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Aims Recent evidence supports the occurrence of multiple hormonal and metabolic deficiency syndrome (MHDS) in chronic heart failure (CHF). However, no large observational study has unequivocally demonstrated its impact on CHF progression and outcome. The T.O.S.CA. (Trattamento Ormonale nello Scompenso CArdiaco; Hormone Treatment in Heart Failure) Registry has been specifically designed to test the hypothesis that MHDS affects morbidity and mortality in CHF patients. Methods and Results The T.O.S.CA. Registry is a prospective, multicentre, observational study involving 19 Italian centres. Thyroid hormones, insulin-like growth factor-1, total testosterone, dehydropianoandrosterone sulfate, insulin resistance, and the presence of diabetes were evaluated. A MHDS was defined as the presence of ≥2 hormone deficiencies (HDs). Primary endpoint was a composite of all-cause mortality and cardiovascular hospitalizations. Four hundred and eighty heart failure patients with ejection fraction ≤45% were enrolled. MHDS or diabetes was diagnosed in 372 patients (77.5%). A total of 271 events (97 deaths and 174 cardiovascular hospitalizations) were recorded, 41% in NO-MHDS and 62% in MHDS (P Conclusion MHDS is common in CHF and independently associated with increased all-cause mortality and cardiovascular hospitalization, representing a promising therapeutic target. Trial registration ClinicalTrials.gov identifier: NCT023358017

Background: Patients with Parkinson’s disease (PD) and dysautonomia often present elevated blood pressure (BP) variability. However if the elevate BP variability is correlated with subclinical echocardiography abnormalities have been poorly investigated yet. Our aim was to evaluate the correlation between indices of left ventricular function and 24/h BP variability in patients with PD. Methods: We studied 21 patients with diagnosed PD and autonomic dysfunction and 20 hypertensive age-matched subjects. All patients underwent 24/h ambulatory blood pressure monitoring (ABPM) and echocardiography. Left ventricular (LV) systolic function was evaluated by ejection fraction (EF), tissue Doppler s wave and global longitudinal strain (GLS). BP variability was evaluated through average real variability. Results: At ABPM, patients with PD had an higher occurrence of nocturnal hypertension, orthostatic hypotension and post-prandial hypotension compared to hypertensive subjects. GLS, tissue Doppler s velocity, LVEF, LV mass index, and E/e’ ratio were similar between the patients with PD and those with hypertension. In patients with PD there was a significant correlation between GLS and 24/h systolic BP variability (r= 0.44; p=0.01). a trend through significance between 24 systolic BP variability and tissue Doppler s velocity (r= -0.31; p=0.06). Conclusions: In PD patients, short-term BP variability was inversely related to GLS. GLS seems to be an early detector of LV dysfunction in patients with PD and autonomic dysfunction.

A 50 years old male patient with heart failure with reduced ejection fraction and permanent atrial fibrillation, referred to our centre for a cardiac rehabilitation program. He had a very limited exercise tolerance and presented a very compromised atrial function at 2D spleckle tracking echocardiography. Both exercise tolerance and left atrial function improved greatly after a comprehensive intervention including sacubitrilvalsartan administration and exercise training. These benefits, partially, persisted 8 weeks after training cessation. This is the first demonstration of an improvement in left atrial function in a patient, with heart failure and atrial fibrillation, produced by a therapeutic intervention.

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 3years. 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 VO 2 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.

Background Parkinson"s disease (PD) patients often present cardiac blood pressure (BP) derangement as a result of autonomic dysfunction. However their echocardiography pattern have been poorly investigated yet . Study aim: to evaluate the correlation between indices of left ventricular function ad 24/h blood pressure pattern in patients with PD Methods We evaluated 20 patients with diagnosed PD and autonomic dysfunction and 15 hypertensive age-matched subjects. All patients performed 24/h blood pressure monitoring (ABPM) and echocardiography. Left ventricular systolic function was evaluated through ejection fraction (EF), tissue doppler S wave and global longitudinal strain (GLS). BP variability (BPV) was evaluated through average real variability. Results GLS (17.6 vs 22.8; p = 0.04) was reduced in the PD group compared to hypertensive patients. Conversely EF and S wave was similar between the two groups. Patients with PD had an inverse significant correlation between GLS and 24/h systolic BPV (r= -0.64; p = 0.003) and a trend through significance between S wave and systolic BPV (r= -0.31; p = 0.07). sNocturnal diastolic BP was inversely related to GLS (r= -0.44; p = 0.001) . There were no correlation between GLS and BPV and values in hypertensive patients. Conclusions In PD patients GLS is related to indices of poor BP control. GLS appears to be an early detector of LV dysfunction in patients with PD and autonomic dysfunction.

In heart failure, in addition to the renin-angiotensin-aldosterone system and sympathetic nervous system, the natriuretic peptide (NP) system plays a fundamental role among compensating mechanisms. The NPs undergo rapid enzymatic degradation that limits their vasorelaxant, natriuretic, and diuretic actions. Degradation of NPs is partially due to the action of neprilysin, which is a membrane-bound endopeptidase found in many tissues. This article summarizes recent findings on a new natriuretic peptide-enhancing drug and their implication for future pharmacological treatment of patients suffering from heart failure with reduced ejection fraction.

