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Postexercise measurement of heart rate (HR) recovery and QT interval dynamics provides prognostic information in various patient populations.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.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.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.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.

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.To investigate the possible association of the ADAM8 SNPs rs2995300 and rs2275725 with ADAM8 mRNA levels, serum soluble ADAM8 (sADAM8) concentrations, and MI risk.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.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, P0.001 and OR=1.43, P0.001). The risk increase was comparable to that caused by smoking in these cohorts. The risk allele carriers also had higher sADAM8 serum concentrations.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.

Eur J Clin Invest 2010; 40 (11): 994–1001 Abstract 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 6·3 years 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.

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.

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.

Objectives We sought to evaluate the utility of T-wave alternans (TWA) assessment in the immediate post-exercise period to identify and validate cutpoints for the modified moving average (MMA) assessment method. Background The presence of TWA is associated with an increased risk of cardiovascular death (CVD). The immediate post-exercise period, where increased physiologic stress and minimal surface artifact coexist, appears ideal to implement the MMA method. Methods A test (n = 322) and validation cohort (n = 681) provided 1,003 patients with coronary artery disease (CAD). We assessed TWA immediately after exercise. The outcomes, CVD and mortality, were adjudicated independent of the TWA results. Results During 48 months of follow-up 85 deaths, 54 categorized as CVD (64%), were observed. A linear relationship between the magnitude of TWA and the risk of CVD was identified. As a continuous measure TWA voltage was equivalent to ejection fraction in predicting the risk of CVD. To facilitate clinical application, a sensitive, modest predictive accuracy (20 μV) and a specific, greater predictive accuracy MMA cutpoint (60 μV) were identified and validated. Each cutpoint was associated with a 2.5-fold greater risk of CVD, independent of other important variables, including ejection fraction. Conclusions Post-exercise assessment of TWA using the MMA method is a strong, independent predictor of risk in patients with CAD. The 20-μV cutpoint (87% sensitivity) appears to be most suitable in higher-risk patients, whereas the 60-μV cutpoint (95% specificity) appears more appropriate when TWA is used as a single screening test in those at lower risk. (Assessment of Noninvasive Methods to Identify Patients at Risk of Serious Arrhythmias After a Heart Attack; NCT00399503 )

We tested the hypothesis that the change from the peak to recovery values of systolic arterial pressure (SAP recovery) and rate-pressure product (RPP recovery) can be used to predict all-cause and cardiovascular mortality, as well as sudden cardiac death (SCD) in patients referred to a clinical exercise stress test. As a part of the Finnish Cardiovascular Study (FINCAVAS), consecutive patients (n=2029; mean age+/-SD=57+/-13 years; 1290 men and 739 women) with a clinically indicated exercise test using a bicycle ergometer were included in the present study. Capacities of attenuated SAP recovery, RPP recovery and heart rate recovery (HRR) to stratify the risk of death were estimated. During a follow-up (mean+/-s.d.) of 47+/-13 months, 122 patients died; 58 of the deaths were cardiovascular and 33 were SCD. In Cox regression analysis after adjustment for the peak level of the variable under assessment, age, sex, use of beta-blockers, previous myocardial infarction and other common coronary risk factors, the hazard ratio of the continuous variable RPP recovery (in units 1000 mm Hg x b.p.m.) was 0.85 (95% CI: 0.73-0.98) for SCD, 0.87 (0.78-0.97) for cardiovascular mortality, and 0.87 (0.81 to 0.94) for all-cause mortality. SAP recovery was not a predictor of mortality. The relative risks of having HRR below 18 b.p.m., a widely used cutoff point, were as follows: for SCD 1.28 (0.59-2.81, ns), for cardiovascular mortality 2.39 (1.34-4.26) and for all-cause mortality 2.40 (1.61-3.58). In conclusion, as a readily available parameter, RPP recovery is a promising candidate for a prognostic marker.

