Abstract
Background:
Underlying mechanisms of PR‐interval prolongation leading to increased risk of adverse cardiovascular outcomes, including atrial fibrillation, are unclear. This study aims to investigate the relation between PR interval and changes in vascular function.
Hypothesis:
We hypothesize that there exists an intermediate pathological stage between electrocardiographic PR prolongation and adverse cardiovascular outcomes, which could be reflected by changes in surrogate measurements of vascular function.
Methods:
We recruited 88 healthy subjects (mean age 57.5 ± 9.8 y, 46% male) from a community‐based health screening program who had no history of cardiovascular disease or diabetes mellitus. PR interval was determined from a resting 12‐lead electrocardiogram. Vascular function was noninvasively assessed by flow‐mediated dilation (FMD) using high‐resolution ultrasound and brachial‐ankle pulse wave velocity (PWV) using a vascular profiling system.
Results:
Only 3 subjects had a PR‐interval length longer than the conventional cutoff of 200 ms. The PR‐interval length was associated inversely with FMD (Pearson r = −0.30, P = 0.004) and positively with PWV (r = 0.40, P < 0.001). Adjusting for potential confounders, increased PR‐interval length by each 25 ms was independently associated with reduced FMD by −1 unit (absolute %, B = −0.04 [95% confidence interval: −0.080 to −0.002, P = 0.040)] and increased PWV by +103 cm/second (B = +4.1 [95% confidence interval: 0.6–7.6, P = 0.023]).
Conclusions:
This study shows that PR‐interval length, even in the conventionally normal range, is independently associated with endothelial dysfunction and increased arterial stiffness in healthy subjects free of atherosclerotic disease. This suggests the presence of a systemic, intermediate pathologic stage of the vasculature in PR prolongation before clinically manifest cardiovascular events, and could represent a mediating mechanism. © 2011 Wiley Periodicals, Inc.
This study was supported by the CRCG Small Project Funding of the University of Hong Kong (Project No. 200907176063) and the Sun ChiehYeh Heart Foundation, Hong Kong, China. Yap‐Hang received a Best Paper Award at the Third Asian Preventive Cardiology and Cardiac Rehabilitation Conference, Hong Kong, China, December 11–12, 2010. The authors have no other funding, financial relationships, or conflicts of interest to disclose.
Introduction
Prolongation of the PR interval, traditionally defined as duration >200 ms on electrocardiogram (ECG), represents first‐degree atrioventricular block and is a common finding in clinical practice.1Even in the population‐based setting, prevalence of PR prolongation increases exponentially with age, from 0.7%–2% in young, healthy subjects to up to 14% in subjects in their 80s.2 It is more commonly seen among young athletes3, 4, 5, 6 and with a number of clinical conditions (eg, autoimmune diseases,7, 8 electrolyte disturbances,9 and primary cardiac pathologies10) and is affected by pharmacological interventions11, 12 and alcohol consumption,13, 14 as well as ethnic differences.14 In the young it is often associated with increased vagal tone and is reversible,1, 2 whereas etiology in older subjects is likely to be degenerative, with coexisting conduction system disease.15
Although there has been a long‐standing perception that PR prolongation has a “benign” nature with no implications for adverse clinical sequelae, the latest data oppose this traditional school of thought by showing that otherwise‐healthy persons who have a prolonged PR interval are at substantially elevated risk for incident atrial fibrillation (AF; 2‐fold risk), pacemaker implantation (3‐fold risk), and all‐cause mortality (1.4‐fold risk).16, 17 Despite this newly recognized link between PR prolongation and adverse cardiovascular outcomes, the underlying mechanisms remain poorly understood.
Given such disease burdens of PR prolongation, potential opportunities for early detection and intervention could be of great interest. By pioneering our understanding in the pathways of disease progression in PR prolongation, we may be able to identify important targets for potential therapeutic interventions, in turn making early detection/screening of high‐risk individuals meaningful. We propose that there exists an intermediate pathologic stage between electrocardiographic PR prolongation and adverse cardiovascular outcomes. Such intermediate adverse cardiovascular status could be reflected by changes in surrogate measurements of vascular function. We therefore carried out this clinical study to explore the associations between PR interval and markers of vascular function.
Methods
Subjects
Healthy subjects (n = 88) were randomly recruited from a community‐based health screening program within the Hong Kong Island West Cluster network of the Hong Kong Hospital Authority. Subjects with history of any of the following conditions were excluded: coronary artery disease, atherothrombotic/hemorrhagic stroke, peripheral vascular disease, diabetes mellitus, heart failure, significant valvular heart disease, chronic AF, and significant liver/renal impairment. All participants had a stable diet pattern and cardiovascular medications for ≥3 months prior to the date of recruitment. All patients gave written informed consent to the study. The research protocol was approved by the institutional review board (Hong Kong West Cluster/The University of Hong Kong) of the University of Hong Kong.
