Coronary Microvascular Function in Patients With Isolated Systolic and Combined Systolic/Diastolic Hypertension

Abstract

J Clin Hypertens (Greenwich). 2012;14:871–876. ©2012 Wiley Periodicals, Inc.

Isolated systolic hypertension (ISH) is a common condition in the elderly that is associated with endothelial dysfunction. Concerning the effect of type of hypertension on coronary microvascular function, coronary flow reserve (CFR) in patients with ISH was evaluated and the results were compared with patients with combined systolic/diastolic hypertension (SDH). Seventy‐six elderly patients (older than 60 years) who were free of coronary artery disease and diabetes mellitus were enrolled in the study (38 with ISH and 38 with combined SDH). Using transthoracic Doppler echocardiography, CFR was calculated as the ratio of hyperemic to baseline diastolic peak flow velocities. A CFR value of >2 was accepted as normal. The mean age was 68.6±6.3 years and the groups had similar features with regard to demographic and clinical characteristics. Patients with ISH had significantly lower CFR values compared with those with combined SDH (2.22±0.51 vs 2.49±0.56, respectively; P=.03). On multivariate regression analysis, ISH (β=−0.40, P=.004) and dyslipidemia (β=−0.29, P=.04) were the independent predictors of CFR. These findings indicate that CFR, an indicator of coronary microvascular/endothelial function, is impaired more profoundly in patients with ISH than in patients with combined SDH.

Hypertension, which is a common condition in the population, is one of the major and modifiable risk factors for atherosclerosis. Around 50% of people older than 60 years have been demonstrated to have hypertension and in around half of these cases, hypertension was reported to be in the form of isolated systolic hypertension (ISH). ¹ , ² In contrast, in younger patients (younger than 50 years), combined systolic/diastolic hypertension (SDH) is the predominant form of hypertension characterized by increased systolic and diastolic blood pressure (BP) or diastolic BP alone.

Endothelial dysfunction, characterized by decreased nitric oxide bioavailability, is a key event in the progression of atherosclerosis, and when detected in the systemic or coronary circulation, it is an independent predictor of cardiovascular mortality. ³ , ⁴ Atherosclerotic risk factors, including hypertension, are associated with systemic endothelial dysfunction and increased arterial stiffness.

Determining coronary flow reserve (CFR) by transthoracic Doppler echocardiography (TTDE) has been introduced as a reliable and reproducible indicator of coronary microvascular‐endothelial function. Demonstrating CFR noninvasively by TTDE has been shown to have a strong correlation with CFR obtained invasively by intracoronary Doppler wire and positron emission tomography. ⁵ , ⁶

Coronary endothelial dysfunction has been reported to be of prognostic significance and an early manifestation of atherosclerosis and CAD. ⁴ , ⁷ Previously, Erdogan and colleagues ⁸ reported that coronary microvascular function is impaired in patients with hypertension. In that study, patients with prehypertension, compared with controls, were also found to have decreased CFR. However, there are no data describing the impact of ISH on coronary microvascular function.

Keeping these data in mind, and concerning the effect of type of hypertension on coronary microvascular function, we aimed to evaluate CFR in patients with ISH and compare the results with that obtained from patients with SDH.

Methods

Study Patients

Seventy‐six patients 60 years or older were enrolled in the study. The first group was composed of patients with ISH (n=38) and the second group included patients with combined SDH (n=38). Demographic and clinical variables were noted. Dyslipidemia (total cholesterol >200 mg/dL, low‐density lipoprotein cholesterol >130 mg/dL or high‐density lipoprotein cholesterol <40 mg/d, or taking a lipid‐lowering medication), smoking (current cigarette smoking or quit ≤2 years), and family history of premature ischemic heart disease (55 years or younger male first‐degree relatives or 65 years or younger female first‐degree relatives) were recorded as the major coronary risk factors.

Coronary artery disease (CAD) was defined as the presence of one of the following: typical angina, ST‐segment or T‐wave changes specific for myocardial ischemia, Q waves or incidental left bundle‐branch block on electrocardiography, wall motion abnormality on echocardiography, a noninvasive stress test revealing ischemia or any perfusion abnormality, and history of a myocardial infarction/revascularization. A noninvasive stress test (treadmill exercise or myocardial perfusion scintigraphy) was performed in patients who had unequivocal symptoms. Those who had a positive result were excluded.

