Coronary flow velocity reserve (CFVR) of the left anterior descending coronary artery (LAD) and myocardial contractile reserve are often impaired in nonischemic dilated cardiomyopathy (DCM). Whether they are affected by the presence of left bundle branch block (LBBB) remains unaddressed. The aim of the study was to investigate how LBBB influences CFVR of the LAD and myocardial contractile reserve in patients with DCM.
One hundred eighty-one patients with DCM (116 men; mean age, 63 ± 12 years) underwent high-dose dipyridamole (0.84 mg/kg over 6 min) stress echocardiography with CFVR evaluation of the LAD by Doppler. All patients had ejection fractions < 40% (mean, 31 ± 8%) and angiographically normal or near normal coronary arteries. CFVR was defined as the ratio between hyperemic peak and basal peak diastolic coronary flow velocities. CFVR > 2.0 was considered normal. Inotropic reserve was defined as rest-stress variation in wall motion score index ≥ 0.20. This was a prospective analysis of an unselected sample consecutively enrolled and retrospectively selected.
The study group was separated on the basis of presence ( n = 122) or absence ( n = 59) of LBBB. Patients with LBBB were older (64 ± 11 vs 59 ± 12 years, P = .004) and had reduced resting ejection fractions (30 ± 9% vs 33 ± 7%, P = .02), CFVR of the LAD (1.96 ± 0.41 vs 2.23 ± 0.73, P = .001), and myocardial contractile reserve (variation in wall motion score index, −0.18 ± 0.17 vs −0.33 ± 0.28; P < .001). On multivariate logistic regression analysis, resting ejection fraction (hazard ratio [HR], 1.15; 95% CI, 1.03–1.29; P = .01), smoking habit (HR, 2.63; 95% CI, 1.23–5.62; P = .01), and LBBB (HR, 2.29; 95% CI, 1.05–5.04; P = .04) were independently associated with reduced CFVR, while restrictive transmitral pattern (HR, 2.56; 95% CI, 1.18–5.55; P = .02), end-diastolic volume (HR, 0.98; 95% CI, 0.67–0.99; P = .02), and LBBB (HR, 2.20; 95% CI, 1.11−4.34; P = .02) independently predicted reduced myocardial contractile reserve.
CFVR during vasodilator stress echocardiography is a suitable tool for assessing microvascular dysfunction in routine clinical practice. Patients with DCM and LBBB show more severe forms of microvascular dysfunction, which is related to worse left ventricular function and lack of contractile reserve. Therapeutic interventions to restore microvascular function may improve left ventricular function parameters in patients with DCM.
Dual imaging of wall motion and Doppler-derived coronary flow velocity reserve (CFVR) during dipyridamole stress echocardiography has entered the echocardiography laboratory as an effective modality for both diagnostic and prognostic purposes. It has been demonstrated that among patients with nonischemic dilated cardiomyopathy (DCM), abnormal CFVR of the left anterior descending coronary artery (LAD) identifies a subset of patients at higher risk for spontaneous events (death and worsening of clinical status). This information is additive to that provided by echocardiographic assessment of left ventricular (LV) contractile reserve: when both parameters are analyzed, stratification ability improves, as a lack of inotropic reserve and reduced CFVR predict the worst outcome. Left bundle branch block (LBBB) is a quite common disorder and is often associated with organic heart disease. Although LBBB was associated with a three- to fourfold increase in cumulative cardiovascular mortality in the Framingham study, patients with no clinically overt heart disease have an excellent prognosis. LBBB leads to a delay in the mechanical activation of the left ventricle, which causes a disturbance of LV systolic function, together with diastolic function, by leading to interventricular asynchrony. The mechanical consequences of this electrical disorder are a decline in systolic performance, LV wall stress, and LV end-systolic volume increase. Furthermore, the presence of LBBB is an important determinant of diastolic dysfunction; in fact, it has been shown to shorten LV diastolic filling time and directly impair diastolic function.
The aim of this prospective, observational study was to evaluate the potential impact of LBBB on CFVR of the LAD and myocardial contractile reserve in patients with DCM. The study hypothesis was that in patients with DCM and LBBB, Doppler-derived CFVR of the LAD would be reduced, as well as contractile reserve, compared with those without LBBB.
