CORRESPONDENCE: RESEARCH CORRESPONDENCE
Early recovery of impaired coronary flow reserve by carvedilol therapy in patients with idiopathic dilated cardiomyopathy: A serial transthoracic Doppler echocardiographic study
Kenichi Sugioka, MD,
Takeshi Hozumi, MD, FACC*,
Yasuhiko Takemoto, MD,
Keiji Ujino, MD,
Yoshiki Matsumura, MD,
Hiroyuki Watanabe, MD,
Kohei Fujimoto, MD,
Minoru Yoshiyama, MD and
Junichi Yoshikawa, MD, FACC
* Department of Internal Medicine and Cardiology, Osaka City University Medical School, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585 Japan (Email: thozumi{at}med.osaka-cu.ac.jp).
To the Editor: Coronary flow reserve (CFR) is impaired in patients with idiopathic dilated cardiomyopathy (IDC), despite angiographically normal coronary arteries, because of coronary microcirculatory dysfunction (1,2). Furthermore, it has been reported that a decreased hyperemic response of coronary flow is an indicator of a poor prognosis in patients with idiopathic left ventricular (LV) dysfunction (3). This suggests that the restoration of coronary microcirculation may lead to favorable clinical outcomes in IDC patients.
Large clinical trials have demonstrated that carvedilol, a third-generation beta-adrenergic blocking agent endowed with vasodilator and antioxidant properties, reduces morbidity and mortality in patients with heart failure and LV dysfunction, including that caused by IDC (4). However, the mechanisms behind the reduction of mortality in patients with IDC by carvedilol treatment remain unclear. Carvedilol treatment may contribute to a reduction of mortality in patients with IDC by improving CFR. The purpose of this study was to evaluate the short- and long-term effects of administration of carvedilol on CFR, which reflects coronary circulation, as assessed by transthoracic Doppler echocardiography (TTDE) in patients with IDC.
We studied 12 patients with IDC (8 men, 4 women; mean age 57 ± 16 years) who had not taken beta-blockers. All patients had clinically stable New York Heart Association (NYHA) functional class I/II symptoms. Each patient enrolled in the study met the following criteria: 1) normal sinus rhythm; 2) normal coronary arteries confirmed by coronary angiography or thallium-201 single-photon emission computed tomography; and 3) a LV ejection fraction (EF) <40%. Patients were excluded from the study if they had primary valvular heart disease or any known cause of dilated cardiomyopathy. All patients were stabilized using an angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, and diuretic treatment. Each patient received carvedilol in addition to their usual medications for heart failure. The starting dose of carvedilol was 2.5 or 5.0 mg/day, which was then gradually increased to a target dose of 20 mg/day or to a tolerated dose. An echocardiographic examination was performed at baseline, one month, and six months during treatment with carvedilol. Informed, written consent was obtained from each patient.
We used the Sequoia digital ultrasonography system (Siemens, Mountain View, California) or the Vivid 7 digital ultrasonography system (GE Vingmed Ultrasound, Horten, Norway) for echocardiographic measurements. The LV end-diastolic volume, end-systolic volume, and EF were calculated using the biplane Simpson formula. The mitral inflow velocity wave was recorded by pulsed Doppler echocardiography, and the E-wave velocity, A-wave velocity, E/A ratio and E-wave deceleration times were measured. Measurements of CFR in the left anterior descending coronary artery (LAD) by TTDE were performed as previously described (5), using high-frequency transducers (5.0- to 7.5-MHz on the Sequoia digital ultrasonography system or 4.4- to 11.4-MHz on the Vivid 7 digital ultrasonography system). We first recorded a baseline spectral Doppler signal in the LAD. Adenosine triphosphate was then administered intravenously (0.14 mg/kg body weight/min) for 2 min to record the spectral Doppler signal of peak flow response induced by dilation of the coronary microvessels. In the serial studies, we tried to record the spectral Doppler signal of LAD flow at the same portion of the artery in the same patient. All studies were acquired and stored digitally in the ultrasound system for off-line analysis. Mean diastolic coronary flow velocity (CFV) was measured by tracing the contour of the spectral Doppler signal at baseline and at peak flow response. The definition of CFR was the ratio of mean CFV at peak flow response to mean CFV at baseline.
The Friedman test was used to compare the three time points, and the Wilcoxon signed-rank test was performed if significance was found. All tests were two-tailed. A value of p < 0.05 was accepted as statistically significant. The quoted p values in Table 1 and Figure 1 were derived from the Wilcoxon signed-rank test.
View larger version (17K):
[in this window]
[in a new window]
|
Figure 1 The time course of change in coronary flow velocity (CFV) and coronary flow reserve (CFR) during carvedilol therapy. *p < 0.05 vs. baseline.
|
|
Of the 12 patients enrolled in this study, 2 did not complete the study protocol. One patient discontinued carvedilol due to hypotension and one died during follow-up. The mean maintenance dose of carvedilol was 14 ± 7 mg/day.
Hemodynamics and echocardiographic measurements are shown in Table 1. Systolic and diastolic blood pressures were significantly reduced at one month, but the change was not statistically significant at six months. Heart rate and the rate-pressure product were significantly decreased at one month, with no further change at six months. At one month, there was no significant change in LV end-diastolic volume, whereas the LV end-systolic volume decreased significantly. At six months, a significant reduction in both end-diastolic and -systolic volume was observed. Although LVEF did not change at one month, it increased significantly at six months. No significant changes were observed in the E- or A-wave velocity or E/A ratio at one or six months. The E-wave deceleration time increased significantly at one and six months.
