Liver X Receptor Agonist 4ß-Hydroxycholesterol as a Prognostic Factor in Coronary Artery Disease.

BACKGROUND: Regardless of progress in treatment of coronary artery disease (CAD), there is still a significant residual risk of death in patients with CAD, highlighting the need for additional risk stratification markers. Our previous study provided evidence for a novel blood pressure-regulating mechanism involving 4ß-hydroxycholesterol (4ßHC), an agonist for liver X receptors, as a hypotensive factor. The aim was to determine the role of 4ßHC as a prognostic factor in CAD. METHODS AND RESULTS: The ARTEMIS (Innovation to Reduce Cardiovascular Complications of Diabetes at the Intersection) cohort consists of 1946 patients with CAD. Men and women were analyzed separately in quartiles according to plasma 4ßHC. Basic characteristics, medications, ECG, and echocardiography parameters as well as mortality rate were analyzed. At baseline, subjects with a beneficial cardiovascular profile, as assessed with traditional markers such as body mass index, exercise capacity, prevalence of diabetes, and use of antihypertensives, had the highest plasma 4ßHC concentrations. However, in men, high plasma 4ßHC was associated with all-cause death, cardiac death, and especially sudden cardiac death (SCD) in a median follow-up of 8.8 years. Univariate and comprehensively adjusted hazard ratios for SCD in the highest quartile were 3.76 (95% CI, 1.6-8.7; P=0.002) and 4.18 (95% CI, 1.5-11.4; P=0.005), respectively. In contrast, the association of cardiac death and SCD in women showed the lowest risk in the highest 4ßHC quartile. CONCLUSIONS: High plasma 4ßHC concentration was associated with death and especially SCD in men, while an inverse association was detected in women. Our results suggest 4ßHC as a novel sex-specific risk marker of cardiac death and especially SCD in chronic CAD. REGISTRATION INFORMATION: clinicaltrials.gov. Identifier NCT01426685.

Recovery of rate-pressure product and cardiac mortality in coronary artery disease patients with type 2 diabetes.

AIMS: To investigate prognostic significance of post-exercise recovery of rate-pressure product (RPP) in patients with stable coronary artery disease (CAD) and type 2 diabetes (T2D). METHODS: Patients with angiographically documented CAD and T2D (n = 697) underwent symptom-limited bicycle exercise test. Exercise capacity (EC), heart rate, blood pressure and RPP responses to peak exercise and recovery (2' and 5' after cessation of exercise) were analyzed. Cardiac death was the primary and sudden cardiac death (SCD) secondary endpoint. RESULTS: During a median follow-up of 76 months, 49 cardiac deaths (7.0%) and 28 SCDs (4.0%) were observed. The recovery of RPP at 5' was the strongest univariate predictor of cardiac death (hazard ratio [HR]: 2.55 per SD decrease, 95%CI: 1.82-3.58, p < 0.001) and SCD (HR: 2.34, 95%CI: 1.51-3.62, p < 0.001). In multivariate analysis, it remained significantly associated to cardiac death and SCD without (HR: 1.66, 95%CI: 1.14-2.41, p < 0.01 and HR: 1.75, 95%CI: 1.08-2.85, p < 0.05, respectively) and with additional adjustment for EC and peak RPP (HR: 1.45, 95%CI: 1.09-1.92, p < 0.05 and HR: 1.52, 95%CI: 1.01-2.27, p < 0.05, respectively). CONCLUSIONS: The recovery of RPP after exercise is a potent predictor of cardiac death in patients with CAD and T2D. It provides significant prognostic information beyond EC and peak RPP.

Effect of Changes in Physical Activity on Risk for Cardiac Death in Patients With Coronary Artery Disease.

