Allelic variant of NOS1AP effects on cardiac alternans of repolarization during exercise testing.

INTRODUCTION: A repolarization abnormality manifested as T-wave alternans (TWA) in electrocardiogram (ECG) predicts cardiovascular mortality. A common variant in the NOS1AP gene is associated with mortality and QT interval duration, possibly in a gender-specific manner, but data is lacking on potential association with TWA. This study tested association between rs10494366 in NOS1AP and both TWA and 4-year mortality. MATERIAL AND METHODS: A total of 1963 Finnish Cardiovascular Study participants (36.6% female, 57.1 ± 13.0 years) were genotyped and their maximal TWA values were measured from continuous ECG recordings during clinical exercise test at rest, exercise and recovery. RESULTS: We observed a significant gender-specific effect of NOS1AP genotype on TWA. In all subjects, there was no statistically significant difference between the three genotypes (TT, TG, GG) in the responses of TWA over the entire exercise test (time-by-genotype interaction p = 0.057). In women, after adjustment for age, coronary heart disease and ß-blocker medication status, changes of TWA over different phases of exercise test were significantly associated with NOS1AP genotype (time-by-genotype interaction p = 0.001). In men, NOS1AP rs10494366 was not associated with TWA. During follow-up (mean 47 months), 113 patients died. NOS1AP rs10494366 was not a statistically significant predictor of mortality. CONCLUSION: The NOSIAP variant rs10494366 influences TWA and TWA response during clinical exercise test in females. Gender-specific effects have also been previously reported for the influence of the variant on QT interval. If replicated, these findings should prompt studies to further elucidate the mechanisms underlying the gender differences in NOS1AP effects on repolarization.

QRS-T morphology measured from exercise electrocardiogram as a predictor of cardiac mortality.

AIMS: Total cosine R-to-T (TCRT) measured from the standard 12-lead electrocardiogram (ECG) reflects the spatial relationship between depolarization and repolarization wavefronts and a low TCRT value is a marker of poor prognosis. We tested the hypothesis that measurement of TCRT or QRS/T angle from exercise ECG would provide even more powerful prognostic information. METHODS AND RESULTS: The prognostic significances of TCRT and QRS/T angle were assessed from exercise ECG recordings in 1297 patients [age 56 ± 13 years (mean ± SD), 67% males] undergoing a clinically indicated bicycle stress-test and the subsequent follow-up. During an average follow-up of 45 ± 12 months, 74 patients died (5.7%); 34 (2.6%) were cardiac deaths, and 24 (1.9%) were sudden cardiac deaths. Total cosine R-to-T and QRS/T angle exhibited a correlation with the RR intervals in the total cohort, but the individual responses were variable, e.g. median correlation of TCRT-RR was 0.89 with an inter-quartile range from 0.55 to 0.98. A reduced correlation of TCRT-RR during the recovery phase of exercise ECG predicted cardiac death [adjusted heart rate (HR) 3.5, 95% confidence interval (CI): 1.8-6.8, P= 0.001] similarly as the baseline TCRT measured from ECG at rest (adjusted HR 3.4, 95% CI: 1.4-8.1, P= 0.01). The poor correlation between the TCRT-RR both during the exercise and recovery was specifically related to a risk of sudden cardiac death (adjusted HR 6.2, 95% CI: 2.1-17.8, P< 0.001). CONCLUSIONS: Loss of rate-adaptation of the spatial relationship between depolarization and repolarization wavefronts is a strong predictor of cardiac death, especially of sudden cardiac death.

IL-18 gene polymorphism, cardiovascular mortality and coronary artery disease.

