Vascular cell adhesion molecule 1: a marker for atrial fibrillation and heart failure risk

See related article, pp 590–596 Hypertension is, due to the high prevalence in the general population, by far the most important risk factor for the development of atrial fibrillation (AF). A recent study confirmed that blood pressures even in the upper normal or prehypertensive range are associated with an increased risk of AF.1 Independently, in people with high cardiovascular risk,2 left ventricular hypertrophy, serum creatinine, history of hypertension, and history of cerebrovascular disease were highly significant predictors, as were body mass index and history of coronary heart disease. This analysis2 of populations participating in 2 large outcome trials of similar design (n=30 424) documented the connection between hypertension, or its end-organ damage as well as risk factors, and the risk of incident AF. The relationship between the history of hypertension and risk of AF persists, despite confounding by the extensive vascular disease or complicated diabetes mellitus that the participants had,2 or maybe these diseases even escalated the relationship. The dominating role of high blood pressure in the pathogenesis, pathophysiology, prediction, diagnosis, and treatment of AF has been extensively reviewed by a working group of the European Society of Hypertension.3 Perhaps the most remarkable finding was that up to ≈90% of patients with AF who participated in some of the recent large randomized clinical outcome trials of new anticoagulant or antiarrhythmic medications in people with AF had a history of hypertension3 even without baseline workup using ambulatory 24-hour blood pressure measurements to detect people with masked hypertension. This suggests that AF is in most cases a typical complication of hypertension, and even more so than stroke or heart failure. It is not entirely surprising but confirmatory in a slightly different type of population that left ventricular hypertrophy is a strong predictor of AF. In a large …

Recent Trends in the Incidence, Treatment, and Prognosis of Patients With Heart Failure and Atrial Fibrillation (the Worcester Heart Failure Study)

Age at menopause and risk of heart failure and atrial fibrillation: a nationwide cohort study.

Introduction: Ceramides and sphingomyelins (sphingolipids) are circulating lipids involved in multiple physiological pathways relevant to heart failure (HF) and atrial fibrillation (AF), including apoptosis, oxidative stress, and inflammation. Experimental studies suggest that sphingolipids with different saturated fatty acids exhibit different biological activities, but their relationships with HF and AF are unknown. Hypothesis: Higher levels of plasma ceramide and sphingomyelin that contain the fatty acid 16:0 are associated with higher risks of HF and AF; and higher levels of ceramides and sphingomyelins that contain the fatty acid 20:0, 22:0 or 24:0 are associated with lower risks. Methods: We measured sphingolipids in the Cardiovascular Health Study (CHS) in plasma samples from 1994-95 (N=4026) or from 1992-93 (N=586). We assessed the separate associations of the levels of 8 sphingolipids with risks of incident HF and incident AF using Cox regression. A p-value threshold of 0.006 was used to account for multiple testing. Results: Among 4,612 participants, 1179 incident HF and 1198 incident AF occurred during >40,000 person-years of follow-up. In adjusted analyses, higher levels of Cer-16 (ceramide with 16:0) and SM-16 (sphingomyelin with 16:0) were associated with higher risk of incident HF, but not with risk of incident AF (Table). In contrast, higher levels of Cer-20, Cer-22 and Cer-24 were each associated with lower risk of AF, but not with risk of HF. Higher levels of SM-20, SM-22, and SM-24 tended to be associated with lower risks of AF and HF, with only the association of SM-20 with AF significant. Conclusions: Plasma levels of ceramide and sphingomyelin with 16:0 show different associations with HF and AF than species with 20:0, 22:0 or 24:0. Associations of Cer-16 and SM-16 specifically with higher risk of HF may be due to a role of apoptosis in HF. The novel findings that Cer-20, Cer-22, and Cer-24 are associated with lower risk of AF warrant further examination of the role of these sphingolipids in protecting from AF.