A longer heart-rate corrected QT interval (QTc) is associated with increased risk of ventricular arrhythmias. Women have longer resting QTc and are more likely than men to develop drug-induced QT prolongation. Recent studies have shown association between resting QTc and a common variant (rs10494366) of the NOS1 regulator, NOS1AP. We investigated the association between rs10494366 in NOS1AP and QTc, and assessed gender-specific NOS1AP associations with QTc during rest and after exercise.We investigated the SNP associations with resting QTc in 919 women and 918 men from 504 representative families in the UK GRAPHIC study, and with QTc at rest and at 3 min recovery after exercise in 699 women and 1225 men referred for exercise testing in the Finnish FINCAVAS study.In the GRAPHIC study the minor allele (G) of the NOS1AP SNP rs10494366 prolonged QTc by 4.59 ms (95% CI 2.77-6.40; P = 7.63/10(7)) in women, but only by 1.62 ms (95% CI -0.15 to 3.38; P = 0.073) in men (gender-SNP interaction term P = 0.025). In the FINCAVAS study the G allele significantly prolonged QTc in both women (P = 0.0063) and men (P = 0.0043) at 3 min recovery after exercise, but at rest an association was only seen in women (P = 0.020 excluding outliers).A common NOS1AP variant prolongs QTc with a difference between genders. Further studies should aim to confirm this finding and to assess whether NOS1AP genotype influences the risk of drug-induced QT prolongation and risk of consequent arrhythmias.

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.

Aims As a part of the Finnish Cardiovascular Study, we tested the hypothesis that T-wave alternans (TWA) predicts mortality in a general population of patients referred for a clinical exercise test. Methods and results A total of 1037 consecutive patients (mean age+SD of 58+13 years, 673 men and 364 women) with a clinically indicated exercise test and with technically successful electrocardiographic (ECG) data during a bicycle ergometer test were included in the study. Digital ECGs were recorded and TWA was analysed continuously with the time-domain modified moving average method. The maximum TWA value at heart rate (HR) ,125 b.p.m. was derived and its capacity to stratify risk for all-cause death, cardiovascular death, and sudden cardiac death (SCD) was tested. During a follow-up of 44+7 months (mean+SD), 59 patients died; 34 were due to cardiovascular causes and 20 were due to SCD. In multivariate analysis after adjustment for age, sex, use of b-blockers, functional class, maximal HR during exercise, previous myocardial infarction, and other common coronary risk factors, the relative risk of TWA � 65 mV for SCD was 7.4 (95% CI, 2.8–19.4; P , 0.001), for cardiovascular mortality 6.0 (95% CI, 2.8–12.8; P , 0.001), and for all-cause mortality 3.3 (95% CI, 1.8–6.3; P ¼ 0.001). Conclusion Time-domain TWA analysis powerfully predicts mortality in a general population undergoing a clinical exercise test.

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.

We tested whether the Arg389Gly and Ser49Gly polymorphisms of the β1-adrenergic receptor gene ADRB1 and the T393C polymorphism of the G protein α-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 × time interaction in HR over the three study phases ( P = 0.04, RANOVA). None of the polymorphisms presented genotype × 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.

ST segment depression/heart rate (ST/HR) hysteresis is a recently introduced novel computer method for integrating the exercise and recovery phase ST/HR analysis for improved detection of coronary artery disease (CAD). It is a continuous diagnostic variable that extracts the prevailing direction and average magnitude of the hysteresis in ST depression against HR during the first 3 consecutive minutes of postexercise recovery. This article reviews the development and evaluation of this new method in a clinical population of 347 patients referred for a routine bicycle exercise electrocardiographic (ECG) test at Tampere University Hospital, Finland. Of these patients, 127 had angiographically proven CAD, whereas 13 had no CAD according to angiography, 18 had no perfusion defect according to Tc-99m-sestamibi myocardial imaging and single photon emission computed tomography, and 189 were clinically normal with respect to cardiac diseases. For each patient, the values for ST/HR hysteresis, ST/HR index, end-exercise ST depression, and recovery ST depression were determined for each lead of the Mason-Likar modification of the standard 12-lead exercise ECG and maximum value from the lead system (aVL, aVR, and V1 excluded). The area under the receiver operating characteristics curve (ie, the discriminative capacity) of the ST/HR hysteresis was 89%, which was significantly larger than that of the end-exercise ST depression (76%, P < .0001), recovery ST depression (84%, P = .0063) or ST/HR index (83%, P = .0023), indicating the best diagnostic performance of the ST/HR hysteresis in detection of CAD regardless of the partition value selection. Furthermore, the superior diagnostic performance of the method was relatively insensitive to the ST segment measurement point or to the ECG lead selection. These results suggest that the ST/HR hysteresis improves the clinical utility of the exercise ECG test in detection of CAD.

