Multiple hormonal and metabolic deficiency syndrome in chronic heart failure: rationale, design, and demographic characteristics of the T.O.S.CA. Registry.

Recent evidence supports the concept that progression of chronic heart failure (CHF) depends upon an imbalance of catabolic forces over the anabolic drive. In this regard, multiple hormonal deficiency syndrome (MHDS) significantly has impacts upon CHF progression, and is associated with a worse clinical status and increased mortality. The T.O.S.CA. (Trattamento Ormonale nello Scompenso CArdiaco; Hormone Therapy in Heart Failure) Registry (clinicaltrial.gov = NCT02335801) tests the hypothesis that anabolic deficiencies reduce survival in a large population of mild-to-moderate CHF patients. The T.O.S.CA. Registry is a prospective multicenter observational study coordinated by "Federico II" University of Naples, and involves 19 centers situated throughout Italy. Thyroid hormones, insulin-like growth factor-1, total testosterone, dehydroepiandrosterone , and insulin are measured at baseline and every year for a patient-average follow-up of 3 years. Subjects with CHF are divided into two groups: patients with one or no anabolic deficiency, and patients with two or more anabolic deficiencies at baseline. The primary endpoint is the composite of all-cause mortality and cardiovascular hospitalization. Secondary endpoints include the composite of all-cause mortality and hospitalization, the composite of cardiovascular mortality and cardiovascular hospitalization, and change of VO2 peak. Patient enrollment started in April 2013, and was completed in July 2017. Demographics and main clinical characteristics of enrolled patients are provided in this article. Detailed cross-sectional results will be available in late 2018. The T.O.S.CA. Registry represents the most robust prospective observational trial on MHDS in the field of CHF. The study findings will advance our knowledge with regard to the intimate mechanisms of CHF progression and hopefully pave the way for future randomized clinical trials of single or multiple hormonal replacement therapies in CHF.

The Tosca Registry: An Ongoing, Observational, Multicenter Registry for Chronic Heart Failure.

The ageing of the population in western countries, the continuous increase of the prevalence of chronic diseases, the frequent coexistence of several morbid conditions (comorbidity) requires health professionals and Institutions to face difficult challenges, including increasing costs, need for more effective and sustainable therapies, and organizational issues. The European Innovation Partnership on Active and Healthy Ageing aims at enabling European citizens to lead healthy, active and independent lives while ageing. We herein discuss some key concepts bearing a special significance in the light of the Partnership aims, and present research and educational projects active in our local environment. Among these, the multicentre project TOSCA (Trattamento Ormonale nello Scompenso CArdiaco) that, although primarily focused on the understanding of the interactions between hormones and chronic heart failure (CHF), is also aimed at developing more effective models of clinical care. We provide the scientific background and current stage of the project. In the context of a growing complexity of the patients' clinical management, the polipharmacy is a new arising challenge for clinicians, bearing direct economic, organizational and clinical implications. A better understanding, characterization and management of this issue represent an additional target of the TOSCA network.

P1007Aortic root diameters and aortic regurgitation in hypertensive patients and normal subjects.

PURPOSE: : The association between aortic root diameters and aortic regurgitation in hypertension (HT) is disputed with lack of understanding of the underline mehanisms lT. We investigate the relationship between aortic root diameters and aortic regurgitation in newly diagnosed and never treated hypertensive patients and in a group healthy subjects. METHOD: Participants were 175 hypertensives (42 F and 133 M) and 305 normotensives (134 F, 168 M) age matched (mean age 52.4±13 vs 52.6 ±15.2 years). Antropometric, office blood pressure (BP) measurements, a comprehensive echocardiography and local carotid stiffness study were performed. Aortic measures for annulus, sinuses of Valsalva, sinotubular junction and ascending aorta were taken in late diastole according to the leading edge method. The sinotubular junction/annulus ratio was calculated. RESULTS: Hypertensive patients had significantly higher body surface area (BSA), systolic (SBP) and diastolic pressure (DBP), mean arterial pressure (MAP) and pulse?pressure (PP) (p<0.0001) than normotensives. Annulus and sinotubular junction diameters, indexed by BSA and after adjustment for gender, MAP, heart rate?(HR), were significantly higher in normotensives than hypertensives. Considering subjects with aortic regurgitation (trivial or mild) we found a higher prevalence in?hypertensives (25.7 % vs 10.2%, p<0.0001). Moreover in hypertensives we found no difference in aortic diameters between patients with or without aortic regurgitation?but ascending aorta /BSA (p=0.002) whereas in healthy subjects aortic regurgitation was associated with larger aortic root diameters included sinotubular junction/annulus ratio (table 1). In the logistic regression analysis, aortic regurgitation was associated with age, gender, BP parameters, one point carotid stiffness parameters. CONCLUSIONS: Hypertensive patients had smaller indexed aortic root dimensions than normal subjects but they had heigher prevalence of trivial-mild aortic regurgitation in contrast to normotensives who had aortic regurgitation combined with larger aortic diameters.

