Impaired coronary blood flow reserve in prehypertension and function

Patients with a systolic blood pressure of 120 to 139 mm Hg and/or a diastolic blood pressure of 80 to 89 mm Hg based on 2 or more seated blood pressure readings on 2 or more office visits are considered to have prehypertension.¹ The risk of cardiovascular morbidity and mortality is higher in patients with prehypertension than in individuals with normal blood pressure.² It is assumed that the mechanism of excess risk from prehypertension is the same as that from hypertension. In addition, prehypertension has been linked to subclinical atherosclerosis, increased coronary atherosclerosis, and target-organ damage.^3,4

Patients with hypertension may have signs and symptoms of myocardial ischemia despite angiographically normal coronary arteries, which may be related to impaired coronary microvascular function.⁵ In the absence of epicardial coronary artery stenosis, coronary flow reserve (CFR) may be considered a marker of coronary microvascular function, and attenuated CFR is mostly the result of changes in minimal coronary resistance that are independent of vascular tone.⁶ Therefore, structural changes in the coronary vasculature are most likely to be the major contributors to altered CFR. Despite the fact that prehypertension has been shown to be associated with atherosclerosis and target-organ damage, no studies evaluating CFR in patients with prehypertension have been done. We used thoracic Doppler echocardiography to assess CFR in subjects with prehypertension.

Subjects and methods

The 150 subjects enrolled in the study were divided into 3 groups according to their blood pressures: normotensive, hypertensive, and prehypertensive. Definitions of normotension, hypertension, and prehypertension were based on the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7).¹ Subjects with a systolic blood pressure < 120 mm Hg and a diastolic blood pressure < 80 mm Hg were considered to be normotensive; subjects with a systolic blood pressure ≥ 140 and/or a diastolic blood pressure ≥ 90 mm Hg were considered to be hypertensive; and subjects with a systolic blood pressure of 120 to 139 mm Hg and/or a diastolic blood pressure of 80 to 89 mm Hg were considered to be prehypertensive. None of the subjects had symptoms or cardiovascular disease. Subjects with any disease that might cause CFR impairment, such as impaired glucose tolerance or diabetes, and subjects with a systemic disease, such as renal, hepatic, or hemolytic disease, were excluded from the study. We also excluded patients with left ventricular hypertrophy, those who were taking vasoactive drugs, and those with ST-segment or T-wave changes specific for myocardial ischemia, Q waves, and incidental left bundle branch block on electrocardiogram.

A high-resolution transducer with second harmonic capability (5V2c, attached to a Sequoia C256 echocardiography system; Acuson Corp, Mountain View, California) was used to visualize the distal left anterior descending coronary artery in a modified, foreshortened 2-chamber view achieved by sliding the transducer on the upper part and medially from an apical 2-chamber view. Color Doppler flow mapping with the color Doppler velocity set in the range of 8.9 to 24.0 cm/second was used to assess coronary flow in the distal left anterior descending artery. Coronary diastolic peak velocity was measured at baseline and after dipyridamole infusion (0.56 mg/kg over 4 minutes) by averaging the highest 3 Doppler signals for each measurement. Coronary flow reserve was defined as the ratio of hyperemic diastolic peak flow velocity (DPFV) to baseline DPFV.

Table.

Demographic characteristics and data from echocardiographic examinations of the study groups.

Characteristic

Prehypertensive

Hypertensive

Normotensive

Age, years

44.6 ± 5.9

44.2 ± 7.3

44.0 ± 6.0

Men/women, n

17/23

28/32

23/27

Body mass index, kg/m²

29.8 ± 4.1

29.0 ± 4.6

28.3 ± 2.8

Systolic BP, mm Hg

133.2 ± 4.3^*

150.1 ± 7.5^*†

111.8 ± 5.6

Diastolic BP, mm Hg

86.7 ± 2.4^*

96.5 ± 5.3^*†

72.3 ± 5.0

Heart rate, bpm

73.1 ± 5.4

72.2 ± 9.5

74.4 ± 9.0

Total cholesterol, mg/dL

195.1 ± 29.4

194.8 ± 33.2

189.1 ± 27.9

HDL cholesterol, mg/dL

42.7 ± 8.2^‡

48.2 ± 11.3

45.8 ± 12.0

LDL cholesterol, mg/dL

123.7 ± 23.6

119.1 ± 27.5

116.0 ± 23.3

Glucose, mg/dL

95.5 ± 8.2

95.2 ± 7.4

93.4 ± 7.7

Ejection fraction,%

66.9 ± 2.0

67.5 ± 2.2

67.3 ± 2.3

LVMI, g/m

59.2 ± 10.9^‡

63.9 ± 11.9^§

58.7 ± 9.2

Mitral E max, cm/s

72.3 ± 13.7

72.3 ± 16.1

75.2 ± 15.2

Mitral A max, cm/s

65.8 ± 12.9

70.2 ± 14.5

66.0 ± 11.4

E/A

1.12 ± 0.25

1.06 ± 0.29

1.16 ± 0.24

Mitral E deceleration time, s

195.3 ± 31.8

208.7 ± 43.6^§

188.6 ± 22.9

Baseline DPFV, cm/s

24.7 ± 5.0

25.7 ± 4.9

23.7 ± 4.5

Hyperemic DPFV, cm/s

62.1 ± 14.7

57.4 ± 16.4^§

68.4 ± 15.5

CFR

2.23 ± 0.47^§‡

2.54 ± 0.48^*

2.91 ± 0.53

CFR< 2,%

18^§‡

35^*

0

P

^* < .001 vs normotensive.

