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Moreover, they focus on the effects of insulin resistance and chronic hyperglycemia in determining micro- and macrovascular complications (cardiovascular disease, heart failure, hypertension, chronic kidney disease, and atherosclerosis). The Special Issue "Metabolic Regulation in the Development of Cardiovascular Disease and Heart Failure" focused on how metabolic diseases could cause a predisposition to cardiovascular diseases and, in particular, heart failure due to systolic or diastolic dysfunction or a combination thereof. In patients with chronic HF, a significant negative correlation was observed between PACAP and NT-proBNP levels, whereas the correlation was positive in patients with acute HF. The original article of Szabó et al. [[7]] evaluated the role of pituitary adenylate cyclase-activating polypeptide (PACAP) and its specific PAC1 receptor in the plasma and myocardial tissue of patients with heart failure (HF). [Extracted from the article]

Background: Over the last years, several trials offered new evidence on heart failure (HF) treatment. Design and results: For HF with reduced left ventricular ejection fraction, type 2 sodium—glucose cotransporter inhibitors, aside from sacubitril—valsartan, demonstrated extraordinary efficacy in ameliorating patients' prognosis. Some new molecules (eg vericiguat, omecamtiv mecarbil and ferric carboxymaltose) correct iron deficiency and have shown to be capable of furthering reducing the burden of HF hospitalisation. Finally, there is new evidence on the possible therapeutic approaches of HF patients with mid‐range or preserved left ventricular ejection fraction. Conclusions: This review aimed to revise the main novelties in the field of HF therapy and focus on how the daily clinical approach to patient treatment is changing. [ABSTRACT FROM AUTHOR]

Objective: To measure competition amongst providers and to examine whether a correlation exists with hospitals mortality for congestive heart failure (CHF), acute myocardial infarction (AMI), isolated-coronary artery bypass graft (CABG) or valve surgery.Design: Cross-sectional study based on publically available data from the National Outcome Evaluation Program (Edition 2016) of the Italian Agency for Regional Health Services.Setting and Participants: Patients discharged during 2015 for CHF or AMI, and between 2014 and 2015 for cardiac surgery (respectively, from 662, 395 and 91 hospitals).Main Outcome Measures: Risk-adjusted mortality rates at 30 days and measures of hospital competition for areas centred on hospital' location (fixed-radius 50-150 km, variable-radius to capture 10-30 hospitals and 6-10% of national volume). Competition was estimated as number of providers and Herfindahl-Hirschman Index (HHI).Results: Indicators of competitions varied by condition and were sensitive to method used for the area definition. Hospital mortality after AMI and valve surgery increased with competition in areas identified by the variable-radius method (higher rates for a greater number of hospitals or lower HHIs). In area with fixed radius of 100-150 km, competition reduced mortality after CABG procedures (lower rates for a greater number of hospitals or smaller HHIs). Neither the number of hospitals nor HHI correlated with outcomes in CHF.Conclusions: The measures of hospital competition changed according to definition of local market and results in mortality correlations varied among conditions. Understanding the relationship between hospital competition and outcomes is important to identify strategies to improve quality of care. [ABSTRACT FROM AUTHOR]

In case of unexplained post‐PCI coronary thrombosis, a HIT should be always considered. A pragmatic approach with bivalirudin may be reasonable, even in absence of confirmed laboratory diagnosis. [ABSTRACT FROM AUTHOR]

Aim of the study To evaluate whether right ventriculo-arterial coupling obtained by the estimation of the two-dimensional right ventricular (RV) longitudinal strain and of the pulmonary arterial systolic pressure (PASP) could improve prognostic stratification of chronic heart failure (CHF) outpatients. Methods CHF outpatients in a stable clinical condition and in conventional therapy were enrolled. The global RV longitudinal strain (RV-GLS) and the strain of the RV free wall (RV-fwLS) were evaluated. PASP was estimated on the basis of tricuspid regurgitation velocity and the estimated central venous pressure. Both RV-GLS and RV-fwLS were then indexed for PASP. Results Of the 315 patients evaluated, 69 died during follow-up. Both RV-GLS/PASP and RV-fwLS/PASP were significantly associated with an increased risk of death at univariate (HR: 0.43; 95%CI: 0.34–0.56; p < 0.001 and HR: 0.44; 95% CI: 0.34–0.57; p < 0.001, respectively) and multivariate analysis (HR: 0.66; 95% CI: 0.49–0.89; p: 0.008 and HR: 0.65; 95% CI: 0.49–0.85; p: 0.002, respectively) after correction for age, NYHA class, mean arterial pressure, left ventricular ejection fraction, natremia, glomerular filtration rate and NT-proBNP. Conclusions Indexing RV function, assessed by speckle-tracking analysis, with an estimation of pulmonary systolic arterial pressure provides a parameter of ventricular arterial coupling that is independently associated with an increased risk of mortality. [ABSTRACT FROM AUTHOR]

Background It is not clear whether correlations exist within hospitals or operators among risk-adjusted mortality rates (RAMRs) for the most common cardiac interventions and how much of variations in outcomes are residually explained by providers and physicians. We examined these aspects by using recent national data on percutaneous coronary intervention (PCI) and cardiac surgery. Methods Publically available data from New York State aggregated at hospital and operator level were downloaded by Department of Health website for in-hospital/30-day mortality after PCI, coronary artery bypass graft (CABG) and valve surgery. Correlations between RAMRs were evaluated by using Spearman's coefficient (rho). The proportion of mortality variation attributed to hospitals and operators was estimated. Results During the period 2008–2013, 390 cardiologists from 63 hospitals and 163 surgeons from 41 centres were evaluated. The RAMRs during 2008–2010 correlated with the RAMRs during 2011–2013 for valve surgery within providers (rho = 0.55; p < 0.001) and within interventionists for PCI (rho = 0.21; p < 0.001), isolated CABG (rho = 0.25; p = 0.009), and any valve surgery or CABG procedure (rho = 0.49; p < 0.001). The most recent hospital's RAMRs (year 2012 and 2013) significantly correlated in PCI (rho = 0.40; p = 0.002) but not in CABG (rho = 0.13; p = 0.413). < 2% of mortality variations was attributed to providers and 2–3% to difference between operators. Conclusions A correlation exists at provider and operator level in RAMRs for PCI and cardiac surgery procedures performed in New York State. Beyond patient's risk profile, that is the strongest predictor of early mortality after a cardiac procedure, hospitals and operators have a small but statistically significant contribution to variation in post-operative outcome. [ABSTRACT FROM AUTHOR]

Objective: To examine whether a correlation exists in hospitals among 30-day mortality rates for different types of hospitalizations.Design: Cross-sectional study of hospital care based on publically available Italian data from the National Outcome Evaluation Program Edition 2015 of the Italian Agency for Regional Health Services.Setting and Participants: Patients hospitalized with a diagnosis of congestive heart failure, acute myocardial infarction, chronic renal failure, chronic obstructive pulmonary disease exacerbation, femoral neck fracture, ischemic stroke and non-variceal upper gastrointestinal bleeding, or those who underwent isolated cardiac valve procedure, isolated coronary artery bypass graft surgery, non-ruptured abdominal aortic aneurysm repair and interventions for the following tumors: colon, kidney, brain, lung, stomach, rectal, liver or pancreatic cancer.Main Outcome Measures: Condition-specific 30-day crude and risk-adjusted mortality rates.Results: A total of 808 280 admissions were reported from 844 institutions (median of 4 conditions evaluated per hospital; interquartile range 2-8). Volumes and outcome varied by clinical and surgical conditions across hospitals. Out of 153 pairs of different conditions, 41 were statistically significant in terms of concordance with crude mortality rates and 44 for their adjusted values. The hospital mean percentile rank for 30-day mortality, a composite measure that summarized the multiple indicators, increased significantly alongside number of conditions per hospital with a significant reduction of mortality when most of the studied conditions were treated in the same hospital.Conclusions: The variability in 30-day mortality rates at hospital level and the correlation between risk mortality rates suggest that there may be common hospital-wide factors influencing short-term mortality. [ABSTRACT FROM AUTHOR]

