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(Hypertension. 1997;29:551-559.)
© 1997 American Heart Association, Inc.

Articles

Mechanisms of Coronary Flow Reserve Impairment in Human Hypertension

An Integrated Approach by Transthoracic and Transesophageal Echocardiography

Michaela Kozakova; Carlo Palombo; Lorenza Pratali; Giuseppe Pittella; Fabio Galetta; Antonio L'Abbate

the Institute of Clinical Physiology, National Research Council (CNR), Pisa, and Department of Internal Medicine of the University of Pisa (F.G.) (Italy).

Correspondence to Michaela Kozakova, MD, Institute of Clinical Physiology, CNR, Via Savi 8, 56126 Pisa, Italy.

	Abstract

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The purpose of this study was to investigate the different mechanisms responsible for an impairment of coronary vasodilator capacity in hypertensive subjects by an integrated echocardiographic approach, including transesophageal Doppler echocardiography, which allows noninvasive monitoring of coronary flow velocity in the left anterior descending artery during pharmacological vasodilation. The study population consisted of 17 healthy control subjects and 33 hypertensive subjects: 10 without hypertrophy, 16 with mild to moderate hypertrophy, and 7 with severe left ventricular hypertrophy. Mean systolic and diastolic flow velocities were monitored basally (together with indexes of myocardial oxygen demand, such as heart rate, myocardial inotropism, and left ventricular wall stress) and during infusion of low-dose (0.56 mg/kg per 4 minutes) and high-dose (0.84 mg/kg per 9 minutes) dipyridamole. Coronary reserve was assessed as the ratio of mean diastolic velocity after high-dose dipyridamole and basal diastolic velocity, and minimum coronary resistance as the ratio of diastolic blood pressure and diastolic velocity after high-dose dipyridamole. Compared with the control group, in all hypertensive groups, coronary reserve was similarly decreased (3.54±0.84 versus 2.59±0.42, 2.29±0.46, and 2.43±0.71; P<.01) and minimum resistance increased (0.56±0.15 versus 0.75±0.31, 0.75±0.19, and 0.78±0.21 mm Hg·s^-1·cm^-1; P=NS). These results confirm that coronary reserve in hypertensive individuals is reduced even before the occurrence of left ventricular hypertrophy. The reduction in coronary reserve depends on both an increase in resting coronary flow and an impairment in maximal vasodilator capacity. An increase in resting flow is dependent on higher heart rate and wall stress in hypertensive subjects without ventricular hypertrophy and on increased myocardial mass in hypertensive subjects with hypertrophy. Hypertensive subjects with ventricular hypertrophy also demonstrated a significantly blunted response to low-dose dipyridamole.

Key Words: echocardiography • hypertension, arterial • hypertrophy • vasodilation

	Introduction

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Angina may occur in hypertensive individuals in the absence of coronary artery disease. Pressure-induced LVH is a well-established mechanism responsible for an impaired coronary vasodilating capacity, eventually leading to myocardial ischemia and angina.^{1 2 3 4 5} However, a number of hypertensive individuals have angina despite the absence of both coronary artery disease and LVH.⁶

Several myocardial and vascular factors are supposed to modify coronary vasodilator response in hypertensive individuals. The resting coronary flow can be increased as a result of increased myocardial oxygen demand caused by higher resting heart rate, systemic blood pressure, systolic wall stress, diastolic LV pressure, and myocardial mass. The maximal flow response to physiological or pharmacological stimuli can be limited by a reduction in the total maximal cross-sectional area of the microcirculatory bed caused by structural abnormalities of intramyocardial coronary arteries, increased coronary arteriolar tone, inadequate myocardial neoangiogenesis in the presence of LVH, dysfunction of the microvascular endothelium, or extravascular systolic compression.^{7 8 9 10 11 12 13 14}

The mechanisms that may be involved in the alteration of CFR in hypertension have been extensively studied in animal models,^{8 10 15 16 17 18} but studies in humans are more limited because of the complexity and/or invasiveness of the techniques used so far. For clinical studies, a safe technique is needed with low invasiveness allowing real-time measurements of the instantaneous changes in both the systolic and diastolic components of biphasic coronary flow in response to vasodilating agents. In this way, the impairment of coronary vasodilator capacity in different subsets of hypertensive individuals could be easily and repeatedly studied. Furthermore, the direct comparison with control groups of healthy individuals, which would be made possible by a noninvasive approach, would be important for the stratification of different degrees of coronary reserve impairment in hypertensive individuals, particularly through the detection of early abnormalities.

