QRS Fragmentation in Preserved Ejection Fraction Heart Failure: Functional Insights, Pathological Correlates, and Prognosis.

Background Fragmented QRS (fQRS) morphology as a surrogate marker of the possible presence of myocardial scarring has been shown to confer a higher risk in patients with reduced ejection fraction heart failure. We aimed to investigate the pathophysiological correlates and prognostic implications of fQRS in patients with heart failure with preserved ejection fraction (HFpEF). Methods and Results We consecutively studied 960 patients with HFpEF (76.4±12.7 years, men: 37.2%). fQRS was assessed using a body surface ECG during hospitalization. QRS morphology was available and classified into 3 categories among 960 subjects with HFpEF as non-fQRS, inferior fQRS, and anterior/lateral fQRS groups. Despite comparable clinical features in most baseline demographics among the 3 fQRS categories, anterior/lateral fQRS showed significantly higher B-type natriuretic peptide/troponin levels (both P<0.001), with both the inferior and anterior/lateral fQRS HFpEF groups demonstrating a higher degree of unfavorable cardiac remodeling, greater extent of myocardial perfusion defect, and slower coronary flow phenomenon (all P<0.05). Patients with anterior/lateral fQRS HFpEF exhibited significantly altered cardiac structure/function and more impaired diastolic indices (all P<0.05). During a median of 657 days follow-up, the presence of anterior/lateral fQRS conferred a doubled HF re-admission risk (adjusted hazard ratio 1.90, P<0.001), with both inferior and anterior/lateral fQRS having a higher risk of cardiovascular and all-cause death (all P<0.05) by using Cox regression models. Conclusions The presence of fQRS in HFpEF was associated with more extensive myocardial perfusion defects and worsened mechanics, which possibly denotes a more severe involvement of cardiac damage. Early recognition in such patients with HFpEF likely benefits from targeted therapeutic interventions.

Insights on Distinct Left Atrial Remodeling Between Atrial Fibrillation and Heart Failure With Preserved Ejection Fraction.

Background: Heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF) commonly coexist with overlapping pathophysiology like left atrial (LA) remodeling, which might differ given different underlying mechanisms. Objectives: We sought to investigate the different patterns of LA wall remodeling in AF vs. HFpEF. Methods: We compared LA wall characteristics including wall volume (LAWV), wall thickness (LAWT), and wall thickness heterogeneity (LAWT[SD]) and LA structure, function among the controls (without AF or HFpEF, n = 115), HFpEF alone (n = 59), AF alone (n = 37), and HFpEF+AF (n = 38) groups using multi-detector computed tomography and echocardiography. Results: LA wall remodeling was most predominant and peak atrial longitudinal strain (PALS) was worst in HFpEF+AF patients as compared to the rest. Despite lower E/e' (9.8 ± 3.8 vs. 13.4 ± 6.4) yet comparable LA volume, LAWT and PALS in AF alone vs. HFpEF alone, LAWV [12.6 (11.6-15.3) vs. 12.0 (10.2-13.7); p = 0.01] and LAWT(SD) [0.68 (0.61-0.71) vs. 0.60 (0.56-0.65); p < 0.001] were significantly greater in AF alone vs. HFpEF alone even after multi-variate adjustment and propensity matching. After excluding the HFpEF+AF group, both LAWV and LAWT [SD] provided incremental values when added to PALS or LAVi (all p for net reclassification improvement <0.05) in discriminating AF alone, with LAWT[SD] yielding the largest C-statistic (0.78, 95% CI: 0.70-0.86) among all LA wall indices. Conclusions: Despite a similar extent of LA enlargement and dysfunction in HFpEF vs. AF alone, larger LAWV and LAWT [SD] can distinguish AF from HFpEF alone, suggesting the distinct underlying pathophysiological mechanism of LA remodeling in AF vs. HFpEF.

Left ventricular dysfunction in atrial fibrillation and heart failure risk.

