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Background: Current guidelines recommend considering multiple factors while deciding between cardiac resynchronization therapy with a defibrillator (CRT-D) or a pacemaker (CRT-P). Nevertheless, it is still challenging to pinpoint those candidates who will benefit from choosing a CRT-D device in terms of survival., Objective: We aimed to use topological data analysis (TDA) to identify phenogroups of CRT patients in whom CRT-D is associated with better survival than CRT-P., Methods: We included 2603 patients who underwent CRT-D (54%) or CRT-P (46%) implantation at Semmelweis University between 2000 and 2018. The primary endpoint was all-cause mortality. We applied TDA to create a patient similarity network using 25 clinical features. Then, we identified multiple phenogroups in the generated network and compared the groups' clinical characteristics and survival., Results: Five- and 10-year mortality were 43 (40-46)% and 71 (67-74)% in patients with CRT-D and 48 (45-50)% and 71 (68-74)% in those with CRT-P, respectively. TDA created a circular network in which we could delineate five phenogroups showing distinct patterns of clinical characteristics and outcomes. Three phenogroups (1, 2, and 3) included almost exclusively patients with non-ischemic etiology, whereas the other two phenogroups (4 and 5) predominantly comprised ischemic patients. Interestingly, only in phenogroups 2 and 5 were CRT-D associated with better survival than CRT-P (adjusted hazard ratio 0.61 [0.47-0.80], p < 0.001 and adjusted hazard ratio 0.84 [0.71-0.99], p = 0.033, respectively)., Conclusions: By simultaneously evaluating various clinical features, TDA may identify patients with either ischemic or non-ischemic etiology who will most likely benefit from the implantation of a CRT-D instead of a CRT-P., (© 2023. The Author(s).)

Aims: Patients with obesity have an overall higher cardiovascular risk, at the same time obesity could be associated with a better outcome in a certain subgroup of patients, a phenomenon known as the obesity paradox. Data are scarce in candidates for cardiac resynchronization therapy (CRT). We aimed to investigate the association between body mass index (BMI) and all-cause mortality in patients eligible for CRT., Methods: Altogether 1,585 patients underwent cardiac resynchronization therapy between 2000-2020 and were categorized based on their BMI, 459 (29%) patients with normal weight (BMI < 25 kg/m2), 641 (40%) patients with overweight (BMI 25- < 30 kg/m2) and 485 (31%) with obesity (BMI ≥ 30 kg/m2). The primary endpoint was all-cause mortality, heart transplantation, and left ventricular assist device implantation. We assessed periprocedural complications and 6-month echocardiographic response., Results: Normal-weight patients were older compared to patients with overweight or obesity (70 years vs. 69 years vs. 68 years; P ‹0.001), respectively. Sex distribution, ischaemic aetiology, and CRT-D implantation rates were similar in the three patient groups. Diabetes mellitus (BMI < 25 kg/m 2 26% vs. BMI 25- < 30 kg/m 2 37% vs. BMI ≥ 30 kg/m 2 48%; P ‹0.001) and hypertension (BMI < 25 kg/m 2 71% vs. BMI 25- < 30 kg/m 2 74% vs. BMI ≥ 30 kg/m 2 82%; P ‹0.001) were more frequent in patients with overweight and obesity. During the mean follow-up time of 5.1 years, 973 (61%) reached the primary endpoint, 66% in the BMI < 25 kg/m 2 group, 61% in the BMI 25- < 30 kg/m 2 group and 58% in the BMI ≥ 30 kg/m 2 group (log-rank P‹0.05). Patients with obesity showed mortality benefit over normal-weight patients (HR 0.78; 95%CI 0.66-0.92; P = 0.003). The obesity paradox was present in patients free from diabetes, atrial fibrillation, and ischemic events. Periprocedural complication rates did not differ in the three groups (BMI < 25 kg/m 2 25% vs. BMI 25- < 30 kg/m 2 28% vs. BMI ≥ 30 kg/m 2 26%; P = 0.48). Left ventricular ejection fraction