In this study, we used transesophageal Doppler echocardiography to study the response of the systolic and diastolic components of coronary flow velocity in the proximal part of the LAD to stepwise administration of the vasodilating agent dipyridamole in hypertensive subjects without and with mild to moderate or severe LVH as well as in healthy subjects. We also evaluated the diameter of the epicardial coronary vessel and the relations between coronary flow parameters and echocardiographic indexes of LV mass, myocardial contractility, and wall stress in the different groups.

	Methods

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Study Population
The overall study population consisted of 50 subjects, 17 healthy volunteers and 33 hypertensive individuals (at least three measurements of "casual" systemic blood pressure during 3 months 160/90 mm Hg). All subjects were asked about any history of chest pain and were investigated by means of basal and exercise ECG as well as transthoracic basal and dipyridamole-atropine echocardiography. Individuals with valvular or primary myocardial heart disease, previous myocardial infarction, and heart failure were excluded, as were those with diabetes and dyslipidemia. In subjects in whom the suspicion of coronary artery disease, based on anginal symptoms and/or a positive exercise ECG, could not be ruled out on the basis of the noninvasive diagnostic workup (14 of 33 patients), coronary angiography was performed. In all subjects, a basal echocardiogram did not show regional LV asynergy, and high-dose dipyridamole-atropine echocardiography was negative for regional wall motion abnormalities. Coronary angiography, when performed, was negative for coronary artery stenosis.

Among the group of healthy control subjects, 11 had sedentary habits, and 6 were involved in regular physical training.

LV mass was determined by transthoracic echocardiography.¹⁹ LVH in hypertensive subjects was defined as an LVMI value greater than or equal to 117 g/m² for men and 104 g/m² for women.²⁰ Hypertensive subjects with LVH were further divided into two groups (mild to moderate and severe LVH) according to the diastolic thickness of the interventricular septum (>11 and <15 mm and 15 mm, respectively), ie, the region mainly perfused by the LAD. LVH, when present, was concentric in all subjects (ratio of interventricular septum to posterior wall <1.3; relative wall thickness 0.44).^{21 22} According to these criteria, 10 hypertensive subjects showed no LVH, 16 showed mild to moderate LVH, and 7 showed severe LVH.

The main demographic characteristics as well as history of angina and data on effort ECG and LV geometry in the study population are summarized in Table 1. The relatively high average LVMI value in control subjects resulted from the coexistence of 6 trained healthy subjects with the feature of physiological LVH (LVMI=151.1±22.8 g/m²) and 11 sedentary healthy subjects (LVMI=88.5±27.7 g/m²).

View this table: [in this window] [in a new window]   Table 1. Main Vital Characteristics and Left Ventricular Geometry in Study Subjects

None of the control subjects was receiving any therapy at the time of the study; as for hypertensive subjects, calcium antagonists were discontinued at least 72 hours before the study, and all other medication had been interrupted for at least 1 week before the study began.

The study was approved by the internal ethics committee. All participants were informed about the procedure and provided informed consent according to the Declaration of Helsinki.

Study Protocol
In all 50 study subjects, the transesophageal evaluation of coronary flow was preceded by complete 2-D and M-mode transthoracic echocardiographic examinations for assessment of LV function and mass. After xylocaine anesthesia of oropharynx and mild sedation (5 to 10 mg diazepam IV), the transesophageal echocardiographic probe was introduced into the upper esophagus, and the flow in the proximal part of the LAD was pinpointed by color and spectral Doppler. After the coronary flow signal was detected, the subject was allowed to calm down for 2 minutes before basal recording of the spectral Doppler signal (Fig 1). A 2-D image showing the position of the Doppler sample volume in the LAD was stored in the cine-loop memory and was repeatedly retrieved during the study to ensure that coronary flow velocity was always measured at the same LAD segment. "Zoomed" 2-D images of the LMA were obtained for measurement of the luminal diameter of the vessel (Fig 2).

View larger version (150K): [in this window] [in a new window]   Figure 1. Coronary blood flow velocity profile from proximal part of the LAD shows biphasic pattern, with smaller systolic and larger diastolic components. Dotted line on the y axis indicates velocity scale; distance between two points corresponds to 20 cm/s.