The assessment of right ventricular (RV) function still remains a challenge. Two-dimensional (2D) speckle tracking has recently been proposed to evaluate right ventricular function by analyzing myocardial deformation. The aim of this study was to evaluate the role of 2D systolic strain measures of RV in predicting mortality in patients with chronic heart failure (HF). We enrolled 332 outpatients in a stable clinical condition and in conventional therapy. A right ventricular-focused four-chamber view was analyzed by 2D speckle tracking to evaluate the global longitudinal strain of RV (RV-GLS) and the strain of RV free wall (RV-fwLS). During a mean follow-up of 36 ± 26 months, 64 patients died. Both RV-GLS and RV-fwLS were associated with all-cause mortality in univariate (HR: 1.16; 95% CI: 1.10-1.23; P < 0.001; C-index: 0.72; and HR: 1.10; 95% CI: 1.06-1.15; P < 0.001; C-index: 0.68, respectively) as well as multivariate analysis (HR: 1.13; 95% CI: 1.05-1.21; P:0.001; C-index: 0.85; and HR: 1.07; 95% CI: 1.02-1.12; P:0.004; C-index: 0.84, respectively). In conclusion, our findings demonstrate the role of RV 2D strain measures to independently predict mortality. These data highlight the clinical usefulness of this echocardiographic approach in the daily management of HF outpatients. [ABSTRACT FROM AUTHOR]

Aims: The renal arterial resistance index (RRI) is a measure of renal blood flow obtained by Doppler ultrasonography, which has been demonstrated to reflect both vascular and parenchymal renal abnormalities. The aim of the study was to evaluate clinical correlates and the prognostic relevance of RRI in a group of patients affected by chronic heart failure (CHF). Methods and Results: We enrolled 250 CHF outpatients in a stable clinical condition and receiving conventional therapy. Peak systolic velocity and end-diastolic velocity of a segmental renal artery were obtained by pulsed Doppler flow. Then the RRI was calculated. Standard renal function assessment was obtained by the measurement of creatinine serum levels and the estimation of the glomerular filtration rate (GFR). During follow-up (21.4 ± 11.3 months), 41 patients experienced heart failure progression (hospitalization and/or heart transplantation and/or death due to worsening heart failure). Considered as a continuous variable, RRI was associated with events at univariate [hazard ratio (HR) 1.14; 95% confidence interval (CI) 1.09-1.19; P < 0.001] as well as at multivariate Cox regression analysis (HR 1.08; 95% CI 1.02-1.13; P = 0.004) after correction for independent predictors of the reference model. When the RRI was added to the reference model including GFR, a significant improvement of reclassification according to both category-free net reclassification improvement (NRI, 47%; 95% CI 13-80%; P = 0.006) and integrated discrimination improvement (IDI, 0.034; 95% CI 0.006-0.061; P = 0.016) was observed. Conclusions: Quantification of arterial renal perfusion provides a new parameter that independently predicts CHF patient outcome, thus strengthening its possible role in current clinical practice in order to better characterize renal function and stratify patients' prognosis. [ABSTRACT FROM AUTHOR]

Aims The renal arterial resistance index ( RRI) is a measure of renal blood flow obtained by Doppler ultrasonography, which has been demonstrated to reflect both vascular and parenchymal renal abnormalities. The aim of the study was to evaluate clinical correlates and the prognostic relevance of RRI in a group of patients affected by chronic heart failure ( CHF). Methods and results We enrolled 250 CHF outpatients in a stable clinical condition and receiving conventional therapy. Peak systolic velocity and end-diastolic velocity of a segmental renal artery were obtained by pulsed Doppler flow. Then the RRI was calculated. Standard renal function assessment was obtained by the measurement of creatinine serum levels and the estimation of the glomerular filtration rate ( GFR). During follow-up (21.4 ± 11.3 months), 41 patients experienced heart failure progression (hospitalization and/or heart transplantation and/or death due to worsening heart failure). Considered as a continuous variable, RRI was associated with events at univariate [hazard ratio ( HR) 1.14; 95% confidence interval ( CI) 1.09-1.19; P < 0.001] as well as at multivariate Cox regression analysis ( HR 1.08; 95% CI 1.02-1.13; P = 0.004) after correction for independent predictors of the reference model. When the RRI was added to the reference model including GFR, a significant improvement of reclassification according to both category-free net reclassification improvement ( NRI, 47%; 95% CI 13-80%; P = 0.006) and integrated discrimination improvement ( IDI, 0.034; 95% CI 0.006-0.061; P = 0.016) was observed. Conclusions Quantification of arterial renal perfusion provides a new parameter that independently predicts CHF patient outcome, thus strengthening its possible role in current clinical practice in order to better characterize renal function and stratify patients' prognosis. [ABSTRACT FROM AUTHOR]

Aims To evaluate the independent prognostic role of two-dimensional (2D) strain measures reflecting global longitudinal left ventricular ( LV) systolic function in outpatients affected by chronic heart failure ( CHF). Methods and results Global longitudinal LV systolic strain ( GLS) was assessed in 308 outpatients affected by CHF, by analyzing standard views with 2D speckle tracking technique. During a mean follow-up of 26 ± 13 months 37 patients died (29 due to cardiovascular causes), 10 patients underwent heart transplantation, and 75 patients experienced at least 1 episode of hospitalization due to acute decompensated heart failure ( ADHF). Thirty-one patients without a history of major ventricular arrhythmic events experienced the occurrence of ventricular fibrillation and/or tachycardia or sudden death was observed. Multivariate Cox regression analysis showed that GLS was significantly associated with all-cause mortality ( HR: 1.15; 95% CI: 1.02-1.30; P: 0.026), cardiovascular death ( HR: 1.20; 95% CI: 1.04-1.39; P: 0.011), cardiovascular death or heart transplantation ( HR: 1.24; 95% CI: 1.09-1.41; P: 0.001), ADHF-related hospitalizations ( HR: 1.15; 95% CI: 1.05-1.25; P: 0.003), and arrhythmic events ( HR: 1.17; 95% CI: 1.03-1.33; P: 0.018). Conclusions Quantifying LV longitudinal systolic function in CHF outpatients on the basis of 2D speckle tracking analysis provides a new parameter that independently predicts patient outcome, thus, strengthening its possible role in current clinical practice. [ABSTRACT FROM AUTHOR]

The kidneys and heart work together to balance the body's circulation, and although their physiology is based on strict inter dependence, their performance fulfills different aims. While the heart can rapidly increase its own oxygen consumption to comply with the wide changes in metabolic demand linked to body function, the kidneys physiology are primarily designed to maintain a stable metabolic rate and have a limited capacity to cope with any steep increase in renal metabolism. In the kidneys, glomerular population filters a large amount of blood and the tubular system has been programmed to reabsorb 99% of filtrate by reabsorbing sodium together with other filtered substances, including all glucose molecules. Glucose reabsorption involves the sodium–glucose cotransporters SGLT2 and SGLT1 on the apical membrane in the proximal tubular section; it also enhances bicarbonate formation so as to preserve the acid–base balance. The complex work of reabsorption in the kidney is the main factor in renal oxygen consumption; analysis of the renal glucose transport in disease states provides a better understanding of the renal physiology changes that occur when clinical conditions alter the neurohormonal response leading to an increase in glomerular filtration pressure. In this circumstance, glomerular hyperfiltration occurs, imposing a higher metabolic demand on kidney physiology and causing progressive renal impairment. Albumin urination is the warning signal of renal engagement over exertion and most frequently heralds heart failure development, regardless of disease etiology. The review analyzes the mechanisms linked to renal oxygen consumption, focusing on sodium–glucose management. [ABSTRACT FROM AUTHOR]

