Growth Hormone Deficiency Is Associated with Worse Cardiac Function, Physical Performance, and Outcome in Chronic Heart Failure: Insights from the T.O.S.CA. GHD Study.

BACKGROUND: Although mounting evidence supports the concept that growth hormone (GH) deficiency (GHD) affects cardiovascular function, no study has systematically investigated its prevalence and role in a large cohort of chronic heart failure (CHF) patients. Aim of this study is to assess the prevalence of GHD in mild-to-moderate CHF and to explore clinical and functional correlates of GHD. METHODS: One-hundred thirty CHF patients underwent GH provocative test with GHRH+arginine and accordingly categorized into GH-deficiency (GHD, n = 88, age = 61.6±1.1 years, 68% men) and GH-sufficiency (GHS, n = 42, age = 63.6±1.5 years, 81% men) cohorts. Both groups received comprehensive cardiovascular examination and underwent Doppler echocardiography, cardiopulmonary exercise testing, and biochemical and hormonal assay. RESULTS: GHD was detected in roughly 30% of CHF patients. Compared to GHD, GHS patients showed smaller end-diastolic and end-systolic LV volumes (-28%, p = .008 and -24%, p = .015, respectively), lower LV end-systolic wall stress (-21%, p = .03), higher RV performance (+18% in RV area change, p = .03), lower estimated systolic pulmonary artery pressure (-11%, p = .04), higher peak VO2 (+20%, p = .001) and increased ventilatory efficiency (-12% in VE/VCO2 slope, p = .002). After adjusting for clinical covariates (age, gender, and tertiles of LV ejection fraction, IGF-1, peak VO2, VE/VCO2 slope, and NT-proBNP), logistic multivariate analysis showed that peak VO2 (ß = -1.92, SE = 1.67, p = .03), VE/VCO2 slope (ß = 2.23, SE = 1.20, p = .02) and NT-proBNP (ß = 2.48, SE = 1.02, p = .016), were significantly associated with GHD status. Finally, compared to GHS, GHD cohort showed higher all-cause mortality at median follow-up of 3.5 years (40% vs. 25%, p < .001, respectively), independent of age, sex, NT-proBNP, peak VO2 and LVEF. CONCLUSIONS: GH deficiency identifies a subgroup of CHF patients characterized by impaired functional capacity, LV remodeling and elevated NT-proBNP levels. GHD is also associated with increased all-cause mortality.

Mesoglycan improves vascular reactivity and insulin sensitivity in patients with metabolic syndrome.

OBJECTIVES: The aim of this study was to evaluate the acute and chronic effects of mesoglycan on the endothelial function and arterial elastic properties in patients with metabolic syndrome (MetS). BACKGROUND: MetS is defined by a clustering of vascular risk factors that demand both pharmacologic and non-pharmacologic interventions, including body weight reductions and physical activity. The correction of endothelial dysfunction and arterial wall distensibility associated with MetS have lately received increasing interest. METHODS: Thirty consecutive ambulatory patients affected by MetS were 2:1 randomized in a double-blind fashion to receive mesoglycan or placebo, respectively. In the first phase of the study, we evaluated the acute effects of a single i.m. administration of mesoglycan (60 mg) or placebo on vascular reactivity, as assessed by brachial flow-mediated dilation (FMD). Then, patients were chronically treated with mesoglycan per os (50 mg twice a day) or placebo for 90 days. At the end of this period, vascular reactivity and the arterial wall elastic properties were evaluated. RESULTS: In the mesoglycan group, FMD increased above baseline after acute administration, with a maximum increment of 52% after 2 h. FMD was also significantly greater than baseline after 90 days of chronic treatment. In the placebo group, FMD was unaffected by both acute and chronic mesoglycan administration. Moreover, after 90 days of mesoglycan treatment, a marked improvement in arterial distensibility and compliance was detected and arterial stiffness reduced significantly. CONCLUSIONS: This small, preliminary study shows that mesoglycan exerts relevant effects on vascular physiology, both in an acute setting as well as after prolonged, three-month treatment, in patients affected by metabolic syndrome.

ALERT-HF: adherence to guidelines in the treatment of patients with chronic heart failure.

