Associations of relative fat mass and BMI with all-cause mortality: Confounding effect of muscle mass.

OBJECTIVE: The study objective was to examine associations of relative fat mass (RFM) and BMI with all-cause mortality in the Dutch general population and to investigate whether additional adjustment for muscle mass strengthened these associations. METHODS: A total of 8433 community-dwelling adults from the PREVEND general population cohort (1997-1998) were included. Linear regression models were used to examine associations of RFM and BMI with 24-h urinary creatinine excretion, a marker of total muscle mass. Cox regression models were used to examine associations of RFM and BMI with all-cause mortality. RESULTS: The mean age of the cohort was 49.8 years (range: 28.8-75.7 years), and 49.9% (n = 4209) were women. In age- and sex-adjusted models, both RFM and BMI were associated with total muscle mass (24-h urinary creatinine excretion), and these associations were stronger with BMI (standardized beta [Sß]RFM : 0.29; 95% CI: 0.27-0.31 vs. SßBMI : 0.38; 95% CI: 0.36-0.40; pdifference < 0.001). During a median follow-up period of 18.4 years, 1640 deaths (19.4%) occurred. In age- and sex-adjusted models, RFM was significantly associated with all-cause mortality (hazard ratio per 1-SD [HRRFM ]: 1.16; 95% CI: 1.09-1.24), whereas BMI was not (HRBMI : 1.04; 95% CI: 0.99-1.10). After additional adjustment for muscle mass, associations of both RFM and BMI with all-cause mortality increased in magnitude (HRRFM : 1.24; 95% CI: 1.16-1.32 and HRBMI : 1.12; 95% CI: 1.06-1.19). Results were broadly similar in multivariable adjusted models. CONCLUSIONS: In the general population, a higher RFM was significantly associated with mortality risk, whereas a higher BMI was not. Adjusting for total muscle mass increased the strength of associations of both RFM and BMI with all-cause mortality.

Women have less progression of paroxysmal atrial fibrillation: data from the RACE V study.

BACKGROUND: Sex differences in atrial fibrillation (AF) are observed in terms of comorbidities, symptoms, therapies received, AF progression and cardiovascular complications. METHODS: We assessed the differences in prevalence and the determinants of AF progression, as well as the clinical characteristics and quality of life (QoL), between women and men with paroxysmal AF included in the RACE V (Reappraisal of Atrial Fibrillation: Interaction between hyperCoagulability, Electrical remodeling, and Vascular Destabilisation in the Progression of AF) study. At baseline, extensive phenotyping was done. To assess AF progression, implantable loop recorder (ILR) monitoring was used throughout follow-up. AF progression was defined as (1) progression to persistent or permanent AF or (2) progression of paroxysmal AF (>3% burden increase). RESULTS: 417 patients were included, 179 (43%) of whom were women. Women were older (median 67 years vs 63 years, p<0.001), less often had coronary artery disease (n=11 (6%) vs n=36 (16%), p=0.003), had more obesity (n=57 (32%) vs n=50 (21%), p=0.013), had less epicardial and pericardial fat (median 144 (interquartile range [IQR] 94-191) mL vs 199 (IQR 146-248) mL, p<0.001; and median 89 (ICQ 61-121) mL vs 105 (IQR 83-133) mL, p<0.001, respectively) and had more impaired left atrial function. The median follow-up was 2.2 (1.6-2.8) years. 51 of 417 patients (5.5% per year) showed AF progression (15/179 (8.4%) women and 36/238 (15.1%) men, p=0.032). Multivariable analysis showed tissue factor pathway inhibitor, N-terminal prohormone brain natriuretic peptide (NT-proBNP) and PR interval being associated with AF progression in women and factor XIIa:C1 esterase, NT-proBNP and proprotein convertase subtilisin/kexin type 9 in men. QoL was not different between sexes. CONCLUSION: Despite older age, the incidence of AF progression was lower in women. Parameters associated with AF progression varied in part between sexes, suggesting different underlying pathophysiological mechanisms.

Cardiovascular and renal multimorbidity increase risk of atrial fibrillation in the PREVEND cohort.