AIMS: This study aimed to investigate the functional correlate, clinical relevance, and prognostic implications of novel left ventricular (LV) deformations in patients with atrial fibrillation (AF). METHODS AND RESULTS: LV deformational indices, including peak global longitudinal strain (GLS), systolic strain rates (SRs), and early diastolic strain rates (SRe) were measured in a large-scale AF population. We related such measures to key clinical heart failure (HF) markers, conventional echocardiographic ventricular parameters, and clinical outcomes. Among 1483 subjects with newly diagnosed AF (mean age, 71.6 ± 12.4 years; 55.5% male), worsened GLS (mean, - 12.6 ± 3.9%) and strain rates (SRs and SRe: mean, - 0.86 ± 0.27 and 1.25 ± 0.41 1/s, respectively) by our three-beat measures were independently correlated with higher C-reactive protein, N-terminal pro-B-type natriuretic peptide, higher E/e', more impaired LV ejection fraction (LVEF < 50%), lower estimated glomerular filtration rate, permanent AF, and prevalent HF (all P < 0.05). LV deformations by three-beat analysis well correlated with the respective results of traditional methods. Abnormal GLS (>- 14.7%) was common in our cohort (67.8%) despite an averaged preserved LVEF (58.4 ± 14.2%), with worse GLS and SRe being associated with higher composite HF re-admissions/death during the 2.9 year follow-up (inter-quartile range, 1.6-4.1 years) in multivariate models incorporating key LV indices (LVEF, LV mass index, and E/e') (all P < 0.001). Sensitivity analysis by excluding those with regional wall motion abnormality showed broadly similar findings. An improved risk reclassification was observed when GLS and SRe were separately added to the LVEF. Comparison of the AF cohort with a fully matched independent non-AF cohort at the same baseline LVEF level showed a substantially lower GLS [- 13.2 ± 3.8% (AF) vs. 18.1 ± 3.2% (non-AF)] and higher clinical events rate (hazard ratio, 1.41 [95% confidence interval, 1.14-1.75]; log-rank P = 0.002) in the AF cohort. CONCLUSIONS: Impaired LV function defined by myocardial deformation was common in patients with AF and provides independent prognostic values over conventional measures with improved risk prediction. Our data highlight the need for implementing cardiac deformations in daily practice for patients with AF.

Electrocardiographic characteristics for predicting idiopathic right ventricular outflow tract premature ventricular complex-induced cardiomyopathy.

PURPOSE: In spite of several proposed predictors for premature ventricular complex (PVC)-induced cardiomyopathy (PVC-CMP), the specific ECG features of idiopathic right ventricular outflow tract (RVOT) PVC-CMP remain unknown. METHODS: A total of 130 patients (49 males, mean age 44 years) with symptomatic and drug-refractory idiopathic RVOT PVCs undergoing radiofrequency catheter ablation (RFCA) were enrolled. The patients were categorized into two groups, including those with and without RVOT PVC-CMP (left ventricular ejection fraction (LVEF) < 50%, n = 25 and LVEF ≥ 50%, n = 105, respectively). The 12-lead PVC morphologies were assessed. RESULTS: Patients with RVOT PVC-CMP had a lower LVEF (42 ± 5% vs. 60 ± 7%, P < 0.01) and higher PVC burden (24 ± 14% vs. 15 ± 11%, P = 0.02) when compared to patients without RVOT PVC-CMP. The PVC features in those with PVC-CMP displayed a significantly wider QRS duration (143 ± 14 ms vs. 132 ± 17 ms, P < 0.01) and higher peak deflection index (PDI; 0.60 ± 0.07 vs. 0.55 ± 0.08, P < 0.01). A multivariate analysis demonstrated that the QRS duration (odds ratio (OR) 1.130, 95% confidence interval (CI) 1.020-1.253, P = 0.02) and PDI (OR 1.240, 95% CI 1.004-1.532, P = 0.04) were independently associated with RVOT PVC-CMP. Based on the receiver-operating characteristic analysis, a QRS duration > 139 ms and PDI > 0.57 could predict RVOT PVC-CMP (area under the curve (AUC) 0.710 and AUC 0.690, respectively). The elimination and suppression of PVCs by RFCA resulted in the recovery of the LVEF in RVOT PVC-CMP. CONCLUSIONS: The ECG parameters, including a wider QRS duration and higher PDI, could predict the development of RVOT PVC-CMP, which could be effectively treated by RFCA.

