Impact of growth hormone hypersecretion on the adult human kidney

Acromegaly is most often secondary to a GH-secreting pituitary adenoma with increased Insulin-like Growth Factor type 1 (IGF-1) level. The consequences of GH/IGF-1 hypersecretion reflect the diversity of action of these hormones. The genes of the GH receptor (GHR), IGF-1, IGF-1 receptor (IGF-1R) and IGF-binding proteins (IGF-BP) are physiologically expressed in the adult kidney, suggesting a potential role of the somatotropic axis on renal structure and functions. The expression of these proteins is highly organized and differs according to the anatomical and functional segments of the nephron suggesting different roles of GH and IGF-1 in these segments. In animals, chronic exposure to high doses of GH induces glomerulosclerosis and increases albuminuria. Studies in patients with GH hypersecretion have identified numerous targets of GH/IGF-1 axis on the kidney: 1) an impact on renal filtration with increased glomerular filtration rate (GFR), 2) a structural impact with an increase in kidney weight and glomerular hypertrophy, and 3) a tubular impact leading to hyperphosphatemia, hypercalciuria and antinatriuretic effects. Despite the increased glomerular filtration rate observed in patients with GH hypersecretion, GH is an inefficient treatment for chronic renal failure. GH and IGF-1 seem to be involved in the physiopathology of diabetic nephropathy; this finding offers the possibility of targeting the GH/IGF-1 axis for the prevention and the treatment of diabetic nephropathy.     

The GH/IGF-1 Axis and Heart Failure

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.     

Novel roles of the IGF-IGFBP axis in etiopathophysiology of diabetic nephropathy

Mechanisms contributing to development of diabetic nephropathy (DN) remain unclear. High ambient glucose level transforms intracellular pathways, promoting stable phenotypic changes in the glomerulus such as mesangial cell hypertrophy, podocyte apoptosis, and matrix expansion. Insulin-like growth factors (IGFs) and the high affinity IGF binding proteins (IGFBPs) exert major effects on cell growth and metabolism. Compared with diabetic patients without microalbuminuria (MA), MA diabetic patients display perturbed GH-IGF-IGFBP homeostasis, including increased circulating IGF-I and IGFBP-3 protease activity, increased excretion of bioactive GH, IGF-I, and IGFBP-3, but decreased circulating IGFBP-3 levels. In diabetic animal models, expression of IGF-I and IGFBP-1 to -4 increases in key renal tissues and glomerular ulrafiltrate. Epithelial, mesangial, and endothelial cells derived from the kidney respond to IGF-I binding with increased protein synthesis, migration, and proliferation. This article reviews classic and emerging concepts for the roles of the GH-IGF-IGFBP axis in the etiopathophysiology, treatment, and prevention of diabetic renal disease. We report IGF-independent actions of IGFBP-3 in the podocyte for the first time.     

hrGH treatment of glucocorticoid-induced short stature in children

The treatment of systemic diseases with glucocorticoids is often associated with decreased height velocity (HV), and can result in shorter final height. Interactions between adrenal and GH-IGF axis have been described and can occur at hypothalamic-pituitary level or at the regulation of IGF system, including the IGF1R signaling. The clinical state of these patients may be considered as an absolute and/or functional IGF-1 deficiency. Interventions aiming to restore the normal function of GH-IGF axis might reduce the glucocorticoids-induced growth suppression in these children. It has been shown that recombinant human GH (hrGH) induces an increase in HV and a decrease in protein loss in patients with juvenile idiopathic arthritis treated with glucocorticoids. Significant increment in HV was also described after hrGH treatment in children under glucocorticoid therapy due to inflammatory bowel disease or renal transplantation. There is a positive correlation between HV and the dose of hrGH. The results support that the IGF-1 deficiency in these children may be counteract by hrGH therapy. The effect of hrGH is observed only during the treatment period and depends on the replacement strategy, nutritional status and disease control.     