OBJECTIVE: Atrial fibrillation (AF) is a condition that occurs in the presence of comorbidities. With the accumulation of comorbidities (multimorbidity), some combinations may more often occur together than others. Information on the impact of clustering of these on incident AF is sparse. We aimed to investigate clustering of cardiovascular and renal comorbidities and study the association between comorbidity clusters and incident AF. METHODS: We used the community-based Prevention of Renal and Vascular ENd-stage Disease (PREVEND) cohort in which 8592 individuals participated. Latent class analysis was performed to assess clustering of 10 cardiovascular and renal comorbidities. RESULTS: We excluded individuals with prior AF or missing ECG data, leaving 8265 individuals for analysis (mean age 48.9±12.6 years, 50.2% women). During 9.2±2.1 years of follow-up, 251 individuals (3.0%) developed AF. A model with three clusters was the optimal model, with one cluster being young (44.5±10.8 years) and healthy, carrying a low (1.0%) risk of incident AF; one cluster being older (63.0±8.4 years) and multimorbid, carrying a high (16.2%) risk of incident AF and a third middle-aged (57.0±11.3 years), obese and hypertensive cluster carrying an intermediate risk (5.9%) of incident AF. While the prevalence of the comorbidities differed between classes, no clear combination(s) of comorbidities was observed within the classes. CONCLUSIONS: We identified three clusters of comorbidities in individuals in the community-based PREVEND cohort. The three clusters contained different amount of comorbidities carrying different risks of incident AF. However, there were no differences between the clusters regarding specific combination(s) of comorbidities.

Clinical utility of the 4S-AF scheme in predicting progression of atrial fibrillation: data from the RACE V study.

AIMS: The recent 4S-AF (scheme proposed by the 2020 ESC AF guidelines to address stroke risk, symptom severity, severity of AF burden and substrate of AF to provide a structured phenotyping of AF patients in clinical practice to guide therapy and assess prognosis) scheme has been proposed as a structured scheme to characterize patients with atrial fibrillation (AF). We aimed to assess whether the 4S-AF scheme predicts AF progression in patients with self-terminating AF. METHODS AND RESULTS: We analysed 341 patients with self-terminating AF included in the well-phenotyped Reappraisal of Atrial Fibrillation: Interaction between HyperCoagulability, Electrical remodelling, and Vascular Destabilization in the Progression of AF (RACE V) study. Patients had continuous monitoring with implantable loop recorders or pacemakers. AF progression was defined as progression to persistent or permanent AF or progression of self-terminating AF with >3% burden increase. Progression of AF was observed in 42 patients (12.3%, 5.9% per year). Patients were given a score based on the components of the 4S-AF scheme. Mean age was 65 [interquartile range (IQR) 58-71] years, 149 (44%) were women, 103 (49%) had heart failure, 276 (81%) had hypertension, and 38 (11%) had coronary artery disease. Median CHA2DS2-VASc (the CHA2DS2-VASc score assesses thromboembolic risk. C, congestive heart failure/left ventricular dysfunction; H, hypertension; A2, age ≥ 75 years; D, diabetes mellitus; S2, stroke/transient ischaemic attack/systemic embolism; V, vascular disease; A, age 65-74 years; Sc, sex category (female sex)) score was 2 (IQR 2-3), and median follow-up was 2.1 (1.5-2.6) years. The average score of the 4S-AF scheme was 4.6 ± 1.4. The score points from the 4S-AF scheme did not predict the risk of AF progression [odds ratio (OR) 1.1 95% CI 0.88-1.41, C-statistic 0.53]. However, excluding the symptoms domain, resulting in the 3S-AF (4S-AF scheme without the domain symptom severity, only including stroke risk, severity of AF burden and substrate of AF) scheme, predicted the risk of progression (OR 1.59 95% CI 1.15-2.27, C-statistic 0.62) even after adjusting for sex and age. CONCLUSIONS: In self-terminating AF patients, the 4S-AF scheme does not predict AF progression. The 3S-AF scheme, excluding the symptom domain, may be a more appropriate score to predict AF progression. TRIAL REGISTRATION NUMBERS: Clinicaltrials.gov NCT02726698 for RACE V.

Risk prediction of atrial fibrillation and its complications in the community using hs troponin I.