We have studied the effect of the number and ordering of exercise electrocardiographic (ECG) leads when using the maximum value of the ST segment depression/heart rate (ST/HR) hysteresis over a different number of leads for the detection of coronary artery disease (CAD). The study population consisted of 127 patients with CAD and 220 patients with a low likelihood of the disease referred for an exercise test at Tampere University Hospital, Finland. The lead system used was the Mason-Likar modification of the standard 12-lead system, and exercise tests were performed on a bicycle ergometer. The number of leads was studied using lead sets consisting of first 2 leads, then 3 leads, and so on, up to all 12 leads. The criterion for the order of inclusion of the next lead in the new lead set was based on the maximized area under the receiver operating characteristic (ROC) curve for the new lead set. The importance of the number of leads was evaluated by means of three different approaches: ROC analysis; using a fixed partition criterion of 0.01 mV; and using a fixed specificity value of 80%. According to the results, the most powerful diagnostic capacity of an individual lead was in lead V5, and the most deficient diagnostic capacities were in leads aVL and V1. Using the maximum search procedure, it was possible to improve the diagnostic capacity of the ST/HR hysteresis by anything from 4 up to a maximum of 8 leads. After that it started to decrease rapidly. In conclusion, this study suggests that the diagnostic capacity of the ST/HR hysteresis could be improved by increasing the number of leads. However, the selection of leads is of major importance when using the maximum value of the ST/HR hysteresis over the leads in the detection of CAD.

In this study we compared the diagnostic characteristics of the individual exercise electrocardiographic leads, 3 different lead sets comprising standard leads and the effect of the partition value in the detection of coronary artery disease (CAD). The diagnostic variable used was ST-segment depression at peak exercise, and the study population consisted of 101 patients with CAD and 100 patients with a low likelihood of the disease. The lead system used was the Mason-Likar modification of the standard 12-lead system and exercise tests were performed on a bicycle ergometer. The comparisons were performed by means of receiver-operating characteristic analysis and by determining sensitivities at a fixed 95% specificity. These properties, defined here as diagnostic capacity, were the most efficacious in leads I, −aVR, V 4 , V 5 , and V 6 . Diagnostic capacities in leads aVL, aVF, III, V 1 , and V 2 were quite poor; statistical comparisons indicated significant differences between these leads and lead V 5 (p ≤0.0001 in each case). Use of the maximum value of ST-segment depression at peak exercise derived from all 12 leads produced a considerable decrease in the diagnostic capacity of the exercise electrocardiogram compared with lead V 5 . The exclusion of leads aVL, V 1 , and III improved the diagnostic capacity compared with the 12-lead set, but it was still smaller than that of lead V 5 . With use of a lead set with the 5 best leads increased the diagnostic capacity over other lead sets and over any individual lead. Further improvement was noted when a 50% smaller partition value was applied to leads I and −aVR than for the other leads (p = 0.041). In conclusion, this study suggests that use of leads I, −aVR, V 4 , V 5 , and V 6 is the most influential when differentiating between patients with CAD and patients with a low likelihood of disease using peak exercise ST-segment depression. The effective use of leads I and −aVR requires the partition value applied for these leads to be 50% smaller than that used for the lateral precordial leads.