From January 28th to February 10th, 2008 the Italian Society of Cardiac Rehabilitation and Prevention (GICR) conducted a national web-based survey aimed to provide specific and updated information on organization and core components of cardiac rehabilitation (CR) in Italy, and to describe, both in residential and out-patient settings, indications for CR, clinical characteristics of referred patients, risk profile, performed diagnostic procedures, exercise and educational programme, treatments and arrangements for the follow-up [1, 2]. The ISYDE-2008 is a multicenter, longitudinal, prospective observation study whose design was previously described [1, 2].

Low-density lipoprotein cholesterol (LDL-C) reduction is associated with a significant decrease in mortality, and statins represent the most effective drugs to achieve this. However, side effects of statins are very common and may lead to treatment discontinuation. Nutraceuticals are a combination of natural components that have shown efficacy in lowering LDL-C concentration when used alone or in association with other agents in patients who are intolerant to high-dose statins. Our aim was to compare the efficacy and tolerability of low-dose statin (LDS) therapy versus combined therapy of LDS plus a nutraceutical combination containing red yeast rice, policosanol, berberine, folic acid, coenzyme Q10 and astaxanthin (Armolipid Plus) in high-risk patients. We performed a randomized (1:1), prospective, parallel group, single-blind trial in which participants had coronary artery disease (n = 100), had undergone percutaneous coronary intervention in the preceding 12 months, were high-dose statin intolerant, and did not achieve ≥50% reduction in LDL-C with LDS treatment alone. After 3 months, patients in the LDS + Armolipid Plus (n = 50) group presented with a significantly greater reduction of LDL-C and total cholesterol (p 0.0001), and 70% of patients in this group achieved the therapeutic target (LDL-C 70 mg/dl), whereas patients in the LDS group did not. Six patients (3 from each group) dropped out due to myalgia. In conclusion, in patients with coronary artery disease and high-dose statin intolerance, the combination of LDS and nutraceuticals represents a valuable therapeutic option.

This study sought to prospectively assess which factors were related to short-term worsening heart failure (HF) leading to or not to hospital admission, in long-term outpatients followed by cardiologists. The subsequent decision-making process was also analyzed. The study population consisted of 2,701 outpatients enrolled in the registry of the Italian Network on Congestive Heart Failure (IN-CHF) and followed by 133 cardiology centers (19% of all existing Italian cardiology centers). Clinical and follow-up data were collected by local trained clinicians; 215 patients (8%) had short-term decompensation (on average 2 months after the index outpatient visit). Multivariate analysis showed that previous hospitalization, long duration of symptoms, ischemic etiology, atrial fibrillation, higher functional class (New York Heart Association classification III to IV), higher heart rate, and low systolic blood pressure were independently associated with HF destabilization. Poor compliance (21%) and infection (12%) were the most frequent precipitating factors, but a precipitating factor was not identified in 40% of the patients. Poor compliance was more common in women, but no other clinical characteristics emerged as being related with a specific precipitating factor. Fifty-seven percent of the patients with a short-term recurrence of worsening HF required hospital admission; infusion treatment with inotropes and/or vasodilators was necessary in 19% of them. Long-term therapy was changed in 48% of the patients. Thus, in ambulatory HF patients, short-term worsening HF can be predicted according to the clinical characteristics on an outpatient basis. Nearly 1/3 of precipitating factors can be prevented. Patient education and avoidance of inappropriate treatment may reduce the number of relapses.

Background Treatment with angiotensin-converting-enzyme (ACE) inhibitors reduces the rate of cardiovascular events among patients with left-ventricular dysfunction and those at high risk of such events. We assessed whether the ACE inhibitor perindopril reduced cardiovascular risk in a low-risk population with stable coronary heart disease and no apparent heart failure. Methods We recruited patients from October, 1997, to June, 2000. 13655 patients were registered with previous myocardial infarction (64%), angiographic evidence of coronary artery disease (61%), coronary revascularisation (55%), or a positive stress test only (5%). After a run-in period of 4 weeks, in which all patients received perindopril, 12218 patients were randomly assigned perindopril 8 mg once daily (n=6110), or matching placebo (n=6108). The mean follow-up was 4.2 years, and the primary endpoint was cardiovascular death, myocardial infarction, or cardiac arrest. Analysis was by intention to treat. Findings Mean age of patients was 60 years (SD 9), 85% were male, 92% were taking platelet inhibitors, 62% beta blockers, and 58% lipid-lowering therapy. 603 (10%) placebo and 488 (8%) perindopril patients experienced the primary endpoint, which yields a 20% relative risk reduction (95% CI 9-29, p=0.0003) with perindopril. These benefits were consistent in all predefined subgroups and secondary endpoints. Perindopril was well tolerated. Interpretation Among patients with stable coronary heart disease without apparent heart failure, perindopril can significantly improve outcome. About 50 patients need to be treated for a period of 4 years to prevent one major cardiovascular event. Treatment with perindopril, on top of other preventive medications, should be considered in all patients with coronary heart disease.