BACKGROUND: Interleukin 18(IL-18) is a pro-atherosclerotic cytokine. Elevated IL-18 levels and the genetic variation of the IL-18 have been previously linked with acute coronary events and cardiovascular mortality among patients with coronary artery disease (CAD). We studied the possible association between the IL-18 gene polymorphism and cardiovascular mortality during follow-up among Finnish patients who had undergone a clinical exercise stress test, in addition to the possible effect on the expression of angiography-verified CAD. MATERIALS AND METHODS: A total of 2152 patients of the Finnish Cardiovascular Study (cohort study) were followed up for 6·3years and cardiovascular mortality was recorded. Angiography was performed on 461 patients. Genotyping of five common single nucleotide polymorphisms (SNPs) of the IL-18 gene was performed using the 5'nuclease assay for allelic discrimination with the ABI Prism 7900HT Sequence Detection System. RESULTS: Among the study population, IL-18 gene polymorphism did not associate with cardiovascular mortality. According to adjusted binary regression analysis, the male carriers of one major haplotype (the only ones carrying the t allele of the +127 C/t SNP) had a lower occurrence rate for significant CAD defined as > 50% stenosis in at least one of the main branches of the coronary arteries (OR 0·495, 95% CI 0·862-0·284, P=0·041). No associations were observed among women. The sex-by-genotype interaction was significant (P=0·033). CONCLUSIONS: The IL-18 gene was not found to associate significantly with mortality. Among patients who had coronary angiography, one major haplotype of the IL-18 gene has a gender-dependent different impact on the expression of CAD.

Pattern of crescendo TWA may disclose the underlying cardiac pathology.

We present an exercise test case in which crescendo TWA preceded ventricular tachycardia (VT). The patient was examined due to suspicion of ischemic heart disease. The ST-segment became elevated simultaneously with a distinct alternation in the ST-segment and the first half of the T-wave, and the patient developed polymorphic VT. Coronary angiography disclosed marked stenoses. Earlier reports of TWA in patients with congenital long QT syndrome show a pattern in which the T wave frequently alternates above and below the isoelectric line without concomitant ST-segment changes. In Brugada syndrome patients, the signature ST-T wave pattern is the locus of alternation. Future investigation should elucidate whether specific TWA morphologies may expose underlying heart disease.

Enhanced predictive power of quantitative TWA during routine exercise testing in the Finnish Cardiovascular Study.

INTRODUCTION: We examined whether quantification of T-wave alternans (TWA) enhances this parameter's capacity to evaluate the risk for total and cardiovascular mortality and sudden cardiac death (SCD). METHODS AND RESULTS: The Finnish Cardiovascular Study (FINCAVAS) enrolled consecutive patients (n = 2,119; 1,342 men and 777 women) with a clinically indicated exercise test with bicycle ergometer. TWA (time domain-modified moving average method) was analyzed from precordial leads, and the results were grouped in increments of 10 microV. Hazard ratios (HR) for total and cardiovascular mortality and SCD were estimated for preexercise, routine exercise, and postexercise stages. Cox regression analysis was performed. During follow-up of 47.1 +/- 12.9 months (mean +/- standard deviation [SD]), 126 patients died: 62 were cardiovascular deaths, and 33 of these deaths were sudden. During preexercise, TWA >or= 20 microV predicted the risk for total and cardiovascular mortality (maximum HR >4.4 at 60 microV, P < 0.02 for both). During exercise, HRs of total and cardiovascular mortality were significant when TWA measured >or=50 microV, with 90 microV TWA yielding maximum HRs for total and cardiovascular death of 3.1 (P = 0.03) and 6.4 (P = 0.002), respectively. During postexercise, TWA >or=60 microV indicated risk for total and cardiovascular mortality, with maximum HR of 3.4 at 70 microV (P = 0.01) for cardiovascular mortality. SCD was strongly predicted by TWA levels >or=60 microV during exercise, with maximum HR of 4.6 at 60 microV (P = 0.002), but was not predicted during pre- or postexercise. CONCLUSION: Quantification of TWA enhances its capacity for determination of the risk for total and cardiovascular mortality and SCD in low-risk populations. Its prognostic power is superior during exercise compared to preexercise or postexercise.

The Duke treadmill score with bicycle ergometer: Exercise capacity is the most important predictor of cardiovascular mortality.

