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Circulation. 1995;91:2916-2923

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(Circulation. 1995;91:2916-2923.)
© 1995 American Heart Association, Inc.

Articles

Reduced Epicardial Coronary Vasodilator Capacity in Patients With Left Ventricular Hypertrophy

Giuseppe Vassalli, MD; Philipp Kaufmann, MD; Bruno Villari, MD; Markus Jakob, MD; Hildegard Boj, RN; Wolfgang Kiowski, MD; Otto M. Hess, MD

From the Department of Internal Medicine, Cardiology, University Hospital, Zurich, Switzerland.

Correspondence to Otto M. Hess, MD, Cardiology, University Hospital, Raemistrasse 100, 8091 Zurich, Switzerland.


*    Abstract
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 *Abstract
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Background Enlargement of the epicardial coronary arteries occurs in left ventricular (LV) hypertrophy as an adaptation to the increased coronary blood flow.

Methods and Results Vasodilator capacity of the epicardial coronary arteries was determined in 44 patients. The dose-response relation of intracoronary nitroglycerin was assessed in 14 patients (7 control subjects and 7 patients with aortic stenosis [study A]) using quantitative coronary angiography. In a second study (B), vasodilator capacity of the epicardial coronary arteries was determined in 15 control subjects and 15 patients with valvular heart disease. In study A, a curvilinear dose-response relation with maximal vasodilation after 90 µg intracoronary nitroglycerin was found in both control subjects and patients with aortic stenosis. Vasodilator capacity was reduced in those with aortic stenosis, although sensitivity to nitroglycerin was similar in both groups. In study B, coronary circumferential length at baseline was larger in those with LV hypertrophy (12.2±2.2 mm) than in control subjects (8.6±1.5 mm; P<.001); after 100 µg intracoronary nitroglycerin, it increased to 12.9±2.2 mm (6±5%) in those with LV hypertrophy and to 10.3±1.5 mm (21±8%; P<.001) in control subjects. An inverse relation between baseline circumferential length and its percent increase after nitroglycerin was found (r=-.71, P<.001).

Conclusions Vasodilator capacity of the epicardial coronary arteries is reduced in patients with LV hypertrophy, although sensitivity to nitroglycerin is normal. This may be due to a flow-mediated decrease in coronary vasomotor tone and/or the occurrence of vascular remodeling with an enlargement of the coronary arteries.


Key Words: vasodilation • hypertrophy • nitroglycerin • stenosis • ventricles


*    Introduction
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 *Introduction
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Normal as well as stenotic coronary arteries have been shown to change their size with different pharmacological interventions and physiological stress.1 2 Changes in blood flow and arterial diameter are closely correlated, ie, an increase in flow is accompanied by an increase in vascular diameter, and vice versa.3 4 An enlargement of the coronary arteries has been reported in patients with left ventricular (LV) hypertrophy due to valvular heart disease,5 6 7 hypertension,8 and cardiomyopathy.9 The purpose of the present study was to assess epicardial coronary artery size at rest and after nitroglycerin administration and to determine the vasodilator capacity of the large coronary arteries in patients with LV hypertrophy.


*    Methods
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 *Methods
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Patients
Forty-four patients with normal coronary arteries were included in the present analysis. In a dose-response study (study A), 14 patients were examined with increasing doses of intracoronary nitroglycerin. Seven patients (age, 63±9 years) had severe aortic stenosis, and 7 healthy subjects (age, 54±8 years), who were examined because of atypical chest pain, served as the control group.

In a second study (study B), 30 patients were examined with a maximal vasodilating dose of 100 µg intracoronary nitroglycerin. Fifteen patients (age, 63±13 years) had LV hypertrophy secondary to valvular heart disease: 9 of them had aortic stenosis, 3 had aortic regurgitation, and 3 had severe mitral regurgitation. Fifteen patients (age, 48±6 years) with atypical chest pain served as control subjects. Mean body surface area was similar in patients with LV hypertrophy (1.81±0.28 m2) and control subjects (1.85±0.32 m2). Coronary arteriography was performed in all patients for diagnostic purposes. Patients with LV hypertrophy were selected for the study when the following inclusion criteria were fulfilled: severe valve lesion (preoperative evaluation), normal coronary arteries, and adequate opacification of the coronary arteries for quantitative evaluation.

