Clin. Cardiol. 30, 475–479 (2007)
Effects of Atorvastatin on Coronary Flow Reserve in Patients with Slow Coronary Flow Mustafa Caliskan, M.D.,∗ Dogan Erdogan, M.D.,† Hakan Gullu, M.D.,∗ Semra Topcu, Aylin Yildirir, M.D., F.E.S.C.,∗ Haldun Muderrisoglu, M.D., F.E.S.C.∗
University, Konya Teaching and Medical Research Center, Cardiology Department, Konya; † Suleyman Demirel University Medical Center, Cardiology Department, Ispaita, Turkey
Summary Background: Statins improve endothelial functioning in patients with coronary artery disease and hypercholesterolemia, while substantially little is known about induced changes in myocardial microcirculation. However, although previous studies have suggested that microvascular abnormalities and endothelial dysfunction is responsible for slow coronary flow (SCF), there is no study investigating possible effects of statins on coronary microvascular function in patients with SCF. Hypothesis: We prospectively investigated the effects of short-term lipid-lowering therapy with atorvastatin on coronary flow reserve (CFR) reflecting coronary microvascular function in patients with SCF assessed by transthoracic Doppler echocardiography (TTDE). Methods: In an open clinical trial, CFR was studied in 20 subjects with SCF. TTDE was used to assess CFR at baseline as well as after 8 weeks of atorvastatin therapy. Coronary flow was quantified according to TIMI frame count (TFC). Coronary diastolic peak flow velocities were measured at baseline and after dipyridamole infusion. CFR was calculated as the ratio of hyperemic to baseline diastolic peak velocities. Results: CFR was independently correlated with TFC. After 8 weeks of atorvastatin therapy, CFR values
Address for reprints: Mustafa Caliskan, M.D. Baskent University Konya Teaching and Medical Research Center Cardiology Department, Hoca Cihan Mah., Saray Cad., No: 1, Selcuklu, Konya, Turkey e-mail: [email protected]
Received: December 7, 2006 Accepted with revision: February 5, 2007 Published online in Wiley InterScience (www.interscience.wiley.com). DOI:10.1002/clc.20140 2007 Wiley Periodicals, Inc.
increased significantly (1.95 ± 0.38 vs. 2.54 ± 0.56, (p < 0.001). No change in hemodynamic parameters was noted during the entire study. The improvement in CFR was not correlated to the amount of lipid-lowering effect of atorvastatin. Conclusions: These findings suggest that short-term lipid-lowering therapy with atorvastatin improved CFR, which reflects coronary microvascular functioning in patients with SCF. Key words: slow coronary flow, coronary flow reserve, echocardiography, atorvastatin Clin. Cardiol. 2007; 30: 475–479. 2007 Wiley Periodicals, Inc.
Introduction It has strongly been shown that lipid-lowering therapy with statins, including atorvastatin, leads to a significant reduction in cardiovascular morbidity and mortality, whether or not patients have a history of coronary artery disease.1 – 4 The antiatherogenic effects of these drugs not only depend on their lipid-lowering properties, but also depend on their pleiotrophic effects on vascular and cardiac cells independent of cholesterol synthesis.5 Slow coronary flow (SCF) phenomenon, which is characterized by delayed opacification of epicardial coronary arteries in the absence of stenotic lesion, was first defined by Tambe in 1972 on 6 patients with chest pain.6 Clinic and histopathologic studies have shown the existence of the loss of luminary diameter, diffused intimal thickening, longitudinally extended massive calcification, impaired fractional flow reserve, and capillary and endothelial damage of coronary arteries in most patients with SCF.7 On the basis of these findings, it is hypothesized that the SCF phenomenon may be a form, at least the early phase, of atherosclerosis that involve both small vessels and epicardial coronary arteries.
Clin. Cardiol. Vol. 30, September 2007
CFR measurement is used both to assess epicardial coronary arteries and to examine the integrity of coronary microvascular circulation. Impairment of endothelial function and reduced CFR, which reflects coronary microvascular function, has been shown to be the early manifestation of atherosclerosis and coronary artery disease.8 Recently, Britten et al.9 emphasized the prognostic importance of CFR with respect to atherosclerosis in subjects with normal coronary arteries or mildly diseased coronary arteries. Although Britten et al. used coronary Doppler to measure CFR, in recent years, using second harmonic transthoracic Doppler echocardiography (TTDE) for evaluating CFR has become very popular, and in several studies its feasibility has been validated in evaluating CFR in the middle to distal portion of the LAD.8,10 The present study assessed the effects of short-term atorvastatin therapy on CFR by TTDE in patients with SCF.