View larger version (108K): [in this window] [in a new window]   Figure 2. "Zoomed" diastolic 2-D image of LMA, from which the luminal diameter of the vessel was measured.

The probe was then briefly advanced to the stomach, and the transgastric short-axis view of the left ventricle at the level of the papillary muscles was recorded.²³

Subsequently, the probe was withdrawn to the upper esophagus and the Doppler signal from the LAD was obtained once again. Special care was taken to place the sample volume at the same position as on the stored 2-D image. Basal coronary flow velocity was remeasured, and stepwise infusion of dipyridamole was started. The Doppler signal from the LAD was recorded continuously during dipyridamole infusion and for the following 3 minutes after dipyridamole administration was stopped. At the end of infusion, the diameter of the LMA was remeasured.

At the end of the study, a transthoracic 2-D echocardiographic examination was performed, and 80 mg aminophylline was injected as an intravenous bolus.

Throughout the study, a three-lead ECG was continuously monitored and 12-lead ECG was recorded every 2 minutes. Blood pressure was continuously monitored by a Finapres device (Ohmeda).

Dipyridamole Administration
Dipyridamole was infused peripherally through an indwelling 18-gauge cannula in an antecubital vein at an overall dose of 0.84 mg/kg per 9 minutes: the first dose of 0.56 mg/kg per 4 minutes (low-dose dipyridamole) was followed after 3 minutes by a second dose of 0.28 mg/kg per 2 minutes (high-dose dipyridamole).

Echocardiographic Examination
The transthoracic echocardiographic examination was performed by means of a commercially available echocardiographic instrument (SONOS 1500 or 2500, Hewlett-Packard Co) with either a 2.5- or 3.5-MHz transducer. At the basal examination, the regional kinesis of the left ventricle was evaluated in 2-D, and the LV diastolic diameter (LVDd) as well as the diastolic thickness of the LV posterior wall (LVPWd) and interventricular septum (IVSd) were assessed in M-mode images of the parasternal long-axis view. At the end of the study, regional LV kinesis was checked by 2-D transthoracic echocardiography.

Transesophageal-Doppler examination was performed by means of the same echocardiographic instrument with an omniplane probe operating at a frequency of 5.0 MHz, with options for color flow mapping, pulsed Doppler, and continuous wave.

After introduction of the probe, the proximal part of the LAD was visualized just above the semilunar aortic valves. The sample volume for pulsed Doppler was placed into the proximal third of the LAD, after visualization had been improved by color flow mapping and the spectral Doppler signal of coronary flow had been detected. Flow velocity was assessed by pulsed Doppler, and when the velocity exceeded the Doppler limit (during maximal vasodilation), continuous wave evaluation was used. The angle between the ultrasonic beam and the direction of the LAD was maintained as close to zero as possible and never exceeded 30°.

When the transesophageal echocardiographic probe was temporarily placed into the stomach, the transgastric short-axis view of the left ventricle at the level of the papillary muscles was recorded in both 2-D and M-mode images. Regional LV kinesis was evaluated in 2-D, and the diastolic (LVDd) and systolic (LVDs) diameters of the left ventricle as well as the diastolic and systolic thicknesses of the LV posterior wall (LVPWd, LVPWs) and anterior wall (LVAWd, LVAWs) were measured in M-mode images.

The measurements of the different parameters of the left ventricle as well as those on the spectral Doppler signal from the LAD were provided off-line on videotape. For each Doppler parameter, the average of five beats was used for statistical analysis.

The variability of coronary flow velocity acquisition was determined by comparison of the basal systolic and diastolic mean velocities obtained before and after transient positioning of the transesophageal echocardiographic probe in the stomach for LV function assessment.

Intraobserver variability was assessed by having one observer (M.K.) remeasure coronary flow velocities at baseline and after low- and high-dose dipyridamole in 14 subjects (with an interval between readings of at least 1 month). For assessment of interobserver variability, flow velocities in the same 14 subjects were measured also by a second observer (C.P.).

