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Introduction Arrhythmia‐induced cardiomyopathy (AIC) is an underrecognized condition resulting in left ventricular systolic dysfunction (LVSD) that is primarily caused by atrial fibrillation (AFib). The relationship between AIC, right ventricular (RV) function, and quality of life (QoL) has not been well studied. Methods We performed a post‐hoc analysis of our AIC trial in which we prospectively screened for patients with tachyarrhythmia and newly diagnosed, otherwise unexplained LVSD. Following rhythm restoration, patients were followed up at 2, 4, and 6 months. Only patients with persistent sinus rhythm were analyzed. RV function was assessed via echocardiography (tricuspid annular plane systolic excursion [TASPE] and fractional area change [FAC]) and QoL by the Minnesota Living with Heart Failure Questionnaire. Results Of a total of 50 patients recovering from LVSD, 41 were diagnosed with AIC and 9 with non‐AIC. Initially, RV function was reduced in the AIC group and recovered after rhythm restoration, whereas no relevant changes were noted in the non‐AIC group. QoL was reduced in both groups and also improved after rhythm restoration. Regression analysis identified low TAPSE as a predictive parameter for AIC diagnosis and worse QoL in AIC patients. Conclusion We demonstrated that RV function and QoL are impaired in patients with AIC. Six months after rhythm restoration, TAPSE may serve as an early indicator of AIC while also correlating with QoL. This underscores the importance of detailed echocardiographic evaluation with a focus on RV function in patients with concomitant tachyarrhythmia and LVSD. Initial tricuspid annular plane systolic excursion (TAPSE), quality of life (QoL) as measured by the Minnesota Living with Heart Failure Questionnaire and left ventricular ejection fraction (LVEF) during atrial fibrillation (AFib) or atrial flutter (AFlut) were reduced in patients with arrhythmia‐induced cardiomyopathy (AIC) compared with values at the end of 6 months of follow‐up in sinus rhythm. In this paper we show that low TAPSE (optimal cut‐off 18.5 mm) has good predictive power for the diagnosis of AIC and that a low quality of life is associated with low TAPSE. Values in red indicate the relative percent the baseline values were reduced compared with the post‐recovery measurement at the end of follow‐up.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure and cardiovascular death among patients with chronic heart failure and a left ventricular ejection fraction of 40% or less. Whether SGLT2 inhibitors are effective in patients with a higher left ventricular ejection fraction remains less certain. We randomly assigned 6263 patients with heart failure and a left ventricular ejection fraction of more than 40% to receive dapagliflozin (at a dose of 10 mg once daily) or matching placebo, in addition to usual therapy. The primary outcome was a composite of worsening heart failure (which was defined as either an unplanned hospitalization for heart failure or an urgent visit for heart failure) or cardiovascular death, as assessed in a time-to-event analysis. Over a median of 2.3 years, the primary outcome occurred in 512 of 3131 patients (16.4%) in the dapagliflozin group and in 610 of 3132 patients (19.5%) in the placebo group (hazard ratio, 0.82; 95% confidence interval [CI], 0.73 to 0.92; P<0.001). Worsening heart failure occurred in 368 patients (11.8%) in the dapagliflozin group and in 455 patients (14.5%) in the placebo group (hazard ratio, 0.79; 95% CI, 0.69 to 0.91); cardiovascular death occurred in 231 patients (7.4%) and 261 patients (8.3%), respectively (hazard ratio, 0.88; 95% CI, 0.74 to 1.05). Total events and symptom burden were lower in the dapagliflozin group than in the placebo group. Results were similar among patients with a left ventricular ejection fraction of 60% or more and those with a left ventricular ejection fraction of less than 60%, and results were similar in prespecified subgroups, including patients with or without diabetes. The incidence of adverse events was similar in the two groups. Dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death among patients with heart failure and a mildly reduced or preserved ejection fraction. (Funded by AstraZeneca; DELIVER ClinicalTrials.gov number, NCT03619213.).

