Salvatore Longobardi

Left ventricular function in young adults with childhood and adulthood onset growth hormone deficiency

The impairment of heart structure and function in adults with childhood onset GH deficiency has been recently described. However, previous echocardiographic studies have reported no differences in cardiac mass and function between adulthood onset GH deficient patients and healthy subjects.

Abnormal Vascular Reactivity in Growth Hormone Deficiency

Background —The reason why patients with growth hormone (GH) deficiency (GHD) are at increased risk for premature cardiovascular death is still unclear. Although a variety of vascular risk factors have been identified in GHD, little is known regarding vascular reactivity and its contribution to premature arteriosclerosis. Methods and Results —We assessed vascular function in 7 childhood-onset, GH-deficient nontreated patients (age 22±3 years, body mass index [BMI] 25±1 kg/m2) and 10 healthy subjects (age 24±0.4 years, BMI 22±1 kg/m2) by using strain gauge plethysmography to measure forearm blood flow in response to vasodilatory agents. The increase in forearm blood flow to intrabrachial infusion of the endothelium-dependent vasodilator acetylcholine was significantly lower in GH-deficient nontreated patients than in control subjects (P <0.05). Likewise, forearm release of nitrite and cGMP during acetylcholine stimulation was reduced in GH-deficient nontreated patients (P <0.05 and P <0.002 versus controls). The response to the endothelium-independent vasodilator sodium nitroprusside was also markedly blunted in GH-deficient patients compared with control subjects (P <0.005). To confirm that abnormal vascular reactivity was due to GHD, we also studied 8 patients with childhood-onset GHD (age 31±2 years, BMI 24±1 kg/m2) who were receiving stable GH replacement therapy. In these patients, the response to both endothelium-dependent and -independent vasodilators, as well as forearm nitrite and cGMP, release was not different from that observed in normal subjects. Peak hyperemic response to 5-minute forearm ischemia was significantly reduced in GH-deficient nontreated patients (17.2±2.6 mL · dL−1 · min−1, P <0.01) but not in GH-treated patients (24.8±3.3 mL · dL−1 · min−1) compared with normal subjects (29.5±3.2 mL · dL−1 · min−1). Conclusions —The data support the concept that GH plays an important role in the maintenance of a normal vascular function in humans.

Cardiovascular aspects in acromegaly: Effects of treatment

Patients with acromegaly have significant morbidity and mortality, associated with cardiovascular disease. Acromegaly is often complicated by other diseases such as diabetes mellitus, hypertension, and coronary artery disease, so the existence of acromegalic cardiomyopathy remains uncertain. Cardiac performance was investigated in patients with uncomplicated acromegaly. A subgroup of hypertensive acromegalics was also studied. In addition, the effects of chronic octreotide therapy or surgery on cardiac structure and function in acromegaly were studied. Twenty-six patients and 15 healthy controls underwent gated blood-pool cardiac scintigraphy and echocardiography at rest and during exercise. Echocardiography was repeated after 6 months of octreotide therapy (n = 11). Cardiac scintigraphy was repeated after 12 and 24 months of octreotide therapy (n = 10) or 12 to 24 months after surgery (n = 8). ECG, blood pressure, and heart rate were monitored during cardiac scintigraphy. Left ventricular mass (LVM) was calculated from the findings of the echocardiography. Serum growth hormone (GH) levels and plasma insulin-like growth factor-1 (IGF-1) levels were monitored. LVM index was significantly higher (P < .003) in acromegalics than controls and in hypertensive acromegalics than normotensives, but all other indices of cardiac function were similar. Chronic octreotide decreased GH and IGF-1 levels and improved the structural abnormalities as measured by echocardiography. Chronic octreotide or surgery did not alter cardiac function parameters. Thus, important changes in cardiac structure and function occur in uncomplicated acromegaly, and improvements can be demonstrated after chronic octreotide therapy. Heart disease in acromegaly appears to be secondary to high circulating GH levels.

A preliminary randomized study of growth hormone administration in Becker and Duchenne muscular dystrophies

AIMnSince growth hormone (GH) has proven beneficial in experimental heart failure, and the natural history of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) is frequently complicated by the development of dilated cardiomyopathy, we administered GH to six patients with DMD and 10 with BMD, with the evidence of cardiac involvement.nnnMETHODS AND RESULTSnPatients were randomized to receive for 3 months either placebo or recombinant human GH, in a double-blind fashion. In GH-treated patients, left ventricular (LV) mass increased by 16% in BMD and by 29% in DMD (both p<0.01), with a significant increase of relative wall thickness (+19%). Systemic blood pressure remained unchanged, while LV end-systolic stress fell significantly by 13% in BMD and by 33% in DMD, with a slight increase of systolic function indexes. No changes were observed related to cardiac arrhythmias and skeletal muscle function in the patient groups during the treatment period, nor any side effects were observed. Brain natriuretic peptide, interleukin-6, and tumor necrosis factor-alpha circulating levels were elevated at baseline. While brain natriuretic peptide decreased by 40%, cytokine levels did not exhibit significant variations during the treatment period.nnnCONCLUSIONSnThe 3-month GH therapy in patients with DMD and BMD induces a hypertrophic response associated with a significant reduction of brain natriuretic peptide plasma levels and a slight improvement of systolic function, no changes in skeletal muscle function, and no side effects.

