Prolonged QRS associated with left bundle branch conduction defect is a prognostic red flag in asymptomatic patients at risk for heart failure (ACCF/AHA stages A and B): Insights from the DAVID-Berg study

Electrocardiographic abnormalities are often observed in patients with heart failure. One of the most frequent is prolonged QRS duration (QRS > 120 ms), with a prevalence ranging from 14% to 47%,^1,–3 increasing in patients with lower left ventricular ejection fraction (LVEF) and higher New York Heart Association class.^2,4 In patients with heart failure and reduced ejection fraction a prolonged QRS (electrocardiogram (ECG)) has been associated with poor outcome and, along with the presence of left bundle branch block (LBBB), is considered a marker of worse prognosis.^1,–3,5,6 Similar findings have been reported in patients with heart failure and preserved LVEF. Indeed, in the I-Preserve (Irbesartan in Patients with Heart Failure and Preserved Ejection Fraction) trial, those patients with prolonged QRS were more likely to have signs and symptoms of decompensated heart failure.⁷

These studies suggest that in symptomatic chronic heart failure patients may exist a direct correlation between QRS duration and structural/functional myocardial abnormalities.

As a matter of fact, an ECG vector study of 146 patients with LBBB or right bundle branch block (RBBB) demonstrated that QRS prolongation was associated with myocardial infarction, ventricular hypertrophy and altered strain.⁸ Although the authors did not provide any clinical data regarding the study population, it could be inferred that comorbidities, associated with higher risk of myocardial ischaemia and hypertrophy (i.e. diabetes mellitus and hypertension) may have a crucial role in inducing a QRS prolongation.

While QRS duration has been extensively investigated in symptomatic heart failure patients, no data have been reported in patients at high risk for heart failure (American College of Cardiology Foundation/American Heart Association stages A and B).

We aimed to assess whether the presence of a prolonged QRS is associated with poor outcome in a clinical setting of patients at high risk for heart failure enrolled in the prospective DAVID-Berg (Detection of Asymptomatic VentrIcular Dysfunction in Bergamo) study.⁹ Patients aged 55 to 80 years were screened between January 2008 and May 2009. We selected patients without signs and symptoms of heart failure and with at least one of the following criteria: (a) ischaemic heart disease, as defined by angina pectoris with documented ischaemic changes at stress test, or angiographic evidence of coronary stenosis >70% in at least one epicardial vessel, previous myocardial infarction, previous percutaneous or surgical myocardial revascularization; (b) cerebrovascular disease, as defined by previous transient ischaemic attack, or stroke, or asymptomatic carotid stenosis >50%; (c) peripheral vessel disease, as defined by claudication or asymptomatic iliac/femoral artery stenosis >50%; (d) diabetes mellitus, as defined by fasting blood glucose ≥126 mg/dL, or by 2-h post-challenge serum glucose ≥200 mg/dL, or use of insulin, or oral hypoglycaemic agents; (e) hypertension, defined as systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg, or use of antihypertensive drugs.

The study sample consisted of 623 patients. All patients had a physical examination, 12-lead ECG, blood sample and echocardiogram.

All patients provided written informed consent to participate in the study, which conforms to the ethical guidelines of the Declaration of Helsinki as revised in 2000.

The endpoint used was the composite major adverse cardiac events (MACEs) including heart failure onset, cardiovascular hospitalization and all cause death. Heart failure onset was defined as hospital admission for heart failure, or as the appearance of heart failure signs and symptoms associated with change in diuretic therapy (introduction of loop diuretics or increased dose of any class of diuretics).

Univariate and multivariable Cox regression analyses were performed. Adjusted models considered age, sex, history of diabetes mellitus, atrial fibrillation, previous cardiovascular disease, N-terminal pro-B-type natriuretic peptide, LVEF and diastolic dysfunction. A generalized proportional hazards additive model was used to obtain multivariable-adjusted estimates of baseline QRS duration’s log(hazard) for MACEs.

We considered QRS duration as both continuous and categorical variable (cut off point 120 ms). Statistical analyses were performed using Stata version 13.0 (College Station, Texas, USA).

