Atrial fibrillation ablation in heart failure patients: Where do we stand in 2023? - State of the art review.

Atrial fibrillation (AF) and heart failure are common overlapping cardiovascular disorders. Despite important therapeutic advances over the past several decades, controversy persists about whether a rate control or rhythm control approach constitutes the best option in this population. There is also considerable debate about whether antiarrhythmic drug therapy or ablation is the best approach when rhythm control is pursued.  A brief historical examination of the literature addressing this issue will be performed. An analysis of several important clinical outcomes observed in the prospective, randomized studies, which have compared AF ablation to non-ablation treatment options, will be discussed. This review will conclude with recommendations to guide clinicians on the status of AF ablation as a treatment option when considering management options in heart failure patients with atrial fibrillation.

Association Between Pre-Ablation Glycemic Control and Outcomes Among Patients With Diabetes Undergoing Atrial Fibrillation Ablation.

OBJECTIVES: The aim of this study was to investigate the impact of improved glycemic control on atrial fibrillation (AF) recurrence rates after ablation. BACKGROUND: Diabetes is associated with increased rates of AF. The impact of improved pre-ablation glycemic control remains unknown. METHODS: The 12-month pre-ablation trends in glycemic control were studied in 298 patients with diabetes undergoing AF ablation. Recurrence data were obtained during a mean follow-up period of 25.92 ± 20.26 months post-ablation. RESULTS: Higher glycated hemoglobin (HbA1c) at the time of ablation was associated with higher post-ablation recurrence rates. More than two-thirds (68.75%) of patients with HbA1c >9% at the time of ablation developed recurrent AF, compared with 32.4% of those with HbA1c <7% (p < 0.0001). On multivariate analysis, only the 12-month trend in HbA1c was significantly associated with AF recurrence. Although 91.1% of patients with a worsening trend in HbA1c during the 12 months prior to ablation developed recurrent AF, only 2% of patients with improvements in HbA1c of 10% or more experienced AF recurrence (p < 0.0001). CONCLUSIONS: The trend in glycemic control prior to ablation predicts arrhythmia recurrence after ablation. A multidisciplinary approach to reduce HbA1c is imperative in patients with diabetes with AF to reduce recurrence rates after ablation.

Reversal of pathological cardiac hypertrophy via the MEF2-coregulator interface.

Cardiac hypertrophy, as a response to hemodynamic stress, is associated with cardiac dysfunction and death, but whether hypertrophy itself represents a pathological process remains unclear. Hypertrophy is driven by changes in myocardial gene expression that require the MEF2 family of DNA-binding transcription factors, as well as the nuclear lysine acetyltransferase p300. Here we used genetic and small-molecule probes to determine the effects of preventing MEF2 acetylation on cardiac adaptation to stress. Both nonacetylatable MEF2 mutants and 8MI, a molecule designed to interfere with MEF2-coregulator binding, prevented hypertrophy in cultured cardiac myocytes. 8MI prevented cardiac hypertrophy in 3 distinct stress models, and reversed established hypertrophy in vivo, associated with normalization of myocardial structure and function. The effects of 8MI were reversible, and did not prevent training effects of swimming. Mechanistically, 8MI blocked stress-induced MEF2 acetylation, nuclear export of class II histone deacetylases HDAC4 and -5, and p300 induction, without impeding HDAC4 phosphorylation. Correspondingly, 8MI transformed the transcriptional response to pressure overload, normalizing almost all 232 genes dysregulated by hemodynamic stress. We conclude that MEF2 acetylation is required for development and maintenance of pathological cardiac hypertrophy, and that blocking MEF2 acetylation can permit recovery from hypertrophy without impairing physiologic adaptation.

Utilization and adverse outcomes of percutaneous left atrial appendage closure for stroke prevention in atrial fibrillation in the United States: influence of hospital volume.

