GH and Cardiac Failure

Ross C. Cuneo

Metabolic Research Unit Department of Medicine University of Queensland and Department of Diabetes and Endocrinology Princess Alexandra Hospital Brisbane, Australia 4102

Address all correspondence and requests for reprints to: Ross C. Cuneo, MBBS, FRACP, Ph.D., Associate Professor of Medicine, Metabolic Research Unit, Department of Medicine, University of Queensland, and Department of Diabetes and Endocrinology, Princess Alexandra Hospital, Brisbane, Australia 4102. E-mail: cuneo2{at}medicine.pa.uq.edu.au

The earliest clues that human GH (hGH) therapy may have been beneficial to cardiac function came from clinical researchers in Denmark and the United Kingdom. Thuesen et al. (1) from Aarhaus assessed the effect of 1 wk’s supraphysiological recombinant hGH (rhGH) treatment in a small group of young adults and showed echocardiographic changes interpreted as showing increased ventricular contractility. Professor Peter Sonksen’s group (2) at St. Thomas’s Hospital, London, reported the case of a diabetic man with panhypopituitarism and near-terminal, refractory ventricular failure due to a dilated cardiomyopathy. Treatment with rhGH resulted in a dramatic clinical improvement, increased ventricular wall mass, resting cardiac output and stroke volume, and reduced systemic vascular resistance and pulmonary venous pressures (2). A very similar case was described by Frustaci and Italian colleagues where endomyocardial biopsies before and after rhGH treatment showed increased myocardial fiber diameter suggesting an anabolic effect.

Adult patients with GH deficiency (GHD) provide an important and well documented model to understand the effects of GH in human cardiac physiology (see Ref. 3) for review). A number of studies have shown that rhGH replacement therapy has anabolic, inotropic, and perhaps chronotropic effects in this patient population. Placebo-controlled and double-blinded studies of up to 6 months duration have shown that modest doses of rhGH increased ventricular muscle mass, stroke volume, maximal oxygen uptake, maximal exercise capacity, and cardiac output both at rest and during maximal exercise, and reduced systemic vascular resistance. Effects have been most evident in studies using higher doses of rhGH and for durations of at least 6 months. Patients who developed GHD during childhood seemed to have more profound deficiencies in cardiac mass and function compared with patients developing GHD during adult life, perhaps reflecting the greater severity and/or longer duration of GHD in those of childhood onset. One can conclude that GH is necessary for the maintenance of normal cardiac function.

It has long been appreciated that GH excess is detrimental to the heart. The acromegalic cardiomyopathy is characterized by bi-ventricular hypertrophy without coronary disease. Detriments to cardiac output are evident in patients both with and without hypertension (3). Correction of hypersomatotrophism improves cardiac function and blood pressure. While apparently at variance with the benefits of replacement doses of rhGH in adults with GHD, the cardiac manifestations of acromegaly reflect the result of a decade or more of sustained hypersomatotrophism, nonfunctional hypertrophy, and interstitial fibrosis. In the current context of rhGH treatment in non-GHD adults, an important message would be for us to remain alert to the early signals of a GH excess syndrome.

The pathophysiological mechanisms whereby GH has a beneficial effect on the heart have received recent attention and are important for an interpretation of the clinical trial results in cardiac failure. GH and IGF-I receptors and local IGF-I expression have been found in cardiac myocytes, providing a mechanism for both direct and indirect actions of GH (4). Firstly, in vitro experiments on isolated heart muscle fibers have shown clear evidence for a GH-mediated effect to increase contractility. The exact mechanism for the increase in contractility in such short-term studies is unclear but may relate, in part, to ß-sympatho-adrenergic mechanisms. The GHD Dwarf-rat model has been shown to have reduced isoproteronol-stimulated contractility, suggesting that ß-sympatho-adrenergic receptor-mediated effects may be an important component of the GH action on heart muscle (5). Secondly, GH may augment cardiac function by means of restoring or augmenting ventricular wall mass. GH has well documented anabolic actions in a variety of tissues, including cardiac muscle, and IGF-I may reduce myocardial apoptosis. Physical principles predict a reduction in ventricular wall stress as a result of increased ventricular wall mass. Thirdly, GH treatment clearly reduces systemic vascular resistance. Nitric oxide production is reduced in GH-deficient adults compared with matched normal subjects, and rhGH replacement increased nitric oxide production. The relative contribution of each of these differing actions to improve cardiac function is unknown.