Aims Myocardial injury (MI) in coronavirus disease‐19 (COVID‐19) is quite prevalent at admission and affects prognosis. Little is known about troponin trajectories and their prognostic role. We aimed to describe the early in‐hospital evolution of MI and its prognostic impact. Methods and results We performed an analysis from an Italian multicentre study enrolling COVID‐19 patients, hospitalized from 1 March to 9 April 2020. MI was defined as increased troponin level. The first troponin was tested within 24 h from admission, the second one between 24 and 48 h. Elevated troponin was defined as values above the 99th percentile of normal values. Patients were divided in four groups: normal, normal then elevated, elevated then normal, and elevated. The outcome was in‐hospital death. The study population included 197 patients; 41% had normal troponin at both evaluations, 44% had elevated troponin at both assessments, 8% had normal then elevated troponin, and 7% had elevated then normal troponin. During hospitalization, 49 (25%) patients died. Patients with incident MI, with persistent MI, and with MI only at admission had a higher risk of death compared with those with normal troponin at both evaluations (P

Patients with heart failure (HF) who contract SARS-CoV-2 infection are at a higher risk of cardiovascular and non-cardiovascular morbidity and mortality. Regardless of therapeutic attempts in COVID-19, vaccination remains the most promising global approach at present for controlling this disease. There are several concerns and misconceptions regarding the clinical indications, optimal mode of delivery, safety and efficacy of COVID-19 vaccines for patients with HF. This document provides guidance to all healthcare professionals regarding the implementation of a COVID-19 vaccination scheme in patients with HF. COVID-19 vaccination is indicated in all patients with HF, including those who are immunocompromised (e.g. after heart transplantation receiving immunosuppressive therapy) and with frailty syndrome. It is preferable to vaccinate against COVID-19 patients with HF in an optimal clinical state, which would include clinical stability, adequate hydration and nutrition, optimized treatment of HF and other comorbidities (including iron deficiency), but corrective measures should not be allowed to delay vaccination. Patients with HF who have been vaccinated against COVID-19 need to continue precautionary measures, including the use of facemasks, hand hygiene and social distancing. Knowledge on strategies preventing SARS-CoV-2 infection (including the COVID-19 vaccination) should be included in the comprehensive educational programmes delivered to patients with HF. This article is protected by copyright. All rights reserved. [Abstract copyright: This article is protected by copyright. All rights reserved.]

Importance: Myocardial injury, detected by elevated plasma troponin levels, has been associated with mortality in patients hospitalized with coronavirus disease 2019 (COVID-19). However, the initial data were reported from single-center or 2-center studies in Chinese populations. Compared with these patients, European and US patients are older, with more comorbidities and higher mortality rates. Objective: To evaluate the prevalence and prognostic value of myocardial injury, detected by elevated plasma troponin levels, in a large population of White Italian patients with COVID-19. Design, Setting, and Participants: This is a multicenter, cross-sectional study enrolling consecutive patients with laboratory-confirmed COVID-19 who were hospitalized in 13 Italian cardiology units from March 1 to April 9, 2020. Patients admitted for acute coronary syndrome were excluded. Elevated troponin levels were defined as values greater than the 99th percentile of normal values. Main Outcomes and Measures: Clinical characteristics and outcomes stratified as elevated or normal cardiac troponin levels at admission, defined as troponin T or troponin I at a level greater than the 99th percentile of normal values. Results: A total of 614 patients with COVID-19 were included in this study (mean age [SD], 67 [13] years; 70.8% male), of whom 148 patients (24.1%) died during the hospitalization. Elevated troponin levels were found in 278 patients (45.3%). These patients were older (mean [SD] age, 64.0 [13.6] years vs 71.3 [12.0] years; P

Background Pulmonary embolism (PE) has been described in coronavirus disease 2019 (COVID-19) critically ill patients, but the evidence from more heterogeneous cohorts is limited. Methods Data were retrospectively obtained from consecutive COVID-19 patients admitted to 13 Cardiology Units in Italy, from March 1st to April 9th, 2020, and followed until in-hospital death, discharge, or April 23rd, 2020. The association of baseline variables with computed tomography-confirmed PE was investigated by Cox hazards regression analysis. The relationship between d-dimer levels and PE incidence was evaluated using restricted cubic splines models. Results The study included 689 patients (67.3 ± 13.2 year-old, 69.4% males), of whom 43.6% were non-invasively ventilated and 15.8% invasively. 52 (7.5%) had PE over 15 (9–24) days of follow-up. Compared with those without PE, these subjects had younger age, higher BMI, less often heart failure and chronic kidney disease, more severe cardio-pulmonary involvement, and higher admission d-dimer [4344 (1099–15,118) vs. 818.5 (417–1460) ng/mL, p p p = 0.06). In multivariate regression, only d-dimer was associated with PE (HR 1.72, 95% CI 1.13–2.62; p = 0.01). The relation between d-dimer concentrations and PE incidence was linear, without inflection point. Only two subjects had a baseline d-dimer Conclusions PE occurs in a sizable proportion of hospitalized COVID-19 patients. The implications of bleeding events and the role of d-dimer in this population need to be clarified. Graphic abstract

Aims To assess the clinical relevance of a history of atrial fibrillation (AF) in hospitalized patients with coronavirus disease 2019 (COVID-19). Methods and results We enrolled 696 consecutive patients (mean age 67.4 ± 13.2 years, 69.7% males) admitted for COVID-19 in 13 Italian cardiology centres between 1 March and 9 April 2020. One hundred and six patients (15%) had a history of AF and the median hospitalization length was 14 days (interquartile range 9–24). Patients with a history of AF were older and with a higher burden of cardiovascular risk factors. Compared to patients without AF, they showed a higher rate of in-hospital death (38.7% vs. 20.8%; P 0.05 for both) and was not related to stroke or bleeding events. Conclusion Among hospitalized patients with COVID-19, a history of AF contributes to worse clinical course with a higher mortality and in-hospital events including new-onset AF, acute HF, and multiorgan failure. The mortality risk remains significant after adjustment for variables associated with COVID-19 severity and comorbidities.

