Clerico A, Giannoni A, Vittorini S, Passino C. Thirty years of the heart as an endocrine organ: physiological role and clinical utility of cardiac natriuretic hormones. Am J Physiol Heart Circ Physiol 301: H12-H20, 2011. First published May 6, 2011; doi:10.1152/ajpheart.00226.2011 reported that atrial extracts contain some biologically active peptides, which promote a rapid and massive diuresis and natriuresis when injected in rats. It is now clear that the heart also exerts an endocrine function and in this way plays a key role in the regulation of cardiovascular and renal systems. The aim of this review is to discuss some recent insights and still-debated findings regarding the cardiac natriuretic hormones (CNHs) produced and secreted by cardiomyocytes (i.e., atrial natriuretic peptide and B-type natriuretic peptide). The functional status of the CNH system depends not only on the production/secretion of CNHs by cardiomyocytes but also on both the peripheral activation of circulating inactive precursor of natriuretic hormones and the transduction of the hormone signal by specific receptors. In this review, we will discuss the data supporting the hypothesis that the production and secretion of CNHs is the result of a complex integration among mechanical, chemical, hemodynamic, humoral, ischemic, and inflammatory inputs. The cross talk among endocrine function, adipose tissue, and sex steroid hormones will be discussed more in detail, considering the clinically relevant relationships linking together cardiovascular risk, sex, and body fat development and distribution. Finally, we will review the pathophysiological role and the clinical relevance of both peripheral maturation of the precursor of B-type natriuretic peptides and hormone signal transduction.B-type natriuretic peptide; sex steroids; adipokines; heart failure; cardiovascular risk THIRTY YEARS AGO, De Bold et al. (20) reported that atrial extracts contain some biological active peptides, which promote a rapid and massive diuresis and natriuresis when injected in rats. Several endogenous peptide hormones with natriuretic and vasodilator activity have been identified in the human blood and peripheral tissues (3,30,69,85,86). Atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and their related peptides are predominantly produced by atrial and ventricular cardiomyocytes. The term "cardiac natriuretic hormones" (CNHs) will be used in this review to indicate these two families of natriuretic peptides. Another natriuretic peptide, named C-type natriuretic peptide (CNP), is predominantly produced by the endothelial cells, including those of cardiac vessels. Finally, urodilatin is an NH 2 -terminal (NT) 4-amino acid (aa) extented form of ANP, which is produced by the same ANP gene and secreted into the urine by renal tubular cells (16,34,69).From the original observations made 30 years ago, the advances in this particular research field have determined a complete revision about the role of the heart. It is now clear that the heart also exerts a...

Both oxidative stress and inflammation are enhanced in chronic heart failure. Dysfunction of cardiac mitochondria is a hallmark of heart failure and a leading cause of oxidative stress, which in turn exerts detrimental effects on cellular components, including mitochondria themselves, thus generating a vicious circle. Oxidative stress also causes myocardial tissue damage and inflammation, contributing to heart failure progression. Furthermore, a subclinical inflammatory state may be caused by heart failure comorbidities such as obesity, diabetes mellitus or sleep apnoeas. Some markers of both oxidative stress and inflammation are enhanced in chronic heart failure and hold prognostic significance. For all these reasons, antioxidants or anti-inflammatory drugs may represent interesting additional therapies for subjects either at high risk or with established heart failure. Nonetheless, only a few clinical trials on antioxidants have been carried out so far, with several disappointing results except for vitamin C, elamipretide and coenzyme Q10. With regard to anti-inflammatory drugs, only preliminary data on the interleukin-1 antagonist anakinra are currently available. Therefore, a comprehensive, deep understanding of our current knowledge on oxidative stress and inflammation in chronic heart failure is key to providing some suggestions for future research on this topic.

Background: Cardiac amyloidosis (CA) is a serious though increasingly treatable cause of heart failure. Diagnosis is challenging and frequently unclear at echocardiography, which remains the most often used imaging tool. Objectives:We aimed to study the accuracy of a broad range of echocardiographic variables to develop multiparametric scores to diagnose CA in patients with proven light chain (AL) amyloidosis or those with increased heart wall thickness (IWT) in whom amyloid was suspected. We also aimed to further characterise structural and functional changes associated with amyloid infiltration. Methods:We studied 1187 consecutive patients evaluated at 3 referral centres for CA and analysed morphological, functional and strain-derived echo parameters with the aim of developing a score-based diagnostic algorithm. Cardiac amyloid burden was quantified using extracellular volume measurements at cardiac magnetic resonance.Results: 332 patients were diagnosed with AL amyloidosis and 339 patients with transthyretin (ATTR) CA. Concentric remodelling and strain-derived parameters displayed the best diagnostic performance. A multivariable logistic regression model incorporating relative wall thickness, E/e'ratio, longitudinal strain and tricuspid annular plane systolic excursion had greatest diagnostic performance in AL amyloidosis (area under the curve -AUC-0.90[95% confidence interval 0.87-0.92]), whilst addition of septal apical-to -base ratio yielded the best diagnostic accuracy in the IWT group (AUC 0.87[0.85-0.9]).Conclusions: Specific functional and structural parameters characterize different burdens of CA deposition with different diagnostic performances, and enable to define two scores that are sensitive and specific tools to diagnose or exclude CA.