Metabolomics of the tryptophan–kynurenine degradation pathway and risk of atrial fibrillation and heart failure: potential modification effect of Mediterranean diet

Atrial fibrillation (AF) has a substantial genetic component. The importance of polygenic risk is well established, while the contribution of rare variants to disease risk warrants characterization in large cohorts. To identify rare predicted loss-of-function (pLOF) variants associated with AF and elucidate their role in risk of AF, cardiomyopathy (CM), and heart failure (HF) in combination with a polygenic risk score (PRS). This was a genetic association and nested case-control study. The impact of rare pLOF variants was evaluated on the risk of incident AF. HF and CM were assessed in cause-specific Cox regressions. End of follow-up was July 1, 2022. Data were analyzed from January to October 2023. The UK Biobank enrolled 502 480 individuals aged 40 to 69 years at inclusion in the United Kingdom between March 13, 2006, and October 1, 2010. UK residents of European ancestry were included. Individuals with prior diagnosis of AF were excluded from analyses of incident AF. Rare pLOF variants and an AF PRS. Risk of AF and incident HF or CM prior to and subsequent to AF diagnosis. A total of 403 990 individuals (218 489 [54.1%] female) with a median (IQR) age of 58 (51-63) years were included; 24 447 were diagnosed with incident AF over a median (IQR) follow-up period of 13.3 (12.4-14.0) years. Rare pLOF variants in 6 genes (TTN, RPL3L, PKP2, CTNNA3, KDM5B, and C10orf71) were associated with AF. Of these, TTN, RPL3L, PKP2, CTNNA3, and KDM5B replicated in an external cohort. Combined with high PRS, rare pLOF variants conferred an odds ratio of 7.08 (95% CI, 6.03-8.28) for AF. Carriers with high PRS also had a substantial 10-year risk of AF (16% in female individuals and 24% in male individuals older than 60 years). Rare pLOF variants were associated with increased risk of CM both prior to AF (hazard ratio [HR], 3.13; 95% CI, 2.24-4.36) and subsequent to AF (HR, 2.98; 95% CI, 1.89-4.69). Rare and common genetic variation were associated with an increased risk of AF. The findings provide insights into the genetic underpinnings of AF and may aid in future genetic risk stratification.

Heart failure (HF) is the most concerning morbidity in atrial fibrillation (AF) through mutual influence on a poor prognosis. A polygenic risk score (PRS) has recently been proposed to improve the risk prediction for cardiovascular disease. The additive predictive role of PRS for incident HF in patients with AF who inherently carry a high risk of HF is unknown. From the UK Biobank, we identified 21 167 White Caucasian participants with newly diagnosed AF without a prior history of HF. The PRS for HF was constructed using genetic instruments from previous genome-wide association studies. The primary outcome was the occurrence of incident HF. The prediction of incident HF was evaluated using the tertile categorization of PRS for HF (low vs. moderate-high PRS) across the entire AF cohort, as well as within age subgroups (young AF, age <60 years; old AF, age ≥60 years, respectively). The mean age was 69.0 ± 6.9 years in the total population (55.2 ± 3.9 years in age <60 years; 70.7 ± 5.0 years in age ≥60 years group). During a median follow-up of 3.8 (1.4-7.2) years, the incidence rate (1000-patient year) of HF was 29.9. In the total population, AF patients with moderate-high PRS for HF were associated with a higher risk of HF than those with low PRS for HF [adjusted hazard ratio (HR) 1.18 (95% confidence interval (CI), 1.05-1.32), P = 0.005]. The higher risk of HF in the moderate-high PRS group was particularly accentuated in young AF patients: adjusted HR, 2.14 (95% CI 1.29-3.57) in young AF, and 1.13 (95% CI 1.01-1.27) in old AF, P-for-interaction = 0.015. In young AF, the onset of incident HF was earlier in those with the moderate-high PRS group [median time from AF diagnosis to incident HF, 4.2 (0.8-7.1) years in low PRS vs. 1.5 (0.3-4.7) years in the moderate-high PRS group, P = 0.001]. The prediction of HF was significantly improved by adding PRS to the clinical risk factors for HF, especially in young AF patients, with a net reclassification improvement of 29.7% (P = 0.003). PRS for HF can significantly improve the prediction of incident HF in patients with AF, especially in the young population, providing clinical utility of an individualized approach to integrated management of AF.

Uric acid and risk of incident heart failure in individuals with cardiovascular disease

