Impact of Weight Gain on Cardiovascular Outcomes in Patients With Atrial Fibrillation.

BACKGROUND: The long-term impact of weight gain (WG) on cardiovascular outcomes among patients with atrial fibrillation (AF) is unclear. METHODS AND RESULTS: We studied 62 871 (mean age, 72±12, 43% women) adult patients with AF evaluated at the University of Pittsburgh Medical Center between January 1, 2010, and May 13, 2021. Serial body mass index, risk factors, comorbidities, and subsequent death and hospitalization were ascertained and stratified according to percentage WG (≥0% to <5%, ≥5% to <10%, and ≥10%). Over 4.9±3.19 years of follow-up, 27 114 (43%) patients gained weight (61%, ≥0% to <5%; 23%, ≥5% to <10%; 16%, ≥10%). Patients with progressive WG were incrementally younger (P<0.001) women (40%, 42%, and 47%) with lower median household income (P=0.002) and active smoking (8%, 13% and 13%), and they were less likely to be on a non-vitamin K oral anticoagulant (39%, 37%, and 32%). WG was incrementally associated with a significant increase in risk of hospitalization for AF (≥10% WG; hazard ratio [HR], 1.2 [95% CI, 1.2-1.3]; P<0.0001), heart failure (≥10% WG; HR, 1.44 [95% CI, 1.3-1.6]; P<0.001; ≥5% to <10% WG; HR, 1.17 [95% CI, 1.1-1.2]; P<0.001), myocardial infarction (≥10% WG; HR, 1.2 [95% CI, 1.3-1.6]; P<0.001) and all-cause stroke (4.2%, 4.3%, and 5.6%) despite significantly lower mean CHADS2Vasc score (2.9±1.7, 2.7±1.6, and 2.7±1.7). Patients with more WG were significantly more likely to receive cardiac and electrophysiologic interventions. CONCLUSIONS: Among patients with AF, WG is incrementally associated with increased hospitalization for cardiovascular causes, particularly heart failure, stroke, myocardial infarction, and AF.

Non-vitamin K oral anticoagulants versus warfarin for left atrial appendage thrombus resolution in nonvalvular atrial fibrillation or flutter.

BACKGROUND: Non-vitamin K oral anticoagulants (NOACs) have emerged as alternatives to vitamin K antagonists in select situations. For left atrial (LA) appendage thrombus in nonvalvular atrial fibrillation (AF) or flutter, guidelines recommend oral anticoagulation (OAC) for at least 3 weeks prior to reassessment. Data comparing NOACs to warfarin in this scenario are scarce. METHODS: A retrospective study identified subjects with nonvalvular AF or flutter who were: a) noted to have LA thrombus detected on transesophageal echocardiography (TEE), b) previously not receiving long-term OAC; and c) evaluated for resolution of LA thrombus by follow-up TEE between 3 weeks to less than 1 year of the initial TEE. RESULTS: The study included 45 subjects with mean age 63.2 years, 69% male, 78% white race/ethnicity, 42% paroxysmal, and mean CHA2 DS2 -VASc score 3.4 ± 1.7. All LA thrombi were confined to the appendage. OAC received included apixaban (3), dabigatran (13), rivaroxaban (6), and warfarin (23), The median follow-up time to repeat TEE was 67 (interquartile range, 49-96) days. LA appendage thrombus resolution rates were 76% for the entire cohort, 77% for NOACs, and 74% for warfarin. In univariable logistic regression analysis, LA appendage thrombus resolution was similar for NOACs when compared to warfarin (odds ratio, 1.20; 95% confidence interval, 0.31-4.69; P = .79). CONCLUSIONS: In patients nonvalvular AF or flutter who were OAC naïve at the time of diagnosis with LA appendage thrombus, complete resolution was similar between NOACs and warfarin.

Sex-specific clinical outcomes after cardiac resynchronization therapy in left bundle branch block-associated idiopathic nonischemic cardiomyopathy: A NEOLITH II substudy.