Background: To compare head-up tilt testing (HUT) outcomes and hemodynamic responses, and the prevalence and correlates of prodromes, in elderly and younger patients with suspected vasovagal syncope (VVS). Methods: Consecutive outpatients with a history of recurrent unexplained syncope underwent HUT by being tilted to 70°; the test was potentiated by the administration of 300 μg of nitroglycerine after 20 minutes. Occurrence of VVS and hemodynamic responses during passive and nitroglycerine phases of HUT were evaluated; symptoms preceding HUT-induced syncope were recorded, together with heart rate and arterial blood pressure values. Results: Four hundred and sixty of the 743 patients were HUT positive: 156 fainted during the unmedicated phase and 304 after nitroglycerine administration. The patients aged ≥65 years (n = 102) experienced VVS more frequently during the pharmacological stage of HUT; the overall rate of positive results was similar to that observed in the patients aged 36-64 years (n = 329) and only slightly lower than that observed in those aged ≤35 years (n = 312). In the older patients, who experienced fewer and mainly prodrome-free spontaneous syncopal episodes, HUT increased the number of premonitory symptoms, and there were no significant age-related differences in symptom prevalence or timing or the patients' hemodynamic characteristics. Conclusions: The rate of VVS induced by nitroglycerine-potentiated HUT is similar in elderly and younger patients. In the former, nitroglycerine-potentiated HUT significantly increases the prevalence of prodromes in comparison with spontaneous episodes, which suggests that it may be useful not only for diagnosis but also for patient counseling. (PACE 2010; 33:1210-1216) [ABSTRACT FROM AUTHOR]

Nitrate-stimulated head-up tilt testing (HUT) is currently recommended to confirm the diagnosis of vasovagal syncope in subjects with syncope of unknown origin. Given the few data currently available, the aim of this study was to assess correlations between nitrate-induced HUT outcomes and the clinical characteristics of patients. Two hundred and thirty consecutive, otherwise healthy subjects with a history of recurrent unexplained syncope underwent HUT. After 10 min supine rest, they were tilted to 70°, and the test was potentiated by the administration of 300 μg of nitroglycerin after 20 min. Out of 178 subjects who underwent nitroglycerin administration during HUT, 95 fainted. At univariate Cox regression analysis, a reduced probability of VVS occurrence after nitrates was associated with greater systolic blood pressure and body mass index values, to male gender and smoking. At multivariate Cox regression analysis, only male gender (HR = 0.61; P = 0.039) and smoking (HR = 0.18; P = 0.001) remained significantly associated with HUT outcomes during the pharmacological phase of the test. Smokers and males are less likely to faint after nitrate administration during HUT than non-smokers and females. Further studies should clarify the possibility of improving the diagnostic power of HUT in these patients. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this work was to evaluate whether ventricular repolarization dynamicity predicts major arrhythmic events in patients with idiopathic dilated cardiomyopathy (DCM). Background: Arrhythmic risk stratification in patients with DCM is still an open issue. Ventricular repolarization analysis should provide relevant information, but QT interval and QT dispersion failed in predicting arrhythmic risk. Methods: The following parameters were evaluated in 179 consecutive DCM patients without history of sustained ventricular tachycardia (VT) and/or ventricular fibrillation (VF) at enrollment: QRS duration, QT interval corrected for heart rate, and QT dispersion at electrocardiogram (ECG); left ventricular ejection fraction (LVEF) and left ventricular end-diastolic diameter at echocardiogram; and nonsustained ventricular tachycardia (NSVT), heart rate variability (standard deviation of RR intervals), and ventricular repolarization dynamicity as measured by means of 24-h ECG monitoring, by calculating the slope of linear regression analysis of QT end and RR intervals (QTe-slope) and the value of mean QT end corrected for heart rate. Results: During a mean follow-up of 39 months, 9 patients died suddenly and 15 experienced VT and/or VF. At multivariate analysis, LVEF (p = 0.047), NSVT (p = 0.022), and QTe-slope (p = 0.034) were significantly associated with arrhythmic events. Among the patients with a low LVEF, NSVT and/or steeper QTe-slope identified a subgroup at highest arrhythmic risk. Conclusions: In patients with DCM, QT dynamicity is independently associated with the occurrence of major arrhythmic events and improves the predictive accuracy of stratifying arrhythmic risk of these patients. [Copyright &y& Elsevier]

Objective: To evaluate the role of brain natriuretic peptide (BNP) in predicting the progression of heart failure (HF) after cardiac resynchronization therapy (CRT).Background: It has been shown that BNP predicts the prognosis and can guide the treatment of HF.Methods: We studied 50 consecutive patients (61+/-10 years, 23 male) with HF (8 with ischaemic cardiomyopathy), NYHA class III, left bundle branch block, left ventricular ejection fraction (LVEF) Results: During follow-up (mean 19+/-12 months), HF progression was observed in 14 patients (11 were hospitalised and 3 died after worsening of HF). Multivariate analysis showed that BNP levels before (HR: 2.07; CI: 1.19-3.62; p=0.01) and 1 month after CRT (HR: 2.23; CI: 1.26-3.94; p=0.006) were significantly related to events. At 1 month, a BNP level >91.5 pg/ml had 89% sensitivity, 59% specificity, and negative and positive predictive values of 96% and 33%, respectively, for HF progression after 12 months.Conclusions: HF patients with high BNP values after 1 month of CRT have worse prognosis during follow-up. Therefore, in these patients other therapeutic options should be considered. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to evaluate whether the clinical benefit of cardiac resynchronization therapy (CRT) can be prospectively predicted by means of the baseline evaluation of left ventricular asynchrony. Background: The reverse remodeling associated with CRT is more evident in patients with severe heart failure (HF) and left bundle branch block (LBBB) who have left ventricular asynchrony. Methods: Baseline left ventricular asynchrony was assessed in 60 patients with severe HF and LBBB by calculating the electrocardiographic duration of QRS and the echocardiographic septal-to-posterior wall motion delay (SPWMD). Left ventricular size and left ventricular ejection fraction (LVEF), mitral valve regurgitation, and functional capacity were also evaluated. The progression toward HF (defined as a worsening clinical condition leading to a sustained increase in conventional therapies, hospitalization, cardiac transplantation, and death) was assessed during follow-up, as were the changes in LVEF after six months. Results: During the median follow-up of 14 months, 16 patients experienced HF progression. Univariate analysis showed that ischemic cardiomyopathy, changes in the QRS duration after implantation, and SPWMD significantly correlated with events. At multivariate analysis, a long SPWMD remained significantly associated with a reduced risk of HF progression (hazard ratio: 0.91; 95% confidence interval: 0.83 to 0.99; p < 0.05). An improvement in LVEF was observed in 79% of the patients with a baseline SPWMD of ≥130 ms and in 9% of those with an SPWMD of <130 ms (p < 0.0001). Conclusions: Baseline SPWMD is a strong predictor of long-term clinical improvement after CRT in patients with severe HF and LBBB. [Copyright &y& Elsevier]