Cardiac Catheterization
Informed consent to undergo cardiac catheterization and coronary angiography was obtained from all patients. Premedication consisted of 10 mg oral chlordiazepoxide administered 1 hour before catheterization. Vasoactive substances were withheld for at least 24 hours before catheterization. LV and aortic pressures were measured with an 8F pigtail catheter introduced retrogradely from the right femoral artery in patients with aortic and mitral regurgitation and in control subjects. In patients with aortic stenosis, transeptal catheterization was carried out, and systolic pressure gradient was calculated from simultaneous LV and aortic pressure measurements. LV angiograms were recorded simultaneously in the right and left anterior oblique projections at a filming rate of 50 frames per second.10 LV volume and ejection fraction were calculated using the "area–length" method.11 Aortic and mitral regurgitation fraction was determined from LV angiography and cardiac output (Fick). LV muscle mass was obtained according to the method of Rackley et al.12 Selective left coronary arteriography was carried out from the right femoral artery (Judkins technique, 8F catheters) using multiple views for optimal visualization of the coronary arteries.

In study A, the dose-response relation of intracoronary nitroglycerin was determined from biplane coronary arteriograms in the right and left anterior oblique projections. First, a control run was performed; then, 10, 30, 90, and 150 µg intracoronary nitroglycerin were administered with an interval of 5 minutes between the different steps. Heart rate and mean aortic pressure were recorded before and after each injection.

In study B, a maximal vasodilating dose of 100 µg intracoronary nitroglycerin was administered, and coronary angiography was repeated immediately after injection.

Quantitative Coronary Arteriography
Quantitative evaluation of the coronary angiograms was performed with a semiautomatic computer system.13 14 The system is based on a 35-mm film projector (Tagarno 35 CX), a slow-scan CCD camera (image digitization) that has been developed at the Institute for Biomedical Engineering in Zurich, and a computer work station (Apollo DN 3000) for image storage and processing. Contour detection was carried out using a geometric-densitometric edge-detection algorithm (Fig 1Down). The methodology for computerized analysis of coronary angiograms has been described previously.15 16



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  		Figure 1. Coronary angiograms (left anterior oblique view) of the left anterior descending (LAD) and circumflex (LCX) coronary arteries in a patient with left ventricular hypertrophy under baseline conditions (left) and after administration of 0.1 mg intracoronary nitroglycerin (NTG; right). Cross-sectional areas of the LAD and the LCX increased from 17.5 to 18.2 mm2 and from 18.2 to 19.3 mm2, respectively, after NTG administration.

The proximal cross-sectional area of the left anterior descending and the left circumflex coronary arteries, defined as the vessel segments immediately beyond the bifurcation of the left main coronary artery over the length of approximately 1 cm, was measured using one to three end-diastolic cine-frames. The computer traced these segments automatically and calculated their mean cross-sectional area (Fig 1Up). Calibration was performed automatically using either the isocenter technique13 or the tip of the 8F Judkins catheter. Vasodilator capacity was defined as circumferential length after nitroglycerin minus circumferential length at rest divided by resting length multiplied by 100.

Statistical Analysis
Statistical comparisons of hemodynamic and angiographic data between control subjects and patients with LV hypertrophy were performed with an unpaired Student's t test, whereas a paired Student's t test was used for comparisons of angiographic data before and after nitroglycerin administration. The analysis of the dose-response relation in the two groups was carried out with a two-way ANOVA for repeated measurements. If the analysis was significant, the Scheffé procedure was applied. An exponential regression analysis between coronary circumferential length at rest and its percent increase after nitroglycerin administration was performed using the least-squares method.


*    Results
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*Results
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Clinical Data
Patients' characteristics in studies A and B are summarized in Table 1Down. In study A, 1 patient with aortic stenosis was in New York Heart Association (NYHA) functional class I, 3 were in class II, and 3 were in class III. In study B, 2 patients with valvular heart disease were in NYHA functional class I, 8 were in class II, and 5 were in class III. Mean physical working capacity (in percent of the age-, sex-, and height-corrected normal values17 ) was 95±19% in control subjects and 71±14% (P<.01) in patients with LV hypertrophy. Seven of 44 patients (3 control subjects and 4 patients with LV hypertrophy) were receiving long-acting nitrates, and 6 were receiving angiotensin-converting enzyme inhibitors before catheterization. Cardiovascular medication is summarized in Table 1Down.


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  		Table 1. Patient Characteristics

Hemodynamic and Ventriculographic Data
In study A, mean systolic pressure gradient was 57±9 mm Hg (range, 44 to 68 mm Hg), and the opening area of the aortic valve was 0.7 cm2 (range, 0.5 to 0.9 cm2) in patients with aortic stenosis. LV muscle mass index was 142±21 g/m2 in these patients and 82±11 g/m2 (P<.01) in control subjects (upper limit of normal, 118 g/m210 ). Heart rate and mean aortic pressure after each dose of intracoronary nitroglycerin in the two groups are shown in Table 2Down.


