Pentti M. Rautaharju

Inflammation as a Risk Factor for Atrial Fibrillation

Background—The presence of systemic inflammation determined by elevations in C-reactive protein (CRP) has been associated with persistence of atrial fibrillation (AF). The relationship between CRP and prediction of AF has not been studied in a large population-based cohort. Methods and Results—CRP measurement and cardiovascular assessment were performed at baseline in 5806 subjects enrolled in the Cardiovascular Health Study. Patients were followed up for a mean of 6.9±1.6 (median 7.8) years. AF was identified by self-reported history and ECGs at baseline and by ECGs and hospital discharge diagnoses at follow-up. Univariate and multivariate analyses were used to assess CRP as a predictor of baseline and future development of AF. At baseline, 315 subjects (5%) had AF. Compared with subjects in the first CRP quartile (<0.97 mg/L), subjects in the fourth quartile (>3.41 mg/L) had more AF (7.4% versus 3.7%, adjusted OR 1.8, 95% CI 1.2 to 2.5; P =0.002). Of 5491 subjects without AF at baseline, 897 (16%) developed AF during follow-up. Baseline CRP predicted higher risk for developing future AF (fourth versus first quartile adjusted hazard ratio 1.31, 95% CI 1.08 to 1.58; P =0.005). When treated as a continuous variable, elevated CRP predicted increased risk for developing future AF (adjusted hazard ratio for 1-SD increase, 1.24; 95% CI 1.11 to 1.40; P <0.001). Conclusions—CRP is not only associated with the presence of AF but may also predict patients at increased risk for future development of AF.

The Electrocardiogram in Population Studies A Classification System

Information now available about the prevalence and incidence of coronary heart disease is seriously deficient because of the lack of standardized and objective methods of collection, tabulation, interpretation, and reporting of survey data. Chief reliance in the objective diagnosis of coronary heart disease rests on the electrocardiogram, a crucial tool in population studies. A classification system for the electrocardiogram in epidemiologic studies has been developed, tested, and herein presented. It is adapted to the usual clinical reading technics of the electrocardiographer. It embodies criteria widely employed and of diagnostic and prognostic import, but no stipulations about interpretation are made. The system permits more valid comparisons of data on heart disease between populations. It is susceptible to modern methods of data processing.

Association of cardiac autonomic function and the development of hypertension : The ARIC study

To relate cardiac autonomic function measured by heart rate variability (HRV) with prevalent and incident hypertension at the population level, the authors examined a stratified random sample of 2,061 examinees from the biracial Atherosclerosis Risk in Communities (ARIC) cohort. Baseline, supine, resting beat-to-beat heart rate data were collected. High frequency (HF, 0.15 to 0.35 Hz), low frequency (LF, 0.025 to 0.15 Hz) spectral powers, and LF/HF ratio, estimated from spectral analysis, and standard deviation of all normal RR intervals (SDNN), calculated from time domain analysis, were used as the conventional indices of cardiac autonomic function. From this sample, 650 prevalent hypertensives were identified. Of those normotensive at baseline (n = 1,338), 64 participants developed hypertension during 3 years of follow-up. In the cross-sectional analysis, the adjusted geometric means of HF were 1.26, 1.20, and 1.00 (beat/min)2 for normotensives, untreated hypertensives, and treated hypertensives, respectively; means of LF were 3.24, 3.26, and 2.58; means of LF/HF ratio were 2.57, 2.70, and 2.56; and means of SDNN were 39, 34, and 35 (ms) respectively. In the prospective analysis, a statistically significant, graded inverse association between baseline HF and the risk of incident hypertension was observed: the adjusted incident odds ratios (95% CI) were 1.00, 1.46 (0.61, 3.46), 1.50 (0.65, 3.50) and 2.44 (1.15, 5.20) from the highest to the lowest quartile of HF. No clear pattern of association was observed for LF. Significant trends of association for LF/HF and SDNN and incident hypertension were also found. These results suggest that cardiac autonomic function is associated with prevalent hypertension, and that reduced vagal function and the imbalance of sympatho-vagal function are associated with the risk of developing hypertension.