Exclusion criteria were as follows: known or suspected CAD, diabetes mellitus, moderate to severe aortic or mitral regurgitation, hypertrophic cardiomyopathy, renal dysfunction, asthma, malignancy, and poor echocardiographic image.

Blood samples were withdrawn from each participant after an overnight fasting. Biochemical parameters were studied by the enzymatic colorimetric assays (the Roche/Hitachi, Mannheim, Germany).

All the patients provided written informed consent and the ethics committee at our institution approved the study protocol.

BP Measurements

Using a mercury sphygmomanometer, BP was measured from the left arm at sitting position as recommended in the recent guideline. ⁹ At least three readings were obtained from each patient in a quiet room, after at least 5 minutes of rest on separate occasions. Systolic and diastolic BP were recorded at the first appearance (phase I) and disappearance of Korotkoff sounds (phase V). The average of three measurements was noted as the baseline BP value. Hypertension was defined as a systolic BP ≥140 mm Hg and/or a diastolic BP ≥90 mm Hg or being treated with an antihypertensive medication. ISH was defined as a systolic pressure ≥140 mm Hg and a diastolic pressure <90 mm Hg. ⁹

Echocardiographic Examination

Transthoracic echocardiographic examinations were carried out using a commercially available system (the Acuson Sequoia C256, Mountain View, CA). Two‐dimensional, M‐mode and Doppler echocardiographic measurements were performed according to recommendations for chamber quantification and recommendations for the evaluation of left ventricular (LV) diastolic function by echocardiography by the American Society of Echocardiography. ¹⁰ , ¹¹ LV mass was calculated according to Devereux, ¹² and LV hypertrophy was defined as LV mass index ≥110 g/m² in women and ≥125 g/m² in men. LV systolic dysfunction was defined as global or regional wall‐motion abnormality on echocardiography or ventriculography, ejection fraction (EF) <50%, or fractional shortening <25%.

Diastolic dysfunction was defined as a mitral E/A ratio <1 and isovolumetric relaxation time ≥110 ms or mitral E‐wave deceleration time ≥240 ms on Doppler echocardiography. All echocardiographic measurements were recorded on a VHS videotape and analyzed by a single observer who was blinded to the study protocol.

Determination of CFR

As described by Hozumi and associates, ⁶ a modified, foreshortened, two‐chamber view was used to achieve optimal alignment to the interventricular sulcus and to visualize the mid‐distal part of the left anterior descending (LAD) coronary artery. Color Doppler and pulsed Doppler recordings of the mid to distal LAD was obtained from each patient. To optimize color‐flow imaging, frame rate and flow velocity cut‐off were minimized and wall motion signals were eliminated. The Doppler sampler was adjusted to incorporate LAD data alone and flow was analyzed. Sample volume was placed on the color signal; spectral Doppler of LAD displayed the characteristic biphasic flow pattern, with larger diastolic and smaller systolic components (Figure 1). One of the major limitations of echocardiographically obtained CFR is suboptimal image quality. Concerning technical accuracy, we also excluded patients with poor image quality. If the incident angle between the Doppler beam and blood flow is large, assessment of absolute blood velocity can be limited. In addition, the drug used for induction of hyperemia should not affect the conduit function of coronary arteries. For this reason, we used dipyridamole. At baseline and after dipyridamole infusion (0.56 mg/kg over 4 minutes), coronary diastolic peak velocities (DPVs) were measured and the highest three Doppler recordings were averaged for each measurement. CFR was calculated as the ratio of hyperemic to baseline DPV. ¹³ , ¹⁴ A CFR value ≥2 was accepted as normal. ¹⁵

Figure 1.

 Assessment of coronary flow reserve. Spectral Doppler coronary blood flow by sampling the mid‐ to distal segment of the left anterior descending coronary artery. At baseline (A) and at hyperemia induced by dipyridamole infusion (B).

Data Analysis

Statistical analyses were performed with SPSS software (version 11.0; SSPS Inc, Chicago, IL). Using power analysis, the sample size was calculated. Mean CFR value obtained from 10 control patients was 2.5±0.5. To detect a 15% reduction in CFR and to give the trial a power of 85% (for alpha <0.05), power analysis revealed that 33 patients per group were needed.

