Michele Arcopinto

Growth Hormone Deficiency in Patients with Chronic Heart Failure and Beneficial Effects of Its Correction

CONTEXT A reduced activity of the GH/IGF-I axis in chronic heart failure (CHF) has been described by several independent groups and is associated with poor clinical status and outcome. OBJECTIVE The aim of the current study was to investigate the prevalence of GH deficiency in a patient population with CHF and evaluate the cardiovascular effects of GH replacement therapy. DESIGN AND SETTING The randomized, single-blind, controlled trial was conducted at the Federico II University. PARTICIPANTS One hundred fifty-eight patients with CHF, New York Heart Association class II-IV, underwent a GH stimulation test. Sixty-three patients satisfied the criteria for GH deficiency, and 56 of them were enrolled in the trial. INTERVENTION The treated group (n = 28) received GH at a replacement dose of 0.012 mg/kg every second day (approximately 2.5 IU). MAIN OUTCOMES MEASURES Changes in physical performance and various cardiovascular indexes were measured. RESULTS GH replacement therapy improved quality of life score (from 46 +/- 5 to 38 +/- 4; P < 0.01), increased peak oxygen uptake and exercise duration (from 12.9 +/- .9 to 14.5 +/- 1 ml/kg x min and from 520 +/- 36 to 586 +/- 43 sec, respectively; P < 0.01), and flow-mediated vasodilation (from 8.8 +/- 1.3 to 12.7 +/- 1.2%; P < 0.01). GH increased left ventricular ejection fraction (from 34 +/- 2 to 36 +/- 2%; P < 0.01) and reduced circulating N-terminal pro-brain natriuretic peptide levels (from 3201 +/- 900 to 2177 +/- 720 pg/ml; P = 0.006). No significant changes from baseline were observed in controls. CONCLUSIONS As many as 40% of patients with CHF are GH deficient. GH replacement therapy in these patients improves exercise capacity, vascular reactivity, left ventricular function, and indices of quality of life.

Cardiovascular abnormalities in Klinefelter Syndrome

BACKGROUND Several epidemiological studies have demonstrated an increased mortality from cardiovascular causes in patients with Klinefelter Syndrome (KS). Little information is available about the nature of the underlying cardiovascular abnormalities. Aim of the study was to investigate exercise performance, left ventricular architecture and function, vascular reactivity, and carotid intima-media thickness in a group of patients with KS. MATERIALS AND METHODS Sixty-nine patients with KS and 48 age-matched controls participated in our population-controlled study. Forty-eight Klinefelter subjects were on testosterone treatment at the time of the investigation while 21 were naive and underwent a complete Doppler echocardiographic examination, a cardiopulmonary exercise test as well as a vascular study including measures of carotid intima-media thickness and endothelial function with flow-mediated dilation of the brachial artery. Patients with KS on testosterone therapy (n=48) were also matched against a population of men with treated secondary hypogonadism (n=21). RESULTS Patients with KS exhibited a wide array of cardiovascular abnormalities including left ventricular diastolic dysfunction, reduced maximal oxygen consumption (p<0.01), increased intima-media thickness (p<0.05) (-34% and +42% vs. controls, respectively) and a high prevalence of chronotropic incompetence (55% of patients, p<0.01). No significant difference was found between treated and untreated KS in variance with men treated for secondary hypogonadism. CONCLUSION Left ventricular diastolic dysfunction, impaired cardiopulmonary performance, chronotropic incompetence, and increased intima-media thickness suggest that cardiovascular abnormalities are a common finding in KS that is not reversed by testosterone replacement therapy and may represent the pathophysiological underpinnings of the increased risk of dying from heart disease.

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.

Growth Hormone Replacement Delays the Progression of Chronic Heart Failure Combined With Growth Hormone Deficiency An Extension of a Randomized Controlled Single-Blind Study

OBJECTIVES This study sought to evaluate the efficacy and safety of long-term growth hormone (GH) replacement therapy in GH-deficient patients with chronic heart failure (CHF). BACKGROUND Recent evidence indicates that growth hormone deficiency (GHD) affects as many as 40% of patients with CHF, and short-term GH replacement causes functional benefit. Whether long-term GH replacement also affects CHF progression is unknown. METHODS The study is an extension of a previous randomized, controlled single-blind trial that screened 158 consecutive CHF patients (New York Heart Association classes II to IV) and identified 63 who had GHD by the growth hormone releasing hormone plus arginine test. Fifty-six patients were randomized to receive either GH therapy or standard CHF therapy. Patients were evaluated at baseline and after a 4-year follow-up. The primary endpoint was peak oxygen consumption (VO2). Secondary endpoints included left ventricular (LV) ejection fraction and volumes, serum amino terminal fragment of the pro-hormone brain-type natriuretic peptide, quality of life, and safety. RESULTS Seventeen patients in the GH group and 14 in the control group completed the study. In the GH group, peak VO2 improved over the 4-year follow-up. The treatment effect was 7.1 ± 0.7 ml/kg/min versus -1.8 ± 0.5 ml/kg/min in the GH and control groups, respectively. At 4 years, LV ejection fraction increased by 10 ± 3% in the GH group, whereas it decreased by 2 ± 5% in control patients. The treatment effect on LV end-systolic volume index was -22 ± 6 ml and 8 ± 3 ml/m(2) in the GH and control groups, respectively (all p < 0.001). No major adverse events were reported in the patients who received GH. CONCLUSIONS Although this is a preliminary study, the finding suggests a new therapeutic approach to a large proportion of GHD patients with CHF.