: ObjectivesThe value of interventricular and intraventricular echocardiographic asynchrony parameters in predicting reverse remodeling after cardiac resynchronization therapy (CRT) was investigated.: BackgroundCardiac resynchronization therapy has been suggested as a promising strategy in patients with severe heart failure and left bundle branch block (LBBB), but the entity of benefit is variable and no criteria are yet available to predict which patients will gain.: MethodsInterventricular and intraventricular mechanical asynchrony was evaluated in 20 patients (8 men and 12 women, 63 ± 10 years) with advanced heart failure caused by ischemic (n = 4) or nonischemic dilated cardiomyopathy (n = 16) and LBBB (QRS duration of at least 140 ms) using echocardiographic Doppler measurements. Left ventricular end-diastolic volume index (LVEDVI) and left ventricular end-systolic volume index (LVESVI) were calculated before and one month after CRT. Patients with a LVESVI reduction of at least 15% were considered as responders.: ResultsCardiac resynchronization therapy significantly improved ventricular volumes (LVEDVI from 150 ± 53 ml/m2 to 119 ± 37 ml/m2, p < 0.001; LVESVI from 116 ± 43 ml/m2 to 85 ± 29 ml/m2, p < 0.0001). At baseline, the responders had a significantly longer septal-to-posterior wall motion delay (SPWMD), a left intraventricular asynchrony parameter; only QRS duration and SPWMD significantly correlated with a reduction in LVESVI (r = −0.54, p < 0.05 and r = −0.70, p < 0.001, respectively), but the accuracy of SPWMD in predicting reverse remodeling was greater than that of the QRS duration (85% vs. 65%).: ConclusionsIn patients with advanced heart failure and LBBB, baseline SPWMD is a strong predictor of the occurrence of reverse remodeling after CRT, thus suggesting its usefulness in identifying patients likely to benefit from biventricular pacing. [Copyright &y& Elsevier]

Left ventricular ejection fraction (LVEF) is universally accepted as a cardiac systolic function index and it provides intuitive interpretation of cardiac performance. Over the last two decades, it has erroneously become the leading feature used by clinicians to characterize the left ventricular function in heart failure (HF). Notably, LVEF sets the basis for structural and functional HF phenotype classification in current guidelines. However, its diagnostic and prognostic role in patients with preserved or mildly reduced contractile function is less clear. This is related to several concerns due to intrinsic technical, methodological and hemodynamic limitations entailed in LVEF measurement that do not describe the chamber's real contractile performance as expressed by pressure volume loop relationship. In patients with HF and preserved ejection fraction (HFpEF), it does not reflect the effective systolic function because it is prone to preload and afterload variability and it does not account for both longitudinal and torsional contraction. Moreover, a repetitive measurement could be assessed over time to better identify HF progression related to natural evolution of disease and to the treatment response. Current gaps may partially explain the causes of negative or neutral effects of traditional medical agents observed in HFpEF. Nevertheless, recent pooled analysis has evidenced the positive effects of new therapies across the LVEF range, suggesting a potential role irrespective of functional status. Additionally, a more detailed analysis of randomized trials suggests that patients with higher LVEF show a risk reduction strictly related to overall cardiovascular (CV) events; on the other hand, patients experiencing lower LVEF values have a decrease in HF-related events. The current paper reports the main limitations and shortcomings in LVEF assessment, with specific focus on patients affected by HFpEF, and it suggests alternative measurements better reflecting the real hemodynamic status. Future investigations may elucidate whether the development of non-invasive stroke volume and longitudinal function measurements could be extensively applied in clinical trials for better phenotyping and screening of HFpEF patients. [ABSTRACT FROM AUTHOR]

Background. The assessment of long-term mortality in acute decompensated heart failure (ADHF) is challenging. Respiratory failure and congestion play a fundamental role in risk stratification of ADHF patients. The aim of this study was to investigate the impact of arterial blood gases (ABG) and congestion on long-term mortality in patients with ADHF. Methods and results. We enrolled 252 patients with ADHF. Brain natriuretic peptide (BNP), blood urea nitrogen (BUN), phase angle as assessed by means of bioimpedance vector analysis, and ABG analysis were collected at admission. The endpoint was all-cause mortality. At a median follow-up of 447 d (interquartile range [IQR]: 248–667), 72 patients died 1–840 d (median 106, IQR: 29–233) after discharge. Respiratory failure types I and II were observed in 78 (19%) and 53 (20%) patients, respectively. The ROC analyses revealed that the cut-off points for predicting death were: BNP > 441 pg/mL, BUN > 1.67 mmol/L, partial pressure in oxygen (PaO2) ≤69.7 mmHg, and phase angle ≤4.9°. Taken together, these four variables proved to be good predictors for long-term mortality in ADHF (area under the curve [AUC] 0.78, 95% CI 0.72–0.78), thus explaining 60% of all deaths. A multiparametric score based on these variables was determined: each single-unit increase promoted a 2.2-fold augmentation of the risk for death (hazard ratio [HR] 2.2, 95% CI 1.8–2.8, p<.0001). Conclusions. A multiparametric approach based on measurements of BNP, BUN, PaO2, and phase angle is a reliable approach for long-term prediction of mortality risk in patients with ADHF. [ABSTRACT FROM AUTHOR]

In the essential homeostatic role of kidney, two intrarenal mechanisms are prominent: the glomerulotubular balance driving the process of Na+ and water reabsorption in the proximal tubule, and the tubuloglomerular feedback which senses the Na+ concentration in the filtrate by the juxtaglomerular apparatus to provide negative feedback on the glomerular filtration rate. In essence, the two mechanisms regulate renal oxygen consumption. The renal hyperfiltration driven by increased glomerular filtration pressure and by glucose diuresis can affect renal O2 consumption that unleashes detrimental sympathetic activation. The sodium-glucose co-transporters inhibitors (SGLTi) can rebalance the reabsorption of Na+ coupled with glucose and can restore renal O2 demand, diminishing neuroendocrine activation. Large randomized controlled studies performed in diabetic subjects, in heart failure, and in populations with chronic kidney disease with and without diabetes, concordantly address effective action on heart failure exacerbations and renal adverse outcomes. [ABSTRACT FROM AUTHOR]

Background: Findings from the T.O.S.CA. Registry recently reported that patients with concomitant chronic heart failure (CHF) and impairment of insulin axis (either insulin resistance—IR or diabetes mellitus—T2D) display increased morbidity and mortality. However, little information is available on the relative impact of IR and T2D on cardiac structure and function, cardiopulmonary performance, and their longitudinal changes in CHF. Methods: Patients enrolled in the T.O.S.CA. Registry performed echocardiography and cardiopulmonary exercise test at baseline and at a patient-average follow-up of 36 months. Patients were divided into three groups based on the degree of insulin impairment: euglycemic without IR (EU), euglycemic with IR (IR), and T2D. Results: Compared with EU and IR, T2D was associated with increased filling pressures (E/e′ratio: 15.9 ± 8.9, 12.0 ± 6.5, and 14.5 ± 8.1 respectively, p < 0.01) and worse right ventricular(RV)-arterial uncoupling (RVAUC) (TAPSE/PASP ratio 0.52 ± 0.2, 0.6 ± 0.3, and 0.6 ± 0.3 in T2D, EU and IR, respectively, p < 0.05). Likewise, impairment in peak oxygen consumption (peak VO2) in TD2 vs EU and IR patients was recorded (respectively, 15.8 ± 3.8 ml/Kg/min, 18.4 ± 4.3 ml/Kg/min and 16.5 ± 4.3 ml/Kg/min, p < 0.003). Longitudinal data demonstrated higher deterioration of RVAUC, RV dimension, and peak VO2 in the T2D group (+ 13% increase in RV dimension, − 21% decline in TAPSE/PAPS ratio and − 20% decrease in peak VO2). Conclusion: The higher risk of death and CV hospitalizations exhibited by HF-T2D patients in the T.O.S.CA. Registry is associated with progressive RV ventricular dysfunction and exercise impairment when compared to euglycemic CHF patients, supporting the pivotal importance of hyperglycaemia and right chambers in HF prognosis. Trial registration ClinicalTrials.gov identifier: NCT023358017 [ABSTRACT FROM AUTHOR]

