Although statins reduce cardiac events in hypertensive patients with cardiovascular risk factors, the effect of statins on coronary flow reserve (CFR) has not been examined. We tried to examine the effect of rosuvastatin on CFR in hypertensive patients at cardiovascular risk. CFR was studied in 56 hypertensive patients (40 men, 61 ± 9 years) with cardiovascular risk factors and without coronary artery disease in a prospective clinical trial. Using Doppler echocardiography, coronary flow velocity in the distal left anterior descending artery was recorded at baseline and during intravenous adenosine infusion, and CFR was defined as the ratio of hyperemic to basal average peak diastolic flow velocity. The primary efficacy measure was defined as the change in CFR after rosuvastatin therapy for 12 months. CFR was measured successfully in 55 of 56 enrolled patients (98%). CFR was 3.16 ± 0.44 at baseline and negatively correlated with age (R = −0.30, p = 0.025). All patients continued rosuvastatin 10 mg/day without any serious adverse events. After rosuvastatin therapy, serum total cholesterol, low-density lipoprotein cholesterol, and high-sensitivity C-reactive protein significantly decreased from 222 ± 18 to 142 ± 20 mg/dl, 148 ± 21 to 85 ± 18 mg/dl, and 1.7 ± 2.9 to 1.2 ± 3.1 mg/L, respectively (all p <0.01). CFR significantly increased from 3.16 ± 0.44 to 3.31 ± 0.42 (p <0.001). The change in CFR correlated with the change in low-density lipoprotein cholesterol (R = −0.28, p = 0.040) but not with the change in high-sensitivity C-reactive protein. In conclusion, CFR was significantly improved after 12 months of rosuvastatin therapy in hypertensive patients at cardiovascular risk and average levels of serum cholesterol.
Highlights
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Measurement of coronary flow reserve (CFR) by Doppler echocardiography is feasible.
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Rosuvastatin improves CFR in hypertensive patients at risk.
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The change in CFR correlated with the change in low-density lipoprotein cholesterol.
Statin therapy improves coronary flow reserve (CFR) and decreases cardiac morbidity and mortality in patients with coronary artery disease (CAD) and hypercholesterolemia. Lipid lowering with a statin also provided beneficial effects in hypertensive patients with average levels of serum total cholesterol in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm. Improvements in endothelial dysfunction and CFR may be related to the beneficial effects of statins in hypertensive patients without hypercholesterolemia. However, the effect of statins on CFR has not been examined in such patients because CFR could be invasively measured using a Doppler guidewire in a cardiac catheterization laboratory. Recent advances in echocardiographic imaging techniques have made it feasible to measure CFR in patients without CAD, which highly correlates with the CFR measured by invasive means. Accordingly, we tried to examine the hypothesis that statins improve CFR in hypertensive patients at cardiovascular risk by measuring the change in CFR after 1-year treatment with rosuvastatin and correlating the change in CFR with the change in low-density lipoprotein (LDL) cholesterol and high-sensitivity C-reactive protein (hsCRP).
Methods
The Rosuvastatin Effect on Serial Echocardiographic Measurement of Coronary Flow Velocity Reserve was a prospective clinical trial with a single-arm and open-label design ( ClinicalTrials.gov , NCT01490398 ). Patients eligible for inclusion were men and women aged from 35 to 80 years with controlled hypertension and hypercholesterolemia who were not currently taking a statin or a fibrate. Hypercholesterolemia was defined as a LDL cholesterol level ≥130 mg/dl, and controlled hypertension was defined as treated systolic blood pressure <140 mm Hg and diastolic blood pressure <90 mm Hg. In addition, patients were required to have at least one of the following cardiovascular risk factors: smoking, age ≥55 years (men) or ≥65 years (women), type 2 diabetes, peripheral arterial disease, previous stroke, premature family history of CAD, or high-density lipoprotein cholesterol level <40 mg/dl. Exclusion criteria were history of intolerance to statins, uncontrolled hypertension, secondary hypertension, currently treated angina, previous myocardial infarction, stroke or transient ischemic attack within the previous 3 months, heart failure, left ventricular hypertrophy, uncontrolled arrhythmia, fasting triglyceride level >500 mg/dl, or concomitant clinically important hematologic, gastrointestinal, hepatic, renal, or other diseases.
At an initial screening visit, blood pressure was measured by standard procedures, and fasting blood samples for total cholesterol, high-density lipoprotein cholesterol, LDL cholesterol, triglycerides, glucose, and hsCRP were obtained. Patient eligibility was assessed, and written informed consent was obtained from all patients. From January 2011 to August 2012, baseline echocardiographic evaluation and measurement of CFR were performed on 56 consecutive patients, 2 of whom had diabetes. Rosuvastatin 10 mg was given to study patients after a baseline assessment and continued for 1 year without further dose titration. Follow-up took place for all patients enrolled in the study at 1, 2, and 6 months and 1 year, and patients continued taking their antihypertensive medication, which was unchanged during the entire follow-up period. At 1-year follow-up, we collected fasting blood samples and performed echocardiographic follow-up measurement of CFR. The study protocol was approved by the Institutional Review Board of our institution.
