Explaining the inconsistent associations of PR interval with mortality: The role of P-duration contribution to the length of PR interval
Introduction
There is a strongly emerging interest in using the electrocardiographic (ECG) PR interval as a predictor for adverse outcomes, including atrial fibrillation (AF), stroke, pacemaker implantation, and mortality.1, 2, 3, 4, 5, 6, 7, 8 The regulatory agencies have also become concerned about PR-interval prolongation resulting from cardioactive drugs.9, 10 This renewed interest in PR interval and the idea that it could serve as a simple ECG marker with potential prognostic value have been further emphasized by results from the Genome-Wide Association (GWAS) studies, which showed that the genetic background of PR interval overlaps with that of many cardiovascular diseases.11, 12, 13 In addition, PR interval has been linked to several cardiovascular risk factors.14, 15, 16
Notably, however, inconsistencies in the reported associations of prolonged PR interval with adverse outcomes started to emerge after the results were validated in different populations. In the Framingham Heart Study, prolonged PR interval was associated with an approximately 40% increase in all-cause mortality.7 However, reports from the Third National Health and Nutrition Examination Survey (NHANES-III),8 the Health, Aging, and Body Composition Study (Health ABC),6 and the Finnish Social Insurance Institution's Coronary Heart Disease Study (CHD Study)5 showed no significant associations between prolonged PR interval and all-cause mortality. Similar conflicting results have been reported regarding the usefulness of prolonged PR interval as a predictor for AF. Currently, prolonged PR interval is one of the components of the Framingham AF risk score,2 which was further validated in the Age, Gene/Environment Susceptibility-Reykjavik Study (AGES) and the Cardiovascular Health Study (CHS).3 However, prolonged PR interval did not add to the prediction of AF in the Atherosclerosis Risk in Communities (ARIC) study,17 and paradoxically short PR interval was even more predictive of AF than prolonged PR interval in a meta-analysis using data from multiple U.S. and European cohorts.4
At this time, there is no clear explanation for these inconsistencies and paradoxical associations of PR interval. Although racial and gender differences in the distribution of PR interval exist,1, 18, 19 these differences are not reflected as differences in the magnitude of associations of PR interval with outcomes.1, 3, 4, 6, 8, 17 That is to say, PR-interval associations with adverse outcomes were consistent (whether positive or negative) across all subgroups of races/ethnicities and sexes (i.e., no interaction by race/ethnicity or sex). Hence, the conflicting predictive ability of PR interval in different studies cannot be simply explained by differences in the demographic structure of these studies.
In contrast to PR interval, prolonged P duration (which is part of PR interval) has been consistently associated with adverse outcomes,1, 6, 8, 20 yet racial and gender differences in the distribution of P duration have been reported in a similar fashion as PR interval.1, 18 Therefore, we hypothesized that PR-interval associations with adverse outcomes are dependent on the level of contribution of P duration to the overall length of PR interval, a contribution that varies across populations. We tested our hypothesis using data from NHANES III.
Section snippets
Study population
Participant characteristics, ECG methodology, and ascertainment of mortality in the NHANES study have been reported elsewhere.8 Briefly, NHANES is a periodic survey of a representative sample of the civilian noninstitutionalized U.S. population. Its principal aim is to determine estimates of disease prevalence and health status of the U.S. population. The National Center for Health Statistics of the Centers for Disease Control and Prevention institutional review board approved the protocol for
Results
This analysis included 7501 participants (age 59.3 ± 13.3 years, 53% female, 51% nonwhites). Mean PR interval, P duration, and PR segment were 164.5 ± 27.1 ms, 112.4 ± 13.4 ms, and 52.2 ± 22.2 ms, respectively. The contribution of P duration to length of the PR interval ranged from 30% to 90% (median 70%). P/PR ratio was highest (i.e., more contribution of P duration to PR interval) in individuals with short PR interval and trended downward through normal and prolonged PR interval, respectively
Discussion
In this analysis from the NHANES III, we sought to provide an explanation for the emerging inconsistent and paradoxical associations of PR interval with adverse outcome. We hypothesized that PR-interval associations with adverse outcomes are dependent on the level of contribution of P duration to the overall length of PR interval, a contribution that varies across populations. We quantified the contribution of P duration to the length of PR interval using P duration/PR interval ratio * 100 as a
Conclusion
We showed that PR-interval association with mortality is dictated by the level of contribution of P duration to its length, a contribution that has a wide range and hence would vary across populations. This could explain the inconsistent results of the relationship between PR interval and adverse outcomes and calls for caution in using PR interval as a component in risk prediction models. Replicating these results in an independent population and extending the outcome to include AF are
References (25)
- et al.