P

^† <.0001 vs prehypertensive.

P

^‡ < .05 vs hypertensive.

P

^§ < .01 vs normotensive.

BP indicates blood pressure; bpm, beats per minute; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LVMI, left ventricular mass index; DPFV, diastolic peak flow velocity of left anterior descending coronary artery; CFR; coronary flow reserve. (Adapted from Erdogan D, Yildirim I, Ciftci O, et al. Effects of normal blood pressure, prehypertension, and hypertension on coronary microvascular function. Circulation. 2007;115:593-599 with permission from the American Heart Association.)

Results

The subjects' characteristics and echocardiographic measurements are shown in the Table. There were no significant differences in left ventricular ejection fraction among the 3 groups. Subjects with hypertension had a significantly higher left ventricular mass index (LVMI) than the prehypertensive and normotensive groups. Hypertensive subjects also had significantly higher mitral E deceleration than the normotensive group. Although other left ventricular diastolic measurements were slightly different between the hypertensive and the other 2 groups, these differences were not statistically significant.

P

P

P

The DPFV of the left anterior descending artery at baseline was similar between the prehypertension and normotension group, and between the prehypertension and the hypertension group; the DPFV was slightly higher in the hypertension group than in the normotension group, however ( = .06). Hyperemic DPFV was slightly lower in the prehypertension group compared with the normotension group and significantly lower in the hypertension group. Subjects in the prehypertension and hypertension groups had significantly lower CFR than the normotension group. Coronary flow reserve was significantly different and hyperemic DPFV was slightly different between the prehypertensive subjects and the hypertensive subjects. Abnormal CFR (< 2) was found in 35% of subjects with hypertension, whereas all the normotensive subjects had normal CFR. The presence of hypertension (beta = -0.31; < .01) and prehypertension (beta = -0.31; < .01) were shown to be significant predictors of lower CFR on multivariable analyses. Coronary flow reserve was used as a dependent variable; the hypertensive status, left ventricular mass index, and diastolic function measurements were used as independent variables.

Discussion

Although it is well known that patients with hypertension have reduced CFR, there are no studies documenting the effect of normal blood pressure, prehypertension, and hypertension on CFR in patients without clinical artery disease. Our study assessed coronary microvascular function in these 3 groups of subjects. Results showed that CFR was significantly decreased in subjects with prehypertension compared with normal control subjects, although not as markedly as in hypertensive subjects.

The JNC-7 guidelines established the category of prehypertension between documented hypertension and normal blood pressure. The rationale for redefining this new category was to emphasize the excess cardiovascular risk associated with blood pressure in this range and to highlight the high risk of developing hypertension in these patients, for whom lifestyle modifications are recommended.¹ In the Trials of Hypertension Prevention study, there was only an 8% decrease in absolute reduction in the incidence of new-onset hypertension with the most successful lifestyle modifications.⁷ The Framingham Heart Study has provided the most important epidemiologic information about prehypertension.⁸ In one analysis, subjects with above optimal or high-normal blood pressure, which were combined into the category of prehypertension in the JNC-7 guidelines, had a significantly elevated risk of developing hypertension within 4 years compared with subjects with optimal blood pressure (< 120/80 mm Hg). In another analysis, high-normal blood pressure correlated with a risk-factor-adjusted hazard ratio for cardiovascular disease of 1.6 (95% confidence interval [CI], 1.1-2.2) for men and 2.5 (95% CI, 1.6-4.1) for women compared with optimal blood pressure.⁹ Furthermore, it has been shown that prehypertension is associated with a 27% increase in all-cause mortality and a 66% increase in cardiovascular mortality.¹⁰ The significance of prehypertension has been examined recently, but its management remains controversial. More studies are needed to determine the risk profile for target-organ damage and the prognostic importance of prehypertension.

To date, the mechanisms that may be involved in the alteration of CFR in hypertension have not been studied extensively in humans because of the complex and invasive techniques used to evaluate CFR. Transthoracic Doppler echocardiography (TTDE), a recently developed technique, is capable of measuring coronary blood flow velocity in the middle to distal portion of the left anterior descending artery. Pharmacologic stress TTDE is a highly reproducible tool in evaluating CFR, and its feasibility has been validated.¹¹ Furthermore, CFR measured by TTDE has recently been shown to have an excellent correlation with CFR measured by positron emission tomography, which has been validated as the gold standard for CFR measurement.¹² Because structural changes in the coronary vasculature are most likely to be the major contributors to impaired CFR, and these structural changes may be qualitatively similar to the well-described effects of hypertension on the peripheral circulation,¹³ we investigated whether impaired CFR might add valuable information on cardiovascular risk assessment of hypertensive patients.

Conclusions

The results of our study indicate that patients with prehypertension have impaired coronary microvascular function, as indicated by decreased CFR.

These data are in accord with the idea that the presence of mildly elevated blood pressure is associated with abnormal coronary flow response.