BACKGROUND: The prognosis of chronic heart failure (CHF) may be substantially improved by strict adherence to current therapeutic guidelines. AIM AND METHODS: To assess the adherence to current guidelines, 660 CHF patients consecutively referred to the ARCA (Associazioni Regionali Cardiologi Ambulatoriali Campania) cardiologists were evaluated. As indicators of adherence to the guidelines, we considered use of angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers, beta-blockers, loop diuretics, aldosterone antagonists, digoxin, anticoagulant therapy, and implantation of cardiac devices. RESULTS: The adherence to guidelines has been characterized in patients with reduced ejection fraction, who represent the majority in the ALERT-HF (Adherence to Guidelines in the Treatment of patients with Chronic Heart Failure) trial and in whom the current guidelines are well defined and shared. Among 528 patients affected by CHF with ejection fraction 45% or less, 399 (75.6%) were treated with a beta-blocker, 282 (53.4%) received an angiotensin-converting enzyme inhibitor and 199 (37.7%) an angiotensin receptor blocker. Four hundred and sixty-nine patients (88.9%) used loop diuretics, but only 163 patients (30.9%) an aldosterone antagonist. Among 148 patients with atrial fibrillation, 95 (64.2%) were treated with anticoagulants. As few as 31 patients received cardiac electrical stimulation devices: 10 patients were implanted with a cardioverter-defibrillator and 21 received a device for cardiac resynchronization therapy. CONCLUSION: The study reveals poor adherence to current therapeutic guidelines for CHF, particularly with regard to aldosterone antagonists and anticoagulant therapy in the presence of atrial fibrillation. Even poorer is the adherence to guidelines as regards the use of implantable cardiac devices. The underlying reasons are discussed in relation to the data of other registries.

Migraine attack restores the response of vascular smooth muscle cells to nitric oxide but not to norepinephrine.

AIM: To clarify whether the vasoconstrictory response is impaired and to study vascular function in patients with migraine during the headache attack. METHODS: We studied vascular reactivity in the resistance arteries by using the forearm perfusion technique associated with plethysmography. We measured forearm blood flow by strain-gauge plethysmography during intra-brachial infusion of acetylcholine, sodium nitroprusside or norepinephrine in 11 controls and 13 patients with migraine, 11 of them (M) in the interval between the migraine attacks and 4 during a headache attack (MH). Written informed consent was obtained from patients and healthy controls, and the study was approved by the Ethics Committee of the University Federico II. RESULTS: Compared to healthy control subjects, in patients with migraine studied during the interictal period, the vasodilating effect of acetylcholine, that acts through the stimulation of endothelial cells and the release of nitric oxide, was markedly reduced, but became normal during the headache attack (P < 0.05 by analysis of variance). The response to nitroprusside, which directly relaxes vascular smooth muscle cells (VSMCs), was depressed in patients with migraine studied during the interictal period, but normal during the headache attack (P < 0.005). During norepinephrine infusion, forearm blood flow decreased in control subjects (-40% ± 5%, P < 0.001). In contrast, in patients with migraine, either when studied during or free of the headache attack forearm blood flow did not change compared to the baseline value (-3% ± 13% and -10.4% ± 15%, P > 0.05). CONCLUSION: In migrainers, the impaired relaxation of VSMCs is restored during the headache attack. The vasoconstrictory response is impaired and remains unchanged during the migraine attack.

A giant pseudoaneurysm of the forearm as unusual complication of bacterial endocarditis.

A 59-year-old man with fever was diagnosed with endocarditis due to Streptococcus bovis. Two weeks after antibiotic therapy was started, he presented with red and painful swelling of the forearm without any sign of systemic inflammation. A giant hematoma connected to the radial artery was detected with ultrasound. Surgical intervention with the removal of multiple, sterile clots from the hematoma was performed, and the multiple lacerations of the artery detected were corrected. This is the first case reporting rupture of the radial artery as a complication of infective endocarditis.

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.

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.

Metformin prevents the development of chronic heart failure in the SHHF rat model.

