Methods

From June 2005 to November 2007, we prospectively enrolled 31 consecutive patients with stable primary heart failure and LV dysfunction who underwent stress RTMCE before and after 4-month exercise-based rehabilitation with medical treatment or medical treatment alone. Inclusion criteria were symptoms of heart failure for ≥1 year, optimized medical treatment, and LV ejection fraction <45%. Exclusion criteria were inability to exercise, malignant arrhythmias, ischemic cardiomyopathy, second- or third-degree atrioventricular block, severe obstructive pulmonary disease, severe valvar disease, decompensated heart failure within 2 weeks of stress RTMCE, and severe hypertension (blood pressure >180/110 mm Hg). Patients who did not complete ≥85% of exercise program were also excluded. The study was approved by the ethical committee and all patients gave written informed consent.

Enrolled patients were randomized to receive medical treatment (control group) or medical treatment plus a 4-month exercise training program in a supervised hospital-based setting according to the same protocol (trained group). They underwent dipyridamole stress RTMCE and cardiopulmonary exercise testing at baseline, when they were enrolled in the study, and after 4 months. Before stress testing, patients were requested to abstain from xanthine-containing food and drinks for ≥24 hours. All medications in use were obtained from patient information and chart registers.

RTMCE was performed using a commercially available ultrasound scanner (Sonos 7500, Philips Medical Systems, Andover, Massachusetts) equipped with an S3 transducer (1.8 to 3.6 MHz). A complete 2-dimensional echocardiogram was obtained at rest. Cardiac chamber diameters were determined according to recommendations of the American Society of Echocardiography. End-diastolic volume, end-systolic volume, and LV ejection fraction were calculated using a modified Simpson biplane method. Diastolic dysfunction was classified as I for patients with abnormal relaxation, II for a pseudo-normal pattern, and III for a restrictive pattern. The left ventricle was divided in 17 segments. Basal segments were not considered for quantitative analysis because of attenuation.

The contrast agent used was the commercially available lipid encapsulated microbubble Definity (Bristol-Myers Squibb Medical Imaging, Inc., North Billerica, Massachusetts). Color-coded power-modulation images were adjusted to achieve optimal nonlinear signals at a mechanical index of 0.2 and frame rate ≥25 Hz. Time-gain compensation and 2-dimensional gain settings were adjusted to suppress any nonlinear signals from tissue before contrast injection. After optimization, contrast was started intravenously at a continuous infusion rate. At this time, equipment settings were readjusted and then kept unchanged throughout the study. To assess the replenishment kinetics, microbubble destruction in the myocardium was induced by manually deflagrated flash containing 5 consecutive high-mechanical index (1.4) impulses. Sequences of low-power myocardial perfusion images containing ≥15 cardiac cycles after the flash were acquired. Contrast-enhanced images were obtained in the apical 4-, 2-, and 3-chamber views at baseline and after dipyridamole (0.84 mg/kg).

MBF was quantified using Q-Lab 4.0 (Philips Medical Systems, Bothell, Washington). Real-time myocardial contrast echocardiographic sequences were analyzed in end-systolic frames starting in the frame immediately after the flash and including 15 subsequent cardiac cycles. Regions of interest were placed and tracked manually within the myocardium of each segment with careful exclusion of epicardial and endocardial borders. Regions of interest of similar size and shape were drawn in baseline and peak dipyridamole stress images. To determine the ratio between plateau acoustic intensity in the myocardium and left ventricle, a region of interest of the same size was also set in the adjacent LV cavity, just near the myocardial sample (blood pool acoustic intensity). The software package automatically calculated the mean acoustic intensity of each region of interest and generated time-intensity curves that were subsequently fitted to a mono-exponential function: y = A (1 − e ^−βt ), where y is the acoustic intensity at sequence of images in time, A is the plateau acoustic intensity, and β is the replenishment velocity, the rate constant of acoustic intensity increase, and represents mean microbubble velocity. When curves did not fit to the mono-exponential function, or when we could not obtain adequate goodness of fitness, the segment was considered not analyzable. When a segment was considered not analyzable at rest or at peak stress in the 2 studies, it was disposed at all stages and studies (rest and peak). A was then normalized for the blood pool acoustic-intensity using equation: normalized A = 10 ([A − blood pool]/10) × 100.

An index of MBF was calculated as the product of normalized A × β. The average of all analyzable segments was considered for each patient. Intraobserver variabilities for measurements of β and MBF reserves in our laboratory have been previously described and were 2.1% (r = 0.99) and 7.4% (r = 0.95), respectively. Interobserver variabilities for the same parameters were 6.8% (r = 0.98) and 5.5% (r = 0.97), respectively.