A novel miR-371a-5p-mediated pathway, leading to BAG3 upregulation in cardiomyocytes in response to epinephrine, is lost in Takotsubo cardiomyopathy.

Molecular mechanisms protecting cardiomyocytes from stress-induced death, including tension stress, are essential for cardiac physiology and defects in these protective mechanisms can result in pathological alterations. Bcl2-associated athanogene 3 (BAG3) is expressed in cardiomyocytes and is a component of the chaperone-assisted autophagy pathway, essential for homeostasis of mechanically altered cells. BAG3 ablation in mice results in a lethal cardiomyopathy soon after birth and mutations of this gene have been associated with different cardiomyopathies including stress-induced Takotsubo cardiomyopathy (TTC). The pathogenic mechanism leading to TTC has not been defined, but it has been suggested that the heart can be damaged by excessive epinephrine (epi) spillover in the absence of a protective mechanism. The aim of this study was to provide more evidence for a role of BAG3 in the pathogenesis of TTC. Therefore, we sequenced BAG3 gene in 70 TTC patients and in 81 healthy donors with the absence of evaluable cardiovascular disease. Mutations and polymorphisms detected in the BAG3 gene included a frequent nucleotide change g2252c in the BAG3 3'-untranslated region (3'-UTR) of Takotsubo patients (P<0.05), resulting in loss of binding of microRNA-371a-5p (miR-371a-5p) as evidenced by dual-luciferase reporter assays and argonaute RNA-induced silencing complex catalytic component 2/pull-down assays. Moreover, we describe a novel signaling pathway in cardiomyocytes that leads to BAG3 upregulation on exposure to epi through an ERK-dependent upregulation of miR-371a-5p. In conclusion, the presence of a g2252c polymorphism in the BAG3 3'-UTR determines loss of miR-371a-5p binding and results in an altered response to epi, potentially representing a new molecular mechanism that contributes to TTC pathogenesis.

Corrigendum to: 2014 ESC Guidelines on the diagnosis and treatment of aortic diseases.

Corrigendum to: 2014 ESC Guidelines on the diagnosis and treatment of aortic diseases [Eur Heart Journal (2014) 35, 2873­2926,doi:10.1093/eurheartj/ehu281]. In Table 3, the radiation for MRI is "0" and not "-". The corrected table is shown below.

Physiologic and pathophysiologic changes in the right heart in highly trained athletes.

Exercise causes changes in the heart in response to the hemodynamic demands of increased systemic and pulmonary requirements during exercise. Understanding these adaptations is of great importance, since they may overlap with those caused by pathological conditions. Initial descriptions of athlete's heart focused mainly on chronic adaptation of the left heart to training. In recent years, the substantial structural and functional adaptations of the right heart have been documented, highlighting the complex interplay with left heart. Moreover, there is evolving evidence of acute and chronic cardiac damage, mainly involving the right heart, which may predispose subjects to atrial and ventricular arrhythmias, configuring an exercise-induced cardiomyopathy. The aim of this article is to review the current knowledge on the physiologic and pathophysiologic changes in the right heart in highly trained athletes.

Pulmonary arterial hypertension-related myopathy: an overview of current data and future perspectives.