Aims: Patients with heart failure (HF) remain often undertreated for multiple reasons, including treatment inertia, contraindications, and intolerance. The OPTIimal PHARMacological therapy for patients with Heart Failure (OPTIPHARM‐HF) registry is designed to evaluate the prevalence of evidence‐based medical treatment prescription and titration, as well as the causes of its underuse, in a broad real‐world population of consecutive patients with HF across the whole ejection fraction spectrum and among different clinical phenotypes. Methods: The OPTIPHARM‐HF registry (NCT06192524) is a prospective, multicenter, observational, national study of adult patients with symptomatic HF, as defined by current international guidelines, regardless of ejection fraction. Both outpatients and inpatients with chronic and acute decompensated HF will be recruited. The study will enroll up to 2500 patients with chronic HF at approximately 35 Italian HF centres. Patients will be followed for a maximum duration of 24 months. The primary objective of the OPTIPHARM‐HF registry is to assess prescription and adherence to evidence‐based guideline‐directed medical therapy (GDMT) in patients with HF. The primary outcome is to describe the prevalence of GDMT use according to target guideline recommendation. Secondary objectives include implementation of comorbidity treatment, evaluation of sequence of treatment introduction and up‐titration, description of GDMT implementation in the specific HF population, main causes of GDMT underuse, and assessment of cumulative rate of cardiovascular events. Conclusion: The OPTIPHARM‐HF registry will provide important implications for improving patient care and adoption of recommended medical therapy into clinical practice among HF patients. [ABSTRACT FROM AUTHOR]

Background: Type 2 sodium-glucose cotransporter inhibitors (SGLT2i) are among the main therapeutic options for patients with chronic heart failure with reduced ejection fraction (HFrEF). The aim of this study was to evaluate the effects of SGLT2i on the echocardiographic parameters of left (LV) and right (RV) ventricular function among outpatients with a long history of HFrEF, in optimized therapy. Methods: We evaluated consecutive patients affected by HFrEF in whom the SGLT2i therapy was prescribed. Following a baseline evaluation (T0), in which SGLT2i was prescribed, patients were re-evaluated at 3 (T3), 6 (T6), and 12 (T12) months. Results: We considered 60 patients for the analysis with a median history of HFrEF of more than seven years in optimal medical and electrical therapy. After SGLT2i therapy, LV ejection fraction and LV global longitudinal strain improved from baseline at T3, T6, and T12. Analogously, RV global and free wall longitudinal strain improved at T3 and T6. Conclusions: Our study shows that the addition of SGLT2i to the optimized therapy for HFrEF was associated with a significant improvement in both LV and RV function, thus highlighting a possible mechanism responsible for the benefit obtained with this class of drugs. [ABSTRACT FROM AUTHOR]

The mechanism of action of SGLT2i in HF is different from that of other HF therapies that focused on reverse left ventricular remodeling, blocking the neurohormonal activation (such as renin-angiotensin-aldosterone system inhibitors), or enhancing the natriuretic peptide system (such as neprilysin inhibitors) [[4]]. Current guidelines propose therapeutic algorithms based on left ventricular ejection fraction values and clinical presentations; however, these guidelines do not specify which of the four pillar drugs to start first. However, considering the most recent updates on SGLT2i, I would compare SGLT2i to ACE-inhibitors rather than statins, mainly due to nephroprotection and the multitarget action of ACE-inhibitors and SGLT2i. [Extracted from the article]

Over the last decades, the relevance of genetics in cardiovascular diseases has expanded, especially in the context of cardiomyopathies. Its relevance extends to the management of patients diagnosed with heart failure (HF), given its capacity to provide invaluable insights into the etiology of cardiomyopathies and identify individuals at a heightened risk of poor outcomes. Notably, the identification of an etiological genetic variant necessitates a comprehensive evaluation of the family lineage of the affected patients. In the future, these genetic variants hold potential as therapeutic targets with the capability to modify gene expression. In this complex setting, collaboration among cardiologists, specifically those specializing in cardiomyopathies and HF, and geneticists becomes paramount to improving individual and family health outcomes, as well as therapeutic clinical results. This review is intended to offer geneticists and cardiologists an updated perspective on the value of genetic research in HF and its implications in clinical practice. [ABSTRACT FROM AUTHOR]

Background: The sodium–glucose cotransporter-2 inhibitors (SGLT2i) have emerged as a crucial therapeutic option for patients with chronic heart failure with reduced ejection fraction (HFrEF). The aim of this study was to evaluate, in a real-world population from a single centre, the feasibility of introducing SGLT2i and their interaction with other recommended drug classes. Methods: Consecutive patients affected by chronic heart failure (CHF) were evaluated beginning in January 2022. At the baseline clinical visit, both the patient's current medication and the prescribed treatments were recorded. Over a 6- to 12-month follow-up, changes in concomitant therapy were analysed. Results: At baseline, among 350 patients evaluated, only 17 (5%) were already taking SGLT2i: 13 with HFrEF, five with mildly reduced (HFmrEF), preserved (HFpEF) or improved (HFimpEF) ejection fraction. After the baseline assessment, SGLT2i were prescribed to 224 (64%) of the patients, including 179 (84%) with HFrEF, 27 (42%) with HFmrEF/HFimpEF, and 18 (22%) with HFpEF/HFimpEF. After follow-up, SGLT2i therapy was well tolerated and was associated with a significant increase in sacubitril/valsartan prescriptions and a decrease in diuretic use. Finally, a significant improvement in functional status and left ventricular systolic function after SGLT2i therapy was observed. Conclusions: In this single-centre, real-world study, SGLT2i were primarily prescribed to HFrEF patients who were already on other recommended drug classes for their treatment. Additionally, there was a noticeable enhancement in the prescribed therapy during a short-term follow-up. These findings further bolster the inclusion of this therapeutic approach in regular clinical practice. [ABSTRACT FROM AUTHOR]

Background: Two‐dimensional speckle tracking evaluation (2D‐STE) is a useful tool to evaluate the complexity of atrial function by the analysis of the different phases of atrial deformation and by the combination with Doppler measurements of diastolic function. Aim of the study: To evaluate the role of the left atrial (LA) strain parameters to predict worsening chronic heart failure (CHF). Methods: We enrolled outpatients affected by CHF referred to our heart failure unit. Each patient underwent a medical visit, an electrocardiogram (ECG), and an echocardiographic examination. LA function was assessed by 2D‐STE. The three phases of LA strain, that is, the reservoir (LAr), the conduit (LAcd), and the contraction (LAct)—were evaluated. Moreover, the ratio between E and LAr (E/LAr) and those between LAr and septal (LAr/Ees), lateral (LAr/Eel), and septal‐lateral (LAr/Eem) E/e' were measured. During follow‐up, the events related to worsening of heart failure were evaluated. Results: Two hundred eleven patients were enrolled. During a mean follow‐up of 14 ± 7 months, 37 patients showed at least one event related to heart failure worsening. At univariate Cox regression analysis, LAr, LAcd, LAct, E/LAr, LAr/Ees, LAr/Eel, and LAr/Eem were all associated with events related to heart failure worsening, but at multivariate regression analyses, only LAr (Hazard Ratio, HR:.95; 95% Confidence Interval, CI:.92–.99; p:.031), LAct (HR: 1.06; 95% CI: 1.01–1.12; p:.027), E/LAr (HR: 1.10; 95%CI: 1.0–1.16; p <.001), LAr/Ees (HR:.57; 95% CI:.37–.87; p:.010), and LAr/Eem (HR:.71; 95% CI:.53–.96; p:.026) remained significantly associated with the events. Finally, in a predictive model including the other relevant echocardiographic parameters LAr < 18%, LAct > −10.0%, LAr/Ees < 1.28, and E/LAr > 3.70 were associated with a statistically significant overall net reclassification improvement. Conclusions: In CHF patients, the measure of the LA reservoir and contraction by 2D‐STE is independently associated with heart failure worsening, but the accuracy in predicting the events is even greater when the reservoir is combined with the Doppler measures of diastolic function. [ABSTRACT FROM AUTHOR]