Continuous variables are presented as mean±standard deviation (SD) and differences between the groups were examined using the unpaired t test. Mann‐Whitney U test was employed for the variables that did not have a normal distribution with skewness and kurtosis. Categorical variables are given as group percentages, and the comparison of the two groups were obtained using the chi‐square test. Correlations were established by the Pearson correlation analysis or the Spearman rank correlation test as appropriate. Multivariate linear regression analysis was employed using parameters that were shown to have an impact on CFR on previous trials or parameters that could be clinically related to CFR in order to determine independent determinants of CFR. All P values are 2‐sided, and values <.05 were considered statistically significant.

Results

Clinical and Laboratory Data

Baseline demographic and clinical characteristics of the patients in both groups are provided in Table I. Mean age of the study population was 68.6±6.3 years and the groups were homogenous with respect to demographic features including age and sex. Distribution of the atherosclerotic risk factors, including the prevalence of dyslipidemia, smoking, and family history of premature CAD, were similar in both groups (Table I).

Table I.

 Clinical and Laboratory Characteristics of the Study Groups

Clinical Characteristics	Combined SDH (n=38)	ISH (n=38)	P Value
Age, y	67.6±6.3	69.6±6.2	.1a
Women/men	30/8	28/	.7b
Body mass index, g/m2	28.2±4.0	28.4±4.6	.8a
Atherosclerotic risk factors
Dyslipidemia, %	60.5	65.8	.8b
Tobacco smoking, %	7.9	18.4	.3b
Family history of early CAD, %	32.4	36.8	.8b
Medications
ACE inhibitor, %	44.7	39.5	.8b
ARB, %	18.4	15.8	1.0b
CCB, %	34.2	55.3	.1b
Diuretic, %	55.3	76.3	.09b
β‐Blocker, %	34.2	28.9	.8b
Statin, %	21.1	26.3	.7b
Laboratory variables
Glucose, mg/dL	94±11	98±14	.2a
Total cholesterollevel, mg/dL	205±50	212±40	.5a
LDL level, mg/dL	127±26	123±30	.5a
HDL level, mg/dL	58±16	57±14	.8a
Triglyceride level, mg/dL	109.0 (82.0–183.0)	111.0 (85.5–147.5)	.9c
C‐reactive protein, mg/L	3.1 (1.4–6.9)	3.3 (1.7–7.7)	.7c
ALT, U/L	19.0 (12.2–26.0)	16.5 (12.0–22.7)	.4c
Creatinine, mg/dL	0.93±0.29	0.96±0.31	.6a
Leukocyte, thousand/μL	6.7±1.4	7.7±2.4	.03a

Abbreviations: ACE, angiotensin‐converting enzyme; ALT, alanine aminotransferase; ARB, angiotensin receptor blocker; CAD, coronary artery disease; CCB, calcium channel blocker; HDL, high‐density lipoprotein; ISH, isolated systolic hypertension; LDL, low‐density lipoprotein; SDH, systolic/diastolic hypertension.. Data are expressed as mean±standard deviation, median (interquartile range), or frequency counts (percentages), as appropriate. ^aStudent t test. ^bChi‐square test. ^cMann‐Whitney U test.

Echocardiographic Examination Data

Two‐dimensional, M‐mode, and Doppler echocardiographic examination findings are presented in Table II. LV end‐diastolic and end‐systolic diameters, fractional shortening, and EF were similar between the groups (P>.05). LV hypertrophy parameters such as mean values of LV mass index and interventricular and posterior wall thicknesses were similar between patients with ISH and combined SDH (P>.05). The percentage of patients with diastolic dysfunction and Doppler parameters related to diastolic function such as mitral E/A ratio, deceleration time, and isovolumic relaxation time did not differ between the study groups.

Table II.

 Echocardiographic Examination and Doppler Findings of the Study Groups

Echocardiographic Data	Combined SDH (n=38)	ISH (n=38)	P Value
IVS, cm	1.14±0.11	1.12±0.12	.4
PW, cm	1.12±0.11	1.12±0.12	.8
EF, %	58.0±2.7	57.7±3.6	.7
EDV, mL	90.0±14.6	93.0±15.9	.4
ESV, mL	37.3±6.7	39.1±7.9	.3
SV, mL	52.7±8.7	54.5±11.0	.4
LVMI, g/m2	118.8±25.7	119.2±23.7	.9
Mitral E wave, cm/s	68.2±15.1	68.0±17.3	.9
Mitral A wave, cm/s	90.0±16.4	87.1±14.8	.4
E/A ratio	0.77±0.19	0.78±0.21	.8
Mitral E‐wave DT, ms	224±42	237±45	.2
IVRT, ms	108±13	115±15	.09
Baseline heart rate, beats/min	71.4±9.1	72.3±9.3	.6
Baseline SBP, mm Hg	140.9±8.9	143.2±11.5	.3
Baseline DBP, mm Hg	92.7±4.3	77.1±69	<.001
Peak heart rate, beats/min	87.1±12.2	86.6±8.9	.8
Peak SBP, mm Hg	138.4±9.5	136.4±14.5	.4
Peak DBP, mm Hg	89.6±5.9	76.1±7.2	<.001

