Growth hormone in heart failure revisited: An old story retold

Heart failure (HF) is a disease characterized by increasing prevalence, huge direct and indirect costs, and an ominous prognosis, worse than many cancers. At the beginning of the 90s, growth hormone (GH) was proposed as potential adjunctive therapy in HF mostly due to its growth-promoting, vasodilating, and anti-apoptotic actions. However, although several uncontrolled clinical studies showed that GH therapy improved several cardiovascular parameters, two robust trials failed to confirm these findings. Dwelling upon potential explanations for such apparent discrepancy led to the hypothesis that HF patients exhibit an inhomogeneous basal activity of the GH/insulin-like growth factor 1 (IGF-1) axis, ranging from GH/IGF-1 deficiency to GH resistance. This complex phenomenon was then reconsidered in the context of the so-called multiple hormone deficiency syndrome (MHD), that is the recognition that HF is characterized not only by the hyperactivation of several signaling pathways including the adrenergic, the renin-angiotensin-aldosterone and cytokine systems, but also by a reduced anabolic drive leading to a state of anabolic/catabolic imbalance. Mounting evidence support the concept that such imbalance is not a mere epiphenomen, since it exerts a significant impact on clinical performance and more importantly, on survival. Therefore, the paradigm shift to reconsider HF as MHD represented the underpinning to implement clinical trials focused on hormone replacement therapies in congestive heart failure (CHF). With regard to GH replacement therapy, one controlled single-blind study yielded promising results, and we are currently conducting a double-blind controlled trial, as well a large Registry study to evaluate the impact of MHD on HF progression

GH and the cardiovascular system: an update on a topic at heart

In this review, the importance of growth hormone (GH) for the maintenance of normal cardiac function in adult life is discussed. Physiological effects of GH and underlying mechanisms for interactions between GH and insulin-like growth factor I (IGF-I) and the cardiovascular system are covered as well as the cardiac dysfunction caused both by GH excess (acromegaly) and by GH deficiency in adult hypopituitary patients. In both acromegaly and adult GH deficiency, there is also increased cardiovascular morbidity and mortality possibly linked to aberrations in GH status. Finally, the status of the GH/IGF-I system in relation to heart failure and the potential of GH as a therapeutic tool in the treatment of heart failure are reviewed in this article. © 2014 The Author(s)

Effects of growth hormone on exercise capacity and cardiopulmonary performance in patients with chronic heart failure.

BACKGROUND: Because GH exerted beneficial effects in various experimental models of heart failure, we investigated the effects of GH on physical exercise capacity and cardiopulmonary performance in patients with dilated cardiomyopathy and chronic heart failure (CHF). METHODS: Twenty-two patients with CHF (New York Heart Association functional class II-III) underwent spirometry and a symptom-limited, cardiopulmonary exercise testing before and after 3 months of GH (n = 11; seven males; seven idiopathic; 57 +/- 11 yr; 4 IU sc every other day) or placebo (n = 11; eight males; six idiopathic; 54 +/- 10 yr) administration, in a randomized, double-blind trial. Background CHF therapy remained unchanged. RESULTS: GH, but not placebo, increased IGF-I serum concentration (from 144 +/- 35 to 293 +/- 58 ng/ml; P < 0.005) and improved New York Heart Association functional class (from 2.4 +/- 0.5 to 1.8 +/- 0.4; P < 0.005), exercise duration (from 831 +/- 273 to 925 +/- 266 sec; P < 0.005), peak power output (from 245 +/- 127 to 280 +/- 132 W; P < 0.05), peak minute ventilation (from 52.5 +/- 16.1 to 61.3 +/- 17.3 liters/min; P < 0.05), peak oxygen consumption (from 19.8 +/- 5.6 to 25.1 +/- 5.6 ml/kg.min; P < 0.005), and anaerobic threshold (from 14.9 +/- 4.8 to 20.0 +/- 4.5 ml/kg.min; P < 0.005) without affecting lung function parameters. Furthermore, the slope of the relationship between minute ventilation and pulmonary carbon dioxide production (ventilatory efficiency) decreased from 34.7 +/- 5.1 to 31.7 +/- 5.3 (P < 0.005), whereas the slope of the relation between percent predicted heart rate reserve used and percent observed metabolic reserve used (chronotropic index) rose from 0.57 +/- 0.20 to 0.69 +/- 0.18 (P < 0.005). CONCLUSION: Given the predictive value of physical exercise capacity and cardiopulmonary performance in CHF progression, these data provide additional insights into the mechanisms by which GH may potentially benefit CHF patients