improved significantly in all patient groups (BMI < 25 kg/m 2 median ∆ $$ \Delta $$ -LVEF 7% vs. BMI 25- < 30 kg/m 2 median ∆ $$ \Delta $$ -LVEF 7.5% vs. BMI ≥ 30 kg/m 2 median ∆ $$ \Delta $$ -LVEF 6%; P < 0.0001) with a similar proportion of developing reverse remodeling (BMI < 25 kg/m 2 58% vs. BMI 25- < 30 kg/m 2 61% vs. BMI ≥ 30 kg/m 2 57%; P = 0.48); P = 0.75)., Conclusions: The obesity paradox was present in our HF cohort at long-term, patients underwent CRT implantation with obesity and free of comorbidities showed mortality benefit compared to normal weight patients. Patients with obesity showed similar echocardiographic response and safety outcomes compared to normal weight patients., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Frailty is a complex clinical syndrome associated with aging and comorbidities, which correlates with unfavorable outcomes. However, in heart failure patients, frailty is very common, data is scarce about those, who are eligible for Cardiac Resynchronization Therapy (CRT) implantation. We investigated the incidence of frailty and the association of Frailty Index (FI) with the outcome. Thirty baseline clinical parameters were used by the Rockwood cumulative deficit method to determine patients' FI in our single-center cohort. Based on previous studies, patients with FI ≤ 0.210 were considered as non-frail, those with FI 0.10-0.210 were classified in Frail-1, with FI > 0.10 in Frail-2 groups, respectively. Echocardiographic response after 12 months and all-cause mortality were investigated by frailty groups. Among 1004 included patients, 75 (7%) were considered Non-frail, 271 (27%) grouped in Frail-1, and 658 (66%) in Frail-2 with a median FI of 0.36 (0.28-0.43). Patients in Frail-2 group were older, with more comorbidities compared with non-frail patients or those in Group Frail-1. During the median follow-up time of 4.8 years, 29 (39%) patients died in the Non-frail, 140 (52%) in Frail-1, and 471 (72%) in the Frail-2 groups (log-rank p < 0.001). Group Frail-2 showed an unfavorable outcome compared to the non-frail (HR 2.49, 95%CI 1.92-3.22; p < 0.001) and the Frail-1 group (1.83, 95%CI 1.55-2.16; p < 0.001). In our HFrEF patients eligible for CRT implantation, patients were exceedingly vulnerable with a high prevalence of frailty. The calculated frailty index was associated with outcome and proved to be prevalent in individual risk stratification., (© 2023. The Author(s).)

Choosing the optimal device during cardiac resynchronization therapy (CRT) upgrade can be challenging. Therefore, we sought to provide a solution for identifying patients in whom upgrading to a CRT-defibrillator (CRT-D) is associated with better long-term survival than upgrading to a CRT-pacemaker (CRT-P). To this end, we first applied topological data analysis to create a patient similarity network using 16 clinical features of 326 patients without prior ventricular arrhythmias who underwent CRT upgrade. Then, in the generated circular network, we delineated three phenogroups exhibiting significant differences in clinical characteristics and risk of all-cause mortality. Importantly, only in the high-risk phenogroup was upgrading to a CRT-D associated with better survival than upgrading to a CRT-P (hazard ratio: 0.454 (0.228-0.907), p = 0.025). Finally, we assigned each patient to one of the three phenogroups based on their location in the network and used this labeled data to train multi-class classifiers to enable the risk stratification of new patients. During internal validation, an ensemble of 5 multi-layer perceptrons exhibited the best performance with a balanced accuracy of 0.898 (0.854-0.942) and a micro-averaged area under the receiver operating characteristic curve of 0.983 (0.980-0.986). To allow further validation, we made the proposed model publicly available ( https://github.com/tokmarton/crt-upgrade-risk-stratification )., (© 2023. The Author(s).)

