Background: Unlike heart failure with reduced ejection fraction, there is no approved treatment for heart failure with preserved ejection fraction, the predominant phenotype in women. Therefore, there is a greater heart failure therapeutic deficit in women compared with men. Methods: In a prespecified subgroup analysis, we examined outcomes according to sex in the PARAGON-HF trial (Prospective Comparison of ARNI With ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction), which compared sacubitril-valsartan and valsartan in patients with heart failure with preserved ejection fraction. The primary outcome was a composite of first and recurrent hospitalizations for heart failure and death from cardiovascular causes. We also report secondary efficacy and safety outcomes. Results: Overall, 2479 women (51.7%) and 2317 men (48.3%) were randomized. Women were older and had more obesity, less coronary disease, and lower estimated glomerular filtration rate and NT-proBNP (N-terminal pro–B-type natriuretic peptide) levels than men. For the primary outcome, the rate ratio for sacubitril-valsartan versus valsartan was 0.73 (95% CI, 0.59–0.90) in women and 1.03 (95% CI, 0.84–1.25) in men ( P interaction = 0.017). The benefit from sacubitril-valsartan was attributable to reduction in heart failure hospitalization. The improvement in New York Heart Association class and renal function with sacubitril-valsartan was similar in women and men, whereas the improvement in Kansas City Cardiomyopathy Questionnaire clinical summary score was less in women than in men. The difference in adverse events between sacubitril-valsartan and valsartan was similar in women and men. Conclusions: As compared with valsartan, sacubitril-valsartan seemed to reduce the risk of heart failure hospitalization more in women than in men. Whereas the possible sex-related modification of the effect of treatment has several potential explanations, the present study does not provide a definite mechanistic basis for this finding. Clinical Trial Registration: https://www.clinicaltrials.gov . Unique identifier: NCT01920711.

Our aim was to develop a machine learning (ML)-based risk stratification system to predict 1-, 2-, 3-, 4-, and 5-year all-cause mortality from pre-implant parameters of patients undergoing cardiac resynchronization therapy (CRT). Multiple ML models were trained on a retrospective database of 1510 patients undergoing CRT implantation to predict 1- to 5-year all-cause mortality. Thirty-three pre-implant clinical features were selected to train the models. The best performing model [SEMMELWEIS-CRT score (perSonalizEd assessMent of estiMatEd risk of mortaLity With machinE learnIng in patientS undergoing CRT implantation)], along with pre-existing scores (Seattle Heart Failure Model, VALID-CRT, EAARN, ScREEN, and CRT-score), was tested on an independent cohort of 158 patients. There were 805 (53%) deaths in the training cohort and 80 (51%) deaths in the test cohort during the 5-year follow-up period. Among the trained classifiers, random forest demonstrated the best performance. For the prediction of 1-, 2-, 3-, 4-, and 5-year mortality, the areas under the receiver operating characteristic curves of the SEMMELWEIS-CRT score were 0.768 (95% CI: 0.674–0.861; P < 0.001), 0.793 (95% CI: 0.718–0.867; P < 0.001), 0.785 (95% CI: 0.711–0.859; P < 0.001), 0.776 (95% CI: 0.703–0.849; P < 0.001), and 0.803 (95% CI: 0.733–0.872; P < 0.001), respectively. The discriminative ability of our model was superior to other evaluated scores. The SEMMELWEIS-CRT score (available at semmelweiscrtscore.com) exhibited good discriminative capabilities for the prediction of all-cause death in CRT patients and outperformed the already existing risk scores. By capturing the non-linear association of predictors, the utilization of ML approaches may facilitate optimal candidate selection and prognostication of patients undergoing CRT implantation.

De novo implanted cardiac resynchronization therapy with defibrillator (CRT-D) reduces the risk of morbidity and mortality in patients with left bundle branch block, heart failure and reduced ejection fraction (HFrEF). However, among HFrEF patients with right ventricular pacing (RVP), the efficacy of CRT-D upgrade is uncertain. In this multicentre, randomized, controlled trial, 360 symptomatic (New York Heart Association Classes II–IVa) HFrEF patients with a pacemaker or implantable cardioverter defibrillator (ICD), high RVP burden ≥ 20%, and a wide paced QRS complex duration ≥ 150 ms were randomly assigned to receive CRT-D upgrade (n = 215) or ICD (n = 145) in a 3:2 ratio. The primary outcome was the composite of all-cause mortality, heart failure hospitalization, or <15% reduction of left ventricular end-systolic volume assessed at 12 months. Secondary outcomes included all-cause mortality or heart failure hospitalization. Over a median follow-up of 12.4 months, the primary outcome occurred in 58/179 (32.4%) in the CRT-D arm vs. 101/128 (78.9%) in the ICD arm (odds ratio 0.11; 95% confidence interval 0.06–0.19; P < .001). All-cause mortality or heart failure hospitalization occurred in 22/215 (10%) in the CRT-D arm vs. 46/145 (32%) in the ICD arm (hazard ratio 0.27; 95% confidence interval 0.16–0.47; P < .001). The incidence of procedure- or device-related complications was similar between the two arms [CRT-D group 25/211 (12.3%) vs. ICD group 11/142 (7.8%)]. In pacemaker or ICD patients with significant RVP burden and reduced ejection fraction, upgrade to CRT-D compared with ICD therapy reduced the combined risk of all-cause mortality, heart failure hospitalization, or absence of reverse remodelling. Main inclusion criteria and randomization by arms showing the result of 360 patients (215 CRT-D vs. 145 ICD) analysed by intention to treat. Primary and secondary outcomes showing a substantial treatment effect of CRT-D compared with ICD alone. Among patients with HF and reduced LVEF with intermittent or permanent RV pacing, CRT-D upgrade resulted in a lower incidence of the composite of all-cause mortality, HF hospitalization, or <15% decrease in LVESV as the primary outcome. Secondary outcome of all-cause mortality and HF hospitalization also proved a substantially lower incidence in CRT-D patients compared with ICD. CI, confidence interval; CRT-D, cardiac resynchronization therapy with defibrillator; HF, heart failure; HR, hazard ratio; ICD, implantable cardioverter defibrillator; LVEF, left ventricular ejection fraction; LVESV, left ventricular end-systolic volume; OR, odds ratio; RV, right ventricular.

