Epidemiology and Outcomes associated with PR Prolongation

Abstract

PR prolongation (first-degree AV block) is defined primarily as delayed conduction through the atrioventricular (AV) node, but can also signify delayed electrical impulse propagation through any part of the specialized conduction system. The prevalence of PR prolongation ranges from 1-5% in patients younger than 50 years of age, with increasing prevalence, particularly after the sixth decade of life and in patients with organic heart disease. While classical studies suggest no adverse associations linked to PR prolongation, contemporary studies have documented increased risk of atrial arrhythmias, heart failure, and mortality in patients with PR prolongation. Future studies are needed to risk stratify elderly patients with PR prolongation who may be at increased risk of adverse outcomes and determine the optimal monitoring strategy for future follow-up.

Introduction/History/Definitions/Background

The PR interval reflects the time of electrical impulse propagation from the onset of atrial depolarization to the onset of ventricular depolarization and represents timing from the onset of the P wave to the start of the QRS complex on the surface electrocardiogram. The normal PR interval ranges from 0.12-0.20 seconds (120-200ms) with the upper limit of normal defined as a time interval of 0.20-0.22 second.¹ Most PR prolongation is due to delayed impulse conduction through the atrioventricular node, although conduction delay in the atrium and His-Purkinje system can contribute to PR prolongation.

The etiologies of PR prolongation include organic heart disease from ischemia, inflammatory and infiltrative diseases, medications, autonomic influences, and collagen vascular disorders as well as idiopathic causes in patients without a history of cardiovascular disease. While PR prolongation has classically been considered a benign finding, many of the original studies analyzing outcomes in patients with PR prolongation are confounded by selection bias including enrollment of primarily healthy, young male subjects with low burden of comorbid medical conditions.^2-6 More contemporary analyses have linked PR prolongation with adverse outcomes including progression of conduction system disease, increased risk of atrial remodeling and atrial arrhythmias^7,8, and increased risk of all-cause mortality.⁹

This review aims to discuss the epidemiology and adverse outcomes associated with PR prolongation as well as the impact of PR prolongation in specific populations including patients with coronary artery disease, heart failure with reduced ejection fraction, and neuromuscular disease.

Discussion

Epidemiology of PR prolongation

Epidemiologic data on the incidence of PR prolongation has been reported in classical analyses, which primarily analyzed younger, male populations with a low burden of co-morbid medical illness. Mymin and colleagues presented 30 year follow-up data on 3983 healthy men enrolled in the Manitoba cohort.³ The incidence of PR prolongation increased with age, and after adjustment for heart rate, was 1.13 per 1000 person-years over the entire study period. Hiss and colleagues documented PR prolongation of 0.21 and 0.22 seconds in approximately two per 1000 records. Similar to Mymin and colleagues, the frequency of longer PR intervals was noted in older participants.¹⁰ In a second study by Hiss and colleagues analyzing the electrocardiographic findings in 122,043 individuals, 802 electrocardiograms (6.5 per thousand) were noted to have a PR interval greater than 0.20 seconds.² There was no significant difference in the incidence rate in subjects less than 50 years of age; the proportion of subjects older than 50 years of age were small and precluded a calculation of incidence and prevalence. Packard and colleagues analyzed electrocardiograms from 1000 young health aviators (mean age 23.7 years) with follow-up after 10-12 year from baseline recordings. The number of electrocardiograms demonstrating PR prolongation was low (N=11/1000) overall and as such an incidence rate could was not calculated.⁴ In a similar cohort of healthy young men, Erikssen et al. analyzed changes in the PR interval from baseline to 7 years follow-up in males with no history of cardiovascular disease. No differences were seen in the prevalence of PR prolongation at baseline and follow-up (5.4%)(Table 1).¹¹

Table 1.

