Decreased cerebral blood flow is frequently observed in patients with heart failure, and this could be the result of impaired cardiac systolic function. Cardiac resynchronization therapy (CRT) improves cardiac function and heart failure symptoms in selected patients. The effects of CRT on cerebral blood flow have not been previously evaluated. In the present study, left ventricular systolic function and cerebral blood flow were assessed in 35 patients with heart failure, before and 6 months after CRT. Additionally, 15 patients with heart failure, who were not candidates for CRT, were included as a control group. The peak systolic velocity, end-diastolic velocity, mean velocity, and pulsatility index ([peak systolic velocity − end-diastolic velocity]/mean velocity) were obtained using transcranial Doppler from the right middle cerebral artery from the temporal window in all subjects. Response to CRT was defined as a reduction in the left ventricular end-systolic volume of ≥15%. At 6 months of follow-up, the peak systolic velocity had significantly increased from 83 ± 20 cm/s to 100 ± 20 cm/s (p = 0.001), the end-diastolic velocity had increased from 29 ± 7 cm/s to 37 ± 8 cm/s (p <0.001), and the mean velocity had increased from 47 ± 10 cm/s to 58 ± 11 cm/s (p <0.001) only in the responders to CRT. In contrast, no significant changes in cerebral blood flow were observed in the nonresponders and the controls. In conclusion, CRT induced an increase in cerebral blood flow in patients with heart failure. This increase in cerebral blood flow was related to the improvement in left ventricular systolic function.
Transcranial Doppler (TCD) has been validated as a reliable noninvasive technique to measure cerebral blood flow and is widely used. In the present study, cerebral blood flow was measured using TCD in patients with heart failure before cardiac resynchronization therapy (CRT) implantation and at 6 months of follow-up. The aim of the present study was to evaluate whether the cerebral blood flow was altered after CRT and whether the changes in cerebral blood flow were related to the improvement in cardiac systolic function after CRT.
Methods
A total of 35 patients scheduled for CRT were evaluated in the present study. The local ethics committee approved the present study, and all patients provided written informed consent. The selection criteria for CRT included advanced symptoms of heart failure (New York Heart Association [NYHA] functional class III or IV), left ventricular (LV) ejection fraction <35%, sinus rhythm, and a wide QRS complex (>120 ms). Patients with recent myocardial infarction (<3 months), decompensated heart failure, a history of ischemic stroke/transient ischemic attack, or known carotid stenosis were not included. The etiology of heart failure was considered ischemic in the presence of significant coronary artery disease (>50% stenosis in ≥1 of the major epicardial coronary arteries) and/or a history of myocardial infarction or previous revascularization.
Before CRT device implantation, the clinical status, including NYHA class, 6-minute walking distance, and Minnesota Living with Heart Failure Questionnaire (MLHFQ) score was assessed. Cognitive function was specifically evaluated using the psychometric subscore of the MLHFQ. This psychometric properties subscore has recently been validated against the more extensive Medical Outcomes Study 36-Item Short Form Health Survey.
In addition, the LV volumes and LV ejection fraction were measured using real-time 3-dimensional echocardiography. Cerebral blood flow was evaluated using TCD. At 6 months of follow-up, these measurements were repeated to assess the effect of CRT on cerebral blood flow, cognitive function, and LV performance. Patients with a reduction of ≥15% of LV end-systolic volume, reflecting improvement in LV systolic function, were considered responders to CRT.
Finally, 15 patients with heart failure, who were matched for age, gender, NYHA class, and LV function and were not candidates for CRT according to current guidelines (QRS duration <120 ms), were included as a control group. These patients underwent the same clinical, echocardiographic, and TCD assessments as the CRT recipients. All patients were taking stable heart failure medication, and the medical therapy was unchanged during the study period.
Complete echocardiographic methods have been previously described. In brief, patients underwent imaging in the left lateral decubitus position with a commercially available system (iE33, Philips Medical Systems, North America, Bothell, Washington) equipped with a ×3, fully sampled matrix transducer. Real-time 3-dimensional echocardiographic data sets were stored digitally and quantitative analysis of the 3-dimensional data set was performed off-line using a semiautomated contour tracing algorithm (Q-Lab, version 6.0, Philips Medical Systems) for a complete heart cycle.