Aims To analyse the predictive value of advanced markers of right ventricular (RV) function and RV‐pulmonary arterial (PA) coupling in forecasting long‐term left ventricular (LV) improvement in de novo heart failure with reduced ejection fraction (HFrEF). Methods and results 260 patients (mean age 57 years, 68% men) from the PROLONG‐II study were included. PROLONG‐II analysed patients with new‐onset HFrEF receiving a wearable cardioverter‐defibrillator. For this substudy, RV free wall longitudinal strain (RVFWS), tricuspid annular plane systolic excursion (TAPSE), fractional area change (FAC), and right ventricular‐pulmonary artery (RV‐PA) coupling ratios [RVFWS/systolic pulmonary artery pressure (PASP), TAPSE/PASP and FAC/PASP] at baseline and 3‐month follow‐up (early follow‐up) were examined. LV improvement and non‐improvement were defined as an LV ejection fraction (LVEF) of >35% or ≤35% at last available (long‐term) follow‐up. The median follow‐up was 31.5 months (IQR: 18.2–45.4), and 151 (58%) patients experienced LV improvement in the long term. No significant differences of RV function and markers of RV‐PA coupling were observed at baseline; however, the subgroup of patients with long‐term LVEF improvement showed better RV function at early follow‐up (RVFWS −20.9 ± 4.3 vs. −18.5 ± 5.1%, TAPSE 19.7 ± 5.1 vs. 17.4 ± 4.9 mm, FAC 39.7 ± 8.5 vs. 35.2 ± 9.4%, all P < 0.01). In multivariable analysis, RVFWS at early follow‐up was shown to be an independent predictor of later LV recovery [odds ratio 1.078 (95% confidence interval 1.010–1.150), P < 0.05]. The non‐improvers exhibited worse RV‐PA coupling at early follow‐up [RVFWS/PASP 0.82 ± 0.35 vs. 0.65 ± 0.35%/mmHg, TAPSE/PASP 0.71 (0.55–1.00) vs. 0.54 (0.35–0.75) mm/mmHg, FAC/PASP 1.54 ± 0.61 vs. 1.24 ± 0.75%/mmHg, all P < 0.01]. RVFWS/PASP identified RV‐PA uncoupling was associated with a higher risk of all‐cause mortality (hazard ratio 4.64, 95% confidence interval 1.34–16.09, P = 0.033). Conclusions Persistent RV dysfunction, as indicated by both standard and advanced echocardiographic markers during the early follow‐up period, implies a reduced potential for long‐term LV recovery in patients with newly diagnosed HFrEF.

Background Liraglutide is an antidiabetic agent with cardioprotective effect. The purpose of this study is to test efficacy of liraglutide to improve diabetic cardiomyopathy in patients with diabetes mellitus type 2 (DM2) without cardiovascular disease. Methods Patients with DM2 were randomly assigned to receive liraglutide 1.8 mg/day or placebo in this double-blind trial of 26 weeks. Primary outcome measures were LV diastolic function (early (E) and late (A) transmitral peak flow rate, E/A ratio, early deceleration peak (Edec), early peak mitral annular septal tissue velocity (Ea) and estimated LV filling pressure (E/Ea), and systolic function (stroke volume, ejection fraction, cardiac output, cardiac index and peak ejection rate) assessed with CMR. Intention-to-treat analysis of between-group differences was performed using ANCOVA. Mean estimated treatment differences (95% confidence intervals) are reported. Results 23 patients were randomized to liraglutide and 26 to placebo. As compared with placebo, liraglutide significantly reduced E (− 56 mL/s (− 91 to − 21)), E/A ratio (− 0.17 (− 0.27 to − 0.06)), Edec (− 0.9 mL/s 2  * 10 −3 (− 1.3 to − 0.2)) and E/Ea (− 1.8 (− 3.0 to − 0.6)), without affecting A (3 mL/s (− 35 to 41)) and Ea (0.4 cm/s (− 0.9 to 1.4)). Liraglutide reduced stroke volume (− 9 mL (− 16 to − 2)) and ejection fraction (− 3% (− 6 to − 0.1)), but did not change cardiac output (− 0.4 L/min (− 0.9 to 0.2)), cardiac index (− 0.1 L/min/m 2 (− 0.4 to 0.1)) and peak ejection rate (− 46 mL/s (− 95 to 3)). Conclusions Liraglutide reduced early LV diastolic filling and LV filling pressure, thereby unloading the left ventricle. LV systolic function reduced and remained within normal range. Future studies are needed to investigate if liraglutide-induced left ventricular unloading slows progression of diabetic cardiomyopathy into symptomatic stages. Trial registration ClinicalTrials.gov: NCT01761318.