Heart failure (HF) is a leading cause of mortality and hospitalization in the elderly. However, data are scarce about their response to device treatment such as cardiac resynchronization therapy (CRT). We aimed to evaluate the age-related differences in the effectiveness of CRT, procedure-related complications, and long-term outcome. Between 2000 and 2020, 2656 patients undergoing CRT implantation were registered and analyzed retrospectively. Patients were divided into 3 groups according to their age: group I, < 65; group II, 65-75; and group III, > 75 years. The primary endpoint was the echocardiographic response defined as a relative increase > 15% in left ventricular ejection fraction (LVEF) within 6 months, and the secondary endpoint was the composite of all-cause mortality, heart transplantation, or left ventricular assist device implantation. Procedure-related complications were also assessed. After implantation, LVEF showed significant improvement both in the total cohort [28% (IQR 24/33) vs. 35% (IQR 28/40); p < 0.01)] and in each subgroup (27% vs. 34%; p < 0.01, 29% vs. 35%; p < 0.01, 30% vs. 35%; p < 0.01). Response rate was similar in the 3 groups (64% vs. 62% vs. 56%; p = 0.41). During the follow-up, 1574 (59%) patients died. Kaplan-Meier curves revealed a significantly lower survival rate in the older groups (log-rank p < 0.001). The cumulative complication rates were similar among the three age groups (27% vs. 28% vs. 24%; p = 0.15). Our results demonstrate that CRT is as effective and safe therapy in the elderly as for young ones. The present data suggest that patients with appropriate indications benefit from CRT in the long term, regardless of age., (© 2023. The Author(s).)

Aims: Primary prevention of sudden cardiac death (SCD) in non-ischemic heart failure (HF) patients remains a topic of debate at cardiac resynchronization therapy (CRT) implantation requiring individual risk assessment. Using the Goldenberg SCD risk score, we aimed to predict, which non-ischemic HF patients will benefit from the addition of an implantable cardioverter defibrillator (ICD) to CRT at long-term., Methods: Between 2000 and 2018 non-ischemic HF patients undergoing CRT implantation were collected into our retrospective registry. The Goldenberg risk score (GRS) was calculated by the presence of atrial fibrillation, New York Heat Association (NYHA) class > 2, age > 70 years, blood urea nitrogen > 26 mg/dl and QRS > 120 ms. The primary endpoint was all-cause mortality, heart transplantation or left ventricular assist device implantation., Results: From 667 patients, 347 (52%) underwent cardiac resynchronization therapy-pacemaker (CRT-P), 320 (48%) cardiac resynchronization therapy-defibrillator (CRT-D) implantations. During the median follow up time of 4.3 years, 306 (46%) patients reached the primary endpoint (CRT-D 37% vs. CRT-P 63%; p < 0.001). CRT-D patients were younger (64 vs. 69 years; p < 0.001), infrequently females (26 vs. 39%; p < 0.001), and had a lower ejection fraction (27 vs. 29%; p < 0.01) compared to CRT-P patients. After GRS calculation, patients were dichotomized by low (< 3) and high (≥ 3) scores. CRT-D patients with low GRS showed a mortality benefit compared to CRT-P (HR 0.68; 95% CI 0.48-0.96; p = 0.03), high-risk patients did not (HR 0.84; 95% CI 0.62-1.13; p = 0.26)., Conclusion: In our non-ischemic cohort, patients with low GRS showed a clear long-term mortality benefit by adding ICD to CRT, however, in high-risk patients no further benefit could be observed., Competing Interests: AK receives consulting fees from Medtronic and Biotronik, and receives payment or honoraria for lectures from Novartis, Bayer, Boehringer Ingelheim, Astra Zeneca, Medtronic Biotronik, and Boston Scientific. BM receives grants or has contracts with Abbott, Astra Zeneca, Argint International, Biotronik, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, CSL Behring, Daiichi Sankyo, Cerenis Therapeutics SA DUKE Clinical Institut, Eli Lilly, Medtronic, Novartis, Terumo, St. Jude, Zoll and VIFOR Pharma, and receives lecture fees from Abbott, Astra Zeneca, Biotronik, Boehringer Ingelheim, and Novartis. LG receives lecture fees from Biotronik, Medtronic, Johnson & Johnson Medical, and Abbott outside the submitted work. EZ reports lecture and advisory fees from Biotronik, Medtronic, Boston Scientific, and Zoll Medical, outside the submitted work. RP reports lecture fees from Biotronik, Medtronic, and Abbott outside the submitted work. LM reports lecture fees from Biotronik, Medtronic, and Abbott outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Merkel, Schwertner, Behon, Kuthi, Veres, Osztheimer, Papp, Molnár, Zima, Gellér, Kosztin and Merkely.)