AIMS: Atrial fibrillation (AF) is becoming increasingly common. Traditional cardiovascular risk factors (CVRF) do not explain all AF cases. Blood-based biomarkers reflecting cardiac injury such as high-sensitivity troponin I (hsTnI) may help close this gap. METHODS: We investigated the predictive ability of hsTnI for incident AF in 45,298 participants (median age 51.4 years, 45.0% men) across European community cohorts in comparison to CVRF and established biomarkers (C-reactive protein, N-terminal pro B-type natriuretic peptide). RESULTS: During a median follow-up of 7.7 years, 1734 (3.8%) participants developed AF. Those in the highest hsTnI quarter (≥4.2 ng/L) had a 3.91-fold (95% confidence interval (CI) 3.30, 4.63; p < .01) risk for developing AF compared to the lowest quarter (<1.4 ng/L). In multivariable-adjusted Cox proportional hazards models a statistically significant association was seen between hsTnI and AF (hazard ratio (HR) per 1 standard deviation (SD) increase in log10(hsTnI) 1.08; 95% CI 1.01, 1.16; p = .03). Inclusion of hsTnI did improve model discrimination (C-index CVRF 0.811 vs. C-index CVRF and hsTnI 0.813; p < .01). Higher hsTnI concentrations were associated with heart failure (HR per SD 1.37; 95% CI 1.12, 1.68; p < .01) and overall mortality (HR per SD 1.24; 95% CI 1.09, 1.41; p < .01). CONCLUSION: hsTnI as a biomarker of myocardial injury does not improve prediction of AF incidence beyond classical CVRF and NT-proBNP. However, it is associated with the AF-related disease heart failure and mortality likely reflecting underlying subclinical cardiovascular impairment.

Resting membrane potential is less negative in trabeculae from right atrial appendages of women, but action potential duration does not shorten with age.

AIMS: The incidence of atrial fibrillation (AF) increases with age. Women have a lower risk. Little is known on the impact of age, sex and clinical variables on action potentials (AP) recorded in right atrial tissue obtained during open heart surgery from patients in sinus rhythm (SR) and in longstanding AF. We here investigated whether age or sex have an impact on the shape of AP recorded in vitro from right atrial tissue. METHODS: We performed multivariable analysis of individual AP data from trabeculae obtained during heart surgery of patients in SR (n = 320) or in longstanding AF (n = 201). AP were recorded by sharp microelectrodes at 37 °C at 1 Hz. Impact of clinical variables were modeled using a multivariable mixed model regression. RESULTS: In SR, AP duration at 90% repolarization (APD90) increased with age. Lower ejection fraction and higher body mass index were associated with smaller action potential amplitude (APA) and maximum upstroke velocity (Vmax). The use of beta-blockers was associated with larger APD90. In tissues from women, resting membrane potential was less negative and APA as well as Vmax were smaller. Besides shorter APD20 in elderly patients, effects of age and sex on atrial AP were lost in AF. CONCLUSION: The higher probability to develop AF at advanced age cannot be explained by a shortening in APD90. Less negative RMP and lower upstroke velocity might contribute to lower incidence of AF in women, which may be of clinical relevance.

Vertebral Fractures Assessed by Dual-Energy X-Ray Absorptiometry and All-Cause Mortality: The Tromsø Study, 2007-2020.

Vertebral fractures have been associated with increased mortality, but findings are inconclusive, and many vertebral fractures avoid clinical attention. We investigated this association in a general population of 2,476 older adults aged ≥55 years from Tromsø, Norway, who were followed over 2007-2020, using dual-energy x-ray absorptiometry (DXA) at baseline to evaluate vertebral fractures (mild, moderate, or severe). We used multiple Cox regression models to estimate hazard ratios (HRs) for all-cause mortality, adjusted for age, sex, body mass index, education, smoking, alcohol intake, cardiovascular disease, and respiratory disease. Mean follow-up in the cohort was 11.2 (standard deviation, 2.7) years; 341 participants (13.8%) had ≥1 vertebral fracture at baseline, and 636 participants (25.7%) died between baseline and follow-up. Full-adjustment models showed a nonsignificant association between vertebral fracture status (yes/no) and mortality. Participants with ≥3 vertebral fractures (HR = 2.43, 95% confidence interval: 1.57, 3.78) or ≥1 severe vertebral fracture (HR = 1.65, 95% confidence interval: 1.26, 2.15) had increased mortality compared with those with no vertebral fractures. Dual-energy x-ray absorptiometry-based screening could be a potent and feasible tool in detecting vertebral fractures that are often clinically silent yet independently associated with premature death. Our data indicated that detailed vertebral assessment could be warranted for a more accurate survival estimation.

Prevalence and determinants of atrial fibrillation progression in paroxysmal atrial fibrillation.