Epidemiologic Studies of PR prolongation

	Cohort Location	Study Design; Year	Participants	Findings
Du et al.16	Rural areas of Liaoning Province, China	Cross-sectional study from September 2017 to May 2018	10,926 participants aged ≥40 years (85.3% of those who were eligible)	Prevalence of first-degree AV block (> 0.20s) was 3.4% (95% confidence interval:3.0-3.8%)
Erikssen et al.11	Male employees in five major companies and governmental agencies in Oslo, Norway	Cross sectional cardiovascular survey. Follow-up 7 years	1832 health men aged 40-59	Baseline and follow-up prevalence of prolonged PR (≥0.22 seconds)
Hiss et al.2	United States Air Force School of Aerospace Medicine, Headquarters Aerospace Medical Division	Prospective cohort study	122,043 healthy male subjects. Predominantly aviators and cadet applicants	6.5 electrocardiograms per thousand (N=802/122,043) were noted to have a PR interval greater than 0.20 seconds.
Hiss et al.37	United States Air Force School of Aerospace Medicine, Headquarters Aerospace Medical Division	Cross sectional survey	67,37 electrocardiograms in asymptomatic subjects	Incidence of first-degree AV block in the total surveyed population was 5.2 per thousand and did not change significantly in different age groups
Mymin et al.3	Manitoba Province, Canada	Population based cohort with 30-year longitudinal starting on July 1st, 1948	3983 health men enrolled in the Manitoba cohort	The incidence of PR prolongation increased with age, and after adjustment for heart rate, was 1.13 per 1000 person years
Nikolaidou et al.38	Consecutive patients with suspected heart failure referred to a community clinic in the United Kingdom between 2001-2014	Prospective cohort study; 2017	1420 patients with HeFREF; 1094 HeFNEF; 1150 no HeF	The prevalence of first-degree heart block (heart rate corrected PR interval > 200ms) was higher in patients with heart failure (21% HeFRF, 20% HeFNEF, 9% without heart failure).
Packard et al.4	United States Naval School of Aviation Medicine, Naval Air Station, Pensacola, Florida	Prospective cohort study; 10 year follow-up. Published in 1951	1000 young health aviators from July 1940 to March 1942	No formal incidence or prevalence calculation was made but 11/1000 electrograms demonstrated PR prolongation (PR> 0.2 seconds)
Perlman et al.5	Prospective Epidemiology study of chronic disease including cardiovascular disease in Tecumseh, Michigan	Prospective cohort study ;1971	N=4678	PR prolongation was detected in 95 of 4678 electrocardiograms in participants greater than the age of 20 PR prolongation was not observed in participants less than 20 years of age Among the 95 persons with PR prolongation, there was no excess incidence of death or new events of coronary heart disease
Upshaw Jr. et al.15	Caucasian and African patients (inpatients, outpatients, and the emergency department) attending Piedmont Hospital in Atlanta, GA	Prospective cohort study; 2004	N=2123	First-degree atrioventricular block was more prevalent in African-American patients compared to Caucasian patients. The prevalence of first-degree AV block began to increase at age 50 in both groups

Contemporary analyses from community based cohorts have provided epidemiological data of PR prolongation, taking into account real world populations that vary by race/ethnicity, socioeconomic status, and burden of comorbid medical disease. Perlman and colleagues performed an epidemiologic study of PR prolongation in Tecumseh, Michigan; PR prolongation was defined as 0.22 seconds or longer.⁵ PR prolongation was detected in 95 of 4678 participants (2.0%) with similar rates between males and females. The prevalence rates of PR prolongation increased significantly after the sixth decade of life. The prevalence of organic heart disease was 20% (N=19/95) with the majority of these patients being older than 60 years of age. Kwok and colleagues performed a systematic review and meta-analysis of studies on PR prolongation and adverse cardiovascular outcomes. A total of 400,750 participants from 14 studies conducted in the United States, Europe, and Asia between the years of 1972 and 2011.¹² The prevalence of PR prolongation ranged between 2% to 14% across seven studies with a mean prevalence of 7%. The definition of PR prolongation varied across studies from > 196ms to > 220ms.

