The Association between HDL-C and Subclinical Atherosclerosis Depends on CETP Plasma Concentration: Insights from the IMPROVE Study.

The impact of cholesteryl ester transfer protein (CETP) on atherosclerosis is highly debated. This study aimed to investigate the associations between plasma CETP or CETP genotypes and carotid intima-media thickness (cIMT) and the influence of high-density lipoprotein cholesterol (HDL-C) on these associations. Plasma CETP and HDL-C concentrations were measured in 552 subjects free of any pharmacological treatment from the IMPROVE cohort, which includes 3711 European subjects at high cardiovascular risk. CETP single-nucleotide polymorphisms (SNPs) and cIMT measures (cIMTmax; cIMTmean-max of bifurcations, common and internal carotids; plaque-free common carotid [PF CC]-IMTmean) were available for the full cohort. In drug-free subjects, plasma CETP correlated with HDL-C levels (r = 0.19, p < 0.0001), but not with cIMT variables. When stratified according to HDL-C quartiles, CETP positively correlated with cIMTmax and cIMTmean-max, but not with PF CC-IMTmean, in the top HDL-C quartile only. Positive associations between the CETP concentration and cIMTmax or cIMTmean-max were found in the top HDL-C quartile, whereas HDL-C levels were negatively correlated with cIMTmax and cIMTmean-max when the CETP concentration was below the median (HDL-C × CETP interaction, p = 0.001 and p = 0.003 for cIMTmax and cIMTmean-max, respectively). In the full cohort, three CETP SNPs (rs34760410, rs12920974, rs12708968) were positively associated with cIMTmax. rs12444708 exhibited a significant interaction with HDL-C levels in the prediction of cIMTmax. In conclusion, a significant interplay was found between plasma CETP and/or CETP genotype and HDL-C in the prediction of carotid plaque thickness, as indexed by cIMTmax. This suggests that the association of HDL-C with carotid atherosclerosis is CETP-dependent.

Chronotropic incompetence and mortality in middle-aged men with known or suspected coronary heart disease.

AIMS: The objective is to study whether a heart rate (HR) increase from 40 to 100% of maximal work capacity in the exercise test (HR40-100) independently predicts mortality in men with known or suspected coronary heart disease (CHD). METHODS AND RESULTS: The subjects were 294 men, 42-61 years of age, from eastern Finland with known or suspected CHD but without use of HR-lowering medication at baseline. HR was measured at rest and during a maximal, symptom-limited exercise test. During an average follow-up of 11.0 years, there were 61 all-cause deaths. In Cox-multivariable model, mortality increased by 41% (95% confidence interval, 12-79%) with a 1-SD (15 b.p.m.) decrement in HR40-100. HR increase from rest to 40% of maximal work capacity was not associated with an increased risk of death. Synergism was observed between HR40-100 and workload achieved at HR of 100 b.p.m. so that men having low values for both these HR variables had a particularly adverse prognosis compared with men with high values for these variables. CONCLUSION: An attenuated HR increase particularly during the latter half of a maximal exercise test is an independent predictor of death in men with known or suspected CHD.

Usefulness of chronotropic incompetence in response to exercise as a predictor of myocardial infarction in middle-aged men without cardiovascular disease.

An attenuated heart rate (HR) response to exercise, or chronotropic incompetence, has been shown to predict adverse cardiac events in subjects without known cardiovascular disease (CVD). The aim of the present study was to investigate whether chronotropic incompetence independently predicts acute myocardial infarction (AMI) in middle-aged men. In addition to previously established chronotropic incompetence variables, we focused on a new chronotropic incompetence variable, the HR increase from 40% to 100% of maximal work capacity (HR40-100), as a predictor of AMI. The subjects were a representative sample of 1,176 middle-aged men who did not have CVD and did not use HR-lowering medication at baseline. The association of chronotropic incompetence variables with the risk of AMI was examined by Cox regression models including numerous known risk factors for AMI. During an average follow-up of 11.0 years, there were 106 AMIs (9.0%). In Cox multivariable model, the risk of AMI increased by 33% for each SD decrement of 13 beats/min in HR40-100 (95% confidence interval [CI] 9 to 64). When considered concurrently, HR40-100 was the only chronotropic incompetence variable that improved the predictive value of the model containing other risk factors for AMI. Men with a low HR40-100 (<46 beats/min) and a heightened increase in systolic blood pressure (SBP) (>67 mm Hg) were at particularly high risk, with a 3.1-times higher incidence of AMI than those with a normal HR40-100 and SBP increase (95% CI 1.7 to 5.7). In conclusion, a low HR40-100 predicted AMI in men without previous CVD independent of other exercise test or clinical variables.

Effectiveness of workload at the heart rate of 100 beats/min in predicting cardiovascular mortality in men aged 42, 48, 54, or 60 years at baseline.

The magnitude of work an individual is able to perform at the heart rate (HR) of 100 beats/min (WL(100)) is a simple, integrated measure of HR at rest, HR response to light dynamic exercise, as well as cardiorespiratory performance. Because a high HR at rest and a low cardiorespiratory performance are previously established risk factors for cardiovascular disease (CVD) mortality, it can be deduced that WL(100) is a potential predictor of CVD and coronary heart disease (CHD) mortality. The aim of the present study was to investigate whether WL(100) independently predicts CVD and CHD mortality in middle-aged men. The subjects were a representative sample of 1,314 middle-aged men who did not have CHD and did not use HR-lowering medication at baseline. The association of WL(100) with CVD and CHD mortality was examined by Cox regression models with backward stepwise selection, including numerous known risk factors for CVD death. During an average follow-up of 11.5 years, there were 51 CVD deaths, of which 35 were due to CHD. In Cox multivariable models, CVD mortality increased by 72% (95% confidence interval 27% to 138%, p = 0.001) and CHD mortality by 89% (95% confidence interval 28% to 178%, p = 0.001) with 1 SD (31 W) decrement in WL(100). WL(100) improved the predictive power of the adjusted Cox models, including other HR-derived and exercise test variables. In conclusion, WL(100) predicts CVD and CHD mortality in men without previous CHD. The association of WL(100) with CVD and CHD mortality is not explained by maximal cardiorespiratory performance.

Heart rate response during exercise test and cardiovascular mortality in middle-aged men.

AIMS: The objective is to study whether a heart rate (HR) response during exercise test independently predicts cardiovascular disease (CVD) mortality. METHODS AND RESULTS: The subjects were a representative sample of 1378 men, 42-61 years of age, from eastern Finland with neither prior coronary heart disease (CHD) nor use of beta-blockers at baseline. HR was measured at rest and during a maximal, symptom-limited exercise test at 20, 40, 60, 80, and 100% of maximal workload. During an average follow-up of 11.4 years, there were 56 deaths due to CVD. The slope of HR increase during exercise test was steeper in survivors when compared with those who died due to CVD during follow-up (P<0.001), and the difference in the steepness of HR slope between the groups was the strongest at interval 40-100% (P<0.001). In Cox-multivariable models, maximal HR-HR at 40% workload as a continuous variable was inversely associated with CVD (P=0.04), CHD (P=0.004), and all-cause (P=0.002) mortality after adjustment for known risk factors for CVD death. CONCLUSION: By considering an HR response throughout an exercise test, we found that a blunted HR increase at 40-100% of maximal workload was associated with increased CVD mortality.