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  		Table 2. Hemodynamic Data in Study A

The hemodynamic data of study B are summarized in Table 3Down. Mean systolic pressure gradient was 61±24 mm Hg in patients with pure or predominant aortic stenosis and 28±21 mm Hg in patients with predominant aortic regurgitation. Aortic regurgitant fraction was 24±14% in patients with predominant aortic stenosis and 59±10% in those with predominant aortic regurgitation. Mitral regurgitant fraction was 67±5% in patients with mitral regurgitation and 21±15% in patients with aortic valve disease. LV muscle mass index was 145±23 g/m2 in patients with LV hypertrophy and 85±12 g/m2 (P<.01) in control subjects.


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  		Table 3. Hemodynamic and Angiographic Data in Study B

Dose-Response Relation of Intracoronary Nitroglycerin
Percent increase in coronary artery size was significantly less at each intracoronary nitroglycerin dose in patients with aortic stenosis than in control subjects (Fig 2Down). In both groups, the dose-response relation was curvilinear, leveling off after a dose of 30 µg. Mean increase in coronary circumferential length after 150 µg intracoronary nitroglycerin was 21±4% in control subjects and 10±6% (P<.001) in patients with aortic stenosis. After a dose of 90 µg nitroglycerin, 96% of the respective increase was reached in both groups. The dose-response curve in patients with aortic stenosis appeared to be shifted to the right compared with that of control subjects. Because coronary flow has not been measured in the present study but has been previously shown to increase proportionately with LV mass, LV muscle mass has been used to correct for dilution effects caused by increased flow in LV hypertrophy. After normalization for LV muscle mass, the rightward shift of the dose-response curve was no longer seen.



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  		Figure 2. Top, Dose-response curves of the epicardial coronary arteries with increasing doses of intracoronary nitroglycerin (i.c. NTG [µg]). Bottom, Normalized dose-response curve; the doses of i.c. NTG are normalized for 100 g left ventricular muscle mass (LMM) (i.c. NTG/LMM, x10). {Delta}L indicates increase in coronary circumferential length (%; mean±1 SEM); C, control subjects (n=7); and AS, aortic stenosis (n=7). Rightward shift of the curve in the patients with AS is no longer present after normalization for LMM.

Coronary Artery Size and Vasodilating Capacity
Circumferential length of the left anterior descending and circumflex coronary arteries in the patients of study B is shown in Fig 3Down. At baseline, it was significantly higher in patients with LV hypertrophy (12.2±2.2 mm) compared with control subjects (8.6±1.5 mm; P<.001). After intracoronary nitroglycerin administration, coronary circumference increased to 12.9±2.2 mm in patients with LV hypertrophy and to 10.3±1.5 mm in control subjects (P<.001 versus baseline in both groups). Thus, the percent increase in coronary circumference was significantly less in patients with LV hypertrophy (6±5%) than in control subjects (21±8%; P<.001). Interestingly, coronary artery size after nitroglycerin administration in control subjects was still lower than the baseline values of patients with LV hypertrophy. An exponential relation (r=-.71, P<.001) between coronary circumferential length at baseline and its percent change after nitroglycerin was found in the study population as a whole (Fig 4Down).



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  		Figure 3. Plot of proximal circumferential length (L [mm]; mean±1 SD) of the left anterior descending and left circumflex coronary arteries in control subjects (n=30) and patients with left ventricular (LV) hypertrophy (n=30) at baseline and after administration of 0.1 mg intracoronary nitroglycerin (NTG).



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  		Figure 4. Correlation between proximal coronary artery circumferential length at rest (LR [mm]) and its percent increase after administration of 0.1 mg intracoronary nitroglycerin ({Delta}L [%]) in control subjects (n=30) and patients with left ventricular (LV) hypertrophy (n=30).


*    Discussion
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*Discussion
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The modulation of coronary vascular tone allows the heart to match for changes in metabolic demands by adjusting coronary blood flow. Many studies on chronic LV hypertrophy in experimental animals18 19 20 21 22 23 24 25 and in patients with aortic valve disease,26 27 28 29 30 31 hypertension,32 or hypertrophic cardiomyopathy33 have shown that coronary flow per unit mass is normal in the basal state. Parallel to the increase in flow, an increase in coronary artery size has been described in patients with valvular heart disease.5 6 7 The exact mechanism responsible for the growth of the vessels, however, is not known, although increased coronary blood flow has been postulated to be the major growth stimulus. Several other factors might be involved in the enlargement of the coronary arteries, such as perfusion pressure, the endothelium-derived relaxing factor,34 35 36 circulating neurohormones, and local growth factors.36 37 38

Vasodilator Capacity of Epicardial Coronary Arteries in LV Hypertrophy
The major finding of the present study is that the vasodilator capacity of the large coronary arteries is reduced in patients with LV hypertrophy. This concept has not yet been evaluated in humans. Recent data39 40 41 from healthy subjects are comparable to our results showing an increase in coronary circumferential length of 21% (increase in cross-sectional area, 40%) after administration of 100 µg intracoronary nitroglycerin. In patients with coronary artery disease, Brown et al42 found an increase in the cross-sectional area of 18% after administration of 0.4 mg nitroglycerin SL in angiographically normal coronary artery segments.