Aims: To assess the prognostic value of a history of heart failure (HF) in patients with coronavirus disease 2019 (COVID-19). Methods and results: We enrolled 692 consecutive patients admitted for COVID-19 in 13 Italian cardiology centres between 1 March and 9 April 2020. Mean age was 67.4± 13.2 years, 69.5% of patients were males, 90 (13.0%) had a history of HF, median hospitalization length was 14 days (interquartile range 9–24). In-hospital death occurred in 37 of 90 patients (41.1%) with HF history vs. 126 of those with no HF history (20.9%). The increased risk of death associated with HF history remained significant after adjustment for clinical variables related to COVID-19 and HF severity, including comorbidities, oxygen saturation, lymphocyte count and plasma troponin [adjusted hazard ratio (HR) for death: 2.25; 95% confidence interval (CI) 1.26–4.02; P= 0.006 at multivariable Cox regression model including 404 patients]. Patients with a history of HF also had more in-hospital complications including. acute HF (33.3% vs. 5.1%, P< 0.001), acute renal failure (28.1% vs. 12.9%, P< 0.001), multiorgan failure (15.9% vs. 5.8%, P= 0.004) and sepsis (18.4% vs. 8.9%, P= 0.006). Other independent predictors of outcome were age, sex, oxygen saturation and oxygen partial pressure at arterial gas analysis/fraction of inspired oxygen ratio (PaO2/FiO2). In-hospital treatment with corticosteroids and heparin had beneficial effects (adjusted HR for death: 0.46; 95% CI 0.29–0.74; P= 0.001; n= 404 for corticosteroids, and adjusted HR 0.41; 95% CI 0.25–0.67; P< 0.001; n= 364 for heparin). Conclusions: Hospitalized patients with COVID-19 and a history of HF have an extremely poor outcome with higher mortality and in-hospital complications. HF history is an independent predictor of increased in-hospital mortality.

The establishment of permanent cover crops is becoming a common practice in vineyard floor management. Turfgrass science may provide species and techniques with a high potential for improving the sustainability of vineyard floor management. Based on this assumption, an experiment was carried out during 2018 and 2019 at the Donna Olimpia Vineyard, Bolgheri, Italy. The trial aimed at comparing an innovative floor management system based on a turf-type cultivar of bermudagrass mown with an autonomous mower with a conventional floor management system. Ground cover percentage, energy consumption, CO2 emissions, grapevine water status, leaf nitrogen content, fruit yield and must composition have been assessed in order to perform the comparison. The innovative vineyard floor management produced an almost complete ground cover (98%) at the end of the second growing season, with the resident species reduced to a small percentage (4%). Resident species growing under-trellis were efficiently controlled without herbicide applications. A lower primary energy consumption and a reduction in CO2 emissions were observed for the innovative management system compared to the conventional management system. Grapevine water status, leaf chlorophyll content, soil&ndash, plant analyses development (SPAD), fruit yields and must composition were similar between the different soil management systems. Based on results obtained in this trial, turf-type bermudagrass and innovative mowing machines may contribute to enhance the sustainability of vineyard floor management.

High-dose statin (HDS) therapy is recommended to reduce low-density lipoprotein cholesterol (LDL-C); however, some patients are unable to tolerate the associated side effects. Nutraceuticals have shown efficacy in lowering LDL-C. The aim of this study was to evaluate whether the combination of low-dose statin (LDS) plus ezetimibe (EZE) or LDS plus nutraceutical (Armolipid Plus [ALP] containing red yeast rice, policosanol, and berberine) can lead to a higher proportion of high-risk patients achieving target LDL-C. A secondary objective was to assess the efficacy of triple combination LDS + EZE + ALP in resistant patients (LDL-C >70 mg/dl). A randomized, prospective, parallel-group, single-blind study was conducted in patients with coronary artery disease (n = 100) who had undergone percutaneous coronary intervention in the preceding 12 months, were HDS-intolerant, and were not at LDL-C target (