From the prospective data bank of five different Italian institutions (in Mestre, Benevento, Lucca, Cesena, and Pisa), 190 patients with DCM tested with dual imaging stress echocardiography between 2005 and 2010 were initially selected according to the following criteria: (1) global LV dysfunction (ejection fraction < 40% by the biplane area-length method on resting echocardiography), (2) no history of ischemic heart disease, (3) angiographically normal (no detectable lesion on invasive coronary angiography) or near normal (no limiting stenosis on angiography) coronary arteries, (4) transthoracic echocardiogram adequate for assessing both resting regional systolic function (≥13 of 17 segments visualized in at least one projection) and LAD coronary flow by Doppler, and (5) enrollment in a follow-up program. Patients with hemodynamic instability, life-threatening ventricular arrhythmias, significant comorbidities reducing life expectancy to 1 year, or unwillingness to give informed consent were excluded. Of the 190 initially selected patients, four were excluded because of inadequate echocardiographic image quality during stress precluding satisfactory assessment of LAD flow ( n = 2) or wall motion analysis ( n = 2). Additionally, five patients were lost to follow-up. Thus, 181 patients (116 men; mean age, 63 ± 12 years) undergoing dipyridamole stress echocardiography with evaluation of CFVR of the LAD with available follow-up information formed the study group. Of them, 122 (64%) had complete LBBB on resting electrocardiography, defined as QRS complex duration ≥120 msec; upright notched or slurred R wave in leads I, aVL, and V 6 ; rS or a QS complex in lead V 1 ; absence of septal Q wave in leads V 5 and V 6 ; and displacement of the ST segment and T wave in the opposite direction from the QRS complex. All patients were receiving optimal and maximally tolerated pharmacologic therapy, according to the current guidelines. The study was approved by the institutional review board. All patients gave written informed consent when they underwent stress echocardiography. When patients provided written informed consent, they also authorized physicians to use their clinical data according to Italian law.
Resting and Stress Echocardiography
Each patient underwent M-mode and two-dimensional echocardiography, followed by color flow imaging and pulsed- and continuous-wave Doppler ultrasound. Transthoracic stress echocardiographic studies were performed using a commercially available ultrasound machine (iE33; Philips Medical Systems, Andover, MA) equipped with a 2.5- to 3.5-MHz phased-array sector scan probe (S3–S8) and second-harmonic technology. M-mode echocardiograms were obtained from the two-dimensional images under direct anatomic visualization. Left atrial and LV end-diastolic and end-systolic diameters were measured from the M-mode trace obtained in the parasternal long-axis view. LV ejection fraction was obtained in the four- and two-chamber views using the biplane area-length method.
Two-dimensional echocardiography and 12-lead electrocardiographic monitoring were performed in combination with a high dose of dipyridamole (up to 0.84 mg/kg over 6 min). During the procedure, blood pressure and electrocardiogram were recorded each minute. Wall motion score index (WMSI) (from 1 = normal to 4 = dyskinetic in a 17-segment model of the left ventricle) was assessed according to the recommendations of the American Society of Echocardiography and the European Association of Echocardiography.
CFVR was assessed during the standard stress echocardiographic examination by intermittent imaging of both wall motion and LAD flow. Coronary flow in the mid-distal portion of the LAD was searched in the low parasternal long-axis section under the guidance of color Doppler flow mapping. All studies were digitally stored to simplify offline review and measurements. Coronary flow parameters were analyzed offline using the built-in calculation package of the ultrasound unit. Flow velocities were measured at least two times for each study, namely, at baseline and at peak stress (before aminophylline injection). At each time point, three optimal profiles of peak diastolic Doppler flow velocities were measured, and the results were averaged. CFVR was defined as the ratio between hyperemic peak and basal peak diastolic coronary flow velocities. CFVR ≤ 2.0 was considered abnormal. The previously assessed intra- and interobserver variability for measurements of Doppler recordings and regional wall motion analysis assessment was <10%.
Contractile reserve was also dichotomized as the presence or absence of a rest-stress variation ≥ 0.20 in WMSI, on the basis of a previously identified diagnostically significant cutoff. LV end-diastolic and end-systolic volumes were also measured at baseline and at peak stress.
Data are expressed as mean ± SD for continuous variables and as number (percentage) for categorical variables. Continuous variables were compared using paired-samples t tests. Proportions were compared using χ 2 tests; Fisher exact tests were used when appropriate. Independent predictors of CFVR of the LAD and myocardial contractile reserve were assessed using multivariate logistic regression analysis. Proportionality for each predictor was tested as indicated by Kleinbaum and Klein. A significance level of .05 was required for a variable to be included in the multivariate model, while .10 was the cutoff value for exclusion. Hazard ratios (HRs) with corresponding 95% CIs were estimated. The following covariates were analyzed: age, gender, LBBB, diabetes mellitus, arterial hypertension, smoking habit, resting end-diastolic and end-systolic volumes, ejection fraction and WMSI, LV mass, and β-blocking therapy at the time of testing. P values < .05 were considered to indicate statistical significance. All statistical calculations were performed using SPSS for Windows version 16.0 (SPSS, Chicago, IL).