OBJECTIVE: Atrial fibrillation (AF) often progresses from paroxysmal AF (PAF) to more permanent forms. To improve personalised medicine, we aim to develop a new AF progression risk prediction model in patients with PAF. METHODS: In this interim-analysis of the Reappraisal of AF: Interaction Between HyperCoagulability, Electrical Remodelling, and Vascular Destabilisation in the Progression of AF study, patients with PAF undergoing extensive phenotyping at baseline and continuous rhythm monitoring during follow-up of ≥1 year were analysed. AF progression was defined as (1) progression to persistent or permanent AF or (2) progression of PAF with >3% burden increase. Multivariable analysis was done to identify predictors of AF progression. RESULTS: Mean age was 65 (58-71) years, 179 (43%) were female. Follow-up was 2.2 (1.6-2.8) years, 51 of 417 patients (5.5%/year) showed AF progression. Multivariable analysis identified, PR interval, impaired left atrial function, mitral valve regurgitation and waist circumference to be associated with AF progression. Adding blood biomarkers improved the model (C-statistic from 0.709 to 0.830) and showed male sex, lower levels of factor XIIa:C1-esterase inhibitor and tissue factor pathway inhibitor, and higher levels of N-terminal pro-brain natriuretic peptide, proprotein convertase subtilisin/kexin type 9 and peptidoglycan recognition protein 1 were associated with AF progression. CONCLUSION: In patients with PAF, AF progression occurred in 5.5%/year. Predictors for progression included markers for atrial remodelling, sex, mitral valve regurgitation, waist circumference and biomarkers associated with coagulation, inflammation, cardiomyocyte stretch and atherosclerosis. These prediction models may help to determine risk of AF progression and treatment targets, but validation is needed. TRIAL REGISTRATION NUMBER: NCT02726698.

Risk Factors, Subsequent Disease Onset, and Prognostic Impact of Myocardial Infarction and Atrial Fibrillation.

Background Although myocardial infarction (MI) and atrial fibrillation (AF) are frequent comorbidities and share common cardiovascular risk factors, the direction and strength of the association of the risk factors with disease onset, subsequent disease incidence, and mortality are not completely understood. Methods and Results In pooled multivariable Cox regression analyses, we examined temporal relations of disease onset and identified predictors of MI, AF, and all-cause mortality in 108 363 individuals (median age, 46.0 years; 48.2% men) free of MI and AF at baseline from 6 European population-based cohorts. During a maximum follow-up of 10.0 years, 3558 (3.3%) individuals were diagnosed exclusively with MI, 1922 (1.8%) with AF but no MI, and 491 (0.5%) individuals developed both MI and AF. Association of sex, systolic blood pressure, antihypertensive treatment, and diabetes appeared to be stronger with incident MI than with AF, whereas increasing age and body mass index showed a higher risk for incident AF. Total cholesterol and daily smoking were significantly related to incident MI but not AF. Combined population attributable fraction of cardiovascular risk factors was >70% for incident MI, whereas it was only 27% for AF. Subsequent MI after AF (hazard ratio [HR], 1.68; 95% CI, 1.03-2.74) and subsequent AF after MI (HR, 1.75; 95% CI, 1.31-2.34) both significantly increased overall mortality risk. Conclusions We observed different associations of cardiovascular risk factors with both diseases indicating distinct pathophysiological pathways. Subsequent diagnoses of MI and AF significantly increased mortality risk.

Validating risk models versus age alone for atrial fibrillation in a young Dutch population cohort: should atrial fibrillation risk prediction be expanded to younger community members?

BACKGROUND: Advancing age is the primary selection criterion for community screening for atrial fibrillation (AF), with selection often restricted to those aged ≥65 years. If multivariable models were shown to have considerable additional value over age alone in predicting AF risk among younger individuals, AF screening could be expanded to patients with lower age, but with high AF risk as per a validated risk model. METHODS: We validated risk models CHARGE-AF (Cohorts for Heart and Aging Research in Genomic Epidemiology model for AF) and FHS-AF (Framingham Heart Study model for AF), and risk scores CHA2DS2-VASc and CHA2DS2-VA, and presented their predictive abilities for 5-year and 10-year AF risk versus that of age alone in a young Dutch population cohort (PREVEND) free from AF at baseline. We assessed discrimination by the C-statistic and calibration by the calibration plot and stratified Kaplan-Meier plot using survey-weighted Cox models. RESULTS: During 5-year and 10-year follow-up there were n=98 (2.46/1000 person-years) and n=249 (3.29/1000 person-years) new AF cases, respectively, among 8265 participants with mean age 49±13 years. CHARGE-AF and FHS-AF both showed good discrimination for 5-year and 10-year AF (C-statistic range 0.83-0.86) with accurate calibration for 5-year AF, but overestimation of 10-year AF risk in highest-risk individuals. CHA2DS2-VASc and CHA2DS2-VA relatively underperformed. Age alone showed similar discrimination to that of CHARGE-AF and FHS-AF both in the overall, young PREVEND cohort and in subgroups for lower age and lower stroke risk. CONCLUSION: Multivariable models accurately discriminate for 5-year and 10-year AF risk among young European community-dwelling individuals. However, their additional discriminatory value over age alone was limited. Selection strategies for primary AF screening using multivariable models should not be expanded to younger individuals.