Cardiomyopathies are a heterogeneous group of heart muscle diseases and an important cause of heart failure (HF). Current knowledge on incidence, pathophysiology and natural history of HF in cardiomyopathies is limited, and distinct features of their therapeutic responses have not been systematically addressed. Therefore, this position paper focuses on epidemiology, pathophysiology, natural history and latest developments in treatment of HF in patients with dilated (DCM), hypertrophic (HCM) and restrictive (RCM) cardiomyopathies. In DCM, HF with reduced ejection fraction (HFrEF) has high incidence and prevalence and represents the most frequent cause of death, despite improvements in treatment. In addition, advanced HF in DCM is one of the leading indications for heart transplantation. In HCM, HF with preserved ejection (HFpEF) affects most patients with obstructive, and similar to 10% of patients with non-obstructive HCM. A timely treatment is important, since development of advanced HF, although rare in HCM, portends a poor prognosis. In RCM, HFpEF is common, while HFrEF occurs later and more frequently in amyloidosis or iron overload/haemochromatosis. Irrespective of RCM aetiology, HF is a harbinger of a poor outcome. Recent advances in our understanding of the mechanisms underlying the development of HF in cardiomyopathies have significant implications for therapeutic decision-making. In addition, new aetiology-specific treatment options (e.g. enzyme replacement therapy, transthyretin stabilizers, immunoadsorption, immunotherapy, etc.) have shown a potential to improve outcomes. Still, causative therapies of many cardiomyopathies are lacking, highlighting the need for the development of effective strategies to prevent and treat HF in cardiomyopathies.

Sacubritil ∗ valsartan (Entresto, Novartis, still commonly referred to as LCZ696) is a combination drug described as a new class of dual-acting angiotensin receptor–neprilysin inhibitor (ARNi). This combination drug has been successfully studied in patients with heart failure with both preserved (HFpEF) and reduced ejection fraction (HFrEF). In this review, the evidences in patients with HFpEF and HFrEF are summarized, including the results of more recent studies.

WOS: 000383604800016, PubMed ID: 27170530, AimsTo assess the tolerability of initiating/uptitrating sacubitril/valsartan (LCZ696) from 50 to 200 mg twice daily (target dose) over 3 and 6 weeks in heart failure (HF) patients (ejection fraction 35%). Methods and resultsA 5-day open-label run-in (sacubitril/valsartan 50 mg twice daily) preceded an 11-week, double-blind, randomization period [100 mg twice daily for 2 weeks followed by 200 mg twice daily (condensed' regimen) vs. 50 mg twice daily for 2 weeks, 100 mg twice daily for 3 weeks, followed by 200 mg twice daily (conservative' regimen)]. Patients were stratified by pre-study dose of angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker (ACEI/ARB; low-dose stratum included ACEI/ARB-naive patients). Of 540 patients entering run-in, 498 (92%) were randomized and 429 (86.1% of randomized) completed the study. Pre-defined tolerability criteria were hypotension, renal dysfunction and hyperkalaemia; and adjudicated angioedema, which occurred in (condensed' vs. conservative') 9.7% vs. 8.4% (P = 0.570), 7.3% vs. 7.6% (P = 0.990), 7.7% vs. 4.4% (P = 0.114), and 0.0% vs. 0.8% of patients, respectively. Corresponding proportions for pre-defined systolic blood pressure 5.5 mmol/L, and serum creatinine >3.0 mg/dL were 8.9% vs. 5.2% (P = 0.102), 7.3% vs. 4.0% (P = 0.097), and 0.4% vs. 0%, respectively. In total, 378 (76%) patients achieved and maintained sacubitril/valsartan 200 mg twice daily without dose interruption/down-titration over 12 weeks (77.8% vs. 84.3% for condensed' vs. conservative'; P = 0.078). Rates by ACEI/ARB pre-study dose stratification were 82.6% vs. 83.8% (P = 0.783) for high-dose/condensed' vs. high-dose/conservative' and 84.9% vs. 73.6% (P = 0.030) for low-dose/conservative' vs. low-dose/condensed'. ConclusionsInitiation/uptitration of sacubitril/valsartan from 50 to 200 mg twice daily over 3 or 6 weeks had a tolerability profile in line with other HF treatments. More gradual initiation/uptitration maximized attainment of target dose in the low-dose ACEI/ARB group., World Health Organization [001]

Di Rienzo M, Castiglioni P, Iellamo F, Volterrani M, Pagani M, Mancia G, Karemaker JM, Parati G. Dynamic adaptation of cardiac baroreflex sensitivity to prolonged exposure to microgravity: data from a 16-day spaceflight. J Appl Physiol 105: 1569-1575, 2008. First published August 28, 2008; doi:10.1152/japplphysiol.90625.2008.-This study explored the process of arterial baroreflex adaptation to microgravity, starting from the first day of flight, during the 16-day STS-107 Columbia Space Shuttle mission. Continuous blood pressure (BP), ECG, and respiratory frequency were collected in four astronauts on ground (baseline) and during flight at days 0-1, 6-7, and 12-13, both at rest and during moderate exercise (75 W) on a cycle ergometer. Sensitivity of the baroreflex heart rate control (BRS) was assessed by sequence and spectral alpha methods. Baroreflex effectiveness index (BEI); low-frequency (LF) power and high-frequency (HF) power of systolic BP (SBP), diastolic BP (DBP), and R-R interval (RRI); the RRI LF/HF ratio; and the RRI root mean square of successive differences (RMSSD) index were also estimated. We found that, at rest, BRS increased in early flight phase, compared with baseline (means +/- SE: 18.3 +/- 3.4 vs. 10.4 +/- 1.2 ms/mmHg; P