BACKGROUND: Sex differences in clinical outcomes for left bundle branch block (LBBB)-associated idiopathic nonischemic cardiomyopathy (NICM) after cardiac resynchronization therapy (CRT) are not well described. METHODS: A retrospective cohort study at an academic medical center included subjects with LBBB-associated idiopathic NICM who received CRT. Cox regression analyses estimated the hazard ratios (HRs) between sex and clinical outcomes. RESULTS: In 123 total subjects (mean age 62 years, mean initial left ventricular ejection fraction 22.8%, 76% New York Heart Association class III, and 98% CRT-defibrillators), 55 (45%) were men and 68 (55%) were women. The median follow-up time after CRT was 72.4 months. Similar risk for adverse clinical events (heart failure hospitalization, appropriate implantable cardioverter-defibrillator shock, appropriate antitachycardia pacing therapy, ventricular assist device implantation, heart transplantation, and death) was observed between men and women (HR, 1.20; 95% confidence interval [CI] 0.57-2.51; p = 0.63). This persisted in multivariable analyses. Men and women had similar risk for all-cause mortality in univariable analysis, but men had higher risk in the final multivariable model that adjusted for age at diagnosis, QRS duration, and left ventricular end-diastolic dimension index (HR, 4.55; 95% CI, 1.26-16.39; p = 0.02). The estimated 5-year mortality was 9.5% for men and 6.9% for women. CONCLUSIONS: In LBBB-associated idiopathic NICM, men have higher risk for all-cause mortality after CRT when compared to women.

Myocardial recovery after cardiac resynchronization therapy in left bundle branch block-associated idiopathic nonischemic cardiomyopathy: A NEOLITH II substudy.

BACKGROUND: Baseline predictors of myocardial recovery after cardiac resynchronization therapy (CRT) in left bundle branch block (LBBB)-associated idiopathic nonischemic cardiomyopathy (NICM) are unknown. METHODS: A retrospective study included subjects with idiopathic NICM, left ventricular ejection fraction (LVEF) ≤35%, and LBBB. Myocardial recovery was defined as post-CRT LVEF ≥50%. Logistic regression analyses described associations between baseline characteristics and myocardial recovery. Cox regression analyses estimated the hazard ratio (HR) between myocardial recovery status and adverse clinical events. RESULTS: In 105 subjects (mean age 61 years, 44% male, mean initial LVEF 22.6% ± 6.6%, 81% New York Heart Association class III, and 98% CRT-defibrillators), myocardial recovery after CRT was observed in 56 (54%) subjects. Hypertension, heart rate, and serum blood urea nitrogen (BUN) had negative associations with myocardial recovery in univariable analyses. These associations persisted in multivariable analysis: hypertension (odds ratio (OR), 0.40; 95% confidence interval (CI), 0.17-0.95; p = 0.04), heart rate (OR per 10 bpm, 0.69; 95% CI, 0.48-0.997; p = 0.048), and serum BUN (OR per 1 mg/dl, 0.94; 95% CI, 0.88-0.99; p = 0.04). Subjects with post-CRT LVEF ≥50%, when compared to <50%, had lower risk for adverse clinical events (heart failure hospitalization, appropriate implantable cardioverter-defibrillator shock, appropriate anti-tachycardia pacing therapy, ventricular assist device implantation, heart transplantation, and death) over a median follow-up of 75.9 months (HR, 0.38; 95% CI, 0.16-0.88; p = 0.02). CONCLUSION: In LBBB-associated idiopathic NICM, myocardial recovery after CRT was associated with absence of hypertension, lower heart rate, and lower serum BUN. Those with myocardial recovery had fewer adverse clinical events.

Oral anticoagulation and left atrial thrombi resolution in nonrheumatic atrial fibrillation or flutter: A systematic review and meta-analysis.