The novacode criteria for classification of ECG abnormalities and their clinically significant progression and regression

Electrocardiographic (ECG) manifestations of clinical and subclinical cardiovascular disease are used as an important component in the evaluation of clinical trials, and there is an increasing demand for well-defined criteria for clinically significant evolution of ECG abnormalities. The Novacode ECG classification system provides a comprehensive hierarchical set of criteria for prevalent ECG abnormalities and for clinically significant serial ECG changes, both adverse and favorable, as a response to pharmacologic, surgical, and other interventions. These criteria are used to grade Q wave and ischemic abnormalities in order to achieve stable classification of both prevalent and incident myocardial infarctions by minimizing false classifications due to clinically insignificant ECG variations. This approach differs from the traditional Minnesota Code classification system, in which incident events are determined by changes in classification categories, with the application of additional elaborate validation rules to exclude frequent false classifications. Novacode hierarchy is so structured that for each abnormality, a general class is first determined with the simplest possible classification criteria and more specific abnormality subgroups are then classified with more elaborate criteria. This approach will satisfy differing needs of clinical trials for detail in classification. Explicit definition of ECG variables and condition statements for the classification criteria facilitate implementation of the Novacode with computer ECG programs.

Relation between electrocardiography and echocardiography for left ventricular mass in mild systemic hypertension (results from Treatment of Mild Hypertension Study).

Clinical recognition of hypertensive cardiac involvement depends primarily on use of noninvasive methods. The performance of 8 electrocardiographic (ECG) criteria sets were compared with an echocardiographic standard in the treatment of Mild Hypertension Study. Electrocardiograms were computer processed to define the following ECG criteria sets: (1) Casale/Devereux, (2) Cornell product, (3) Cornell voltage, (4) 12-lead voltage product, (5) sum of 12-lead voltage, (6) Rautaharju, (7) Sokolow-Lyon, and (8) Romhilt-Estes. Echocardiographic left ventricular (LV) mass index was calculated by using the Penn convention on a biracial population of 834 men and women. Correlations between ECG and echocardiographic LV mass index were modest (<0.40). ECG-LV hypertrophy sensitivity at 95% specificity was < 34%. The Casale/Devereux ECG criteria showed the highest average sensitivity (17%) at 95% specificity for all race-sex groups. Whites had significantly higher correlation values than blacks. ECG correlations with LV mass index were consistently improved by including systolic blood pressure and body mass index. ECG criteria sets appear to be optimized for white men. The study findings confirm the poor ECG sensitivity and correlation with echocardiographic LV mass and suggest: (1) further refinement of ECG criteria alone in white men is unlikely to improve its relationship with LV mass; and (2) combining the electrocardiogram with other non-ECG variables or noninvasive measurements offers the best strategy for improving ECG sensitivity and its prognostic value.

Linearly scaled, rate-invariant normal limits for QT interval: eight decades of incorrect application of power functions.

Rate‐Invariant Normal Limits for QT Interval. Introduction: Normal limits for QT traditionally are derived as mean ± 2*SD, with rate adjustment done by dividing QT values by power functions such as RR1/2 (proportional scaling).

Usefulness of T-axis deviation as an independent risk indicator for incident cardiac events in older men and women free from coronary heart disease (the Cardiovascular Health Study).

T-axis shift has been reported to be an indicator of increased mortality risk. We evaluated the association of spatial T-axis deviation with incident coronary heart disease (CHD) events in older men and women free from clinically overt CHD. Spatial T-axis deviation was measured from the standard 12-lead electrocardiogram of a subgroup of 4,173 subjects considered free of CHD at baseline in the Cardiovascular Health Study, a prospective cohort study of risk factors for CHD and stroke in older men and women. Cox regression analysis was used to evaluate the association of altered repolarization with the risk of incident CHD events. The prevalence of marked T-axis deviation (> or =45 degrees ) was 12%. During the median follow-up of 7.4 years, there were 161 CHD deaths, 743 deaths from all causes, and 679 incident CHD events. Adjusting for demographic and clinical risk factors, including other electrocardiographic abnormalities, there was a nearly twofold excess risk of CHD death, and approximately a 50% excess risk of incident CHD and all-cause mortality for those with marked T-axis deviation. From other electrocardiographic abnormalities, only QT prolongation was associated with excess risk for incident CHD comparable to that for abnormal T-axis deviation. These results suggest that T-axis deviation is an easily quantified marker for subclinical disease and an independent indicator for the risk of incident CHD events in older men and women free of CHD.