Telemedicine is the provision of health care services, through the use of information and communication technology, in situations where the health care professional and the patient, or 2 health care professionals, are not in the same location. It involves the secure transmission of medical data and information, through text, sound, images, or other forms needed for the prevention, diagnosis, treatment, and follow-up of a patient. First data on implementation of telemedicine for the diagnosis and treatment of acute myocardial infarction date from more than 10 years ago. Telemedicine has a potential broad application to the cardiovascular disease continuum and in many branches of cardiology, at least including heart failure, ischemic heart disease and arrhythmias. Telemedicine might have an important role as part of a strategy for the delivery of effective health care for patients with cardiovascular disease. In this document the Working Group on Telecardiology and Informatics of the Italian Society of Cardiology intends to remark some key-points regarding potential benefit achievable with the implementation of telemedicine support in the continuum of cardiovascular disease.

Aims We studied the induction of monocytic inducible nitric oxide synthase expression and the tumour necrosis factor-alpha system in patients with congestive heart failure. Methods and Results Forty-three congestive heart failure patients and 15 healthy subjects were studied. Antigenic tumour necrosis factor-a and its soluble receptors, measured by ELISA. were increased in chronic heart failure and the increase was related to the clinical severity of the syndrome (tumour necrosis factor-a from 8.2 +/- 5.2 in NYHA class II to 18.2 +/- 7.2 in class III and 26.9 +/- 13.2 pg, ml(-1) in class IV, P < 0.0001 classes III and IV vs class II; soluble tumour necrosis factor receptor I from 1.0 +/- 0.2 in class II to 2.3 +/- 1.1 in class III and 5.5 +/- 3.2 ng. ml(-1) in class IV, P < 0.0001 classes III and IV vs class II; soluble tumour necrosis factor receptor II from 2.7 +/- 0.7 in class II to 4.9 +/- 1.9 in class III and 8.4 +/- 5.0 ng.ml(-1) in class IV, P < 0.002 classes III and IV vs class II). Monocytic inducible nitric oxide synthase assessed by Western blot, was expressed only in congestive heart failure patients (13 out of 43). The association among monocytic inducible nitric oxide synthase expression, tumour necrosis factor-alpha system activation, neurohormones and other clinical parameters was studied. The univariate logistic regression showed that inducible nitric oxide synthase expression was strictly associated with NYHA class (P < 0.05), antigenic tumour necrosis factor-alpha (P < 0.01) and its soluble receptors (P < 0.05). The multivariate analysis showed that antigenic tumour necrosis factor-alpha was the only predictor for monocytic inducible nitric oxide synthase expression (P < 0.05, RR = 2.75, CI 1.34-5.43). Conclusions Inducible nitric oxide synthase is expressed in circulating monocytes of patients with severe congestive heart failure. This phenomenon is linked to the activation of the tumour necrosis factor-alpha system. (C) 1999 The European Society of Cardiology.

Recent studies have shown that growth hormone (GH) deficiency may deteriorate post-ischemic myocardial reperfusion damage. Furthermore, GH has been reported to be a promising therapeutic option in the treatment of chronic myocardial dysfunction. However, the exact mechanisms of action of GH on the cardiovascular system, particularly in the acute setting, are still unclear. The aim of our study consisted of monitoring the acute effects of GH infusion on isolated blood-perfused rabbit heart according to dose-response pattern and during ischemic conditions to test its anti-ischemic property. Seven blood-donors perfused isolated hearts were used as experimental model. The mechanical and metabolic data of the isolated organs were continuously monitored. Under aerobic conditions, dose-response curves were initially tested after intracoronary infusion of GH at increasing dosages (1, 2, 3 mg/l). After a stabilization period, the effects of GH infusion (5 mg/kg) administered 30 minutes prior to acute global myocardial ischemia (30 minutes) were also investigated. At the doses tested, GH did not induce any changes either in the developed or in the diastolic pressures of the isolated organ. However, transient reduction of the coronary perfusion pressure was observed at the dosage of 3 mg/l. During the ischemia/reperfusion study, at the dosages used in this study, GH did not modify either the degree of stunning in the early reperfusion or the recovery of the developed pressure at the end of reperfusion. In addition, GH did not prevent either the increase of diastolic pressure during ischemia or the release of lactate and CPK during reperfusion. Tissue content of high-energy phosphates was also not changed by GH infusion. In our experimental model, acute GH infusion did not reduce the ischemic/reperfusion damage of the myocardium. However, GH transiently induced coronary vasodilation without modifying the myocardial contractility. Acute effects of GH appear, therefore, to predominantly relate to vascular dilation suggesting that the effects on myocardial contractility may require long-lasting intake being likely linked to enhancement of specific protein synthesis or gene expression of cardiac myocytes.