Racial and ethnic differences in PR interval measurements have been documented in community cohorts. Santhanakrishnan and colleagues documented racial differences in electrocardiographic characteristics from Asians and Whites from two large community-based cohorts: Whites from the Framingham Heart Study and Asians from the Singapore Longitudinal Aging Study. Longer PR intervals were documented in Asian men and women compared to White men and women (β estimate 5.0±1.4ms and 6.6±0.9ms, both P<0.0006) after adjustment for potential confounders including age, blood pressure, antihypertensive therapy, heart rate, body mass index, and diabetes mellitus.¹³ In a study of racial and ethnic electrocardiogram predictors of atrial fibrillation and its impact on ischemic stroke in the Atherosclerosis Risk in Communities study, Blacks demonstrated statistically longer PR intervals than whites (defined as longer than the 95^th percentile in the entire study population) in both the unadjusted and adjusted analysis.¹⁴ In a comparison of the prevalence of first-degree atrioventricular block in African-American and Caucasian, Upshaw and colleagues analyzed 2123 electrocardiograms from patients aged 20-99. The overall prevalence of PR prolongation was (7.0%, N=84/1201) and (6.9%, N=64/922) among Caucasian and African Americans, respectively. PR prolongation was more prevalent in African-American patients compared with Caucasian patients in all age groups except for those patients in the eight decade of life.¹⁵ A limited number of studies have analyzed the incidence and prevalence of PR prolongation in Asian populations. Du and colleagues analyzed the prevalence of PR prolongation among a rural cohort of over 10,000 Chinese participants greater than 40 years of age. In this cross sectional study, the prevalence of PR prolongation, defined as a PR interval > 0.2 seconds, was 3.4% (95% confidence interval: 3.9-3.8%).¹⁶ Males had a higher prevalence than females (5.1% vs. 2.2%, P < 0.001). Independent risk factors associated with PR prolongation in this cohort included age, male sex, height and systolic blood pressure. In a Japanese cohort from the National Integrated Project for Prospective Observation of Non-communicable Disease And its Trends in the Aged (NIPPON DATA), over 9000 community-dwelling participants, the prevalence of PR prolongation was 1.9%, N=180/9051).¹⁷

Future epidemiological studies are needed to understand the incidence and prevalence of PR prolongation in patients of Hispanic ethnicity and additional underrepresented racial and ethnic groups. Additionally, caution should be taken when interpretating the association of race, which is largely a social construct, and PR prolongation.

PR prolongation and Adverse Outcomes

PR interval prolongation has historically been considered a low-risk rhythm disturbance of little consequence in healthy, asymptomatic individuals.^3-5,11,18 However, more recent analyses from large, longitudinal cohort studies have failed to show any meaningful connection between PR prolongation and adverse outcomes in healthy participants. For example, Aro et al. examined the electrocardiograms of 10957 individuals (aged 30–59 years) recorded between 1966 and 1972, and followed prospectively for 30 ± 11 years in the Finnish Social Insurance Institution's Coronary Heart Disease Study (CHD Study).¹ They observed that PR prolongation was not associated with an increased risk of stroke, atrial fibrillation, heart failure, or mortality, even after multivariable adjustment and subgroup analyses.¹ On the other hand, in an analysis of 2722 participants from the Health, Aging, and Body Composition Study(aged 74±3 years, 49.1% men), Mangani et al. observed that after multivariate adjustment that PR interval prolongation was associated with a 46% increased risk of incident heart failure (95% confidence interval [CI], 1.11–1.93), but was not associated with increased all-cause mortality.⁸