Leisure-time physical activity (LTPA) is associated with longevity in patients with coronary artery disease (CAD). However, less is known about prognostic significance of longitudinally assessed LTPA in patients with stable CAD. The present study assessed the relationship between changes in LTPA and cardiac mortality in patients with CAD. Patients with angiographically documented CAD (n = 1,746) underwent clinical examination and echocardiography at the baseline. Lifestyle factors, including LTPA (inactive, irregularly active, active, highly active), were surveyed at baseline and after 2 years' follow-up. Thereafter, the patients entered the follow-up (median: 4.5 years; first to third quartile: 3.4 to 5.8 years) during which cardiac deaths were registered (n = 68, 3.9%). The patients who remained inactive (n = 114, 18 events, 16%) and became inactive (n = 228, 18 events, 8%) had 7.6- (95% confidence interval [CI] 4.2 to 13.6) and 3.7-fold (95% CI 2.1 to 6.7) univariate risk for cardiac death compared with those who remained at least irregularly active (n = 1,351, 30 events, 2%), respectively. After adjustment for age, gender, body mass index, diabetes, previous myocardial infarction, left ventricular ejection fraction, angina pectoris grading, cardiovascular event during initial 2-year follow-up, smoking and alcohol consumption, the patients who remained inactive and became inactive still had 4.9- (95% CI 2.4 to 9.8, p <0.001) and 2.4-fold (95% CI 1.3 to 4.5, p <0.01) risk for cardiac death, respectively, compared with patients remaining at least irregularly active. In conclusion, LTPA has important prognostic value for cardiac death in patients with stable CAD. Even minor changes in LTPA over 2 years were related to the subsequent risk for cardiac death.

Association of sST2 and hs-CRP levels with new-onset atrial fibrillation in coronary artery disease.

BACKGROUND: The data on biomarkers as predictors of atrial fibrillation (AF) in patients with coronary artery disease (CAD) are limited. METHODS: A total of 1946 patients with CAD were recruited to the ARTEMIS study. At baseline, the study patients underwent clinical and echocardiographic examinations and had laboratory tests. The patients (n=1710) with the information about the occurrence of new-onset AF during the follow-up were included in the present analysis. RESULTS: During 5.7±1.5years of follow-up, 143 (8.4%) patients developed a new-onset AF. Higher values of soluble ST2 (sST2) (20.2±10.8 vs. 17.5±7.2ng/mL, p=0.005), high-sensitivity troponin T (hs-TnT) (11.9±10.2 vs. 10.3±8.3ng/L, p=0.005), high-sensitivity C-reactive protein (hs-CRP) (3.3±5.9 vs. 2.0±4.4mg/L, p<0.001) and brain natriuretic peptide (BNP) (85.6±77.5 vs. 64.9±73.5ng/L, p<0.001) had significant associations with the occurrence of new-onset AF. In the Cox clinical hazards model, higher age (p=0.004), greater weight (p=0.045), larger left atrial diameter (p=0.001), use of asthma/chronic obstructive pulmonary disease medication (p=0.001) and lack of cholesterol lowering medication (p=0.008) had a significant association with the increased risk of AF. When the biomarkers were tested in the Cox clinical hazards model, sST2 (HR=1.025, 95% CI=1.007-1.043, p=0.006) and hs-CRP (HR=1.027, 95% CI=1.008-1.047, p=0.006) retained their significant power in predicting AF. CONCLUSION: A biomarker of fibrosis, sST2, and a biomarker of inflammation, hs-CRP, predict the risk of occurrence of new-onset AF in patients with CAD. These biomarkers contributed to the discrimination of the AF risk model, but did not improve it markedly.

Presence of atrial fibrillation is associated with liver stiffness in an elderly Finnish population.

BACKGROUND: Chronic liver injury from different etiologies drives liver fibrosis. However, little is known about the associated factors, systemic factors in particular. Recently, non-alcoholic fatty liver disease (NAFLD) and atrial fibrillation have been shown to be associated with each other. Thereby, we aimed to study the association between atrial fibrillation and liver stiffness. STUDY: Extensive clinical measurements including echocardiography of the heart, transient elastography (TE) of the liver and the presence of atrial fibrillation were determined in elderly Finnish study subjects (n = 76, mean age 73 years) from OPERA (Oulu Project Elucidating the Risk of Atherosclerosis) study cohort. Half of the study subjects had non-alcoholic fatty liver disease, whereas others did not have any known hepatic morbidity. The present study was cross-sectional by nature. RESULTS: The subjects with atrial fibrillation had higher TE values (with atrial fibrillation TE = 9.3kPa, without atrial fibrillation TE = 6.3kPa, p = 0.018). When the cohort was divided to four subgroups (those without NAFLD or atrial fibrillation, with NAFLD but without atrial fibrillation, with both conditions, and with atrial fibrillation but without NAFLD), the TE value was the highest in the subjects with both conditions (5.3kPa, 7.4kPa, 10.8kPa and 7.8kPa, respectively, p = 0.019). Moreover, the higher the TE value, the more prevalent atrial fibrillation was (the atrial fibrillation prevalence by tertiles of TE 27% / 36% / 77%, p = 0.001). Likewise, the greater the TE value, the greater the left atrial diameter, a collateral of atrial fibrillation (left atrial diameters by tertiles of TE 39mm / 45mm / 48mm, p<0.001) was. All these p-values for continuous variables remained statistically significant even after adjustment for common clinically relevant risk factors. CONCLUSIONS: There is an association between atrial fibrillation and liver stiffness. This novel association may have multiple explanations and mechanistic links, which are discussed here and need further studies, prospective studies in particular.

