Introduction

Coronary artery disease (CAD) is the primary source of disability and even death worldwide (1). The World Health Organization estimates that CAD mortality will reach 23.4 million in 2030 (2). The most frequent presentation of ischemic heart disease is chronic stable angina (3). Diagnostic algorithms based on history, physical examinations, and electrocardiograms are well established. While invasive coronary angiography (ICA) has been considered the “gold standard” test for the detection of CAD, it is invasive and has also potential disadvantages such as predisposure to cerebrovascular events, bleeding, and even death (4). In patients without unstable conditions, current guidelines stipulate the first-line use of non-invasive tests to define the need for invasive tests such as coronary angiography, especially in patients with intermediate pre-test probability (5). Depending on patient selection, the predictive values of current pre-test probability models are still not optimal. In addition, obstructive coronary lesions are found in 41% of patients with positive results from non-invasive tests (6). Since successful revascularization of lesions in the left main and/or proximal left anterior descending (LM and/or pLAD) coronary artery improves survival when compared with medical therapy only, the accurate identification of high-risk patients with stable angina pectoris is crucial. Using cost-effective, easy obtainable, and non-invasive methods that can detect an obstructive LM and/or pLAD coronary arteries may be beneficial in clinical practice. Electrocardiography (ECG) is still an important part of the initial evaluation of patients presenting with cardiac complaints, despite its existence that spans out more than a century. Left anterior fascicular block (LAFB), an ECG pattern representing failure or delay of conduction in the left anterior fascicle, was initially defined as left anterior hemiblock by Rosenbaum et al. (7,8). Although there are conflicting results in different study populations regarding the clinical importance of LAFB (9-14), CAD remains one of the most common causes of LAFB (15). The His bundle splits into the two bundle branches at the fibrous and muscular boundaries joint of the interventricular septum. Then, the left bundle branch gives an anterior, posterior, and, in some cases, septal fascicles. The left anterior fascicle is nourished by the septal perforators from the LAD coronary artery mainly and therefore, is more sensitive to ischemia. Since the septal perforators of the LAD coronary artery are the main source of blood supply for the left anterior fascicle, we hypothesized that the presence of LAFB can predict obstructive stenoses of the LM and/or pLAD coronary arteries in patients with stable angina pectoris.

Methods

Study Population

We included 790 consecutively enrolled patients with stable angina pectoris and referred to ICA between September 2016 and January 2020. Each patient was included doing a coronary angiography. Those with angina pectoris and complaints equivalent to angina were considered eligible for the study. Afterward, a detailed medical history and at least one non-invasive diagnostic test was performed by an experienced cardiologist to determine CAD. Patients with acute coronary syndrome, history of CAD and cardiovascular consequence, malignancy, congenital heart disease, moderate-to-severe liver and/or renal diseases, acute or chronic inflammatory diseases, moderate-to-severe valvular heart disease, and cardiomyopathies were excluded from the study as well as those with preexisting right bundle branch block (RBBB), left bundle branch block (LBBB), pace rhythm, pre-excitation syndromes, and associated ischemic ST-T abnormalities. Sociodemographic and medical history parameters were recorded. Included patients were separated into two groups depending on the occurrence of LAFB. Patients were also grouped according to the presence of obstructive LM and/or pLAD lesions.

Informed consent was granted by all patients before enrollment. The approval form the Clinical Research Ethics Committee of University of Health Sciences Turkey, Kanuni Sultan Süleyman Training and Research Hospital was obtained (approval number: 2020/62, date: 12.11.2020).

Electrocardiographic Evaluation

A standard surface 12-lead electrocardiogram ECG, with a paper speed of 25 mm/s and a voltage of 10 mm/mV was employed for investigations (Nihon Kohden, cardiofax GEM, ECG-9020K, Japan). All ECGs were recorded and analyzed by one experienced cardiologist blinded to the clinical data of the participants. LAFB was defined according to specified criteria: 1) QRS axis on frontal plan between -45 and -90 degrees, 2) qR pattern in lead aVL 3) R-peak time in lead aVL of 45 ms or more 4) QRS duration less than 120 ms (16).

Coronary Angiography and Echocardiography

Trans-radial or trans-femoral Judkins techniques were used to explore the coronary arteries in all patients. Obtained fluoroscopic images were judged by an experienced interventional cardiologist. Patients were categorized as individuals without CAD, with mild CAD, with significant CAD, and with obstructive CAD. Mild CAD was considered if lumen-diameter narrowing was less than 50% within any epicardial coronaries. In addition, significant CAD was accepted as lumen-diameter narrowing of more than 50% within any epicardial coronaries. Lastly, obstructive CAD was described as a lumen-diameter narrowing of more than 50% of the LM coronary artery or narrowing ≥70% within any epicardial coronaries. SYNTAX scores (version 2.28) were calculated in arteries with ≥1.5 mm diameter and have luminal obstruction ≥50%. Decisions related to revascularization strategies were made based on the preference of the attending physicians.