The value of echocardiographic measurement of epicardial adipose tissue in heart failure patients.

AIMS: Epicardial adipose tissue (EAT) is increasingly recognized as an important factor in the pathophysiology of heart failure (HF). Cardiac magnetic resonance (CMR) imaging is the gold-standard imaging modality to evaluate EAT size, but in contrast to echocardiography, CMR is costly and not widely available. We investigated EAT thickness on echocardiography in relation to EAT volume on CMR, and we assessed the agreement between observers for measuring echocardiographic EAT. METHODS AND RESULTS: Patients with HF and left ventricular ejection fraction >40% were enrolled. All patients underwent CMR imaging and transthoracic-echocardiography. EAT volume was quantified on CMR short-axis cine-stacks. Echocardiographic EAT thickness was measured on parasternal long-axis and short-axis views. Linear regression analyses were used to assess the association between EAT volume on CMR and EAT thickness on echocardiography. Intraclass correlation coefficient (ICC) was used to assess the interobserver agreement as well as the intraobserver agreement. EAT on CMR and echocardiography was evaluated in 117 patients (mean age 71 ± 10 years, 49% women and mean left ventricular ejection fraction 54 ± 7%). Mean EAT volume on CMR was 202 ± 64 mL and ranged from 80 to 373 mL. Mean EAT thickness on echocardiography was 3.8 ± 1.5 mm and ranged from 1.7 to 10.2 mm. EAT volume on CMR and EAT thickness on echocardiography were significantly correlated (junior-observer: r = 0.62, P < 0.001, senior-observer: r = 0.33, P < 0.001), and up to one-third of the variance in EAT volume was explained by EAT thickness (R2  = 0.38, P < 0.001). The interobserver agreement between junior and senior observers for measuring echocardiographic EAT was modest [ICC, 0.65 (95% confidence interval (CI) 0.47-0.77], whereas the intraobserver agreement was good (ICC 0.98, 95% CI 0.84-0.99). CONCLUSIONS: There was a modest correlation between EAT volume on CMR and EAT thickness on echocardiography. Limited agreement between junior and senior observers for measuring echocardiographic EAT was observed. EAT thickness on echocardiography is limited in estimating EAT volume.

Tissue-specific multi-omics analysis of atrial fibrillation.

Genome-wide association studies (GWAS) for atrial fibrillation (AF) have uncovered numerous disease-associated variants. Their underlying molecular mechanisms, especially consequences for mRNA and protein expression remain largely elusive. Thus, refined multi-omics approaches are needed for deciphering the underlying molecular networks. Here, we integrate genomics, transcriptomics, and proteomics of human atrial tissue in a cross-sectional study to identify widespread effects of genetic variants on both transcript (cis-eQTL) and protein (cis-pQTL) abundance. We further establish a novel targeted trans-QTL approach based on polygenic risk scores to determine candidates for AF core genes. Using this approach, we identify two trans-eQTLs and five trans-pQTLs for AF GWAS hits, and elucidate the role of the transcription factor NKX2-5 as a link between the GWAS SNP rs9481842 and AF. Altogether, we present an integrative multi-omics method to uncover trans-acting networks in small datasets and provide a rich resource of atrial tissue-specific regulatory variants for transcript and protein levels for cardiovascular disease gene prioritization.

Does mechanical dyssynchrony in addition to QRS area ensure sustained response to cardiac resynchronization therapy?

AIMS: Judicious patient selection for cardiac resynchronization therapy (CRT) may further enhance treatment response. Progress has been made by using improved markers of electrical dyssynchrony and mechanical discoordination, using QRSAREA, and systolic rebound stretch of the septum (SRSsept) or systolic stretch index (SSI), respectively. To date, the relation between these measurements has not yet been investigated. METHODS AND RESULTS: A total of 240 CRT patients were prospectively enrolled from six centres. Patients underwent standard 12-lead electrocardiography, and echocardiography, at baseline, 6-month, and 12-month follow-up. QRSAREA was derived using vectorcardiography, and SRSsept and SSI were measured using strain-analysis. Reverse remodelling was measured as the relative decrease in left ventricular end-systolic volume, indexed to body surface area (ΔLVESVi). Sustained response was defined as ≥15% decrease in LVESVi, at both 6- and 12-month follow-up. QRSAREA and SRSsept were both strong, multivariable adjusted, variables associated with reverse remodelling. SRSsept was associated with response, but only in patients with QRSAREA ≥ 120 µVs (AUC = 0.727 vs. 0.443). Combined presence of SRSsept ≥ 2.5% and QRSAREA ≥ 120 µVs significantly increased reverse remodelling compared with high QRSAREA alone (ΔLVESVi 38 ± 21% vs. 22 ± 21%). As a result, 92% of left bundle branch block (LBBB)-patients with combined electrical and mechanical dysfunction were 'sustained' volumetric responders, as opposed to 51% with high QRSAREA alone. CONCLUSION: Parameters of mechanical dyssynchrony are better associated with response in the presence of a clear underlying electrical substrate. Combined presence of high SRSsept and QRSAREA, but not high QRSAREA alone, ensures a sustained response after CRT in LBBB patients.