There are several possible explanations for the inconsistencies in observations between prolonged PR interval and outcomes. Researchers have suggested that earlier studies may have suffered from important limitations such as confounding, small sample sizes, inconsistent populations, inadequate follow-up periods to detect outcomes, and insufficient event ascertainment.¹² Yet, while the significance of PR prolongation in healthy populations remains unclear, there are a preponderance of studies that demonstrate PR prolongation in older individuals may portend an overall increased risk of morbidity and mortality, possibly as a signal of subclinical cardiovascular disease.¹⁹ For instance in a prospective, cohort including 7575 individuals from the Framingham Heart Study (mean age, 47 years; 46% men), Cheng et al. observed that those with first-degree AV block are at a moderately elevated risk of all-cause mortality (HR 1.44, 95% CI, 1.09-1.91; p =0.01), with an approximate two-fold increased risk of future atrial fibrillation (HR 2.06; 95% CI, 1.36-3.12; p <0.001), and about a three-fold increased risk of pacemaker implantation compared to patients without first-degree AV block (HR 2.89; 95% CI 1.83-4.57; p < 0.001).⁹ These findings were consistent even after adjusting for traditional risk factors and excluding patients with intraventricular conduction abnormalities or who were on AV nodal-blocking medications.⁹ Of note, roughly 27% of the patients with baseline first-degree AV block went on to develop second or third degree AV block and/or complete heart block.⁹

Another illustration of this shift in understanding was demonstrated by Nielsen et al.²⁰ Using a primary care cohort of over 280,000 patients with a median follow-up of 5.7 years. Researchers observed that having a PR interval ≥ 200ms was associated with a hazard ratio of 1.26 (95% confidence interval [CI] 1.17–1.35; p < 0.001) for atrial fibrillation compared with the reference group.²⁰ Interestingly, shorter PR intervals (< 123ms) were also associated with an elevated risk of developing AF with a hazard ratio of 1.21 (95% CI 1.06–1.37; p = 0.004).²⁰ In a similar analysis, Park et al. showed that a prolonged PR interval signaled atrial fibrillation related remodeling of the atria, greater left atrium size, a higher prevalence of hypertension and persistent atrial fibrillation.²¹ In addition, prolonged PR was also a predictor of recurrence of atrial fibrillation after radiofrequency ablation (HR=1.969, 95% CI 1.343-2.886; p=0.001).²¹

Further support was shown in a systematic analysis of fourteen studies evaluating outcomes associated with prolonged PR intervals.¹² Kwok et al. examined the data of over 400,000 individuals gathered between 1972 and 2011.¹² Pooled data showed that prolonged PR interval was associated with an increased risk of left ventricular dysfunction and heart failure (risk ratio [RR]1.39, 95% CI 1.18 to 1.65), atrial fibrillation (RR 1.45 95% CI 1.23 to 1.71), and overall mortality (RR 1.24, 95% CI 1.02 to 1.51).¹² Curiously, investigators did not find a significant association between prolonged PR and coronary disease, vascular events such as myocardial infarction and stroke, or cardiovascular mortality.¹²

From a pathophysiological standpoint there are several theories as to the underlying multifactorial mechanism that links PR prolongation to adverse cardiovascular outcomes. Firstly, PR prolongation could simply be viewed as an ECG representation of aging and degeneration of the native conduction system. As atherosclerotic disease is closely correlated with advancing age, it is postulated that PR prolongation could possibly serve as a marker for advanced atherosclerosis and cardiovascular events.²²

Additionally, coronary artery disease could affect perfusion of the AV nodal artery, a branch of the right coronary artery in most individuals, thus manifesting as AV prolongation. Research has also suggested that PR prolongation is independently associated with abnormal vascular function and increased arterial stiffness^22,23. Furthermore, PR prolongation could be a proxy of other alterations in the cardiovascular or neurohormonal/autonomic system that herald a worse overall prognosis.²² While the mechanistic effect of PR prolongation on outcomes has not been definitively described, it is evident that further research is needed to reinforce our knowledge on this question.

