a Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
b Department of Clinical Pathophysiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
c Nagoya University School of Health Sciences, Nagoya, Japan
* Corresponding author: Hideo Izawa, MD, PhD, Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. Tel.: +81/52-744-2147; fax: +81/52-744-2977
E-mail address: izawa{at}med.nagoya-u.ac.jp
Received 10 November 2002; revised 11 February 2003; accepted 8 April 2003
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Abstract |
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Methods and results Left ventricular pressures and dimensions were measured simultaneously during supine bicycle exercise in 23 patients with nonobstructive hypertrophic cardiomyopathy, before and after intravenous injection of either nicorandil (0.1mg/kg) or propranolol (0.15mg/kg). Exercise thallium-201 scintigraphy was also performed. Patients were grouped according to the changes in left ventricular end-diastolic pressure during exercise before treatment. Group I comprised 13 patients in whom left ventricular end-diastolic pressure increased progressively to abnormal values during exercise; group II comprised 10 patients in whom left ventricular end-diastolic pressure changed biphasically. The extents of both left ventricular hypertrophy and ischemic burden during exercise were greater in group I than in group II. Of the eight group I patients who received nicorandil, four individuals exhibited biphasic changes in left ventricular end-diastolic pressure during exercise after its administration whereas four subjects showed no such effect of the drug. Left ventricular end-diastolic pressure increased progressively during exercise after propranolol treatment in all 6 group II patients given this drug.
Conclusion Nicorandil has a salutary effect on the changes in left ventricular end-diastolic pressure during exercise in patients with hypertrophic cardiomyopathy.
Key Words: Coronary microcirculation Exercise Hypertrophic cardiomyopathy Left ventricular end-diastolic pressure Nicorandil
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1. Introduction |
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Nicorandil exhibits complex pharmacological effects, including effects similar to those of nitrate,10ischaemic preconditioning,11activation of not only sarcolemmal potassium channels but also mitochondrial ATP-sensitive potassium channels,10and therefore eliciting cardioprotective effects.12We therefore examined the hypothesis that nicorandil may favourably affect exercise-induced changes in left ventricular end-diastolic pressure in patients with hypertrophic cardiomyopathy.
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2. Methods |
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2.2. Study protocol
An externally balanced and calibrated 6F pigtail angiographic micromanometer-tipped catheter was advanced into the left ventricle through the right radial artery for measurement of left ventricular pressure. A 7F triple-lumen thermistor Swan-Ganz catheter was advanced into the pulmonary artery through the right brachial vein. Micromanometer pressure signals and standard electrocardiograms were recorded with a multichannel recorder throughout the study protocol. Two-dimensional echocardiographic measurements were performed from recordings of at least five consecutive cardiac cycles by two observers who were unaware ofthe patients clinical status. The degree of left ventricular hypertrophy was evaluated semiquantitatively as previously described.14
After we had collected baseline data, patients performed a symptom-limited supine bicycle ergometer exercise test as described previously.14The workload was 25W initially and increased by 25W every 3min. We were unable to obtain clear echocardiographic recordings at workloads of >50W, probably because of an increase in the air content of the lungs. We therefore analyzed echocardiographic data during exercise at a workload of 50W. During exercise, no patients developed a new outflow tract pressure gradient or more than a mild level of mitral regurgitation as revealed by Doppler echocardiography.
After completion of the exercise study, patients were randomly selected to receive an intravenous injection of nicorandil (0.1mg/kg, 12 patients) or propranolol (0.15mg/kg, 11 patients). The exercise protocol was repeated 15min after injection of these drugs.
Blood (5ml) was collected from the brachial artery at rest and at peak exercise. Plasma samples were prepared and stored at 70°C until determination of norepinephrine concentration by high-performance liquid chromatography. Exercise thallium-201 scintigraphic studies were also performed 2 days before catheterization.
2.3. Analysis of haemodynamic data
Left ventricular pressure signals were digitized at 3-ms intervals and analyzed with software developed in our laboratory and a personal computer system.15The left ventricular pressure data at baseline and at 7 to 10 points during exercise were selected for analysis. We calculated the maximum first derivative of left ventricular pressure as an index of contractility. To evaluate left ventricular isovolumic relaxation, we computed the pressure half-time directly as previously described.16We defined the critical heart rate as the heart rate at which the left ventricular end-diastolic pressure reached a maximal value during the exerciseprotocol.