Podocytes as a target of insulin

Diabetic nephropathy (DN) presents with a gradual breakdown of the glomerular filtration barrier to protein, culminating in widespread glomerular damage and renal failure. The podocyte is the central cell of the glomerular filtration barrier, and possesses unique architectural and signaling properties guided by the expression of key podocyte specific proteins. How these cellular features are damaged by the diabetic milieu is unclear, but what is becoming increasingly clear is that damage to the podocyte is a central event in DN. Here we present accumulating evidence that insulin action itself is important in podocyte biology, and may be deranged in the pathomechanism of early DN. This introduces a rationale for therapeutic intervention to improve podocyte insulin sensitivity early in the presentation of DN.     

Ghrelin in chronic liver disease

BACKGROUND/AIMS: Ghrelin is a novel endogenous ligand for the growth hormone (GH) secretagogue receptor involved in energy metabolism, glucose homeostasis and food intake. We investigated the role of ghrelin and insulin-like growth factor-1 (IGF-1), the mediator of the GH axis, in patients with chronic liver diseases (CLD). METHODS: Ghrelin and IGF-1 serum levels were determined in 105 CLD patients and 97 healthy controls and correlated with clinical and biochemical parameters. RESULTS: Ghrelin was significantly elevated and IGF-1 reduced in CLD patients compared with healthy controls. IGF-1 serum levels inversely correlated with Child's classification. Ghrelin levels were significantly elevated in Child C cirrhosis patients independent of the aetiology of liver disease. Ghrelin levels did not correlate with liver function. In contrast, there was a correlation of ghrelin with clinical (gastrointestinal bleeding, ascites, encephalopathy) and biochemical (anaemia, inflammatory markers, hypoglycaemia, renal dysfunction) parameters. In a subgroup of patients with CLD and hepatocellular carcinoma (HCC), we observed a strong inverse correlation between alpha-fetoprotein (AFP) and ghrelin levels. CONCLUSIONS: Unlike IGF-1, ghrelin is not correlated with liver function, but increases in Child C cirrhosis and with complications of CLD. The inverse correlation with AFP in HCC patients requires further studies on the potential impact of ghrelin on the pathogenesis of anorexia-cachexia syndrome.     

Disturbed Synthesis of Insulinlike Growth Factor I and Its Binding Proteins May Influence Renal Function Changes in Liver Cirrhosis

Insulinlike growth factor-1 (IGF-1) is an anabolic hormone synthesized by the liver upon stimulation by growth hormone (GH). IGF-1 exerts important effects on renal hemodynamics and renal sodium handling. The bioactivity of this hormone is influenced by its binding proteins (BP) of which IGF-BP3 favors retention in the capillary lumen while IGF-BP1 facilitates the transport to the target tissues. IGF-BP1 modulates the actions of IGF-1 on target cells including renal tubules. Although a number of reports have dealt with disturbances of the IGF-1/IGF-BP system in cirrhosis, no studies have yet addressed the relationship between alterations in this system and renal function changes in cirrhosis. In the present study we have included 20 patients with cirrhosis and 10 healthy subjects (control group). As compared with the controls, patients showed lower circulating levels of IGF-1 and IGF-BP3, higher IGF-BP1 levels, and a tendency to higher insulinemia and GH values. The index IGF-1 × IGF-BP1/IGF-BP3 (IGF-1–IGF-BP index, reflecting the accessibility of circulating IGF-1 to target cells) was higher in patients with ascites. IGF-1 directly correlated with renal blood flow (P < 0.05), with IGF-BP3 (P < 0.001) and inversely with the Pugh's score (P < 0.02). A negative correlation was found between IGF-1–IGF-BP index and fractional sodium excretion (P < 0.01) and between IGF-BP1 and urinary sodium excretion (P < 0.02). Our findings support the hypothesis that the disturbance of the IGF-1/IGF-BP axis may be related to the degree of renal vasodilation and renal sodium retention in cirrhotic patients.     

艾塞那肽对糖尿病肾病小鼠足细胞的保护作用

目的:探讨艾塞那肽对糖尿病肾病小鼠足细胞的作用。方法:通过给予C57BL/6J小鼠高脂饮食并注射链脲佐菌素建立糖尿病肾病模型,按随机数字表法将其分为糖尿病肾病对照组(DN组, n＝8)、艾塞那肽干预组(DN＋Ex组, n＝8)。同时将普通饲料喂养的C57BL/6J小鼠作为正常对照组(NC组, ...     