BACKGROUND: Safety data on percutaneous left atrial appendage closure arises from centers with considerable expertise in the procedure or from clinical trial, which might not be reproducible in clinical practice. We sought to estimate the frequency and predictors of adverse outcomes and costs of percutaneous left atrial appendage closure procedure in the US. METHODS AND RESULTS: The data were obtained from the Nationwide Inpatient Sample from the years 2006 to 2010. The Nationwide Inpatient Sample is the largest all-payer inpatient data set in the US. Complications were calculated using patient safety indicators and International Classification of Diseases-Ninth Revision, Clinical Modification codes. Annual hospital volume was calculated using unique hospital identifiers. Weights provided by the Nationwide Inpatient Sample were used to generate national estimates. A total of 268 (weighted=1288) procedures were analyzed. The overall composite rate of mortality or any adverse event was 24.3% (65), with 3.4% patients required open cardiac surgery after procedure. Average length of stay was 4.61±1.05 days and cost of care was 26,024±34,651. Annual hospital procedural volume was significantly associated with reduced complications and mortality (every unit increase: odds ratio, 0.89; 95% confidence interval, 0.85-0.94; P<0.001), decrease in length of stay (every unit increase: hazard ratio, 0.95; 95% confidence interval, 0.92-0.98; P<0.001) and cost of care (every unit increase: hazard ratio, 0.96; 95% confidence interval, 0.93-0.98; P<0.001). CONCLUSIONS: Our study demonstrates that the frequency of inhospital adverse outcomes associated with percutaneous left atrial appendage closure is higher in the real-world population than in clinical trials. We also demonstrate that higher annual hospital volume is associated with safer procedures, with lower length of stay and cost.

Influence of left ventricular remodeling on atrial fibrillation recurrence and cardiovascular hospitalizations in patients undergoing rhythm-control therapy.

BACKGROUND: Atrial fibrillation (AF) patients with left ventricular hypertrophy (LVH) and diastolic dysfunction may derive benefit from being in sinus rhythm but no data are available to support this strategy in them. We sought to investigate effect of left ventricular remodeling on cardiovascular outcomes in AF patients undergoing rhythm control strategy. METHODS: We identified 1088 patients with echocardiographic data on left ventricular mass (LVM) enrolled in the AFFIRM trial. Using the American Society of Echocardiography (ASE) criteria, patients were divided into 4 categories: 1) normal geometry, 2) concentric remodeling, 3) eccentric hypertrophy, and 4) concentric hypertrophy. The primary endpoint was AF recurrence and the secondary endpoint was cardiovascular hospitalization (CVH). RESULTS: In rhythm control arm, median time to recurrence in patients with concentric LVH was 13.3 months (95% CI 8.2-24.5) vs. 28.3 months (95% CI 20.2-48.6) in patients without LVH. Concentric left ventricular hypertrophy (LVH) was independently predictive of AF recurrence (HR 1.49, 95% CI 1.10-2.01, p=0.01) in rhythm control arm, but not in overall population or rate control arm. Both concentric and eccentric LVH were independently predictive of cardiovascular hospitalization (CVH) in the overall population, with respective HRs of 1.36 (1.04-1.78, p=0.03) and 1.38 (1.02-1.85, p=0.04). CONCLUSION: Concentric LVH is predictive of AF recurrences when a predominantly pharmacologic rhythm-control strategy is employed. Different patterns of LVH seem to be important determinants of outcomes (AF recurrence and CVH). These findings may have important clinical implications for the management of patients with AF and LVH. Further studies are warranted to confirm our findings.

ST-T wave abnormality in lead aVR and reclassification of cardiovascular risk (from the National Health and Nutrition Examination Survey-III).