Transthoracic echocardiography (Philips Epiq 7 systems, Andover, MA) was performed on all participants at the time of their first examination. The left ventricular ejection fraction (LVEF) was obtained using the modified Simpson’s method (17). Left ventricular hypertrophy (LVH) was equally detected by calculating the left ventricular mass (LVM) according to the Devereux formula (18). The LVM index (LVMI) was then derived by correcting the LVM for body surface area.

Statistical Analysis

Statistical analysis was performed using SPSS version 22.0 (SPSS Inc. Chicago, Illinois, USA). Continuous variables were evaluated for normality distribution using the Kolmogorov‐Smirnov test. If variables were normally distributed, they were expressed as the means ± standard deviation. Whereas, if the distribution was not normal, variables were expressed as median and inter‐quartile ranges. However, categorical variables were expressed as numbers and percentages and were compared using the chi-square test. An Independent sample t-test was employed for parametric variables, whiel the Mann-Whitney U test was employed for non-parametric variables. Propensity scores for all individuals were estimated using a logistic regression model including age, sex, occurrence of diabetes mellitus (DM), hypertension and dyslipidemia, current smoking, and family history of CAD. A 1:1 nearest neighbor matching was performed with a caliper width of 0.2. The score-matched pairs were reanalyzed. A logistic regression analysis was performed to predict the presence of obstructive LM and/or pLAD lesions. First, we separately analyzed the relationships between the dependent variable and risk factors for CAD and LAFB. The variables that have p-value of <0.1 in a univariate regression analysis were included in the multivariate logistic regression analysis (forced entry method). A p-value <0.05 (2-tailed) was considered statistically significant.

Results

We observed that 750 patients (94.9%) undertook at least one non-invasive test, and 40 patients (5.1%) were referredfor ICA directly (Table 1). The median age was 58 years old and 532 (67.3%) of them were males. The number of patients with LAFB was 68 (8.6%). Furthermore, 218 patients (27.6%) had obstructive CAD and had been treated with PCI, coronary artery bypass graft, or optimal medical therapy alone (18.5%, 7.6%, and 1.5%, respectively). The prevalence of obstructive CAD and CABG use was significantly different across LAFB and non-LAFB. Also, the prevalence of obstructive LM and/or pLAD lesions was higher in patients with LAFB. Patients with LAFB had a significantly higher LVMI. The prevalence of LAFB increased with increasing LVH grades (19) (Figure 1). Patients with obstructive LM and/or pLAD lesions were older and had a higher prevalence of hypertension, DM, dyslipidemia, family history of CAD, and LAFB (Table 2).

After propensity score matching (68 vs 68 patients), the age, sex, DM, smoking status, hypertension, dyslipidemia, family history of CAD were similar between groups (Table 3). The obstructive LM and/or pLAD lesion rate remained significantly higher in patients with LAFB [8 (11.8%) vs 22 (32.2%), p=0.004].

In univariate analyses, the presence of LAFB was a significant predictor of obstructive LM and/or pLAD lesions (odds ratio: 3,587; 95% confidence interval: 1,465-5,785; p=0.005). Multivariate logistic regression analysis, using significant parameters obtained from univariate analysis, was conducted to reveal independent predictors of obstructive LM and/or pLAD lesions. A history of hypertension and DM were found to be independent predictors of obstructive LM and/or pLAD lesions. Although there was a significant relationship between the presence of LAFB and dependent variable in univariate logistic regression models, only known cardiovascular risk factors showed a direct significant association after adjusting for confounders. Thus, the presence of LAFB was not an independent predictor of obstructive LM and/or pLAD lesions (Table 4).

Discussion

We aimed at assessing the relationship between LAFB and obstructive LM and/or pLAD lesions in patients referred to ICA with stable angina pectoris. The cross-sectional analysis of our study revealed an association between the presence of LAFB and obstructive LM and/or pLAD lesions, advanced age, prevalence of dyslipidemia, and LVMI. Even though LAFB had a significant predictive value from univariate analysis, this association disappeared after adjustment for other cardiovascular risk factors. We found that the presence of LAFB has no independent role in predicting obstructive LM and/or pLAD lesions. Therefore, it should be considered a marker rather than a determinant of LM and/or pLAD lesions in patients with suspected stable angina pectoris.