Adult growth hormone deficiency in patients with fibromyalgia

Adult growth hormone (GH) deficiency is a welldescribed clinical syndrome with many features reminiscent of fibromyalgia. There is evidence that GH deficiency as defined in terms of a low insulin-like growth factor-1 (IGF-1) level occurs in approximately 30% of patients with fibromyalgia and is probably the cause of some morbidity. It seems most likely that impaired GH secretion in fibromyalgia is related to a physiologic dysregulation of the hypothalamic-pituitary-adrenal axis (HPA) with a resulting increase in hypothalamic somatostatin tone. It is postulated that impaired GH secretion is secondary to chronic physical and psychological stressors. It appears that impaired GH secretion is more common than clinically significant GH deficiency with low IGF-1 levels. The severe GH deficiency that occurs in a subset of patients with fibromyalgia is of clinical relevance because it is a treatable disorder with demonstrated benefits to patients.     

Influence of Growth Hormone on Cardiovascular Health and Disease

Experimental and clinical studies indicate that growth hormone (GH) and insulin-like growth factor-1 (IGF-1) are involved in heart development. Impaired cardiovascular function, as recently demonstrated, could potentially reduce life expectancy both in GH deficiency (GHD) and excess. Patients with childhood- or adult-onset GHD may have both cardiac structural and functional abnormalities, i.e. reduced cardiac mass, reduced diastolic filling, and impaired left ventricular response to peak exercise. In addition, GHD patients may present with an increase in vascular intima-media thickness and a higher occurrence of atheromatous plaques that can further aggravate the hemodynamic conditions and contribute to the increased cardiovascular and cerebrovascular risk. However, some evidence has been provided to show that cardiovascular abnormalities can be partially reversed after somatropin (recombinant GH) therapy in patients with GHD. Recently, somatropin administration was shown to induce improvement in hemodynamics and clinical status in some patients with heart failure. Although these data need to be confirmed in more extensive studies, such promising results open new perspectives for somatropin therapy. The role of GH secretagogues in heart failure is still unknown.     

Differential effects on kidney and liver growth of a non-viral hGH-expression vector in hypophysectomized mice

Non-viral gene transfer was investigated as a potential modality for the treatment of growth hormone deficiency (GHD) using hypophysectomized (Hx) mice as a model. Hx mice were injected with a control plasmid or a plasmid containing the human (h) GH gene driven by a ubiquitin promoter, or left untreated. Treatment with the hGH gene has previously been shown to normalize longitudinal growth and serum insulin-like growth factor I (IGF-I). The present study was conducted to examine the renal/hepatic changes and gene/peptide expression of the GH/IGF-I axis in animals chronically expressing hGH. Following a single hydrodynamic administration of a plasmid DNA containing the hGH gene, a sustained elevation of the circulating hGH level was observed throughout the entire observation period, with a concomitant normalization of circulating IGF-I and IGF-binding protein 3 (IGFBP-3). In addition, longitudinal growth was corrected by normalizing tibia length, tail length, and body weight gain. Interestingly, kidney weights were only partly normalized, whereas kidney glomerular volume and liver weights were fully normalized. Kidney and liver IGF-I protein content was reduced in the Hx mice, but was normalized by hGH treatment. Kidney and liver GH receptor (GHR) mRNA levels were unchanged in the Hx mice, whereas the liver IGF-I mRNA level was reduced in the Hx mice, but was normalized by hGH treatment.We conclude that non-viral hGH gene transfer in Hx mice, which normalizes longitudinal growth and serum IGF-I levels, has differential effects on renal growth and glomerular volume. The potential effects of such excess glomerular growth induced by this intervention require further investigation.     