Electrocardiographic lead aVR is often ignored in clinical practice. The aim of this study was to investigate whether ST-T wave amplitude in lead aVR predicts cardiovascular (CV) mortality and if this variable adds value to a traditional risk prediction model. A total of 7,928 participants enrolled in the National Health and Nutrition Examination Survey (NHANES) III with electrocardiographic data available were included. Each participant had 13.5 ± 3.8 years of follow-up. The study sample was stratified according to ST-segment amplitude and T-wave amplitude in lead aVR. ST-segment elevation (>8 µV) in lead aVR was predictive of CV mortality in the multivariate analysis when not accounting for T-wave amplitude. The finding lost significance after including T-wave amplitude in the model. A positive T wave in lead aVR (>0 mV) was the strongest multivariate predictor of CV mortality (hazard ratio 3.37, p <0.01). The addition of T-wave amplitude in lead aVR to the Framingham risk score led to a net reclassification improvement of 2.7% of subjects with CV events and 2.3% of subjects with no events (p <0.01). Furthermore, in the intermediate-risk category, 20.0% of the subjects in the CV event group and 9.1% of subjects in the no-event group were appropriately reclassified. The absolute integrated discrimination improvement was 0.012 (p <0.01), and the relative integrated discrimination improvement was 11%. In conclusion, T-wave amplitude in lead aVR independently predicts CV mortality in a cross-sectional United States population. Adding T-wave abnormalities in lead aVR to the Framingham risk score improves model discrimination and calibration with better reclassification of intermediate-risk subjects.

Comparison of inferolateral early repolarization and its electrocardiographic phenotypes in pre- and postadolescent populations.

Inferolateral early repolarization (ER) patterns on standard electrocardiogram (ECG) are associated with increased risk for cardiac and arrhythmic death in general adult population cohorts. We sought to determine the prevalence of inferolateral ER on surface ECG in multiracial pre- and postadolescent populations and to analyze its association with age, race, gender, and ST-segment patterns. A retrospective review was conducted of all ECGs recorded from preadolescent (aged 8-12 years, n = 719) and postadolescent (aged 21-25 years, n = 755) patients seen at a large academic medical center between January 1, 2009, and December 31, 2010. The overall prevalence of inferolateral ER was similar in the preadolescent and postadolescent populations (17% vs 16%, NS). The prevalence of ER increased after puberty in male patients (16% to 25%, p <0.001) and decreased in female patients (18% to 9%, p <0.001). Prevalence of ascending early repolarization (benign variant) also increased in males after puberty (15% to 23%, p <0.004) and decreased in females (11% to 4%, p <0.001). There were no differences in the prevalence of the risk-associated horizontal/descending pattern (3% in both groups). Subgroup analysis was performed on ECGs from the cohort of outpatients without cardiac disease, and the statistical trends remained the same. In conclusion, the overall prevalence of inferolateral ER was higher in pre- and postadolescent populations than in adult populations. However, the prevalence of the risk-associated horizontal/descending ST-segment pattern was only 3%, comparable to prevalence rates in the adult population. The variations in prevalence by gender and age suggest a possible influence of reproductive hormones.

Dysfunctional potassium channel subunit interaction as a novel mechanism of long QT syndrome.