Dose-related ethanol intake, Cx43 and Nav1.5 remodeling: Exploring insights of altered ventricular conduction and QRS fragmentation in excessive alcohol users.

BACKGROUND: Chronic, excessive ethanol intake has been linked with various electrical instabilities, conduction disturbances, and even sudden cardiac death, but the underlying cause for the latter is insufficiently delineated. METHODS: We studied surface electrocardiography (ECG) in a community-dwelling cohort with moderate-to-heavy daily alcohol intake (grouped as >90g/day, ≤90g/day, and nonintake). RESULTS: Compared with nonintake, heavier alcohol users showed markedly widened QRS duration and higher prevalence of QRS fragmentation (64.3%, 50.9%, and 33.7%, respectively, χ2 12.0, both p<0.05) on surface ECG across the 3 groups. These findings were successfully recapitulated in 14-week-old C57BL/6 mice that were chronically given a 4% or 6% alcohol diet and showed dose-related slower action potential upstroke, reduced resting membrane potential, and disorganized or decreased intraventricular conduction (all p<0.05). Immunodetection further revealed increased ventricular collagen I depots with Cx43 downregulation and remodeling, together with clustered and diminished membrane Nav1.5 distribution. Administration of Cx43 blocker (heptanol) and Nav1.5 inhibitor (tetrodotoxin) in the mice each attenuated the suppression ventricular conduction compared with nonintake mice (p<0.05). CONCLUSIONS: Chronic excessive alcohol ingestion is associated with dose-related phenotypic intraventricular conduction disturbances and QRS fragmentation that can be recapitulated in mice. The mechanisms may involve suppressed gap junction and sodium channel functions, together with enhanced cardiac fibrosis that may contribute to arrhythmogenesis.

Genetic Polymorphisms of Alcohol Metabolizing Enzymes and Alcohol Consumption are Associated With Asymptomatic Cardiac Remodeling and Subclinical Systolic Dysfunction in Large Community-Dwelling Asians.

AIMS: Excessive consumption of alcoholic beverages is associated with cardiac remodeling and cardiomyopathy. We examined the possible association of alcohol use, common Asian genetic variants in genes involved in alcohol metabolism, and cardiac structures/functions alterations. METHODS: A prospective, community-dwelling survey among individuals with available complete echocardiography examined the associations of alcohol use, cardiac structure/functions, and three common alcohol metabolizing genetic variants, including aldehyde dehydrogenase 2 (ALDH2), alcohol dehydrogenase 1B (ADH1B) and cytochrome P450 (CYP) isoform 2E1 (CYP2E1). RESULTS: Among 1577 participants (mean age: 53 ± 9, 59.7% female), we observed that in subjects with more frequent weekly ethanol intake showed greater left ventricle (LV) mass, more impaired diastolic functions, and reduced global longitudinal strain (GLS), systolic (SRs) and early diastolic strain rates (SRe) (P<0.05). After propensity matching for clinical confounders (n = 330:30 for frequent users and non-users), frequent alcohol use and subjects carrying ALDH2 (A/G or A/A), ADH1B (A/A) or CYP2E1(T/C or T/T) polymorphisms were all associated with worse GLSRs and GLSRe, with combined alcohol use and any given genetic variant aggravated these associations (all P < 0.05). Finally, we observed Gene-Gene synergistic effects on LV functional decline in frequent alcohol users by using linear mixed effect model (all interaction P < 0.05). CONCLUSIONS: Among East Asians, even moderate alcohol consumption can confer subclinical adverse effects on cardiac systolic functions, which was most pronounced in subjects carrying common variants in alcohol metabolizing genes. These findings challenge the notion of beneficial influences of less heavy ethanol consumption on the heart, especially among East Asians. SHORT SUMMARY: This study evaluated the association of level of alcohol consumption and genetic variants in genes involved in alcohol metabolism with changes in cardiac function in East Asians. Even moderate alcohol use conferred subclinical adverse effects on cardiac systolic functions, which were most pronounced in subjects carrying common alcohol metabolizing genes.