BACKGROUND: The Duke treadmill score, a widely used treadmill testing tool, is a weighted index combining exercise time or capacity, maximum ST-segment deviation and exercise-induced angina. No previous studies have investigated whether the Duke treadmill score and its individual components based on bicycle exercise testing predict cardiovascular death. DESIGN: Two populations with a standard bicycle testing were used: 3936 patients referred for exercise testing (2371 men, age 56 ± 13 years) from the Finnish Cardiovascular Study (FINCAVAS) and a population-based sample of 2683 men (age 53 ± 5.1 years) from the Kuopio Ischaemic Heart Disease study (KIHD). METHODS: Cox regression was applied for risk prediction with cardiovascular mortality as the primary endpoint. RESULTS: In FINCAVAS, during a median 6.3-year (interquartile range (IQR) 4.5-8.2) follow-up period, 180 patients (4.6%) experienced cardiovascular mortality. In KIHD, 562 patients (21.0%) died from cardiovascular causes during the median follow-up of 24.1 (IQR 18.0-26.2) years. The Duke treadmill score was associated with cardiovascular mortality in both populations (FINCAVAS, adjusted hazard ratio (HR) 3.15 for highest vs. lowest Duke treadmill score tertile, 95% confidence interval (CI) 1.83-5.42, P < 0.001; KIHD, adjusted HR 1.71, 95% CI 1.34-2.18, P < 0.001). However, after progressive adjustment for the Duke treadmill score components, the score was not associated with cardiovascular mortality in either study population, as exercise capacity in metabolic equivalents of task was the dominant harbinger of poor prognosis. CONCLUSIONS: The Duke treadmill score is associated with cardiovascular mortality among patients who have undergone bicycle exercise testing, but metabolic equivalents of task, a component of the Duke treadmill score, proved to be a superior predictor.

Heart rate variability derived from exercise ECG in the detection of coronary artery disease.

The diagnostic performance of heart rate variability (HRV) analysis from exercise ECG in the detection of coronary artery disease (CAD) is unknown. Bicycle exercise ECG recordings from The Finnish Cardiovascular Study (FINCAVAS) of angiography-proofed CAD patients (n = 112) and a patient group with a low likelihood of CAD (n = 114) were analyzed. HRV parameters (SDNN, RMSSD, Poincaré SD1 and SD2) were calculated from 1 min segments before exercise, during exercise and after exercise. All the parameters were in addition calculated from heart rate (HR)-corrected RR-interval segments. The ST-segment depressions in each stage were also determined. The diagnostic performance of the parameters was evaluated with the area under the receiver operating characteristic (ROC) curve method. The uncorrected HRV parameters showed the best diagnostic performance in the recovery segments but the correlation with HR was also high (SDNN: 0.758/-0.64, RMSSD: 0.747/-0.60; area under the ROC/correlation coefficient). The HR correction decreased the correlation and the diagnostic performance in recovery segments (SDNN: 0.515/-0.12, RMSSD: 0.609/0.20). The diagnostic performance of ST-level at its best was higher than any of HRV parameters (ST-level: 0.795/0.36). According to the results, the HR correction decreased the diagnostic performance of the recovery phase. The HRV parameters calculated from 1 min segments of exercise test ECG were not as capable as traditional ST-segment analysis. In conclusion, the HRV analysis from exercise or recovery phase seems to be inadequate in the detection of CAD.

Age and gender biases in secondary prevention of coronary heart disease in a Finnish university hospital setting.

BACKGROUND AND OBJECTIVES: Several studies have shown that treatment of coronary heart disease (CHD) does not meet the goals set in recommendations. The aim of this study was to investigate the adequacy of CHD drug treatment and secondary prevention measures, particularly with respect to age and gender biases, in a Finnish university hospital setting. METHODS: The participant pool consisted of patients in FINCAVAS (Finnish Cardiovascular Study), which is a cohort study recruiting consecutive patients performing a clinical exercise test at Tampere University Hospital, Tampere, Finland. 802 patients (581 men, 221 women) with a prior diagnosis of CHD recruited between October 2001 and December 2004 were included in the analysis. RESULTS: Only roughly 12% of both men and women had an optimal risk factor profile. High blood pressure and hypercholesterolaemia were more common in women than in men, whereas smoking was more frequent among men. Men used ACE inhibitors (32.9% vs 20.4%, respectively), beta-adrenoceptor antagonists (80.8% vs 68.3%, respectively) and aspirin (acetylsalicylic acid) [69.7% vs 58.8%, respectively] more frequently than women, but the frequency of use of these medications was also not at the recommended levels in men. Risk factor control is poorer in older than younger age groups. CONCLUSIONS: CHD patients, particularly women, who performed an exercise stress test in a university hospital are suboptimally treated.