Calculation of Echocardiographic Indexes
LV mass (grams) was calculated according to the formula¹⁹ LV Mass=1.04x[(IVSd+LVPWd+LVDd)³-LVDd³]-13.6. LVMI was expressed as LV mass per meter squared of body surface area. LV contractile function was assessed as midwall fractional shortening (MFS, percent)²⁴ with the following formula:

where Inner Shell Myocardial Thickness=³[(LVDd+LVPWd/2+LVAWd/2)³-LVDd³+LVDs³]-LVDs. LV peak systolic wall stress (PSWS, pascals) and end-systolic wall stress (ESWS, pascals) were calculated with the following formulas^{25 26} :

where SBP is systolic blood pressure.

Coronary Blood Flow Velocity Measurement
Coronary blood flow velocity profile from the proximal part of the LAD showed a typical biphasic pattern, with a smaller systolic and larger diastolic component (Fig 1). For the purpose of this study, mean systolic and diastolic flow velocities were measured separately at baseline and after low- and high-dose dipyridamole (Fig 3).

View larger version (71K): [in this window] [in a new window]   Figure 3. Differences in basal coronary flow velocity (B) in coronary flow velocity response to low-dose (Dip L) and high-dose (Dip H) dipyridamole between healthy control subject and hypertensive subject with LVH. Basal systolic (SMV) and diastolic (DMV) mean velocities were significantly higher in the hypertensive than the control subject. Ratios of SMV after low-dose and high-dose dipyridamole are 0.96 in the control subject and 0.52 in the hypertensive subject; ratios of DMV after low-dose and high-dose dipyridamole are 1.04 in the control subject and 0.72 in the hypertensive subject. In the hypertensive subject, continuous-wave Doppler was used for measurement of high flow velocity after high-dose dipyridamole. Distance between two white points in the velocity scale (dotted line in the y axis) in each panel corresponds to a velocity increase of 20 cm/s.

The ratio of mean velocity (either systolic or diastolic) after low-dose dipyridamole to the corresponding values after high-dose dipyridamole indicated the proportion of maximal flow velocity response, for both systolic and diastolic flow components, obtained after low-dose dipyridamole.

The maximal coronary vasodilator response to dipyridamole was expressed as CFR and calculated as the ratio of diastolic flow velocity after high-dose dipyridamole to resting diastolic flow velocity.

CVR values at baseline and after low- and high-dose dipyridamole were calculated as the ratio of diastolic pressure and simultaneously measured diastolic flow velocity.

The correlation of basal flow velocities (ie, flow velocities in autoregulation) and determinants of myocardial oxygen demand and the correlation of CFR and LVMI were investigated by means of regression analysis.

Evaluation of Coronary Artery Caliber
The LMA diameter in 2-D images was measured basally and after high-dose dipyridamole, and LMA cross-sectional area was calculated. Measurements were provided by bow-compasses from digitized "zoomed" diastolic images (Fig 2) printed onto high-density printing paper (Sony Corp). The correlations of LMA area (basally and after high-dose dipyridamole) with age and LVMI were investigated by means of regression analysis.

Data Analysis
Data are expressed as mean±SD. Where appropriate, ANOVA was used; to assess statistical significance between groups, we applied Scheffe's F test, with a value of P<.05 considered significant. Regression analysis was performed with a simple linear model. We used ANCOVA to remove the effect of age when present.

Agreement between the two readings performed by two observers was evaluated estimating the consistent bias between readings, as recommended by Bland and Altman²⁷ for the comparison of two methods of clinical measurement. Bias in two measurements was assessed by calculation of the mean of the differences. Using limits of agreement as 2 SD about the mean of the differences, we examined the agreement between the two measurements by plotting the differences against the mean values (Fig 4). Statistical analysis was performed with commercially available software (BMDP Statistical Software, Inc).

View larger version (19K): [in this window] [in a new window]   Figure 4. Interindividual variability of systolic and diastolic coronary flow velocity determinations: plot of the difference of velocity values from two observers versus the mean of measured values. Good agreement is seen, with a zero bias (mean difference, 0.68±4.38 cm/s). Lines represent boundaries of ±2 SD.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Variability of Coronary Flow Velocity Measurements
Intraobserver variability was 4.5±2.4% and interobserver variability 5.3±3.3%. A plot of the difference between the two observers in each velocity measurement versus the mean of the two measurements (Fig 4) showed a mean difference (or bias) of 0.68±4.38 cm/s and good agreement (all points but four within 2 SD of the mean difference).