To evaluate the effect of ST-segment measurement point on diagnostic performance of the ST-segment/heart rate (ST/HR) hysteresis, the ST/HR index, and the end-exercise ST-segment depression in the detection of coronary artery disease, we analysed the exercise electrocardiograms of 347 patients using ST-segment depression measured at 0, 20, 40, 60 and 80 ms after the J-point. Of these patients, 127 had and 13 had no significant coronary artery disease according to angiography, 18 had no myocardial perfusion defect according to technetium-99m sestamibi single-photon emission computed tomography, and 189 were clinically 'normal' having low likelihood of coronary artery disease. Comparison of areas under the receiver operating characteristic curves showed that the discriminative capacity of the above diagnostic variables improved systematically up to the ST-segment measurement point of 60 ms after the J-point. As compared to analysis at the J-point (0 ms), the areas based on the 60-ms point were 89 vs. 84% (p=0.0001) for the ST/HR hysteresis, 83 vs. 76% (p

In this comparative cross-sectional study, we evaluated whether a novel computerized diagnostic variable, ST-segment depression/heart rate ( ST HR ) hysteresis, which integrates the efficient ST HR analysis during both the exercise and postexercise recovery phases of the exercise electrocardiography (ECG) test, can detect coronary artery disease more accurately than methods using either exercise or recovery phase alone. The study population comprised 347 clinical patients referred for a routine bicycle exercise ECG test at Tampere University Hospital, Finland. Of these, 127 had angiographically proven coronary artery disease, whereas 13 had no coronary artery disease according to angiography, 18 had no perfusion defect according to technetium-99m sestamibi single-photon emission computed tomography, and 189 were clinically normal with respect to cardiac diseases. For each patient, the maximum values of the ST HR hysteresis, ST HR index, end-exercise ST depression, and recovery ST depression were determined from the Mason-Likar modification of the standard 12-lead exercise electrocardiogram (aVL, aVR, and V1 excluded). The diagnostic performance of these continuous diagnostic variables was compared by means of receiver-operating characteristic analysis. The area under the receiver-operating characteristic curve of the ST HR hysteresis was 89%, which was significantly larger than that of the end-exercise ST depression (76%, p ST HR index (83%, p = 0.0023), indicating superior diagnostic performance of the ST HR hysteresis independent of the partition value selection. In conclusion, computerized analysis of the HR-adjusted ST depression pattern during the exercise phase, integrated with the HR-adjusted ST depression pattern during the recovery phase after exercise, can significantly improve the diagnostic performance and clinical utility of the exercise ECG test for the detection of coronary artery disease.

The ST-segment depression/heart rate ( ST HR ) analysis has been found to improve the diagnostic accuracy of the exercise ECG test in detecting myocardial ischemia. Recently, three different continuous diagnostic variables based on the ST HR analysis have been introduced; the ST HR slope, the ST HR index and the ST HR hysteresis. The latter utilises both the exercise and recovery phases of the exercise ECG test, whereas the two former are based on the exercise phase only. This present article presents a computer program which not only calculates the above three diagnostic variables but also plots the full diagrams of ST-segment depression against heart rate during both exercise and recovery phases for each ECG lead from given ST HR data. The program can be used in the exercise ECG diagnosis of daily clinical practice provided that the ST HR data from the ECG measurement system can be linked to the program. At present, the main purpose of the program is to provide clinical and medical researchers with a practical tool for comprehensive clinical evaluation and development of the ST HR analysis.

To improve the diagnostic power of the exercise electrocardiographic test in detecting myocardial ischemia, the authors have recently developed a diagnostic method called multivariate ST-segment/heart rate (ST/HR) analysis (MUSTA). The goal of this study was to evaluate the validity of MUSTA in different clinical populations and to compare its performance characteristics with ST-segment depression, the ST/HR slope, and the ΔST/HR index in these populations. The computerized exercise electrocardiographic measurements were performed on 1,507 cases, and 382 patients were selected as the study population: 161 with significant coronary artery disease according to coronary angiography and 221 with a low likelihood of coronary artery disease. The diagnostic accuracy of MUSTA in the pooled population was 77.7% (297 out of 382 patients), which was clearly better than the accuracy of 69.6% (266 out of 382 patients) using the conventional ST-segment depression criterion of 0.10 mV in detecting coronary artery disease and exercise-induced myocardial ischemia. According to receiver operating characteristics analysis, MUSTA had significantly better diagnostic power than the other classifiers. These findings suggest that multivariate and compartmental analysis methods like MUSTA can further improve the clinical importance of the exercise electrocardiogram.