Long-term outcome of targeted therapy of underlying conditions in patients with early persistent atrial fibrillation and heart failure: data of the RACE 3 trial.

AIMS: The Routine vs. Aggressive risk factor driven upstream rhythm Control for prevention of Early persistent atrial fibrillation (AF) in heart failure (HF) (RACE 3) trial demonstrated that targeted therapy of underlying conditions improved sinus rhythm maintenance at 1 year. We now explored the effects of targeted therapy on the additional co-primary endpoints; sinus rhythm maintenance and cardiovascular outcome at 5 years. METHODS AND RESULTS: Patients with early persistent AF and mild-to-moderate stable HF were randomized to targeted or conventional therapy. Both groups received rhythm control therapy according to guidelines. The targeted group additionally received four therapies: angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers (ARBs), statins, mineralocorticoid receptor antagonists (MRAs), and cardiac rehabilitation. The presence of sinus rhythm and cardiovascular morbidity and mortality at 5-year follow-up were assessed. Two hundred and sixteen patients consented for long-term follow-up, 107 were randomized to targeted and 109 to conventional therapy. At 5 years, MRAs [76 (74%) vs. 10 (9%) patients, P < 0.001] and statins [81 (79%) vs. 59 (55%), P < 0.001] were used more in the targeted than conventional group. Angiotensin-converting enzyme inhibitors/ARBs and physical activity were not different between groups. Sinus rhythm was present in 49 (46%) targeted vs. 43 (39%) conventional group patients at 5 years (odds ratio 1.297, lower limit of 95% confidence interval 0.756, P = 0.346). Cardiovascular mortality and morbidity occurred in 20 (19%) in the targeted and 15 (14%) conventional group patients, P = 0.353. CONCLUSION: In patients with early persistent AF and HF superiority of targeted therapy in sinus rhythm maintenance could not be preserved at 5-year follow-up. Cardiovascular outcome was not different between groups. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT00877643.

Atrial fibrillation detected at screening is not a benign condition: outcomes in screen-detected versus clinically detected atrial fibrillation. Results from the Prevention of Renal and Vascular End-stage Disease (PREVEND) study.

AIMS: It is unknown whether screen-detected atrial fibrillation (AF) carries cardiovascular risks similar to clinically detected AF. We aimed to compare clinical outcomes between individuals with screen-detected and clinically detected incident AF. METHODS: We studied 8265 participants (age 49 ± 13 years, 50% women) without prevalent AF from the community-based Prevention of Renal and Vascular End-stage Disease (PREVEND) study. By design of the PREVEND study, 70% of participants had a urinary albumin concentration >10 mg/L. Participants underwent 12-lead ECG screening at baseline and every 3 years. AF was considered screen-detected when first diagnosed during a study visit and clinically detected when first diagnosed during a hospital visit. We analysed data from the baseline visit (1997-1998) up to the third follow-up visit (2008). We used Cox regression with screen-detected and clinically detected AF as time-varying covariates to study the association of screen-detected and clinically detected AF with all-cause mortality, incident heart failure (HF) and vascular events. RESULTS: During a follow-up of 9.8 ± 2.3 years, 265 participants (3.2%) developed incident AF, of whom 60 (23%) had screen-detected AF. The majority of baseline characteristics were comparable between individuals with screen-detected and clinically detected AF. Unadjusted, both screen-detected and clinically detected AF were strongly associated with mortality, incident HF, and vascular events. After multivariable adjustment, screen-detected and clinically detected AF remained significantly associated with mortality (HR 2.21 (95% CI 1.09 to 4.47) vs 2.95 (2.18 to 4.00), p for difference=0.447) and incident HF (4.90 (2.28 to 10.57) vs 3.98 (2.49 to 6.34), p for difference=0.635). After adjustment, screen-detected AF was not significantly associated with vascular events, whereas clinically detected AF was (1.12 (0.46 to 2.71) vs 1.92 (1.21 to 3.06), p for difference=0.283). CONCLUSION: Screen-detected incident AF was associated with an increased risk of adverse outcomes, especially all-cause mortality and incident HF. The risk of outcomes was not significantly different between screen-detected AF and clinically detected AF.