The p22phox C242T gene polymorphism is associated with a reduced risk of angiographically verified coronary artery disease in a high-risk Finnish Caucasian population. The Finnish Cardiovascular Study.

BACKGROUND: Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is a major source of the superoxide anion, which may play an important role in the development of atherosclerosis and coronary artery disease (CAD). The p22phox, a component of the NADPH oxidase, is essential for the activation of this enzyme, and intensive expression of the p22phox has been reported in human atherosclerotic arteries. However, studies on the association of the C242T polymorphism in the p22phox gene with CAD have produced conflicting results, and the relation of this polymorphism with CAD is not well known in a population with acquired risk factors enhancing the NADPH-dependent superoxide production. METHODS: As part of the Finnish Cardiovascular Study, a case-control study was conducted with 402 high-risk Finnish Caucasian patients undergoing coronary angiography. Genotyping was performed using the 5' nuclease TaqMan assay. RESULTS: The prevalence of the T allele (TT + TC genotypes) was significantly lower among angiographically verified CAD patients (n = 250) than among control subjects (n = 152, P = .013). In contrast to subjects with the CC genotype, the T allele was found protective against CAD (odds ratio = 0.531, 95% CI 0.331-0.852, P = .009), and the results remained significant after adjustment for other significant coronary risk factors. CONCLUSIONS: The T allele in the C242Tpolymorphism of the p22phox gene had a protective effect against the development of CAD despite the exposure of study subjects to risk factors related to excessive NADPH-dependent superoxide production.

Effects of polymorphisms in beta1-adrenoceptor and alpha-subunit of G protein on heart rate and blood pressure during exercise test. The Finnish Cardiovascular Study.

We tested whether the Arg389Gly and Ser49Gly polymorphisms of the beta1-adrenergic receptor gene ADRB1 and the T393C polymorphism of the G protein alpha-subunit gene GNAS1 modulate heart rate (HR) and blood pressure responses during an exercise stress test. The study population comprised 890 participants (563 men and 327 women, mean age 58.1 +/- 12.6 yr) of the Finnish Cardiovascular Study. Their HR, systolic (SAP), and diastolic arterial pressures (DAP) at rest, during exercise, and 4 min after the test were measured and analyzed by repeated-measurement ANOVA (RANOVA). Genotypes were detected by TaqMan 5' nuclease assay. In all subjects, and in men and women separately, the T393C of GNAS1 was the only polymorphism with genotype x time interaction in HR over the three study phases (P = 0.04, RANOVA). None of the polymorphisms presented genotype x time interaction in SAP or DAP responses (P > 0.10, RANOVA). In all subjects at rest, the Ser49Gly polymorphism of ADRB1 tended (P = 0.06, ANOVA) to differentiate HR. Arg389Gly polymorphism of ADRB1 affected maximal SAP during exercise (P = 0.04, ANOVA) and the change in SAP from rest to maximal (P = 0.03, ANOVA). Arg389 homozygotes, particularly men, were less likely to have ventricular extrasystoles during the exercise (odds ratio = 0.68, 95% confidence interval = 0.51-0.91, P = 0.009, and odds ratio = 0.60, 95% confidence interval = 0.42-0.86, P = 0.006, respectively) than did Gly389 carriers. In conclusion, polymorphisms examined appear to have modulatory effects on hemodynamics in a clinical exercise test setting. However, the effects in absolute numbers were minor and clinically possibly insignificant.

The Finnish Cardiovascular Study (FINCAVAS): characterising patients with high risk of cardiovascular morbidity and mortality.

