Coronary flow reserve (CFR) is impaired and urinary albumin excretion is increased in patients with essential hypertension. Our aim was to investigate the associations between CFR and cardiac and renal damage in hypertensives. For this purpose we studied 37 never-treated hypertensives (57.9 years old, 16 men) without chest pain but with a positive ischemia stress test result and normal coronary arteries on coronary angiogram. CFR was calculated by a 0.014-inch Doppler guidewire (Flowire, Volcano, San Diego) in the left anterior descending artery in response to bolus intracoronary administration of adenosine (60 μg) as the ratio of hyperemic to basal average peak velocity of the distal vessel. All participants underwent complete echocardiographic study including left ventricular diastolic function evaluation by tissue Doppler imaging (peak early diastolic velocity/peak atrial systolic velocity) and determination of the albumin-to-creatinine ratio (ACR). Hypertensives with low CFR (<2.5, n = 22) compared to those with high CFR (n = 15) exhibited a larger left ventricular mass index by 10.9 g/m 2 (p = 0.045) and ACR values by 10 mg/g (p <0.001). CFR was negatively correlated with logACR (r = −0.511, p = 0.001). LogACR (beta −0.792, p <0.001), male gender (beta 0.313, p = 0.005), left ventricular mass index (beta −0.329, p = 0.007), and peak early diastolic velocity/peak atrial systolic velocity (beta 0.443, p <0.001) were the only independent predictors of CFR in linear regression analysis (adjusted R 2 = 0.672). In conclusion, never-treated asymptomatic hypertensives who exhibit impaired CFR and angiographically normal epicardial arteries are characterized by intrarenal vascular damage as reflected by increased ACR. These findings suggest a plausible role of ACR estimation in the identification of hypertensive subjects with early coronary microvascular dysfunction.
Recent advances have highlighted the mainstay involvement of the microcirculation in the course of cardiovascular diseases including hypertension. Research on coronary flow reserve (CFR), an index of coronary microvascular dysfunction, has shown that it is usually impaired despite the presence of angiographically normal coronary arteries and decreased CFR is associated with increased left ventricular (LV) mass, abnormal LV geometry, and diastolic function in essential hypertension. In microalbuminuria it constitutes an independent predictor of atherosclerotic cardiovascular events in diabetics, hypertensives, and the general population and is associated with diverse indexes of hypertensive target organ damage at the level of heart, large arteries, and coronary microcirculation. The available data thus far on the association of CFR with albuminuria have derived mainly from studies in patients with cardiac syndrome X and the coexistence of major cardiovascular risk factors particularly diabetes mellitus and renal dysfunction. Therefore, in the present study in nondiabetic hypertensive patients without chest pain and angiographically “normal” epicardial coronary arteries we investigated whether invasively determined CFR is related to albuminuria.
Methods
From the pool of patients who were referred or self-referred for evaluation of high blood pressure (BP) to the outpatient hypertension unit of our institute, we identified 37 consecutive never-treated essential hypertensives (57.9 years old, 16 men, Caucasian, daytime systolic BP >135 mm Hg) with positive ischemia treadmill exercise test results confirmed with thallium scintigraphy or dobutamine stress echocardiography who had no angiographically significant (<30%) stenoses in their coronary arteries. None of the participants exhibited any chest pain and angina-related symptoms at rest or during stress testing.
Exclusion criteria included the presence of moderate to severe valvular heart disease, fasting glucose >125 mg/dl, familial dyslipidemia, augmented serum creatinine concentration (≥1.3 mg/dl for women and ≥1.5 mg/dl for men), contraindication for adenosine (previous chronic obstructive pulmonary disease, use of xanthine, bradyarrhythmia), iodate contrast allergy, and any other clinically significant systemic disease. We also excluded subjects with left or right bundle brunch block, preexcitation syndromes, pacing rhythm, and atrial fibrillation. The study protocol complied with the Declaration of Helsinki and was approved by our institutional ethics committee. All participants gave written informed consent after a detailed description of the procedure.
BP measurement was performed at 3 different visits in our outpatient clinic by 1 physician using a mercury sphygmomanometer with the patient in the sitting position at rest for ≥5 minutes according to current guidelines. Ambulatory BP was recorded on a working day (Monday through Friday) using the automatic Spacelabs Units 90207 (Spacelabs, Redmond, Washington).