BACKGROUND AND AIM: Exercise intolerance is one of the key features of pulmonary arterial hypertension (PAH). The main determinants of exercise impairment include hypoxemia, reduced right ventricular output, perfusion/ventilation mismatch, and weakness of skeletal and breathing muscles. The aim of the current review is to describe the findings in the existing literature about respiratory and muscle dysfunction in PAH. Animal and clinical studies regarding both respiratory and peripheral skeletal muscles and the effect of exercise training on muscle function in PAH patients are analyzed. DATA SYNTHESIS: PAH myopathy is characterized by reduced skeletal muscle mass, reduced volitional and non-volitional contractility, reduced generated force, a fiber switch from type I to type II, increased protein degradation through ubiquitin-proteasome system (UPS) activation, reduced mitochondrial functioning, and impaired activation-contractility coupling. Increased inflammatory response, impaired anabolic signaling, hypoxemia, and abnormalities of mitochondrial function are involved in the pathophysiology of this process. Exercise training has been shown to improve exercise capacity, peak oxygen uptake, quality of life, and possibly clinical outcomes of PAH patients. CONCLUSIONS: The skeletal muscles of PAH patients show a wide spectrum of cellular abnormalities that finally culminate in muscle atrophy and reduced contractility. Exercise training improves muscle function and bears a positive impact on the clinical outcomes of PAH patients.

Diagnosis of acute aortic syndromes : imaging and beyond.

Acute aortic syndromes are fatal medical conditions including classic acute aortic dissection, intramural hematoma, and penetrating atherosclerotic ulcer. Given the nonspecific symptoms and signs, a high clinical index of suspicion followed by an imaging study, namely transesophageal echocardiography, computed tomography, and magnetic resonance imaging (sensitivity 98-100% and specificity 95-100%), is a conditio sine qua non for prompt diagnosis of acute aortic syndromes. This article provides an overview of established and emerging approaches for the assessment of acute aortic syndromes, with focus on imaging and biomarkers. In this regard, D-dimer levels (cut-off: 500 ng/ml) may be useful to rule out aortic dissection, if used within the first 24 h after symptom onset.

Acute aortic syndromes.

Acute aortic syndromes (AAS) comprise a group of potentially lethal conditions that require prompt recognition, diagnosis as well as acute medical stabilization and surgical intervention. The purpose of this article is to review the relevant variants of AAS presentation, as well as diagnostic and management issues, including adequate long-term medical therapy and follow-up imaging. In this context, the American College of Cardiology and the American Heart Association recently published guidelines on the management of thoracic aortic disease, drawing greater attention to these processes.

Exercise stress echocardiography for the study of the pulmonary circulation.

Exercise stress tests have been used for the diagnosis of pulmonary hypertension, but with variable protocols and uncertain limits of normal. The pulmonary haemodynamic response to progressively increased workload and recovery was investigated by Doppler echocardiography in 25 healthy volunteers aged 19-62 yrs (mean 36 yrs). Mean pulmonary artery pressure ((Ppa)) was estimated from the maximum velocity of tricuspid regurgitation. Cardiac output (Q) was calculated from the aortic velocity-time integral. Slopes and extrapolated pressure intercepts of (Ppa)-Q plots were calculated after using the adjustment of Poon for individual variability. A pulmonary vascular distensibility alpha was calculated from each (Ppa)-Q plot to estimate compliance. (Ppa) increased from 14+/-3 mmHg to 30+/-7 mmHg, and decreased to 19+/-4 mmHg after 5 min recovery. The slope of (Ppa)-Q was 1.37+/-0.65 mmHg x min(-1) x L(-1) with an extrapolated pressure intercept of 8.2+/-3.6 mmHg and an alpha of 0.017+/-0.018 mmHg(-1). These results agree with those of previous invasive studies. Multipoint (pa)-Q plots were well described by a linear approximation, from which resistance can be calulated. We conclude that exercise echocardiography of the pulmonary circulation is feasible and provides realistic resistance and compliance estimations. Measurements during recovery are unreliable because of rapid return to baseline.

Acute aortic dissection in the young: clinical series.