The present dose-response study showed a reduced dilation of the coronary arteries in response to intracoronary nitroglycerin in patients with aortic stenosis (Fig 2Up). The dose-response curve flattened off after 30 µg nitroglycerin in both the control subjects and the patients with aortic stenosis, indicating that a dose of 100 µg is adequate to induce maximal vasodilation. However, a rightward shift of the dose-response curve was found in patients with aortic stenosis compared with control subjects. This finding suggests either a reduced sensitivity of the smooth muscle to nitroglycerin or a greater dilution of the injected nitroglycerin because of the increased coronary blood flow in patients with aortic stenosis.26 27 28 29 In the present study, arterial blood concentrations of nitroglycerin were not determined since coronary flow measurements were not carried out. However, previously data26 from our group have demonstrated that coronary blood flow is proportional to LV muscle mass in patients with aortic stenosis and, thus, LV muscle mass has been used for normalization purposes (Fig 2Up). The rightward shift of the dose-response curve in the aortic stenosis group was abolished when the nitroglycerin dose was divided by LV muscle mass. This observation suggests a similar sensitivity of the coronary arteries to nitroglycerin in control subjects and in patients with aortic stenosis, although maximum vasodilator response was reduced in LV hypertrophy.

Functional and Structural Factors Determining Epicardial Coronary Vasodilating Capacity
Data from the present study do not allow differentiation between functional and structural factors responsible for the decrease of coronary vasodilator capacity in patients with LV hypertrophy. From a theoretical point of view, the following two mechanisms are possible.

Functional Factors
In the absence of vascular remodeling, each smooth muscle cell is expected to elongate to the same extent in response to nitroglycerin (Fig 5Down). In control subjects, nitroglycerin leads to an increase in coronary circumferential length of 21% (1.7/8.8 mm), whereas the increase is only 6% (0.7/12.2 mm) in patients with LV hypertrophy. Because baseline length was different in the two groups, an increase of 21% in control subjects is equal to an increase of 14% (1.7/12.2 mm) in patients with LV hypertrophy. However, the observed increase is clearly less than this predicted value. Thus, the reduced coronary vasodilator capacity in LV hypertrophy cannot be explained by functional factors alone but suggests the occurrence of vascular remodeling.



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  		Figure 5. Schematic representation of the effect of nitroglycerin (NTG) on coronary arterial cross section. One circumferential muscle cell layer is shown at rest and after maximal vasodilation with NTG. Two theoretical possibilities are illustrated. In the absence of vascular remodeling, each muscle cell elongates approximately to the same extent in response to NTG. In the presence of cellular enlargement and hyperplasia, a variable elongation of the individual muscle cells in response to NTG can be expected. {Delta}L indicates change in length; LV, left ventricular; and i.c., intracoronary.

Because coronary flow is increased in LV hypertrophy,18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 flow-mediated vasodilation can be expected as a result of the enhanced release of the endothelium-derived relaxing factor.36 43 44 45 46 47 This release is mediated by the shear stress of the streaming blood48 as well as by local and circulating agonists, such as acetylcholine, bradykinin, and serotonin.43 Therefore, the increased blood flow in LV hypertrophy leads to a "predilation" of the large coronary artery and reduces its functional vasodilator capacity. Predilation of the coronary arteries tends to normalize coronary flow velocity and, thus, shear stress, resulting in a reduced release of the endothelium-derived relaxing factor.

In the present study, however, the maximally dilated coronary arteries in control subjects were not as large as the coronary arteries in patients with LV hypertrophy under baseline conditions (Fig 3Up). This suggests structural enlargement of the coronary arteries in patients with LV hypertrophy and, thus, true vascular remodeling.