Background and aim of the study: The response to the increase in heart rate (HR) could be characterized by failure in both left ventricular (LV) and left atrial (LA) functions. This study aimed to evaluate the relationship between the increase in paced HR and the changes in LV and LA functions, assessed by two‐dimensional speckle tracking analysis. Methods: In a group of patients with an implantable cardioverter defibrillator (ICD) or pacemaker, the atrial paced rhythm was progressively increased from 60 to 70, from 70 to 80, and from 80 to 90 beats per minute (bpm). For each paced HR, using two‐dimensional speckle tracking analysis, LA reservoir (LAr), LA conduit (LAc), LA contraction (LAct), and LV global longitudinal strain (LV‐GLS) were evaluated every 10 bpm. Results: Of the 45 patients enrolled, a significant reduction in LAr was observed at higher HR. However, when the patients were dichotomized according to the HR‐related response of LV‐GLS, the worsening of LAr was observed in those with LV‐GLS worsening and not in those without (maximum LAR absolute changes −2.7 ± 7.2% vs. +2.7 ± 7.2%, respectively, p.028). Moreover, the worsening of LA and LV strain measures was associated with an increase in the estimated filling pressures. Conclusions: In patients with atrial paced rhythm, the increase in HR could be associated with worsening of LA and LV functions, as assessed by two‐dimensional speckle tracking analyses. These results offer new data on HR‐related atrioventricular function and could be useful for guiding the optimal HR responsiveness of the implanted devices. [ABSTRACT FROM AUTHOR]

(1) Background: Previous studies showed left ventricular (LV) and left atrial (LA) improvement and reverse remodeling after therapy with Sacubitril/Valsartan (S/V) in patients affected by heart failure with reduced ejection fraction (HFrEF). Therefore, we sought to investigate predictors of LA structural and functional reverse remodeling (LARR) in this setting of patients after therapy with S/V, focusing on left atrial strain parameters, such as peak atrial longitudinal strain (PALS). (2) Methods: Patients with HFrEF underwent clinical and echocardiographic evaluation at baseline and after six months of therapy with S/V. Measures of LA structure (LA volume index, LAVi) and function (LA emptying fraction (LAEF), PALS, LA conduit strain and peak atrial contraction strain (PACS) were also analyzed. Patients were divided in two groups, those with a LARR (relative reduction in LAVi > 15%, LARR+) and those without (LARR−). (3) Results: A total of 47 consecutive patients (66 ± 8 years, 85% male, mean LVEF 28 ± 6%) were enrolled in the study and followed up. A significant increase of LAEF (46 ± 13 vs. 37 ± 11%, p < 0.001) and a significant reduction of LAVi (42 ± 15 vs. 45 ± 15 mL/m2, p = 0.008) were found after 6 months of S/V therapy; 47% of the population showed LA reverse remodeling. LA strain parameters, PALS (19 ± 8 vs. 15 ± 7 %, p < 0.001) and LA conduit (−9.7 ± 5.2% vs. −7.6 ± 4.1%, p = 0.007) significantly improved after 6 months of S/V therapy. At multivariable stepwise regression analysis, changes in LV End Diastolic Volume (LVEDV) and PALS were significantly proportional to changes in LAVi values. (4) Conclusions: Six months of treatment with S/V in patients with HFrEF was associated with an improvement in LA functional reverse remodeling in a real-world scenario. LARR was not significantly correlated to baseline echocardiographic variables, but was proportional to changes in LV volumes and LA strain parameters. Finally, after S/V therapy, a strict connection between LA and LV reverse remodeling and between LA anatomical and functional reverse remodeling seems to be outlined. [ABSTRACT FROM AUTHOR]

Sacubitril/valsartan reduces heart failure (HF)-related hospitalizations and cardiovascular mortality in PARADIGM-HF and has become a foundational treatment for HF with reduced ejection fraction (HFrEF). However, data of its routine real-world use are limited, and evidence from Italian settings is lacking. The REAL.IT study aimed to characterize the demographics, pharmacotherapy, clinical characteristics and outcomes of sacubitril/valsartan-treated Italian patients with HFrEF. Electronic medical records of patients initiating sacubitril/valsartan from October 2016 to June 2019 at nine specialized hospital outpatient HF centers across Italy were reviewed. Overall, 924 adults (mean age 64.5 years, 84.6% male) were included. At baseline, 38.7% had an ischemic HF etiology, 45.9% hypertension, 23.2% atrial fibrillation, 25.4% diabetes mellitus, 26.1% an implantable cardioverter-defibrillator and 31.9% coronary artery bypass grafting. There were no clear patterns of patient selection over time. During follow-up, NYHA class improved in 37.5% of patients after a mean of 5.3 ± 3.8 months; 36.1% and 16.7% of patients were in NYHA class III during characterization and after one year of follow-up, respectively. Left ventricular ejection fraction (LVEF) improved ≥5% in 56.3% of patients at one year; 39.7% had ≥30% reduction of N-terminal pro-B-type natriuretic peptide; 2.2% had hyperkalemia during characterization and 2.6% during follow-up; and 3.8% had hypotension during characterization and 12% during follow-up. A total of 50 (5.8%) of patients had device implantation (ICD/CRT) during follow-up. HF-related hospitalization was recorded in 19.6% of patients during follow-up; 3.8% of patients died, approximately 1.3% from cardiovascular causes. Our real-world data confirm the favorable effectiveness and tolerability of sacubitril/valsartan observed in pivotal randomized controlled trials. [ABSTRACT FROM AUTHOR]

Pharmacotherapy of chronic heart failure with mildly reduced (HFmrEF) and preserved ejection fraction (HFpEF) remains challenging. We aimed to assess whether combined neuro-humoral modulation (NHM) (renin–angiotensin system inhibitors, betablockers, mineralocorticoid receptor antagonists) was differentially associated with outcome according to phenotype and age groups. Between 1999 and 2018 we recruited in a nationwide cardiology registry 4707 patients (HFmrEF n = 2298, HFpEF n = 2409) from three age groups: <65, 65–79 and 80+ years old. We analyzed clinical characteristics and 1 year all-cause mortality/cardiovascular hospitalization according to none/single, any double, or triple NHM. Prescription rates of no/single and triple NHM were 25.1% and 26.7% for HFmrEF; 36.5% and 17.9% for HFpEF patients, respectively. Older age was associated with higher prescription of no/single NHM in HFmrEF (ptrend = 0.001); the reverse was observed among HFpEF (ptrend = 0.005). Triple NHM increased over time in both phenotypes (all p for trend < 0.0001). Compared to no/single NHM, triple, but not double, NHM was associated with better outcomes in both HFmrEF (HR 0.700, 95%CI 0.505–0.969, p = 0.032) and HFpEF (HR 0.700, 95%CI 0.499–0.983, p = 0.039), with no interaction between NHM treatment and age groups (p = 0.58, p = 0.80, respectively). In a cardiology setting, among HF outpatients with EF > 40%, triple NHM treatment increased over time and was associated with better patient outcomes. [ABSTRACT FROM AUTHOR]