Background In chronic heart failure, several hormonal systems are activated with diagnostic and prognostic implications. We tested the hypotheses that serum Chromogranin-A (CgA) - a 49 kDa acid protein present in the secretor granules of neuroendocrine cells - is increased in chronic heart failure and that CgA levels are a predictive factor for mortality. Methods and Results In 160 patients with chronic heart failure, we measured serum CgA and other neuroendocrine hormones. The results showed that CgA is increased in chronic heart failure and the increase is related to the clinical severity of the syndrome: CgA levels in New York Heart Failure (NYHA) class II (median 146.9 ng. ml(-1), inter-quartiles 108.3-265.5) were significantly higher (P

Congestive heart failure is a multiple aetiology, high prevalence, poor prognosis cardiovascular disorder. Medical treatment of dilated cardiomyopathy is aimed at alleviating the symptoms of heart failure. Diuretics, ACE inhibitors and very recently, beta-blockers have been shown to have favourable effects on symptoms, exercise capacity and mortality. Growth hormone (GH) and insulin-like growth factor (IGF)-1 are involved in several physiological processes such as the control of muscle mass and function, body composition and regulation of nutrient metabolism. The roles of GH and IGF-1 as modulators of myocardial structure and function are well established. Receptors for both GH and IGF-1 are expressed by cardiac myocytes; therefore, GH may act directly on the heart or via the induction of local or systemic IGF-1, whereas IGF-1 may act by endocrine, paracrine or autocrine mechanisms. Patients with acromegaly have an increased propensity to develop ventricular hypertrophy and cardiovascular diseases and, in addition, an impaired cardiac efficiency is observed in patients with GH deficiency. Animal models of pressure and volume overload have demonstrated up-regulation of cardiac IGF-1 production and expression of GH and IGF-1 receptors, implying that the local regulation of these factors is influenced by haemodynamic changes. Moreover, experimental studies suggest that GH and IGF-1 have stimulatory effects on myocardial contractility, possibly mediated by changes in intracellular calcium handling. Heart failure is caused by ventricular dilatation with abnormal wall thickening, which leads to impaired cardiac performance; therefore, based on the evidence available for GH we would expect beneficial effects from the use of GH in these patients. Several papers highlight the positive influence of GH in the regulation of heart development and performance. In patients with GH deficiency, GH administration dramatically improves cardiac function. In small nonblind studies, both short and long term GH treatment have demonstrated beneficial effects in patients with heart failure secondary to ischaemic or idiophatic cardiomyopathy. Recently, two randomised, placebo-controlled studies, did not show significant GH-mediated improvement in cardiac performance in patients with dilated cardiomyopathy, despite significant increases in IGF-1. Acquired GH resistance, might be an important feature of severe heart failure and explain the different responses to GH therapy seen in different patients. Whether GH treatment will finally find a place, and with which modalities, in the treatment of heart failure remains to be established.

Background The aim of our study was to assess whether there could be any clinical and/or endocrine (spontaneous growth hormone [GH] secretion rate, baseline insulin-like growth factor-1 [IGF-1]) predictors and/or determinants of the acute effects of continuous intravenous infusion of recombinant human GH on hemodynamic parameters in 12 patients with dilated cardiomyopathy and congestive heart failure (CHF). Methods And Results The study involved 12 male patients with chronic CHF (ischemic in 8 patients and idiopathic in 4). Ten patients were in New York Heart Association functional class III or IV and 2 in class II. The first 24 hours were considered the control period; in fact, during the following 24 hours, all the patients underwent intravenous constant pump infusion of recombinant human GH. Blood samples for GH assay were taken every 20 minutes during the first night of the study (from 10 PM to 6 AM). Moreover, blood samples for GH assay were also taken during exogenous GH infusion. Blood samples for IGF-1 assays were taken at 8 AM of each of the 3 days of the study. Pulmonary artery pressure (PAP) and capillary wedge (PCWP) pressure, cardiac index, and arterial blood pressure were measured 30 minutes after right heart catheterization (baseline 1), at the end of the control period (baseline 2), and every 4 hours during GH infusion. A negative correlation has been found between mean nocturnal GH levels and baseline IGF-1 levels (r = –0.47, P = .124) and between mean nocturnal GH levels and both postinfusion absolute (r = –0.67, P < .05) and delta (postinfusion–preinfusion) (r = –0.58; P < 005) IGF-1 levels. No significant correlations have been found between several parameters of liver function (albumin, bilirubin, and pseudocholinesterase) and mean nocturnal GH. However, baseline IGF-1 levels showed a negative significant correlation (r = –0.76, P < .01) with total bilirubin and a positive correlation (r = 0.72, P < .01) with pseudocholinesterase. Baseline IGF-1 levels showed a significant negative correlation with baseline mean PAP (r = –0.68, P < .05) and PCWP (r = –0.70, P < .05) and a positive correlation with baseline cardiac index (r = 0.71, P < .05). Baseline IGF-1 levels also showed a significant negative correlation with absolute mean PAP (r = –0.63, P < .05) and mean PCWP (r = –0.67, P < .05) after GH infusion. After GH infusion, IGF-1 levels also negatively correlated with post–GH infusion mean PAP (r = –0.50, P = .09) and mean PCWP (r = –0.66, P < .05). The positive correlation between either baseline or postinfusion IGF-1 and the postinfusion cardiac index (r = 0.40 and 0.43, respectively) did not reach statistical significance. Conclusions GH has acute functional effects on the heart in patients with CHF, including both an increase in myocardial contractility and a decrease in vascular resistances, and among patients with CHF, those with low baseline IGF-1 are likely to have fewer beneficial effects from GH infusion. (Am Heart J 1999;137:1035-43.)

