Unveiling the Association Between Left Ventricular Conduction Disease and Hypertensive Mediated Organ Damage

Nearly 60 years have passed since Rosenbaum and his coworkers described the trifascicular nature of the intraventricular conduction system [1]. Based on extensive anatomical, physiological, experimental, clinical, and pathological findings, it has been demonstrated that the intraventricular conduction system has three, and not two, terminals: one on the right ventricle and two to the left ventricle, namely left anterior fascicular block (LAFB) and left posterior fascicular block (LPFB). While isolated LPFB is extremely rare and is almost invariably associated with right bundle branch block (RBBB), as LPFB and RBBB share etiology and pathogenesis, LAFB is by far the most common intraventricular conduction disorder. Despite the growing amount of research accumulated over the last few decades, the clinical and prognostic significance of LAFB remains a topic of debate. Indeed, the finding of isolated LAFB in a healthy population does not seem to reflect an increased risk of cardiovascular (CV) morbidity or mortality, whereas this is not the case in different clinical settings such as coronary heart disease, heart failure, valvular heart disease, hypertension, and diabetes. The paper by Yetim et al. [2], recently published in this Journal, addressing the relationship between LAFB and markers of subclinical target organ damage, as determined by echocardiography and vascular ultrasonography, in a cohort of essential hypertensives, offers a new piece of information on this issue, revealing that patients with LAFB have a greater likelihood of cardiac (i.e., increased left ventricular mass index and left atrial diameter) and large artery remodeling (i.e., increased common intima-media thickness). Before describing in more detail and commenting on the novel contribution of this study, we believe it may be useful to summarize the available evidence on the prevalence of LAFB in different clinical settings, its clinical correlates, as well as the association of this conduction disorder with CV risk factors, namely systemic hypertension, and its prognostic significance. Intraventricular conduction disease is the result of disruption of regular electrical depolarization and may occur at any level of the conduction system, and is considered a nonreversible condition, unlike other electrophysiologic disorders that cause alterations in cardiac rhythm [3]. Numerous studies have investigated the prevalence of intraventricular conduction disorders in subjects with different demographic, clinical, and ethnic characteristics. In a large population of 69,186 aircrew members, evaluated within a primary prevention program in an aeromedical center, intraventricular conduction disturbances were detected in 3.09% of cases [4]. LAFB accounted for approximately one-third of the total alterations (1.1%), whereas complete left bundle branch block (LBBB) and LPFB were rare findings in this low-risk cohort (i.e., 0.08% and 0.13%). An observational retrospective study on 264 324 consecutive primary care patients in 658 cities in Brazil showed that the prevalence of LFAB increased across the 20- to 80-year-old age strata, from 2.39% to 20.1% in men and 1.09% to 13.2% in women [5]. Corresponding values for LPFB were found to be less than 1% in all age groups in both sexes. The Kailuan Study, a prospective cohort study conducted in the Chinese community of Kailuan, assessed the prevalence and incidence of intraventricular conduction disturbances in 101 510 participants (aged 18–98, 81 110 men and 20 400 women) [6]. In the entire population, RBBB (1.58%) was the most prevalent, followed by incomplete RBBB (0.66%) and LAFB (0.66%). As for the incidence, RBBB (0.78%; 1.58 cases per 1 000 person-years), LAFB (0.44%; 0.87 cases per 1 000 person-years), and incomplete RBBB (0.42%; 0.84 cases per 1,000 person-years) were, in decreasing order, the most common conduction disorders. Relatively few studies have examined the prevalence/incidence of left ventricular (LV) conduction disease and the effects of blood pressure (BP) lowering drugs in the setting of arterial hypertension. A post hoc analysis of the 2-arm multicenter Systolic Blood Pressure Intervention Trial (SPRINT) revealed that a total of 203 out of 3918 participants randomized to standard treatment and 3956 to intensive treatment developed LV conduction disease (2.6%), with approximatey 30% of cases represented by LAFB, over a median (IQR) follow-up of 3.5 (0.02–5.2) years [7]. More interestingly, this study documented that participants assigned to intensive BP treatment exhibited a 26% lower risk of LV conduction disease (HR, 0.74; 95% CI, 0.56–0.98; p = 0.04). On the contrary, no differences in the risk of RBBB were observed by randomization assignment. While tight BP control, as shown by researchers from the SPRINT study, appears to offer a promising approach to reducing the incidence of LV conduction disease, the question of whether specific anti-hypertensive drugs may be more effective than others in this context is still a hypothesis to be verified, as evidence on the matter is scarce. A secondary analysis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), based on data of 21 004 