Insulin resistance is a recently identified mechanism involved in the pathophysiology of chronic heart failure (CHF). We investigated the effects of two insulin-sensitizing drugs (metformin and rosiglitazone) in a genetic model of spontaneously hypertensive, insulin-resistant rats (SHHF). Thirty SHHF rats were randomized into three treatment groups as follows: 1) metformin (100 mg/kg per day), 2) rosiglitazone (2 mg/kg per day), and 3) no drug. Ten Sprague-Dawley rats served as normal controls. At the end of the treatment period (12 months), the cardiac phenotype was characterized by histology, echocardiography, and isolated perfused heart studies. Metformin attenuated left ventricular (LV) remodeling, as shown by reduced LV volumes, wall stress, perivascular fibrosis, and cardiac lipid accumulation. Metformin improved both systolic and diastolic indices as well as myocardial mechanical efficiency, as shown by improved ability to convert metabolic energy into mechanical work. Metformin induced a marked activation of AMP-activated protein kinase, endothelial nitric oxide synthase, and vascular endothelial growth factor and reduced tumor necrosis factor-α expression and myocyte apoptosis. Rosiglitazone did not affect LV remodeling, increased perivascular fibrosis, and promoted further cardiac lipid accumulation. In conclusion, long-term treatment with metformin, but not with rosiglitazone, prevents the development of severe CHF in the SHHF model by a wide-spectrum interaction that involves molecular, structural, functional, and metabolic-energetic mechanisms.

Complementary therapeutic effects of dual delivery of insulin-like growth factor-1 and vascular endothelial growth factor by gelatin microspheres in experimental heart failure.

AIMS: Strategies to prevent adverse left ventricular (LV) remodelling after myocardial infarction have included several traditional approaches and novel cell-based or gene therapies. Delivery of growth factors in post-infarction heart failure has emerged as a valuable alternative strategy. Our aim was to investigate the effects of sequential release of vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1) from biodegradable gelatin microspheres in experimental heart failure. METHODS AND RESULTS: Gelatin hydrogel microspheres were known to guarantee a sustained release of encapsulated growth factors, characterized by an initial burst followed by a slower release. Rats with moderate myocardial infarction were randomized to receive empty microspheres (MI), microspheres loaded with IGF-1 or VEGF, or a combination thereof (DUAL). Myocardial injections of microspheres were performed at the time of surgery, and treatment lasted 4 weeks. Echocardiography, LV catheterization, morphometric histology and immunohistochemistry, and molecular assessment of downstream mediators [e.g. Akt, endothelial nitric oxide synthase (eNOS), and sarco/endoplasmic reticulum calcium ATPase-2 (SERCA-2)] were assessed at the end of the treatment period. Infarct sizes were 33 ± 2, 28 ± 4, 24 ± 3, and 16 ± 3% in the MI, IGF-1, VEGF, and DUAL groups, respectively. IGF-1 attenuated LV remodelling, improved LV systolic and diastolic function, increased myocyte size, and reduced apoptotic deaths, capillary loss, and indexes of inflammation. VEGF-treated animals displayed a marked myocardial neoangiogenesis that led to the formation of mature vessels if combined with IGF-1 delivery. Downstream effects of IGF-1 were principally mediated by the Akt-mTOR (mammalian target of rapamycin)-dependent pathway, and both growth factors, particularly VEGF, induced a robust and sustained increase of eNOS. CONCLUSION: IGF-1 and VEGF exerted complementary therapeutic effects in post-infarction heart failure. Biodegradable gelatin microspheres provide sustained and controlled growth factor release locally, exposing myocardial tissue without the side effects of systemic administration.

The T.O.S.CA. Project: research, education and care.

Despite recent and exponential improvements in diagnostic-therapeutic pathways, an existing "GAP" has been revealed between the "real world care" and the "optimal care" of patients with chronic heart failure (CHF). We present the T.O.S.CA. Project (Trattamento Ormonale dello Scompenso CArdiaco), an Italian multicenter initiative involving different health care professionals and services aiming to explore the CHF "metabolic pathophysiological model" and to improve the quality of care of HF patients through research and continuing medical education.

Impaired diastolic function in naïve untreated human immunodeficiency virus infected patients.

AIM: To evaluate cardiac function and structure in untreated human immunodeficiency virus (HIV) patients without clinical evidence of cardiovascular disease. METHODS: Fifty-three naïve untreated HIV-infected patients and 56 healthy control subjects underwent clinical assessment, electrocardiography (ECG) and echocardiography, including tissue doppler imaging. Moreover, a set of laboratory parameters was obtained from all subjects, including HIV-RNA plasma levels, CD4 cell counts and tumor necrosis factor-α levels. RESULTS: The two groups showed normal ECG traces and no differences regarding systolic morphologic parameters. In contrast, a higher prevalence of left ventricular diastolic dysfunction (abnormal relaxation or pseudonormal filling pattern) was found in the HIV patients (36% vs 9% in patients and controls, respectively, P <0.001). CONCLUSION: Subclinical cardiac abnormalities appear in an early stage of the HIV infection, independent of antiretroviral therapy. The data suggest that HIV per se plays a role in the genesis of diastolic dysfunction.