Basal mean systolic and diastolic velocities measured before and after transient positioning of the probe in the stomach were comparable (systolic: 24.1±7.8 and 23.8±7.8 cm/s, respectively, P=NS; diastolic: 42.6±14.1 and 42.9±14.3 cm/s, P=NS).

Systemic Hemodynamic Responses and Echocardiographic Measurements
During measurement of basal coronary flow velocity, systolic and diastolic pressures were significantly higher in all hypertensive groups than in the control group; during dipyridamole infusion, the differences in blood pressure decreased (Table 2).

View this table: [in this window] [in a new window]   Table 2. Systemic Hemodynamic Responses to Stepwise Infusion of Dipyridamole

Basal heart rate was significantly increased only in hypertensive subjects without LVH; during dipyridamole infusion, this difference disappeared (Table 2). Consequently, the rate-pressure product was significantly higher in the hypertensive groups than the control group in basal conditions but not after high-dose dipyridamole (Table 2).

As indicated in Table 1, LVMI was significantly higher in hypertensive subjects with mild to moderate and severe LVH than in control subjects and hypertensive subjects without LVH.

Midwall fractional shortening of the left ventricle measured at baseline (ie, almost simultaneously with the measurement of resting coronary flow velocity) was comparable in the control group and hypertensive group without LVH (18.0±1.7% and 17.4±1.8%, respectively; P=NS), whereas it was significantly lower in the hypertensive groups with mild to moderate (14.7±2.4%, P<.01) and severe (13.8±1.0%, P<.01) LVH. No correlation was observed between midwall fractional shortening and end-systolic wall stress in either control or hypertensive subjects.

In the hypertensive group without LVH, LV peak systolic wall stress during the recording of resting coronary flow velocity was significantly increased compared with the hypertensive group with mild to moderate LVH (165.3±51.1x10² and 117.2±43.9x10² Pa, respectively; P<.05) and nonsignificantly increased compared with the control group (128.1±20.4x10² Pa) or hypertensive group with severe LVH (111.8±21.1x10² Pa). Also, end-systolic wall stress tended to be higher in hypertensive subjects without LVH (74.0±23.1x10² Pa) than in control subjects (55.4±11.1x10² Pa, P=NS) and hypertensive subjects with mild to moderate LVH (58.7±22.5x10² Pa, P=NS), and it was 67.2±14.2x10² Pa in hypertensive subjects with severe LVH.

Coronary Blood Flow Velocity, CFR, and CVR
Mean systolic and diastolic coronary flow velocities at baseline were higher in the overall hypertensive group than the control group (systolic: 26.4±8.4 and 19.7±4.6, respectively; diastolic: 46.7±15.0 and 35.1±9.6; P<.01), without significant differences for hypertensive subgroups. Systolic and diastolic flow velocities after high-dose dipyridamole were comparable in the study groups (Table 3).

View this table: [in this window] [in a new window]   Table 3. Systolic and Diastolic Mean Flow Velocities in the Left Anterior Descending Artery, Coronary Reserve and Vascular Resistance, and Left Main Coronary Artery Diameter and Area at Different Steps of Dipyridamole Infusion

The proportion of maximal systolic and diastolic flow responses after low-dose dipyridamole was significantly lower in the hypertensive groups with LVH than the control group (Table 3). CFR was significantly decreased in all hypertensive groups compared with the control group. CVR at baseline was comparable in all study groups. CVR after high-dose dipyridamole (minimum CVR) was significantly higher in all hypertensive subjects than in control subjects (0.76±0.22 versus 0.56±0.16 mm Hg·s^-1·cm^-1, P<.01), without significant differences for the hypertensive subgroups. CVR after low-dose dipyridamole was comparable to that after high-dose dipyridamole in control subjects, whereas it was significantly higher in hypertensive subjects with LVH (Table 3).

No correlation between CFR and LVMI was observed in control or hypertensive subjects. CFR was inversely related to age in hypertensive subjects only (r=-.442, P<.05). However, in the covariance analysis, the tests for equality of adjusted means and slopes were not significant between control and hypertensive subjects. In control subjects, basal diastolic flow velocity correlated directly to the basal rate-pressure product (r=.716, P<.001) and heart rate (r=.634, P<.01) and nonsignificantly also to peak systolic wall stress (r=.440, P=.07) (Fig 5), whereas no correlation was demonstrated with age, LVMI, basal midwall fractional shortening, and end-systolic wall stress. In hypertensive subjects, no correlation was found between basal diastolic flow velocity and basal rate-pressure product, heart rate, LVMI, basal midwall fractional shortening, and peak systolic or end-systolic wall stress. Basal systolic flow velocity was directly related to systolic pressure (r=.36, P<.02) in the overall study group.