Leptin predicts short-term major adverse cardiac events in patients with coronary artery disease.

INTRODUCTION: Leptin is an adipose tissue-derived hormone associated with cardiovascular risk factors. We examined whether leptin predicts major adverse cardiac events (MACE) in coronary artery disease (CAD) patients. METHODS: Fasting plasma leptin levels were measured in 1327 male and 619 female CAD patients. The patients were followed up for two years. The primary endpoint (MACE) was the composite of a hospitalisation for congestive heart failure (CHF) or a cardiac death. The secondary endpoint was the composite of an acute coronary syndrome (ACS) or a stroke. RESULTS: In regression analysis including established risk variables, high leptin levels were associated with a significantly increased risk of MACE (HR 3.37; 95%CI 1.64-6.90; p = 0.001) and ACS or stroke (HR 1.95; 95%CI 1.29-2.96; p = 0.002). Adding leptin to the risk model for MACE increased the C-index from 0.78 (95%CI 0.71-0.85) to 0.81 (0.74-0.88) and improved classification (NRI 0.36; 95%CI 0.13-0.60; p = 0.002) and discrimination of the patients (IDI 0.016; 95%CI 0.001-0.030; p = 0.031). CONCLUSIONS: High plasma leptin levels predict short-term occurrence of CHF or cardiac death and ACS or stroke in patients with CAD independently of established risk factors. The possible harmful effects of leptin should be thoroughly investigated. Key messages Leptin is a peptide hormone secreted mainly by adipose tissue. It has been associated with several cardiovascular risk factors. High leptin levels predict the short-term occurrence of congestive heart failure or cardiac death and ACS or stroke in patients with CAD independently of established risk factors. The possible detrimental effects of leptin on the cardiovascular system should be thoroughly investigated.

Exercise capacity and heart rate responses to exercise as predictors of short-term outcome among patients with stable coronary artery disease.

Although exercise capacity (EC) and autonomic responses to exercise predict clinical outcomes in various populations, they are not routinely applied in patients with coronary artery disease (CAD). We hypothesized that the composite index of EC and exercise heart rate responses would be a powerful determinant of short-term risk in CAD. Patients with angiographically documented stable CAD and treated with ß blockers (n = 1,531) underwent exercise testing to allow the calculation of age- and gender-adjusted EC, maximal chronotropic response index (CRI), and 2-minute postexercise heart rate recovery (HRR, percentage of maximal heart rate). Cardiovascular deaths and hospitalization due to heart failure, registered during a 2-year follow-up (n = 39, 2.5%), were defined as the composite primary end point. An exercise test risk score was calculated as the sum of hazard ratios related to abnormal (lowest tertile) EC, CRI, and HRR. Abnormal EC, CRI, and HRR predicted the primary end point, involving 4.5-, 2.2-, and 6.2-fold risk, respectively, independently of each other. The patients with intermediate and high exercise test risk score had 11.1-fold (95% confidence interval 2.4 to 51.1, p = 0.002) and 25.4-fold (95% confidence interval 5.5 to 116.8, p <0.001) adjusted risk for the primary end point in comparison with the low-risk group, respectively. The addition of this risk score to the established risk model enhanced discrimination by integrated discrimination index and reclassification by categorical and continuous net reclassification index (p <0.001 for all). In conclusion, the composite index of EC and heart rate responses to exercise and recovery is a powerful predictor of short-term outcome in patients with stable CAD.