Baseline characteristics are displayed in Table 1. Mean QRS duration was 97 ± 21 ms, there were 109 patients (18%) with a QRS duration ≥120 ms, 58 (53%) had LBBB, while 51 (47%) had RBBB. Patients with QRS ≥ 120 ms were more often older, male, with lower LVEF and were more likely to be in Stage B compared with those with QRS < 120 ms. During a median follow-up of 5.7 years, there were 149 MACEs: 31 deaths and 118 non-fatal cardiovascular events. QRS duration was associated with an increased risk of worse outcome both at univariate and multivariable analyses (hazard ratio = 1.01; 95% confidence interval (CI) 1.00–1.02; p_adjusted = 0.037) (Figure 1). When QRS was considered as categorical variable, patients with QRS duration ≥120 ms had worse prognosis compared with those with duration <120 ms, both at univariate (hazard ratio 1.71; CI 1.17–2.51; p = 0.006) and at multivariable analysis (hazard ratio 1.57; CI 1.06–2.33; p = 0.02) (Figure 1). Among subjects with QRS duration ≥120 ms, the presence of LBBB further increased the risk of an adverse outcome (hazard ratio 2.08; CI 1.01–3.12; p = 0.002), while a RBBB pattern had a similar risk compared with the group of patients with QRS duration <120 ms (hazard ratio 1.33; CI 0.75–2.36; p = 0.3).

Figure 1.

Multivariable-adjusted relations of baseline QRS duration and incidence of composite endpoint on follow-up. Solid line shows the relation of estimated function of log(hazard) and QRS shaded area is 95% confidence interval.

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Table 1.

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Baseline characteristics of the study patients divided according to QRS duration.

.	QRS < 120 ms .	QRS ≥ 120 ms .	p value .
N (%)	514 (82)	109 (18)
Age, y (SD)	69 (±7)	70 (±7)	0.012
Male, n (%)	274 (53)	75 (69)	0.003
ACC/AHA stage			0.009
Stage A, n (%)	142 (28)	17 (16)
Stage B, n (%)	372 (72)	92 (84)
BMI, kg/m2 (SD)	28.7 (±5.1)	29.6 (±5.3)	0.08
HR, beats/min (SD)	75 (±13)	72 (±17)	0.13
SBP, mmHg (SD)	151 (±24)	152 (±24)	0.91
NT-pBNP, pg/mL median (IQR)	169 (87–340)	211 (111–553)	0.02
Tot. chol, mg/dL (SD)	203 (±42)	198 (±40)	0.30
History
Smokers, n (%)	63 (12)	16 (15)	0.49
Hypertension, n (%)	452 (88)	98 (90)	0.84
DM, n (%)	183 (36)	36 (33)	0.61
CKD, n (%)	117 (23)	24 (22)	0.94
Previous CVD, n (%)	258 (50)	63 (58)	0.30
AF, n (%)	16 (3)	7 (6)	0.01
Drugs (%)
ACE/ARB (%)	361 (70)	76 (70)	0.87
Beta-blockers (%)	181 (35)	49 (45)	0.16
Statin (%)	208 (40)	48 (44)	0.78
Diuretics (%)	80 (16)	14 (13)	0.77
Echocardiography
LVEF, % (SD)	61 (±9)	58 (±11)	0.003
Med E′, m/sec (SD)	0.07 (±0.02)	0.07 (±0.04)	0.26
E/E′	10.7 (±4.3)	11.8 (±5.1)	0.027
DD (%)	174 (34)	44 (40)	0.2
LAVi, ml/m2 (SD)	30 (±15)	33 (±20)	0.09