BACKGROUND: The purpose of the Finnish Cardiovascular Study (FINCAVAS) is to construct a risk profile--using genetic, haemodynamic and electrocardiographic (ECG) markers--of individuals at high risk of cardiovascular diseases, events and deaths. METHODS AND DESIGN: All patients scheduled for an exercise stress test at Tampere University Hospital and willing to participate have been and will be recruited between October 2001 and December 2007. The final number of participants is estimated to reach 5,000. Technically successful data on exercise tests using a bicycle ergometer have been collected of 2,212 patients (1,400 men and 812 women) by the end of 2004. In addition to repeated measurement of heart rate and blood pressure, digital high-resolution ECG at 500 Hz is recorded continuously during the entire exercise test, including the resting and recovery phases. About 20% of the patients are examined with coronary angiography. Genetic variations known or suspected to alter cardiovascular function or pathophysiology are analysed to elucidate the effects and interactions of these candidate genes, exercise and commonly used cardiovascular medications. DISCUSSION: FINCAVAS compiles an extensive set of data on patient history, genetic variation, cardiovascular parameters, ECG markers as well as follow-up data on clinical events, hospitalisations and deaths. The data enables the development of new diagnostic and prognostic tools as well as assessments of the importance of existing markers.

Prognostic capacity of a clinically indicated exercise test for cardiovascular mortality is enhanced by combined analysis of exercise capacity, heart rate recovery and T-wave alternans.

BACKGROUND: Exercise capacity, heart rate recovery and T-wave alternans are independent predictors of cardiovascular mortality. We tested whether these parameters contain supplementary prognostic information. METHODS: A total of 3609 consecutive patients (2157 men) referred for a routine, clinically indicated bicycle exercise test were enrolled in the Finnish Cardiovascular Study (FINCAVAS). Exercise capacity was measured in metabolic equivalents, heart rate recovery as the decrease in heart rate from maximum to one minute post-exercise, and T-wave alternans by time-domain Modified Moving Average method. RESULTS: During 57-month median follow-up (interquartile range 35-78 months), 96 patients died of cardiovascular causes (primary endpoint) and 233 from any cause. All three parameters were independent predictors of cardiovascular mortality when analysed as continuous variables. Adding metabolic equivalents (p < 0.001), heart rate recovery (p = 0.002) or T-wave alternans (p = 0.01) to the linear model improved its predictive power for cardiovascular mortality. The combination of low exercise capacity (<6 metabolic equivalents), reduced heart rate recovery (≤12 beats/min) and elevated T-wave alternans (≥60 µV) yielded the highest hazard ratio for cardiovascular mortality of 16.5 (95% confidence interval 4.0-67.7, p < 0.001). Harrell's C index was 0.719 (confidence interval 0.665-0.772) for cardiovascular mortality with previously defined cutpoints (<8 units for metabolic equivalents, ≤18 beats/min for heart rate recovery and ≥60 µV for T-wave alternans). CONCLUSION: The prognostic capacity of the clinical exercise test is enhanced by combined analysis of exercise capacity, heart rate recovery and T-wave alternans.

Effect of heart rate correction on pre- and post-exercise heart rate variability to predict risk of mortality-an experimental study on the FINCAVAS cohort.

The non-linear inverse relationship between RR-intervals and heart rate (HR) contributes significantly to the heart rate variability (HRV) parameters and their performance in mortality prediction. To determine the level of influence HR exerts over HRV parameters' prognostic power, we studied the predictive performance for different HR levels by applying eight correction procedures, multiplying or dividing HRV parameters by the mean RR-interval (RRavg) to the power 0.5-16. Data collected from 1288 patients in The Finnish Cardiovascular Study (FINCAVAS), who satisfied the inclusion criteria, was used for the analyses. HRV parameters (RMSSD, VLF Power and LF Power) were calculated from 2-min segment in the rest phase before exercise and 2-min recovery period immediately after peak exercise. Area under the receiver operating characteristic curve (AUC) was used to determine the predictive performance for each parameter with and without HR corrections in rest and recovery phases. The division of HRV parameters by segment's RRavg to the power 2 (HRVDIV-2) showed the highest predictive performance under the rest phase (RMSSD: 0.67/0.66; VLF Power: 0.70/0.62; LF Power: 0.79/0.65; cardiac mortality/non-cardiac mortality) with minimum correlation to HR (r = -0.15 to 0.15). In the recovery phase, Kaplan-Meier (KM) survival analysis revealed good risk stratification capacity at HRVDIV-2 in both groups (cardiac and non-cardiac mortality). Although higher powers of correction (HRVDIV-4and HRVDIV-8) improved predictive performance during recovery, they induced an increased positive correlation to HR. Thus, we inferred that predictive capacity of HRV during rest and recovery is augmented when its dependence on HR is weakened by applying appropriate correction procedures.