Acute aortic dissection (AAD) is an uncommon lethal cardiovascular emergency demanding prompt diagnosis and aggressive therapeutic intervention. Although it usually affects males over 60 years of age, it may also occur in young adults with specific risk factors such as Marfan syndrome, bicuspid aortic valve and larger aortic dimensions. Moreover, it should be underlined that it is frequently associated with unusual presentation and that the mortality risk is similar to older AAD patients. Thus ''a call to arms'' of the medical community is needed to better understand the spectrum of acute aortic syndromes and to define appropriate diagnostic and therapeutic pathways. We report a series of 6 young patients with type A - AAD referred over the past years at our institute.

Secondary pulmonary hypertension--diagnosis and management.

Secondary pulmonary hypertension (SPHtn) is generally attributable to abnormalities in structure or function of the heart or lung parenchyma. While often defined as a physiologic parameter, pulmonary hypertension (PHtn) can be a major contributor to death and disability in cardiopulmonary diseases. Both detection and management are a challenge. We will review the pathophysiology, diagnostic tools, and treatment strategies in SPHtn with an emphasis on cor pulmonale associated with chronic obstructive pulmonary disease (COPD), pulmonary vasculopathies, and pulmonary embolus. The pathophysiology and common etiologies of SPHtn can be divided into three major categories: (1) elevated pulmonary venous pressure (LV failure and mitral valve disease), (2) pulmonary vascular occlusive disease with or without pulmonary parenchymal disease (pulmonary emboli, COPD, connective tissue diseases), and (3) hypoxemia (sleep apnea). The echo-Doppler is a simple cost-effective tool for detecting PHtn, evaluating right ventricular function, and distinguishing common etiologies such as abnormal systolic and diastolic left ventricular function and mitral valve disease. The ventilation-perfusion radionuclide scan can be used to exclude thromboembolic PHtn, but a helical computer tomography with contrast or pulmonary angiography are necessary to distinguish patients that may benefit from a pulmonary thromboendarterectomy. The six minute walk oxygen saturation test is useful as a quantitative measure of functional capacity, prognosis, response to therapy, and oxygen requirement. Treatment strategies in cor pulmonale are tailored to the specific diagnosis, but generally include proper nutrition, exercise, oxygen supplementation, medications such as digoxin, diuretics, anti-coagulation, and pulmonary vasodilator therapy in selected patients.

Chronobiology of rupture and dissection of aortic aneurysms.

A growing body of evidence suggests that the occurrence of cardiovascular events is not evenly distributed over time, but shows peculiar temporal patterns that vary with time of day, day of the week, and month (season) of the year. These patterns coincide with the temporal variation in the pathophysiologic mechanisms that trigger cardiovascular events and the physiologic changes in body rhythms. These two factors in combination contribute to the periodicity in susceptibility to acute cardiovascular events. The classic assumption of epidemiologic studies that there is a constancy in risk for disease during the various time domains has now been challenged by the emerging new concept of chronorisk. In the last two decades temporal patterns (circadian, weekly, seasonal) have been identified for several acute cardiovascular diseases, such as acute myocardial infarction, sudden death, pulmonary embolism, and stroke, with peak incidence for most in the morning and during winter. One of the most life-threatening cardiovascular emergencies, aortic aneurysm rupture or dissection, also demonstrates periodicity, characterized by a similar temporal distribution, which suggests a common pathophysiologic mechanism or triggers similar to other cardiovascular acute emergencies. We review the data on chronobiology of acute aortic rupture or dissection, and discuss various pathophysiologic mechanisms that account for this variability. It is likely that identification of consistent recurring patterns in the underlying risk mechanisms could provide potential new insights for more precise diagnosis and efficacious therapeutic intervention.

Association of left ventricular hypertrophy and aortic dilation in patients with acute thoracic aortic dissection.