The sample was separated according to the presence (122 patients) or absence (59 patients) of LBBB. The clinical and echocardiographic characteristics of the study population are summarized in Table 1 .
|Variable||LBBB ( n = 122)||No LBBB ( n = 59)||P|
|Age (y)||64 ± 11||59 ± 12||.004|
|NYHA functional class I/II||55 (45%)||41 (69%)||.002|
|NYHA functional class III||67 (47%)||18 (30%)|
|Men||79 (65%)||37 (63%)||NS|
|β-blocking therapy||92 (75%)||46 (78%)||NS|
|LV end-diastolic volume (mL)||217 ± 70||194 ± 79||NS|
|LV end-systolic volume (mL)||149 ± 54||131 ± 64||NS|
|LV mass index (g/m 2 )||170 ± 42||163 ± 60||NS|
|LV ejection fraction at rest (%)||30 ± 9||33 ± 7||.018|
|LV ejection fraction at peak (%)||38 ± 11||41 ± 10||NS|
|WMSI at rest||2.08 ± 0.35||2.03 ± 0.36||NS|
|WMSI at peak||1.89 ± 0.41||1.71 ± 0.42||.006|
|ΔWMSI||−0.18 ± 0.17||−0.33 ± 0.28||<.001|
|Myocardial contractile reserve (%)||51 (34%)||39 (66%)||.003|
|Restrictive transmitral pattern||37 (30%)||12 (20%)||NS|
|CFVR of the LAD||1.96 ± 0.41||2.23 ± 0.73||<.001|
On individual patient analysis, 91 patients (51%) had CFVR of the LAD ≤ 2, and 90 patients (49%) had ΔWMSI < 0.20. No patient had positive results for myocardial ischemia.
Patients with LBBB were older (64 ± 11 vs 59 ± 12 years, P = .004) and had reduced resting ejection fractions (30 ± 9% vs 33 ± 7%, P = .02), CFVR of the LAD (1.96 ± 0.41 vs 2.23 ± 0.73, P = 0.001), and myocardial contractile reserve (ΔWMSI, −0.18 ± 0.17 vs −0.33 ± 0.28; P < .001) than those without LBBB. CFVR of the LAD and myocardial contractile reserve were inversely correlated in the group with LBBB ( r = −0.353, P < .001) as well as the group without LBBB ( r = −0.433, P < .001) ( Figure 1 ).
Similar proportions of patients with normal ( n = 65) and abnormal ( n = 73) CFVR (72% vs 81%, P = NS) were taking β-blockers. Likewise, β-blocking therapy was evenly distributed between patients with normal ( n = 70) and abnormal ( n = 66) myocardial contractile reserve (77% vs 72%, P = NS). LV mass index was not correlated with CFVR of the LAD ( r = −0.114, P = NS) or myocardial contractile reserve ( r = 0.133, P = NS). The main hemodynamic rest and stress parameters are reported in Table 2 .
|Variable||CFVR < 2||CFVR ≥ 2||P|
|Heart rate at rest (beats/min)||74 ± 13||72 ± 10||NS|
|Heart rate at peak stress (beats/min)||87 ± 15||88 ± 13||NS|
|Systolic blood pressure at rest (mm Hg)||124 ± 18||127 ± 20||NS|
|Systolic blood pressure at peak stress (mm Hg)||114 ± 18||118 ± 17||NS|
|Diastolic blood pressure at rest (mm Hg)||72 ± 13||72 ± 10||NS|
|Diastolic blood pressure at peak stress (mm Hg)||64 ± 10||65 ± 10||NS|
|Diastolic flow velocity at rest (cm/sec)||31 ± 6||30 ± 8||NS|
|Diastolic flow velocity at peak stress (cm/sec)||53 ± 12||72 ± 26||.001|
A multiple linear regression analysis was performed to identify the independent associations of CFVR, by including age, gender, smoking habit, β-blocking therapy, diabetes mellitus, arterial hypertension, LBBB, end-diastolic and end-systolic volumes, LV mass, LV ejection fraction, and restrictive transmitral pattern ( Table 3 ). CFVR was independently associated with ejection fraction at rest (HR, 1.15; 95% CI, 1.03–1.29; P = 001), smoking habit (HR, 2.63; 95% CI, 1.23–5.62; P = .01), and LBBB (HR, 2.29; 95% CI, 1.05–5.04; P = .04). When sequential models for the prediction of CFVR were used, LBBB showed incremental value compared with smoking habit and LV ejection fraction ( Figure 2 ). Interestingly, the presence of LBBB per se represented a risk for reduced CFVR onefold higher than a reduced ejection fraction.
|Variable||Univariate analysis||Multivariate analysis|
|HR (95% CI)||P||HR (95% CI)||P|
|Gender (male)||0.86 (0.45–1.57)||.62|
|Smoking habit||2.05 (1.09–3.87)||.03||2.63 (1.23–5.62)||.01|
|β-blocking therapy||1.23 (0.63–2.39)||.55|
|Diabetes mellitus||0.82 (0.349–1.91)||.64|
|Arterial hypertension||0.64 (0.36–1.16)||.14|
|LBBB||2.34 (1.236–4.43)||.009||2.29 (1.05–5.03)||.04|
|End-diastolic volume||1.01 (1.00–1.01)||.003|
|End-systolic volume||1.01 (1.01–1.02)||<.001|
|LV mass||0.99 (0.98–1.00)||.052|
|LV ejection fraction||1.13 (1.08–1.19)||<.001||1.15 (1.03–1.29)||.01|
|Restrictive transmitral pattern||3.21 (1.58–6.49)||.001|