Development of a risk score for atrial fibrillation (Framingham Heart Study): a community-based cohort study
Lancet
(2009) - et al.
P wave duration is associated with cardiovascular and all-cause mortality outcomes: the National Health and Nutrition Examination Survey
Heart Rhythm
(2011) - et al.
A clinical risk score for atrial fibrillation in a biracial prospective cohort (from the Atherosclerosis Risk in Communities [ARIC] study)
Am J Cardiol
(2011) - et al.
Heart rate adjustment of PR interval in middle-aged and older adults
J Electrocardiol
(2012) - et al.
Risk of atrial fibrillation as a function of the electrocardiographic PR interval: results from the Copenhagen ECG Study
Heart Rhythm
(2013) - et al.
Reverse remodeling of the atria after treatment of chronic stretch in humans: implications for the atrial fibrillation substrate
J Am Coll Cardiol
(2010) - et al.
Ethnic distribution of electrocardiographic predictors of atrial fibrillation and its impact on understanding the ethnic distribution of ischemic stroke in the Atherosclerosis Risk in Communities Study (ARIC)
Stroke
(2009) - et al.
Validation of an atrial fibrillation risk algorithm in whites and African Americans
Arch Intern Med
(2010) - et al.
Simple risk model predicts incidence of atrial fibrillation in a racially and geographically diverse population: the CHARGE-AF Consortium
J Am Heart Assoc
(2013) - et al.
Prognostic significance of prolonged PR-interval in the general population
Eur Heart J
(2013 May 14)
Electrocardiographic PR-interval and adverse outcomes in older adults: the Health, Aging, and Body Composition Study
Circ Arrhythm Electrophysiol
Long-term outcomes in individuals with prolonged PR-interval or first-degree atrioventricular block
JAMA
Cited by (43)
PR prolongation as a predictor of atrial fibrillation onset: A state-of-the-art review
2024, Current Problems in CardiologyAssociation between cardiac conduction block and cardiovascular disease and all-cause mortality: The kailuan study
2024, International Journal of CardiologyRelationship between abnormal P-wave axis, chronic obstructive pulmonary disease and mortality in the general population
2023, Journal of ElectrocardiologyAnalysis and classification of heart rate using CatBoost feature ranking model
2021, Biomedical Signal Processing and ControlCitation Excerpt :The selection of training and testing data set was random as manual selection makes the model more error-prone and time-consuming [26]. The training and testing dataset were shuffled to validate the extracted features because the machine learning algorithms depend on the input features and also to check the robustness of the considered machine learning classifiers [27–29]. This work's only hardware requirement is to record the ECG signals using EDAN SE 1010 PC ECG instrument.
Prognostic value of Goldberger's electrocardiographic criteria for left ventricular dysfunction
2021, Journal of ElectrocardiologyCitation Excerpt :Therefore, the purpose of this study was to examine the risk of all-cause and cardiovascular mortality associated with Goldberger's triad in the general population using data from the Third National Health and Nutrition Examination (NHANES III) [13]. The design and conduct of NHANES III has been previously reported [14,15]. Briefly, NHANES III is a periodic survey conducted to assess disease prevalence and health status of the United States population.
Prevalence of P wave dispersion and interatrial block in patients with systolic heart failure and their relationship with functional status, hospitalization and one year mortality
2018, Egyptian Heart JournalCitation Excerpt :However, there are conflicting data and uncertainty in literature regarding the association of prolonged PR interval with morbidity and mortality.3–5 A study conducted on 2541 deaths retrospectively reported that the association between PR interval and mortality was dependent on the level of P-wave duration, not the PR segment (P < 0.008).3 Many other studies concluded that no increased mortality among individuals with prolonged PR interval (>200 ms), whereas it was the contribution of the P-wave duration that was associated with morbidity and mortality.4,5