In this multicenter, randomized trial comparing early rhythm control with usual care in patients with early atrial fibrillation and cardiovascular conditions, early rhythm control reduced the rate of death from cardiovascular causes and cardiovascular complications and did not affect the number of nights in the hospital.

Background: Minors are considered the main consumer group of energy drinks (EDs). The aim of this study was to investigate the acute effects of ED consumption on left ventricular (LV) hemodynamics and efficiency in healthy children and teenagers. Methods: This study was a randomized, single-blind, placebo-controlled, crossover clinical trial. Study participants consumed a weight-adjusted amount of an ED or a placebo on two consecutive days. LV hemodynamics and efficiency parameters were evaluated non-invasively by generating LV pressure–volume loops (PVLs) through simultaneous echocardiography and blood pressure measurement. Results: A total of 24 children and teenagers (14.90 ± 2.27 years, 13 male) were included in the present study. Conventional echocardiographic parameters of LV function did not show significant differences between both beverage groups. The non-invasive generation of LV PVLs revealed a significantly lower cardiac efficiency 240 min after the ED consumption compared to the placebo intake (140.72 (133.21–149.73) mmHg vs. 135.60 (124.78–140.33) mmHg, p < 0.01). Conclusions: Acute ED consumption is associated with a significantly lower cardiac efficiency in healthy minors. The generation of non-invasive LV PVLs might be beneficial in the assessment of subtle changes in LV efficiency. Further studies need to investigate the influence of chronic ED consumption on LV function and morphology.

The optimal timing of aortic valve replacement in asymptomatic patients with aortic stenosis is uncertain. Replacement fibrosis, as assessed by midwall (nonischemic) late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) imaging, is an irreversible marker of left ventricular decompensation in aortic stenosis. Once established, it progresses rapidly and is associated with poor long-term prognosis in a dose-dependent manner. The objective of this multicenter prospective randomized controlled trial is to determine whether early aortic valve replacement in asymptomatic patients with severe aortic stenosis can improve the adverse prognosis associated with midwall LGE. Patients will be screened for likelihood of having LGE with electrocardiography or high-sensitivity troponin I. Those at high risk will proceed to CMR imaging. Approximately 400 patients with midwall LGE will be randomized 1:1 to early valve replacement or routine care. Those who do not exhibit midwall LGE will continue with routine care and be randomized to a study registry or no further follow-up. Follow-up will be annual for approximately 3 years until the number of required outcome events is achieved. The primary endpoint is a composite of all-cause mortality and unplanned aortic stenosis–related hospitalization. The expected event rate is 25.0% in the routine care arm and 13.4% in the early intervention arm over the first 2 years; 88 observed primary outcome events will give 90% power at 5% significance level. Key secondary endpoints include all-cause mortality, sudden cardiac death, stroke, and symptomatic status. The EVOLVED trial is the first multicenter randomized controlled trial to compare early aortic valve replacement to routine care in asymptomatic patients with severe aortic stenosis and midwall LGE.

