Biomarkers have shown promising results in risk assessment of cardiovascular events. Their role in predicting the risk of sudden cardiac death (SCD) is not well established. We tested the performance ...of several biomarkers in risk assessment for SCD in patients with coronary artery disease (CAD) and preserved left ventricular function.
The study population consisted of 1,946 CAD patients (68% male; mean age 66.9±8.6 yrs; type 2 diabetes (T2D) 43%) enrolled in the ARTEMIS study. The study subjects underwent examinations with echocardiography and measurement of several biomarkers. The primary endpoint of the study was SCD. During the mean follow up of 76±20 months 50 patients experienced SCD. Elevated high sensitive CRP (hs-CRP, p = 0.001), soluble ST2 (sST2, p<0.001), B-type natriuretic peptide (BNP, p<0.001), and highly sensitive TroponinT (hs-TnT, p<0.001) predicted the occurrence of SCD in univariate analysis. Using the optimal cutoff points, elevated sST2 (≥27.45ng/mL; hazard ratio HR 2.7; 95%CI 1.4-5.1, p = 0.003) and hs-TnT (≥15 ng/mL; HR 2.9; 95% CI 1.5-5.6, p = 0.002) were the strongest predictors of SCD followed by hs-CRP (HR 2.4; 95% CI 1.3-4.4, p = 0.004) and BNP (HR 1.9; 95% CI 1.0-3.7, p = 0.046) in adjusted analysis. Combination of elevated hs-TnT and sST2 resulted in adjusted HR of 6.4 (95% CI 2.6-15.5, p<0.001).
Elevated sST2 and hs-TnT predict the occurrence of SCD among patients with CAD and preserved left ventricular function. The association between sST2, hs-TnT and SCD may be explained by an ongoing myocardial apoptosis followed by fibrosis leading to vulnerability to malignant arrhythmias.
To compare cardiac mortality in patients with CAD and prediabetes with that in CAD patients with normal glycemic status and type 2 diabetes.
The Innovation to Reduce Cardiovascular Complications of ...Diabetes at the Intersection (ARTEMIS) study included patients with CAD after revascularization (79%), optimal medical therapy, or both. Patients had type 2 diabetes (
= 834), impaired glucose tolerance (IGT;
= 314), impaired fasting glucose (IFG;
= 103), or normal glycemic status (
= 697) as defined on the basis of the results of an oral glucose tolerance test. The primary end point was cardiac death. Major adverse cardiac event (MACE: cardiac death, heart failure, or acute coronary syndrome) and all-cause mortality were secondary end points.
During a mean ± SD follow-up of 6.3 ± 1.6 years, 101 cardiac deaths, 385 MACEs, and 208 deaths occurred. Patients with IGT tended to have 49% lower adjusted risk for cardiac death (
= 0.069), 32% lower adjusted risk for all-cause mortality (
= 0.076), and 36% lower adjusted risk for MACE (
= 0.011) than patients with type 2 diabetes. The patients with IFG had 82% lower adjusted risk for all-cause mortality (
= 0.015) than the patients with type 2 diabetes, whereas risks for cardiac death and MACE did not differ significantly between the two groups. The adjusted risks for cardiac death, MACE, and all-cause mortality among patients with IGT and IFG did not significantly differ from those risks among patients with normal glycemic status.
Cardiac mortality or incidence of MACE in patients with CAD with prediabetes (i.e., IGT or IFG after revascularization, optimal medical therapy, or both) does not differ from those values in patients with normal glycemic status.
The data on biomarkers as predictors of atrial fibrillation (AF) in patients with coronary artery disease (CAD) are limited.
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.
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.
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.
The aim of this study was to test the hypothesis that novel biomarkers may predict cardiac events in diabetic patients with stable coronary artery disease (CAD). Serum levels of highly sensitive ...troponin T (hs-TnT), B-type natriuretic peptide, highly sensitive C-reactive protein (hs-CRP), galectin-3, and soluble suppressor of tumorigenicity-2 (sST2) were analyzed in 1,137 patients with CAD and with type 2 diabetes, impaired glucose tolerance, or fasting glycaemia (diabetic group) and in 649 patients with normal glucose state. Cardiac death or hospitalization for congestive heart failure was the major end point during the follow-up of 2 years. Forty patients in the diabetic group (3.5%) and 9 patients in the nondiabetic group (1.4%) reached the primary end point. High hs-TnT level (≥14 ng/l) was the strongest predictor of the primary end point with hazard ratio of 24.5 (95% confidence interval 8.7 to 69.0; p <0.001) and remained so when adjusted for clinical variables, ejection fraction, renal, lipid, and glycemic status and other biomarkers (hazard ratio 9.9, 95% confidence interval 3.2 to 30.8; p <0.001). In the multivariate model, hs-CRP, B-type natriuretic peptide, and sST2 also predicted the primary end point in the diabetic group (p <0.01 for all). Only sST2 (p <0.001) and hs-CRP (p = 0.02) predicted the primary end point in nondiabetic group. The inclusion of hs-TnT in the model significantly improved discrimination (integrated discrimination improvement 0.050) and reclassification of the patients (net reclassification index 0.21). In conclusion, hs-TnT is a strong predictor of cardiac death or hospitalization for heart failure independently from traditional risk markers or other biomarkers in diabetic patients with stable CAD.
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 β 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.
Early repolarization (ER) in inferior/lateral leads of standard ECGs increases the risk of arrhythmic death. We tested the hypothesis that variations in the ST-segment characteristics after the ER ...waveforms may have prognostic importance.
