Alberto M. Marra

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.

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.

SOCS1 gene transfer accelerates the transition to heart failure through the inhibition of the gp130/JAK/STAT pathway

AIMS The suppressors of cytokine signalling (SOCS) are identified inhibitors of cytokine and growth factor signalling that act via the Janus kinase (JAK) signal transducers and activators of transcription (STAT) pathways. Aberrant JAK/STAT signalling promotes progression from hypertrophy to heart failure. Little information is available concerning the role of SOCS in the transition from hypertrophy to heart failure. To this aim, we investigated the effects of SOCS1 overexpression obtained by in vivo adeno-associated gene transfer using an aortopulmonary cross-clamping technique in a chronic pressure-overload cardiac rat model. METHODS AND RESULTS Rats were randomized into four groups: sham-operated (n = 18), aortic banding (AB) (n = 18), AB + viral vector encoding for haemoagglutinin (AB + HA, n = 16), and AB + viral vector encoding for SOCS1 (AB + SOCS1, n = 18). Echocardiographic and haemodynamic measurements were performed 15 weeks after banding. While SOCS3 was upregulated during the hypertrophic phase, SOCS1 transcript levels increased significantly between 15 and 20 weeks. Remodelling was markedly worse in AB + SOCS1, showed larger left ventricular internal dimensions (+16%), higher end-diastolic pressures (+57%) and wall stress (+45%), and reduced fractional shortening (-32%) compared with AB + HA; apoptotic rate was increased three-fold and the gp130 pathway was inhibited. Ex vivo experiments showed that mechanical stretch upregulated SOCS1 expression, which was in turn attenuated by tumour necrosis factor-α (TNF-α) inhibition. CONCLUSION Enhanced SOCS1 myocardial signalling is associated with accelerated transition from hypertrophy to failure in an established model of pressure overload. SOCS1 may represent an attractive target for the prevention of heart failure progression.

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.

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.

Gender differences in cardiovascular prophylaxis: Focus on antiplatelet treatment

Graphical abstract Figure. No Caption available. ABSTRACT Cardiovascular disease (CVD) represents the leading cause of death worldwide, and equally affects both sexes although women develop disease at an older age than men. A number of clinical evidence has identified the female sex as an independent factor for poor prognosis, with the rate of mortality and disability following an acute cardiovascular (CV) event being higher in women than men. It has been argued that the different level of platelet reactivity between sexes may account for a different responsiveness to anti‐platelet therapy, with consequent important implications on clinical outcomes. However, conclusive evidence supporting the concept of a gender‐dependent effectiveness of platelet inhibitors are lacking. On the contrary, sex‐related dissimilarities have been evidenced in cardiovascular patients in terms of age of presentation, comorbidities such as obesity, diabetes and renal disease, and a different pharmacological approach to and effectiveness in controlling classical cardiovascular risk factors such as hypertension, glucose profile and lipid dysmetabolism. All these factors could place women at an increased level of cardiovascular risk compared to men, and may concur to an enhanced pro‐thrombogenic profile. The purpose of this manuscript is to provide an overview of gender‐related differences in cardiovascular treatment, in order to highlight the need to improve the pharmacological prophylaxis adopted in women through a more accurate evaluation of the overall cardiovascular risk profile with consequent establishment of a more effective and targeted anti‐thrombotic strategy which is not limited to the use of anti‐platelet agents.

Reference ranges for and determinants of right ventricular area in healthy adults by two-dimensional echocardiography.

Background: The right ventricular (RV) area is important for diagnosis and follow-up in patients with various diseases, such as in pulmonary hypertension. Objectives: The aim of this study was to define the reference ranges of the end-diastolic RV area in healthy adults and to assess the determining factors. Methods: In the first part of the study 860 healthy subjects (37.6% female; mean age 28 ± 5.84; 395 endurance athletes, 255 strength athletes and 210 non-athletes) were prospectively assessed. In the second part we performed a pooled analysis of studies published between 1979 and 2014 describing the RV area in healthy subjects (n = 5,248). Statistical analysis included the calculation of reference ranges and the analysis of determining factors. Results: Mean end-diastolic RV areas in 860 healthy subjects were significantly larger in endurance athletes (25.1 ± 2.0 cm2) compared with strength athletes (22.9 ± 1.7 cm2) and non-athletes (16.7 ± 2.0 cm2, p < 0.001). In the synopsis of both data sets, mean end-diastolic RV area was significantly larger in European/American males (17 cm2) compared with females (14 cm2, p < 0.001) and in Asian males (16 cm2) compared with females (13 cm2, p < 0.001). The area increased with body surface area and older age. Conclusion: This is the largest data set to define RV size in healthy adults aged <50 years. RV area was determined by age, gender, body surface area, ethnicity and high-level exercise training. High standard deviations resulted in high values for the upper limit of the reference range, which might therefore not be useful as cut-off values for screening purposes. Gender- and ethnicity-specific reference ranges should be used. Further studies in subjects aged >50 years as well as in children are needed.

Principles of Rehabilitation and Reactivation: Pulmonary Hypertension

Most recently, a specialized and carefully monitored exercise training and rehabilitation program has been recommended as add-on to medical treatment in patients with pulmonary arterial hypertension (class I, level of evidence A). Three prospective randomized, controlled trials, 10 prospective uncontrolled trials, 2 retrospective studies and 2 case series in more than 470 patients with severe pulmonary hypertension (PH) and right heart failure reported beneficial effects of a specialized exercise training and rehabilitation program, i.e. significant improvement in symptoms, exercise capacity, cardiorespiratory function and quality of life, compared with untrained controls. All training studies reported an acceptable safety profile, and some uncontrolled studies showed excellent 1- and 2-year survival rates. However, most studies had a quite small sample size (ranging from 2 to 183 patients) and an uncontrolled design, and they were not designed to assess hemodynamic changes, time to clinical worsening and survival. Nevertheless, there is large evidence that exercise training programs should be performed by centers experienced in both PH patient care and rehabilitation. The best method and duration of the training, characteristics of supervision, and the mechanisms resulting in symptom improvement and increased functional capacity are unclear. In this review, we summarize data of molecular and clinical effects of exercise training in PH patients. Furthermore, we discuss safety data and the role of a self-care management of exercise training in these patients.