Standard transthoracic echocardiographic examination was carried out by the same expert in a dimly light room using a Vivid 3 PRO ultrasound imager (General Electric, Milwaukee, Wisconsin) equipped with a 2.5- to 5-MHz (harmonics) phased-array transducer according to current recommendations. LV mass was calculated with the method of Devereux et al and normalized for body surface area to obtain the LV mass index. LV diastolic function was determined using conventional Doppler parameters (peak velocities of E/A waves of transmitral flow) and tissue Doppler imaging-derived indexes (ratio of peak early diastolic velocity to peak atrial systolic velocity [Em/Am]) and averaging mean values obtained from measurements at the basal site of the lateral, septal, anterior, and inferior walls in 5 consecutive cardiac cycles as previously described.
Urinary albumin excretion was expressed as the albumin-to-creatinine ratio (ACR). In all subjects ACR was determined as the average of 2 nonconsecutive morning spot urine samples using a quantitative assay (DCA 2000, Bayer Diagnostics Europe, Dublin, Ireland) with a coefficient of variation of 2.8%. Serum creatinine was measured in a morning blood sample. Glomerular filtration rate was estimated by the Cockcroft–Gault formula.
Diagnostic coronary angiography was performed with a standard femoral percutaneous approach using nonionic contrast material. Once the diagnostic coronary angiography was completed, a 6Fr Judkins guiding catheter without side holes was inserted into the left coronary artery ostium without damping of the aortic pressure signal. All patients received heparin 5,000 IU and intracoronary nitroglycerin 0.2 mg. A 0.014-inch Doppler guidewire (FloWire, Volcano, San Diego) was advanced into the proximal part of left anterior descending artery. Electrocardiogram, coronary ostial pressure, instantaneous spectral peak velocity, and time-averaged spectral peak flow velocity were continuously and simultaneously recorded online. For offline analysis, angiography and Doppler measurements were recorded on compact disk and videotape, respectively. Baseline parameters were recorded when a stable and high-quality baseline signal without significant artifacts could be obtained.
In all participants intracoronary bolus adenosine was administered into the left coronary artery and further measurements were obtained under peak hyperemic conditions. To ensure maximal hyperemia, serial incremental adenosine doses were administered (30 to 60 μg of a solution of adenosine 6 mg in saline 1 L) until a plateau was achieved. Time-averaged spectral peak flow velocity returned to baseline values before each incremental bolus dose. CFR was calculated as the ratio of hyperemic to baseline time-averaged spectral peak flow velocity. All measurements were performed 2 times and mean values were calculated from 2 consecutive measurements. In the first 5 hypertensive patients we tested whether saline intrarenal infusion instead of adenosine had any impact on CFR.
Based on a CFR cut-off value of 2.5 hypertensives were classified as having normal (n = 15) or low (n = 22) CFR. Differences between hypertensives with normal and low CFR were evaluated using independent-sample Student’s t test for continuous variables and chi-square test for categorical variables. Pearson correlations were calculated to examine univariate relations of clinical and target organ damage parameters to CFR. Stepwise multiple linear regression analysis was used to test the independent relation of several variables to CFR. Descriptive statistics were arithmetic means ± SDs or medians (ranges) for skewed data. All statistical assumptions were met and no multicolinearity problems were found to exist in our analyses. Statistical significance was set at a p value <0.05.
Results
Hypertensive patients with low CFR compared to those with normal CFR did not differ in age, gender, body mass index, waist circumference, and metabolic profile (p = NS for all comparisons). Moreover, the difference in 24-hour systolic and diastolic BP values between study groups was not statistical significant (p = NS for the 2 comparisons). No change in CFR was detected in the 5 subjects who received the infusion of the normal saline solution.
Hypertensives with low CFR compared to those with normal CFR exhibited significantly increased ACR levels by 10 mg/g (p <0.001), whereas no difference was observed in creatinine values and glomerular filtration rates (p = NS for the 2 comparisons; Table 1 ). Analysis of covariance revealed that ACR remained significantly different between groups after adjustment for age, gender, smoking status, 24-hour BP, glomerular filtration rate, and glucose and lipid levels (p = NS).
