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Communications to the Editor |

Coronary Endothelial Dysfunction in Patients With Hypertrophic Cardiomyopathy FREE TO VIEW

Pawel Petkow Dimitrow, MD
Author and Funding Information

Affiliations: Collegium Medicum Jagiellonian University Krakow, Poland,  1 Yawatahama General Hospital Ehime, Japan,  2 Ehime University School of Medicine Ehime, Japan,  3 Ehime Prefectural Central Hospital Ehime, Japan,  4 Kinki Central Hospital Hyogo, Japan

Correspondence to: Pawel Petkow Dimitrow, MD, 2nd Department of Cardiology, Collegium Medicum, Jagiellonian University, 17 Kopernika St, Krakow, Poland 31-501



Chest. 2002;121(4):1374. doi:10.1378/chest.121.4.1374
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To the Editor:

I read with great interest the letter by Kodama-Takahashi et al,1 and I disagree with their comments on several points, outlined here.

First, temporal occlusion of the left anterior descending (LAD) coronary artery that developed in some patients was induced by acetylcholine infusion at the highest dose.2 This occlusive response was also classified as a marker of coronary endothelium-dependent dysfunction.2 Importantly, at a lower dose, acetylcholine constricted the LAD in these patients.2

Second, in some patients, even a high dose of acetylcholine (100 μg) induced mild vasodilatation (not vasoconstriction) in LAD.3

Last, Maseri et al4proposed that it would be reasonable to assume that nonocclusive spasm (defined as segmental constriction reducing local diameter by at least 50% in arteries without significant stenosis) represents the obligatory substrate of occlusive spasm in response to a stronger stimuli. In the article by Kodama et al,5 the stronger stimulus seems to be the highest dose of acetylcholine. In some patients with endothelial dysfunction, acetylcholine induced vasoconstriction, reducing the diameter > 50%.2,6 To evaluate whether patients in the study by Kodama et al5 have coronary endothelial dysfunction, I postulated that the authors should present precise data. The dose-dependent effect of acetylcholine (according to the method description, acetylcholine was infused to LAD in increasing doses of 20, 50, and 100 μg) on reduction of LAD diameter should be provided. Also data concerning the occurrence of risk factors of endothelial dysfunction (hypertension, hypercholesterolemia, smoking, and/or diabetes mellitus) are needed to explore whether endothelial dysfunction is a primary defect (due to intrinsic coronary vascular abnormality in hypertrophic cardiomyopathy) or is secondary to the above-mentioned risk factors (as postulated in a previous article of Kodama et al7).

Kodama-Takahashi, K, Shigematsu, Y, Hamada, M, et al (2001) Coronary vasospasm in hypertrophic cardiomyopathy.Chest119,1290-1291
 
Zeiher, AM, Drexler, H, Wollschlager, H, et al Modulation of coronary vasomotor tone in humans: progressive endothelial dysfunction with different early stages of coronary atherosclerosis.Circulation1991;83,391-401. [PubMed] [CrossRef]
 
Cannon, RO, III, Curiel, RV, Prasad, A, et al Comparison of coronary endothelial dynamics with electrocardiographic and left ventricular contractile response to stress in the absence of coronary artery disease.Am J Cardiol1998;82,710-714. [PubMed]
 
Maseri, A, Davies, C, Hackett, D, et al Coronary artery spasm and vasoconstriction: the case for distinction.Circulation1990;81,1983-1991. [PubMed]
 
Kodama, K, Shigematsu, Y, Hamada, M, et al The effect of coronary vasospasm on the direction of ST-segment deviation in patients with both hypertrophic cardiomyopathy and vasospastic angina.Chest2000;117,1300-1308. [PubMed]
 
Hodgson, JM, Marshall, JJ, et al Direct vasoconstriction and endothelium-dependent vasodilatation: mechanisms of acetylcholine effects on coronary flow and arterial diameter in patients with nonstenotic coronary arteries.Circulation1989;79,1034-1051
 
Kodama, K, Hamada, M, Kazatani, Y, et al Clinical characteristics in Japanese patients with coexistent hypertrophic cardiomyopathy and coronary vasospasm.Angiology1998;49,849-855. [PubMed]
 
To the Editor:

We wish to thank Dr. Dimitrow for his continued interest in our articles.13 In his letter, he disagreed with our comment that from our two studies alone we are unable to conclude that endothelial dysfunction is an intrinsic abnormality in the coronary artery system of patients with hypertrophic cardiomyopathy (HCM).3On the basis of his previous work,45 he has demonstrated that impaired endothelium-dependent vasodilatation of coronary resistance vessels, which is one of the potential mechanisms of myocardial ischemia, is seen in HCM, and that verapamil therapy improves this endothelial dysfunction.