View larger version (22K): [in this window] [in a new window]   Figure 5. Correlation between diastolic mean velocity (basal DMV) of LAD flow and basal heart rate (HR), rate-pressure product (RPP), and peak systolic wall stress (PSWS) in healthy control subjects. DMV directly correlates with HR and RPP significantly and with PSWS nonsignificantly. HR is shown in bpm; RPP/100, bpm·mm Hg·10-2; PSWS/100, Pa·10-2.

Sixteen hypertensive subjects had angina pectoris, and 17 were asymptomatic; those with angina pectoris had higher, although not significantly, basal diastolic flow velocity than those without (51.2±14.2 versus 41.8±14.7 cm/s, P=.07). Exercise ECG was positive in 10 hypertensive subjects, nondiagnostic in 11, and negative in 12. The hypertensive subjects with positive exercise ECG had nonsignificantly higher basal diastolic flow velocity than those with negative exercise ECG (52.4±16.8 versus 41.0±10.6 cm/s, P=.07). After high-dose dipyridamole, hypertensive subjects with and without angina pectoris as well as hypertensive subjects with positive and negative exercise ECG did not differ in diastolic flow velocity as well as in LVMI, basal rate-pressure product, midwall fractional shortening, and wall stress.

Response of Coronary Artery Caliber to Dipyridamole Infusion
The diameter of the LMA could be measured reliably only in 34 subjects (68%) (12 control subjects, 6 hypertensive subjects without LVH, 9 with mild to moderate LVH, and 7 with severe LVH). At baseline, LMA diameter and area in control and hypertensive subjects without LVH or with mild to moderate and severe LVH did not differ significantly (Table 3). After high-dose dipyridamole, the LMA cross-sectional area slightly increased in all groups. The increment was higher, although not significantly, in control subjects and hypertensive subjects without LVH (Table 3). No correlation was found between LMA area, both basally and after dipyridamole, and age or LVMI in any group.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Transesophageal Doppler echocardiography allows beat-by-beat assessment of coronary flow velocity in the LAD^{28 29 30 31} in basal conditions and during pharmacologically induced coronary vasodilation, also making it possible to differentiate between the systolic and diastolic components of coronary flow.³² Furthermore, this approach allows simultaneous evaluation of autoregulatory coronary flow and LV inotropic function and wall stress, ie, the major determinants of myocardial oxygen consumption, in addition to heart rate and the rate-pressure product. These features, together with a good reproducibility of coronary flow velocity measurements,^{28 29} make transesophageal Doppler echocardiography particularly relevant in the investigation of coronary flow dynamics in hypertensive individuals. Up to now, however, the method has been used sporadically,^{33 34} and systematic studies on hypertension and hypertension-related LVH have not been performed.

In the present study, we used a complex echocardiographic approach to investigate the interplay of different factors contributing to the impairment of coronary vasodilating capacity in systemic hypertension. CFR was reduced in all subgroups of hypertensive subjects, in keeping with a number of previous experimental and clinical studies^{1 2 3 6 7 8 9 10 11 13 14 15 16} ; however, the separate analysis of systolic and diastolic components of coronary flow, the evaluation of the time course and dose dependence of the response, and the assessment of some echocardiographic indexes of LV anatomy and function, taken together, revealed differences related to various mechanisms responsible for the reduction of CFR in different subgroups.