PR prolongation in special populations

Coronary Artery Disease

As mentioned previously, PR prolongation has been shown to be strongly associated with coronary artery disease and other adverse cardiovascular events. For example, Chan et al. found that in patients with coronary atherosclerosis or equivalent disease that prolonged PR interval independently predicted cardiovascular death (HR 14.1, 95% CI: 3.8–51.4; p < 0.001), new-onset ischemic stroke (HR 8.6, 95% CI: 1.9–37.8; p = 0.005), and combined cardiovascular endpoints (HR 2.4, 95% CI: 1.30–4.43; p = 0.005), which included occurrences of any primary endpoints or congestive heart failure.²² At an exploratory cut-off of PR interval > 162ms, the PR was also found to be predictive of new-onset MI (HR:8.0, 95% CI: 1.65–38.85; p =0.010; C-statistic 0.70, p = 0.001).²² In a separate study of 205 patients with non-ST segment elevation MI or unstable angina, Nabati et al. observed that PR prolongation was associated with clinically significant coronary disease (p = 0.024) with a positive trend toward a higher frequency of left main or three-vessel disease, and higher Gensini scores (an intensity index for coronary artery disease).²⁴ Furthermore, Nabati and colleagues did not observe a difference when risk factors such as the presence of hypertension, diabetes, hyperlipidemia, or family history were compared.²⁴ Additionally, Xue et al. found that in a cohort of 915 patients who had suffered an ST-elevation myocardial infarction that approximately 9.5% went on to develop PR interval prolongation.²⁵ Furthermore, after adjusting for possible confounders, PR interval prolongation was independently associated with worse outcomes (hazard ratio 5.37; 95% confidence interval, 1.85–15.62; p = 0.002) and increased long-term death.²⁵

In contrast, Holmqvist et al. observed conflicting findings in a analysis of 9,637 patients with at least single vessel disease who had undergone coronary angiography between 1989 and 2010.²⁶ Investigators found that after adjusting for pertinent variables that prolonged PR interval (in this study >162ms) did not predict a significant difference in the risk of all-cause mortality, death/stroke composite, or composite of cardiovascular death or rehospitalization.²⁶ Curiously, instead they found a decreasing PR interval (10ms decrements) was associated with these adverse cardiovascular endpoints.²⁶ Holmqvist et al. did however observe an association between all-cause mortality and PR prolongation in subgroup analysis of patients not on antiarrhythmic drugs.²⁶ While there is not a clear explanation for these inconsistent findings, a possible signal exisit pointing to increased risk in patients with alterations in AV conduction.

Heart Failure

Heart failure is associated with extensive electrophysiological reconstruction of the cardiac conduction system resulting in both QRS and PR interval prolongation and the development of atrial fibrillation.¹⁹ In a subgroup analysis of the Heart and Soul study including 938 patients with stable coronary disease, Crisel et al. found that patients with PR prolongation (mean age 73 ± 10 years) were more than twice as likely to be hospitalized for heart failure exacerbations or to die from cardiovascular causes.²⁷ The majority of the data regarding the epidemiology of PR prolongation in patients with heart failure originates from device trials and subsequent analyses.¹⁹ In a retrospective study of the Danish Pacemaker and ICD Register, Kronborg et al. observed that 47% of patients who underwent cardiac resynchronization therapy (CRT) implantation had first degree AV block and that a long native PR interval was an independent predictor of all-cause and cardiac death.²⁸ Separately, in a subgroup analysis of CARE-HF, Gervais et al. observed that, even after adjusting for CRT, baseline PR prolongation and a longer PR interval at 3 months status post CRT implantation (paced PR for the intervention group and native PR for the control group) was associated with increased all-cause mortality and heart failure hospitalization.²⁹ Atwater et al. observed that heart failure patients who had baseline PR prolongation and subsequently received CRT had a shorter survival free of LVAD implantation or heart transplant.³⁰ Researchers theorized that patients with PR prolongation at baseline diminished effective resynchronization relative to patients with normal PR intervals.³⁰ Furthermore, data from Olshansky et al. suggests that PR prolongation may be a modifiable risk factor, as those patients seemed to derive the most benefit from CRT implantation.³¹ Further studies are needed on the epidemiology and clinical significance of PR prolongation in patients with heart failure in real-world populations outside of device trials.