ST segments after ER were classified as horizontal/descending or rapidly ascending/upsloping on the basis of observations from 2 independent samples of young healthy athletes from Finland (n=62) and the United States (n=503), where ascending type was the dominant and common form of ER. Early repolarization was present in 27/62 (44%) of the Finnish athletes and 151/503 (30%) of the US athletes, and all but 1 of the Finnish (96%) and 91/107 (85%) of US athletes had an ascending/upsloping ST variant after ER. Subsequently, ECGs from a general population of 10 864 middle-aged subjects were analyzed to assess the prognostic modulation of ER-associated risk by ST-segment variations. Subjects with ER ≥0.1 mV and horizontal/descending ST variant (n=412) had an increased hazard ratio of arrhythmic death (relative risk 1.43; 95% confidence interval 1.05 to 1.94). When modeled for higher amplitude ER (>0.2 mV) in inferior leads and horizontal/descending ST-segment variant, the hazard ratio of arrhythmic death increased to 3.14 (95% confidence interval 1.56 to 6.30). However, in subjects with ascending ST variant, the relative risk for arrhythmic death was not increased (0.89; 95% confidence interval 0.52 to 1.55).
ST-segment morphology variants associated with ER separates subjects with and without an increased risk of arrhythmic death in middle-aged subjects. Rapidly ascending ST segments after the J-point, the dominant ST pattern in healthy athletes, seems to be a benign variant of ER.
Serum biomarkers have been proposed to reflect fibrosis of several human tissues, but their specific role in the detection of myocardial fibrosis has not been well-established. We studied the ...association between N-terminal propeptide of type I and III procollagen (PINP, PIIINP, respectively), galectin-3 (gal-3), soluble ST2 (ST2), and myocardial fibrosis measured by late gadolinium enhanced cardiac magnetic resonance imaging (LGE CMR) and their relation to left ventricular diastolic filling properties measured by tissue Doppler echocardiography (E/e') in patients with stable coronary artery disease (CAD).
We determined the PINP, PIIINP, gal-3, and ST2 serum levels and performed LGE CMR and echocardiography on 63 patients with stable CAD without a history of prior myocardial infarction. Myocardial late gadolinium enhancement T1 relaxation time was defined as a specific marker of myocardial fibrosis. ST2, PINP, and PIIINP did not have a significant correlation with the post-LGE T1 relaxation time tertiles (NS for all), but the lowest post-LGE T1 relaxation time tertile had significantly higher gal-3 values than the other two tertiles (p = 0.002 and 0.002) and higher E/é-values (p = 0.009) compared to the highest T1 relaxation time tertile. ST2 (p = 0.025 and 0.029), gal-3 (p = 0.003 and < 0.001) and PIIINP (p = 0.001 and 0.007) levels were also significantly higher in the highest E/é tertile, compared to the other two tertiles.
Elevated serum levels of gal-3 reflect the degree of myocardial fibrosis assessed by LGE CMR. Gal-3, ST2, and PIIINP are also elevated in patients with impaired LV diastolic function, suggesting that these biomarkers are useful surrogates of structural and functional abnormality of the myocardium.
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 4β-hydroxycholesterol (4βHC), an agonist for liver X receptors, as a hypotensive factor. The aim was to determine the role of 4βHC as a prognostic factor in CAD.
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 4βHC. 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 4βHC concentrations. However, in men, high plasma 4βHC 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;
=0.002) and 4.18 (95% CI, 1.5-11.4;
=0.005), respectively. In contrast, the association of cardiac death and SCD in women showed the lowest risk in the highest 4βHC quartile.
High plasma 4βHC concentration was associated with death and especially SCD in men, while an inverse association was detected in women. Our results suggest 4βHC as a novel sex-specific risk marker of cardiac death and especially SCD in chronic CAD.
clinicaltrials.gov. Identifier NCT01426685.
Leisure-time physical activity (LTPA) and exercise training are essential parts of current guidelines for patients with coronary artery disease (CAD). However, the contributions of LTPA and exercise ...training to cardiovascular (CV) risk in CAD patients with type 2 diabetes (T2D) are not well established.
We examined the effects of LTPA (n = 539 and n = 507; with and without T2D, respectively) and 2-year controlled, home-based exercise training (n = 63 plus 64 control subjects with T2D and n = 72 plus 68 control subjects without T2D) on the CV risk profile and composite end point among CAD patients.
During the 2-year follow-up, patients with reduced LTPA at baseline had an increased risk of CV events (adjusted hazard ratio 2.3 95% CI 1.1-5.1; P = 0.033, 2.1 1.1-4.2; P = 0.027, and 2.0 1.0-3.9; P = 0.044 for no LTPA, LTPA irregularly, and LTPA two to three times weekly, respectively) compared with those with LTPA more than three times weekly. Among patients who completed the 2-year exercise intervention, exercise training resulted in favorable changes in exercise capacity both in CAD patients with T2D (+0.2 ± 0.8 vs. -0.1 ± 0.8 MET, P = 0.030) and without T2D (+0.3 ± 0.7 vs. -0.1 ± 0.5 MET, P = 0.002) as compared with the control group but did not have any significant effects on major metabolic or autonomic nervous system risk factors in CAD patients with or without T2D.
There is an inverse association between habitual LTPA and short-term CV outcome, but controlled, home-based exercise training has only minor effects on the CV risk profile in CAD patients with T2D.
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