Heart Rate Turbulence and T-Wave Alternans in Patients with Coronary Artery Disease: The Influence of Diabetes.

BACKGROUND: Patients with diabetes mellitus (DM) have a higher risk of sudden cardiac death. Factors associated with the risk profiles of coronary artery disease (CAD) patients with DM are not well established. Heart rate turbulence (HRT) and T-wave alternans (TWA) are often used to predict arrhythmia events. METHODS AND RESULTS: HRT and TWA were measured in two independent groups: the ARTEMIS cohort study and the REFINE-ICD randomized trial. ARTEMIS assesses risk 3-12 months after coronary angiography in patients with CAD. The initial 1001 patients in ARTEMIS, 526 with and 475 without DM, are included in this analysis. REFINE-ICD compares usual care versus usual care plus ICD therapy in patients with left ventricular (LV) ejection fraction (EF) values of 36-50% assessed 2-15 months after myocardial infarction. The initial 275 patients screened in REFINE ICD are included in this analysis. Abnormal HRT plus TWA was more common in patients with versus without DM in ARTEMIS (125/526, 24% vs 63/475, 13%; P < 0.001) and REFINE-ICD (43/55, 78% vs 55/220, 25%; P < 0.001), respectively. Abnormal HRT plus TWA was also more common in patients with LVEF values < 50% (28%) vs ≥ 50% (18%; P < 0.001) in ARTEMIS and LVEF values below the population median of 42% (60/138, 43%) versus above the median (38/137, 28%; P < 0.01) in REFINE-ICD. CONCLUSIONS: Abnormal HRT plus TWA is more common in CAD patients with DM compared with the patients without DM and is related to the severity of LV dysfunction. CLINICAL TRIAL REGISTRATION INFORMATION: http://www.clinicaltrials.gov, NCT01426685; http://www.clinicaltrials.gov, NCT00673842.

Acute post-exercise change in blood pressure and exercise training response in patients with coronary artery disease.

We tested the hypothesis that acute post-exercise change in blood pressure (BP) may predict exercise training responses in BP in patients with coronary artery disease (CAD). Patients with CAD (n = 116, age 62 ± 5 years, 85 men) underwent BP assessments at rest and during 10-min recovery following a symptom-limited exercise test before and after the 6-month training intervention (one strength and 3-4 aerobic moderate-intensity exercises weekly). Post-exercise change in systolic BP (SBP) was calculated by subtracting resting SBP from lowest post-exercise SBP. The training-induced change in resting SBP was -2 ± 13 mmHg (p = 0.064), ranging from -42 to 35 mmHg. Larger post-exercise decrease in SBP and baseline resting SBP predicted a larger training-induced decrement in SBP (ß = 0.46 and ß = -0.44, respectively, p < 0.001 for both). Acute post-exercise decrease in SBP provided additive value to baseline resting SBP in the prediction of training-induced change in resting SBP (R(2) from 0.20 to 0.26, p = 0.002). After further adjustments for other potential confounders (sex, age, baseline body mass index, realized training load), post-exercise decrease in SBP still predicted the training response in resting SBP (ß = 0.26, p = 0.015). Acute post-exercise change in SBP was associated with training-induced change in resting SBP in patients with CAD, providing significant predictive information beyond baseline resting SBP.

Impact of type 2 diabetes on cardiac autonomic responses to sympathetic stimuli in patients with coronary artery disease.

Type 2 diabetes (T2D) has shown limited impact on cardiac autonomic function in patients with cardiac disease at rest. The effect of T2D on autonomic responses to sympathetic stimuli, such as passive tilt and static exercise, is not well known in patients with coronary artery disease (CAD). Heart rate, arterial pressure, and their variability along with baroreflex sensitivity (BRS) were analyzed at supine rest and during passive head-up tilt (TILT) and static handgrip exercise (HG) in CAD patients with (T2D+, n=68, 61±6 years, 14 women) and without T2D (T2D-, n=68, 62±6 years, 17 women). The effect of T2D at rest and in responses to TILT and HG was examined. In T2D+, the normalized low-frequency (0.04-0.15 Hz) power of R-R intervals was higher at rest (44±17 vs. 38±17 nu, p=0.015) and its response to TILT and HG was lower than that in T2D- (8±21 vs. 2±17 nu, p=0.041 and 3±18 vs. -4±15 nu, p=0.019, respectively). Vagally mediated heart rate variability indices and BRS were not different between T2D+ and T2D-. We concluded that T2D has a specific impact on low-frequency oscillation of R-R interval among patients with angiographically documented CAD. This may indicate increased basal sympathetic modulation of sinoatrial node and lower sympathetic responsiveness to sympathetic activation by baroreceptor unloading and exercise pressor response. Limited effects of T2D on vagally mediated heart rate variability and baroreflex were observed in the patients with CAD.