Coronary flow velocity was recorded by an experienced sonographer (Hwang) who was blind to the patient data. Echocardiographic examinations were performed by placing a high-frequency (5 MHz) transducer at the fourth or fifth intercostal space in the midclavicular line of the left decubitus. After obtaining the longitudinal cross section of the lower interventricular sulcus, the distal left anterior descending coronary artery was visualized under the guidance of color flow mapping, and the coronary flow velocity was recorded using a pulse-wave Doppler. The diastolic coronary flow velocity was obtained for 5 heart beats at baseline and the maximum hyperemic period during intravenous adenosine infusion (0.14 mg/kg/min). All echocardiographic images were stored digitally in Digital Imaging and Communications in Medicine format, and 1 reader (Kang) measured peak diastolic flow velocities by batch reading of stored images on an off-line digital review workstation in a blind manner. The reader was unaware of the sequence to minimize bias. CFR was calculated as the ratio of hyperemic to basal averaged peak diastolic flow velocity. To determine measurement variability, 1 reader (Kang) reviewed 15 studies at 2 separate times and 2 readers (Kang and Sun) independently analyzed the same sample of images. Interobserver and intraobserver variabilities were calculated as the SD of the measurement differences and are expressed as percent of the average value. Interobserver and intraobserver variabilities for the measurement of CFR were 5.1% and 4.6%, respectively.
Categorical variables are presented as numbers and percentages, and continuous variables are expressed as mean ± SD and were compared using the Student unpaired and paired t tests. Sample size was calculated on the basis of the ability to detect a difference in the CFR from the baseline to the end of the study. Assuming a baseline CFR value of 2.5 ± 0.6 in patients without CAD, a sample size of 54 (85% power) was needed to show a 10% increase in CFR (2-sided α-level of 0.05). The change in the CFR value after rosuvastatin treatment for 12 months was analyzed using a paired t test. The correlation between the change in the CFR value and the change in LDL cholesterol and hsCRP values was also analyzed. All reported p values were 2-sided, and a value of p <0.05 was considered statistically significant. SAS software, version 9.1 (SAS Institute, Inc., Cary, North Carolina), was used for statistical analyses.
Results
CFR was measured successfully in 55 of 56 enrolled patients (98%); 1 patient with poor Doppler signals was excluded from the analysis. A total of 40 men (73%) and 15 women (27%) with a mean age of 61 ± 9 years were included in this study. Hypertension was adequately controlled at baseline with lifestyle modification alone (n = 1), single drug therapy (n = 16), or combination therapy (n = 38). All patients continued their antihypertensive medications and rosuvastatin 10 mg/day without any serious adverse events. The baseline hemodynamic, laboratory, and echocardiographic characteristics of the study patients are listed in Table 1 . CFR was 3.16 ± 0.44 at baseline and negatively correlated with age (R = −0.30, p = 0.025) but not with blood pressure, baseline cholesterol level, or hsCRP level. Baseline CFR was not significantly different according to antihypertensive medication ( Table 2 ).
| Variable | Baseline | 12 Months | p-Value |
|---|---|---|---|
| Systolic blood pressure (mm Hg) | 115 ± 13 | 112 ± 18 | 0.40 |
| Diastolic blood pressure (mm Hg) | 68 ± 9 | 69 ± 9 | 0.46 |
| Heart rate (bpm) | 68 ± 12 | 65 ± 8 | 0.033 |
| Total cholesterol (mg/dL) | 222 ± 18 | 142 ± 20 | <0.001 |
| LDL cholesterol (mg/dL) | 148 ± 21 | 85 ± 18 | <0.001 |
| HDL cholesterol (mg/dL) | 52 ± 10 | 48 ± 9 | <0.001 |
| Triglycerides (mg/dL) | 158 ± 97 | 122 ± 51 | 0.002 |
| C-reactive protein (mg/L) | 1.7 ± 2.9 | 1.2 ± 3.1 | 0.007 |
| Glucose (mg/dL) | 106 ± 17 | 107 ± 16 | 0.37 |
| Creatinine (mg/dL) | 1.0 ± 0.2 | 0.9 ± 0.2 | <0.001 |
| Coronary flow velocity (cm/s) | |||
| Baseline | 23 ± 6 | 23 ± 5 | 0.42 |
| Hyperemia | 73 ± 17 | 75 ± 14 | 0.16 |
| Coronary flow reserve | 3.16 ± 0.44 | 3.31 ± 0.42 | <0.001 |
| Coronary Flow Reserve | ARBs or ACEIs | CCBs | Diuretics | Beta-Blockers | ||||
|---|---|---|---|---|---|---|---|---|
| With (n = 49) | Without (n = 6) | With (n = 34) | Without (n = 21) | With (n = 15) | Without (n = 40) | With (n = 9) | Without (n = 46) | |
| Baseline | 3.15 ± 0.46 | 3.25 ± 0.33 | 3.17 ± 0.43 | 3.14 ± 0.48 | 3.08 ± 0.44 | 3.19 ± 0.45 | 3.12 ± 0.32 | 3.17 ± 0.47 |
| 12-month | 3.31 ± 0.44 | 3.30 ± 0.15 | 3.33 ± 0.42 | 3.29 ± 0.43 | 3.19 ± 0.50 | 3.36 ± 0.38 | 3.18 ± 0.27 | 3.34 ± 0.44 |
| Change | 0.16 ± 0.26 | 0.05 ± 0.25 | 0.16 ± 0.26 | 0.14 ± 0.27 | 0.12 ± 0.26 | 0.16 ± 0.26 | 0.06 ± 0.26 | 0.17 ± 0.26 |
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