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.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.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 β-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.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.

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.

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.

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.

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.

Because sudden cardiac death (SCD) is due to cardiac electrical instability, we postulated that prediction of this mode of death by exercise capacity will be enhanced by combined assessment with T-wave alternans (TWA), an index of repolarization abnormality.The Finnish Cardiovascular Study enrolled consecutive patients (n=2,044) with a routine clinically indicated exercise test. Exercise capacity was measured in metabolic equivalents (METs) and TWA by time-domain modified moving average method.During 47.2+/-12.8-month follow-up (mean+/-SD) 120 patients died; 58 were cardiovascular deaths, and 29 were SCD. In multivariate analysis after adjustment for sex, age, smoking, use of beta-blockers, as well as other common coronary risk factors, the relative risk of patients whose exercise capacity was depressed (MET8) was 8.8 (95% CI 2.0-38.9, P=0.004) for SCD. The combination of low exercise capacity (MET8) and elevated TWA (or =65 microV) yielded relative risks for SCD of 36.1 (6.3-206.0, P0.001), for cardiovascular mortality of 21.1 (6.7-66.2, P0.001), and for all-cause mortality of 7.8 (3.5-17.4, P0.001) over patients with neither factor.Reduced exercise capacity, particularly in combination with heightened TWA, indicating enhanced cardiac electrical instability, powerfully predicts risk for SCD in patients referred for exercise testing.

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 μV. 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 ≥ 20 μV predicted the risk for total and cardiovascular mortality (maximum HR >4.4 at 60 μV, P < 0.02 for both). During exercise, HRs of total and cardiovascular mortality were significant when TWA measured ≥50 μV, with 90 μV 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 ≥60 μV indicated risk for total and cardiovascular mortality, with maximum HR of 3.4 at 70 μV (P = 0.01) for cardiovascular mortality. SCD was strongly predicted by TWA levels ≥60 μV during exercise, with maximum HR of 4.6 at 60 μV (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.

T-wave alternans (TWA) in electrocardiography (ECG) is a marker of cardiac repolarization, the molecular regulation of which is incompletely understood. High TWA and prolonged QT intervals are both associated with ventricular arrhythmias and sudden death. Therefore, we tested the hypothesis of whether the same mutations that influence the QT interval also affect TWA variation. We examined the effect of 3 ion channel gene single nucleotide polymorphisms (SNPs), rs1805127, rs727957 KCNE1, and rs1805124 SCN5A, on TWA during a clinical exercise test. A total of 2008 subjects from the Finnish Cardiovascular Study underwent an exercise test with online ECG recording. TWA was measured by using the time-domain, modified moving average method. Maximum values at rest, during maximal exercise, and during recovery were used as outcome measures in statistical analysis. Moreover, 4-year survival data were collected and ion channel SNPs were determined. TWA was lowest in subjects with the TT genotype of rs1805127 during all phases of the exercise test (RANOVA main effect for genotype, P = 0.018). The result remained significant after adjustment for age, existing coronary heart disease, and β-blocker medication status (RANCOVA, P = 0.035). Of the polymorphisms studied, only rs1805127 had a significant association with mortality ( P = 0.047). The most common G-C haplotype, formed by rs727957 and rs1805127, was associated with TWA (RANOVA, P = 0.007) but not with mortality. The rs1805124 polymorphism was not associated with TWA. The common KCNE1 gene variant rs1805127 is associated with TWA during an exercise test in a Finnish population, which provides additional evidence that KCNE1 genetics may influence cardiac repolarization and cardiovascular mortality.

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. 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. 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), β-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. CHD patients, particularly women, who performed an exercise stress test in a university hospital are suboptimally treated.

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.