Structural Factors
In the presence of vascular remodeling, a variable elongation of the smooth muscle cells occurs in response to nitroglycerin (Fig 5Up). An increase in coronary artery size in hypertrophic hearts has been reported in necropsy studies more than 30 years ago.49 50 51 Further evidence of vascular remodeling has been provided by histological examination of intramyocardial coronary arteries in patients with hypertension52 53 54 or hypertrophic cardiomyopathy.52 A parallel increase in LV muscle mass and carotid artery wall thickness has been reported in hypertensive patients.55 Langille and O'Donnell4 observed a 21% decrease in vascular diameter 2 weeks after a 70% reduction in blood flow through the rabbit carotid artery. This effect was believed to be due to vascular remodeling after long-term changes in flow rather than to a sustained contraction of the vascular smooth musculature, since papaverine did not attenuate this response.

Several growth or angiogenic factors, such as platelet- and monocyte-derived growth factors, as well as fibroblast growth factors56 and transforming growth factor-ß136 37 38 possibly promote this vascular remodeling. Shear stress itself enhances the proliferation of coronary smooth muscle cells57 via the release of the platelet-derived growth factor.58 On the other hand, nitric oxide inhibits both mitogenesis and proliferation of vascular smooth muscle cells59 as well as the production of excessive matrix molecules. Angiotensin II is a bifunctional vascular smooth muscle cell growth modulator capable of inducing hypertrophy or inhibiting mitogen-stimulated DNA synthesis.37

Thus, a complex balance exists between proliferative and antiproliferative stimuli that modulate the growth response of vascular smooth muscle cells to LV hypertrophy. This interplay between functional and structural factors in the adaptation of the arterial wall to long-term hemodynamic changes appears to be important for the reduced coronary vasodilator capacity in patients with LV hypertrophy.

Study Limitations
Coronary blood flow was not measured in the present study and, thus, no conclusion on the effect of blood flow on coronary vasomotion can be made. However, because an increased coronary flow can be assumed in the presence of severe LV hypertrophy,18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 arterial blood concentration of nitroglycerin can be expected to be reduced in these patients. Therefore, data from control subjects and patients with LV hypertrophy are not really comparable with respect to arterial blood concentration of nitroglycerin.

Control subjects and patients with LV hypertrophy were not perfectly matched with respect to medication before catheterization. Although all drugs were discontinued at least 24 hours before the intervention, some residual pharmacological effects cannot be completely ruled out, especially from ß-blockers or angiotensin-converting enzyme inhibitors. However, only 4 patients were receiving ß-blockers, and 6 were receiving angiotensin-converting enzyme inhibitors. Because 3 control subjects but only 1 patient with LV hypertrophy was receiving ß-blockers, a potential bias would have caused an underestimation of vasodilator capacity in control subjects but not in patients with LV hypertrophy and, thus, would not have affected our conclusions. Seven of the 44 patients were receiving long-acting nitrates. Although tachyphylaxis to nitrates is possible, it is unlikely to have significantly modified our results, since a drug-free interval of 24 hours was respected and the number of patients receiving nitrates was relatively small; furthermore, the two groups of patients were well balanced in this regard.

Control injections with saline have not been performed in the present study. However, repeated injections of nonionic contrast agents have shown only minor effects on coronary vasomotion with variations in vessel diameter of less than 5% of the control value.60

Because our analysis was not blinded, some observer-dependent bias cannot be ruled out, although the differences in coronary artery size between the two groups were quite large compared with changes observed after other pharmacological interventions.

Factors other than muscle mass may also influence coronary artery size, such as age, sex, body size, and physical working capacity. Variable effects of age on the size of the left coronary artery have been described.61 62 63 In the present study, age was higher in patients with LV hypertrophy than in control subjects, but no correlation was found between age and coronary artery size at baseline (r=.31; P=NS). Body size may also influence coronary artery size. Because body surface area was similar in control subjects and in patients with LV hypertrophy (see Table 1Up), this factor appears to have no influence on the results of the present study.

Physical working capacity may also affect coronary artery size. In fact, a recent study41 reported an increased coronary vasodilator capacity in marathon runners. In study B, a difference in physical working capacity between control subjects (95±19% of the age-, sex-, and height-corrected normal value17 ) and patients with LV hypertrophy (71±14%; P<.05) has been observed; however, this difference can probably not account for the marked decrease in vasodilator capacity in the patients with LV hypertrophy since there was no correlation between these two factors (r=.28, P=NS).

In conclusion, vasodilator capacity of the large coronary arteries is reduced in patients with LV hypertrophy, probably due to a flow-mediated decrease in coronary tone and a structural remodeling of the vascular wall with long-term vessel enlargement.


*    Acknowledgments
 
This study was supported by the Swiss National Science Foundation, Berne, Switzerland. We thank Hetty van Hoeven and the cardiac catheterization team for their excellent technical assistance.

Received October 5, 1994; revision received December 14, 1994; accepted December 27, 1994.


*    References
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*References
 

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