The LV systolic performance was quantified by measuring the LV outflow tract velocity time integral using pulsed wave Doppler during end-expiratory apnea.
TCD images were acquired after the patient was in supine position for a minimum of 10 minutes, with the same system used for the echocardiographic examinations (iE33, Philips Medical Systems), equipped with a broadband, pure wave, S5-1 transducer. All TCD measurements were taken from the right middle cerebral artery from the temporal window. The blood flow velocities were measured by placing a sample volume of 2.5 mm in the bloodstream at a depth (range 40 to 65 mm) giving the greatest values. The software (HighQ) automatically calculated the peak systolic velocity, end-diastolic velocity, mean velocity, and pulsatility index ([peak systolic velocity − end-diastolic velocity]/mean velocity) using the automatic trace of the Doppler spectrum. For each patient, the blood flow velocities were obtained from a minimum of 10 cardiac cycles.
Continuous data are presented as the mean ± SD and dichotomous data as numbers and percentages. A comparison of the continuous data between the 2 groups was performed using the Mann-Whitney U test. For comparisons between >2 groups, the Kruskal-Wallis test with manual Bonferroni post hoc testing was performed. Fisher’s exact tests or chi-square tests were used to compare the dichotomous data. A comparison of continuous data within patient groups (at baseline and 6 months of follow-up) was performed using the Wilcoxon test. Additionally, linear regression analysis was performed to evaluate the relation between the reduction in LV end-systolic volume and increase in mean TCD velocity. All analyses were performed using the Statistical Package for Social Sciences for Windows, version 16.0 (SPSS, Chicago, Illinois). A p value of <0.05 was considered statistically significant.
Results
Adequate visualization of the middle cerebral artery was not feasible in 3 patients in the CRT group and in 1 control patient. These patients were excluded from additional analysis; therefore, the final study population consisted of 32 CRT recipients and 14 control patients. The baseline characteristics of the study population are summarized in Table 1 . By definition, the CRT patients and controls were comparable in terms of age, gender, NYHA class, and LV function. Control patients had a significantly shorter QRS duration (110 ± 8 ms vs 152 ± 25 ms, p <0.0001). No differences in baseline TCD measurements (ie, depth, number of samples, peak systolic velocity, end-diastolic velocity, mean velocity, and pulsatility index) were observed between CRT patients and controls.
| Variable | Patients (n = 32) | Controls (n = 14) | p Value |
|---|---|---|---|
| Men/women | 25/7 | 11/3 | 0.648 |
| Age (years) | 68 ± 10 | 66 ± 10 | 0.583 |
| Etiology of heart failure | |||
| Ischemic | 16 (50%) | 10 (71%) | 0.153 |
| Nonischemic | 16 (50%) | 4 (29%) | |
| QRS duration (ms) | 152 ± 25 | 110 ± 8 | <0.001 ⁎ |
| Systolic blood pressure (mm Hg) | 123 ± 15 | 121 ± 12 | 0.696 |
| Diastolic blood pressure (mm Hg) | 71 ± 10 | 73 ± 7 | 0.349 |
| New York Heart Association class | 3.0 ± 0 | 2.9 ± 0.3 | 0.132 |
| Medication | |||
| Angiotensin-converting enzyme inhibitors/angiotensin type II blockers | 30 (94%) | 13 (93%) | 1.000 |
| β Blockers | 24 (75%) | 13 (93%) | 0.240 |
| Diuretics | 29 (91%) | 10 (71%) | 0.176 |
| Spironolactone | 20 (63%) | 6 (43%) | 0.333 |
| Echocardiography | |||
| Heart rate | 70 ± 17 | 68 ± 13 | 0.558 |
| Left ventricular end-diastolic volume (ml) | 189 ± 68 | 158 ± 32 | 0.272 |
| Left ventricular end-systolic volume (ml) | 137 ± 55 | 109 ± 24 | 0.073 |
| Left ventricular ejection fraction (%) | 29 ± 6 | 32 ± 4 | 0.101 |
| Left ventricular outflow tract velocity time integral (cm) | 13 ± 4 | 14 ± 3 | 0.510 |
At 6 months of follow-up, the mean NYHA class improved in the CRT group from 3.0 ± 0 to 2.3 ± 0.7 (p <0.0001). In addition, the MLHFQ score decreased from 32 ± 16 to 24 ± 20 (p = 0.010) and MLHFQ-psychometric subscore decreased from 7.1 ± 5.3 to 4.8 ± 5.1 (p = 0.031), and the 6-minute walking distance increased from 333 ± 89 m to 374 ± 114 m (p = 0.024). Furthermore, significant LV reverse remodeling was observed, with a decrease in LV end-systolic volume from 137 ± 55 to 120 ± 50 ml (p = 0.001) and an improvement in LV ejection fraction from 29 ± 6% to 35 ± 8% (p <0.0001). Finally, a significant increase occurred in the LV outflow tract velocity time integral from 13 ± 4 to 14 ± 4 cm (p = 0.027).