Coronary flow data are shown in Figure 1. Resting CFV remained unchanged at one month (22 ± 6 cm/s) and at six months (21 ± 5 cm/s), as compared with baseline (24 ± 6 cm/s). A significant increase in adenosine-induced peak CFV was observed at one month (60 ± 21 cm/s vs. 75 ± 15 cm/s; p < 0.05) and at six months (78 ± 21 cm/s; p < 0.05). The CFR increased significantly at one month (2.6 ± 0.9 vs. 3.5 ± 0.7; p < 0.05), and this increase was confirmed at six months (3.7 ± 0.6; p < 0.05).
Previous studies reported that CFR was improved by an acute effect of beta-blockers in patients with coronary heart disease and healthy volunteers (6,7). In the present study, we observed that CFR in IDC patients was improved after both short- and long-term administration of carvedilol.
Therapeutic interventions could affect CFR by changing resting or peak coronary flow. It has been reported that the increase of peak CFV, rather than the decrease of resting CFV, may be of major importance in improved CFR after beta-blocker treatment (6,7). Resting coronary flow is determined by myocardial oxygen demand (6,8). An acute effect of beta-blockers decreases myocardial oxygen demand by reduced myocardial contractility and work, possibly leading to a reduction of resting coronary flow. However, the autoregulation for coronary circulation may work to preserve resting coronary flow volume within the autoregulatory range of coronary perfusion pressure (8). The mechanisms of the increase in peak coronary flow after carvedilol therapy are not fully defined. One possibility is that the action of beta-adrenergic blockade may decrease coronary vascular resistance by a diminution of the extravascular compressive forces, due to a reduced LV filling pressure (6,7). Second, the blunted heart rate response during beta-blockade may have beneficially affected the diastolic phase of myocardial perfusion during hyperemia (6). Third, the alpha1-adrenergic blocking action of carvedilol may induce the additional vasodilation of the coronary microcirculation by blockade of alpha1-mediated coronary vasoconstrictor tone during hyperemia (9).
Transthoracic Doppler echocardiography provides noninvasive, accurate, and repeatable CFR measurements (5). We describe the time course of change in CFR affected by carvedilol therapy in patients with IDC. In this study, LVEF improved significantly after six months of treatment, but there was no statistically significant change in EF at one-month follow-up, despite a rapid increase in CFR. Thus, the improvement of CFR is attained before improvement of LV systolic function, suggesting an early recovery of the coronary circulation in IDC patients by carvedilol therapy, followed by improved LV systolic function.
The administration of carvedilol improves impaired CFR in IDC patients. These data indicate that the improvement in CFR may be one of the mechanisms by which carvedilol has a favorable effect on the prognosis in IDC patients. Furthermore, carvedilol therapy improves CFR earlier than it does LV dysfunction in IDC patients.
 |
References
|
|---|
1. Cannon 3rd RO, Cunnion RE, Parrillo JE, et al. Dynamic limitation of coronary vasodilator reserve in patients with dilated cardiomyopathy and chest pain J Am Coll Cardiol 1987;10:1190-1200.[Abstract]
2. Inoue T, Sakai Y, Morooka S, et al. Coronary flow reserve in patients with dilated cardiomyopathy Am Heart J 1993;125:93-98.[CrossRef][Web of Science][Medline]
3. Neglia D, Michelassi C, Trivieri MG, et al. Prognostic role of myocardial blood flow impairment in idiopathic left ventricular dysfunction Circulation 2002;105:186-193.[Abstract/Free Full Text]
4. Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure N Engl J Med 2001;344:1651-1658.[Abstract/Free Full Text]
5. Hozumi T, Yoshida K, Akasaka T, et al. Noninvasive assessment of coronary flow velocity and coronary flow velocity reserve in the left anterior descending coronary artery by Doppler echocardiography: comparison with invasive technique J Am Coll Cardiol 1998;32:1251-1259.[Abstract/Free Full Text]
6. Bottcher M, Czernin J, Sun K, Phelps ME, Schelbert HR. Effect of beta1-adrenergic receptor blockade on myocardial blood flow and vasodilatory capacity J Nucl Med 1997;38:442-446.[Abstract/Free Full Text]
7. Billinger M, Seiler C, Fleisch M, Eberli FR, Meier B, Hess OM. Do beta-adrenergic blocking agents increase coronary flow reserve? J Am Coll Cardiol 2001;38:1866-1871.[Abstract/Free Full Text]
8. Hoffman JI. Maximal coronary flow and the concept of coronary vascular reserve Circulation 1984;70;:153-159.[Medline]
9. Lorenzoni R, Rosen SD, Camici PG. Effect of alpha1-adrenoceptor blockade on resting and hyperemic myocardial blood flow in normal humans Am J Physiol 1996;271:H1302-6.
This article has been cited by other articles:
|
|
|
|
 
H Oe, T Hozumi, E Murata, H Matsuura, K Negishi, Y Matsumura, S Iwata, K Ogawa, K Sugioka, Y Takemoto, et al.
Arachidonic acid and docosahexaenoic acid supplementation increases coronary flow velocity reserve in Japanese elderly individuals
Heart,
March 1, 2008;
94(3):
316 - 321.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Erdogan, H. Gullu, M. Caliskan, O. Ciftci, S. Baycan, A. Yildirir, and H. Muderrisoglu
Nebivolol improves coronary flow reserve in patients with idiopathic dilated cardiomyopathy
Heart,
March 1, 2007;
93(3):
319 - 324.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Takemoto, T. Hozumi, K. Sugioka, Y. Takagi, Y. Matsumura, M. Yoshiyama, T. P. Abraham, and J. Yoshikawa
Beta-Blocker Therapy Induces Ventricular Resynchronization in Dilated Cardiomyopathy With Narrow QRS Complex
J. Am. Coll. Cardiol.,
February 20, 2007;
49(7):
778 - 783.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
Top
References