P-Wave Morphology and the Risk of Incident Ischemic Stroke in the Multi-Ethnic Study of Atherosclerosis
Background and Purpose—Emerging data suggest that left atrial disease may cause ischemic stroke in the absence of atrial fibrillation or flutter (AF). If true, this condition may provide a cause for many strokes currently classified as cryptogenic.
Methods—Among 6741 participants in the Multi-Ethnic Study of Atherosclerosis who were free of clinically apparent cerebrovascular or cardiovascular disease (including AF) at baseline, we examined the association between markers of left atrial abnormality on a standard 12-lead ECG—specifically P-wave area, duration, and terminal force in lead V1—and the subsequent risk of ischemic stroke while accounting for incident AF.
Results—During a median follow-up of 8.5 years, 121 participants (1.8%) had a stroke and 541 participants (8.0%) were diagnosed with AF. In Cox proportional hazards models adjusting for potential baseline confounders, P-wave terminal force in lead V1 was more strongly associated with incident stroke (hazard ratio per 1 SD increase, 1.21; 95% confidence interval, 1.02–1.44) than with incident AF (hazard ratio per 1 SD, 1.11; 95% confidence interval, 1.03–1.21). The association between P-wave terminal force in lead V1 and stroke was robust in numerous sensitivity analyses accounting for AF, including analyses that excluded those with any incident AF or modeled any incident AF as having been present from baseline.
Conclusions—We found an association between baseline P-wave morphology and incident stroke even after accounting for AF. This association may reflect an atrial cardiopathy that leads to stroke in the absence of AF.
Atrial ECG signs have been associated with stroke in the absence of atrial fibrillation (AF),1–3 suggesting that atrial disease may promote embolization without manifesting with AF. We have shown that P-wave area and terminal force are associated with stroke risk,4 but did not control for AF, which may mediate the relationship between P-wave morphology and stroke. Therefore, we examined the association between P-wave morphology and stroke while accounting for incident AF.
The Multi-Ethnic Study of Atherosclerosis (MESA) is a prospective cohort study of risk factors for progression from subclinical to clinical cardiovascular disease.5 Institutional review boards at all participating sites approved this study, and all participants provided written, informed consent.
MESA enrolled 6814 men and women aged 45 to 84 years who were free of clinically apparent cerebrovascular or cardiovascular disease, including AF. We excluded 48 participants with missing ECGs, 24 participants receiving warfarin at baseline, and 1 participant whose baseline ECG showed AF.
All sites obtained standard digital 12-lead ECGs at the first and last study visits. All ECGs were obtained using GE MAC 1200 ECG machines (GE, Milwaukee, WI) calibrated at 10 mm/mV with a speed of 25 mm/s. After initial screening for inadequate quality, all ECGs were centrally interpreted at the Wake Forest Epidemiological Cardiology Research Center for abnormalities including AF. The core ECG laboratory automatically measured P-wave areas, amplitudes, and durations using the 12-SL program (version 2001; GE Marquette). P-wave terminal force in lead V1 (PTFV1) is the most widely accepted marker of left atrial abnormality; P-wave area and duration may also be useful.6 Based on this and prior work,4 we prespecified predictor variables as PTFV1, mean and maximum P-wave area, and mean and maximum P-wave duration on the baseline 12-lead ECG. Using standard methodology, we defined PTFV1 as the duration (ms) of the downward deflection (terminal portion) of the P wave in lead V1 multiplied by the absolute value of its amplitude (μV; Figure).7 P-wave areas were a summation of all P-wave amplitudes at respective sampling points multiplied by the sampling interval. P-wave areas were calculated by summing the absolute values of the areas of the upward and downward deflections of the P wave; in other words, the areas of downward deflections were assigned positive rather than negative values.4 To adjust for technical differences in units of measurement and harmonize the 12-SL program’s calculations with other machines, we multiplied P-wave areas by a factor of 19.52.4,8
We accounted for incident AF as a potential mediator and adjusted for the following potential confounders: age, sex, race, hypertension, left ventricular hypertrophy, total cholesterol level, high- and low-density lipoprotein levels, diabetes mellitus, chronic obstructive pulmonary disease, chronic kidney disease, body mass index, and smoking status (see the online-only Data Supplement).