Abbreviations: A, late diastolic myocardial velocity; DBP, diastolic blood pressure; DT, decelaration time; EDV, end diastolic volume; EF, ejection fraction; E, early diastolic myocardial velocity; ESV, end systolic volume; ISH, isolated systolic hypertension; IVRT, isovolumic relaxation time; IVS, interventricular septum; LVMI, left ventricular mass index; LVSD, left ventricular systolic diameter; PW, posterior wall; SBP, systolic blood pressure; SDH, systolic/diastolic hypertension; SV, stroke volume.

CFR Measurement Findings

Dipyridamole infusion was well tolerated by all patients without any limiting adverse effects. As expected, mean values of diastolic BP at baseline and peak values after dipyridamole infusion were lower in patients with ISH than in patients with combined SDH (P<.05). Compared with baseline, heart rate was increased after dipyridamole infusion to a similar extent in both groups.

When CFR was compared between the groups, we found significantly lower CFR values in patients with ISH than in patients with combined SDH (2.22±0.51 vs 2.49±0.56, respectively; P=.03) (Figure 2). The ratio of the patients with low CFR (<2) was 39.5% in the ISH group and 23.7% in the combined SDH group, but this difference did not reach statistical significance (P=.2).

Figure 2.

 Comparison of the coronary flow reserve values between the study groups. Compared with combined systolic/diastolic hypertension (SDH), patients with isolated systolic hypertension (ISH) had significantly decreased coronary flow reserve values.

CFR was significantly and inversely correlated with age (r=−0.2, P=.034), baseline systolic BP (r=−0.2, P=.01), and group (r=−0.2, P=.02) and positively correlated with peak diastolic BP after dypridamole infusion (r=0.2, P=.04). Smoking, lipid levels, C‐reactive protein concentration, and LV mass index were also inversely correlated with CFR, but these correlations did not reach statistical significance. On multivariate linear regression analyses in which CFR was taken as a dependent variable and group, age, atherosclerotic risk factors, body mass index, and other confounding factors including EF and LV mass index were taken as independent variables, we found that ISH (β=−0.40, P=.004) and dyslipidemia (β=−0.29, P=.04) were independent predictors of CFR.

Discussion

The present paper shows that compared with patients with combined SDH, CFR is decreased in ISH patients. This indicates that coronary microvascular dysfunction, an early finding of atherosclerosis, is more prominent in patients with ISH.

Hypertension is among the major factors that impairs endothelial function. ⁸ Impaired coronary vasodilator reserve has been reported as a common finding in patients with hypertension and might be responsible for ischemic symptoms in these patients. ¹⁶ A recent study revealed that in elderly patients, systolic hypertension was associated with endothelial dysfunction in conduit arteries, while diastolic hypertension was mainly associated with endothelial dysfunction in resistance arteries. ¹⁷ A number of previous studies have shown that elevated pulse pressure is associated with endothelial dysfunction. ¹⁸ , ¹⁹ However, to our knowledge, CFR, a marker of coronary microvascular‐endothelial function, has not been assessed in patients with ISH. In the current study, using pharmacologic stress TTDE, which has been shown to have a strong correlation with CFR obtained invasively by intracoronary Doppler wire, ⁶ we evaluated CFR values of patients with combined SDH and ISH. We demonstrated that compared with those with combined SDH, patients with ISH had decreased CFR. These findings suggest that endothelial dysfunction is more prominent in the coronary circulation of patients with ISH.

The importance of pulse pressure has been emphasized in the recent European Society of Cardiology guidelines, which might be used to identify patients with systolic hypertension who are at high risk. ⁹ In elderly patients, a high pulse pressure is a marker of a pronounced increase in arterial stiffness and is a known risk factor independently associated with adverse cardiovascular outcomes. ¹⁹ , ²⁰ Wallace and colleagues ²¹ have demonstrated that, compared with age‐matched controls, endothelium‐dependent vasomotor function is depressed in patients with ISH.

