Cluster Individuals Based on Phenotype and Determine the Risk for Atrial Fibrillation in the PREVEND and Framingham Heart Study Populations.

BACKGROUND: Risk prediction of atrial fibrillation (AF) is of importance to improve the early diagnosis and treatment of AF. Latent class analysis takes into account the possible existence of classes of individuals each with shared risk factors, and maybe a better method of incorporating the phenotypic heterogeneity underlying AF. METHODS AND FINDINGS: Two prospective community-based cohort studies from Netherlands and United States were used. Prevention of Renal and Vascular End-stage Disease (PREVEND) study, started in 1997, and the Framingham Heart Study (FHS) Offspring cohort started in 1971, both with 10-years follow-up. The main objective was to determine the risk of AF using a latent class analysis, and compare the discrimination and reclassification performance with traditional regression analysis. Mean age in PREVEND was 49±13 years, 49.8% were men. During follow-up, 250(3%) individuals developed AF. We built a latent class model based on 18 risk factors. A model with 7 distinct classes (ranging from 341 to 1517 individuals) gave the optimum tradeoff between a high statistical model-likelihood and a low number of model parameters. All classes had a specific profile. The incidence of AF varied; class 1 0.0%, class 2 0.3%, class 3 7.5%, class 4 0.2%, class 5 1.3%, class 6 4.2%, class 7 21.7% (p<0.001). The discrimination (C-statistic 0.830 vs. 0.842, delta-C -0.013, p = 0.22) and reclassification (IDI -0.028, p<0.001, NRI -0.090, p = 0.049, and category-less-NRI -0.049, p = 0.495) performance of both models was comparable. The results were successfully replicated in a sample of the FHS study (n = 3162; mean age 58±9 years, 46.3% men). CONCLUSIONS: Latent class analysis to build an AF risk model is feasible. Despite the heterogeneity in number and severity of risk factors between individuals at risk for AF, latent class analysis produces distinguishable groups.

Incidence of Atrial Fibrillation and Relationship With Cardiovascular Events, Heart Failure, and Mortality: A Community-Based Study From the Netherlands.

BACKGROUND: Important improvements have been made in treatment of diseases associated with atrial fibrillation (AF), such as hypertension, myocardial infarction, and heart failure. Incidence rates and risk factors may have changed with the aging of the population and changing lifestyles. Currently, the risk for AF is only partially explained, possibly because of differences between older cohorts and contemporary populations. OBJECTIVES: This study investigated the incidence of AF in a contemporary cohort in the Netherlands, together with comorbidities associated with AF and associations of AF with cardiovascular outcomes. METHODS: Incident AF was ascertained for hospital and study electrocardiograms in 8,265 participants of the PREVEND (Prevention of Renal and Vascular End-Stage Disease) study in Groningen, the Netherlands. RESULTS: During 9.7 ± 2.3 years of follow-up, 265 participants developed AF, with a resulting overall AF incidence of 3.3 per 1,000 person-years. Advancing age, male sex, antihypertensive drug use, higher body mass index, previous myocardial infarction, and previous stroke were associated with AF. After multivariable adjustment, AF was associated with cardiovascular events (hazard ratio [HR]: 2.24; 95% confidence interval [CI]: 1.06 to 4.75; p = 0.035), heart failure with either reduced or preserved ejection fraction (HR: 4.52; 95% CI: 2.02 to 10.09; p < 0.001), and all-cause mortality (HR: 3.02; 95% CI: 1.73 to 5.27; p < 0.001). CONCLUSIONS: The incidence of AF in the present cohort was comparable to that shown in data of older studies. Obesity has become a major risk factor for incident AF. Although overall cardiovascular event rates were lower in the present study, the present study confirms the association of incident AF with such events.

Symptom severity is associated with cardiovascular outcome in patients with permanent atrial fibrillation in the RACE II study.

AIMS: Symptoms and symptom burden have a central place in diagnosis and management of atrial fibrillation (AF). The aim of the present study is to investigate whether severity of AF symptoms impacts prognosis in permanent AF. METHODS AND RESULTS: We studied the relation between AF symptom severity [quantified with the Toronto AF Severity Scale (AFSS)] and cardiovascular outcome in patients included in the RACE II study. The primary endpoint was a composite of cardiovascular morbidity and mortality. Secondary outcome was cardiovascular hospitalizations. Of 614 permanent AF patients in RACE II, AFSS questionnaires were available in 558 patients (91%). Mean age was 68 ± 8 years. One hundred and seventy-four patients (31%) reported a low score (score 0-3; lowest tertile), 190 patients (34%) reported a moderate score (score 4-9; middle tertile), and 194 (35%) reported a high score (score 10-35; highest tertile). Patients with the most severe symptoms were more often women, had higher N-terminal prohormone of brain natriuretic peptide concentrations, and had more previous heart failure hospitalizations. Median follow-up was 3.0 (interquartile range 2.3-3.0) years. The primary endpoint occurred most frequently in the highest tertile of the AFSS [16 (9%), 19 (10%), 36 (19%), respectively, P = 0.01], being mainly driven by heart failure hospitalizations [4 (2%), 1 (1%), 16 (8%), respectively, P < 0.001]. After multivariable adjustment, higher AFSS scores were associated with the primary endpoint [hazard ratio 1.38 (1.15-1.66), P = 0.001], as well as with cardiovascular hospitalizations [hazard ratio 1.33 (1.14-1.54), P < 0.001]. CONCLUSION: In permanent AF, after multivariable adjustment, symptom severity is associated with cardiovascular outcome.

