BACKGROUND: Current recommendations for echocardiographic assessment of diastolic function (2016 guidelines of the American Society of Echocardiography (ASE)/European Association of Cardiovascular Imaging (EACVI) in patients with metabolic syndrome and overweight/obesity result in a significant number of patients with indeterminate diastolic dysfunction (LVDD). The aim of this article is to study whether the use of the left atrial strain criterion (LALS) reduces the number of indeterminate patients. METHODS: 229 patients were studied with a complete echocardiographic study that included left ventricular longitudinal strain (LVLS) analysis, LALS and a maximal ergospirometry test with assessment of oxygen uptake (VO2max). RESULTS: The mean age was 65 ± 5 years, 153 (67%) males, with a mean EF of 60 ± 5%. The mean LVLS was -19.4 ± 2% and the LALS Reservoir was 23.8 ± 7%. There were 140 patients who did not meet LVDD criteria and 82 who did meet the indeterminate LVDD criterion. When the left atrial volume index (LAVI) >34 ml/m2 criterion was replaced in the 2016 ASE/EACVI algorithm by LALS Reservoir ≤20%, the number of indeterminate patients was reduced from 36% to 23% (p < 0.001) at the expense of increasing normal studies (61% and 74%). Adding the LALS Reservoir criterion ≤23% in the 82 patients of the indeterminate group resulted in two groups with a different VO2max (11.6 ± 3 and 18 ± 5 ml/kg/min, p:0.081). CONCLUSIONS: This study confirms the low prevalence of diastolic dysfunction in overweight/obese patients with metabolic syndrome. Adding left atrial strain criterion to the current recommendations significantly reduces the number of indeterminate patients by reclassifying them as normal.

Adverse atrial remodeling is associated with increased risk of atrial fibrillation (AF) and can be detected by a shift in P-wave axis. We aimed to determine whether an analysis of P-wave axis can be used to improve risk prediction of AF. We included 15,102 Atherosclerosis Risk in Communities Study participants who were free of AF at baseline. Abnormal P-wave axis (aPWA) was defined as any value outside 0 to 75 degrees on study visit 12-lead electrocardiograms. AF was determined using study visit electrocardiograms, death certificates, and hospital discharge records. Multivariable Cox regression was used to estimate hazard ratios and 95% confidence intervals (CIs) for the association of aPWA with AF. The Cohorts for Heart and Aging Research in Genomic Epidemiology-AF (CHARGE-AF) risk prediction model variables served as our benchmark. Improvement in 10-year AF prediction was assessed by C-statistic, category-based net reclassification improvement, and relative integrated discrimination improvement. During a mean follow-up of 20.2 years, there were 2,618 incident AF cases. aPWA was independently associated with a 2.34-fold (95% CI 2.12 to 2.58) increased risk of AF after adjusting for CHARGE-AF risk score variables. The use of aPWA improved the C-statistic from 0.719 (95% CI 0.702 to 0.736) to 0.722 (95% CI 0.705 to 0.739), which corresponded with a net reclassification improvement of 0.021 (95% CI 0.001, 0.040) and relative integrated discrimination improvement of 0.043 (95% CI 0.018, 0.069). In conclusion, aPWA is independently associated with AF in the general population. The use of this maker modestly improves AF prediction.

Background: Data are needed on the use of oral anticoagulation in patients with atrial fibrillation (AF) in rural versus urban areas, including the initiation of direct oral anticoagulants (DOACs). Objective: We used Medicare data to examine rural/urban differences in anticoagulation use in patients with AF. Methods: We identified incident AF in a 20% sample of fee-for-service Medicare beneficiaries (aged ≥ 65 years) from 2011 to 2016 and collected ZIP code and covariates at the time of AF. We identified the first anticoagulant prescription filled, if any, following AF diagnosis. We categorized beneficiaries into four rural/urban areas using rural–urban commuting area codes and used Poisson regression models to compare anticoagulant use. Results: We included 447,252 patients with AF (mean age 79 ± 8 years), of which 82% were urban, 9% large rural, 5% small rural, and 4% isolated. The percentage who initiated an anticoagulant rose from 34% in 2011 to 53% in 2016, paralleling the uptake of DOACs. In a multivariable-adjusted analysis, those in rural areas (vs. urban) were more likely to initiate an anticoagulant. However, rural beneficiaries (vs. urban) were less likely to initiate a DOAC; those in isolated areas were 17% less likely (95% confidence interval [CI] 13–20), those in small rural areas were 12% less likely (95% CI 9–15), and those in large rural areas were 10% less likely (95% CI 8–12). Conclusion: Among Medicare beneficiaries with AF, anticoagulation use was low but increased over time with the introduction of DOACs. Rural beneficiaries were less likely to receive a DOAC.