Our primary outcome was an adjudicated diagnosis of ischemic stroke, defined as the rapid onset of a neurological deficit that persisted for >24 hours or until death or was accompanied by report of a clinically relevant infarction on brain imaging, in the absence of a nonvascular cause or brain hemorrhage.
We excluded P-wave measurements >99.9th percentile as outliers. Using separate Cox proportional hazards models for each P-wave predictor variable, we standardized these variables around their means and reported their associations with stroke in 1 SD increments. To explore whether AF mediated associations between P-wave morphology and stroke, we compared models with and without a time-varying covariate for incident AF and performed multiple sensitivity analyses accounting for AF in other ways (see the online-only Data Supplement).
The 6741 eligible participants were followed for a median of 8.5 years (interquartile range, 7.7–8.6). Ischemic stroke occurred in 121 participants (1.8%), and 541 participants (8.0%) were diagnosed with AF. Participants with stroke were older, had more vascular risk factors, and manifested significantly higher PTFV1 (Table 1; Table I in the online-only Data Supplement).
In Cox proportional hazards analysis, PTFV1 was more strongly associated with incident stroke (hazard ratio per 1 SD increase, 1.21; 95% confidence interval, 1.02–1.44; Table 2) than with incident AF (hazard ratio per 1 SD, 1.11; 95% confidence interval, 1.03–1.21). The association between PTFV1 and stroke was similar when we adjusted for incident AF (hazard ratio per 1 SD, 1.21; 95% confidence interval, 1.02–1.44) or removed the AF covariate from our model (hazard ratio per 1 SD, 1.22; 95% confidence interval, 1.03–1.45). The association held true in numerous sensitivity analyses accounting for AF in other ways, such as excluding those with any incident AF or modeling any incident AF as having been present from baseline (see the online-only Data Supplement).
In a prospective cohort study, we found a significant association between PTFV1 and subsequent ischemic stroke. This association persisted in participants without any AF during the study period, suggesting that atrial disease may cause stroke even in the absence of AF. Prior studies have suggested that atrial ECG markers besides AF may be associated with stroke1,2,4,9; this study represents an important advance because it supports an association between a simple 12-lead ECG measure and stroke and demonstrates that AF does not mediate this association. Instead, elevated PTFV1 may reflect an underlying atrial cardiopathy that predisposes to embolization even in the absence of AF.
This study has several limitations. First, we may have missed subclinical AF that could have mediated the association between PTFV1 and stroke. However, PTFV1 was less strongly associated with AF than with stroke, which would not be expected if AF were an important mediator. Second, we were unable to examine associations with embolic-appearing or cryptogenic stroke specifically. Third, we lacked power to assess interactions between ethnicity and P-wave morphology in relation to stroke risk.4 Fourth, we lacked imaging of the left atrium. However, P-wave measurements reflect important aspects of atrial disease—such as elevated filling pressures, poor conduction, and fibrosis—that are not necessarily captured by imaging data.6 Further work will be necessary to fully delineate the ECG, imaging, and biomarker characteristics of atrial cardiopathy as it relates to stroke risk. Eventually, a combination of such markers may better identify the risk of left atrial embolization than simply the presence of AF, which can be difficult to screen for and, as we have shown, may be an imperfect marker of risk.
Sources of Funding
This analysis was supported by grant K23NS082367 (H. Kamel) from the National Institute of Neurological Disorders and Stroke. Additionally, this research was supported by contracts N01HC95159 through N01HC95169 from the National Heart, Lung, and Blood Institute and by grants UL1RR024156 and UL1RR025005 from the National Center for Research Resources. The authors thank the other investigators, staff, and participants of the Multi-Ethnic Study of Atherosclerosis (MESA) for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org.
Dr Kamel reports having served on a medical advisory board and serving as a lecturer for Genentech, Inc on the topic of alteplase for the acute treatment of ischemic stroke. Dr Nazarian reports serving as a scientific advisor to and principal investigator for research funding awarded to Johns Hopkins University by Biosense Webster, Inc on the topic of imaging and ablation for atrial fibrillation. Dr Okin reports serving on a medical advisory board for GE Medical Systems on the topic of new product development.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.114.006364/-/DC1.
- Received June 3, 2014.
- Accepted July 8, 2014.
- © 2014 American Heart Association, Inc.
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