2.4. Scintigraphic analysis
Perfusion was assessed semiquantitatively on the basis of analysis of the apical, midventricular, and basal short-axis and of vertical long-axis tomograms. The left ventricular myocardium was divided into 20 segments (18 from the short-axis images and 2 from the vertical long-axis images). The defect score was defined according to a five-point scale (0=normal, 1=equivocal, 2=mildly reduced perfusion, 3=severely reduced perfusion, 4=absent perfusion) by two observers without knowledge of the clinical data.17The summed stress score and summed rest score were calculated as the sum of the scores for the 20 segments for the stress and rest images, respectively. The sum of the differences between the 20 segments from the stress and rest images was defined as the summed difference score.18
2.5. Statistical analysis
Data are expressed as means±standard deviation. Differences among subgroups of group I (see Results) were compared by one-way factorial analysis of variance together with Scheffes multiple comparison test. Other comparisons were performed by paired or unpaired Students t-test as appropriate. A P value of <0.05 was considered statistically significant.
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3. Results |
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3.2. Changes in haemodynamic and echocardiographic variables during exercise in group I
Six out of 13 patients in group I complained of chest pain during exercise without drugs, and significant ST segment depression was apparent in two of these six patients. Eight and five of the 13 patients in group I received an intravenous injection of nicorandil or propranolol, respectively (Fig. 1). Nicorandil had no effect on the pattern of changes in left ventricular end-diastolic pressure induced by exercise in four of the eight patients in group I treated with this drug (nicorandil-A group), whereas the remaining four patients exhibited a biphasic pattern of changes in pressure duringexercise after nicorandil injection (nicorandil-B group). Nicorandil slightly reduced left ventricular end-diastolic pressure at baseline from 16±4 to 13±6mmHg in the nicorandil-A group and from 14±8 to 11±6mmHg in the nicorandil-B group. There were no differences in age, plasma norepinephrine concentrations, or the prevalence of risk factors for coronary artery disease, including smoking, hypertension, diabetes mellitus, and hypercholesterolemia between the nicorandil-A and nicorandil-B groups. Haemodynamic and echocardiographic variables at baseline, with or without nicorandil, did not differ significantly between the nicorandil-A and nicorandil-B groups. The both two patients with ST segment depression during exercise without drug belonged to the nicorandil-A group.
Changes in these variables from baseline to peak exercise with or without drugs in the three subgroups of group I are shown in Table 2. Left ventricular end-diastolic pressure increased from13±6mmHg at baseline with nicorandil to 28±6mmHg at peak exercise in the nicorandil-A group. In the nicorandil-B group, left ventricular end-diastolic pressure increased from 11±6mmHg at baseline with nicorandil to 20±6mmHg at the critical heart rate, then it gradually returned to the baseline value (12±9mmHg). The mean critical heart rate in the nicorandil-B group was 93±13bpm. Propranolol had no effect on the pattern of changes in left ventricular end-diastolic pressure during exercise in any of the five patients in group I who received this drug (Fig. 1).
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4. Discussion |
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Patients with hypertrophic cardiomhyopathy could be divided into two groups on the basis of differences in the pattern of changes in left ventricular end-diastolic pressure induced by dynamic exercise described previously.8Group I comprised patients in whom left ventricular end-diastolic pressure increased steadily up to abnormal values during exercise, whereas group II consisted of patients in whom this parameter exhibited a biphasic pattern of changes during exercise. The extents of both left ventricular hypertrophy (as revealed by echocardiography) and ischemic burden during exercise (as revealed by thallium-201 scintigraphy) were more severe in the patients in group I than in those in group II. The exercise-induced biphasic pattern of changes in left ventricular end-diastolic pressure in group II patients was no longer apparent after injection of propranolol. Conversely, half of the patients in group I who received nicorandil exhibited a biphasic pattern of exercise-induced changes in left ventricular end-diastolic pressure after drug administration, whereas nicorandil had no effect on the remaining patients injected with this drug in group I.
4.1. Coronary microcirculation as a potential determinant of biphasic changes in left ventricular end-diastolic pressure during exercise
Left ventricular end-diastolic pressure is commonly considered to be an index of left ventricular diastolic dysfunction, given that increases in left ventricular end-diastolic volume are usually accompanied by increases in left ventricular end-diastolic pressure. However, left ventricular end-diastolic pressure may be elevated without an increase in left ventricular end-diastolic volume as a result of diminished ventricular compliance.19In the present study, our observation that patients in groups I and II exhibited similar changes in left ventricular internal dimensions indicated that exercise induced a substantial deterioration of left ventricular compliance in patients in group I and a substantial improvement in left ventricular compliance in patients in group II. One of the major factors responsible for a diminished left ventricular compliance is myocardial ischemia.19Various studies have suggested that coronary microcirculation is abnormal in patients with hypertrophic cardiomyopathy.15Autopsy revealed a qualitative abnormality of intramural coronary arteries in most patients examined with hypertrophic cardiomyopathy.1In addition, coronary flow reserve was shown to be reduced, indicating a serious disturbance in coronary microcirculation, in patients with hypertrophic cardiomyopathy[20].