Cardiovascular abnormalities and impaired exercise performance in adolescents with congenital adrenal hyperplasia

Context: Patients with classic Congenital Adrenal Hyperplasia (CAH) are treated with lifelong glucocorticoids (GCS). Cardiovascular (CV) and metabolic effects of such therapy in adolescents have never been quantified. Objective: To investigate left ventricular (LV) morphology, function and exercise performance in adolescents with CAH. Design and Setting: cross-sectional and controlled study conducted at a tertiary referral centre. Patients: Twenty patients with classic CAH (10 females) aged 13.6±2.5 years and 20 healthy controls comparable for sex and pubertal status were enrolled in the study and compared to a group of 18 patients without CAH receiving a similar dose of GCS for Juvenile Idiopathic Arthritis (JIA). Main Outcomes Measures: Echocardiographic assessment and symptom-limited exercise testing were performed. Anthropometric, hormonal and biochemical parameters were also measured. Results: Compared to healthy controls, patients with CAH exhibited an increased BMI (p<0.001), waist-to-height ratio (p<0.001), percentage of body fat (p<0.001) as well as higher insulin concentrations and HOMA index even after adjustment for BMI (p=0.03 and p=0.05, respectively). Moreover, CAH patients exhibited an impaired exercise capacity as shown by reduced peak workload (99±27 vs 126±27 W, p<0.01) and higher systolic blood pressure response at peak (156±18 vs 132±11 mmHg, p<0.01; Δ=45±24 vs 22±10 mmHg, p=0.05) with respect to healthy controls. CAH males displayed mild LV diastolic dysfunction as documented by significant prolongation of both isovolumic relaxation time (IRT) (118±18 vs 98±11ms, p<0.05) and mitral deceleration time (MDT) (138±25 vs 111±15 ms, p<0.01). No significant differences in CV function were found between CAH and JIA patients. Conclusion: Adolescents with CAH exhibit impaired exercise performance and enhanced systolic blood pressure response during exercise. In our population, such abnormalities appear related to GCS therapy rather than CAH per se. CAH males, but no females, present mild LV diastolic dysfunction that correlates with testosterone concentrations suggesting a sex hormone related difference

Epoetin alfa increases frataxin production in Friedreich's ataxia without affecting hematocrit.

Objective of the study was to test the efficacy, safety, and tolerability of two single doses of Epoetin alfa in patients with Friedreich's ataxia. Ten patients were treated subcutaneously with 600 IU/kg for the first dose, and 3 months later with 1200 IU/kg. Epoetin alfa had no acute effect on frataxin, whereas a delayed and sustained increase in frataxin was evident at 3 months after the first dose (+35%; P < 0.05), and up to 6 months after the second dose (+54%; P < 0.001). The treatment was well tolerated and did not affect hematocrit, cardiac function, and neurological scale. Single high dose of Epoetin alfa can produce a considerably larger and sustained effect when compared with low doses and repeated administration schemes previously adopted. In addition, no hemoglobin increase was observed, and none of our patients required phlebotomy, indicating lack of erythropoietic effect of single high dose of erythropoietin. © 2010 Movement Disorder Society

Exercise training modalities in chronic heart failure: does high intensity aerobic interval training make the difference?

Exercise training (ET) is strongly recommended in patients with chronic heart failure (CHF). Moderate-intensity aerobic continuous ET is the best established training modality in CHF patients. In the last decade, however, high-intensity interval exercise training (HIIT) has aroused considerable interest in cardiac rehabilitation community. Basically, HIIT consists of repeated bouts of high-intensity exercise alternated with recovery periods. In CHF patients, HIIT exerts larger improvements in exercise capacity compared to moderate-continuous ET. These results are intriguing, mostly considering that better functional capacity translates into an improvement of symptoms and quality of life. Notably, HIIT did not reveal major safety issues; although CHF patients should be clinically stable, have had recent exposure to at least regular moderate-intensity exercise, and appropriate supervision and monitoring during and after the exercise session are mandatory. The impact of HIIT on cardiac dimensions and function and on endothelial function remains uncertain. HIIT should not replace other training modalities in heart failure but should rather complement them. Combining and tailoring different ET modalities according to each patient's baseline clinical characteristics (i.e. exercise capacity, personal needs, preferences and goals) seem the most astute approach to exercise prescription