BACKGROUND: Oral anticoagulation (OAC) is prescribed for left atrial thrombi (LAT) in nonrheumatic atrial fibrillation (AF) and/or atrial flutter (AFL). The study objective was to review the existing evidence regarding LAT resolution in nonrheumatic AF and/or AFL with OAC agents. METHODS: Data sources included PubMed, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) between January 1, 1991 and February 10, 2017. English-language studies that assessed LAT resolution with OAC agents in subjects with nonrheumatic AF and/or AFL, by serial transesophageal echocardiography, and with follow-up times ≥ 3 weeks and < 1 year, were selected. Study quality was assessed using recommendations adapted from the Agency for Healthcare Research and Quality. Pooled LAT resolution rates were evaluated for vitamin K antagonist (VKA) studies and low risk of bias warfarin studies. RESULTS: The pooled LAT resolution rate of 619 subjects from 16 VKA studies was 63.7% (95% confidence interval [CI], 53.3%-72.9%). The pooled LAT resolution rate of 94 subjects from four studies that specified warfarin use, exclusion of prior long-term therapeutic OAC, and target international normalized ratio (INR) ≥ 2.0 and/or average achieved INR ≥ 2.0 was 79.3% (95% CI, 69.8%-86.4%). Two studies in direct-acting oral anticoagulants (DOACs) reported LAT resolution rates of 89.5% (17 of 19) for dabigatran and 41.5% (22 of 53) for rivaroxaban. CONCLUSIONS: Warfarin is the most studied initial OAC agent for treating LAT in nonrheumatic AF and/or AFL with a resolution rate of nearly 80%. Further studies in DOACs are warranted.

A common variant alters SCN5A-miR-24 interaction and associates with heart failure mortality.

SCN5A encodes the voltage-gated Na+ channel NaV1.5 that is responsible for depolarization of the cardiac action potential and rapid intercellular conduction. Mutations disrupting the SCN5A coding sequence cause inherited arrhythmias and cardiomyopathy, and single-nucleotide polymorphisms (SNPs) linked to SCN5A splicing, localization, and function associate with heart failure-related sudden cardiac death. However, the clinical relevance of SNPs that modulate SCN5A expression levels remains understudied. We recently generated a transcriptome-wide map of microRNA (miR) binding sites in human heart, evaluated their overlap with common SNPs, and identified a synonymous SNP (rs1805126) adjacent to a miR-24 site within the SCN5A coding sequence. This SNP was previously shown to reproducibly associate with cardiac electrophysiological parameters, but was not considered to be causal. Here, we show that miR-24 potently suppresses SCN5A expression and that rs1805126 modulates this regulation. We found that the rs1805126 minor allele associates with decreased cardiac SCN5A expression and that heart failure subjects homozygous for the minor allele have decreased ejection fraction and increased mortality, but not increased ventricular tachyarrhythmias. In mice, we identified a potential basis for this in discovering that decreased Scn5a expression leads to accumulation of myocardial reactive oxygen species. Together, these data reiterate the importance of considering the mechanistic significance of synonymous SNPs as they relate to miRs and disease, and highlight a surprising link between SCN5A expression and nonarrhythmic death in heart failure.

New-onset left bundle branch block-associated idiopathic nonischemic cardiomyopathy and time from diagnosis to cardiac resynchronization therapy: The NEOLITH II study.

BACKGROUND: The optimal timing for cardiac resynchronization therapy (CRT) after diagnosis of new-onset left bundle branch block (LBBB)-associated idiopathic nonischemic cardiomyopathy (NICM) and treatment with guideline-directed medical therapy (GDMT) is unknown. The purpose of this study was to describe relationships between time from diagnosis to CRT and outcomes in new-onset LBBB-associated idiopathic NICM with left ventricular ejection fraction (LVEF) ≤35%. METHODS: A retrospective cohort study examined associations between time from diagnosis to CRT (≤9 months vs >9 months) and clinical and echocardiographic outcomes. RESULTS: In 123 subjects with LBBB-associated idiopathic NICM, time from diagnosis to CRT was ≤9 months in 60 (49%) subjects and 9 months in 63 (51%) subjects. Clinical outcomes were similar for those implanted ≤9 months versus >9 months for adverse clinical events (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.41-1.78; P = 0.67) and all-cause mortality (HR, 0.57; 95% CI, 0.19-1.70; P = 0.31). Multivariable analyses demonstrated similar results. In 105 subjects with post-CRT echocardiograms, LVEF improvement to >35% was more likely in those implanted ≤9 months when compared to >9 months (odds ratio [OR], 3.53; 95% CI, 1.32-9.46; P = 0.01). This association persisted in the final multivariable model adjusted for age at diagnosis, sex, QRS duration, post-GDMT LVEF, and time from CRT to post-CRT echocardiogram (OR, 5.10; 95% CI, 1.71-15.22; P = 0.004). CONCLUSION: In LBBB-associated idiopathic NICM, earlier CRT implantation was associated with more favorable cardiac remodeling. Delaying CRT may miss a critical period to halt and reverse progressive myocardial damage.