Patients underwent cardiopulmonary exercise testing on a cycle ergometer using an increment protocol (5.0, 7.5, or 10 W/min). The 12-lead electrocardiogram was continuously monitored for ST segment, arrhythmias, and heart rate records at rest and during exercise and recovery period. Blood pressure was recorded at rest and every 2 minutes during exercise and recovery period. Peak oxygen consumption per unit time (V o ₂ ) was obtained on a breath-by-breath analysis of expired gas. Peak V o ₂ was defined as the greatest mean value during exercise when the subject could no longer maintain the pedaling at 60 rpm. Anaerobic threshold was determined to occur at the break point between carbon dioxide production and V o ₂ or the point at which ventilatory equivalent for oxygen and end-tidal oxygen partial pressure curves reached their respective lowest levels before beginning to increase. The respiratory compensation point was determined to occur at the point at which the ventilatory equivalent for carbon dioxide was lowest before systematic increase and when end-tidal carbon dioxide partial pressure reached a maximum and began to decrease.

The 4-month exercise training consisted of 3 60-minute exercise sessions/week; each session consisted of 5-minute stretching exercises, 25-minute cycling on an ergometer bicycle in the first month up to 40 minutes in the final 3 months, 10 minutes of local strengthening exercises, and 5 minutes of cool down stretching exercises.

Continuous variables were expressed as mean ± SD and categorical variables as proportions. Two-tailed unpaired and paired Student’s t tests were used for comparisons of dependent and independent samples. Chi-square test and analysis of variance were used for comparisons of proportions. All data analysis was performed with SPSS 17.0 for Windows (SPSS, Inc., Chicago, Illinois). Statistical significance was set at a p value <0.05.

Results

Of the 31 enrolled patients, 16 were randomized to the trained group and 15 to the control group. Of the 16 patients in the trained group, 1 had intense dyspnea during dipyridamole resulting in stress interruption and 2 did not complete the training program due to noncardiac reasons. Of the 15 patients in the control group, 5 did not agree to repeat RTMCE and cardiopulmonary exercise testing after 4 months and were excluded. The final population was constituted by 23 patients. Their clinical and echocardiographic characteristics are listed in Table 1 .

Table 1

Clinical and echocardiographic data of control and trained patients

	Age (years)/Gender	BMI (kg/m 2 )	Digitalis	ACEI	β Blocker	Diuretics	Baseline				4 Months
							EDV (ml)	ESV (ml)	EF (%)	DD	EDV (ml)	ESV (ml)	EF (%)	DD
Control 1	43/M	26	no	yes	yes	no	216	167	23	II	216	167	23	II
Control 2	46/M	26	no	yes	yes	yes	167	83	50	I	180	88	51	I
Control 3	48/F	26	no	yes	yes	no	167	118	29	I	167	113	32	I
Control 4	53/F	26	no	yes	yes	no	224	173	23	I	231	180	22	II
Control 5	54/F	24	no	yes	yes	yes	180	135	25	II	167	118	29	III
Control 6	60/F	25	no	no	yes	yes	180	118	34	I	187	118	37	I
Control 7	70/M	23	no	yes	yes	yes	247	173	30	II	247	180	27	II
Control 8	72/F	30	no	yes	yes	no	239	167	30	I	239	160	33	I
Control 9	74/F	28	no	no	yes	no	194	141	27	II	194	124	36	II
Control 10	74/M	25	no	no	yes	no	272	201	26	I	281	209	26	I
Trained 1	27/M	28	yes	yes	yes	yes	426	335	21	I	415	307	26	I
Trained 2	41/M	30	no	yes	yes	no	216	118	45	I	224	118	47	I
Trained 3	45/F	28	no	yes	yes	yes	180	102	43	I	173	97	44	I
Trained 4	46/M	28	yes	yes	yes	yes	194	108	45	II	194	97	50	I
Trained 5	49/M	24	no	yes	yes	yes	231	167	28	I	224	154	31	I
Trained 6	50/M	25	no	yes	yes	yes	180	130	28	III	180	124	31	II
Trained 7	54/F	30	yes	yes	yes	yes	255	173	32	I	247	160	35	I
Trained 8	55/M	30	no	yes	yes	yes	154	92	40	I	167	83	50	I
Trained 9	56/M	27	no	yes	yes	no	149	118	34	I	180	113	37	I
Trained 10	59/M	26	yes	yes	yes	yes	141	74	47	I	147	88	41	I
Trained 11	62/F	25	yes	yes	yes	yes	180	113	37	II	180	108	40	I
Trained 12	71/F	24	no	yes	yes	yes	147	88	41	I	147	83	44	I
Trained 13	76/M	26	no	yes	yes	yes	160	83	48	I	160	83	48	I

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