Preventability of hypertension‐associated changes in cardiovascular structure in rats with ISH was examined by Susic and colleagues. ²² They found that ISH develops in these animals with advancing age and its main features (increased pulse pressure, decreased ventricular function, and compromised coronary hemodynamics) are similar to those of ISH in aging humans. A very important finding in that study was that a combined therapy with l‐arginine and angiotensin‐converting enzyme inhibitor ameliorated the cardiovascular consequences associated with ISH. With this therapy. it was reported that an improvement occurs in LV function demonstrated by LV end‐diastolic pressure and LV filling pressure characteristics and coronary hemodynamics demonstrated by higher CFR values. A major determinant of ISH is vascular stiffness, which might result from an increase in extracellular matrix formation. Drugs that inhibit the renin‐angiotensin‐aldosterone system in this regard may have beneficial effects by attenuating extracellular matrix formation in addition to reducing BP. ²³

With regard to these reports and the importance of endothelial dysfunction as a predictor of all‐cause and cardiovascular mortality, we believe that our findings are valuable and may have clinical and therapeutic implications. Therapeutic approaches aimed to obtain more strict BP control and improve endothelial function may alter the adverse cardiovascular consequences associated with endothelial dysfunction, particularly in patients with ISH.

Of note, patients with diabetes mellitus, which is considered a coronary artery disease equivalent, were excluded, and the percentages of dyslipidemia and smoking were similar in both groups. By chance, there was a female preponderance in our study. It would have been more representative of the general population with hypertension if the ratio of both sexes were similar. However, the percentage of female patients in both groups was not different. Therefore, we believe that this does not affect the results obtained.

Potential factors that may affect CFR are listed in Table III. Aging is a factor that might affect coronary microvascular function. Since ISH is mainly a disease of the elderly, in the present study we enrolled patients older than 60 years and both groups were homogenous with regard to age. Antihypertensive medications may have the potential to affect the results obtained. There was no significant difference between the study groups with regard to the type of drugs used. LV hypertrophy is another factor that might affect CFR. In our study, both groups were similar with respect to LV hypertrophy parameters. Therefore, we conclude that in elderly patients with hypertension who have similar baseline characteristics, impairment in coronary microvascular function is more prominent in patients with ISH, which was reflected as lower CFR values.

Table III.

 Factors Affecting Coronary Flow Reserve

Clinical characteristics and atherosclerotic risk factors

Age

Hypertension

Dyslipidemia

Tobacco smoking

Family history of premature atherosclerosis

Diabetes mellitus

Chronic renal failure

Rheumatologic/vasculitic syndromes

Drugs

Calcium channel blockers

Angiotensin‐converting enzyme inhibitors and angiotensin receptor blockers

Nitrates

Statins

Immune supressive drugs

Echocardiographic factors

Left ventricular hypertrophy

Aortic stenosis and regurgitation

Mitral regurgitation

Quality of image

Limitations

Absence of coronary angiographic examination is a limitation to our findings, for which the presence of a stenosis in the epicardial coronary arteries can not be ruled out. It was not performed because of its invasive nature and lack of indication. The lack of an estimate of arterial stiffness, which might be increased in patients with ISH, is another limitation of our study. However, it is well‐known that endothelial dysfunction is a systemically seen condition. It has been shown that coronary endothelial dysfunction determined invasively is strongly correlated with systemic endothelial dysfunction. ²⁴ Female preponderance might be accepted as another limitation of the present study. BP measurements were performed in the clinic, whereas, if it had been obtained with an intraarterial catheter or 24‐hour ambulatory monitor, more reliable results could have been provided.

Conclusions

Our study shows that CFR is more profoundly impaired in patients with ISH, suggesting that coronary microvascular‐endothelial dysfunction, which is an early finding of atherosclerosis, is present in patients with ISH. Considering the prognostic importance of ISH and endothelial dysfunction, our findings may have clinical and therapeutic implications. Further studies with larger populations are needed to better clarify this issue. Effect of therapy on CFR in patients with ISH should also be investigated.

Acknowledgments and disclosures: This work was presented in part at the European Society of Cardiology Congress 2008, August 30–September 3, Munich, Germany. All support for this study came from institutional and departmental resources. The authors report no specific funding in relation to this research and no conflicts of interest to disclose.