Predictors and implications of early left ventricular ejection fraction improvement in new-onset idiopathic nonischemic cardiomyopathy with narrow QRS complex: A NEOLITH substudy.

BACKGROUND: Predictors and implications of early left ventricular ejection fraction (LVEF) improvement with guideline-directed medical therapy (GDMT) in new-onset idiopathic nonischemic cardiomyopathy (NICM) with narrow QRS complex are not well described. The objectives were to describe predictors of LVEF improvement after 3 months on GDMT and adverse cardiac events based on post-GDMT LVEF status (≤35% vs. >35%). METHODS: A retrospective cohort study was performed in subjects with new-onset NICM, LVEF ≤35%, and narrow QRS complex. Associations for baseline variables with post-GDMT LVEF improvement and absolute change in LVEF (∆LVEFGDMT ) were assessed. Cox proportional hazards models assessed associations for post-GDMT LVEF status with adverse cardiac events. RESULTS: In 70 subjects, 31 (44%) had post-GDMT LVEF ≤35% after a median follow-up time of 97.5 days (interquartile range, 84-121 days). In final multivariable models, severely dilated left ventricular end-diastolic diameter (LVEDD), compared with normal LVEDD, strongly predicted post-GDMT LVEF ≤35% (odds ratio, 7.77; 95% confidence interval [CI], 1.39-43.49; p = .02) and ∆LVEFGDMT (ß = -15.709; standard error = 4.622; p = .001). Subjects with post-GDMT LVEF ≤35% were more likely to have adverse cardiac events over a median follow-up time of 970.5 days (unadjusted hazard ratio, 2.15; 95% CI, 0.93-4.96; p = .07). In the post-GDMT LVEF ≤35% group, 9 of 26 subjects (35%) had long-term LVEF > 35%. CONCLUSION: In new-onset NICM with narrow QRS complex, nondilated LVEDD predicted early LVEF improvement. Those with post-GDMT LVEF ≤35% had higher risk of adverse cardiac events, but a substantial proportion demonstrated continued long-term LVEF improvement.

Characteristics and Outcomes of Concurrently Diagnosed New Rapid Atrial Fibrillation or Flutter and New Reduced Ejection Fraction.

BACKGROUND: Characteristics and outcomes of concurrently diagnosed new rapid atrial fibrillation (AF) or atrial flutter (AFL) and new heart failure with reduced left ventricular ejection fraction (LVEF) are not well described. METHODS: A retrospective cohort study of subjects referred for expedited transesophageal echocardiography-guided rhythm-control strategies for concurrent new rapid AF/AFL and new LVEF ≤ 40% diagnosed during the same admission was analyzed. RESULTS: Twenty-five subjects (median age 57 years; 96% male; 96% Caucasian; median CHA2 DS2 -VASc = 2) presented with new AF (n = 18) or AFL (n = 7) with rapid ventricular rate (median 135 beats/min) and new reduced LVEF (median 27%; range, 10-37.5%). Seven (28%) subjects had left atrial appendage thrombi (LAAT) and five (20%) subjects had heavy or binge alcohol use. Baseline characteristics were similar between those with and without LAAT. Thirteen subjects with AF and without LAAT underwent direct-current cardioversion (DCCV) and 10 (77%) had AF recurrence within 90 days. Improvement of long-term LVEF to >40% was comparable for subjects with and without initial LAAT (83% vs 94%; P = 0.46). Three of four subjects who received primary prophylaxis implantable cardioverter-defibrillators improved their LVEF to >35% after sinus rhythm maintenance. The median long-term follow-up time was 3.0 years. CONCLUSIONS: Subjects with concurrently diagnosed new rapid AF/AFL and new reduced LVEF are characterized by a high prevalence of LAAT and significant alcohol use. AF subjects without initial LAAT who underwent DCCV had a high 90-day AF recurrence rate. The presence of LAAT did not have a prognosticative effect on eventual LVEF improvement, which was observed in almost all subjects.