This study was designed to evaluate the impact of left ventricular mass on aortic diameters in patients who presented with acute thoracic aortic dissection where aortic dilation is common. Retrospective review of transthoracic and transesophageal echocardiograms was conducted for 63 patients treated for acute thoracic aortic dissection and for 16 normal subjects who were comparable for gender prevalence, age, heart rate, and blood pressure. The diameter of the aortic root was measured by transthoracic echocardiography. Diameters of the ascending aorta, and of the aorta at locations of 25, 30, and 35 cm from the dental arch were measured by transesophageal echocardiography. The findings indicated that all aortic diameters were significantly larger in patients with aortic dissection. Patients with aortic dissection also presented with greater left ventricular mass indices (p<0.00001) than normal subjects. Fractional shortening and left atrial diameter measurements obtained in patients with aortic dissection were similar to those obtained in the control group. Overall, the left ventricular mass index exhibited univariate relationships with aortic root diameter (r=0.27, p<0.02) and aortic diameters at 25 cm (r=0.51, p<0.00001), 30 cm (r=0.58, p<0.00001), and 35 cm (r=0.55, p<0.00001) distal to the arch but not with the diameter of the ascending aorta. After adjusting for gender, body mass index, history of hypertension and aortic dissection extent (Stanford types) by separate multivariate models, the authors found that the left ventricular mass index was independently associated with aortic diameters at 25 cm (beta=0.32, p<0.001), 30 cm (beta=0.38, p<0.0001), and 35 cm (beta=0.34, p < 0.0005) distal to the arch. They conclude that left ventricular mass is independently associated with aortic arch and descending aorta diameters in patients with acute thoracic aortic dissection. Left ventricular hypertrophy may be considered a risk factor for aortic enlargement and subsequent dissection.

Oxygen desaturation on the six-minute walk test and mortality in untreated primary pulmonary hypertension.

There are no reliable predictors of mortality in primary pulmonary hypertension (PPH). This study assessed whether exercise oxygen desaturation and distance achieved during a six-minute walk are associated with mortality in moderately symptomatic patients with PPH. Thirty-four patients with PPH underwent a pretreatment six-minute walk test, and an invasive haemodynamic assessment of pulmonary vasodilator reserve, to select the best treatment option (epoprostenol in 27 and nifedipine in 7). Median follow-up was 26 months (12 months for the nonsurvivors was 26%), and median survival, >46 months by Kaplan-Maier estimate. The mean+/-SD distance walked was 275+/-155 m and reduction in arterial oxygen saturation (Sa,O2) at maximal distance (deltaSa,O2) was 8.4+/-4.5%). A distance < or =300 m increased mortality risk by 2.4, and a deltaSa,O2 of > or = 10% increased mortality risk by 2.9. Only Sa,O2 at peak distance, deltaSa,O2 and pulmonary vascular resistance (PVR) were related to mortality. After adjusting for PVR, there remained a 27% increase in risk of death for each per cent decrease in Sa,O2. The six-minute walk distance and exercise oxygen saturation may be helpful in selecting patients with primary pulmonary hypertension for whom transplant listing is appropriate.

Cardiac risk assessment for noncardiac surgery: current concepts.

Strategies for perioperative risk assessment in patients undergoing noncardiac surgery vary among physicians and are aimed to estimate the risk and minimize complications. We propose simplistic guidelines for assessing and modifying risk for patients undergoing a wide variety of procedures.

Early spontaneous recovery of left ventricular function in patients with myocarditis.

The natural history of myocarditis is varied. We describe 6 out of a cohort of 15 consecutive patients with histopathologic evidence of myocarditis who showed a remarkable early symptomatic and spontaneous recovery of left ventricular systolic function. The left ventricular ejection fraction increased to > or = 50% at discharge, and this improvement was maintained at late follow-up. The other 9 patients, despite clinical improvement, were not thought to have spontaneous recovery. Neither clinical severity of the illness (NYHA functional class) nor left ventricular ejection fraction at presentation demonstrated any difference in the two groups. By contrast, a smaller left ventricular internal diameter at end-diastole and a smaller left atrial dimension as determined by transthoracic echocardiography were predictive of spontaneous recovery. Firstly, we confirm that the natural history of myocarditis is indeed varied with the possibility of early spontaneous recovery; secondly we suggest that left ventricular internal diameter at end-diastole and left atrial dimension may have prognostic implications in this disease.