.	QRS < 120 ms .	QRS ≥ 120 ms .	p value .
N (%)	514 (82)	109 (18)
Age, y (SD)	69 (±7)	70 (±7)	0.012
Male, n (%)	274 (53)	75 (69)	0.003
ACC/AHA stage			0.009
Stage A, n (%)	142 (28)	17 (16)
Stage B, n (%)	372 (72)	92 (84)
BMI, kg/m2 (SD)	28.7 (±5.1)	29.6 (±5.3)	0.08
HR, beats/min (SD)	75 (±13)	72 (±17)	0.13
SBP, mmHg (SD)	151 (±24)	152 (±24)	0.91
NT-pBNP, pg/mL median (IQR)	169 (87–340)	211 (111–553)	0.02
Tot. chol, mg/dL (SD)	203 (±42)	198 (±40)	0.30
History
Smokers, n (%)	63 (12)	16 (15)	0.49
Hypertension, n (%)	452 (88)	98 (90)	0.84
DM, n (%)	183 (36)	36 (33)	0.61
CKD, n (%)	117 (23)	24 (22)	0.94
Previous CVD, n (%)	258 (50)	63 (58)	0.30
AF, n (%)	16 (3)	7 (6)	0.01
Drugs (%)
ACE/ARB (%)	361 (70)	76 (70)	0.87
Beta-blockers (%)	181 (35)	49 (45)	0.16
Statin (%)	208 (40)	48 (44)	0.78
Diuretics (%)	80 (16)	14 (13)	0.77
Echocardiography
LVEF, % (SD)	61 (±9)	58 (±11)	0.003
Med E′, m/sec (SD)	0.07 (±0.02)	0.07 (±0.04)	0.26
E/E′	10.7 (±4.3)	11.8 (±5.1)	0.027
DD (%)	174 (34)	44 (40)	0.2
LAVi, ml/m2 (SD)	30 (±15)	33 (±20)	0.09

Chronic kidney disease is defined as estimated glomerular filtration rate <60 ml/min per 1.73 m² using the MDRD formula.

ACC/AHA: American College of Cardiology/American Heart Association; ACE: angiotensin-converting enzyme; AF: atrial fibrillation; ARB: angiotensin receptor blocker; BMI: body mass index; CKD: chronic kidney disease; CVD: cardiovascular disease; DD: left ventricular diastolic dysfunction; DM: diabetes mellitus; E/E′: E wave/E′ wave ratio; HR: heart rate; LAVI: left atrial volume index; LVEF: left ventricular ejection fraction; Med E′: medial mitral annulus tissue Doppler; NT-proBNP: N-terminal pro-B-type natriuretic peptide; SBP: systolic blood pressure; Tot. chol.: total cholesterol.

Table 1.

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Baseline characteristics of the study patients divided according to QRS duration.

.	QRS < 120 ms .	QRS ≥ 120 ms .	p value .
N (%)	514 (82)	109 (18)
Age, y (SD)	69 (±7)	70 (±7)	0.012
Male, n (%)	274 (53)	75 (69)	0.003
ACC/AHA stage			0.009
Stage A, n (%)	142 (28)	17 (16)
Stage B, n (%)	372 (72)	92 (84)
BMI, kg/m2 (SD)	28.7 (±5.1)	29.6 (±5.3)	0.08
HR, beats/min (SD)	75 (±13)	72 (±17)	0.13
SBP, mmHg (SD)	151 (±24)	152 (±24)	0.91
NT-pBNP, pg/mL median (IQR)	169 (87–340)	211 (111–553)	0.02
Tot. chol, mg/dL (SD)	203 (±42)	198 (±40)	0.30
History
Smokers, n (%)	63 (12)	16 (15)	0.49
Hypertension, n (%)	452 (88)	98 (90)	0.84
DM, n (%)	183 (36)	36 (33)	0.61
CKD, n (%)	117 (23)	24 (22)	0.94
Previous CVD, n (%)	258 (50)	63 (58)	0.30
AF, n (%)	16 (3)	7 (6)	0.01
Drugs (%)
ACE/ARB (%)	361 (70)	76 (70)	0.87
Beta-blockers (%)	181 (35)	49 (45)	0.16
Statin (%)	208 (40)	48 (44)	0.78
Diuretics (%)	80 (16)	14 (13)	0.77
Echocardiography
LVEF, % (SD)	61 (±9)	58 (±11)	0.003
Med E′, m/sec (SD)	0.07 (±0.02)	0.07 (±0.04)	0.26
E/E′	10.7 (±4.3)	11.8 (±5.1)	0.027
DD (%)	174 (34)	44 (40)	0.2
LAVi, ml/m2 (SD)	30 (±15)	33 (±20)	0.09

