Rami Lehtinen

Accurate detection of coronary artery disease by integrated analysis of the ST-segment depression/heart rate patterns during the exercise and recovery phases of the exercise electrocardiography test

In this comparative cross-sectional study, we evaluated whether a novel computerized diagnostic variable, ST-segment depression/heart rate 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 < or = 0.0001), recovery ST depression (84%, p = 0.0063), or 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.

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 parameters capacity to evaluate the risk for total and cardiovascular mortality and sudden cardiac death (SCD).

Gender and effects of a common genetic variant in the NOS1 regulator NOS1AP on cardiac repolarization in 3761 individuals from two independent populations

BACKGROUND 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. METHODS 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. RESULTS 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). CONCLUSIONS 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.

Post-exercise assessment of cardiac repolarization alternans in patients with coronary artery disease using the modified moving average method.

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 microV) and a specific, greater predictive accuracy MMA cutpoint (60 microV) 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-microV cutpoint (87% sensitivity) appears to be most suitable in higher-risk patients, whereas the 60-microV 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).

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.

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

BackgroundThe 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 designAll 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.DiscussionFINCAVAS 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.

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.

The effect of lead selection on traditional and heart rate–adjusted ST segment analysis in the detection of coronary artery disease during exercise testing

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 electrocardiographic leads has been reported. This article compares the diagnostic performances 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 V1. 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.

Correct Utilization of Exercise Electrocardiographic Leads in Differentiation of Men With Coronary Artery Disease from Patients With a Low Likelihood of Coronary Artery Disease Using Peak Exercise ST-Segment Depression

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, V4, V5, and V6. Diagnostic capacities in leads aVL, aVF, III, V1, and V2 were quite poor; statistical comparisons indicated significant differences between these leads and lead V5 (p < or = 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 V5. The exclusion of leads aVL, V1, and III improved the diagnostic capacity compared with the 12-lead set, but it was still smaller than that of lead V5. 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, V4, V5, and V6 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.

Detection of coronary artery disease using maximum value of ST/HR hysteresis over different number of leads

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.