Systolic Component of Coronary Flow
Systolic antegrade coronary flow is often supposed to be only a reflection of the capacitance of large epicardial arteries^{35 36 37} ; however, experimental studies demonstrated a reduction in antegrade systolic flow with an increase in extravascular compressive forces.^{37 38 39} LV intracavitary pressure and myocardial contraction are considered to be two primary determinants of compressive forces.^{39 40} In our noninvasive study, we calculated peak- and end-systolic wall stress^{25 26} and assessed LV midwall fractional shortening as an index of myocardial inotropic function.^{24 41}

Resting peak systolic and end-systolic wall stress were increased in hypertensive subjects without LVH, whereas basal midwall fractional shortening was significantly decreased in hypertensive subjects with mild to moderate and severe LVH. However, the systolic component of coronary flow appeared to be unaffected by these changes: systolic flow velocity at rest was similarly increased, compared with values in control subjects, in all hypertensive groups despite the differences in wall stress and inotropic function. Actually, on the basis of a direct relation observed between systolic coronary velocity and systolic perfusion pressure, we can assume that a higher systolic pressure in hypertensive subjects may overcome the variable effects of extravascular compressive forces and represents the main factor affecting the systolic component of coronary flow.

At maximal arteriolar vasodilation, ie, after high-dose dipyridamole, the mean systolic velocity of coronary flow reached the same values in control and hypertensive subjects; however, systolic perfusion pressure was still higher in hypertensive subjects. The response of systolic flow velocity to low-dose dipyridamole was blunted in hypertensive subjects with mild to moderate and severe LVH; this finding is discussed below.

Diastolic Component of Coronary Flow
Resting diastolic flow velocity was increased in the overall hypertensive group compared with the control group. In the presence of hypertrophied myocardium, resting total coronary flow is higher, so that flow per unit mass of myocardium remains almost normal^{1 3 7 8} ; however, no differences in resting flow velocity were observed between hypertensive subjects with severe LVH and those with mild to moderate LVH or even without LVH. Hypertensive subjects without LVH had significantly higher basal heart rate, rate-pressure product, and LV wall stress. Heart rate and peak systolic wall stress are strongly related to myocardial oxygen requirements, and the latter was shown to provide the most accurate determination of energy demand.^{7 12 13 42 43 44}

Surprisingly, we did not find any correlation between basal flow and heart rate or rate-pressure product in hypertensive subjects, whereas we did find such a correlation in control subjects (Fig 5). It seems that in the presence of systemic hypertension, the simple relation between flow in autoregulation and heart rate or rate-pressure product is altered by the interplay of other factors such as LVH, wall stress, or LV inotropic function, all of which contribute to a variable extent to changes in resting oxygen demand.

Our finding that hypertensive subjects with angina pectoris or positive exercise ECG had higher basal coronary flow velocity than asymptomatic individuals suggests a clinical relevance of the increased basal coronary flow in hypertensive subjects and can be of interest for the choice of therapeutic approach.

In maximal vasodilation, ie, after high-dose dipyridamole, the mean diastolic flow velocity was similar in the control group and in all hypertensive groups, implying that individuals with LVH should have a reduced maximal flow per unit mass. This finding confirms previous observations^{8 16} and suggests that the overall capacity of coronary circulation does not increase in parallel with myocyte growth.⁴⁵

In hypertensive subjects, diastolic flow velocity values during maximal vasodilation were comparable to those in control subjects but at higher perfusion pressure.⁴⁶ Thus, in order to normalize for different perfusion pressures, we also estimated CVR; during maximal vasodilation, CVR in hypertensive subjects was increased by about 35% compared with that in control subjects.

Several possible mechanisms could explain a reduced maximal vasodilator capacity in hypertensive individuals: inadequate neoangiogenesis, extravascular compression in the presence of hypertrophied myocardium,⁴⁷ and intrinsic vascular factors, both structural and functional. Besides structural remodeling of the intramyocardial coronary arterioles,⁴⁸ two functional factors should be considered, ie, an increase in the tone of coronary resistance vessels⁶ and an impairment in endothelium-dependent vasodilation of resistance vessels.¹⁴ The coronary vasodilation induced by dipyridamole or adenosine is primarily endothelium independent; however, the increment in coronary blood flow may trigger further vasodilation, which is flow induced and endothelium dependent.^{49 50 51 52}

Both an increased coronary tone and impaired endothelium-dependent vasodilation could explain our observation of a reduced response of the systolic and diastolic components of coronary flow to low-dose dipyridamole. Whereas in control subjects the maximal response to dipyridamole was almost fully achieved after a low dose, in hypertensive subjects, especially in those with LVH, the response to a low dose was significantly lower than that to a high dose (Fig 3). The CVR response also mirrors this phenomenon. One can hypothesize that in the presence of systemic hypertension, coronary microvessels need a higher dose and/or longer exposition time to fully respond to vasodilator stimuli and to attain the level of minimal coronary resistance because of either increased basal vascular tone or diminished flow-mediated dilation.