Both short (<7 h per night) and long (≥9 h per night) sleep durations are related to atrial fibrillation (AF) and heart failure (HF), but their causality has not been confirmed. We applied Mendelian randomization (MR) approaches to estimate the causal association between genetically determined sleep duration and the risk of AF and HF. We performed two-sample MR analysis to obtain the effect of sleep duration on AF and HF. Instrumental variables were constructed using genetic variants known to be associated with continuous sleep duration, short sleep duration, and long sleep duration. MR estimates of the effect of sleep duration on AF and HF were derived based on two large meta-analyses of genome-wide association studies. The pooled MR estimate demonstrated a significant protective effect of continuous sleep duration on HF [odds ratio (OR) = 0.765, 95% confidence interval (CI) = 0.675–0.867; P = 2.64 × 10–5] and a suggestive inverse association of continuous sleep duration with AF (OR = 0.893, 95% CI = 0.804–0.991; P = 0.034). In addition, the results showed a suggestive detrimental effect of short sleep duration on the risk of AF (OR = 1.108, 95% CI = 1.017–1.207; P = 0.019) and HF (OR = 1.136, 95% CI = 1.025–1.258; P = 0.015). Conversely, there is no significant evidence for the causal protective effect of long sleep duration on AF (OR = 0.956, P = 0.410) and HF (OR = 0.921, P = 0.202). This MR study indicated that genetically determined continuous sleep duration has a significant protective effect on HF and a suggestive inverse association with AF. Short sleep duration is positively associated with the risk of AF and HF. Nevertheless, there is no significant evidence for the causal protective effect of long sleep duration on AF and HF. Larger intervention studies are required to confirm the effectiveness of improving sleep on reducing the incidence of AF and HF.

Poor oral hygiene can provoke transient bacteremia and systemic inflammation, a mediator of atrial fibrillation and heart failure. This study aims to investigate association of oral hygiene indicators with atrial fibrillation and heart failure risk in Korea. We included 161,286 subjects from the National Health Insurance System-Health Screening Cohort who had no missing data for demographics, past history, or laboratory findings. They had no history of atrial fibrillation, heart failure, or cardiac valvular diseases. For oral hygiene indicators, presence of periodontal disease, number of tooth brushings, any reasons of dental visit, professional dental cleaning, and number of missing teeth were investigated. During median follow-up of 10.5 years, 4911 (3.0%) cases of atrial fibrillation and 7971 (4.9%) cases of heart failure occurred. In multivariate analysis after adjusting age, sex, socioeconomic status, regular exercise, alcohol consumption, body mass index, hypertension, diabetes, dyslipidemia, current smoking, renal disease, history of cancer, systolic blood pressure, blood and urine laboratory findings, frequent tooth brushing (≥3 times/day) was significantly associated with attenuated risk of atrial fibrillation (hazard ratio: 0.90, 95% confidence interval (0.83-0.98)) and heart failure (0.88, (0.82-0.94)). Professional dental cleaning was negatively (0.93, (0.88-0.99)), while number of missing teeth ≥22 was positively (1.32, (1.11-1.56)) associated with risk of heart failure. Improved oral hygiene care was associated with decreased risk of atrial fibrillation and heart failure. Healthier oral hygiene by frequent tooth brushing and professional dental cleaning may reduce risk of atrial fibrillation and heart failure.

Introduction: Heart Failure (HF) has shared genetic architecture with its risk factors, including atrial fibrillation (AF), body mass index (BMI), coronary heart disease (CHD), systolic blood pressure (SBP), and type 2 diabetes (T2D). The risk prediction performance of polygenic risk scores (PRS) for those HF risk factors and HF itself over an established risk equation warrants investigation. Methods: Within the Atherosclerosis Risk in Communities (ARIC) study, six PRSs were constructed for AF, BMI, CHD, SBP, T2D, and HF by summing the product of pre-computed weights from genome-wide association studies and SNP allele dosages in European and African Americans separately. The association between PRSs and incident HF was assessed using cox proportional hazard models, and the 10-, 20-, and 30-year risk prediction performance of PRS over the ARIC HF risk equation was assessed using C-statistics. Associations between AF PRS and HF subtypes, echocardiographic measures, and 4,877 proteins were examined. Results: Over 30 years follow-up, 1,922 (22%) and 735 (29%) HF cases developed in 8,624 European (mean age=54.2, 52% female) and 2,525 African (mean age=53.3, 61% female) Americans. The PRSs for AF and HF were associated with incident HF in both European and African Americans (P&lt;0.05). The AF PRS showed the greatest effect on HF risk in European (HR=1.47, 95% CI: 1.41 to 1.53) and African (HR=1.29, 95% CI: 1.20 to 1.39) Americans. Addition of AF PRS to the ARIC HF risk equation significantly improved the C-statistics for 10-year risk prediction in European (ΔC=0.017, 95% CI: 0.009 to 0.026) and African (ΔC=0.015, 95% CI: 0.004 to 0.026) Americans. The AF PRS was further associated with HF with reduced (HR=1.45, 95% CI: 1.29 to 1.64) and preserved (HR=1.49, 95% CI: 1.34 to 1.66) ejection fraction, and higher left atrial volume index (P=1.67х10 -4 ). Protein analyses revealed that 61 proteins were associated with AF PRS, where NT-proBNP and Coagulation factor X showed the strongest positive and negative associations respectively. Conclusions: The PRS of AF was associated with incident HF, and had significant incremental value over an established HF risk prediction equation. These findings suggest that PRS may be useful in identifying individuals with high risk of HF.