The objective of this study was to apply an artificial neural network in computerized exercise ECG analysis for detection of coronary artery disease (CAD). A multilayer perceptron neural network with backpropagation weight updating was developed and validated with a study population of 347 patients. The neural network was fed with 27 input nodes, two hidden nodes and one output node. The input nodes consisted of three exercise ECG variables, the end-exercise ST-segment depression, ST depression/heart rate (ST/HR) index and ST/HR hysteresis, each of which determined from leads I, II, III, aVF, V2, V3, V4, V5, V6. The desired output was O for patients without CAD and I for patients with CAD which was verified by coronary angiography. The performance of the neural network measured as the area under the receiver operating characteristic (ROC) curve was 91.5% The discriminative capacity of the network was greater than provided by any of the 27 single inputs alone. In conclusion, the results suggest that the diagnostic accuracy of the exercise electrocardiographic ST/HR analysis in detection of CAD can be further improved by using neural networks.

The aim of this study is to improve the diagnosis of ischemic heart diseases by developing new synthesized leads. The synthesized leads were constructed in a learning population (60 CAD and 60 low prevalence of heart disease patients) with mathematical optimization. The optimized parameter was the T value of the Student's t test. Three synthesized leads were constructed as a combination of the three (I, II, V2), five (I, II, V2, V5, V6) and eight (I, II and VI-V6) leads. In the control population (100 CAD and 100 non-CAD) the synthesized leads had 80.3%, 79.7% and 78.1% ROC-areas using three, five and eight leads, respectively. ROC-areas of the standard leads ranged from 52.8% (lead III) to 80.9% (lead I). The results of this study indicated that the detection of the ischemia using exercise ECG can be improved by developing the synthesized leads. Additionally, the developed method would give opportunity to more effective localization of the ischemia. The usefulness of the method and the synthesized leads need further studies.

Decreased heart rate variability (HRV) at rest associates with worse prognosis, while a recent study found that greater HRV during an exercise treadmill test was linked to increased risk of death. As a part of the Finnish Cardiovascular Study (FINCAVAS), we evaluated the prognostic power of HRV during bicycle ergometer test in 1876 patients. During the follow-up (mean±SD 47.5±12.8 months) period, there were 101 (5.4%) deaths. Cox regression analysis was performed during four periods (pre-exercise, first and last minute of exercise, and first 2 min of recovery). During the pre-exercise period, greater HRV was clearly linked to better prognosis. During the first minute of exercise, a single HRV parameter was associated with decreased risk. None of the HRV parameters were connected to mortality at peak exercise or during the recovery phase. In conclusion, HRV does not have prognostic value during the physical exertion in an exercise test. However, our results support previous studies, where decreased HRV at rest has been associated with worse prognosis.

Several methods of heart rate–adjusted ST segment (ST/HR) analysis have been suggested to improve the diagnostic accuracy of exercise electrocardiography in the identification of coronary artery disease compared with traditional ST segment analysis. However, no comprehensive comparison of these methods on a lead-by-lead basis in all 12 electrocardographic leads has been reported. This article compares the diagnostic performance of ST/HR hysteresis, ST/HR index, ST segment depression 3 minutes after recovery from exercise, and ST segment depression at peak exercise in a study population of 128 patients with angiographically proved coronary artery disease and 189 patients with a low likelihood of the disease. The methods were determined in each lead of the Mason-Likar modification of the standard 12-lead exercise electrocardiogram for each patient. The ST/HR hysteresis, ST/HR index, ST segment depression 3 minutes after recovery from exercise, and ST segment depression at peak exercise achieved more than 85% area under the receiver-operating characteristic curve in nine, none, three, and one of the 12 standard leads, respectively. The diagnostic performance of ST/HR hysteresis was significantly superior in each lead, with the exception of leads a VL and V 1 . Examination of individual leads in each study method revealed the high diagnostic performance of leads I and –aVR, indicating that the importance of these leads has been undervalued. In conclusion, the results indicate that when traditional ST segment analysis is used for the detection of coronary artery disease, more attention should be paid to the leads chosen for analysis, and lead-specific cut points should be applied. On the other hand, ST/HR hysteresis, which integrates the ST/HR depression of the exercise and recovery phases, seems to be relatively insensitive to the lead selection and significantly increases the diagnostic performance of exercise electrocardiography in the detection of coronary artery disease. (Am Heart J 1997;134:488-94.)