Levosimendan is an inodilator drug that, given its unique pharmacological actions and safety profile, represents a viable therapeutic option in patients with heart failure with reduced ejection fraction in the advanced stage of the disease (advHFrEF). Pulsed levosimendan infusion in patients with advHFrEF improves symptoms and clinical and hemodynamic status, prevents recurrent hospitalizations, and enables optimization of guidelines-directed medical therapy. Furthermore, considering its proprieties on right ventricular function and pulmonary circulation, levosimendan could be helpful for the prevention and treatment of the right ventricular dysfunction post-implanting a left ventricular assist device. However, to date, evidence on this issue is scarce and has yielded mixed results. Finally, preliminary experiences indicate that treatment with levosimendan at scheduled intervals may serve as a "bridge to transplant" strategy in patients with advHFrEF. In this review, we summarized the clinical pharmacology of levosimendan, the available evidence in the treatment of patients with advHFrEF, as well as a hypothesis for its use in patients with advanced heart failure with preserved ejection fraction. [ABSTRACT FROM AUTHOR]

Objective: Few prospective studies have assessed whether individuals with subclinical thyroid dysfunction are more likely to develop diabetes, with conflicting results. In this study, we conducted a systematic review of the literature and an individual participant data analysis of multiple prospective cohorts to investigate the association between subclinical thyroid dysfunction and incident diabetes. Methods: We performed a systematic review of the literature in Medline, Embase, and the Cochrane Library from inception to February 11, 2022. A two-stage individual participant data analysis was conducted to compare participants with subclinical hypothyroidism and subclinical hyperthyroidism vs euthyroidism at baseline and the adjusted risk of developing diabetes at follow-up. Results: Among 61 178 adults from 18 studies, 49% were females, mean age was 58 years, and mean follow-up time was 8.2 years. At the last available follow-up, there was no association between subclinical hypothyroidism and incidence of diabetes (odds ratio (OR) = 1.02, 95% CI: 0.88-1.17, I2 = 0%) or subclinical hyperthyroidism and incidence of diabetes (OR = 1.03, 95% CI: 0.82-1.30, I2 = 0%), in age- and sex-adjusted analyses. Time-to-event analysis showed similar results (hazard ratio for subclinical hypothyroidism: 0.98, 95% CI: 0.87-1.11; hazard ratio for subclinical hyperthyroidism: 1.07, 95% CI: 0.88-1.29). The results were robust in all sub-group and sensitivity analyses. Conclusions: This is the largest systematic review and individual participant data analysis to date investigating the prospective association between subclinical thyroid dysfunction and diabetes. We did not find an association between subclinical thyroid dysfunction and incident diabetes. Our results do not support screening patients with subclinical thyroid dysfunction for diabetes. Significance statement: Evidence is conflicting regarding whether an association exists between subclinical thyroid dysfunction and incident diabetes. We therefore aimed to investigate whether individuals with subclinical thyroid dysfunction are more prone to develop diabetes in the long run as compared to euthyroid individuals. We included data from 18 international cohort studies with 61 178 adults and a mean follow-up time of 8.2 years. We did not find an association between subclinical hypothyroidism or subclinical hyperthyroidism at baseline and incident diabetes at follow-up. Our results have clinical implications as they neither support screening patients with subclinical thyroid dysfunction for diabetes nor treating them in the hope of preventing diabetes in the future. [ABSTRACT FROM AUTHOR]

Background: Following the availability of new drugs for chronic heart failure (HF) with reduced ejection fraction (HFrEF), we sought to provide an updated and comparative synthesis of the evidence on HFrEF pharmacotherapy efficacy. Methods: We performed a Bayesian network meta‐analysis of phase 2 and 3 randomized controlled trials (RCTs) of medical therapy in HFrEF patient cohorts with more than 90% of the participants with left ventricular ejection fraction less than 45% and all‐cause mortality reported. Results: Sixty‐nine RCTs, accounting for 91,741 subjects, were evaluated. The step‐wise introduction of new drugs progressively decreased the risk of all‐cause death, up to reaching a random‐effects hazard ratio (HR) of 0.43 (95% credible intervals [CrI] 0.27–0.63) with beta blockers (BB), angiotensin‐converting enzyme inhibitors (ACEi), and mineralocorticoid receptor antagonist (MRA) versus placebo. The risk was further reduced by adding sodium–glucose cotransporter‐2 inhibitors (SGLT2i; HR 0.38, 95% CrI 0.22–0.60), ivabradine (HR 0.39, 95% CrI 0.21–0.64), or vericiguat (HR 0.40, 95% CrI 0.22–0.65) to neurohormonal inhibitors, and by angiotensin receptor–neprilysin inhibitor (ARNI), BB, and MRA (HR 0.36, 95% CrI 0.20–0.60). In a sensitivity analysis considering the ARNI and non‐ARNI subgroups of SGLT2i RCTs, the combination SGLT2i + ARNI + BB + MRA was associated with the lowest HR (0.28, 95% CrI 0.16–0.45 vs. 0.40, 95% CrI 0.24–0.60 for SGLT2i + BB + ACEi + MRA). Consistent results were obtained in sensitivity analyses and by calculating surface under the cumulative ranking area, as well as for cardiovascular mortality (information available for 56 RCTs), HF hospitalization (45 RCTs), and all‐cause hospitalization (26 RCTs). Conclusions: Combination medical therapy including neurohormonal inhibitors and newer drugs, especially ARNI and SGLT2i, confers the maximum benefit with regard to HFrEF prognosis. [ABSTRACT FROM AUTHOR]

Background: Sacubitril/valsartan plays a key role in improving left ventricular remodeling and prognosis in patients with heart failure with a reduced ejection fraction (HFrEF). Moreover, some data support its role in preserving renal function. In order to better clarify the effects of sacubitril/valsartan in cardiorenal syndrome, this study evaluated its effects on the renal resistance index (RRI). Methods: A group of patients with HFrEF was enrolled. The RRI was assessed with renal echo-color Doppler at enrollment and again after at least six months of sacubitril/valsartan treatment. In a subgroup of patients, the RRI was also evaluated at least six months before enrollment. The variations in echocardiographic parameters reflecting the left and right ventricular function, as well as creatinine and the estimated glomerular filtration rate, were also evaluated. Results: After treatment with sacubitril/valsartan, significant improvements in the left ventricular ejection fraction, and a decrease in the left atrial and ventricular volumes were observed. The RRI also showed a significant decrease. No relationship was found between the improvements in the parameters reflecting cardiac function and changes in the RRI. Conclusions: Treatment with sacubitril/valsartan is associated with improvements in both left ventricular function and renal perfusion, through decreasing the renal resistance. These data help to clarify the effects of the drug on cardiorenal syndrome progression. [ABSTRACT FROM AUTHOR]

Background: In patients with end‐stage renal disease (ESRD) undergoing hemodialysis, cardiovascular diseases, and in particular chronic heart failure are the leading causes of morbidity and mortality. Nevertheless, few data are available about the impact of fluid optimization on echocardiographic parameters of cardiac function in patients with ESRD. Methods and Results: In five patients with ESRD undergoing hemodialysis who had developed nonischemic dilated cardiomyopathy, an optimal fluid volume management based on a strict bioelectrical impedance analysis‐assisted dry weight target and dietary sodium and water restriction led to left ventricular reverse remodeling and improvement in hemodynamic parameters. The reverse remodeling further improved after kidney transplantation. Conclusions: This case series supports the possible beneficial effect of volume status optimization on cardiac function and the potential reversibility of cardiac dysfunction after kidney transplantation. [ABSTRACT FROM AUTHOR]