Atrial fibrillation (AF) affects at least 60 million individuals globally and is associated with substantial impacts on morbidity, mortality, and health care expenditures. This review focuses on how race and ethnicity influence AF epidemiology, risk prediction, treatment, and outcomes; knowledge gaps in these areas are identified. Most AF studies have predominantly included White populations, with an underrepresentation of racial and ethnic groups, including but not limited to Black, Hispanic, and Indigenous individuals. Enhancement and implementation of AF risk prediction, prevention, and management call for studies that will gather accurate race-based epidemiologic data and evaluate social determinants and genetic factors in the context of multiple races and ethnicities. Available studies highlight inequities in access to treatment as well as outcomes between White individuals and persons of other races/ethnicities. These inequities will need to be addressed by a renewed emphasis on structural and social determinants of health that contribute to AF.

Plasma proteomic profiling may aid in the discovery of novel biomarkers upstream of the development of atrial fibrillation (AF). We used data from the Atherosclerosis Risk in Communities study to examine the relation between large-scale proteomics and incident AF in a cohort of older-aged adults in the United States. We quantified 4,877 plasma proteins in Atherosclerosis Risk in Communities participants at visit 5 (2011–2013) using an aptamer-based proteomic profiling platform. We used Cox proportional hazards models to assess the association between protein levels and incident AF, and explored relation of selected protein biomarkers using annotated pathway analysis. Our study included 4,668 AF-free participants (mean age 75 ± 5 years; 59% female; 20% Black race) with proteomic measures. A total of 585 participants developed AF over a mean follow-up of 5.7 ± 1.7 years. After adjustment for clinical factors associated with AF, N-terminal pro-B-type natriuretic peptide (NT-proBNP) was associated with the risk of incident AF (hazard ratio, 1.82; 95% CI, 1.68 to 1.98; p, 2.91 × 10−45 per doubling of NT-proBNP). In addition, 36 other proteins were also significantly associated with incident AF after Bonferroni correction. We further adjusted for medication use and estimated glomerular filtration rate and found 17 proteins, including angiopoietin-2 and transgelin, that remained significantly associated with incident AF. Pathway analyses implicated the inhibition of matrix metalloproteases as the top canonical pathway in AF pathogenesis. In conclusion, using a large-scale proteomic platform, we identified both novel and established proteins associated with incident AF and explored mechanistic pathways of AF development.

Background: The most prominent risk factor for atrial fibrillation (AF) is chronological age; however, underlying mechanisms are unexplained. Algorithms using epigenetic modifications to the human genome effectively predict chronological age. Chronological and epigenetic predicted ages may diverge in a phenomenon referred to as epigenetic age acceleration (EAA), which may reflect accelerated biological aging. We sought to evaluate for associations between epigenetic age measures and incident AF. Methods: Measures for 4 epigenetic clocks (Horvath, Hannum, DNA methylation [DNAm] PhenoAge, and DNAm GrimAge) and an epigenetic predictor of PAI-1 (plasminogen activator inhibitor-1) levels (ie, DNAm PAI-1) were determined for study participants from 3 population-based cohort studies. Cox models evaluated for associations with incident AF and results were combined via random-effects meta-analyses. Two-sample summary-level Mendelian randomization analyses evaluated for associations between genetic instruments of the EAA measures and AF. Results: Among 5600 participants (mean age, 65.5 years; female, 60.1%; Black, 50.7%), there were 905 incident AF cases during a mean follow-up of 12.9 years. Unadjusted analyses revealed all 4 epigenetic clocks and the DNAm PAI-1 predictor were associated with statistically significant higher hazards of incident AF, though the magnitudes of their point estimates were smaller relative to the associations observed for chronological age. The pooled EAA estimates for each epigenetic measure, with the exception of Horvath EAA, were associated with incident AF in models adjusted for chronological age, race, sex, and smoking variables. After multivariable adjustment for additional known AF risk factors that could also potentially function as mediators, pooled EAA measures for 2 clocks remained statistically significant. Five-year increases in EAA measures for DNAm GrimAge and DNAm PhenoAge were associated with 19% (adjusted hazard ratio [HR], 1.19 [95% CI, 1.09-1.31]; P<0.01) and 15% (adjusted HR, 1.15 [95% CI, 1.05-1.25]; P<0.01) higher hazards of incident AF, respectively. Mendelian randomization analyses for the 5 EAA measures did not reveal statistically significant associations with AF. Conclusions: Our study identified adjusted associations between EAA measures and incident AF, suggesting that biological aging plays an important role independent of chronological age, though a potential underlying causal relationship remains unclear. These aging processes may be modifiable and not constrained by the immutable factor of time.