Postexercise recovery of the spatial QRS/T angle as a predictor of sudden cardiac death.

BACKGROUND: Postexercise measurement of heart rate (HR) recovery and QT interval dynamics provides prognostic information in various patient populations. OBJECTIVE: The purpose of this study was to assess whether the measurement of the spatial relationship between the depolarization and repolarization wavefronts (total cosine R-to-T [TCRT]) during the postexercise recovery phase would yield prognostic information. METHODS: The population consisted of 1297 patients (56 ± 13 years; 67% men) who performed a clinically indicated bicycle stress test. The exercise-recovery hysteresis of TCRT was quantified from the 12-lead exercise electrocardiogram by measuring the TCRT/HR loop area bounded by the exercise and first 3-minute postexercise recovery curves. The HR-corrected TCRT/HR hysteresis was calculated by dividing the area with the HR decrement during the first 3 minutes of recovery. HR recovery was measured at 1 minute postexercise recovery. End points were cardiac death and sudden cardiac death. RESULTS: During an average follow-up of 45 ± 12 months, 74 patients died (5.7%); 35 (2.6%) were cardiac deaths and 24 (1.9%) were sudden cardiac deaths. Reduced TCRT/HR loop area and TCRT/HR hysteresis were associated with cardiac mortality (P <.001). After adjustments for clinical variables, including ejection fraction, TCRT/HR loop area remained an independent predictor of cardiac death (hazard ratio 5.6; 95% confidence interval 1.6-19.1; P = .007) and sudden cardiac death (10.7; 95% confidence interval 1.4-83.7; P = .024). HR recovery did not remain a significant predictor in the multivariate analysis. CONCLUSIONS: Attenuated hysteresis of the depolarization and repolarization wavefronts during postexercise recovery is associated with an increased risk of cardiac and sudden cardiac death. Analysis of repolarization dynamics from exercise electrocardiogram represents a promising tool for risk stratification.

Importance of regional specificity of T-wave alternans in assessing risk for cardiovascular mortality and sudden cardiac death during routine exercise testing.

BACKGROUND: T-wave alternans (TWA) indicates increased risk for life-threatening arrhythmias. However, the regional distribution and predictivity of TWA among precordial leads remain unknown. OBJECTIVE: We analyzed the magnitude and prognostic power of TWA in precordial leads separately and in combination during routine exercise stress testing in the largest TWA study conducted to date. METHODS: The Finnish Cardiovascular Study (FINCAVAS) enrolled consecutive patients (n = 3,598, 56 ± 13 [mean ± standard deviation] years old, 2,164 men, 1,434 women) with a clinically indicated exercise test with bicycle ergometer. TWA was analyzed with the time-domain modified moving average method. RESULTS: During a follow-up of 55 months (interquartile range of 35-78 months), 231 patients died; 97 deaths were cardiovascular, and 46 were classified as sudden cardiac deaths (SCDs). In Cox analysis after adjustment for common coronary risk factors, each 20-µV increase in TWA in leads V1-V6 multiplied the hazard ratio for cardiovascular mortality by 1.486-fold (95% confidence interval [CI] 1.127-1.952; P = .005). Each 20-µV increase in TWA in lead V5 amplified the hazard ratio for cardiovascular mortality by 1.545 (95% CI 1.150-2.108; P = .004) and for SCD by 1.576 (95% CI 1.041-2.412; P = .033). CONCLUSIONS: Maximum TWA monitored from anterolateral precordial lead V5 is the strongest predictor of cardiovascular mortality and SCD during routine exercise testing in our analysis. Higher TWA values indicate greater cardiovascular mortality and SCD risk, supporting the concept that quantification of TWA should receive more attention.

Common variation in the ADAM8 gene affects serum sADAM8 concentrations and the risk of myocardial infarction in two independent cohorts.