Cardiac remodelling is an adverse phenomenon linked to heart failure progression and an important contributor to heart failure severity. Cardiac remodelling could represent the real therapeutic goal in the treatment of patients with heart failure with reduced ejection fraction, being potentially reversed through different pharmacotherapies. Currently, there are well-established drugs such as angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers and β-blockers with anti-remodelling effects; recently, angiotensin receptor neprilysin inhibitor effects on inhibiting cardiac remodelling (improving N-terminal pro-B-type natriuretic peptide levels, echocardiographic parameters of reverse cardiac remodelling and right ventricular function in patients with heart failure with reduced ejection fraction) were demonstrated. More recently, hemodynamic consequences of gliflozins, reduced cardiac hydrostatic pressure as a possible cause of ventricular remodelling and hypertrophy were proposed to explain potential anti-remodelling effects of gliflozins. Gliflozins exert their cardioprotective effects by attenuating myofibroblast activity and collagen-mediated remodelling. Another postulated mechanism is represented by the reduction in sympathetic activity, through the reduction in renal afferent nervous activity and the suppression of central reflex mechanisms. Benefits of gliflozins on left ventricular hypertrophy, dilation, and systolic and diastolic function were also described. In this review, we aimed to provide a wide overview on cardiac remodelling with a particular focus on possible anti-remodelling effects of angiotensin receptor neprilysin inhibitors and gliflozins. [ABSTRACT FROM AUTHOR]

Brain natriuretic peptide (BNP) and its inactive N-terminal fragment, NT-proBNP, are serum biomarkers with key roles in the management of heart failure (HF). An increase in the serum levels of these peptides is closely associated with the pathophysiological mechanisms underlying HF such as the presence of structural and functional cardiac abnormalities, myocardial stretch associated with a high filling pressure and neuro-hormonal activation. As BNP and NT-proBNP measurements are possible, several studies have investigated their clinical utility in the diagnosis, prognostic stratification, monitoring and guiding therapy of patients with HF. BNP and NT-proBNP have also been used as criteria for enrollment in randomized trials evaluating the efficacy of new therapeutic strategies for HF. Nevertheless, the use of natriuretic peptides is still limited in clinical practice due to the controversial aspect of their use in different clinical settings. The purpose of this review is to discuss the main issues associated with using BNP and NT-proBNP serum levels in the management of patients with HF under current clinical and therapeutic scenarios. [ABSTRACT FROM AUTHOR]

Abstract: Background: A systematic evaluation focused on sensitivity and specificity of head-up tilt testing (HUT) for diagnosing vasovagal syncope has not been previously performed. We conducted a meta-analysis of studies comparing HUT outcome between patients with syncope of unknown origin and control subjects without previous syncope. Methods: We searched Pubmed and Embase databases for all English-only articles concerning case-control studies estimating the diagnostic yield of HUT, and selected 55 articles, published before March 2012, including 4361 patients and 1791 controls. The influence of age, test duration, tilt angle, and nitroglycerine or isoproterenol stimulation on tilt testing outcome was analyzed. Results: Head-up tilt testing demonstrated to have a good overall ability to discriminate between symptomatic patients and asymptomatic controls with an area under the summary receiver-operating characteristics curve of 0.84 and an adjusted diagnostic odds ratio of 12.15 (p<0.001). A significant inverse relationship between sensitivity and specificity of tilt testing for each study was observed (p<0.001). At multivariate analysis, advancing age and a 60° tilt angle showed a significant effect in reducing sensitivity and increasing specificity of the test. Nitroglycerine significantly raised tilt testing sensitivity by maintaining a similar specificity in comparison to isoproterenol. Conclusions: The results from this meta-analysis show the high overall performance of HUT for diagnosing vasovagal syncope. Our findings provide useful information for evaluating clinical and instrumental parameters together with pharmacological stressors influencing HUT accuracy. This could allow the drawing of tilt testing protocols tailored on the diagnostic needs of each patient with unexplained syncope. [Copyright &y& Elsevier]

Abstract: Although the pathophysiology of vasovagal syncope is not completely understood, the involvement of sympathetic nervous system alterations has been suggested. Since predisposition to fainting during orthostatic challenge may be associated with genetic variations, we sought to explore the role of genetic polymorphisms affecting sympathetic nervous system function in the susceptibility to tilt-induced vasovagal syncope. We genotyped 129 subjects with recurrent unexplained syncope who underwent tilt testing, and investigated the recurrence of syncope. The analysed polymorphisms were Arg492Cys (ADRA1A gene), Ser49Gly and Arg389Gly (ADRB1), Arg16Gly and Gln27Glu (ADRB2), 825C/T (GNB3), –1021C/T (DBH) and S/L (SLC6A4). No association of the aforementioned genetic variants with both tilt test outcomes and new syncopal episodes during follow-up was found. None of the considered polymorphisms influencing sympathetic activity is a major risk factor for vasovagal syncope in Italian patients. [Copyright &y& Elsevier]

Genetics may be involved in the pathophysiology of vasovagal syncope. The 3A/4A polymorphism of the EDN1 gene affects the expression of endothelin-1, and the H323H T/C polymorphism of the EDNRA gene encoding for the endothelin type A receptor has been associated with cardiovascular pathologies. As the endothelin system participates in the regulation of cardiovascular homeostasis, the aim of this study was to analyse the role of these genetic variants in influencing tilt-induced vasovagal syncope. We recorded the cardiovascular parameters of 107 otherwise healthy subjects with recurrent unexplained syncope who underwent a head-up tilt test; 58 (54%) fainted. In terms of the EDNRA polymorphism, eight subjects (8%) had the T/T genotype, 41 were heterozygous (38%) and 58 homozygous (54%) for the C allele. Sixty subjects (56%) carried homozygosis for the 3A allele of the EDN1 polymorphism and 47 were heterozygous (44%). The 4A allele was significantly more frequent in the patients who responded positively to the tilt test than in those who did not: the relative odds ratios and confidence intervals at univariate and multivariate analyses were respectively 2.37 (1.07–5.26) and 2.41 (1.05–5.49). Comparisons with a control group further supported these data. Among the tilt-positive patients, the carriers of the 4A allele were more likely to have a vasodepressive pattern than those who were homozygous for the 3A variant. In conclusion, the 3A/4A polymorphism of the EDN1 gene affects susceptibility to syncope, and the 4A variant associated with increased endothhelin-1 expression may promote vasodepressive hemodynamic responses during tilt testing. [ABSTRACT FROM AUTHOR]

As the endothelin system participates in the regulation of cardiovascular homeostasis, the aim of this study was to analyse the role of endothelin system polymorphisms in influencing tilt-induced vasovagal syncope. We evaluated 107 otherwise healthy subjects with recurrent unexplained syncope who underwent a head-up tilt test. All subjects were genotyped for the 3A/4A polymorphism of the EDN1 gene and the H323H T/C polymorphism of the EDNRA gene. Fifty-eight patients (54%) fainted. In terms of the EDNRA polymorphism, eight subjects (8%) had the T/T genotype, 41 were heterozygous (38%) and 58 homozygous (54%) for the C allele. Sixty subjects (56%) carried homozygosis for the 3A allele of the EDN1 polymorphism and 47 were heterozygous (44%). The 4A allele was significantly more frequent in the patients who responded positively to the tilt test than in those who did not: the relative odds ratios and confidence intervals at univariate and multivariate analyses were respectively 2.37 (1.07−5.26) and 2.41 (1.05−5.49). Comparisons with a control group further supported these data. Among the tilt-positive patients, the carriers of the 4A allele were more likely to have a vasodepressive pattern than those who were homozygous for the 3A variant. The 3A/4A polymorphism of the EDN1 gene affects susceptibility to syncope, and the 4A variant associated with increased endothelin-1 expression may promote vasodepressive hemodynamic responses during tilt testing. [ABSTRACT FROM AUTHOR]