First-degree atrioventricular block may not be that benign after all

In this issue of the Journal, Uhm et al.[1] report a study from Korea, which indicates that first-degree atrioventricular block (AVB) is associated with an increased risk of advanced AVB, atrial fibrillation and left ventricular dysfunction in patients with hypertension. First-degree AVB is a result of conduction delay occurring in the right atrium, AV node, His bundle or Purkinje network. Potential underlying mechanisms suggested by the authors include atherosclerosis of the coronary arteries, atrial fibrosis, dilated cardiomyopathy, infiltrative cardiomyopathies, left ventricular dysfunction, neuromuscular disease and insufficient blood pressure control causing left ventricular hypertrophy. Therefore, first-degree AVB may be a marker of underlying heart disease, rather than being an independent predictor of left ventricular dysfunction. The current study by Uhm et al.[1] retrospectively examined 3816 hypertensive middle-aged participants with sinus rhythm on baseline ECG and no cardiac implantable electronic devices, baseline left ventricular dysfunction, ventricular preexcitation or advanced AVB. The 544 (14.3%) participants with first-degree AVB were older, used more nondihydropyridine calcium channel blockers, had more left ventricular hypertrophy and longer QRS duration at baseline. In Cox multivariate analyses, baseline first-degree AVB was associated with subsequent development of atrial fibrillation, left ventricular dysfunction and advanced AVB. In earlier studies, first-degree AVB was not associated with higher morbidity and mortality and has previously been considered a benign finding of no adverse prognostic significance [2,3]. More recently, a growing body of literature has emerged that first-degree AVB might be an ominous sign compared with patients with normal AV conduction [4,5]. In the Heart and Soul Study, including 938 patients with stable coronary artery disease, first-degree AVB defined as P-R interval more than 220 ms was present in 9.3% and associated with an increased risk of heart failure hospitalization, cardiovascular and all-cause mortality, which remained significant after adjusting for several covariables [5]. However, this association seemed to be partly explained by left ventricular systolic and diastolic dysfunction and history of heart failure. In the Framingham Heart Study, baseline first-degree AVB, defined as P-R interval more than 200 ms, was associated with increased risks of atrial fibrillation, pacemaker implantation and all-cause mortality in 7575 participants without use of antiarrhythmic agents, cardiac glycosides, history of pacemaker implantation or history of atrial fibrillation [4]. Compared with the Heart and Soul Study, only 124 (1.6%) had baseline first-degree AVB despite the lower P-R interval cut-off, suggesting inclusion of a healthier patient sample in the Framingham Heart Study with lower prevalence of cardiovascular morbidity and cardiac structural abnormalities than the patients in the Heart and Soul Study. The Health ABC study examined a cohort of healthy, well functioning older adults and showed that the 339 (12%) participants with P-R interval more than 200 ms had a 46% higher risk of incident heart failure after 10 years of follow-up, and when P-R interval was analysed as a continues variable, every 1-SD of the mean increase (29 ms) in P-R interval was associated with a 13% greater 10-year risk of heart failure and a 13% increased risk of incident atrial fibrillation after multivariable adjustment; however, no association was found with all-cause mortality [6]. These findings are consistent with the study by Uhm et al.[1] and the Heart and Soul Study, which both included patients with higher risk of underlying cardiovascular diseases, as well as the Framingham Heart Study that included a healthier sample of participants. As ageing is associated with fibrosis of the myocardium, the older age of the Health ABC Study participants compared with earlier studies [2,3] could in part explain the divergent finding between the previous perception of first-degree AVB as a benign finding and recently published studies suggesting higher rates of morbidity. Furthermore, previous studies on first-degree AVB have mainly been conducted in healthy participants [2,3], which is another possible explanation of the discrepancies. It is still possible that first-degree AVB is a benign finding in a healthy population. However, in the study by Uhm et al.[1], the patients were hypertensive with a substantial proportion of electrocardiographic left ventricular hypertrophy, both of which have shown to be associated with left ventricular dysfunction and poor cardiovascular outcome [7,8] as well as conduction abnormalities [9]. Therefore, the observed poor outcome in the patients with first-degree AVB could well be a surrogate of underlying cardiovascular disease. This thesis could also explain the results of their subanalysis, wherein patients with baseline first-degree AVB were excluded, showing that new-onset first-degree AVB was only associated with subsequent left ventricular dysfunction but not atrial fibrillation or advanced AVB. One could argue that the latter two are secondary to structural changes to the conduction system caused by years of underlying left ventricular dysfunction. On the contrary, after adjustment for baseline differences, baseline first-degree AVB remained associated with subsequent atrial fibrillation, left ventricular dysfunction and advanced AVB. Moreover, the Framingham Heart Study was based on a contemporary, community-based cohort with a relatively low burden of cardiovascular diseases, which supports first-degree AVB as an independent risk factor. Furthermore, heart failure apparently did not attenuate the association of first-degree AVB and outcome in the Framingham Heart Study. Possible explanations of how first-degree AVB independently contributes to poor outcome could be prolonged P-R interval causing delayed and ineffective mitral valve closure and diastolic mitral regurgitation [10]; slowed intraatrial or interatrial conduction, potentially as a marker of atrial fibrosis, directly increasing the risk of AF [11], which is known to be associated with higher mortality in several settings [12]; or Hisian and infra-Hisian conduction delay associated with an increased mortality in patients with established cardiac disease [13]. An obvious limitation in the study by Uhm et al.[1] and the majority of studies on first-degree AVB is that they only examined surface ECGs, and thus were unable to accurately localize the lesion in the conduction system to determine the relative contribution of each component of the P-R interval. Furthermore, absence of myocardial fibrosis assessment by cardiac magnetic resonance, which may account for at least some of the prognostic significance of first-degree AVB, is another limitation. The ECG is an inexpensive and widely available procedure that is already obtained in most patients with signs of cardiovascular disease and provides convincing predictive value in patients with cardiovascular disease beyond modalities such as echocardiography [14,15]. Uhm et al.[1] adjusted their analyses for factors previously known to promote conduction delay and several factors associated with atrial fibrillation and mortality, and thereby support other recently published articles. Their findings suggest that first ventricular degree AVB may be a valuable independent predictor of poor outcome that should remind the physician to evaluate and monitor patients for development of progressive or new underlying cardiovascular disease, as soon as possible after first-degree AVB is detected. Whether first-degree AVB will become a widely utilized marker of cardiovascular risk in the contemporary evaluation of patients will require further assessment in additional populations and under differing treatment conditions. Importantly, it will be critical to determine whether first-degree AVB improves the prognostic value of net reclassification index and c-statistics beyond known risk factors for cardiovascular outcomes. ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.