The earliest clinical trial in congestive cardiac failure (CCF) was reported by Fazio et al. (6) in 1996. They examined the effects of rhGH treatment in dilated cardiomyopathy. In an uncontrolled trial of seven adults with moderate to severe cardiac failure treated with 14 IU/wk for 3 months, serum IGF-I doubled, left wall thickness increased, and ventricular chamber diameter ventricular wall stress was reduced. Cardiac output increased, particularly during exercise, with improvements in cardiac energy efficiency. Treatment effects waned during 3 months following rhGH withdrawal. Osterziel et al. (7) in 1998 treated 50 adults with dilated cardiomyopathy of mostly mild to moderate severity in a randomized, double-blind, placebo-controlled rhGH treatment study at a dose of 2 IU per day for 3 months. Serum IGF-I increased approximately 70%. Left ventricular (LV) wall mass measured by magnetic resonance imaging increased significantly (27%), but LV wall stress, arterial blood pressure, ejection fraction, clinical status, and 6-min walking distance were unaffected. Interestingly, the change in LV wall mass correlated with the change in serum IGF-I. Isgaard et al. (8) treated patients with either dilated and ischemic cardiomyopathy in a randomized, double-blind, placebo-controlled rhGH treatment study at a dose of 0.25 IU/kg·wk (mean dose, 2.6 IU/d) for 3 months. Serum IGF-I more than doubled. No changes were detected in echocardiographically and radionuclide-measured ventricular structure or function, blood pressure, symptoms, or exercise capacity.

In ischemic cardiomyopathy, rhGH treatment in in vivo rodent studies has shown increased myocardial contractility. In humans, Genth-Zotz et al. (9) treated seven adults with stable mild-moderate ischemic CCF with 2 IU rhGH per day for 3 months and restudied them after 3 months of rhGH withdrawal. Serum IGF-I doubled, and cardiac out put increased 16% at rest, exercise capacity increased, posterior wall thickness increased 15%, and ventricular end-systolic and end-diastolic volume indices decreased. All effects deteriorated with rhGH withdrawal. Spallarossa et al. (10) treated 10 adults with ischemic cardiomyopathy in a nonrandomized trial of rhGH for 6 months at a dose of 0.02 IU/kg·d (approximately 1.4–1.6 IU/d). Serum IGF-I increased (1.9-fold), exercise duration increased 28%, but cardiac structure appeared unchanged.

In this issue of JCEM, Smit et al. (11) performed a very careful study, the first randomized, controlled trial of rhGH treatment to focus solely in patients with ischemic CCF. The excellent features of the study include: 1) careful assessment of the power of the study to demonstrate significant changes; 2) selection of a homogeneous population; 3) randomization which resulted in balanced groups; 4) state of the art measurements of cardiac structure and function (with magnetic resonance imaging) and myocardial perfusion (with rest and exercise single photon emission computerized tomography); 5) treatment for 6 months, sufficient to demonstrate clinically meaningful results based on the adult GHD studies; and 6) beautifully presented results and transparent and fair statistical analyses. Twenty-two adults were randomized to either rhGH (2 IU/d) or "no treatment," meaning best conventional medical therapy. Nine patients completed the rhGH treatment. Serum IGF-I increased 24% and IGF-binding protein-3 58% compared with the control group. There were no changes in cardiac structure (LV wall mass), function (resting ejection fraction), or exercise-induced LV myocardial perfusion.

Is this the end of the story for rhGH treatment in CCF? Are there any reasons why this and other studies are not replicating earlier observations, or is the power of the randomized controlled trial telling us the true message? The following areas seem worthy of consideration:

Pretreatment endocrine status

One clear lesson from rhGH treatment in both children and adults with GHD is that the more severely deficient the patient the greater is the increment in rhGH-responsive end points. In relation to patients with CCF, what then is their "GH status": are they GH deficient or replete? Based on serum IGF-I, the available literature suggests a spectrum from mildly "deficient" to normal. Detailed GH sampling studies have not been reported, but the available data has suggested that some patients with CCF have either a degree of GHD or GH resistance (12). Reduced GH responses to some GH stimuli suggest some hypothalamic-pituitary dysfunction, but the mechanisms and prevalence or poorly understood. With respect to GH resistance, hepatically derived, circulating IGF-I may be lower than predicted due to impairment of the GH signaling pathways. One may predict lower serum IGF-I concentrations in patients with hepatic congestion or hypoxia (right heart failure), relative insulin deficiency (acute or chronic nutritional deprivation), deficiencies in thyroid or androgen status, women receiving oral estrogens, or other yet-to-be-defined mechanisms. Clarification of these processes in patients with CCF may assist in selecting patients most likely to respond to rhGH administration. Clearly, the dramatic responses in cardiac function reported following rhGH treatment in the individuals with hypopituitarism and CCF reflects a response that should not be expected in the general population of CCF patients who seem to have minimal GH "deficiency" and some GH resistance.