The objective of the study was to investigate a proposed linear relationship between the extent of myocardial ischemic injury and the ST-segment/heart rate (ST/HR) slope by computer simulation of the injury sources arising in exercise electrocardiographic (ECG) tests. The extent and location of the ischemic injury were simulated for both single- and multivessel coronary artery disease by use of an accurate source-volume conductor model which assumes a linear relationship between heart rate and extent of ischemia. The results indicated that in some cases the ST/HR slope in leads II, aVF, and especially V5 may be related to the extent of ischemia. However, the simulations demonstrated that neither the ST-segment deviation nor the ST/HR slope was directly proportional to either the area of the ischemic boundary or the number of vessels occluded. Furthermore, in multivessel coronary artery disease, the temporal and spatial diversity of the generated multiple injury sources distorted the presumed linearity between ST-segment deviation and heart rate. It was concluded that the ST/HR slope and ST-segment deviation of the 12-lead ECG are not able to indicate extent of ischemic injury or number of vessels occluded.

The exercise ECG test is the most widely used method of evaluating myocardial ischemia, but its diagnostic accuracy is only about 70 %. Many studies introducing different diagnostic computerized exercise ECG parameters have been published, but according to the authors' knowledge there is no overall comparison of these parameters. We calculated 52 exercise ECG parameters from the ST-segment value, ST-segment shape and ST-segment/heart rate slope and compared the diagnostic power of these parameters by ROC-analysis. We found that ST-segment/heart rate slope has better diagnostic power than ST-segment depression or ST-segment shape alone. Another result was that the ST-segment shape seemed to be better diagnostic parameter than ST-segment depression when measuring an individual lead. However, further research with larger patient material is needed to get statistically significant differences between the parameters.

SDNN 0.583 (0.29444) 0.699 (0.44344) 0.753 (0.71244) cSDNN 0.763 (-0.35644) 0.631 (-0.1724) 0.500 (0.1794) SD1 0.534 (0.50444) 0.608 (0.20544 0.729 (0.63744) cSD1 0.627 (-0.1754) 0.747 (-0.34444) 0.621 (-0.105) SD2 0.585 (0.27944) 0.740 (0.55744) 0.734 (0.61144) cSD2 0.765 (-0.37144) 0.556 (-0.1634) 0.645 (-0.29844) STD 0.576 (-0.128) 0.626 (-0.035) 0.717 (-0.2554) 4 P b .05. 44 P b .01.

The ST-segment/heart rate (ST/HR) index has been introduced to improve the diagnostic performance of exercise ECG test in detection of coronary artery disease (CAD). The ST/HR index has been described as the overall change (i.e., the difference between the rest and end-exercise stages) in ST depression divided by the overall change in HR. However, in literature the ST/HR index has been defined in two different ways: 1) the ST-elevation (i.e., the negative value of ST depression) at the resting stage is not included and any negative value of ST depression is forced to zero when determining the ST/HR index, or 2) the ST-elevation is included as an negative ST depression and ST/HR index defined purely as the gradient between the ST/HR pairs at the rest and at the end-exercise. In this study, both these ST/HR indices were determined from the study population of 347 exercise tested patients (127 with CAD and 220 references). The computer-determined ST-segment values were defined at 60 ms after J-point. The overall diagnostic performance of the parameters were determined by using the areas under the total receiver operating characteristic (ROC) curves (AUC). The results suggest that including the elevation of the ST-segment in the definition improves the diagnostic accuracy of the ST/HR index. However, it is also important to note that the standard partition value of 1.60 μV/beats/min provide different specificity and sensitivity between the definitions.

The reproducibility of the ST-segment depression against heart rate (ST/HR) hysteresis, ST/HR index, and end-exercise ST depression between the repeated exercise electrocardiographic tests were determined in 61 asymptomatic middle-aged subjects. The findings support the clinical utility of the ST/HR hysteresis, but it is noteworthy that the results also suggest that the magnitude of change in the exercise electrocardiographic variables, which has to be observed to make the clinician confident that a real diagnostic change has occurred, is surprisingly large.

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.The purpose of this study was to analyze heart rate recovery (HRR) in combination with T-wave alternans (TWA) to improve risk assessment.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 rates125 bpm was derived.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.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.