool samples and intestinal probing before and after treatments to keep a watchful eye on gut dwellers.

In this study, the probiotic strains flourished. In the dysbiotic guts, probiotic strains bloomed in the lower gastrointestinal tracks, forming stable, active colonies. This might seem like a good thing. But compared with the control and aFMT groups, the probiotic subjects fared the worst in terms of reestablishing their microbial communities. The participants that got an aFMT saw their healthy, native inhabitant rally within as little as a day of their transplants. Those that got nothing after their antibiotics had their communities recover within 21 days.

But the probiotic group—who were now colonized with the probiotic strains—stayed in a state of dysbiosis for as long as five months after their antibiotic treatment. The load of bacteria in their feces was lower and the microbial communities in their lower GI tracts were still significantly disturbed. With further digging, the researchers found that the probiotic usurpers seemed to spur immune responses in the gut that could inhibit native microbes. In lab studies, the researchers also noted that the probiotic strains seem to secrete unidentified factors that could inhibit the growth of microbiome residents.

The two studies have limitations, of course. They were both small. And other probiotic strains than the 11 tested could prove more useful—or at least less concerning. Probiotics may be beneficial for different patient populations, as well. In both studies, the researchers used healthy adults, while infants, children, or the elderly may have different experiences with probiotics. And people with specific conditions could benefit in specific ways.

Still, in all, the researchers concluded that use of probiotics “may not be risk-free.” And in the case of boosting the microbiome, they conclude:

Like any other medical treatment, [probiotics’] potentially beneficial pathogen-repellant activity (which remains to be proven or refuted) may carry a tradeoff risk of adversely impacting the rate and extent of indigenous microbiome recolonization.

https://arstechnica.com/science/2018...-up-your-guts/

https://imgur.com/a/V03oEpt

Some background.

32 y/o been running AAS for a couple of years not blasting/cruising. For the first 7 weeks of this GH run I was doing 2.25IU of Pfizer Genotropin (from Turkey) w/ a dose of 350mg Test E a week.

I am not really sure if the test above indicates if the GH is legit? On a similar Test dose with Masteron and Anavar I have had my IGF like 20 points higher in the past.

Also to note the last 2 weeks leading into the blood work I increased the dose to 3.6IU and also went into a blast cycle of 900mg Test E/400 Deca and 50 MG of Anadrol a day.

I think the GH is good but just wanted some feedback from more experienced members as this is my first time running it.

Once I run out of this Genotropin I have some Norditropin I got from JINTROPOIN.us that I plan to run at 4IU a day.

Every customer gets 50 x 15mg cialis FREE with any size order !!!!! Only for the month of September!

"Hurricane Florence may end up being the worst natural disaster in recorded history for the Carolinas and Virginia. 3 to 4 feet of rain, IF predictions hold."

South Carolina Gov. Henry McMaster ordered an estimated 1 million people to evacuate from coastal areas of his state as Florence strengthened to a Category 4 storm. While Florence isn't expected to make landfall until Thursday or Friday, hurricane-force winds of 130 mph or more will start whipping up a deadly storm surge late Wednesday. The evacuation order follows a similar order issued by North Carolina Gov. Roy Cooper, who ordered an estimated 250,000 residents and visitors to begin evacuating the Outer Banks barrier islands.

As of noon ET, Florence was about 1,170 miles east-southeast of Cape Fear, North Carolina. Cooper said he has asked President Trump to declare a federal state of emergency for his state. Trump, for his part, tweeted that the federal government is already "mobilizing its assets."

Of course, Florence isn't the only storm headed for the eastern seaboard. At least three other storms (Hurricanes Isaac and Helen), as well as a tropical storm forming on the horizon.

https://www.zerohedge.com/news/2018-...aster-recorded

I never heard anything like this in my fucken life. What the actual fuck. This bitch must have been high or drunk.

________________________________

A Dallas police officer stands charged with manslaughter in the fatal shooting of a man she mistakenly thought was in her apartment, but a prosecutor would not rule out a more serious charge Monday.

"The grand jury will be that entity that will make the final decision in terms of the charge or charges that will come out of this case," Dallas County District Attorney Faith Johnson told reporters. "We prepare to present a thorough case to the grand jury of Dallas County, so that the right decision can be made in this case."

Amber Guyger, was off-duty when she shot Botham Shem Jean in his apartment, police said Thursday. Guyger told police she thought she was entering her own apartment not realizing she was on the wrong floor. Upon encountering Jean, she thought her home was being burglarized and opened fire, according to police.

