Association of Sick Sinus Syndrome with Incident Cardiovascular Disease and Mortality: The Atherosclerosis Risk in Communities Study and Cardiovascular Health Study

<div><p>Background</p><p>Sick sinus syndrome (SSS) is a common indication for pacemaker implantation. Limited information exists on the association of sick sinus syndrome (SSS) with mortality and cardiovascular disease (CVD) in the general population.</p><p>Methods</p><p>We studied 19,893 men and women age 45 and older in the Atherosclerosis Risk in Communities (ARIC) study and the Cardiovascular Health Study (CHS), two community-based cohorts, who were without a pacemaker or atrial fibrillation (AF) at baseline. Incident SSS cases were validated by review of medical charts. Incident CVD and mortality were ascertained using standardized protocols. Multivariable Cox models were used to estimate the association of incident SSS with selected outcomes.</p><p>Results</p><p>During a mean follow-up of 17 years, 213 incident SSS events were identified and validated (incidence, 0.6 events per 1,000 person-years). After adjustment for confounders, SSS incidence was associated with increased mortality (hazard ratio [HR] 1.39, 95% confidence interval [CI] 1.14–1.70), coronary heart disease (HR 1.72, 95%CI 1.11–2.66), heart failure (HR 2.87, 95%CI 2.17–3.80), stroke (HR 1.56, 95%CI 0.99–2.46), AF (HR 5.75, 95%CI 4.43–7.46), and pacemaker implantation (HR 53.7, 95%CI 42.9–67.2). After additional adjustment for other incident CVD during follow-up, SSS was no longer associated with increased mortality, coronary heart disease, or stroke, but remained associated with higher risk of heart failure (HR 2.00, 95%CI 1.51–2.66), AF (HR 4.25, 95%CI 3.28–5.51), and pacemaker implantation (HR 25.2, 95%CI 19.8–32.1).</p><p>Conclusion</p><p>Individuals who develop SSS are at increased risk of death and CVD. The mechanisms underlying these associations warrant further investigation.</p></div

Baseline characteristics by sick sinus syndrome (SSS) diagnosis during follow-up, Atherosclerosis Risk in Communities (ARIC) study and Cardiovascular Health Study (CHS).

<p>Values correspond to means (standard deviations) or proportions. BMI: body mass index; CHD: coronary heart disease; HF: heart failure.</p><p>Baseline characteristics by sick sinus syndrome (SSS) diagnosis during follow-up, Atherosclerosis Risk in Communities (ARIC) study and Cardiovascular Health Study (CHS).</p

Cohort-specific and pooled hazard ratios (95% confidence intervals) of mortality and selected cardiovascular diseases comparing individuals with and without sick sinus syndrome (SSS), Atherosclerosis Risk in Communities (ARIC) study, 1987–2009, and Cardiovascular Health Study (CHS), 1989–2008.

<p>Model 1: Cox proportional hazards model adjusted for age, sex, race, study center, education, smoking, body mass index, hypertension, total cholesterol, HDL cholesterol, diabetes, prevalent coronary heart disease, prevalent heart failure, and prevalent stroke. Model 2: Adjusted as in model 1, and for incident coronary heart disease, incident heart failure, incident stroke and incident atrial fibrillation as time-dependent covariates.</p

Decreased Naive and Increased Memory CD4⁺ T Cells Are Associated with Subclinical Atherosclerosis: The Multi-Ethnic Study of Atherosclerosis

<div><p>Background</p><p>Adaptive immunity has been implicated in atherosclerosis in animal models and small clinical studies. Whether chronic immune activation is associated with atherosclerosis in otherwise healthy individuals remains underexplored. We hypothesized that activation of adaptive immune responses, as reflected by higher proportions of circulating CD4⁺ memory cells and lower proportions of naive cells, would be associated with subclinical atherosclerosis.</p><p>Methods and Findings</p><p>We examined cross-sectional relationships of circulating CD4⁺ naive and memory T cells with biomarkers of inflammation, serologies, and subclinical atherosclerosis in 912 participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Circulating CD4⁺ naive cells were higher in women than men and decreased with age (all p-values <0.0001). European-Americans had higher levels of naive cells and lower levels of memory cells compared with African-Americans and Hispanic-Americans (all p-values ≤0.0005). Lower naive/higher memory cells were associated with interleukin-6 levels. In multivariate models, cytomegalovirus (CMV) and <i>H. Pylori</i> titers were strongly associated with higher memory and lower naive cells (all p-values <0.05). Higher memory cells were associated with coronary artery calcification (CAC) level in the overall population [β-Coefficient (95% confidence interval (CI))  = 0.20 (0.03, 0.37)]. Memory and naive (inversely) cells were associated with common carotid artery intimal media thickness (CC IMT) in European-Americans [memory: β =  0.02 (0.006, 0.04); naive: β = −0.02 (−0.004, −0.03)].</p><p>Conclusions</p><p>These results demonstrate that the degree of chronic adaptive immune activation is associated with both CAC and CC IMT in otherwise healthy individuals, consistent with the known role of CD4⁺ T cells, and with innate immunity (inflammation), in atherosclerosis. These data are also consistent with the hypothesis that immunosenescence accelerates chronic diseases by putting a greater burden on the innate immune system, and suggest the importance of prospective studies and research into strategies to modulate adaptive immune activation in chronic disease states such as atherosclerosis.</p></div