Importance of an intact growth hormone/insulin-like growth factor 1 axis for normal post-infarction healing: studies in dwarf rats

Treatment with GH attenuates remodeling and improves left ventricular function in the setting of experimental heart failure following coronary ligation. This study was designed to test the hypothesis that an intact GH/insulin-like growth factor 1 (IGF-1) axis is required for normal myocardial infarction healing. Myocardial infarction was induced by coronary ligation in GH-deficient dwarf rats and in age-matched controls. In dwarf rats, serum IGF-1 levels were reduced by 50%, and grow rate was 50% less than normal littermates, although no differences in myocardial IGF-1 messenger RNA levels were observed compared with controls. All rats underwent transthoracic echocardiography at baseline, 2 weeks, and 6 weeks after myocardial infarction. Left ventricular end-diastolic pressure was obtained by in vivo closed chest catheterization. At 6 weeks, both infarcted groups exhibited similar myocardial infarction size at transthoracic echocardiography and at morphometric histology. In both groups with myocardial infarction, there was significant left ventricular dilation and reduced systolic function. However, the extent of remodeling as assessed by the increase in end-diastolic dimension (%Delta + 36 +/- 5 vs. +19 +/- 4; P: < 0.01) and depression of function (%Delta fractional shortening -12 +/- 2 vs. -7 +/- 1; P: < 0.01) were both greater in the dwarf group. Furthermore, dwarf rats failed to develop compensatory hypertrophy of noninfarcted posterior wall (%Delta posterior wall +5 +/- 1 vs. +15 +/- 3; P: < 0.01). Therefore, pathologic left ventricular remodeling and functional loss following myocardial infarction is more marked in conditions of GH deficiency. An intact GH/IGF-1 axis appears necessary for a normal response to myocardial infarction injury in the rat.     

Ultrastructural changes in the glomerular filtration barrier and occurrence of proteinuria in Chinese patients with type 2 diabetic nephropathy

AimDiabetic nephropathy (DN) is one of the most important causes of end stage renal disease in the world. Its hallmark is proteinuria. Therefore, we set out to clarify the structural changes that occur in the glomerular filtration barrier in Chinese patients with true type 2 diabetic nephropathy, and to examine the relationship between these structural changes and proteinuria.Methods42 Chinese patients with true T2DN were divided into three groups according to urinary protein excretion. Glomerular volume, endothelial cell density, endothelial cell number, glomerular basement membrane (GBM) width, podocyte density, podocyte number and foot process width were evaluated using light and electron microscopic morphometry.ResultGlomerular volume and endothelial cell number were increased in diabetic patients, but there was no difference between patients with respect to the degree of proteinuria. As proteinuria progressed, endothelial cell density remained unchanged, while the glomerular basement membrane (GBM) and podocyte foot process width increased, podocyte density and number decreased.ConclusionsPodocyte and GBM change more obviously during the development of proteinuria. Besides, proteinuria was inversely related to podocyte density, and directly related to GBM and glomerular volume.     

New concepts: growth hormone, insulin-like growth factor-I and the kidney.

Both growth hormone (GH) and IGF-1 have major effects on normal kidney growth, structure and function and participate in the pathogenesis of certain kidney diseases. Furthermore when the kidneys fail there are profound changes in the circulating GH-IGF-1 system and the renal and systemic responses to these hormones. In this brief review we address the advances that have been made in our understanding of the relationship between growth hormone GH and IGF-1 and the kidney in health and the systemic and local perturbations that occur in kidney disease and identify key unanswered questions.     

Stimulatory effect of insulin-like growth factor-1 on renal Pi transport and plasma 1,25-dihydroxyvitamin D3

