Study Patients

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.

Statistical Analysis

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).