Changes of Atrial Natriuretic Peptides after Defibrillation Threshold Testing Predicted Future Ventricular Arrhythmia Event.

BACKGROUND: We investigated the change of natriuretic peptides during defibrillation threshold (DFT) testing and its relationship with future ventricular arrhythmia (VA) events in patients implanted with an implantable cardioverter defibrillator (ICD). METHODS: Atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and c-type natriuretic peptide (CNP) were measured in 21 patients (mean age 61 ± 13 years; 67% male) undergoing ICD implantation. Blood samples of the patients were drawn at pre-implantation, 30 minutes, 60 minutes, and 24 hours after DFT testing. The patients were followed and divided into two groups according to the occurrence of VA in 18 months. The biomarker levels and their changes were compared in patients with and without further VA. RESULTS: The pre-implantation ANP levels were higher at pre-implantation and increased significantly at 30 minutes after DFT testing (Δ30minANP) among patients with VA events. The BNP and CNP levels did not change significantly after DFT testing in both groups. The area under curve was 0.82 for the change in Δ30minANP determining further ventricular events. The optimal Δ30minANP cutoff value was 0.51 pg/ml, with sensitivity of 0.83 and specificity of 0.68. Multivariable analysis confirmed that patients with Δ30minANP more than 0.51 pg/ml have a higher risk of further ventricular events (hazard ratio 39.8, 95% confidence interval: 2.87-553.01, p = 0.006). The pre-implantation ANP level could not predict future VA events (hazard ratio 1.06, 95% CI: 1.00-1.14, p = 0.06). CONCLUSIONS: The increase of ANP concentration after DFT testing predicted future VA events after ICD implantation while the BNP and CNP levels did not predict future VA events.

The Associations between Various Ectopic Visceral Adiposity and Body Surface Electrocardiographic Alterations: Potential Differences between Local and Remote Systemic Effects.

BACKGROUND: The associations between pericardial adiposity and altered atrial conduction had been demonstrated. However, data comparing differential effects of various body sites visceral adiposity on atrial and ventricular electrocardiographic alterations remains largely unknown. METHODS AND RESULTS: We assessed both peri-cardial fat (PCF) and peri-aortic visceral adiposity (TAT) using dedicated computed tomography (CT) software (Aquarius 3D Workstation, TeraRecon, San Mateo, CA, USA), with anthropometrics including body mass index (BMI) and biochemical data obtained. We further related PCF and TAT data to standardized 12-leads electrocardiogram (ECG), including P and QRS wave morphologies. Among 3,087 study subjects (mean age, 49.6 years; 28% women), we observed a linear association among greater visceral adiposity burden, leftward deviation of P and QRS axes, longer PR interval and widened QRS duration (all p<0.001). These associations became attenuated after accounting for BMI and baseline clinical co-variates, with greater PCF remained independently associated with prolonged QRS duration (ß = 0.91 [95% CI: 0.52, 1.31] per 1-SD increase in PCF, p<0.001). Finally, both PCF and TAT showed incremental value in identifying abnormally high PR interval (>200ms, likelihood-ratio: 33.17 to 41.4 & 39.03 for PCF and TAT) and widened QRS duration (>100ms, likelihood-ratio: 55.67 to 65.4 & 61.94 for PCF and TAT, all X2 p<0.05) when superimposed on age and BMI. CONCLUSION: We show in our data greater visceral fat burden may have differential associations on several body surface electrocardiographic parameters. Compared to remote adiposity, those surrounding the heart tissue demonstrated greater influences on altered cardiac activation or conduction, indicating a possible local biological effect.