The adrenergic stimulation associated with dynamic exercise results in dilation of coronary resistance vessels through both of direct activation of vascular ß-adrenergic receptors and of the secondary effect of an increase in myocardial metabolic demand.9In addition to studies that have concluded that the direct control of coronary resistance vessels is mediated predominantly through ß2-adrenergic receptors,21ß1-adrenergic receptors have also been implicated in such control.22Both 1- and
2-adrenergic receptors contribute to regulation of the degree of vasoconstriction of the smaller resistance vessels.23However, the vasoconstrictive effect of
-adrenergic stimulation is normally overridden by metabolic and direct ß-adrenergic receptor-induced vasodilation. Thus, the net effect of dynamic exercise on coronary microcirculation is coronary vasodilation in individuals with normal coronary arteries. However, in subjects with diseased coronary arteries, dynamic exercise more likely induces vasoconstriction because of decreased endothelium-derived nitric oxide.24
In the present study, the exercise-induced biphasic pattern of changes in left ventricular end-diastolic pressure was no longer apparent in patients of group II after propranolol injection. Taken together with this observation, an amelioration of ischaemia as a result of an improvement in coronary microcirculation induced by ß-adrenergic stimulation during exercise may underlie this biphasic pattern. The fact that both left ventricular contraction and relaxation during exercise were greater in patients of group II than in those of group I might be indicative of the amelioration of ischaemia during exercise in patients of group II. However, given that no single mechanism predominates in the control of coronary vascular tone, especially during exercise, with neural, humoral, and local metabolic mechanisms all participating[25], further studies are required to address this complex issue.
4.2. Effect of nicorandil on left ventricular end-diastolic pressure during exercise in patients with hypertrophic cardiomyopathy
Some patients with hypertrophic cardiomyopathy who normally exhibit a progressive increase in left ventricular end-diastolic pressure during exercise manifest a biphasic pattern of exercise-induced changes after injection with nicorandil. It is noteworthy that exercise with nicorandil increased the maximum first derivative of left ventricular pressure to similar extents in both the nicorandil-A and nicorandil-B groups (54±14 vs 50±21%, respectively). Importantly, the left ventricular end-diastolic pressure in the nicorandil-B group decreased after the critical heart rate was achieved, while the left ventricular end-diastolic pressure increased progressively throughout exercise in the nicorandil-A group. When left ventricular preload is decreased, the maximum first derivative of left ventricular pressure is decreased because of Frank-Staring mechanism. Therefore, this finding strongly suggested the augmented left ventricular contractility during exercise with nicorandil in the nicorandil-B group, indicating the possibility of the improved ischaemia. Nicorandil appears to have two principal mechanisms of its action: First, it has a nitrate-like vasodilatoryeffect,10which, together with arteriolar and venous vasodilation, is likely responsible for the efficacy of this drug in relieving ischaemia caused by an increased myocardial oxygen demand. We previously showed that the ratio of the pressure-rate product to coronary sinus flow, which is an index of the ratio of myocardial oxygen consumption to myocardial oxygen supply, was decreased significantly by nicorandil administration during exercise in patients with old myocardial infarction.26Second, nicorandil also activates mitochondrial ATP-sensitive potassium channels that are cytoprotective during ischemia.11It is mostly the small and intermediate-size resistance vessels (<100µm in diameter) that are dilated by ATP-sensitive potassium channel openers.27
Although it is difficult to evaluate the structural alterations of coronary resistance vessels in intact humans, it is possible that patients in whom left ventricular end-diastolic pressure continues toincrease steadily during exercise after nicorandil injection possess severe structural alterations of their coronary resistance vessels. On the other hand, in patients in whom nicorandil confers a biphasic pattern of changes in left ventricular end-diastolic pressure during exercise, the structural alterations in these vessels might be subtle and the functional coronary flow reserve targeted by nicorandil may be preserved. Nicorandil infusion in conjunction with ergometer exercise assessment may thus prove to be an effective approach for evaluation of structural alterations of coronary resistance vessels in patients with hypertrophic cardiomyopathy. Further investigations at the cellular and molecular levels are required, however, to characterize the functional and structural alterations in the intramural coronary arteries of patients with hypertrophic cardiomyopathy.
4.3. Study limitations
We should discuss the difference between left end-diastolic pressure and pulmonary artery wedge pressure at peak exercise in group II. This discrepancy between these pressures may be caused by several factors. First, the time delay between left end-diastolic pressure and pulmonary artery wedge pressure results in the difference between these pressures at peak exercise. Second, the pulmonary artery wedge pressure may be contaminated by pulmonary artery pressure, yielding greater mean pulmonary artery wedge pressure at peak exercise. Third, the pulmonary artery wedge pressure isaffected by changes in intrathoracic pressure at peak exercise.
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5. Conclusions |
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References |
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