Administration of GH increases both the tubular reabsorption of inorganic phosphate (Pi) and the plasma level of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]. These two effects could be induced by a common mediator, possibly the GH-generated insulin-like growth factor 1 (IGF-1). In the present work, the influence of recombinant human IGF-1 on renal Pi transport and plasma 1,25-(OH)2D3 was examined in hypophysectomized (HPX) rats. IGF-1, infused by miniosmotic pump at the dose of 10 micrograms/h for 6 days, significantly increased the maximal tubular reabsorption of Pi per unit volume of glomerular filtrate (max TRPi/m1GFR): IGF-1 3.50 +/- 0.16; vehicle: 2.78 +/- 0.14 mumol/m1GFR, P less than 0.005. The response was associated with a marked stimulation of plasma 1,25-(OH)2D3 (IGF-1; 409 +/- 23; vehicle: 208 +/- 22 pmol/liter, P less than 0.001). As previously reported for GH, IGF-1 also increased GFR and reduced urinary sodium excretion. In brush border membrane vesicles isolated from renal cortex of HPX rats, the Na-dependent Pi transport was stimulated by IGF-1. Neither the Na-dependent glucose transport nor that of alanine was affected by the growth factor. The stimulatory effect of IGF-1 on maxTRPi/m1GFR was also expressed in thyroparathyroidectomized (TPTX) HPX rats (IGF-1: 5.20 +/- 0.29; vehicle: 3.88 +/- 0.37 mumol/m1GFR, P less than 0.025). In conclusion, administration of IGF-1 in HPX rats mimics the stimulatory effects of GH on maxTRPi/m1GFR and on plasma 1,25-(OH)2D3. As described for GH the change in maxTRPi/m1GFR is mediated by a PTH independent mechanism and is expressed at the level of the luminal membrane of proximal tubules. These results suggest that IGF-1 could be an important factor in the control of Pi metabolism, particularly during growth, and might play a significant role in mediating the effect of GH on the renal handling of Pi and production of 1,25-(OH)2D3.     

糖尿病肾病肾小球滤过膜结构与肾功能及代谢指标的关系

目的:观察2型糖尿病肾病(T2DN)患者肾小球滤过膜超微结构改变与肾功能及代谢指标的关系.方法:将明确诊断的T2DN 75例患者分为:微量白蛋白尿组(尿白蛋白/24h 30～300 mg);蛋白尿组(尿蛋白0.5～2.0g/24h)和大量蛋白尿组(尿蛋白＞3.5g/24h).收集三组患者临床指标,并分别使用Cockcroft-Gault公式、简化的肾脏疾病饮食控制(MDRD)公式等计算患者的肾小球滤过率(eGFR);采用形态学计量分析方法分别测算肾小球体积、肾小球足细胞和内皮细胞的相对密度、绝对数目和足细胞足突宽度及肾小球基膜(GBM)厚度.结果:(1)肾小球滤过膜结构与GFR的关系:微量白蛋白尿组Ccr与肾小球足细胞密度及数日均负相关(分别为r=-0.480,P＜=0.05;r=-0.478,P＜0.05);大量蛋白尿组以SCr估算的eGFR与肾小球足细胞密度正相关(r=0.462,P＜0.05);余均未见明显相关.(2)多元回归分析结果:微量白蛋白尿组中肾小球足细胞密度、糖化血红蛋白、三酰甘油、尿酸与Ccr相关(R~2=0.616,P＜0.01);大量蛋白尿组肾小球足细胞密度、尿酸与以SCr估算的eGFR相关(R~2=0.613,P＜0.01).(3)肾小球滤过膜结构及肾小球体积与糖、脂质代谢指标的关系:①肾小球体积与血糖的关系:微量白蛋白尿组中肾小球体积和糖化血红蛋白正相关(r=0.425,P＜0.05);而在蛋白尿组则为负相关(r=-0.427,P＜0.05).②GBM厚度与血糖、血脂代谢指标的关系:微量白蛋白尿组中,以GBM厚度为因变量,糖及脂质代谢水平为自变量,可见空腹血糖水平和总胆固醇与基膜厚度相关(R~2=0.247,P＜0.05).结论:肾小球滤过膜结构与GFR及糖、脂质代谢水平间存在着密切联系,且与DN发展的不同阶段相关.     