Dose of rhGH and responsiveness

A closely related concept is whether sufficient rhGH has been administered in the trials of ischemic or dilated cardiomyopathy. In adults with GHD physiological replacement doses are in the order of 1–2 IU per day. One might expect only a modest increment in serum IGF-I with a daily dose of 2 IU in non-GH-deficient adults with CCF. The changes described by Smit et al. (11) are in line with such expectations. The greater increment in IGF-binding protein-3 may result in a blunting of the IGF-I stimulus, depending on the net biological effect of the binding protein. The doubling in serum IGF-I described by other studies with similar rhGH doses is surprising. Such discrepancies may reflect different populations of patients with respect to GH responsiveness, and, if so, efforts are required to establish means of identifying "responders." A low pretreatment serum IGF-I and/or high IGF-I increment following treatment may be important criteria. Differing IGF-I responses to rhGH may also directly influence cardiac end points. One pertinent study in this regard is from Osterziel et al. (13), who treated 20 adults with ischemic CCF randomized to receive differing doses of rhGH for 8 d. They found that the change in serum IGF-I correlated with the increase in LV ejection fraction and the reduction in LV end-diastolic and end-systolic volumes. Therefore, it seems critical to define endocrine responsiveness, because cardiac responsiveness is likely to follow. Efforts to define cardiac GH receptor status and IGF-I expression may permit further refinement of selection and monitoring of therapy.

Pretreatment cardiac status

One might also suspect that differences between critical cardiac adaptations to CCF or its treatment with conventional agents may influence the response to rhGH treatment. For example, ventricular hypertrophy, ventricular dilation, circulatory filling pressures, and their interaction may be important. While rhGH may induce ventricular hypertrophy, any functional benefit may depend on local effects on wall stress and whether optimal adaptive hypertrophy has been already achieved. The relationship between ventricular contractility and dilation, described by the Frank-Starling curve, may also play a critical role in determining benefits from rhGH treatment, in that an increment in contractility may depend on the exact degree of fiber stretch. Also, because rhGH is antinatriuretic, some effect to increase circulating volume may or may not be beneficial. Finally, whether the vasodilatory action of rhGH and/or IGF-I is clinically important may depend on the patient’s pretreatment volume status and vasodilatory medications. If these factors prove to be important in defining the benefits of rhGH, careful and sophisticated patient selection may be required.

Dilated or ischemic cardiomyopathy?

Currently, no studies have directly compared rhGH responsiveness between dilated and ischemic cardiomyopathy. It has been argued that ventricular wall stress is high in dilated cardiomyopathy and that an rhGH-induced anabolic increase in wall thickness is specifically beneficial in this condition. Regarding ischemic cardiomyopathy, a variety of experimental studies suggest beneficial effects of GH and/or IGF-I administration in postinfarction animal models, particularly in terms of improved myocardial contractility (14). Nevertheless, the temporal relationship between the ischemic injury, the reparative-remodeling process, and rhGH therapy may be critically important.

Exercise capacity

One end point worthy of increased attention involves cardiac function during exercise. Smit et al. (11) assessed myocardial perfusion in response to exercise but not cardiac output, maximal work, or anaerobic threshold. Such areas have been shown to change dramatically with rhGH treatment in adults with GHD, and to be apparently more sensitive indicators of response than resting endpoints in several of the other clinical trials in patients with CCF. The actions of rhGH on skeletal muscle, for example, may also contribute to a functional improvement.

ß-blocker usage

The experimental in vivo and in vitro data are conflicting, but there is a possibility that some of the benefits of rhGH treatment on contractility are mediated by ß-sympatho-adrenergic receptor-associated mechanisms. Three of nine of Smit’s patients in the rhGH group received ß-blocker therapy, as did a substantial proportion in some of the other rhGH trials. If such therapy minimized the rhGH response, then underpowered studies may have resulted.

Cardiovascular risk factors

Any long-term therapy for ischemic CCF must consider treatment effects on atherosclerotic vascular risk factors. Whereas the literature on rhGH replacement in GH-deficient adults supports an improvement in cholesterol and other vascular risk status, it is fascinating to detect a trend toward a fall in total cholesterol and presumably low-density lipoprotein cholesterol in the study by Smit et al. (11) even in such a small cohort, and where the majority already received HMG-CoA reductase inhibitors.

In summary, there seems to be clear experimental proof and some clinical data that rhGH can benefit patients with CCF. Clinical researchers should be encouraged to pursue this new therapy, paying attention to defining suitable subgroups based on endocrinological, cardiac and hemodynamic criteria, individualization of the rhGH dose, and monitoring critical end points that must include a substantial serum IGF-I increment. What of the future? GH secretagogues are likely to receive attention given 1) their ability to stimulate a physiological GH increment with an orally active preparation, and 2) a direct GH-secretagogue receptor-mediated stimulation of cardiac muscle. Whether a physiological, pulsatile serum GH signal as generated by GH secretagogues or the pharmacological GH signal delivered from sc rhGH administration is more beneficial for patients with CCF also requires study.

Acknowledgments

Footnotes

Abbreviations: CCF, Congestive cardiac failure; GHD, GH deficiency; hGH, human GH; LV, left ventricular; rhGH, recombinant hGH.

Received August 16, 2001.

Accepted August 17, 2001.

References

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