In previous studies, the presence of LAFB differed when evaluated in different groups. In the general population, the prognostic implications of LAFB have been examined in studies with inconsistent results. Miller et al. (14) demonstrated that patients with LAFB had the poorest outcome among patients with uncomplicated ventricular conduction blocks, and emphasized that LAFB is a significant predictor of mortality. Conversely, other epidemiological studies suggested that isolated LAFB may not have adverse prognostic implications (12,20,21). Biagini et al. (13) concluded that LAFB is associated with an increased risk of cardiac death in patients with suspected CAD referred for dobutamine stress echocardiography. Similarly, as a recent study revealed that the presence of LAFB is related to an increased risk of all-cause death when compared with isolated RBBB in patients without apparent ischemic heart disease (22). In another study conducted in patients with no evidence of cardiac disease, investigators found a significant association between LAFB, and hypertension orcardiac disease (11).

Although LAFB has many etiologies, one of the most important causes is CAD (15). Previous studies have shown that high-grade narrowing of the LAD coronary artery can induce the development of LAFB (23-26). Assali et al. (23) reported that patients in whom LAFB develops during inferior wall acute myocardial infarction have a higher prevalence of stenosis in the LAD coronary artery. Lévy et al. (24) found that LAFB is associated with significant stenosis of the LAD coronary artery in patients with significant CAD at ICA. In another study, the same clinicians also showed that transient LAFB during an attack of angina pectoris may be indicative of a severe obstruction of the LAD coronary artery in the vicinity of the first perforator (25). It has been shown that selective opacification of the left coronary artery can cause transient left anterior hemiblock (26).

It is difficult to distinguish between a left axis deviation caused by LAFB and that caused by LVH. In general, LVH does not shift the axis more leftward than -30 degrees. However, these two situations may overlap. Our results indicate that LVMI was higher in the LAFB group. In addition, LAFB prevalence was highest in patients with severely abnormal LVMI. LVH is associated with coronary heart disease mortality and hypertension (27). Moreover, as LVH advances, the deterioration in coronary microvascular circulation (28) can cause conduction abnormality in the left anterior fascicle, which is very sensitive to ischemia. Hypertension is an important cause of increased LVMI and the presence of LAFB. These two clinical parameters, which have a significant but not an independent predictive value in our study, are indirect markers that reflect the role of hypertension in CAD. However, the left conduction system structure is more complex and variable than the simplified trifascicular structure. This may be why an obstructive LM and/or pLAD lesions were not directly and independently associated to LAFB.

DM is a major risk factor for CAD with increasing prevalence. It is also associated with increased LVM and interstitial and perivascular fibrosis (29). Therefore, cardiomyopathy and LVH are two other DM-associated abnormalities in cardiovascular function. There is paucity of data on the relationship between DM and cardiac conduction system disorders. Jeong et al. studied 14,540 patients and found that DM is independently associated with RBBB, but not LBBB (30). In another study, García Rubí and Baduí Dergal (31). detected a high prevalence of bifascicular block among patients with diabetes. Although the increased prevalence of LBBB in patients with DM was not reported, the presence of LBBB in DM indicates advanced cardiovascular involvement and CAD complexity (32,33). In our study, DM was more prevalent in the group with LAFB. This could reveal the direct effect of diabetes on atherosclerosis or LVH. Another possible theory suggests that autonomic neuropathy is another complication in patients with diabetes associated with the emergence of LAFB in this group. However, the evidence for such an association is lacking; therefore, more research is necessary to ascertain this relationship.

Study Limitations

Our study has several limitations. The study was conducted with a relatively small sample. In addition, CAD was only evaluated through visual interpretation.

Conclusion

LAFB is associated with known cardiovascular risk factors, but it acts as a marker rather than a determinant of obstructive LM and/or pLAD lesions in patients with stable angina pectoris. The significantly increased prevalence of obstructive LM and/or pLAD lesions in patients with LAFB might be due to an increased prevalence in hypertension and DM, but there is a need larger studies to ascertain this finding. Nevertheless, LAFB is not frequently a “normal variant,” and the presence of LAFB might help to identify obstructive LM and/or pLAD lesions in patients with suspected stable angina pectoris. Thus, physicians should have a low threshold for further cardiac evaluation if symptoms suggesting CAD are present.

Ethics Committee Approval: The approval form the the Clinical Research Ethics Committee of University of Health Sciences Turkey, Kanuni Sultan Süleyman Training and Research Hospital was obtained (approval number: 2020/62, date: 12.11.2020).

Informed Consent: Informed consent was granted by all patients before enrollment.

Peer-review: Externally and internally peer-reviewed.

Authorship Contributions: Surgical and Medical Practices - Ö.F.Ç., S.Ş.; Concept - Ö.F.Ç., S.Ş.; Design - Ö.F.Ç., A.S.Y.; Data Collection or Processing - Ö.F.Ç., S.Ş.; Analysis or Interpretation - Ö.F.Ç., S.Ş., A.S.Y.; Literature Search - Ö.F.Ç., A.S.Y.; Writing - Ö.F.Ç., A.S.Y.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.