Impaired contractility is a feature of heart failure with reduced ejection fraction. We assessed the pharmacokinetics and effects on cardiac function and structure of the cardiac myosin activator, omecamtiv mecarbil. In this randomised, double-blind study, done at 87 sites in 13 countries, we recruited patients with stable, symptomatic chronic heart failure and left ventricular ejection fraction 40% or lower. Patients were randomly assigned equally, via an interactive web response system, to receive 25 mg oral omecamtiv mecarbil twice daily (fixed-dose group), 25 mg twice daily titrated to 50 mg twice daily guided by pharmacokinetics (pharmacokinetic-titration group), or placebo for 20 weeks. We assessed the maximum concentration of omecamtiv mecarbil in plasma (primary endpoint) and changes in cardiac function and ventricular diameters. This trial is registered with ClinicalTrials.gov, number NCT01786512. From March 17, 2014, to March 5, 2015, we enrolled 150 patients in the fixed-dose omecamtiv mecarbil group and 149 in the pharmacokinetic-titration and placebo groups. Mean maximum concentration of omecamtiv mecarbil at 12 weeks was 200 (SD 71) ng/mL in the fixed-dose group and 318 (129) ng/mL in the pharmacokinetic-titration group. For the pharmacokinetic-titration group versus placebo group at 20 weeks, least square mean differences were as follows: systolic ejection time 25 ms (95% CI 18–32, p<0·0001), stroke volume 3·6 mL (0·5–6·7, p=0·0217), left ventricular end-systolic diameter −1·8 mm (−2·9 to −0·6, p=0·0027), left ventricular end-diastolic diameter −1·3 mm, (−2·3 to 0·3, p=0·0128), heart rate −3·0 beats per min (−5·1 to −0·8, p=0·0070), and N-terminal pro B-type natriuretic peptide concentration in plasma −970 pg/mL (−1672 to −268, p=0·0069). The frequency of adverse clinical events did not differ between groups. Omecamtiv mecarbil dosing guided by pharmacokinetics achieved plasma concentrations associated with improved cardiac function and decreased ventricular diameter. Amgen.

Non-apoptotic forms of cell death can trigger sterile inflammation through the release of danger-associated molecular patterns, which are recognized by innate immune receptors. However, despite years of investigation the mechanisms which initiate inflammatory responses after heart transplantation remain elusive. Here, we demonstrate that ferrostatin-1 (Fer-1), a specific inhibitor of ferroptosis, decreases the level of pro-ferroptotic hydroperoxy-arachidonoyl-phosphatidylethanolamine, reduces cardiomyocyte cell death and blocks neutrophil recruitment following heart transplantation. Inhibition of necroptosis had no effect on neutrophil trafficking in cardiac grafts. We extend these observations to a model of coronary artery ligation-induced myocardial ischemia reperfusion injury where inhibition of ferroptosis resulted in reduced infarct size, improved left ventricular systolic function, and reduced left ventricular remodeling. Using intravital imaging of cardiac transplants, we uncover that ferroptosis orchestrates neutrophil recruitment to injured myocardium by promoting adhesion of neutrophils to coronary vascular endothelial cells through a TLR4/TRIF/type I IFN signaling pathway. Thus, we have discovered that inflammatory responses after cardiac transplantation are initiated through ferroptotic cell death and TLR4/Trif-dependent signaling in graft endothelial cells. These findings provide a platform for the development of therapeutic strategies for heart transplant recipients and patients, who are vulnerable to ischemia reperfusion injury following restoration of coronary blood flow.

Right ventricular (RV) dysfunction following left ventricular (LV) failure is associated with poor prognosis. RV remodeling is thought initiated by the increase in the afterload of RV due to secondary pulmonary hypertension (PH) to impaired LV function; however, RV molecular changes might occur in earlier stages of the disease. cGMP (cyclic guanosine monophosphate)-phosphodiesterase 5 (PDE5) inhibitors, widely used to treat PH through their pulmonary vasorelaxation properties, have shown direct cardiac benefits, but their impacts on the RV in LV diseases are not fully determined. Here we show that RV molecular alterations occur early in the absence of RV hemodynamic changes during LV pressure-overload and are ameliorated by PDE5 inhibition. Two-day moderate LV pressure-overload (transverse aortic constriction) neither altered RV pressure/ function nor RV weight in mice, while it induced only mild LV hypertrophy. Importantly, pathological molecular features were already induced in the RV free wall myocardium, including up-regulation of gene markers for hypertrophy and inflammation, and activation of extracellular signal-regulated kinase (ERK) and calcineurin. Concomitant PDE5 inhibition (sildenafil) prevented induction of such pathological genes and activation of ERK and calcineurin in the RV as well as in the LV. Importantly, dexamethasone also prevented these RV molecular changes, similarly to sildenafil treatment. These results suggest the contributory role of inflammation to the early pathological interventricular interaction between RV and LV. The current study provides the first evidence for the novel early molecular cross-talk between RV and LV, preceding RV hemodynamic changes in LV disease, and supports the therapeutic strategy of enhancing cGMP signaling pathway to treat heart diseases.