Demographic, Clinical, and Laboratory Evaluations
Baseline demographic data, cardiovascular risk factors, and cardiovascular medications (antihypertensives/statins) were documented. Hypertension was defined as either resting systolic or diastolic blood pressure ≥140/90 mm Hg at 2 different clinic visits or on medications. Diabetes mellitus was defined as serum fasting glucose ≥7.0 mmol/L or on medications. Hypercholesterolemia was defined as a fasting total plasma cholesterol level of ≥4.9 mmol/L or on cholesterol‐lowering medications. Body mass index was calculated as weight in kilograms divided by the square of height in meters, taken from measurements during the visit. Smoking status was recorded as either past smoker, current smoker, or nonsmoker. Physical activity was categorized as never, regular, or occasional episodes of aerobic exercise. Family history of coronary artery disease was considered positive in first‐degree relatives with diseases diagnosed at an age younger than 55 years.
Vascular Ultrasound Examination
Vascular ultrasound was performed by an experienced operator with a high‐resolution ultrasound system (Sonos 5500; Philips Healthcare, Andover, MA) using a 7.5‐MHz linear array transducer. All the scanned images were stored digitally and analyzed offline without knowledge of the subjects.
Patients were studied in the fasting state. To avoid any systematic differences in diurnal variation of vascular reactivity, all studies were performed in the morning (between 9 am and 12 pm). All vasoactive medications, cigarette smoking, caffeinated beverages, and alcohol consumption were withheld for ≥12 hours before the assessment. As previously described,18, 19 longitudinal scans of the brachial artery were obtained at rest, and then flow‐mediated dilation (FMD) was induced by inflation of a pneumatic tourniquet placed on the forearm to a pressure of 250 mm Hg for 5 minutes. The cuff was then released, and serial imaging of the brachial artery was recorded for 5 minutes. The brachial artery was allowed to return to baseline. Flow‐mediated dilation was defined as the percentage change in brachial artery diameter by 1 minute after cuff deflation from that on the baseline scan. Interobserver variability testing for FMD measurement revealed an interclass correlation coefficient (2‐way mixed, random‐effect model, absolute agreement) of 0.83 (95% confidence interval [CI]: 0.22–0.97, P = 0.012), with a mean absolute difference of 0.6 ± 0.8%.
Electrocardiography and Arterial Stiffness
A standard 12‐lead ECG was performed in the supine position after resting for 5 minutes. Arterial stiffness was measured noninvasively using a vascular profiling system (VP‐2000; Colin Corp. [Mediana Technologies], San Antonio, TX) in all patients. All measurements were performed by a single experienced operator. Patients were allowed to rest for 5 minutes before the measurement. Sequential recordings of pressure wave forms at the brachial artery and the posterior tibial artery were made using handheld manometer probes with simultaneous ECG gating.20 Measurements were taken after achieving coherent reproduction of signals with maximum amplitudes. Pulse wave velocity (PWV) was defined as the transmission distance between the 2 points of measurement over the brachial and tibial arteries divided by interval pulse transit time, and was calculated using system software synchronized over ≥10 cardiac cycles. Intraobserver variability testing revealed an interclass correlation coefficient (2‐way mixed, random‐effect model, absolute agreement) of 0.87 (95% CI: 0.80–0.91, P<0.001), with a mean absolute difference (±SEM) of 46.1 ± 28.6 cm/second.
Statistical Analysis
Continuous variables were expressed as mean ±1 SD. Statistical comparisons were performed using the Student t test or Fisher exact test, as appropriate. Conventional normal range of the PR interval was adopted as <200 ms. Absolute changes and 95% CI of FMD and PWV were calculated by univariate and multivariate linear regression analysis. The crude model included only PR interval as the explanatory variable. Multivariate analyses were performed with a forward stepwise regression model in which each potentially confounding variable with a P value ≤0.25 (based on the univariate analysis) was entered into the model. Considered variables include age, sex, smoking history, body mass index, physical activity, hypertension, resting heart rate, low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol, triacyglycerol, fasting blood glucose, C‐reactive protein, and the use of β‐blockers, calcium channel blockers, angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers, and statins. All statistical analyses were performed using the SPSS program, version 15.0 (SPSS Inc., Chicago, IL). A P value of <0.05 was considered statistically significant.
Results
The clinical characteristics shown in Table 1 reflect a study sample of relatively young and healthy adults, the majority being nonsmokers. More than half of them had regular physical activity. Mean FMD and PWV reflect satisfactory vascular health overall in terms of vascular endothelial function and arterial stiffness. Only 3 had a PR interval beyond the conventional normal range of 200 ms.
Table 1.