Study Limitations
Transesophageal Doppler echocardiography does not measure the absolute volumetric flow in the LAD but only flow velocity; thus an unchanging vessel diameter is assumed in the assessment of coronary flow response to a vasodilator stimulus. Dipyridamole, adenosine, or papaverine was shown to mildly dilate epicardial coronary vessels.^{49 50 51 52} To test the possible changes in vessel area during the study, we repeatedly measured LMA diameter. The LMA rather than the LAD was chosen because of better visualization of the LMA in 2-D imaging, assuming a similar responsiveness of the two arterial segments to vasoactive agents and flow increase. A mild increment of LMA cross-sectional area after dipyridamole was observed in our study groups. This finding decreases the accuracy of the assessment of CFR by transesophageal Doppler echocardiography, leading to a slight underestimation of the flow response to the vasodilator, especially in healthy control subjects and hypertensive subjects without LVH.

Clinical Significance
CFR in hypertensive individuals has to be determined in a relatively noninvasive way if it has to be assessed in a large number of individuals, including subjects with uncomplicated hypertension, and if it has to provide information useful for better targeting the therapeutic approach. Transesophageal Doppler echocardiography allows continuous monitoring of the systolic and diastolic components of coronary flow together with the assessment of main factors affecting myocardial oxygen demand; thus, it can provide a detailed insight into the relative role of different mechanisms contributing to the impairment of CFR in individuals with systemic hypertension. However, by contrast with other noninvasive techniques, such as positron emission tomography,^{53 54} the relevance of LV mass has to be estimated indirectly through the comparison of hypertensive subjects with a wide range of LV mass values.

In the present study, we confirmed by transesophageal Doppler echocardiography that CFR in hypertensive subjects is reduced before the occurrence of LVH. In particular, CFR reduction in hypertensive subjects without LVH appears to mainly depend on an increased resting coronary flow related to higher heart rate and wall stress. However, an impairment in maximal coronary vasodilator capacity is already detectable; in fact, these subjects attained the same maximal flow velocity as that in control subjects, but at higher perfusion pressure, corresponding to a higher minimum coronary resistance. In addition, the response of mean diastolic velocity to low-dose dipyridamole was already slightly blunted. These facts may indicate either a functional increase in coronary resistance or impaired flow-mediated dilation.

In hypertensive subjects with mild to moderate LVH, an increase in resting flow can be explained by both increased oxygen demand (increased rate-pressure product) and myocardial mass. Maximal coronary vasodilator capacity is further impaired in this subset of subjects; they reached the same maximal velocity as control subjects but in the presence of higher myocardial mass and at higher perfusion pressures. A clearly blunted response to low-dose dipyridamole suggests an impaired recruitment of vasodilator capacity caused by functional vascular factors.

In hypertensive subjects with severe LVH, an increase in resting flow seems to be mainly due to LVH because the rate-pressure product and wall stress did not increase and myocardial inotropic function even decreased compared with control subjects. Relative to the high LV mass, the flow in maximal vasodilation is further reduced compared with hypertensive subjects without LVH or with mild to moderate LVH.

Transesophageal Doppler echocardiography, thanks to its limited invasiveness and the possibility of an integrated evaluation of coronary flow and LV function, could represent an effective method not only for pathophysiological investigation but also for wide-scale, clinical evaluation of hypertensive individuals in both the pretreatment phase and during therapy, thus enabling better individualization of antihypertensive treatment.

	Selected Abbreviations and Acronyms

 

CFR = coronary flow reserve CVR = coronary vascular resistance ECG = electrocardiography LAD = left anterior descending artery LMA = left main coronary artery LV = left ventricular LVH = left ventricular hypertrophy LVMI = left ventricular mass index

	Acknowledgments

 
This study has been partly supported by a grant of the National Research Council (CNR) Targeted Project "FATMA," Rome, Italy. We are grateful to Dr Giovanni de Simone for his useful suggestions, to Guido Nassi for contribution in statistical analysis, and to Dr Edward Farrants for revision of the manuscript for English language use.

Received October 25, 1995; first decision January 23, 1996; first decision September 9, 1996;

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