Growth hormone prolongs survival in experimental postinfarction heart failure

AbstractObjectivesWe evaluated the effects of growth hormone (GH) on survival in experimental heart failure (HF).BackgroundGrowth hormone has been beneficial in various models of experimental HF. Whether GH also affects HF progression and survival is not known.MethodsA total of 119 rats with moderate myocardial infarction were randomized to receive either GH (3.5 mg/kg every other day) or placebo for 28 days. Treatment was initiated one month after coronary ligation; the follow-up lasted 13 months. In the surviving animals, Doppler echocardiography and closed-chest Millar left ventricular (LV) catheterization were performed. Apoptosis, collagen volume fraction, and capillary density in the LV zone remote from infarction were measured. The early effects of GH on apoptosis were also assessed in a subgroup of eight infarcted rats, treated as specified earlier and euthanized at one month.ResultsSurvival rate was 68% in GH-treated rats and 48% in the placebo group (p = 0.0377). Growth hormone had no effect on myocardial architecture, systolic function, and sarcoplasmatic reticulum calcium ATPase-2 messenger ribonucleic acid. Growth hormone improved LV relaxation; this was associated with a 50% reduction in collagen volume fraction and a 27% increase in capillary density. Growth hormone reduced the apoptotic index by 50% at one month and by 33% at 13 months.ConclusionsGrowth hormone prolonged survival of rats with postinfarction HF. This effect was associated with marked attenuation of cardiomyocyte apoptosis and pathologic interstitial remodeling in the surviving myocardium and enhanced LV relaxation

How cardiologists can manage excess body weight and related cardiovascular risk. An expert opinion

Obesity is an important independent cardiovascular (CV) risk factor and a chronic inflammatory disease related to the development of insulin resistance, type 2 diabetes, dyslipidaemia, coronary artery disease, hypertension, heart failure, atrial fibrillation and obstructive sleep apnoea. Body Mass Index (BMI) values >27 Kg/m2 are associated with an exponential increase in the risk for Major Adverse Cardiac Events (MACE). On the other hand, weight reduction can significantly reduce metabolic, CV and oncological risk. Orlistat, bupropion/naltrexone, liraglutide and semaglutide, combined with lifestyle changes, have proven to be effective in weight loss; the last two have been tested in randomized clinical trials (RCTs) with CV outcomes only in diabetic patients, and not in obese patients. To fill a fundamental gap of knowledge, the SELECT trial on patients with obesity and CV disease treated with semaglutide is ongoing, aiming at MACE as the primary endpoint. The battle against the social and clinical stigma towards obesity must be counteracted by promoting an awareness that elevates obesity to a complex chronic disease. Several actions should be implemented to improve the management of obesity, and cardiologists have a key role for achieving a global approach to patients with excess weight also through the correct implementation of available treatment strategies

Antithrombotic therapy in patients undergoing transcatheter aortic valve replacement: the complexity of the elderly

Along with epidemiologic transitions of the global population, the burden of aortic stenosis (AS) is rapidly increasing and transcatheter aortic valve replacement (TAVR) has quickly spread; indeed, it is nowadays also employed in treating patients with AS at intermediate operative risk. Nonetheless, the less invasive interventional strategy still carries relevant issues concerning post-procedural optimal antithrombotic strategy, given the current indications provided by guidelines are not completely supported by evidence-based data. Geriatric patients suffer from high bleeding and thromboembolic risks, whose balance is particularly subtle due to the presence of concomitant conditions, such as atrial fibrillation and chronic kidney disease, that make the post-TAVR antithrombotic management particularly insidious. This scenario is further complicated by the lack of specific evidence regarding the 'real-life' complex conditions typical of the geriatric syndromes, thus, the management of such a heterogeneous population, ranging from healthy ageing to frailty, is far from being defined. The aim of the present review is to summarize the critical points and the most updated evidence regarding the post-TAVR antithrombotic approach in the geriatric population, with a specific focus on the most frequent clinical settings