Botham, a 26-year-old native of St. Lucia, was unarmed. He died at a hospital.

https://www.huffingtonpost.com/entry...b0cf7b0042b550

Hoping everything goes smoothly, seems like everyone has had good luck. Hoping to receive products by the end of the week! Looking forward to doing more business 👍🏻

New btach of Anavar-25 in stock now
GMP standard
Safe and discrete shipping
Factory price
If you have an interest, please feel free to contact me!
diana.srhealthtech@protonmail.com

https://drive.google.com/file/d/1InE...ew?usp=sharing

You can click the link, I do not know why I can't post it directly. Do not have IGF level because it was test by Labs.

Fake News Liberals! :D

___________


Facebook yesterday gave a "false rating" to an article written by a liberal news site after a conservative publication used by Facebook as a fact checker claimed the article was incorrect.

The article in question, published by ThinkProgress, was titled, "Brett Kavanaugh said he would kill Roe v. Wade last week and almost no one noticed." While Supreme Court nominee Kavanaugh didn't literally say that he would vote to overturn the abortion ruling from 1973, ThinkProgress writer Ian Millhiser made a reasonable argument that Judge Kavanaugh's statements show that he believes Roe v. Wade was decided incorrectly.

The right-wing Weekly Standard called ThinkProgress's article false in a fact check, based on the rather obvious fact that Kavanaugh never specifically said he would vote to overturn Roe.

"While ThinkProgress engages in an argument to suggest how Kavanaugh might vote in a Roe v. Wade redo, the article does not provide evidence that 'Kavanaugh said he would kill Roe v. Wade,'" The Weekly Standard wrote.

Because The Weekly Standard is one of five news outlets that Facebook relies on to fact check articles posted by other sites, ThinkProgress was given the dreaded false rating, which could hurt ThinkProgress' business by dramatically reducing referrals to the site.

"Where posts are flagged as potentially false, we pass them to independent fact checkers—such as the Associated Press and The Weekly Standard—to review, and we demote posts rated as false, which means they lose 80 percent of future traffic," Facebook CEO Mark Zuckerberg wrote last week.

The other three fact checkers used by Facebook in the US are Factcheck.org, PolitiFact, and Snopes.com.

A notification that Facebook sent to groups sharing the ThinkProgress article says that "pages and websites that publish or share false news will see their overall distribution reduced and their ability to monetize and advertise removed."

Dispute boils down to the word “said”
ThinkProgress reacted to the false rating today in an article that accuses Facebook of "censoring ThinkProgress because [a] conservative site told them to."

ThinkProgress argues that The Weekly Standard's objection "appears to hinge on the definition of the word 'said.'"

"According to Merriam-Webster's dictionary, the verb 'say' or 'said' can mean to 'indicate,' 'show,' or 'communicate' an idea," ThinkProgress wrote today. "Our argument is that Kavanuagh indicated, showed, or communicated his intention to overrule Roe when he endorsed the Glucksberg test after saying that Glucksberg is inconsistent with Roe." (We'll describe the Glucksberg test later in this article.)

The Weekly Standard doubled down on its claim today, writing that the ThinkProgress article is a "completely fake story" and a "fabrication."

But the new Weekly Standard article seems to support ThinkProgress' contention that this is just a dispute over the word "said" rather than a dispute over what Kavanaugh's statements at his confirmation hearing meant.

"Kavanaugh never 'said' he'd kill 'Roe,'" The Weekly Standard wrote today.

Business hit from losing Facebook traffic
ThinkProgress' article today said that Facebook referrals account for 10 to 15 percent of ThinkProgress readers, so losing 80 percent of that would be a significant hit.

"The difference between keeping those readers and losing them could decide whether we can hire more reporters who will continue to report on subjects that The Weekly Standard may have ideological disagreements about," ThinkProgress wrote.

ThinkProgress also alleged that "The Weekly Standard was added to Facebook's roster of 'fact-checking' outlets as part of a deliberate effort to pander to conservatives."

ThinkProgress says that, when it disputed the false rating to Facebook, "a Facebook employee responded by email that Facebook defers to each independent fact checker's process and publishers are responsible for reaching out to the fact checkers directly to request a correction."

Weekly Standard Managing Editor Rachael Larimore's response to a ThinkProgress writer on Twitter was "or maybe you could just correct your story."

https://arstechnica.com/tech-policy/...ght-wing-site/

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