left and right anterior oblique views. Injection of contrast medium (Iopromide, Ultravist-370; Schering AG, Berlin, Germany) was carried out by an automatic injector, at a speed of 3–4 mL/s for left coronary artery and 2–3 mL/s for right coronary arteriographies were recorded at a speed of 25 frames/s. Coronary flow was quantified objectively by two independent observers, who were blinded to the clinical details of the individual participants, using the corrected TFC method. The first frame was defined by a column of contrast extending across >70% of the arterial lumen anterograde motion.11 The normal frame counts for the left anterior descending (LAD) coronary artery (36 ± 2.3 frames) are 1.7 times greater than the mean for the left circumflex coronary artery (22.2 ± 3.8 frames) and the right coronary artery (21.7 ± 2.8 frames).11 Hence, the longer LAD frame counts were corrected by dividing by 1.7 to derive the corrected TFC as described earlier.11 Definition of Slow Coronary Flow
Methods Study Population
Twenty-two patients with SCF were included in this study. All patients underwent coronary angiography, which showed normal epicardial coronary arteries and left ventricular systolic function. Diagnosis of SCF was based on thrombolysis in myocardial infarction (TIMI) frame count. Inclusion criterion included 18–75 years of age. Exclusion criteria included presence of a valvular or congenital heart disease; cardiac rhythm other than sinus; previous myocardial infarction; systemic diseases or any disease that could impair CFR (e.g. hypertrophic cardiomyopathy and diabetes mellitus), family history of coronary artery disease, and excessive alcohol consumption (>50 g/day). Subjects were excluded from the study if they were current smokers, and had ST-segment or T-wave changes specific for myocardial ischemia, Q-waves, and incidental left bundle branch block on ECG. Individuals were also excluded if they had triglyceride levels >4.56 mmol/L (400 mg/dL), body mass index greater than 35 kg/m2 , or left ventricular mass index 125 g/m2 for men and 110 g/m2 for women. Plasma levels of C-reactive protein were measured by use of a highly sensitive sandwich Elisa technique. Written informed consent was obtained from each subject. The institutional ethics committee approved the study protocol. Coronary Angiography and Documentation of TIMI Frame Count
Patients underwent selective coronary angiography using standard Judkins technique. Coronary arteries were visualized in left and right oblique planes, and cranial and caudal angles. Left ventriculography was performed in
All participants with a corrected TFC greater than two standard deviations from the normal published range for the particular vessel were accepted as having SCF while those whose corrected TFC fell within the standard deviation of the published normal range were considered to have normal coronary flow.11 After assessment of coronary flow in the coronary arteries using the corrected TFC method,11 the mean corrected TFC, which is the mean value of the frame count in the LAD, left circumflex coronary artery and right coronary artery, was obtained from the participants with SCF. Intra- and inter-observer variability for TFC was 0.954 and 0.923, respectively. Study Design and Drug Titration
The study was performed according to an open design. After baseline assessment of CFR by TTDE, patients received atorvastatin 20 mg once daily at night. Patients were scheduled to visit the clinic every 2 weeks. Eight weeks of atorvastatin therapy, serum lipid concentrations and echocardiographic examination were repeated 8 h after administration of atorvastatin. The same investigator who had been blinded to the subjects’ data performed all echocardiographic examinations. Echocardiographic Examination and CFR Measurement
Each subject was examined using an Acuson Sequoia C256 Echocardiography System equipped with 5V2c broadband transducers. (Acuson Corp, Mountain View, CA, USA). Visualization of the distal LAD was performed using a modified, foreshortened, 2-chamber view obtained by sliding the transducer on the upper part and medially from an apical 2-chamber view. Coronary flow Clinical Cardiology DOI:10.1002/clc
M. Caliskan et al.: Statin in slow coronary flow
in the distal LAD was examined by color Doppler flow mapping over the epicardial part of the anterior wall, with the color Doppler velocity range set in the range of 8.9 to 24.0 cm/s.12 The left ventricle was imaged on the long-axis cross-section, and the ultrasound beam was then inclined laterally. Next, coronary blood flow in the LAD (middle to distal) was searched by color Doppler flow mapping. All subjects had Doppler recordings of the LAD with a dipyridamole infusion at a rate of 0.56 mg/kg over 4 min. By placing the sample volume on the color signal, spectral Doppler of the LAD showed the characteristic biphasic flow pattern with larger diastolic and smaller systolic components. Coronary diastolic peak velocities were measured at baseline and after dipyridamole by averaging the highest 3 Doppler signals for each measurement. CFR was defined as the ratio of hyperemic to baseline diastolic peak velocities.12 To test the reproducibility of CFR measurement, in 8 subjects the measurement was repeated 1 month later. Intra-observer intra-class correlation coefficient for coronary flow measurement was 0.898 and 0.844 (baseline and hyperemic, respectively), and for CFR value it was 0.864.
TABLE 1 Demographic, biochemical, graphic characteristics of the patients
Patients with SCF (n = 20) Clinical data Age (year) Male/female Body-mass Index (kg/m2 ) Hypertension Baseline hemodynamics Systolic BP (mmHg) Diastolic BP (mmHg) Heart rate (beats/min) Hematological and biochemical data Hemoglobin (g/dL) Glucose (mmol/L) TFC LADa LCx RCA Mean TFC
54.7 ± 12.1 12/8 28.0 ± 3.0 5/20 (25%) 123.3 ± 8.2 77.0 ± 4.7 66.3 ± 8.1 14.4 ± 1.4 5.53 ± 0.77 58.2 ± 16.2 34.7 ± 14.9 31.9 ± 15.6 42.0 ± 10.4
Abbreviations: BP = blood pressure; TFC = TIMI frame count; LAD = left anterior descending; LCx = left circumflex; RCA = right coronary artery. a Corrected TFC was given for the LAD artery.
The analyses were performed using SPSS 9.0 (SPSS for Windows 9.0, Chicago, IL). Data were expressed as mean ± SD. Before and after treatment comparison analyses were made using paired samples t-test. Pearson’s correlation analysis was used to test univariate relations. Prediction of independent variables was obtained by stepwise, forward, multiple regression model including potential confounders. P values