Age, race, and sex-standardized rates (per 1000 person-years) of mortality and selected cardiovascular events in individuals with and without sick sinus syndrome (SSS), combined Atherosclerosis Risk in Communities study, 1987–2009, and Cardiovascular Health Study, 1989–2008.

<p>CI: confidence interval; IRR: incidence rate ratio.</p><p>Age, race, and sex-standardized rates (per 1000 person-years) of mortality and selected cardiovascular events in individuals with and without sick sinus syndrome (SSS), combined Atherosclerosis Risk in Communities study, 1987–2009, and Cardiovascular Health Study, 1989–2008.</p

Incidence rates of selected cardiovascular diseases by SSS status, overall and by race, sex and age groups, combined Atherosclerosis Risk in Communities study and Cardiovascular Health Study, 1987–2009.

<p>Dark squares correspond to rates in SSS, light diamonds to rates in non SSS. Adj*: Standardized by age, sex and race to the combined ARIC and CHS person-time.</p

Cohort-specific and pooled hazard ratios (95% confidence intervals) for the association of sick sinus syndrome (SSS) with atrial fibrillation and heart failure, adjusting for cardiovascular risk factors and accounting for pacemaker implantation, Atherosclerosis Risk in Communities (ARIC) study, 1987–2009, and Cardiovascular Health Study (CHS), 1989–2008.

a,b<p>Results correspond to Cox proportional hazards model adjusted for age, sex, race, center, education, smoking, BMI, hypertension, total cholesterol, HDL cholesterol, diabetes, prevalent and time-dependent CHD, prevalent and time-dependent HF (for the AF analysis only), prevalent and time-dependent stroke, time-dependent AF (for the HF analysis only). Model ^a additionally adjusted for time-dependent pacemaker implantation.</p><p>Cohort-specific and pooled hazard ratios (95% confidence intervals) for the association of sick sinus syndrome (SSS) with atrial fibrillation and heart failure, adjusting for cardiovascular risk factors and accounting for pacemaker implantation, Atherosclerosis Risk in Communities (ARIC) study, 1987–2009, and Cardiovascular Health Study (CHS), 1989–2008.</p

Characteristics of the MESA sample population being studied.

<p>Data are from MESA exam 4 (2005–2007) unless otherwise noted. *: Data are from MESA baseline (exam 1; 2000–2002). **: Includes all participants with incident cardiovascular events (myocardial infarction, resuscitated cardiac arrest, definite or probable angina, and stroke) from baseline through the start of exam 4. AU: Agatston units; BMI: Body mass index; CAC: Coronary artery calcification; CMV: Cytomegalovirus; CRP: C-reactive protein; CVD: Cardiovascular disease; HSV: Herpes simplex virus; IL-6: Interleukin-6; IMT: Intimal media thickness.</p

Regression models for CD4⁺ naive and memory cell subpopulations.

<p>Backward elimination regression was used to develop multivariate models for CD4⁺ T cell subpopulations. Independent variables were divided by their standard deviations (shown in parentheses). Age, gender, race/ethnicity, seasonality, BMI, IL-6, and CMV and <i>H. pylori</i> titers were included as the candidate starting variables. Only significant variables (p<0.05) were retained in the final models. BMI: Body mass index; CMV: Cytomegalovirus; IL-6: Interleukin-6; ns: non-significant.</p

Typical flow cytometric data for lymphocyte, CD4⁺ memory, and CD4⁺ naive cell populations.

<p>At least 30,000 lymphocytes were evaluated and were gated based on their forward (FCS; X-axis) and side (SCS; Y-axis) scatter (Panels A&B). Memory and naive cell subpopulations were gated by positive surface staining for CD4 (Y-axis, panels C–F); memory cells were gated by positive surface staining for CD45RO (X-axis, panels C&D); naive cells were gated by positive surface staining for CD45RA (X-axis, panels E&F). Typical data from respective isotype controls (Panels A, C, and E) and fluorescently labeled samples (Panels B, D, and F) are shown.</p