Increased chemosensitivity to both hypoxia and hypercapnia, eliciting neurohormonal derangement, ventilation instability, and ventricular arrhythmias, is a very serious adverse prognostic marker in HF.

Increased chemosensitivity has been observed in HF (heart failure) and, in order to clarify its pathophysiological and clinical relevance, the aim of the present study was to investigate its impact on neurohormonal balance, breathing pattern, response to exercise and arrhythmic profile. A total of 60 patients with chronic HF [age, 66+/-1 years; LVEF (left ventricular ejection fraction), 31+/-1%; values are means+/-S.E.M.] underwent assessment of HVR (hypoxic ventilatory response) and HCVR (hypercapnic ventilatory response), neurohormonal evaluation, cardiopulmonary test, 24-h ECG monitoring, and assessment of CSR (Cheyne-Stokes respiration) by diurnal and nocturnal polygraphy. A total of 60% of patients had enhanced chemosensitivity. Those with enhanced chemosensitivity to both hypoxia and hypercapnia (i.e. HVR and HCVR), compared with those with normal chemosensitivity, had significantly (all P<0.01) higher noradrenaline (norepinephrine) and BNP (B-type natriuretic peptide) levels, higher prevalence of daytime and night-time CSR, worse NYHA (New York Heart Association) class and ventilatory efficiency [higher VE (minute ventilation)/VCO(2) (carbon dioxide output) slope], and a higher incidence of chronic atrial fibrillation and paroxysmal non-sustained ventricular tachycardia, but no difference in left ventricular volumes or LVEF. A direct correlation was found between HVR or HCVR and noradrenaline (R=0.40 and R=0.37 respectively; P<0.01), BNP (R=0.40, P<0.01), N-terminal pro-BNP (R=0.37 and R=0.41 respectively, P<0.01), apnoea/hypopnoea index (R=0.57 and R=0.59 respectively, P<0.001) and VE/VCO(2) slope (R=0.42 and R=0.50 respectively, P<0.001). Finally, by multivariate analysis, HCVR was shown to be an independent predictor of both daytime and night-time CSR. In conclusion, increased chemosensitivity to hypoxia and hypercapnia, particularly when combined, is associated with neurohormonal impairment, worse ventilatory efficiency, CSR and a higher incidence of arrhythmias, and probably plays a central pathophysiological role in patients with HF.

Transthyretin (TTR) is a tetrameric protein synthesized mostly by the liver. As a result of gene mutations or as an ageing-related phenomenon, TTR molecules may misfold and deposit in the heart and in other organs as amyloid fibrils. Cardiac involvement in TTR-related amyloidosis (ATTR) manifests typically as left ventricular pseudohypertrophy and/or heart failure with preserved ejection fraction. ATTR is an underdiagnosed disorder as well as a crucial determinant of morbidity and mortality, thus justifying the current quest for a safe and effective treatment. Therapies targeting cardiac damage and its direct consequences may yield limited benefit, mostly related to dyspnoea relief through diuretics. For many years, liver or combined heart and liver transplantation have been the only available treatments for patients with mutations causing ATTR, including those with cardiac involvement. The therapeutic options now include several pharmacological agents that inhibit hepatic synthesis of TTR, stabilize the tetramer, or disrupt fibrils. Following the positive results of a phase 3 trial on tafamidis, and preliminary findings on patisiran and inotersen in patients with ATTR-related neuropathy and cardiac involvement, we provide an update on this rapidly evolving field, together with practical recommendations on the management of cardiac involvement.

The aim of this review is to analyze in detail some possible pathophysiological mechanisms linking obesity and cardiac endocrine function, in order to try to explain the negative association previously observed between BMI and BNP values in both healthy subjects and patients with cardiovascular diseases. In particular, we discuss the hypothesis that the response of the cardiac endocrine system is the integrated resultant of several and contrasting physiological and pathological interactions, including the effects of peptide and steroid hormones, cytokines, cardiovascular hemodynamics, clinical conditions, and pharmacological treatment. Several studies suggested that gonadal function regulates both body fat distribution and cardiac endocrine function. Visceral fat expansion can increase the clearance of active natriuretic peptides by means of an increased expression of clearance receptors on adipocytes, and in this way, it may contribute to decrease the activity of the cardiac endocrine system. Moreover, obesity is associated with ectopic lipid deposition even in the heart, which may directly exert a lipotoxic effect on the myocardium by secreting in loco several cytokines and adipokines. Obese subjects are frequently treated for hypertension and coronary artery disease. Pharmacological treatment reduces plasma level of cardiac natriuretic peptides, and this effect may explain almost in part the lower BNP levels of some asymptomatic subjects with increased BMI values. At present time, it is not possible to give a unique and definitive answer to the crucial question concerning the inverse relationship between the amount of visceral fat distribution and BNP levels. Our explanation for these unsatisfactory results is that the cardiac endocrine response is always the integrated resultant of several pathophysiological interactions. However, only few variables can be studied together; as a result, it is not possible to perform a complete evaluation of pathophysiological mechanisms under study. We are still not able to well integrate these multiple information together; therefore, we should learn to do it.

In HF patients with permanent atrial fibrillation, exercise performance is reduced as reflected by reduced peak VO(2). The finding of unidentified AT is associated with a poor performance. In atrial fibrillation patients, VO(2) is higher at AT whereas lower at peak. This last observation raises uncertainties about the use of AT data to define performance and prognosis of HF patients with atrial fibrillation.