hypertensive individuals randomly assigned to receive amlodipine besylate, lisinopril, or chlorthalidone, investigated the development over a 5 years of incident first-degree atrioventricular block, LAFB, incomplete LBBB, LBBB, incomplete RBBB, and RBBB [8]. Among the 1114 participants who developed any conduction defect, 389 developed LBBB (35%), 570 developed RBBB (51%, and 155 (14%) developed intraventricular conduction delay. Compared with chlorthalidone (and amlodipine), lisinopril was associated with a 19% reduction in conduction events. The Losartan Intervention For Endpoint reduction in hypertension (LIFE) documented that treatment with the angiotensin receptor blocker losartan-based regimen significantly reduced the incidence of new-onset intraventricular conduction delay (−15%, p = 0.005), defined as new QRS duration at least 110 ms, compared with treatment with the beta-blocker atenolol-based regimen in hypertensive patients with electrocardiographic LV hypertrophy (LVH) [9]. The protective effect of renin-angiotensin-aldosterone system inhibitors (like lisinopril and losartan) on conduction disease development may be attributed to their greater efficacy in reducing LV mass and myocardial fibrosis often associated with LVH, compared to diuretics, beta-blockers, and calcium channel blockers [10]. Data on the prognostic significance of LAFB are also scarce and inconsistent. The Cardiovascular Health Study (CHS), which addressed this topic in a cohort of 1664 individuals aged 65 years or older, in whom the prevalence of LAFB at entry was 2.3%, demonstrated that this conduction block was associated with the occurrence of atrial fibrillation (AF), chronic heart failure (CHF) and CV death recorded over a 10-year follow-up period [11]. On the contrary, in a large primary care population free of major CV events, including 227 543 patients (1.6% with LAFB), Nielsen et al. [12] found that the associations between LAFB and the 5-year risk of AF, CHF, and CV death lost their statistical significance after adjustment for age and sex. Starting from the view that chronic pressure overload in systemic hypertension can cause myocyte hypertrophy and interstitial fibrosis, which in turn may interfere with electrophysiological mechanisms, Yetim et al. [2] explored the link between LAFB and subclinical alterations in cardiac and large artery structure. For this purpose, 256 patients with essential hypertension (mean age 61 ± 10 years, 60% women, 14% diabetics) with normal LV conduction (n = 196) and LAFB (n = 60) were included in the study. All patients underwent laboratory tests, office BP measurements, standard Electrocardiogram (ECG) (LAFB: QRS axis between −45° and −90° and QRS duration of less than 0.12 s), conventional echocardiography (LVH: LVMI > 115 g/m2 in men and 95 g/m2 in women), and carotid ultrasonography (common carotid intima-media thickening: > 0.9 mm; carotid plaque: focal thickening > 1.5 mm). The two groups had similar demographics (age, sex) and clinical characteristics (body size, office BP, duration of hypertension, prevalence of diabetes, dyslipidemia, smoking habit, and anti-hypertensive treatment). This was also the case for the parameters of glycolipid metabolism and renal function. Patients with LAFB, however, exhibited significantly higher values of LV wall thickness, left atrial diameter/volume, LVMI, and common intima media thickness. The prevalence of LVH was also approximately two-fold higher (48% vs 24%, p < 0.001), and carotid plaques were found in 30% of patients with LAFB and 20% (p = 0.04) of their normal counterparts, respectively. Finally, multivariate analysis showed that only left atrial diameter and LVM remained independent predictors of LAFB, while this did not hold true for the corresponding indexed parameters and intima media thickness. Although the findings of the present study strongly suggest that LAFB should not be considered a minor conduction defect of uncertain significance and perhaps entirely benign, as it is a marker of undetected cardiac and vascular subclinical alterations, these conclusions deserve to be interpreted in light of the following considerations. The high prevalence of LAFB in the cohort selected by Yetim et al. [2], which translates into the presence of this conduction defect in approximately one quarter of patients, is not reasonably representative of the general hypertensive population [13]. Contrary to what is reported in the literature, where LAFB is associated with a greater burden of CV risk factors, no difference in this regard emerged in the present study, leaving its clinical significance undefined. Furthermore, the association with subclinical organ damage was limited to a pair of non-indexed echocardiographic parameters whose prognostic significance is less robust than the corresponding phenotypes normalized for individual differences in body size [14]. Although we believe that LAFB should be considered as a reliable marker of target organ damage as suggested by Yetim et al. [2], further research in this area on larger cohorts of hypertensives, ideally evaluated with more advanced imaging techniques, is needed to clarify the role of LAFB in CV risk stratification [15]. The authors have nothing to report. The authors report no conflicts of interest.