Appraisal of partial anomalous pulmonary venous drainage through a lumped-parameter mathematical model: a new pathophysiological proof of concept.

OBJECTIVES: Haemodynamic determinants of the ratio between pulmonary and systemic flow (Qp/Qs) in partial anomalous pulmonary venous return (PAPVR) are still not fully understood. Indeed, among patients with the same number of lung segments draining anomalously, a great variability is observed in terms of right ventricular overload. The aim of this study was to test the hypothesis that the anatomic site of drainage, affecting the total circuit impedance, independently influences the magnitude of shunt estimated by Qp/Qs. A zero-dimensional (0D) lumped parameter mathematical model was developed and validated on a sample of patients. METHODS: We developed a 0D lumped parameter model, using time varying elastances for heart chambers, RLC Windkessel circuits for the systemic and pulmonary circulations. Patients, were categorized into vena cava (VC) type (including left drainage to anomimous vein) and right atrium type (RA). The mathematical model is a system of ordinary differential equations that are numerically solved by means of the ode15s solver in the Matlab environment. RESULTS: The model showed an increase of Qp/Qs with the increase of the number of anomalous veins. With the same number of anomalous veins, Qp/Qs was lower in patients with anomalous drainage to the vena cava (VC) as compared with right atrium (RA) The validation sample consisted of 49 patients (27, 55% females). As predicted by the model, patients with PAPVR with VC type displayed a lower invasive and CMR Qp/Qs as compared with drainage to RA: 1.4 (1.2-1.7) and 1.45 (1.25-1.6) versus 2 (1.75-2.1) and 1.9 (1.6-2) p < 0.05. After stratifying for number of lung territories a lower Qp/Qs was measured in patients with VC PAPVR as compared with RA. CONCLUSIONS: In patients with PAPVR, the site of anomalous drainage modulates the Qp/Qs. According to the model, this effect is mediated by the post-capillary impedance of the circuit and significantly decreases with the increase of pulmonary vascular resistances.

Obesity paradox in patients with reduced ejection fraction eligible for device implantation - an observational study.

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 2 26% vs. BMI 25- < 30 kg/m2 37% vs. BMI ≥ 30 kg/m2 48%; P 2 71% vs. BMI 25- < 30 kg/m2 74% vs. BMI ≥ 30 kg/m2 82%; P 2 group, 61% in the BMI 25- < 30 kg/m2 group and 58% in the BMI ≥ 30 kg/m2 group (log-rank P2 25% vs. BMI 25- < 30 kg/m2 28% vs. BMI ≥ 30 kg/m2 26%; P = 0.48). Left ventricular ejection fraction improved significantly in all patient groups (BMI < 25 kg/m2 median ∆ $$ \Delta $$ -LVEF 7% vs. BMI 25- < 30 kg/m2 median ∆ $$ \Delta $$ -LVEF 7.5% vs. BMI ≥ 30 kg/m2 median ∆ $$ \Delta $$ -LVEF 6%; P < 0.0001) with a similar proportion of developing reverse remodeling (BMI < 25 kg/m2 58% vs. BMI 25- < 30 kg/m2 61% vs. BMI ≥ 30 kg/m2 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.

Sodium Zirconium Cyclosilicate in HFrEF and Hyperkalemia: REALIZE-K Design and Baseline Characteristics.

BACKGROUND: Mineralocorticoid receptor antagonists (MRAs) improve outcomes in patients with heart failure and reduced ejection fraction (HFrEF). However, MRAs are often underused because of hyperkalemia concerns. OBJECTIVES: The purpose of this study was to assess whether sodium zirconium cyclosilicate (SZC), a nonabsorbed crystal that traps and rapidly lowers potassium, enables MRA use in patients with HFrEF and prevalent hyperkalemia (or at high risk). METHODS: REALIZE-K is a prospective, double-blind, placebo-controlled trial in patients with HFrEF (NYHA functional class II-IV; left ventricular ejection fraction ≤40%), optimal therapy (except MRA), and prevalent hyperkalemia (or at high risk). During the open-label run-in, all participants underwent protocol-mandated spironolactone titration (target: 50 mg daily); those with prevalent (cohort 1) or incident (cohort 2) hyperkalemia during titration started SZC. Participants achieving normokalemia while on spironolactone ≥25 mg daily were randomized to continuing SZC or matching placebo for 6 months. The primary composite endpoint was proportion of participants with optimal response (normokalemia, on spironolactone ≥25 mg daily, no rescue for hyperkalemia [months 1-6]). RESULTS: Of 365 patients (run-in), 202 were randomized. Baseline characteristics included mean age 70 years, prevalent comorbidities (78% estimated glomerular filtration rate <60 mL/min/1.73 m2, 38% atrial fibrillation/flutter), high N-terminal pro B-type natriuretic peptide (median 1,136 pg/mL), and high HFrEF therapy use (64% sacubitril/valsartan, 96% beta-blocker, 42% sodium glucose co-transporter 2 inhibitor). At randomization, 78% were receiving spironolactone 50 mg daily. CONCLUSIONS: REALIZE-K is the first trial to evaluate whether SZC can enable rapid and safe MRA optimization and long-term continuation in patients with HFrEF and prevalent/high risk of hyperkalemia. (Study to Assess Efficacy and Safety of SZC for the Management of High Potassium in Patients with Symptomatic HFrEF Receiving Spironolactone [REALIZE-K]; NCT04676646).

The prevalence of frailty and its effect on the outcome in cardiac resynchronization therapy patients.

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.

Phenogrouping and risk stratification of patients undergoing cardiac resynchronization therapy upgrade using topological data analysis.

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 ).

Topological data analysis to identify cardiac resynchronization therapy patients exhibiting benefit from an implantable cardioverter-defibrillator.

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. Topological data analysis to identify phenogroups of CRT patients in whom CRT-D is associated with better survival than CRT-P. AF atrial fibrillation, CRT cardiac resynchronization therapy, CRT-D cardiac resynchronization therapy defibrillator, CRT-P cardiac resynchronization therapy pacemaker, DM diabetes mellitus, HTN hypertension, LBBB left bundle branch block, LVEF left ventricular ejection fraction, MDS multidimensional scaling, MRA mineralocorticoid receptor antagonist, NYHA New York Heart Association.

Long-term outcome of cardiac resynchronization therapy patients in the elderly.

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.

The Prognostic Value of Anemia in Patients with Preserved, Mildly Reduced and Recovered Ejection Fraction.

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.

Predicting the survival benefit of cardiac resynchronization therapy with defibrillator function for non-ischemic heart failure-Role of the Goldenberg risk score.

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.

Long-term survival following upgrade compared with de novo cardiac resynchronization therapy implantation: a single-centre, high-volume experience.

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.