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 and metabolic effects of such therapy in adolescents have never been quantified. OBJECTIVE Our objective was to investigate left ventricular (LV) morphology, function, and exercise performance in adolescents with CAH. DESIGN AND SETTING We conducted a cross-sectional and controlled study conducted at a tertiary referral center. 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 with a group of 18 patients without CAH receiving a similar dose of GCs for juvenile idiopathic arthritis. MAIN OUTCOMES MEASURES Echocardiographic assessment and symptom-limited exercise testing were performed. Anthropometric, hormonal and biochemical parameters were also measured. RESULTS Compared with healthy controls, patients with CAH exhibited an increased body mass index (P < .001), waist-to-height ratio (P < .001), and percent body fat (P < .001) as well as higher insulin concentrations and homeostasis model assessment of insulin resistance index even after adjustment for body mass index (P = .03 and P = .05, respectively). Moreover, CAH patients exhibited an impaired exercise capacity as shown by reduced peak workload (99 ± 27 vs 126 ± 27 W, P < .01) and higher systolic blood pressure response at peak (156 ± 18 vs 132 ± 11 mm Hg, P < .01; Δ = 45 ± 24 vs 22 ± 10 mm Hg, P = .05) with respect to healthy controls. CAH males displayed mild LV diastolic dysfunction as documented by significant prolongation of both isovolumic relaxation time (118 ± 18 vs 98 ± 11 milliseconds, P < .05) and mitral deceleration time (138 ± 25 vs 111 ± 15 milliseconds, P < .01). No significant differences in cardiovascular function were found between CAH and juvenile idiopathic arthritis 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 GC therapy rather than CAH per se. CAH males, but not females, present mild LV diastolic dysfunction that correlates with testosterone concentrations suggesting a sex hormone-related difference.

The GH/IGF-1 Axis in Chronic Heart Failure

The classic model of Chronic Heart Failure (CHF) is rooted in the overexpression of neurohormonal molecules. To complement this paradigm, increasing evidence indicates that a variety of hormones may be down-regulated in CHF patients. The list includes growth hormone (GH) and its tissue effector insulin-like growth factor-1 (IGF-1). The GH/IGF-1 axis regulates cardiac growth, stimulates myocardial contractility, and influences the vascular system. The relationship between the GH/IGF-1 axis and the cardiovascular system has been extensively demonstrated in numerous studies in animals models and confirmed by the cardiac derangements secondary to both GH excess and deficiency in humans. Impaired activity of the GH/IGF-1 axis in CHF has been described by several independent groups and includes a wide array of abnormalities, including low IGF-1 levels, GH deficiency (GHD), and GH resistance that may be related to the severity of heart disease. According to several observations, these derangements are associated with poor clinical status and outcome. Since the first study of GH therapy in CHF in 1996, several placebo-controlled trials have been conducted with conflicting results. These discordant findings are likely explained by the degree of CHF-associated GH/IGF-1 impairment that may impact on individual responsiveness to GH administration. Biological actions of GH and IGF-1, cardiovascular implication of GH deficiency and GH excess, relation between somatotrophic axis and CHF are discussed. Results from trials of GH therapy, emerging therapeutic strategies, safety issues, and lack in evidence are also reported.

Hormone replacement therapy in heart failure.

Purpose of review Despite major advances in medical treatments, survival rates of chronic heart failure (CHF) have not significantly changed in the past 50 years, making it imperative to search for novel pathophysiological mechanisms and therapeutic targets. In this article, we summarize the current knowledge regarding the possibility to treat such anabolic deficiencies with hormone replacement therapy (HRT). Recent findings Mounting evidence supports the concept that CHF is a disease characterized not only by excessive neurohormonal activation but also by a reduced anabolic drive that carries functional and prognostic significance. The recent demonstration of overall beneficial effects of HRT in CHF may pave the way to slow the disease progression in patients with coexisting CHF and hormone deficiencies. The hypothesis is to identify a considerable subset of CHF patients also affected with hormone deficiency and to treat them with HRT. Summary Single or multiple HRT may in theory be performed in CHF. Such a novel approach may improve left ventricular architecture, function, and physical capacity as well as quality of life. Larger randomized, controlled trials are needed to confirm this working hypothesis.