Provider Response to QTc Prolongation on Standard 12-Lead EKG: Do We Notice or Do We Care?

BACKGROUND: Drugs and electrolyte imbalances are widely recognized as common triggers of a prolonged QT interval. We conducted a chart review to assess provider response to prolonged QT reported on a standard 12-lead electrocardiogram (EKG). METHODS: We identified all Veterans Affairs Pittsburgh Healthcare System patients in a 6-month period with an EKG reporting a corrected QT (QTc) >500 ms. We excluded confounding or uninterpretable EKGs. Charts were reviewed to assess medications and electrolytes at the time of the EKG as well as the setting (inpatient vs outpatient) in which the EKG was obtained. Provider documentation of QTc and any corrective measures were sought. RESULTS: After exclusions, 106 patients were included in this analysis (87 [82%] inpatient and 19 [18%] outpatient). Most were male (101, 95%) with a mean age of 63.5 ± 10.6 years. At the time of index EKG, most patients were receiving at least one (72, 68%), and frequently two or more (35, 33%), QTc prolonging medications. Providers documented QTc prolongation in 20 inpatients (19%). Drugs were adjusted or discontinued in only two inpatients (2%). There were 14 patients (14%) with potassium level <3.6 mmol/L and 10 of 69 (14%) patients had a magnesium level <1.7 mg/dL. CONCLUSION: Patients with prolonged QTc on EKG were more likely to be inpatients than outpatients. Inpatients were more likely to be receiving multiple types and classes of QTc prolonging medications. In the vast majority of cases, providers did not address the prolonged QTc and only rarely initiated remedial actions.

Inflammatory Mediators and Clinical Outcome in Patients With Advanced Heart Failure Receiving Cardiac Resynchronization Therapy.

Expression of different cytokines and growth factors after myocardial injury has been associated with fibroplasia and dilatation versus reverse remodeling and myocardial repair. Specifically, the proinflammatory/fibrotic mediators: interleukin (IL)-6, epidermal growth factor, and fibroblast growth factor (FGF)-2 cause fibroplasia, whereas reparative cytokines including: IL-1α, IL-1ß, IL-4, and IL-13 can limit fibrosis. In appropriate patients, cardiac resynchronization therapy (CRT) reverses cardiomyopathy and improves outcome. However, a significant proportion will not respond to this therapy. We conducted this study to assess the association of proinflammatory/fibrotic and/or reparative immune response mediators at baseline with outcome after CRT. In the multicenter RISK study, plasma samples were collected prospectively before CRT implantation. Plasma IL-6, epidermal growth factor, FGF-2, IL-1α, IL-1ß, IL-4, and IL-13 were evaluated by Luminex technology. The primary outcome was predefined as freedom from heart failure hospitalization or death and a decrease in echocardiographic end-systolic volume of >15% at 12 months. To determine associations with the outcome, multivariate logistic regression models including baseline clinical characteristics and the specific cytokines and growth factors were constructed. On multivariate analysis of 257 patients, detectable reparative cytokine IL-13 was significantly associated with the primary outcome (odds ratio 3.79; 95% CI 2.10 to 6.82, p <0.0001). In contrast, detectable proinflammatory/fibrotic growth factor FGF-2 was negatively associated (odds ratio 0.31; 95% CI, 0.14 to 0.68; p = 0.004). In conclusion, in CRT recipients, baseline levels of inflammatory mediators affecting cardiac fibrosis versus repair were associated with subsequent clinical outcome.