Asymptomatic persistent atrial fibrillation and outcome: results of the RACE study.

BACKGROUND: Symptoms are a major driver for patients with atrial fibrillation (AF) to seek medical attention and are important to titrate AF therapies. However, a large proportion of patients with AF are asymptomatic. OBJECTIVE: To investigate the clinical profile and prognosis of patients with asymptomatic recurrent persistent AF in the RAte Control versus Electrical cardioversion for persistent atrial fibrillation study. METHODS: Patients with asymptomatic AF (n = 157 [30%]) were compared with patients with symptomatic AF (n = 365 [70%]). The primary end point was a composite of cardiovascular morbidity and mortality. RESULTS: Patients with asymptomatic AF were younger and more often men than were patients with symptomatic AF. Cardiac diseases were less common. Quality of life (the Medical Outcomes Study Short-form health survey questionnaire) was better in patients with asymptomatic AF and comparable to healthy controls. At baseline and during follow-up, there were no differences in rate control, antiarrhythmic, or anticoagulant drugs; cardioversions; and time in sinus rhythm. After a follow-up of 2.3 ± 0.6 years, the primary end point occurred in 21 (13%) patients with asymptomatic AF and 83 (23%) patients with symptomatic AF. After adjusting for relevant covariates, asymptomatic AF was associated with a lower risk of the primary end point (hazard ratio 0.51; 95% confidence interval 0.29-0.92; P = .024). This difference was driven by significantly less heart failure hospitalizations (0 vs 21 [6%]) and severe effects of antiarrhythmic drugs or digoxin (1 [0.6%] vs 13 [4%]). Importantly, no difference in the occurrence of thromboembolic complications was observed. CONCLUSION: Patients with asymptomatic AF were more often men and had less cardiac disease. During follow-up, in patients with asymptomatic AF, heart failure hospitalizations and severe adverse effects of antiarrhythmic and rate control drugs occurred significantly less frequently.

Intravenous clusterin administration reduces myocardial infarct size in rats.

BACKGROUND: Clusterin (Apolipoprotein J), a plasma protein with cytoprotective and complement-inhibiting activities, localizes in the infarcted heart during myocardial infarction (MI). Recently, we have shown a protective effect of exogenous clusterin in vitro on ischaemically challenged cardiomyocytes independent of complement. We therefore hypothesized that intravenous clusterin administration would reduce myocardial infarction damage. METHODS: Wistar rats undergoing experimental MI, induced by 40 min ligation of a coronary vessel, were treated with either clusterin (n=15) or vehicle (n=13) intravenously, for 3 days post-MI. After 4 weeks, hearts were analysed. The putative role of megalin, a clusterin receptor, was also studied. RESULTS: Administration of human clusterin significantly reduced both infarct size (with 75 ± 5%) and death of animals (23% vehicle group vs. 0% clusterin group). Importantly, histochemical analysis showed no signs of impaired wound healing in the clusterin group. In addition, significantly increased numbers of macrophages were found in the clusterin group. We also found that the clusterin receptor megalin was present on cardiomyocytes in vitro which, however, was not influenced by ischaemia. Human clusterin co-localized with this receptor in vitro, but not in the human heart. In addition, using a megalin inhibitor, we found that clusterin did not exert its protective effect on cardiomyocytes through megalin. CONCLUSIONS: Our results thus show that clusterin has a protective effect on cardiomyocytes after acute myocardial infarction in vivo, independent of its receptor megalin. This indicates that clusterin, or a clusterin derivate, is a potential therapeutic agent in the treatment of MI.

Inhibition of type 2A secretory phospholipase A2 reduces death of cardiomyocytes in acute myocardial infarction.

During acute myocardial infarction (AMI), ischemia leads to necrotic areas surrounded by border zones of reversibly damaged cardiomyocytes, showing membrane flip-flop. During reperfusion type IIA secretory phopholipase A(2) (sPLA(2)-IIA) induces direct cell-toxicity and facilitates binding of other inflammatory mediators on these cardiomyocytes. Therefore, we hypothesized that the specific sPLA(2)-IIA-inhibitor PX-18 would reduce cardiomyocyte death and infarct size in vivo. Wistar rats were treated with PX-18 starting minutes after reperfusion, and at day 1 and 2 post AMI. After 28 days hearts were analyzed. Furthermore, the effect of PX-18 on membrane flip-flop and apoptosis was investigated in vitro. PX-18 significantly inhibited sPLA(2)-IIA activity and reduced infarct size (reduction 73 +/- 9%, P < 0.05), compared to the vehicle-treated group, without impairing wound healing. In vitro, PX-18 significantly reduced reversible membrane flip-flop and apoptosis in cardiomyocytes. However, no sPLA(2)-IIA activity could be detected, suggesting that PX-18 also exerted a protective effect independent of sPLA(2)-IIA. In conclusion, PX-18 is a potent therapeutic to reduce infarct size by inhibiting sPLA(2)-IIA, and possibly also by inhibiting apoptosis of cardiomyocytes in a sPLA(2)-IIA independent manner.