Estimated glucose disposal rate (eGDR) was a novel non-insulin-based marker of insulin resistance (IR), which had been used in many studies to evaluate the clinical prognosis of diabetes. However, the association of eGDR with atrial fibrillation (AF), heart failure (HF) and cardiovascular mortality in patients with diabetes remains unclear. The study utilized UK Biobank data from 31,733 participants. Kaplan-Meier curves and Log-rank tests assessed AF, HF, and cardiovascular mortality incidence. Multivariate Cox models and restricted cubic splines analyzed the associations of eGDR with these outcomes. Polygenic Risk Score (PRS) analysis evaluated the joint effects of eGDR and PRS. Boruta algorithm filtered key predictive variables. Subgroup analysis was performed using cardiovascular high-risk factors, and mediation analysis explored the relationships of eGDR with the outcomes. Subjects with higher eGDR were more likely to be female, younger, more physically active, non-smoker, and non-drinker. The cumulative incidence of AF, HF, and cardiovascular mortality in the higher quartiles of GDR were significantly lower than those in the lowest quartile (log-rank P < 0.001 for all). eGDR exhibited an independent negative linear correlation with the risk of AF (HR = 0.94, 95% CI: 0.91-0.96), HF (HR = 0.78, 95% CI: 0.74-0.82), and cardiovascular mortality (HR = 0.86, 95% CI: 0.83-0.88) risk. eGDR made the most significant contribution to the predicted outcomes. In diabetic patients with high genetic susceptibility, high eGDR could reduce the risk of AF (HR = 0.68, 95% CI: 0.51-0.90), HF (HR = 0.43, 95% CI: 0.29-0.62), and cardiovascular mortality (HR = 0.30, 95% CI: 0.22-0.42). Mediation analysis demonstrated that 10.7%, 7.9%, and 10.3% of the relationship between eGDR and AF, HF, and cardiovascular mortality among individuals with diabetes were mediated by eGFR, respectively. This study demonstrated that higher eGDR levels were associated with a decreased risk of AF, HF, and cardiovascular mortality. Therefore, eGDR may serve as a valuable tool for predicting the risk of AF, HF, and cardiovascular mortality in patients with diabetes.

Congenital interatrial shunt can unload the left atrium (LA) and may lower the risk of new-onset heart failure (HF) or atrial fibrillation (AF). We evaluated the risk of new-onset HF or AF in patients with and without interatrial shunt. We enrolled 2660 consecutive patients with acute stroke or transient ischemic attack (TIA) who underwent transesophageal echocardiography at Seoul National University Bundang Hospital from January 1, 2006 to December 31, 2018. The primary outcomes were 10-year new-onset HF, new-onset AF, and new-onset HF or AF composite. Overall, 466 (17.5%) patients with an interatrial shunt had smaller E velocity (0.66 ± 0.21 vs. 0.69 ± 0.22m/s, P = 0.037) and smaller E/e' (9.1 ± 4.0 vs. 10.0 ± 5.0, P = 0.001) than 2194 (82.5%) patients without an interatrial shunt. The 10-year incidence of AF, HF, and AF or HF composite was lower in patients with an interatrial shunt (10-year AF, 11.2 vs. 17.8%, P < 0.001; 10-year HF, 6.2 vs. 10.4%, P = 0.005; 10-year AF or HF composite, 16.5 vs. 23.4%, P = 0.001). In multivariable analysis, the presence of an interatrial shunt was associated with a 38% (HR 0.62, 95% CI 0.40-0.96), 40% (HR 0.60; 95% CI 0.39-0.93), and 26% (HR 0.74; 95% CI 0.57-0.96) reduced risk for new-onset HF, AF, and new-onset HF or AF composite, respectively. In patients with interatrial shunt, the risk of AF and HF was lower. Interatrial shunt may be beneficial, and the closure of an interatrial shunt should be performed only in carefully selected patients. An interatrial shunt can unload the left atrium. In patients with stroke or TIA, the presence of an interatrial shunt was associated with a reduced risk for new-onset HF and AF. AF atrial fibrillation, HF heart failure, HR hazard ratio, LA left atrium.

<i>Circulation:</i> Clinical Summaries

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