New-onset left bundle branch block-associated idiopathic nonischemic cardiomyopathy and left ventricular ejection fraction response to guideline-directed therapies: The NEOLITH study.

BACKGROUND: Left ventricular ejection fraction (LVEF) response to guideline-directed medical therapy (GDMT) and to early cardiac resynchronization therapy (CRT) in new-onset idiopathic nonischemic cardiomyopathy (NICM) and left bundle branch block (LBBB) is not well described. CRT is recommended if LVEF remains ≤35% after at least 3 months of GDMT. OBJECTIVE: The purpose of this study was to describe LVEF response to GDMT at 3 months and to early CRT in new-onset LBBB-associated idiopathic NICM. METHODS: A retrospective cohort study was performed in subjects with new-onset idiopathic NICM, LVEF ≤35%, and LBBB or narrow (<120 ms) QRS complex morphology. LVEF response between groups was evaluated with log-binomial and linear regression. LVEF response within groups was evaluated using the paired Student t test. RESULTS: In 102 subjects (70 with narrow QRS complex and 32 with LBBB), post-GDMT LVEF was >35% in 39 narrow QRS complex subjects (56%) and 2 LBBB subjects (6%) (P < .0001). The absolute difference between post-GDMT LVEF and initial LVEF was greater in the narrow QRS complex group (16.1% ± 14.6% vs. 3.3% ± 10.7%; P < .0001). Narrow QRS complex, referenced to LBBB, was significantly associated with post-GDMT LVEF >35% (relative risk 10.30; 95% confidence interval 2.63-40.27; P = .0008) and absolute difference between post-GDMT LVEF and initial LVEF (ß = 16.296; standard error = 2.977; P < .0001) in final multivariable analyses. CRT super-response, defined as post-CRT LVEF ≥50%, was observed in 8 of LBBB subjects (35%) who received CRT. CONCLUSION: GDMT did not significantly improve LVEF in new-onset LBBB-associated idiopathic NICM at 3 months. Most remained candidates for CRT, and a high percentage were super-responders. Optimal timing for CRT implantation requires further investigation.

Association of BNP and Troponin Levels with Outcome among Cardiac Resynchronization Therapy Recipients.

BACKGROUND: We conducted a prospective multicenter study to assess the prognostic value of combined baseline preimplant plasma levels of the biomarkers cardiac troponin T (TnT) and B-type natriuretic peptide (BNP) among cardiac resynchronization therapy (CRT) with or without defibrillator capability (CRT-D) recipients. METHODS: At CRT-D implant, patients were stratified based on detectable TnT (≥0.01 ng/mL) and elevated BNP (predefined as >440 pg/mL) levels. Patients were classified into three groups: high (both detectable TnT and high BNP), intermediate (either detectable TnT or high BNP), or low (nondetectable TnT and low BNP). Patients were followed for 12 months. Survival curves free from mortality or heart failure hospitalizations (HFH) were assessed. To assess the predictive value of biomarker category, we constructed a multivariate Cox regression model, including the covariates of age, New York Heart Association class, left ventricular ejection fraction (LVEF), and QRS duration. RESULTS: A total of 267 patients (age 66 ± 12 years, males 80%, LVEF 25% ± 8%, ischemic cardiomyopathy 52%, QRSd 155 ± 26 ms) were studied. After 1 year, there were 13 deaths and 25 HFH events. A significant difference in event-free survival among the three groups was observed, with high and intermediate categories having worse survival than low (log-rank test, P < 0.001). In the multivariate model, risk category was a significant predictor of outcome: hazard ratios were 7.34 (95% confidence interval [CI]: 2.48-21.69) and 2.50 (95% confidence interval [CI]: 1.04-6.04) for high-risk and intermediate-risk groups, respectively (P < 0.0001). CONCLUSION: Among CRT-D recipients, baseline TnT and BNP values alone or in combination provide significant prognostic value for the outcome of mortality or HFH.