Diagnostic strategy for growth hormone deficiency: relevance of IGF-1 determination as a screening test

BACKGROUND: Adult growth hormone (GH) deficiency must be diagnosed before prescribing therapeutic recombinant human GH. We studied the clinical relevance of a diagnostic strategy for growth hormone deficiency (GHD) using IGF-1 determination as a first step. METHODS: In 2000 and 2001, we tested 142 adult patients with hypothalamo-pituitary disorders for somatotropic function using Insulin Tolerance Test (ITT), the reference test for the diagnosis of GHD, with concomitant Insulin-like growth factor-1 (IGF-1) determination, a marker of somatotropic function. Patients were classified as GHD (peak GH concentration<3 ng/ml with the ITT) or normal. SETTING: Monocenter prospective study in a tertiary referral center. RESULTS: GHD was diagnosed in 61 subjects. Using a ROC curve, a threshold IGF-1 concentration of 175 ng/ml yielded a negative predictive value of 89+/-5%. A diagnostic strategy with IGF-1 determination as the first step followed by ITT for patients with an IGF-1 concentration below 175 ng/ml missed five of the 61 GHD patients, avoided 46/142 ITT and reduced the cost of diagnosis by 15%. CONCLUSION: We propose the use of a strategy consisting of IGF-1 determination followed, if below 175 ng/ml by confirmatory ITT to diagnose GHD in adults.     

Growth hormone therapy and the heart

The growth hormone (GH)-insulin-like growth factor-1 axis has great relevance for the regulation of cardiac growth, structure, and function. GH deficiency may result in impaired cardiac performance, manifest by a reduction in left ventricular mass and ejection fraction, but data are inconsistent. GH therapy is recommended treatment in adult patients with GH deficiency, but in acromegaly, in which there is excess GH, the main cause of mortality is cardiovascular disease. The purposes of this study were to perform (1) a case-controlled study comparing cardiac morphology and function in 53 GH-deficient patients (34 men, mean age 38.1 +/- 15.2 years, 22 with childhood-onset GH deficiency) and 46 healthy controls (29 men, mean age 37.8 +/- 12.4 years) and (2) a longitudinal study to assess the effect of introducing GH therapy in 37 subjects for a mean period of 26 +/- 22 months. At study entry, all subjects underwent electrocardiography and 24-hour ambulatory electrocardiographic monitoring, systolic and diastolic blood pressure assessment, detailed echocardiography, and exercise tolerance tests. There were no significant differences in left ventricular mass, left ventricular dimensions, systolic or diastolic function indexes, or blood pressure at rest in patients compared with controls. Exercise duration was significantly shorter and peak heart rate during exercise (chronotropic response) lower in the GH-deficiency group than in controls (p <0.05). After GH treatment, there were no significant changes in echocardiographic parameters or blood pressure, but an improvement in exercise duration (p = 0.019) was found, particularly in the subgroup with childhood-onset GH deficiency (n = 16). In conclusion, patients with GH deficiency did not show cardiac structural or functional differences compared with healthy controls, with no significant changes after GH treatment. However, these patients exhibited improved exercise capacity, especially those with childhood-onset GH deficiency.     

Cardioprotective effects of growth hormone-releasing hormone agonist after myocardial infarction

Whether the growth hormone (GH)/insulin-like growth factor 1(IGF-1) axis exerts cardioprotective effects remains controversial; and the underlying mechanism(s) for such actions are unclear. Here we tested the hypothesis that growth hormone-releasing hormone (GHRH) directly activates cellular reparative mechanisms within the injured heart, in a GH/IGF-1 independent fashion. After experimental myocardial infarction (MI), rats were randomly assigned to receive, during a 4-week period, either placebo (n = 14), rat recombinant GH (n = 8) or JI-38 (n = 8; 50 µg/kg per day), a potent GHRH agonist. JI-38 did not elevate serum levels of GH or IGF-1, but it markedly attenuated the degree of cardiac functional decline and remodeling after injury. In contrast, GH administration markedly elevated body weight, heart weight, and circulating GH and IGF-1, but it did not offset the decline in cardiac structure and function. Whereas both JI-38 and GH augmented levels of cardiac precursor cell proliferation, only JI-38 increased antiapoptotic gene expression. The receptor for GHRH was detectable on myocytes, supporting direct activation of cardiac signal transduction. Collectively, these findings demonstrate that within the heart, GHRH agonists can activate cardiac repair after MI, suggesting the existence of a potential signaling pathway based on GHRH in the heart. The phenotypic profile of the response to a potent GHRH agonist has therapeutic implications.