Peak exercise capacity prediction from a submaximal exercise test in coronary artery disease patients.

The purpose of this study was to determine whether a rating of perceived exertion scale (RPE) obtained during submaximal exercise could be used to predict peak exercise capacity (METpeak) in coronary artery disease (CAD) patients. Angiographically documented CAD patients (n = 124, 87% on ß blockade) completed a symptom-limited peak exercise test on a bicycle ergometer, reporting RPE values at every second load on a scale of 6-20. Regression analysis was used to develop equations for predicting METpeak. We found that submaximal METs at a workload of 60/75 W (for women and men, respectively) and the corresponding RPE (METs/RPE ratio) was the most powerful predictor of METpeak (r = 0.67, p < 0.0001). The final model included the submaximal METs/RPE ratio, body mass index (BMI), sex, resting heart rate, smoking history, age, and use of a ß blockade (r = 0.86, p < 0.0001, SEE 0.98 METs). These data suggest that RPE at submaximal exercise intensity is related to METpeak in CAD patients. The model based on easily measured variables at rest and during "warm-up" exercise can reasonably predict absolute METpeak in patients with CAD.

Total testosterone levels, metabolic parameters, cardiac remodeling and exercise capacity in coronary artery disease patients with different stages of glucose tolerance.

OBJECTIVE AND METHODS: The correlation between total testosterone levels, exercise capacity, and metabolic and echocardiographic parameters was studied in 1097 male subjects with coronary artery disease (CAD) and different stages of glucose tolerance. RESULTS: Testosterone level was the lowest among diabetics as compared to prediabetics or controls (P < 0.001). Total and abdominal adiposity were the highest in the subjects with the lowest testosterone. Independent of adiposity, fasting glucose, insulin, and leptin were higher (P < 0.03 to < 0.001) among diabetic and control groups in the lowest, and HbA1c values (P < 0.001) higher among diabetics in the lowest, than in the highest testosterone tertile. Controls and prediabetic subjects with the lowest testosterone levels had the lowest HDL-cholesterol levels, and controls also the highest triglycerides. An association between low testosterone level and low maximal exercise capacity was observed in diabetics (P < 0.001) and controls (P < 0.03). Independent of adiposity and metabolic parameters, low testosterone levels were associated with the highest septal wall thickness (P < 0.03) among diabetics. CONCLUSION: A negative correlation between low testosterone and dysmetabolic features was observed. Independent of metabolic status, low plasma testosterone seems to be an indicator of impaired maximal exercise capacity and cardiac hypertrophy among CAD patients with type II diabetes.

Effects of exercise prescription on daily physical activity and maximal exercise capacity in coronary artery disease patients with and without type 2 diabetes.

BACKGROUND: Promotion of and adherence to increased physical activity (PA) is an important part of the prevention and treatment of coronary artery disease (CAD). We hypothesized that individually tailored home-based exercise prescriptions will increase long-term PA and maximal exercise capacity among CAD patients without and with type 2 diabetes (CAD+T2D). METHODS: Physical activity of patients with CAD (n = 44) and CAD+T2D (n = 39), matched by age, sex and ejection fraction, was measured over 5 days with an accelerometer pre- and postexercise prescription. PA was assessed as the average time per day of moderate (METs = 2-5) and high (METs > 5) intensities. Six-month exercise prescriptions were introduced based on individual maximal heart rate reserve. RESULTS: At the baseline, patients with CAD+T2D engaged in less moderate-intensity PA (2:40 ± 1:23 versus 3:24 ± 1:17 h, P = 0·014) and exhibited a non-significant trend to reduced high-intensity PA (2:08 ± 2:57 versus 5:02 ± 9:19 min, P = 0·091) compared with patients with CAD. High-intensity PA increased markedly in CAD (5:02 ± 9:19 versus 9:59 ± 15:03 min) and patients with CAD+T2D (2:08 ± 2:57 versus 6:14 ± 10:18 min) after exercise prescription (main effect for time P = 0·001). Also maximal exercise capacity increased in both groups (main effect for time P< 0·001). CONCLUSION: Patients with CAD with T2D are physically less active than CAD patients without diabetes in their daily life. Individually tailored home-based exercise prescriptions are an effective way to promote more active lifestyles and improve fitness in both patient groups.