Clinical Characteristics of Study Participants (n = 88)
| Characteristics | N (%) |
|---|---|
| Male, n (%) | 40 (46) |
| Age (y) | 57.5 ± 9.8 |
| BMI (kg/m2) | 24.1 ± 3.4 |
| Hypertension, n (%) | 20 (23) |
| Hyperlipidemia, n (%) | 41 (47) |
| Smoking history, n (%) | |
| Current | 10 (11) |
| Past | 12 (14) |
| Never | 66 (75) |
| Physical activity, n (%) | |
| Never | 24 (27) |
| Regular | 54 (61) |
| Occasional | 10 (11) |
| Mean SBP (mm Hg) | 125 ± 15 |
| Mean DBP (mm Hg) | 75 ± 9 |
| Mean serum LDL level (mmol/L) | 2.9 ± 0.7 |
| Mean serum HDL level (mmol/L) | 1.5 ± 0.5 |
| Mean serum triacylglycerol level (mmol/L) | 1.3 ± 0.7 |
| Mean serum fasting glucose (mmol/L) | 4.9 ± 0.5 |
| Mean serum CRP (mmol/L) | 2.3 ± 2.4 |
| Medications, n (%) | |
| β‐Blocker | 9 (10%) |
| CCB | 7 (8%) |
| ACEI/ARB | 1 (1%) |
| Statin | 2 (2%) |
| Mean FMD (%) | 5.8 ± 3.4 |
| Mean PWV (cm/s) | 1597 ± n 355 |
| Mean PR interval (ms) | 165 ± n 18 |
Abbreviations: ACEI, angiotensin‐converting enzyme inhibitor; ARB, angiotensin receptor blocker; BMI, body mass index; CCB, calcium channel blocker; CRP, C‐reactive protein; DBP, diastolic blood pressure; FMD, flow‐mediated dilation; HDL, high‐density lipoprotein; LDL, low‐density lipoprotein; PWV, pulse wave velocity; SBP, systolic blood pressure.
All values are ±SD except where indicated otherwise.
PR Interval and Vascular Endothelial Function
PR interval was inversely associated with FMD(Pearson r = −0.30, P = 0.004; Figure 1) and positively with PWV. Mean FMD was lower in participants with PR interval >162 ms (median) compared with PR interval ≤162 ms (4.9 ± 2.6% vs 6.7 ± 3.9%, P = 0.017). As shown in Table 2, after adjusting for potential confounders including age, sex, smoking history, hypertension, and resting heart rate, increased PR‐interval length by each 25 ms was independently associated with reduced FMD by −1 unit (absolute %, B = −0.04 [95% CI: −0.080 to −0.002, P = 0.040]).
Figure 1.
Relation between FMD and PR interval. FMD is inversely associated with PR interval (r = −0.30, P = 0.004). Abbreviations: FMD, flow‐mediated dilation.
Table 2.
Crude and Adjusted Association of PR Interval Length and Parameters of Vascular Functiona
| Model | FMD, % | PWV, cm/s | ||
|---|---|---|---|---|
| B (95% CI) | P Value | B (95% CI) | P Value | |
| Crude | −0.06 (−0.01 to −0.02) | 0.004 | 7.9 (3.8–11.9) | <0.001 |
| Adjusted | −0.04 (−0.080 to −0.002)b | 0.040 | 4.1 (0.6–7.6)c | 0.023 |
Abbreviations: CCB, calcium channel blocker; CI, confidence interval; FMD, flow‐mediated dilation; PWV, pulse wave velocity; SD, standard deviation.
Absolute change estimates and 95% CI of FMD and PWV per 1‐SD increase in PR interval length were calculated by univariate and multivariable linear regression.
Adjusted for potential confounders: age, sex, smoking history, hypertension, and resting heart rate. Potential confounders were defined as P<0.25 from univariate linear regression.
Adjusted for potential confounders: age, sex, hypertension, resting heart rate, fasting glucose, and use of β‐blockers and CCBs. Potential confounders were defined as P<0.25 from univariate linear regression.
PR Interval and Arterial Stiffness
PR interval was positively associated with PWV(r = 0.40, P<0.001; Figure 2). Mean PWV was higher in participants with PR interval >162 ms (median) compared with PR interval ≤162 ms (1715 ± 408 cm/svs 1492 ± 264 cm/s, P = 0.004). As shown in Table 2, after adjusting for potential confounders including age, sex, hypertension, resting heart rate, fasting glucose, use of β‐blockers and calcium channel blockers, increased PR‐interval length by each 25 ms was independently associated with increased PWV by +103 cm/second (B = +4.1 [95%CI: 0.6–7.6, P = 0.023]).
Figure 2.
Relation between PWV and PR interval. PWV is positively associated with PR interval (r = 0.40, P < 0.001). Abbreviations: PWV, pulse wave velocity.