OBJECTIVE: The single nucleotide polymorphism (SNP) rs2995300 in the metalloproteinase-disintegrin gene ADAM8 has been shown to affect the areas of complicated coronary plaques and the risk of fatal myocardial infarction (MI) in men. This study was set up to further investigate the role of ADAM8 in MI. AIM: To investigate the possible association of the ADAM8 SNPs rs2995300 and rs2275725 with ADAM8 mRNA levels, serum soluble ADAM8 (sADAM8) concentrations, and MI risk. METHODS: Samples from the Finnish cardiovascular study (FINCAVAS, N=2156) and the angiography and genes study (ANGES, N=1000) were genotyped. Serum sADAM8 concentrations were determined with ELISA (N=443). ADAM8 mRNA levels in atherosclerotic plaques were analysed from the tampere vascular study (TVS, N=53) samples. RESULTS: A significantly increased MI risk for carriers of the rs2995300C allele and the rs2275725 A allele was revealed in the meta-analysis of the ANGES and FINCAVAS patient data (OR=1.42, P<0.001 and OR=1.43, P<0.001). The risk increase was comparable to that caused by smoking in these cohorts. The risk allele carriers also had higher sADAM8 serum concentrations. CONCLUSIONS: The risk alleles of the investigated ADAM8 SNPs were associated with elevated sADAM8 serum levels and MI risk. The present results implicate ADAM8 in the development of CVDs and suggest its prognostic and therapeutic potential.

Value of leads V4R and CM5 in the detection of coronary artery disease during exercise electrocardiographic test.

The usefulness of the right precordial unipolar leads and the value of the bipolar lead CM5 in the detection of coronary artery disease (CAD) with exercise electrocardiographic (ECG) test are not well documented. The objective of this study was to evaluate the diagnostic performance of leads V4R and CM5. The study population comprised 579 patients referred for a bicycle exercise ECG test in the Finnish Cardiovascular Study. Patients were divided into three groups: angiographically proven CAD (CAD, n = 255), no CAD by angiography (NoCAD, n = 126), and low likelihood of CAD (LLC, n = 198). The maximum ST-segment depression at peak exercise was used as a parameter, and the diagnostic accuracy of different leads was assessed by receiver operating characteristic (ROC) analysis. Sensitivity and specificity values at a cut-off criterion of -0.10 mV ST-segment, 1-mm ST depression, were determined. According to the results, incorporating lead V4R with the standard leads decreased the ROC area from 0.71 to 0.69 (comparison CAD versus LLC) and from 0.55 to 0.53 (comparison CAD versus NoCAD) and had no effect on sensitivity or specificity. Adding lead CM5 to the standard leads did not affect the ROC area but increased the sensitivity and decreased the specificity. In conclusion, the use of right precordial lead V4R along with the standard 12-lead system does not improve the performance of the exercise ECG in diagnosing CAD. Adding lead CM5 to the standard leads increases the sensitivity but does not change the overall diagnostic performance.

Atrioventricular conduction and cardiovascular mortality: assessment of recovery PR interval is superior to pre-exercise measurement.

BACKGROUND: A prolonged electrocardiographic PR interval at rest has been considered a benign phenomenon until recently. OBJECTIVE: We hypothesized that measurement of the PR interval during recovery from physical exertion could improve cardiovascular mortality risk stratification because it would track the dynamic influences of homeostatic mechanisms controlling atrioventricular (AV) conduction. METHODS: A total of 1,979 consecutive patients (1,244 men and 735 women) with clinically indicated bicycle ergometer tests enrolled in FINCAVAS (the Finnish Cardiovascular Study) were included in the study. The PR interval was measured at 1 min before and at 2 min after exercise. RESULTS: During the mean follow-up period of 47 months (interquartile range: 37 to 59 months), 50 cardiovascular deaths (end point) were registered. The unadjusted hazard ratios (HR) in Cox regression analyses were significant for both continuous PR interval and first-degree atrioventricular (AV) block for pre- and post-exercise phases. After adjustment for standard markers, the PR interval for 20-ms increments (HR: 1.17, P = .117) and first-degree AV block (HR: 1.85, P = .138) during the pre-exercise phase were not prognostic. However, during recovery from exercise, prolonged AV conduction achieved significance both in continuous (HR: 1.29, P = .006) and dichotomized analyses (HR: 2.41, P = .045). CONCLUSION: The PR interval before exercise is not a robust risk stratifier for cardiovascular death during 4-year follow-up. Post-exercise assessment of AV conduction may offer improved prediction because of functional abnormalities that become manifest only during this physiologic challenge to the heart.