Background: We lack data on the effect of single premature ventricular contractions (PVCs) on the clinical and echocardiographic response after cardiac resynchronization therapy (CRT) device implantation. We aimed to assess the predictive value of PVCs at early, 1 month-follow up on echocardiographic response and all-cause mortality., Methods: In our prospective, single-center study, 125 heart failure patients underwent CRT implantation based on the current guidelines. Echocardiographic reverse remodeling was defined as a ≥ 15% improvement in left ventricular ejection fraction (LVEF), end-systolic volume (LVESV), or left atrial volume (LAV) measured 6 months after CRT implantation. All-cause mortality was investigated by Wilcoxon analysis., Results: The median number of PVCs was 11,401 in those 67 patients who attended the 1-month follow-up. Regarding echocardiographic endpoints, patients with less PVCs develop significantly larger LAV reverse remodeling compared to those with high number of PVCs. During the mean follow-up time of 2.1 years, 26 (21%) patients died. Patients with a higher number of PVCs than our median cut-off value showed a higher risk of early all-cause mortality (HR 0.97; 95% CI 0.38-2.48; P = 0.04). However, when patients were followed up to 9 years, its significance diminished (HR 0.78; 95% CI 0.42-1.46; P = 0.15)., Conclusions: In patients undergoing CRT implantation, lower number of PVCs predicted atrial remodeling and showed a trend for a better mortality outcome. Our results suggest the importance of the early assessment of PVCs in cardiac resynchronization therapy and warrant further investigations., (© 2022. The Author(s).)

Data on the relevance of anemia in heart failure (HF) patients with an ejection fraction (EF) > 40% by subgroup-preserved (HFpEF), mildly reduced (HFmrEF) and the newly defined recovered EF (HFrecEF)-are scarce. Patients with HF symptoms, elevated NT-proBNP, EF ≥ 40% and structural abnormalities were registered in the HFpEF-HFmrEF database. We described the outcome of our HFpEF-HFmrEF cohort by the presence of anemia. Additionally, HFrecEF patients were also selected from HFrEF patients who underwent resynchronization and, as responders, reached 40% EF. Using propensity score matching (PSM), 75 pairs from the HFpEF-HFmrEF and HFrecEF groups were matched by their clinical features. After PMS, we compared the survival of the HFpEF-HFmrEF and HFrecEF groups. Log-rank, uni-and multivariate regression analyses were performed. From 375 HFpEF-HFmrEF patients, 42 (11%) died during the median follow-up time of 1.4 years. Anemia (HR 2.77; 95%CI 1.47-5.23; p < 0.01) was one of the strongest mortality predictors, which was also confirmed by the multivariate analysis (aHR 2.33; 95%CI 1.21-4.52; p = 0.01). Through PSM, the outcomes for HFpEF-HFmrEF and HFrecEF patients with anemia were poor, exhibiting no significant difference. In HFpEF-HFmrEF, anemia was an independent mortality predictor. Its presence multiplied the mortality risk in those with EF ≥ 40%, regardless of HF etiology.

Aims: Patients with a pacemaker or implantable cardioverter-defibrillator are often considered for cardiac resynchronization therapy (CRT). However, limited comprehensive data are available regarding their long-term outcomes., Methods and Results: Our retrospective registry included 2524 patients [1977 (78%) de novo, 547 (22%) upgrade patients] with mild to severe symptoms, left ventricular ejection fraction ≤35%, and QRS ≥ 130ms. The primary outcome was the composite of all-cause mortality, heart transplantation (HTX), or left ventricular assist device (LVAD) implantation; secondary endpoints were death from any cause and post-procedural complications. In our cohort, upgrade patients were older [71 (65-77) vs. 67 (59-73) years; P < 0.001], were less frequently females (20% vs. 27%; P = 0.002) and had more comorbidities than de novo patients. During the median follow-up time of 3.7 years, 1091 (55%) de novo and 342 (63%) upgrade patients reached the primary endpoint. In univariable analysis, upgrade patients exhibited a higher risk of mortality/HTX/LVAD than the de novo group [hazard ratio (HR): 1.41; 95% confidence interval (CI): 1.23-1.61; P < 0.001]. However, this difference disappeared after adjusting for covariates (adjusted HR: 1.12; 95% CI: 0.86-1.48; P = 0.402), or propensity score matching (propensity score-matched HR: 1.10; 95% CI: 0.95-1.29; P = 0.215). From device-related complications, lead dysfunction (3.1% vs. 1%; P < 0.001) and pocket infections (3.7% vs. 1.8%; P = 0.014) were more frequent in the upgrade group compared to de novo patients., Conclusion: In our retrospective analysis, upgrade patients had a higher risk of all-cause mortality than de novo patients, which might be attributable to