.	QRS < 120 ms .	QRS ≥ 120 ms .	p value .
N (%)	514 (82)	109 (18)
Age, y (SD)	69 (±7)	70 (±7)	0.012
Male, n (%)	274 (53)	75 (69)	0.003
ACC/AHA stage			0.009
Stage A, n (%)	142 (28)	17 (16)
Stage B, n (%)	372 (72)	92 (84)
BMI, kg/m2 (SD)	28.7 (±5.1)	29.6 (±5.3)	0.08
HR, beats/min (SD)	75 (±13)	72 (±17)	0.13
SBP, mmHg (SD)	151 (±24)	152 (±24)	0.91
NT-pBNP, pg/mL median (IQR)	169 (87–340)	211 (111–553)	0.02
Tot. chol, mg/dL (SD)	203 (±42)	198 (±40)	0.30
History
Smokers, n (%)	63 (12)	16 (15)	0.49
Hypertension, n (%)	452 (88)	98 (90)	0.84
DM, n (%)	183 (36)	36 (33)	0.61
CKD, n (%)	117 (23)	24 (22)	0.94
Previous CVD, n (%)	258 (50)	63 (58)	0.30
AF, n (%)	16 (3)	7 (6)	0.01
Drugs (%)
ACE/ARB (%)	361 (70)	76 (70)	0.87
Beta-blockers (%)	181 (35)	49 (45)	0.16
Statin (%)	208 (40)	48 (44)	0.78
Diuretics (%)	80 (16)	14 (13)	0.77
Echocardiography
LVEF, % (SD)	61 (±9)	58 (±11)	0.003
Med E′, m/sec (SD)	0.07 (±0.02)	0.07 (±0.04)	0.26
E/E′	10.7 (±4.3)	11.8 (±5.1)	0.027
DD (%)	174 (34)	44 (40)	0.2
LAVi, ml/m2 (SD)	30 (±15)	33 (±20)	0.09

Chronic kidney disease is defined as estimated glomerular filtration rate <60 ml/min per 1.73 m² using the MDRD formula.

ACC/AHA: American College of Cardiology/American Heart Association; ACE: angiotensin-converting enzyme; AF: atrial fibrillation; ARB: angiotensin receptor blocker; BMI: body mass index; CKD: chronic kidney disease; CVD: cardiovascular disease; DD: left ventricular diastolic dysfunction; DM: diabetes mellitus; E/E′: E wave/E′ wave ratio; HR: heart rate; LAVI: left atrial volume index; LVEF: left ventricular ejection fraction; Med E′: medial mitral annulus tissue Doppler; NT-proBNP: N-terminal pro-B-type natriuretic peptide; SBP: systolic blood pressure; Tot. chol.: total cholesterol.

The results of the current study provide relevant and original evidences: (a) a consistent proportion (18%) of asymptomatic patients at high risk for heart failure has prolonged QRS lasting ≥120 ms; (b) prolonged QRS was associated with advanced American College of Cardiology/American Heart Association (ACC/AHA) stage; (c) the presence of QRS duration ≥ 120 ms is associated with a higher risk of adverse clinical outcomes; (d) the presence of LBBB associated with QRS ≥ 120 ms provides an additional risk of MACE. As previously reported, the presence of atrial fibrillation and LBBB has been associated with higher risk of outcome, particularly in mildly symptomatic heart failure patients.¹⁰ However, the low prevalence of atrial fibrillation (4%) in the overall population of DAVID-Berg does not allow further statistical analysis in this regard. To our knowledge, the present study is the first to assess the prognostic relevance of prolonged electrocardiographic QRS duration in the clinical setting of patients with ACCF/AHA stage A–B heart failure. Since ECG is an available screening test, which is commonly performed in primary care, and the measurement of QRS duration is an easy and objective parameter, it may help to assess those patients at higher risk of MACE, which may benefit from specialist referral. Further studies are needed to assess the influence of cardiac (i.e. atrial fibrillation) and extracardiac comorbidities (i.e. chronic kidney disease) on predictive risk of QRS duration in this population setting .

Acknowledgement

The authors thank Marilisa Ambrosio for skilful secretarial support.

References