Aetiology of Heart Failure, Rather than Sex, Determines Reverse LV Remodelling Response to CRT.

INTRODUCTION: Cardiac resynchronization therapy (CRT) is an established therapy for patients with heart failure with reduced ejection fraction (HFrEF). Women appear to respond differently to CRT, yet it remains unclear whether this is inherent to the female sex itself, or due to other patient characteristics. In this study, we aimed to investigate sex differences in response to CRT. METHODS: This is a post-hoc analysis of a prospective, multicenter study (MARC) in the Netherlands, studying HFrEF patients with an indication for CRT according to the guidelines (n = 240). Primary outcome measures are left ventricular ejection fraction (LVEF) and left ventricular end systolic volume (LVESV) at 6 months follow-up. Results were validated in an independent retrospective Belgian cohort (n = 818). RESULTS: In the MARC cohort 39% were women, and in the Belgian cohort 32% were women. In the MARC cohort, 70% of the women were responders (defined as >15% decrease in LVESV) at 6 months, compared to 55% of men (p = 0.040) (79% vs. 67% in the Belgian cohort, p = 0.002). Women showed a greater decrease in LVESV %, LVESV indexed to body surface area (BSA) %, and increase in LVEF (all p < 0.05). In regression analysis, after adjustment for BSA and etiology, female sex was no longer associated with change in LVESV % and LVESV indexed to BSA % and LVEF % (p > 0.05 for all). Results were comparable in the Belgian cohort. CONCLUSIONS: Women showed a greater echocardiographic response to CRT at 6 months follow-up. However, after adjustment for BSA and ischemic etiology, no differences were found in LV-function measures or survival, suggesting that non-ischemic etiology is responsible for greater response rates in women treated with CRT.

Age-specific atrial fibrillation incidence, attributable risk factors and risk of stroke and mortality: results from the MORGAM Consortium.

BACKGROUND: The main aim was to examine age-specific risk factor associations with incident atrial fibrillation (AF) and their attributable fraction in a large European cohort. Additionally, we aimed to examine risk of stroke and mortality in relation to new-onset AF across age. METHODS: We used individual-level data (n=66 951, 49.1% men, age range 40-98 years at baseline) from five European cohorts of the MOnica Risk, Genetics, Archiving and Monograph Consortium. The participants were followed for incident AF for up to 10 years and the association with modifiable risk factors from the baseline examinations (body mass index (BMI), hypertension, diabetes, daily smoking, alcohol consumption and history of stroke and myocardial infarction (MI)) was examined. Additionally, the participants were followed up for incident stroke and all-cause mortality after new-onset AF. RESULTS: AF incidence increased from 0.9 per 1000 person-years at baseline age 40-49 years, to 17.7 at baseline age ≥70 years. Multivariable-adjusted Cox models showed that higher BMI, hypertension, high alcohol consumption and a history of stroke or MI were associated with increased risk of AF across age groups (p<0.05). Between 30% and 40% of the AF risk could be attributed to BMI, hypertension and a history of stroke or MI. New-onset AF was associated with a twofold increase in risk of stroke and death at ages≥70 years (p≤0.001). CONCLUSION: In this large European cohort aged 40 years and above, risk of AF was largely attributed to BMI, high alcohol consumption and a history MI or stroke from middle age. Thus, preventive measures for AF should target risk factors such as obesity and hypertension from early age and continue throughout life.

Antiarrhythmic drugs in patients with early persistent atrial fibrillation and heart failure: results of the RACE 3 study.