Discussion
This study is the first to report a novel positive association between PR‐interval length and abnormal vascular function in subjects free of atherosclerotic disease, as demonstrated by impaired FMD and increased arterial stiffness. The magnitude of vascular‐function impairment has clinical significance, as a 1% decrease in FMD corresponded to a 12% higher risk of incident cardiovascular events observed in a multiethnic cohort after 36‐month follow‐up.21 Increased arterial stiffness by each 50 cm/second increase in PWV is also associated with 7.5% increased risk of cardiovascular events/deaths among patients on renal dialysis.22
Previous studies demonstrated high validity23 and reproducibility of arterial stiffness assessment by PWV using an automated vascular profiling system (VP‐2000), and such simple, noninvasive assessment is well tolerated by subjects and closely correlated with invasive methods of vascular function such as aortic arterial stiffness.24 While choosing to use PWV as a key endpoint in this study based on these advantages, to enhance internal validity we also simultaneously measured endothelial dysfunction as noninvasively assessed by FMD impairment, which is also an independent predictor of incident cardiovascular events.25 Consistent across these 2 different surrogate measures of vascular function, the presence of abnormal vascular function in PR prolongation has 2 groundbreaking implications: First, it serves as first evidence to suggest the existence of an intermediate pathologic stage of adverse systemic arterial profile in individuals with PR prolongation, before clinical manifestation of cardiovascular events. Second, such association was strikingly present, even in the conventionally defined normal range of PR interval <200 ms. This is coherent with the recently observed higher risk of adverse cardiovascular outcomes in subjects with similar range of PR interval (>149 ms) from the Framingham study.17 As impaired vascular function is an independent predictor of future cardiovascular events and is also associated with AF, this observation gives important mechanistic insights into the pathogenesis of adverse cardiovascular outcomes in PR prolongation.
The mediating pathways for the observed vascular function impairment are unclear. Previous studies showed that markers of neurohormonal activation including aldosterone and natriuretic peptides are raised in AF26 and have direct effects on atrial remodeling,27, 28 and such markers are reversed on cardioversion29 and maintenance of sinus rhythm.30 Furthermore, genetic polymorphisms of aldosterone synthesis are determinant of AF in heart failure patients.31 These suggest that neurohormonal activation could be an important mediator in the pathogenesis of AF when intra‐atrial pressure is increased during delayed atrioventricular conduction.32 Meanwhile, aldosterone has been shown to impair vascular endothelial cell function,33 raised levels of which is associated with hypertension‐related impairment of vascular function,34 and such changes are reversed by renin‐angiotensin‐aldosterone system blockade.35 Therefore, as a precursor to AF, PR prolongation may cause abnormal vascular function through increased intra‐atrial pressure and activation of the neurohormonal pathways, in the long term resulting in adverse cardiovascular outcomes. With a recent trial showing that treatment with renin‐angiotensin‐aldosterone blockade can prevent AF,36 findings of our study may have important preventive implications.
In addition to elucidating the pathophysiological mechanisms of PR prolongation, our findings may impact on clinical practice by raising the question whether we need to redefine the normal range of PR interval, which may identify persons who could benefit from early follow‐up and monitoring. Further studies should focus on the range of PR interval that is well below the conventional cutoff of 200 ms; this is also of public health interest, because a larger proportion of the population has a PR interval within this range.
Study Limitations
Several limitations of this study should be noted. First, it is a small, single‐center study of nonconsecutive, randomly recruited subjects, with each assessment done by a single operator. Although we carefully excluded patients with previous history of cardiovascular diseases, whether they are completely free from atherosclerotic disease cannot be completely ascertained. We carefully adjusted, where appropriate based on univariate analysis, for potential confounders related to endothelial dysfunction, including hypertension and obesity, in the final analysis. Despite its small size, the sample has sufficient power to detect the positive associations between PR interval and abnormal vascular function. Second, due to the cross‐sectional design, causality cannot be demonstrated. Further large, prospective studies will be important to establish temporality and also to test for specific mediating pathways. The autonomic nervous system, which may be closely related to PR interval and cannot be tested in this study, should also warrant further investigation. Furthermore, using vascular ultrasound for assessing FMD and a vascular profiling system for PWV as surrogate markers only provided suggestive intermediate indicators of cardiovascular disease. Further studies should also include clinical outcomes of cardiovascular events, death, and hospitalization.
Conclusion
PR‐interval length, even in the conventionally normal range, is independently associated with endothelial dysfunction and increased arterial stiffness in healthy subjects free of atherosclerotic disease. This suggests the presence of a systemic, intermediate pathologic stage of the vasculature before clinically manifest cardiovascular events in PR prolongation, and could represent a mediating mechanism.
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