Neuromuscular Disease

Neuromuscular disorders are associated with a wide range of phenotypic expressions. Cardiac involvement is more commonly seen in the myopathies and less so in the diseases that affect nerves and communication. Cardiac involvement in myopathies oftentimes can take the form of a cardiomyopathy, as well as arrhythmias and conduction disturbances. As it pertains to PR interval prolongation, there are several neuromuscular diseases that have been studied in this area. Given that many of these disorders are rare, the associations made are limited to case series and are observational in nature. For example, Petri et al. observed that patients with myotonic dystrophy Type I, a disease known to effect multiple systems and lead to progressive muscle wasting and weakness, had a prevalence of first degree of AV block of approximately 28.2%, along with numerous other conduction abnormalities.³² Conduction defects ranging from sinus bradycardia, to PR interval prolongation, to complete heart block have also been observed in patients with Emery-Dreifuss muscular dystrophy.³³ Emery-Dreifuss is recognized by a classic triad of 1) early joint contractures, 2) progressive muscle weakness and atrophy in the upper arms/lower legs, and 3) cardiac involvement, typically AV conduction disturbances and atrial arrhythmias.³⁴ Per the 2018 ACC/AHA/HRS Guideline on the Evaluation and Management of Patients With Bradycardia and Cardiac Conduction Delay, patients with PR prolongation and comorbid neuromuscular disease with or without symptoms, such as myotonic dystrophy Type I, may be considered for permanent pacemaker placement due to the unpredictable evolution of conduction disease (class IIb recommendation; level of evidence C).³⁵ Understandably, because of the limited data and expansive clinical heterogeneity that exists, the management of cardiac disease in neuromuscular disorders is extremely difficult. Yet, efforts are being made to try and bridge this gap in knowledge to better care for these complex patients.³⁶

Summary

Our understanding of the prognostic significance of the PR interval continues to evolve. Contemporary analyses have repeatedly demonstrated the association of PR prolongation with adverse outcomes including increased risk of atrial arrhythmias, heart failure, and mortality, particularly in older patients. Whether PR prolongation is a marker for adverse outcomes or itself involved in the casual pathways that lead to cardiac pathology remains to be seen. Future studies are needed to understand the mechanism underlying the pathophysiology associated with PR prolongation, methods to stratify at risk patients, and optimal monitoring strategies, specifically in older patients who have the highest prevalence of PR prolongation. Identification of PR prolongation on electrocardiogram should prompt clinicians to ask patients about the presence of pre-existing heart disease and a family history of heart disease. Older patients with PR prolongation and a history of heart disease should undergo further evaluation for causes of PR prolongation including assessing for coronary artery disease and LV systolic dysfunction, although the utility and cost-effectiveness of additional diagnostic evaluation in asymptomatic patients with PR prolongation is unknown.

Key Points:

• First-degree AV block (PR prolongation) defined as a PR interval > 200ms (0.2 seconds) is common in the general population with a prevalence of 1%-6% depending on age.

• PR prolongation is associated with increased risk of adverse outcomes including atrial arrhythmias, heart failure, and mortality, particularly in older populations.

• Future studies are needed, specifically to risk stratify patients with PR prolongation who may be at increased risk of adverse outcome as well as a basic mechanistic understanding of the role of PR prolongation in cardiovascular disease.

Synopsis:

PR prolongation represents the time of electrical impulse propagation from onset of atrial depolarization (P wave) to the onset of ventricular depolarization (QRS complex). While the prevalence of PR prolongation is less than 1% in persons age < 60, the prevalence increases for persons > 60 years of age (6%). Classical analyses analyzing outcomes associated with PR prolongation were performed in health volunteers and suggested no adverse effects in long term follow-up. Contemporary analyses with enrollment of more heterogeneous populations have demonstrated an association between PR prolongation and adverse cardiovascular outcomes. Future studies are needed to more accurately risk stratify elderly patients with PR prolongation who may be at increased risk of adverse outcomes.

Clinical Care points.

• The incidence and prevalence of PR prolongation increases with age, especially after the sixth decade of life.

• Data from contemporary cohorts suggest a clear association with PR prolongation and adverse outcomes including increased risk of atrial arrhythmias and all-cause mortality.

• Clinicians should be cognizant of PR prolongation that is detected in older patients. In addition, considerations should be given to increased monitoring for future events, although the exact time interval and optimal strategy for monitoring of older patients with PR prolongation is unknown.