Primary prevention of cancer-related thrombosis: Special focus on ambulatory patients

Michele Arcopinto ⁎, Chiara A. Cella , Robert Wesolowski , Andrea Salzano , Eduardo Bossone , Antonio Cittadini , Ragavendra R. Baliga e a Department of Translational Medical Sciences, Federico II University, Naples, Italy b Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy c Division of Medical Oncology, College of Medicine, The Ohio State University, Columbus, OH, USA d Department of Cardiology and Cardiac Surgery, University Hospital “Scuola Medica Salernitana”, Salerno, Italy e Cardio-Oncology Program Division of Cardiovascular Medicine, The Ohio State University, Columbus, OH, USA

IGF-1 predicts survival in chronic heart failure. Insights from the T.O.S.CA. (Trattamento Ormonale Nello Scompenso CArdiaco) registry.

a Department of Cardiac Surgery, IRCCS Policlinico San Donato, Milan, Italy b Department of Internal Medicine, The Sahlgrenska Academy at the University of Gothenburg, Sweden c Department of Traslational Medical Sciences, Federico II University, Naples, Italy d Department of Cardiology and Cardiac Surgery, University Hospital “Scuola Medica Salernitana”, Salerno, Italy e Division of Cardiology, San Daniele del Friuli Hospital, Udine, Italy f Duke Clinical Research Institute, Durham, NC, USA

An unusual case of dilated cardiomyopathy associated with partial hypopituitarism

Dilated cardiomyopathy (DCM) secondary to endocrinologic disease occurs rarely. In a large clinicopathological review of 673 patients, only 1.5% fall in the metabolic category, mostly due to thyroid disorders [1]. Sporadic reports of DCM associated with other endocrinopathies have been subsequently published including acromegaly, GH deficiency, pheochromocytoma, hypoparathyroidism, Sheehan syndrome, and Addison’s disease. We herein describe a rare case of DCM secondary to partial hypopituitarism, in turn related to a previous intracranial surgery, promptly responding to multiple hormonal replacement therapy. A 55-year-old woman was admitted to our Intensive Coronary Unit in February 2008 because of a communityacquired pneumonia complicated by acute heart failure. Her chief complaint was shortness of breath, which had become progressively worse during the prior 4–5 days. She had a productive yellow cough and blood-tinged sputum. Examination revealed a tachycardia (115 bpm), tachypnea 22 breaths/min, BP 90/50 mmHg, a raised venous pressure, fine bilateral basal crepitations, right-sided crackles, and dullness to percussion. She was treated conventionally in a territorial hospital for acute pulmonary edema with partial initial symptomatic recovery. The patient was also started on a ‘‘pneumonia protocol’’ with cefotaxime and azithromycin, and oxygen. Notwithstanding standard therapy for acute heart failure including nitrates, furosemide and digoxin, and the introduction of inotropic support, the patient was still hypotensive, and for this reason she was admitted to the intensive care unit of our tertiary care hospital. The past medical history revealed systemic hypertension, chronic kidney disease (GFR of 25 ml/min), subclinical hypothyroidism (TSH 6.3 lU/mL with normal FT3 and FT4), and surgical intervention for aneurysmectomy of the left middle cerebral artery, which had been performed in 2006. She never smoked or used alcohol EtOH or drugs. She lived with her family. A complete mono-two-dimensional and Doppler echocardiographic examination was performed. The ultrasound analysis displayed a very enlarged poorly contracting left ventricle (EF 13%) with moderate-to-severe mitral regurgitation (see Fig. 1; Table 1). Diastolic function was moderately impaired. Interestingly, a previous echocardiogram obtained in 2006 was reviewed, and only displayed mild LV hypertrophy with normal cavity diameters and a preserved systolic function (EF 55–60%). After resolving the decompensated HF and the right pneumonia, the patient was still in class IV of the NYHA, and could not undergo a cardiopulmonary stress test that we routinely perform in CHF patients. To rule out ischemic etiology, a coronary angiography was performed that revealed no significant coronary stenosis. An endomyocardial biopsy was suggested but not performed since the patient refused the procedure. A complete hormonal panel showed low levels of earlymorning serum cortisol and undetectable levels of serum IGF1 without evidence of secondary gonadal failure (Table 1). Thyroid failure was partial insofar as TSH increased up to 10.9 lU/mL, indicating residual pituitary secretion. We next performed a GHRH ? arginine stimulation test for diagnosis A.M. Marra and M. Arcopinto contributed equally to this work.