Three major mechanisms contribute to right ventricular (RV) pump function: (i) shortening of the longitudinal axis with traction of the tricuspid annulus towards the apex; (ii) inward movement of the RV free wall; (iii) bulging of the interventricular septum into the RV and stretching the free wall over the septum. The relative contribution of the aforementioned mechanisms to RV pump function may change in different pathological conditions. Our aim was to develop a custom method to separately assess the extent of longitudinal, radial and anteroposterior displacement of the RV walls and to quantify their relative contribution to global RV ejection fraction using 3D data sets obtained by echocardiography. Accordingly, we decomposed the movement of the exported RV beutel wall in a vertex based manner. The volumes of the beutels accounting for the RV wall motion in only one direction (either longitudinal, radial, or anteroposterior) were calculated at each time frame using the signed tetrahedron method. Then, the relative contribution of the RV wall motion along the three different directions to global RV ejection fraction was calculated either as the ratio of the given direction’s ejection fraction to global ejection fraction and as the frame-by-frame RV volume change (∆V/∆t) along the three motion directions. The ReVISION (Right VentrIcular Separate wall motIon quantificatiON) method may contribute to a better understanding of the pathophysiology of RV mechanical adaptations to different loading conditions and diseases.

Aims There are limited and contradictory data on the effects of CRT with implantable cardioverter defibrillator (CRT‐D) on mortality as compared with CRT with pacemaker (CRT‐P). Methods and results We evaluated the long‐term outcome of patients implanted with a CRT‐D or CRT‐P device in our high‐volume single‐centre experience. Data on all‐cause mortality were derived from clinic visits and the Hungarian National Healthcare Fund Death Registry. Kaplan–Meier survival analyses and multivariate Cox regression models were used to evaluate all‐cause mortality in patients with CRT‐D vs. CRT‐P, stratified by the aetiology of cardiomyopathy. From 2000 to 2011, 1122 CRT devices, 693 CRT‐P (LVEF 28.2 ± 7.4%) and 429 CRT‐D (LVEF 27.6 ± 6.4%), were implanted at our centre. During the median follow‐up of 28 months, 379 patients died from any cause, 250 patients (36%) with an implanted CRT‐P and 129 patients (30%) with an implanted CRT‐D. There was no evidence of mortality benefit in patients implanted with a CRT‐D compared with a CRT‐P in the total cohort [hazard ratio (HR) 0.98, 95% confidence interval (CI) 0.73–1.32, P = 0.884]. In patients with ischaemic cardiomyopathy, CRT‐D treatment was associated with a significant 30% risk reduction in all‐cause mortality compared with an implanted CRT‐P (HR 0.70, 95% CI 0.51–0.97, P = 0.03). In non‐ischaemic patients, there was no mortality benefit of CRT‐D over CRT‐P (HR 0.98, 95% CI 0.73–1.32, P = 0.894, interaction P‐value = 0.15). Conclusions In heart failure patients with ischaemic cardiomyopathy, CRT‐D was associated with a mortality benefit compared with CRT‐P, but no benefit of CRT‐D over CRT‐P in mortality was observed in non‐ischaemic cardiomyopathy.

Patients with conventional pacemakers or implanted defibrillators are often considered for cardiac resynchronization therapy (CRT). Our aim was to summarize the available evidences regarding the clinical benefits of upgrade procedures. A systematic literature search was performed from studies published between 2006 and 2017 in order to compare the outcome of CRT upgrade vs. de novo implantations. Outcome data on all-cause mortality, heart failure events, New York Heart Association (NYHA) Class, QRS narrowing and echocardiographic parameters were analysed. A total of 16 reports were analysed comprising 489,568 CRT recipients, of whom 468,205 patients underwent de novo and 21,363 upgrade procedures. All-cause mortality was similar after CRT upgrade compared to de novo implantations (RR 1.19, 95% CI 0.88–1.60, p = 0.27). The risk of heart failure was also similar in both groups (RR 0.96, 95% CI 0.70–1.32, p = 0.81). There was no significant difference in clinical response after CRT upgrade compared to de novo implantations in terms of improvement in left ventricular ejection fraction (ΔEF de novo − 6.85% vs. upgrade − 9.35%; p = 0.235), NYHA class (ΔNYHA de novo − 0.74 vs. upgrade − 0.70; p = 0.737) and QRS narrowing (ΔQRS de novo − 9.6 ms vs. upgrade − 29.5 ms; p = 0.485). Our systematic review and meta-analysis of currently available studies reports that CRT upgrade is associated with similar risk for all-cause mortality compared to de novo resynchronization therapy. Benefits on reverse remodelling and functional capacity improved similarly in both groups suggesting that CRT upgrade may be safely and effectively offered in routine practice. Clinical Trial Registration: Prospero Database—CRD42016043747