| Parameter | Low CFR | Normal CFR | p Value |
|---|---|---|---|
| (n = 22) | (n = 15) | ||
| Age (years) | 58 ± 7 | 57 ± 6 | 0.52 |
| Men | 8 (36%) | 8 (53%) | 0.3 |
| Body mass index (kg/m 2 ) | 28 ± 3 | 30 ± 4 | 0.11 |
| Waist (cm) | 96 ± 10 | 101 ± 12 | 0.23 |
| 24-Hour systolic blood pressure (mm Hg) | 141 ± 20 | 133 ± 18 | 0.21 |
| 24-Hour diastolic blood pressure (mm Hg) | 88 ± 13 | 85 ± 10 | 0.41 |
| 24-Hour pulse pressure (mm Hg) | 53 ± 15 | 48 ± 11 | 0.33 |
| 24-Hour heart rate (beats/min) | 75 ± 11 | 72 ± 13 | 0.39 |
| Glucose (mg/dl) | 99 ± 17 | 98 ± 15 | 0.86 |
| Total cholesterol (mg/dl) | 190 ± 36 | 179 ± 33 | 0.33 |
| High-density lipoprotein (mg/dl) | 44 ± 10 | 44 ± 9 | 0.80 |
| Low-density lipoprotein (mg/dl) | 125 ± 34 | 117 ± 29 | 0.47 |
| Triglycerides (mg/dl) | 105 ± 37 | 91 ± 28 | 0.21 |
| Serum creatinine (mg/dl) | 0.82 ± 0.14 | 0.87 ± 0.13 | 0.30 |
| Glomerular filtration rate (ml/min) | 98 ± 26 | 104 ± 25 | 0.49 |
| Albumin/creatinine ratio (mg/g) | 19 (12–45) | 9 (6–12) | <0.001 |
For the echocardiographic parameters, hypertensives with low CFR compared to those with normal CFR had an increased LV mass index, although there was no difference in relative wall thickness. Moreover, hypertensives with low CFR compared to those with normal CFR were characterized by significantly decreased peak velocities of E/A waves of transmitral flow but not tissue Doppler imaging-derived Em and Em/Am ( Table 2 ). With respect to hemodynamic measurements, subjects with low compared to those with normal CFR exhibited significantly increased baseline time-averaged spectral peak flow velocity and baseline aortic systolic BP, pulse pressure, and heart rate ( Table 3 ).
| Low CFR | Normal CFR | p Value | |
|---|---|---|---|
| (n = 22) | (n = 15) | ||
| Left ventricular mass index (g/m 2 ) | 95 ± 18 | 84 ± 11 | 0.045 |
| Relative wall thickness | 0.42 ± 0.05 | 0.44 ± 0.04 | 0.22 |
| Left atrial diameter (mm) | 36.5 ± 4 | 38 ± 4 | 0.26 |
| Peak early transmitral flow velocity (m/s) | 0.74 ± 0.1 | 0.79 ± 0.2 | 0.48 |
| Late transmitral flow velocity (m/s) | 0.85 ± 0.2 | 0.74 ± 0.1 | 0.08 |
| Peak early/late flow velocity ratio | 0.87 ± 0.2 | 1.08 ± 0.4 | 0.038 |
| Peak early myocardial velocity (cm/s) | 7.9 ± 1.5 | 8.9 ± 2.5 | 0.23 |
| Late myocardial velocity (cm/s) | 10.8 ± 2.1 | 10.4 ± 1.3 | 0.49 |
| Peak early/late myocardial velocity ratio | 0.75 ± 0.2 | 0.88 ± 0.4 | 0.15 |
| Flow/myocardial early velocity ratio | 9.2 ± 1 | 8.9 ± 2 | 0.61 |
| Parameter | Low CFR | Normal CFR | p Value |
|---|---|---|---|
| (n = 22) | (n = 15) | ||
| Baseline average peak velocity (cm/s) | 32 ± 10 | 23 ± 2 | 0.001 |
| Baseline aortic systolic blood pressure (mm Hg) | 160 ± 27 | 139 ± 17 | 0.005 |
| Baseline aortic diastolic blood pressure (mm Hg) | 85 ± 16 | 80 ± 12 | 0.32 |
| Baseline aortic pulse pressure (mm Hg) | 75 ± 15 | 57 ± 8 | <0.001 |
| Baseline heart rate (beats/min) | 79 ± 8 | 69 ± 11 | 0.003 |
| Peak average peak velocity (cm/s) | 65 ± 17 | 74 ± 11 | 0.06 |
| Coronary flow reserve | 2.1 ± 0.2 | 3.1 ± 0.2 | <0.001 |
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