A standardized procedure for locating and documenting ECG chest electrode positions : Consideration of the effect of breast tissue on ECG amplitudes in women

Continuing uncertainty exists about standardized procedures for the placement of electrocardiographic (ECG) chest electrodes, technical variability being the largest error source for short-term variations in amplitudes and waveforms of the chest lead ECGs. To avoid presumed attenuation of ECG amplitudes by abundant breast tissue, anterolateral chest electrodes in women are often placed under the breasts and too low. There is also considerable uncertainty about locating the midclavicular line and the V4 electrode, particularly in obese persons and in women. We examined the effect of breast tissue protuberance on ECG amplitudes using ECG and anthropometric data on 6,814 women included in the Atherosclerosis Research in Communities Study (ARIC). The R wave amplitudes in anterolateral chest leads and the Sokolow-Lyon voltage decreased (P < .001 for all), and RaVL and the Cornell voltage increased significantly with increasing breast protuberance (P < .001 for all). However, these effects were small (15 microV or less for each 1-cm increment in breast protuberance), and R2 values were less than .01, indicating that breast protuberance alone explained less than 1% of ECG amplitude variations. When chest size and breast protuberance estimates were entered simultaneously into a multivariate regression model, chest size appeared to dominate, and model R2 values increased for positive associations with RaVL (R2 = .12) and the Cornell voltage (R2 = .04). Combined model R2 values remained < or =.01 for all other ECG amplitudes. A detailed step-by-step standardized electrode placement procedure was formulated. Because of the difficulties encountered in locating the left midclavicular line by visual inspection, we introduced well-defined procedures for identification and documentation of lateral chest electrode placement locations as a quality control method for clinical trials. Population data from the Third National Health and Nutrition Survey on the distributions by sex and race of chest electrode V4 and V6 locations and anthropometric data on chest size and shape are presented in order to facilitate evaluation of the comparability of electrode placement procedures in various studies and for quality control in clinical trials. It is concluded that standardized procedures to document chest electrode placement locations are feasible. Breast tissue appears to have a practically negligible effect on ECG amplitudes, and in women, the placement of chest electrodes on the breast rather than under the breast is recommended in order to facilitate the precision of electrode placement at the correct horizontal level and at the correct lateral positions.

Relation of systemic blood pressure, left ventricular mass, insulin sensitivity, and coronary artery disease to QT interval duration in nondiabetic and type 2 diabetic subjects

A prolonged QT interval has been identified as a risk factor for cardiovascular disease; however, knowledge about etiologic factors is limited. We studied determinants of QT interval duration in the Insulin Resistance Atherosclerosis Study, a large, triethnic population (n = 1,577) with varying degrees of glucose tolerance. In particular, we sought to investigate the relation of QT interval with blood pressure (BP), left ventricular (LV) mass, estimated using electrocardiographic criteria, and insulin sensitivity, directly measured by a frequently sampled intravenous glucose tolerance test. QT interval was measured electronically on electrocardiograms at rest and corrected for heart rate using standard equations. The QT interval was related to various components of the insulin resistance syndrome, including BP and insulin sensitivity. Multivariate analyses showed that BP and LV mass were the main determinants of the QT interval in diabetic and nondiabetic subjects. Additionally, prevalent coronary artery disease was related to the QT interval in subjects with newly diagnosed diabetes. In conclusion, we found that BP and LV mass were the strongest and most consistent determinants of the QT interval in nondiabetic and diabetic subjects. Additional factors potentially contributing to QT interval prolongation in diabetic patients include insulin sensitivity and prevalent coronary artery disease.

Utility of New Electrocardiographic Models for Left Ventricular Mass in Older Adults

Several multivariate statistical models have recently been introduced for estimation of left ventricular mass from standard 12-lead electrocardiographic measurements. The validity of these algorithms has not been adequately evaluated. The objective of this investigation was to compare the associations between echocardiographic and electrocardiographic left ventricular mass values with clinical and subclinical indexes of coronary heart disease. The evaluation was performed with participants of the Cardiovascular Health Study, a population-based sample of 5201 men and women aged 65 years and older. Echocardiographic M-mode measurements of left ventricular mass were performed from videotape recordings with the use of a strictly standardized protocol. Electrocardiographic algorithms of the Novacode program and new algorithms derived from the Cardiovascular Health Study population were used for left ventricular mass prediction. Echocardiographic and electrocardiographic determinations of left ventricular mass were technically successful in 3410 (65.6%) and 5013 (96.4%) participants, respectively. The Novacode model overestimated echocardiographic left ventricular mass. Compared with the Novacode model, the new Cardiovascular Health Study electrocardiographic model, which includes adjustment for body weight, eliminated left ventricular mass prediction bias and improved the correlation between echocardiographic and electrocardiographic left ventricular mass from .33 to .54 in women and from .46 to .51 in men. Echocardiographic and electrocardiographic models both demonstrated similar and about equally strong associations with overt and subclinical disease and with risk factors for left ventricular hypertrophy. These observations demonstrate the potential utility of electrocardiographic models for left ventricular mass estimation.