their more significant comorbidity burden. The occurrence of lead dysfunction and pocket infections was more frequent in the upgrade group., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: The relative importance of variables explaining sex-related differences in outcomes is scarcely explored in patients undergoing cardiac resynchronization therapy (CRT). We sought to implement and evaluate machine learning (ML) algorithms for the prediction of 1- and 3-year all-cause mortality in CRT patients. We also aimed to assess the sex-specific differences in predictors of mortality utilizing ML. Methods: Using a retrospective registry of 2,191 CRT patients, ML models were implemented in 6 partially overlapping patient subsets (all patients, females, or males with 1- or 3-year follow-up). Each cohort was randomly split into training (80%) and test sets (20%). After hyperparameter tuning in the training sets, the best performing algorithm was evaluated in the test sets. Model discrimination was quantified using the area under the receiver-operating characteristic curves (AUC). The most important predictors were identified using the permutation feature importances method. Results: Conditional inference random forest exhibited the best performance with AUCs of 0.728 (0.645-0.802) and 0.732 (0.681-0.784) for the prediction of 1- and 3-year mortality, respectively. Etiology of heart failure, NYHA class, left ventricular ejection fraction, and QRS morphology had higher predictive power, whereas hemoglobin was less important in females compared to males. The importance of atrial fibrillation and age increased, while the importance of serum creatinine decreased from 1- to 3-year follow-up in both sexes. Conclusions: Using ML techniques in combination with easily obtainable clinical features, our models effectively predicted 1- and 3-year all-cause mortality in CRT patients. Sex-specific patterns of predictors were identified, showing a dynamic variation over time., Competing Interests: BM receives lecture fees from Biotronik, Medtronic, and Abbott. ZT is a co-founder and CEO of Argus Cognitive, Inc., holds equity in the company, and receives financial compensation for his work. AS and MC are employees of Argus Cognitive, Inc., and receive compensation for their work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tokodi, Behon, Merkel, Kovács, Tősér, Sárkány, Csákvári, Lakatos, Schwertner, Kosztin and Merkely.)

Aims: Preferring side branch of coronary sinus during cardiac resynchronization therapy (CRT) implantation has been empirical due to the limited data on the association of left ventricular (LV) lead position and long-term clinical outcome. We evaluated the long-term all-cause mortality by LV lead non-apical positions and further characterized them by interlead electrical delay (IED)., Methods and Results: In our retrospective database, 2087 patients who underwent CRT implantation were registered between 2000 and 2018. Those with non-apical LV lead locations were classified into anterior (n = 108), posterior (n = 643), and lateral (n = 1336) groups. All-cause mortality was assessed by Kaplan-Meier and Cox analyses. Echocardiographic response was measured 6 months after CRT implantation. During the median follow-up time of 3.7 years, 1150 (55.1%) patients died-710 (53.1%) with lateral, 78 (72.2%) with anterior, and 362 (56.3%) with posterior positions. When we investigated the risk of all-cause mortality, there was a significantly lower rate of death in patients with lateral LV lead location when compared with those with an anterior (P < 0.01) or posterior (P < 0.01) position. Multivariate analysis after adjustment for relevant clinical covariates such as age, sex, ischaemic aetiology, left bundle branch block morphology, atrial fibrillation, and device type revealed consistent results that lateral position is associated with a significant risk reduction of all-cause mortality when compared with anterior [hazard ratio 0.69; 95% confidence interval (CI) 0.55-0.87; P < 0.01] or posterior (hazard ratio 0.84; 95% CI 0.74-0.96; P < 0.01) position. When echocardiographic response was evaluated within the lateral group, patients with an IED longer than 110 ms (area under the receiver operating characteristic curve, 0.63; 95% CI 0.53-0.73; P = 0.012) showed 2.1 times higher odds of improvement in echocardiographic response 6 months after the implantation., Conclusions: In this study, we proved in a real-world patient population that after CRT implantation, lateral LV lead location was associated with long-term mortality benefit and is superior to both anterior and posterior positions. Moreover, patients with this position showed the greatest echocardiographic response over 110 ms IED., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)