AIMS: Maintaining sinus rhythm in patients with persistent atrial fibrillation (AF) is challenging. We explored the efficacy of class I and III antiarrhythmic drugs (AADs) in patients with persistent AF and mild to moderate heart failure (HF). METHODS AND RESULTS: In the RACE 3 trial, patients with early persistent symptomatic AF and short history of mild to moderate HF with preserved or reduced left ventricular ejection fraction (LVEF) were randomized to targeted or conventional therapy. Both groups received AF and HF guideline-driven treatment. Additionally, the targeted-group received mineralocorticoid receptor antagonists, statins, angiotensin-converting enzyme inhibitors and/or receptor blockers, and cardiac rehabilitation. Class I and III AADs could be instituted in case of symptomatic recurrent AF. Eventually, pulmonary vein isolation could be performed. Primary endpoint was sinus rhythm on 7-day Holter after 1-year. Included were 245 patients, age 65 ± 9 years, 193 (79%) men, AF history was 3 (2-6) months, HF history 2 (1-4) months, 72 (29.4%) had HF with reduced LVEF. After baseline electrical cardioversion (ECV), 190 (77.6%) had AF recurrences; 108 (56.8%) received class I/III AADs; 19 (17.6%) flecainide, 36 (33.3%) sotalol, 3 (2.8%) dronedarone, 50 (46.3%) amiodarone. At 1-year 73 of 108 (68.0%) patients were in sinus rhythm, 44 (40.7%) without new AF recurrences. Maintenance of sinus rhythm was significantly better with amiodarone [n = 29/50 (58%)] compared with flecainide [n = 6/19 (32%)] and sotalol/dronedarone [n = 9/39 (23%)], P = 0.0064. Adverse events occurred in 27 (25.0%) patients, were all minor and reversible. CONCLUSION: In stable HF patients with early persistent AF, AAD treatment was effective in nearly half of patients, with no serious adverse effects reported.

Non-immune risk predictors of cardiac allograft vasculopathy: Results from the U.S. organ procurement and transplantation network.

BACKGROUND: Cardiac allograft vasculopathy (CAV) remains a major long-term complication in heart transplant (HT) recipients related to increased mortality. We aimed to identify non-immune recipient- and donor-related risk factors for the development of CAV in HT patients. METHODS: 40,647 recipients, prospectively enrolled from April 1995 to January 2019 in the Organ Procurement and Transplantation Network (OPTN), were analyzed after exclusion of pediatric patients, those with missing information on CAV, and re-transplantation. Multivariable-adjusted Cox regression analyses were performed to identify recipient- and donor-related risk factors for CAV. 5-year population attributable risk for classical cardiovascular risk factors was calculated to estimate the recipients' CAV risk. Analyses were based on OPTN data (June 30, 2019). RESULTS: Of 40,647 post-transplant patients, 14,698 (36.2%) developed CAV with a higher incidence in males (37.3%) than in females (32.6%) (p < 0.001). The mean follow-up time was 68.2 months. In recipients, male sex, African American and Asian ethnicity, ischemic cardiomyopathy, body mass index and smoking were associated with CAV occurrence. In donors, older age, male sex, smoking, diabetes and arterial hypertension were related to CAV. Results remained fairly stable after analysis of different time periods. 5-year attributable CAV risk for classical cardiovascular risk factors was 9.1%. CONCLUSIONS: In this large registry with known limitations concerning data completeness, CAV incidence was higher in males than in females. Next to male sex and donor age, the classical cardiovascular risk factors were related to incident CAV. Classical cardiovascular risk factors played only a minor role for the 5-year attributable CAV risk.

Risk prediction of atrial fibrillation in the community combining biomarkers and genetics.

AIMS: Classical cardiovascular risk factors (CVRFs), biomarkers, and common genetic variation have been suggested for risk assessment of atrial fibrillation (AF). To evaluate their clinical potential, we analysed their individual and combined ability of AF prediction. METHODS AND RESULTS: In N = 6945 individuals of the FINRISK 1997 cohort, we assessed the predictive value of CVRF, N-terminal pro B-type natriuretic peptide (NT-proBNP), and 145 recently identified single-nucleotide polymorphisms (SNPs) combined in a developed polygenic risk score (PRS) for incident AF. Over a median follow-up of 17.8 years, n = 551 participants (7.9%) developed AF. In multivariable-adjusted Cox proportional hazard models, NT-proBNP [hazard ratio (HR) of log transformed values 4.77; 95% confidence interval (CI) 3.66-6.22; P < 0.001] and the PRS (HR 2.18; 95% CI 1.88-2.53; P < 0.001) were significantly related to incident AF. The discriminatory ability improved asymptotically with increasing numbers of SNPs. Compared with a clinical model, AF risk prediction was significantly improved by addition of NT-proBNP and the PRS. The C-statistic for the combination of CVRF, NT-proBNP, and the PRS reached 0.83 compared with 0.79 for CVRF only (P < 0.001). A replication in the Dutch Prevention of REnal and Vascular ENd-stage Disease (PREVEND) cohort revealed similar results. Comparing the highest vs. lowest quartile, NT-proBNP and the PRS both showed a more than three-fold increased AF risk. Age remained the strongest risk factor with a 16.7-fold increased risk of AF in the highest quartile. CONCLUSION: The PRS and the established biomarker NT-proBNP showed comparable predictive ability. Both provided incremental predictive value over standard clinical variables. Further improvements for the PRS are likely with the discovery of additional SNPs.