Growth Hormone and the Heart

Until a few years ago, growth hormone (GH) and insulin-like growth factor-1 (IGF-1) were considered essential only to the control of linear growth, glucose homeostasis, and for the maintenance of skeletal muscle mass. A large body of evidence recently coming from animal and human studies has unequivocally proven that the heart is a target organ for the GH//IGF-1 axis. Specifically GH exerts both direct and indirect cardiovascular actions. Among the direct effects, the ability of GH to trigger cardiac tissue growth plays a pivotal role. Another direct effect is to augment cardiac contractility, independent of myocardial growth. Direct effects of GH also include the improvement of myocardial energetics and mechanical efficiency. Indirect effects of GH on the heart include decreased peripheral vascular resistance (PVR), expansion of blood volume, increased glomerular filtration rate, enhanced respiratory activity, increased skeletal muscle performance, and psychological well-being. Among them, the most consistently found is the decrease of PVR. GH may also raise preload through its sodium-retaining action and its interference with the hormonal system that regulates water and electrolyte metabolism. Particularly important is the effect of GH on skeletal muscle mass and performance. Taking into account that heart failure is characterized by left ventricular dilation, reduced cardiac contractility, and increase of wall stress and peripheral vascular resistance, GH may be beneficial for treatment of heart failure. Animal studies and preliminary human trials have confirmed the validity of the GH approach to the treatment of heart failure. Larger placebo-controlled human studies represent the main focus of future investigations.

GH therapy in adult GH deficiency: A review of treatment schedules and the evidence for low starting doses

Recombinant human GH has been licensed for use in adult patients with GH deficiency (GHD) for over 15 years. Early weight- and surface area-based dosing regimens were effective but resulted in supraphysiological levels of IGF1 and increased incidence of side effects. Current practice has moved towards individualised regimens, starting with low GH doses and gradually titrating the dose according to the level of serum IGF1 to achieve an optimal dose. Here we present the evidence supporting the dosing recommendations of current guidelines and consider factors affecting dose responsiveness and parameters of treatment response. The published data discussed here lend support for the use of low GH dosing regimens in adult GHD. The range of doses defined as low dose in the studies discussed here (∼1-4u200a mg/week) is in accordance with those recommended in current guidelines and encompasses the dose range recommended by product labels.

Growth hormone therapy in adult growth hormone deficiency: a review of treatment schedules and the evidence for low starting doses

Recombinant human GH has been licensed for use in adult patients with GH deficiency (GHD) for over 15 years. Early weight- and surface area-based dosing regimens were effective but resulted in supraphysiological levels of IGF1 and increased incidence of side effects. Current practice has moved towards individualised regimens, starting with low GH doses and gradually titrating the dose according to the level of serum IGF1 to achieve an optimal dose. Here we present the evidence supporting the dosing recommendations of current guidelines and consider factors affecting dose responsiveness and parameters of treatment response. The published data discussed here lend support for the use of low GH dosing regimens in adult GHD. The range of doses defined as low dose in the studies discussed here (∼1-4u200a mg/week) is in accordance with those recommended in current guidelines and encompasses the dose range recommended by product labels.

Heart Failure: Potential Benefit of Growth Hormone Therapy

Until a few years ago, growth hormone (GH) was considered essential in the control of linear growth, glucose homeostasis, and skeletal muscle mass. More recently, a series of studies have unequivocally proven that the heart is a target organ for the GH/IGF-I axis, which modulates cardiac structure and function. The importance of the GH/IGF-I axis is also supported by several lines of experimental evidence demonstrating that GH/IGF-I affects the determinants of cardiac output (preload, afterload, and contractility), through direct and indirect mechanisms. The therapeutic options available for the treatment of heart failure are few, and the overall prognosis for this disease remains very poor. Recent studies employing growth factors, which activate myocardial growth by inducing a physiological kind of hypertrophy, seem exciting. In this regard, GH and IGF-I may be the best candidates to produce a growth response in the heart. The large amount of novel information derived from the experimental and clinical studies on GH and cardiac function suggests that this field of research will be an important area of future investigations. Basic research is needed to discover the complex intracellular pathways of GH and IGF-I and to clarify their growth-promoting and positive inotropic actions. Furthermore, survival animal studies employing GH may potentially address whether the beneficial hemodynamic effects of GH in experimental heart failure would translate into a better prognosis for human heart failure.