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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 colleagues8 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.
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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 colleagues21 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|
| Tobacco smoking|
| Family history of premature atherosclerosis|
| Diabetes mellitus|
| Chronic renal failure|
| Rheumatologic/vasculitic syndromes|
| Calcium channel blockers|
| Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers|
| Immune supressive drugs|
| Left ventricular hypertrophy|
| Aortic stenosis and regurgitation|
| Mitral regurgitation|
| Quality of image|
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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.