BACKGROUND: The slowly-activating delayed rectifier current IKs contributes to repolarization of the cardiac action potential, and is composed of a pore-forming α-subunit, KCNQ1, and a modulatory ß-subunit, KCNE1. Mutations in either subunit can cause long QT syndrome, a potentially fatal arrhythmic disorder. How KCNE1 exerts its extensive control over the kinetics of IKs remains unresolved OBJECTIVE: To evaluate the impact of a novel KCNQ1 mutation on IKs channel gating and kinetics METHODS: KCNQ1 mutations were expressed in Xenopus oocytes in the presence and absence of KCNE1. Voltage clamping and MODELLER software were used to characterize and model channel function. Mutant and wt genes were cloned into FLAG, Myc and HA expression vectors to achieve differential epitope tagging, and expressed in HEK293 cells for immunohistochemical localization and surface biotinylation assay. RESULTS: We identified 2 adjacent mutations, S338F and F339S, in the KCNQ1 S6 domain in unrelated probands. The novel KCNQ1 S338F mutation segregated with prolonged QT interval and torsade de pointes; the second variant, F339S, was associated with fetal bradycardia and prolonged QT interval, but no other clinical events. S338F channels expressed in Xenopus oocytes had slightly increased peak conductance relative to wild type, with a more positive activation voltage. F339S channels conducted minimal current. Unexpectedly, S338F currents were abolished by co-expression with intact WT KCNE1 or its C-terminus (aa63-129), despite normal membrane trafficking and surface co-localization of KCNQ1 S338F and wt KCNE1. Structural modeling indicated that the S338F mutation specifically alters the interaction between the S6 domain of one KCNQ1 subunit and the S4-S5 linker of another, inhibiting voltage-induced movement synergistically with KCNE1 binding. CONCLUSIONS: A novel KCNQ1 mutation specifically impaired channel function in the presence of KCNE1. Our structural model shows that this mutation effectively immobilizes voltage gating by an inhibitory interaction that is additive with that of KCNE1. Our findings illuminate a previously unreported mechanism for LQTS, and validate recent theoretical models of the closed state of the KCNQ1:KCNE1 complex.

Heterogeneity in SDF-1 expression defines the vasculogenic potential of adult cardiac progenitor cells.

RATIONALE: The adult myocardium has been reported to harbor several classes of multipotent progenitor cells (CPCs) with tri-lineage differentiation potential. It is not clear whether c-kit+CPCs represent a uniform precursor population or a more complex mixture of cell types. OBJECTIVE: To characterize and understand vasculogenic heterogeneity within c-kit+presumptive cardiac progenitor cell populations. METHODS AND RESULTS: c-kit+, sca-1+ CPCs obtained from adult mouse left ventricle expressed stem cell-associated genes, including Oct-4 and Myc, and were self-renewing, pluripotent and clonogenic. Detailed single cell clonal analysis of 17 clones revealed that most (14/17) exhibited trilineage differentiation potential. However, striking morphological differences were observed among clones that were heritable and stable in long-term culture. 3 major groups were identified: round (7/17), flat or spindle-shaped (5/17) and stellate (5/17). Stellate morphology was predictive of vasculogenic differentiation in Matrigel. Genome-wide expression studies and bioinformatic analysis revealed clonally stable, heritable differences in stromal cell-derived factor-1 (SDF-1) expression that correlated strongly with stellate morphology and vasculogenic capacity. Endogenous SDF-1 production contributed directly to vasculogenic differentiation: both shRNA-mediated knockdown of SDF-1 and AMD3100, an antagonist of the SDF-1 receptor CXC chemokine Receptor-4 (CXCR4), reduced tube-forming capacity, while exogenous SDF-1 induced tube formation by 2 non-vasculogenic clones. CPCs producing SDF-1 were able to vascularize Matrigel dermal implants in vivo, while CPCs with low SDF-1 production were not. CONCLUSIONS: Clonogenic c-kit+, sca-1+ CPCs are heterogeneous in morphology, gene expression patterns and differentiation potential. Clone-specific levels of SDF-1 expression both predict and promote development of a vasculogenic phenotype via a previously unreported autocrine mechanism.

A myxoid chondrosarcoma associated with an anti-Hu-positive paraneoplastic encephalomyelitis.

Extraskeletal myxoid chondrosarcoma is a rare tumor with less than 100 cases reported in the literature. The prevalence of anti-Hu positive myxoid chondrosarcoma-associated paraneoplastic subacute cerebellar degeneration is exceedingly rare. We present a report of a patient with confirmed myxoid chondrosarcoma-associated paraneoplastic subacute cerebellar degeneration, who exhibited marked improvement within 1 week of receiving chemotherapy, intravenous immunoglobulin (IVIG), and hydrocortisone treatment.