Background The aim of this study was to elucidate whether beneficial effects of cardiomyoplasty (CMP) in patients with dilated cardiomyopathy are the result of a decrease in existing ventricular dilatation or a prevention of further dilatation. Methods and Results Combined micromanometer-conductance catheters were used to evaluate left ventricular pressure-volume relationships in six patients with dilated cardiomyopathy before and at 6 and 12 months after CMP. Acute changes in preload and afterload were induced by a standardized leg-tilting intervention and a bolus infusion of nitroglycerin. After CMP, end-diastolic volume (EDV) decreased from 138±10 to 103±18 mL/m 2 ( P 2 ( P P P P P P P P 2 ( P 2 ( P P P 2 ( P P Conclusions Our findings show that up to 1 year after CMP, marked decreases in left ventricular volume are present. Our measurements suggest that CMP actively reduced the dilated ventricle but did not prevent a higher EDV on an increased venous return. The latissimus dorsi muscle wrap contraction results in better synchronization of contraction and more rapid emptying of the left ventricle.

Objecti6e: Cardiomyoplasty represents a controversial therapy for chronic heart failure. The aim of this study is to review our experience of such a surgical procedure as an isolated approach to treat refractory left ventricular dysfunction. Methods: Twenty-two patients were considered candidates for cardiomyoplasty because of chronic heart failure. Mean age was 58.795.3 (range 48‐71 years), 19 patients were male and 3 were female. Ischemic or idiopathic etiology was present in 11 cases, respectively. Traditional as well as innovative techniques were used to assess hemodynamic function. Pre-operative hemodynamic profile included mean left ventricular ejection fraction of 2095.8% (9‐28%), absence of severe right ventricular failure, and mean left ventricular end-diastolic diameter of 75.597.4 mm (range 61‐92 mm). All patients were in New York Heart Association Class III or Intermittent IV despite conventional medical therapy. Results: There was no intra-operative death. No additional surgery was performed. Left latissimus dorsi (LD) muscle was used in 20 cases, and right LD in two patients. Early mortality occurred in one patient (low cardiac output syndrome), whereas late mortality in five patients (three sudden deaths, one lung cancer, one heart failure). Mean follow-up is 20.7916.7 months (3‐51 months). Actuarial survival at 4 years is 70%. Cardiac index increased at 6 months (3.0890.5 l:min per m 2 , P0.04), but no other significant changes were observed in the long term (3.039 0.7 l:min per m 2 ,3 90.7 l:min per m 2 , and 2.8590.7 l:min per m 2 , at 12, 24 and 36 months, respectively). Ejection fraction improved at 6 and 12 months (29.191.03%, P0.0017; and 27.39 5.6%, P 0.0091, respectively), while no substantial augmentation was documented at 2 and 3 years (25.692.5% and 25.19 4.0%, respectively). Left ventricular end-diastolic diameter was markedly reduced at 6 (73.298.0 mm, P0.0176), 12 (69.498.5 mm, P 0.002) and 24 months (71.19 7.0 mm, P 0.011), and was then stable (74.099.1 mm, P0.47) at 36 months. Postoperative pressure:volume loop evaluation showed some improvement of hemodynamic function from skeletal muscle assistance. Acute pulmonary edema episodes, as well as number of hospitalizations, were considerably reduced following cardiomyoplasty. Conclusions: In our experience, cardiomyoplasty was shown to exert moderate beneficial influence on left ventricular performance, to significantly reduce cardiac dilatation and to promote the stabilization of the disease course. © 1997 Elsevier Science B.V.

OBJECTIVES We aimed to determine whether growth hormone (GH) resistance is present in patients with chronic heart failure (CHF) and whether it may be linked to the biochemical response to GH treatment. BACKGROUND Acquired GH resistance is a feature of severe illness, in particular, cachexia. In patients with CHF, the response to GH therapy appears to be variable. METHODS Biochemical markers of the GH-insulin-like growth factor-I (IGF-I) axis were compared in 21 cachectic patients with CHF, 51 noncachectic patients and 26 healthy control subjects. In separate studies, the predictive value of baseline biochemical variables for the IGF-I response to GH treatment was analyzed. RESULTS Cachectic patients showed an increase of total GH and immunologically intact GH (p ≤ 0.0002) and a decrease of GH-binding protein (BP) (p = 0.005), IGF-BP3 (p = 0.01) and IGF-I (p = 0.06), compared with noncachectic patients. Similar changes were found when the cachectic group was compared with the control group. No differences were found between noncachectic patients and control subjects. Levels of GH-BP correlated with the IGF-I/GH ratio in all subgroups (all p ≤ 0.002). Baseline GH-BP levels were related to the increase of IGF-I levels in response to GH treatment in patients with CHF after 24 h (r = 0.83, p = 0.005; n = 9; study 2), 44 days (r = 0.52, p = 0.007; n = 25; study 3) and 96 days (r = 0.54, p = 0.006; n = 24; study 3). CONCLUSIONS Most cachectic and some noncachectic patients with CHF show features of acquired GH resistance. The principal predictors of the biochemical features of GH resistance and of the poor biochemical response to short-term and longer-term GH treatment are GH-BP plasma levels. The presence of GH resistance is potentially a major factor determining the response to GH therapy in patients with CHF.