In contrast, the control patients did not show any change in the echocardiographic parameters (LV end-systolic volume from 109 ± 24 to 111 ± 25 ml, p = 0.314; LV ejection fraction from 32 ± 4% to 32 ± 3%, p = 0.810; and LV outflow tract velocity time integral from 14 ± 3 to 15 ± 2 cm, p = 0.180).
At 6 months of follow-up, 16 patients (50%) demonstrated a response to CRT. No differences were found in the baseline clinical characteristics between responders and nonresponders, except for a nonischemic etiology of heart failure, which was more frequently observed in responders. The baseline echocardiographic characteristics were comparable between the 2 groups ( Table 2 ). Only responders showed a significant decrease in both the MLHFQ (from 31 ± 12 to 16 ± 12, p = 0.005) and the MLHFQ-psychometric subscore (from 6.8 ± 4.4 to 3.6 ± 3.3, p = 0.043), reflecting improvement in quality of life and cognitive function.
| Variable | Responders (n = 16) | Nonresponders (n = 16) | p Value |
|---|---|---|---|
| Men/women | 12/4 | 13/3 | 1.000 |
| Age (years) | 67 ± 10 | 69 ± 10 | 0.317 |
| Etiology of heart failure | |||
| Ischemic | 12 (75%) | 4 (25%) | 0.012 ⁎ |
| Nonischemic | 4 (25%) | 12 (75%) | |
| QRS duration (ms) | 159 ± 25 | 145 ± 24 | 0.105 |
| New York Heart Association class | 3.0 ± 0 | 3.0 ± 0 | 1.000 |
| Minnesota Living with Heart Failure Questionnaire | |||
| Baseline | 31 ± 12 | 35 ± 20 | 0.755 |
| Follow-up | 16 ± 12 † | 32 ± 24 | 0.088 |
| Minnesota Living with Heart Failure Questionnaire Psychometric subscore | |||
| Baseline | 6.8 ± 4.4 | 7.4 ± 6.2 | 0.909 |
| Follow-up | 3.6 ± 3.3 † | 6.1 ± 6.3 | 0.413 |
| Echocardiography | |||
| Left ventricular end-diastolic volume (ml) | |||
| Baseline | 188 ± 67 | 190 ± 70 | 0.836 |
| Follow-up | 186 ± 74 | 180 ± 59 | 0.880 |
| Left ventricular end-systolic volume (ml) | |||
| Baseline | 148 ± 65 | 126 ± 43 | 0.429 |
| Follow-up | 114 ± 55 ‡ | 127 ± 46 | 0.214 |
| Left ventricular ejection fraction (%) | |||
| Baseline | 28 ± 8 | 30 ± 4 | 0.557 |
| Follow-up | 40 ± 8 ‡ | 30 ± 4 | <0.001 ⁎ |
| Left ventricular outflow tract velocity time integral (cm) | |||
| Baseline | 12 ± 3 | 14 ± 4 | 0.187 |
| Follow-up | 14 ± 4 § | 14 ± 4 | 0.598 |
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