The uncontrolled clinical trial: scientific, ethical, and practical reasons for being.

According to principles of clinical trial design, the demonstration of efficacy of a new treatment is based on comparing the response in the treated group with that of a control group receiving placebo or another active treatment. The need for a control group is also recommended by the major international institutions that govern the ethics and the practice of clinical research. Despite these principles and recommendations, inspection of a purposive sample of ongoing clinical trials listed in the NIH registry ( http://ClinicalTrials.gov ) reveals that as many as one-third of trials are uncontrolled. Since these trials were approved through a formal evaluation by ethics committees, the lack of adequate control was not perceived as a major deficiency in the study design. Most uncontrolled trials belong to the oncology/hematology area. If two extreme disease conditions for nature and progression are analyzed, such as acute myeloid leukemia (AML) and chronic heart failure (CHF), the difference in the prevalence of uncontrolled trials is very striking. The number of uncontrolled trials is only 13% in CHF, whereas it reaches 66% in the AML group. I believe that the underlying disease condition plays a primary role in orienting the design of the study: oncology and hematology may be fields in which uncontrolled studies are common, whereas in other fields, e.g., cardiology, this phenomenon can be reduced. Within the limitations of the selection process of the examined trials, the current analysis indicates that the clinical trial reality does not strictly follow experimental design theory and official recommendations.

[Anabolic/catabolic imbalance in chronic heart failure]. / Squilibrio anabolico/catabolico nello scompenso cardiaco cronico.

A metabolic imbalance between anabolic drive and catabolic forces is commonly observed in chronic heart failure (CHF) patients, with the latter prevailing over anabolic hormones. Moreover, anabolic deficiencies are independent markers of poor prognosis. This finding represents a solid background for the implementation of therapeutic trials based on replacement therapy. The somatotropic axis (GH/IGF-1) is the most powerful anabolic axis of the body and its decline is related with a poor outcome and a worse clinical status. Growth hormone (GH) administration may enter the therapeutic arena as adjunctive treatment in patients affected by CHF and GH/IGF-1 deficiency. The T.O.S.CA. project aims at investigating the relationship between CHF and hormonal deficiency.

Impaired endothelial- and nonendothelial-mediated vasodilation in patients with acute or chronic hypothyroidism.

OBJECTIVE: Vascular dysfunction and accelerated atherosclerosis are prominent features of hypothyroidism. The relative roles of thyroid hormone (TH) deficiency and the associated vascular risk conditions are still unclear. We studied the impact of acute and chronic hypothyroidism on vascular reactivity. PATIENTS: We studied 12 patients with chronic primary hypothyroidism (cHY; TSH: 52 +/- 14 mU/l), seven patients with acute hypothyroidism secondary to total thyroidectomy (aHY; TSH: 97 +/- 24) and 13 healthy subjects (TSH: 1.2 +/- 0.5). MEASUREMENTS: We measured forearm blood flow (FBF) using plethysmography during intra-brachial infusion of: acetylcholine (ACh), sodium nitroprusside (NP) and norepinephrine (NE). We also measured serum C-reactive protein (CRP), TNF-alpha, asymmetric dimethylarginine (ADMA) and the forearm balance of nitric oxide (NO) during ACh infusion. RESULTS: As compared with the controls, the vasodilatory response to ACh was reduced in cHY (P = 0.001) and aHY (P = 0.04), as was the forearm release of NO (P < 0.05). During NP infusion, FBF rose to 24 +/- 2 ml/dl/min in the controls and to significantly lower values in cHY (12 +/- 1; P = 0.001) and aHY (15 +/- 2; P = 0.004). NE-induced vasoconstriction was similar in the controls and aHY, but blunted in cHY. Serum CRP, TNF-alpha and ADMA were not different in the three groups. CONCLUSIONS: (i) Hypothyroidism associates with endothelial and nonendothelial mediated vascular dysfunction; (ii) these defects are evident even after short-term hypothyroidism, indicating that TH deficiency per se is sufficient to alter vascular homeostasis; and (iii) chronic, but not acute, hypothyroidism impairs the vasoconstrictory effect of NE in the resistance vessels.