Exercise electrocardiography detection of coronary artery disease by ST-segment depression/heart rate hysteresis in women: the Finnish Cardiovascular Study.

INTRODUCTION: The performance of exercise electrocardiography (ECG) for the detection of coronary artery disease (CAD) in women has been limited. The recently developed computerized variable, ST-segment depression/heart rate (ST/HR) hysteresis, has been proved to detect CAD in men more accurately than traditional methods. However, the diagnostic performance of ST/HR hysteresis has not been evaluated in women. MATERIALS AND METHODS: The study population comprised 161 female patients from the Finnish Cardiovascular Study (FINCAVAS). All patients were referred for a routine bicycle exercise test. The maximum values of ST/HR hysteresis, ST/HR index, ST-segment depression at peak exercise (STpeak), at the end of one (ST1rec) and three (ST3rec) minutes of post-exercise were determined. Significant CAD was present in 48, while 65 women showed no angiographic CAD. Also a group of 48 women with low likelihood of CAD (LLC) was formed. Diagnostic performance of variables was assessed by receiver operating characteristic (ROC) analysis. Furthermore, sensitivity values at 80% specificity and specificities at 80% sensitivity were determined. RESULTS: In a comparison between CAD and LLC groups, the ROC areas for ST/HR hysteresis, ST/HR index, STpeak, ST1rec and ST3rec were 0.89, 0.74, 0.65, 0.84 and 0.73, and sensitivities at 80% specificity were 88%, 67%, 52%, 75% and 60%, respectively. Comparing CAD and no-CAD groups, the ROC areas were 0.73, 0.67, 0.56, 0.63 and 0.60, and specificities at 80% sensitivity were 60%, 38%, 27%, 33% and 30%. CONCLUSIONS: ST/HR hysteresis is a more competent method in CAD detection in women than ST-segment depression or ST/HR index.

Combined assessment of heart rate recovery and T-wave alternans during routine exercise testing improves prediction of total and cardiovascular mortality: the Finnish Cardiovascular Study.

BACKGROUND: Identification of individuals who are at risk for cardiovascular death remains a pressing public health challenge. Derangements in autonomic function acting upon an electrically unstable substrate are thought to be critical elements in triggering cardiovascular events. OBJECTIVE: The purpose of this study was to analyze heart rate recovery (HRR) in combination with T-wave alternans (TWA) to improve risk assessment. METHODS: The Finnish Cardiovascular Study (FINCAVAS) enrolled consecutive patients (N = 1,972 [1,254 men and 718 women], age 57 +/- 13 years [mean +/- SD]) with a clinically indicated exercise test using bicycle ergometer. TWA was analyzed continuously with the time-domain modified moving average method. Maximum TWA at heart rates <125 bpm was derived. RESULTS: During 48 +/- 13 months of follow-up (mean +/- SD), 116 patients died; 55 deaths were cardiovascular. In multivariable Cox analysis after adjustment for common coronary risk factors, high exercise-based TWA (> or =60 microV) and low HRR (< or =18 bpm) yielded relative risks for all-cause mortality of 5.0 (95% confidence 2.1-12.1, P <.01) and for cardiovascular mortality of 12.3 (95% confidence interval 4.3-35.3, P <.01). High recovery-based TWA (> or =60 microV) and low HRR (< or =18 bpm) yielded relative risks for all-cause death of 6.1 (95% confidence interval 2.8-13.2, P <.01) and for cardiovascular mortality of 8.0 (95% confidence interval 2.9-22.0, P <.01). Prediction by HRR and TWA, both singly and in combination, exceeded that of standard cardiovascular risk factors. CONCLUSION: Reduced HRR and heightened TWA powerfully predict risk for cardiovascular and all-cause death in a low-risk population. This novel approach could aid in screening of general populations during routine exercise protocols as well as improve insights into pathophysiology.