Background Pulmonary hypertension (PH) is a devastating potential complication of pulmonary embolism, a manifestation of venous thromboembolism (VTE). The incidence of and risk factors for PH in those with prior VTE are poorly characterized. Methods and Results International Classification of Diseases (ICD) codes from inpatient and outpatient medical claims from MarketScan administrative databases for years 2011 to 2018 were used to identify cases of VTE, comorbidities before the VTE event, and PH occurring subsequent to the VTE event. Cumulative incidence and hazard ratios (HR), and their 95% CI, were calculated. The 170 021 VTE cases included in the analysis were on average (±SD) 57.5±15.8 years old and 50.5% were female. A total of 5943 PH cases accrued over an average follow-up of 1.94 years. Two years after incident VTE, the cumulative incidence (95% CI) of PH was 3.5% (3.4%-3.7%) overall. It was higher among older individuals, among women (3.9% [3.8%-4.1%]) than men (3.2% [3.0%-3.3%]), and among patients presenting with pulmonary embolism (6.2% [6.0%-6.5%]) than those presenting with deep vein thrombosis only (1.1% [1.0%-1.2%]). Adjusting for age and sex, risk of PH was higher among patients with VTE with underlying comorbidities. Using the Charlson comorbidity index, there was a dose-response relationship, whereby greater scores were associated with increased PH risk (score ≥5 versus 0: HR, (2.50 [2.30-2.71])). When evaluating individual comorbidities, the strongest associations were observed with concomitant heart failure (HR, 2.17 [2.04-2.31]), chronic pulmonary disease (2.01 [1.90-2.14]), and alcohol abuse (1.66 [1.29-2.13]). Conclusions In this large, real-world population of insured people with VTE, 3.5% developed PH in the 2 years following their initial VTE event. Risk was higher among women, with increasing age, and in those with additional comorbidities at the time of the VTE event. These data provide insights into the burden of PH and risk factors for PH among patients with VTE.

BACKGROUND: Atrial fibrosis is a hallmark of structural remodeling in atrial fibrillation (AF). Plasma procollagen type III N-terminal propeptide (PIIINP) reflects collagen synthesis and degradation while collagen type I carboxy-terminal telopeptide (ICTP) reflects collagen degradation. We aimed to study baseline plasma PIIINP and ICTP and their associations with incident AF in participants initially free of overt cardiovascular disease. METHODS: In a stratified sample of the Multi-Ethnic Study of Atherosclerosis, initially aged 45-84 years, 3071 participants had both PIIINP and ICTP measured at baseline. Incident AF in 10-year follow-up was based on a hospital International Classification of Diseases code for AF or atrial flutter, in- or outpatient Medicare claims through 2011 (primarily in those aged 65-84 years), or ECG 10 years after baseline (n=357). The associations of PIIINP and ICTP with incident AF were estimated using Poisson regression with follow-up time offset. RESULTS: Baseline PIIINP (5.50±1.55 µg/L) and ICTP (mean±SD, 3.41±1.37 µg/L) were positively related (both P<0.0001) to incident AF in a model adjusting for age, race/ethnicity, and sex, with an apparent threshold (relative incidence density 2.81 [1.94-4.08] for PIIINP ≥8.5 µg/L [3.5% of the sample] and 3.46 [2.36-5.07] for ICTP ≥7 µg/L [1.7% of the sample]). Findings were attenuated but remained statistically significant after further adjustment for systolic blood pressure, height, body mass index, smoking, and renal function. Additional adjustment for other risk factors and biomarkers of inflammation did not alter conclusions. CONCLUSIONS: Plasma collagen biomarkers, particularly at elevated levels, were associated with excess risk for AF.

We evaluated the association of longitudinal changes in circulating levels of N-terminal pro B-type natriuretic peptide (NT-proBNP) and high sensitivity cardiac troponin T (hs-cTnT) with the burden of arrhythmias as captured by 2-week ambulatory ECG monitoring. This study included 1,930 Atherosclerosis Risk in Communities Study participants who wore a leadless, ambulatory ECG monitor (Zio XT Patch) at visit 6 (2016 to 2017) and had cardiac biomarkers measured at visit 6 and visit 4 (median of 19 years earlier). The mean age of participants at V6 was 79 ± 5 years, 41% were men, and 22% were black. Adjusting for demographics, body mass index, smoking, diabetes, hypertension, stroke, left ventricular mass, cardiac medications, patch wear time, visit 4 levels of NT-proBNP and hs-cTnT, and relative change in hs-cTnT, each log-transformed unit relative increase in NT-proBNP was associated with a higher likelihood of nonsustained ventricular tachycardia (odds ratio 1.29, 95% confidence interval [CI] 1.12 to 1.48), a higher number of daily atrial tachycardia episodes (geometric mean ratio [GMR] 1.16, 95% CI 1.10 to 1.21), and a higher daily ectopic burden (premature ventricular contractions —GMR 1.42, 95% CI 1.25 to 1.62; premature atrial contractions —GMR 1.40, 95% CI 1.25 to 1.57). In fully adjusted analyses, each log-transformed unit relative increase in hs-cTnT was only found to be weakly associated with a higher daily premature ventricular contraction burden (GMR 1.31, 95% CI 1.01 to 1.70). In conclusion, longitudinal change in NT-proBNP was associated with an increased atrial and ventricular arrhythmia burden.

Patients with atrial fibrillation experience higher mortality rates than those without this condition. Recent studies have explored whether mortality rates in atrial fibrillation patients and the overall impact of atrial fibrillation on mortality has changed. Overall, mortality in atrial fibrillation has decreased over the last few decades, with no strong differences between men and women. These improvements could be caused by advances in preventing thromboembolic complications of atrial fibrillation or better management of comorbidities in these patients. Understanding the mechanisms for these changes and developing novel approaches to improve survival in AF patients are areas deserving of future research.