Unipolar peak-negative voltage as an endocardial electrographic characteristic to predict overlying abnormal epicardial substrates in patients with right epicardial ventricular tachycardia.

INTRODUCTION: The characteristics of endocardial electrograms needed to detect the overlying abnormal epicardial substrates in arrhythmogenic right ventricular cardiomyopathy with epicardial ventricular tachycardia (VT) remain unclear. This study investigated which of the endocardial electrogram characteristics could predict the overlying abnormal epicardial substrates. METHODS AND RESULTS: In 20 consecutive patients (median age: 46 years, 11 men) undergoing epicardial VT ablation, detailed endocardial and epicardial mappings were obtained by using the CARTO 3 system. The endocardial electrographic characteristics (unipolar peak-to-peak voltage, unipolar peak-negative-voltage, bipolar voltage, and bipolar electrogram duration) of the opposite endocardium and epicardium in RV were retrospectively investigated (N = 1,697 paired points, 84 ± 60 pairs/patient). Endocardial predictors of the presence of epicardial dense scar (<0.5 mV), low voltage zones (LVZ; ≤1.5 mV), and ablation targets (by using activation mapping, entrainment mapping, and pace mapping) were analyzed. RESULTS: In the multivariable analysis, (1) unipolar peak-negative voltage independently predicted the presence of epicardial LVZ, epicardial dense scar, and ablation targets; (2) bipolar voltage could not predict epicardial lesions; and (3) bipolar electrogram duration predicted epicardial LVZ, but not dense scar or ablation targets. The endocardial unipolar peak-negative voltage of <1.66 mV (89% sensitivity and 53% specificity) was the optimal cutoff point for predicting epicardial dense scar. CONCLUSIONS: In patients with RV epicardial VT, the presence of unipolar peak-negative voltage of <1.66 mV in the endocardium predicted the presence of epicardial dense scar (<0.5 mV) and potential ablation targets in the overlying epicardium.

Different characteristics and electrophysiological properties between early and late recurrences after acute successful catheter ablation of idiopathic right ventricular outflow tract arrhythmias during long-term follow-up.

BACKGROUND: Radiofrequency catheter ablation (RFCA) is an effective therapeutic strategy in eliminating drug-refractory idiopathic right ventricular outflow tract ventricular arrhythmias (RVOT VAs). It remains unclear what factors affect early and late VA recurrences after ablation. OBJECTIVE: The aim of our study was to elucidate the differences between early and late recurrences after acute successful RFCA of RVOT VAs in a long-term follow-up. METHODS: A total of 220 patients with acute successful RFCA of RVOT VAs were enrolled. Detailed clinical characteristics and assessments by noninvasive and invasive electrophysiology study were explored to predict the overall, early (≤1 year), and late VA (>1 year) recurrences. RESULTS: During a mean follow-up of 34.15 ± 33.74 months, 45 of 220 patients (20.5%) documented recurrence of RVOT VAs after the initial RFCA. Of these patients, 26 patients (57.8%) with recurrent VAs showed similar morphology, and 19 (42.2%) were different. Patients with recurrent VAs were associated with a higher incidence of hypertension, higher systolic blood pressure, identification of foci by pace mapping alone, shorter earliest activation time, more radiofrequency pulses required, and VA originating from the anterior free wall. Multivariate analysis demonstrated that mapping strategy and shorter earliest activation time preceding VA were associated with early recurrences (hazard ratio [HR] 2.26; 95% confidence interval [CI] 1.49-3.42; P < .001; and HR 0.91; 95% CI 0.85-0.98; P = .008, respectively), whereas hypertension was associated with late recurrence (HR 3.48; 95% CI 1.34-9.07; P = .001). CONCLUSION: RFCA is an effective strategy in the elimination of RVOT VAs. However, early and late recurrences occur commonly. Patients with early and late VA recurrences demonstrated nonuniform patterns of clinical characteristics and electrophysiological properties.