Preoperative warfarin treatment and outcome of coronary artery bypass graft surgery.

BACKGROUND: The aim of this case-control study was to evaluate the outcome of isolated coronary artery bypass grafting (CABG) when using a short (median, 2 days) preoperative pause in home warfarin treatment. METHODS: A consecutive series of 162 patients on long-term warfarin treatment (median international normalized ratio at the time of operation, 1.9) who underwent isolated CABG was compared with a matched control group of 162 patients with no oral anticoagulation. RESULTS: The operative risk of warfarin-treated patients was higher (p=0.001) than in the control patients. The in-hospital mortality was comparable in the warfarin and control groups (3.7% versus 2.5%; p=0.52), and there were no significant differences in the postoperative blood loss (818 versus 758 mL), transfused red blood cells (2.1 versus 1.8 units), or reoperations owing to bleeding (5.6% versus 7.4%) between the groups. The warfarin group received more (p<0.0001) fresh-frozen plasma (1.9 versus 0.5 units), needed longer treatment in the intensive care unit (4.1 versus 2.9 days; p<0.0001), and tended to have an increased risk of postoperative stroke (4.9% versus 1.2%; p=0.10). A CHADS2 score greater than 2, but not the international normalized ratio level, was associated with an increased risk of stroke when adjusted for other important comorbidities. Comparable results were observed also in 107 propensity-matched pairs. CONCLUSIONS: The risk of bleeding complications after isolated CABG is not increased when using a short preoperative pause in warfarin treatment. Better preventive strategies for stroke are needed, especially in patients with a high CHADS2 score.

Preoperative C-reactive protein and outcome after coronary artery bypass surgery.

BACKGROUND: C-reactive protein (CRP) is a predictor of early and late outcome after coronary angioplasty, but there is scant data on its impact on the outcome after coronary artery bypass grafting (CABG). METHODS: The predictive value of preoperative CRP was evaluated in a series of 764 patients who underwent on-pump CABG. RESULTS: During the in-hospital stay, 13 patients (1.7%) died, 45 (4.5%) developed low cardiac output syndrome, and 28 (3.7%) suffered minor or major cerebrovascular complications. Patients with a preoperative serum concentration of CRP>/=1.0 mg/dL had a higher risk of overall postoperative death (5.3% vs 1.1%, p = 0.001), cardiac death (4.4% vs 0.8%, p = 0.002), low cardiac output syndrome (8.8% vs 3.7%, p = 0.01), and any cerebrovascular complication (4.4% vs 3.5%, p = 0.66). Preoperative serum concentration of CRP>/=1.0 mg/dL was significantly more frequent among patients with history of myocardial infarction, diabetes, lower limb ischemia, low left ventricular ejection fraction, NYHA class IV, and in those undergoing urgent or emergency operation. At multivariate analysis, preoperative serum concentration of CRP >/= 1.0 mg/dL (p = 0.01, O.R.: 6.97) and left ventricular ejection fraction (p = 0.01, O.R.: 0.95) were independent predictors of postoperative death. Postoperative mortality rate was 0.3% among patients with preoperative CRP < 1.0 mg/dL and an ejection fraction >/=50%, whereas it was 21.4% among those with a preoperative CRP >/= 1.0 mg/dL and an ejection fraction less than 50% (p < 0.0001). CONCLUSIONS: Preoperative serum concentration of CRP in patients undergoing on-pump coronary artery bypass surgery is an important determinant of postoperative outcome.