Markers of Myocardial Stress, Myocardial Injury, and Subclinical Inflammation and the Risk of Sudden Death

Abstract

Background: The majority of sudden cardiac deaths (SCDs) occur in low-risk populations often as the first manifestation of cardiovascular disease (CVD). Biomarkers are screening tools that may identify subclinical cardiovascular disease and those at elevated risk for SCD. We aimed to determine whether the total to high-density lipoprotein cholesterol ratio, high-sensitivity cardiac troponin I, NT-proBNP (N-terminal pro-B-type natriuretic peptide), or high-sensitivity C-reactive protein individually or in combination could identify individuals at higher SCD risk in large, free-living populations with and without cardiovascular disease.

Methods: We performed a nested case-control study within 6 prospective cohort studies using 565 SCD cases matched to 1090 controls (1:2) by age, sex, ethnicity, smoking status, and presence of cardiovascular disease.

Results: The median study follow-up time until SCD was 11.3 years. When examined as quartiles or continuous variables in conditional logistic regression models, each of the biomarkers was significantly and independently associated with SCD risk after mutually controlling for cardiac risk factors and other biomarkers. The mutually adjusted odds ratios for the top compared with the bottom quartile were 1.90 (95% CI, 1.30-2.76) for total to high-density lipoprotein cholesterol ratio, 2.59 (95% CI, 1.76-3.83) for high-sensitivity cardiac troponin I, 1.65 (95% CI, 1.12-2.44) for NT-proBNP, and 1.65 (95% CI, 1.13-2.41) for high-sensitivity C-reactive protein. A biomarker score that awarded 1 point when the concentration of any of those 4 biomarkers was in the top quartile (score range, 0-4) was strongly associated with SCD, with an adjusted odds ratio of 1.56 (95% CI, 1.37-1.77) per 1-unit increase in the score.

Conclusions: Widely available measures of lipids, subclinical myocardial injury, myocardial strain, and vascular inflammation show significant independent associations with SCD risk in apparently low-risk populations. In combination, these measures may have utility to identify individuals at risk for SCD.

Keywords: cholesterol; death, sudden; inflammation; lipids; pro-brain natriuretic peptide (1-76); troponin.

Figure 1.. Increasing Concentrations of Cardiovascular Biomarkers and the Risk of Sudden Cardiac Death

Adjusted odds ratios and 95% confidence intervals for sudden cardiac death according to increasing quartiles of natural logarithm transformed total to high-density lipoprotein cholesterol ratio (Ln-TC:HDL), high-sensitivity cardiac troponin I (hsTnI), NT-proBNP (NTproBNP), and high-sensitivity C-reactive protein (hsCRP). Odds ratios and 95% CI are adjusted for matching factors (age, sex, smoking status, white race and cardiovascular disease status), and further adjusted for age, aspirin use, overweight or obese, weekly exercise, alcohol use, hypertension, parental history of myocardial infarction, history of high cholesterol, and diabetes (Multivariable Model 2).

Figure 2.. Common Clinical Thresholds for Cardiovascular Biomarkers and the Risk of Sudden Cardiac Death

Adjusted odds ratios and 95% confidence intervals for sudden cardiac death for various clinical cutpoints of total to high-density cholesterol ratio (TC:HDL), high-sensitivity cardiac troponin I (hsTnI, in ng/L), NT-proBNP, in ng/L, and high-sensitivity C-reactive protein (hsCRP) in mg/L. Odds ratios are adjusted for matching factors (age, sex, smoking status, white race, and cardiovascular disease status) and further adjusted for age, aspirin use, overweight or obese, weekly exercise, alcohol use, hypertension, parental history of myocardial infarction, history of high cholesterol, and diabetes (Multivariable Model 2).

Figure 3.. Biomarker Score and the Risk of Sudden Cardiac Death

Adjusted odds ratios and 95% confidence intervals for sudden cardiac death according to increasing values for a biomarker risk score constructed from the concentrations of total to high-density cholesterol ratio, high-sensitivity cardiac troponin I, NT-proBNP, and high-sensitivity C-reactive protein at baseline. Each participant is given one point for each biomarker level that falls in the top quartile of the distribution in the control population. Odds ratios are adjusted for matching factors (age, sex, smoking status, white race, and cardiovascular disease status) and further adjusted for age, aspirin use, overweight or obese, weekly exercise, alcohol use, hypertension, parental history of myocardial infarction, history of high cholesterol, and diabetes (Multivariable Model 2).