When provocation tests for coronary vasospasm are performed in the catheterization laboratories of our hospitals, an intracoronary bolus injection of acetylcholine of 20 to 100 μg is used because of its effectiveness and safety.67 In our two previous studies,12 acetylcholine tests were performed in order to evaluate whether vasospasm at the level of epicardial coronary arteries occurred in patients with and without HCM. The purpose of the acetylcholine injections was not to evaluate whether subjects had coronary endothelial dysfunction. In the first study,1 coronary vasospasm was induced in 10 of 36 patients (28%) with HCM. At the dose we used, the specificity of the provocation tests using acetylcholine to detect coronary vasospasm is very high in the Japanese patient population.6 Furthermore, the same dose of acetylcholine does not induce coronary vasospasm in patients without vasospastic angina in Western populations.8 Thus, the transient total or subtotal occlusion of the epicardial coronary artery that is induced by the highest dose of acetylcholine we used is classified as coronary vasospasm, even in HCM patients.

Acetylcholine has two opposing effects: an endothelium-dependent vasodilator effect and a direct vasoconstrictor effect. The net coronary vasomotor response, either vasodilatation or vasoconstriction, depends on the balance between these two effects. In normal coronary arteries with a functionally intact endothelium, a low concentration of acetylcholine will induce vasodilatation. However, in diseased coronary arteries with dysfunctional endothelium, acetylcholine is expected to induce vasoconstriction even at the same concentration. Thus, a low concentration of acetylcholine, which corresponds to an estimated blood concentration in the coronary bed of 10−8 to 10−6 mol/L, has been used as a probe for testing endothelial function.9 However, even normal coronary arteries with intact endothelial function constrict in response to higher concentrations of acetylcholine by the direct effect of the agent on vascular smooth muscle. The dose of acetylcholine that we used, which corresponds to an estimated blood concentration in the coronary bed of approximately 10−5 mol/L, is so high that the direct vasoconstrictor effect overrides the endothelium-dependent vasodilator effect.,8,10 Thus, a relatively high dose of acetylcholine is not suitable for separating the role of endothelial dysfunction from that of smooth-muscle hyperreactivity in epicardial coronary vasoconstriction.

References
Kodama, K, Hamada, M, Kazatani, Y, et al Clinical characteristics in Japanese patients with coexistent hypertrophic cardiomyopathy and coronary vasospasm.Angiology1998;49,849-855. [PubMed] [CrossRef]
 
Kodama, K, Shigematsu, Y, Hamada, M, et al The effect of coronary vasospasm on the direction of ST-segment deviation in patients with both hypertrophic cardiomyopathy and vasospastic angina.Chest2000;117,1300-1308. [PubMed]
 
Kodama-Takahashi, K, Shigematsu, Y, Hamada, M, et al Coronary vasospasm in hypertrophic cardiomyopathy.Chest2001;119,1290-1291
 
Dimitrow, PP, Krzanowski, M, Nizankowski, R, et al Verapamil improves the response of coronary vasomotion to cold pressor test in asymptomatic and mildly symptomatic patients with hypertrophic cardiomyopathy.Cardiovasc Drugs Ther1999;13,259-264. [PubMed]
 
Dimitrow, PP, Krzanowski, M, Nizankowski, R, et al Comparison of the effect of verapamil and propranolol on response of coronary vasomotion to cold pressor test in symptomatic patients with hypertrophic cardiomyopathy.Cardiovasc Drugs Ther2000;14,643-650. [PubMed]
 
Sueda, S, Ochi, N, Kawada, H, et al Frequency of provoked coronary vasospasm in patients undergoing coronary arteriography with spasm provocation test of acetylcholine.Am J Cardiol1999;83,1186-1190. [PubMed]
 
Sueda, S, Saeki, H, Otani, T, et al Major complications during spasm provocation tests with an intracoronary injection of acetylcholine.Am J Cardiol2000;85,391-394. [PubMed]
 
Hodgson, JM, Marshall, JJ Direct vasoconstriction and endothelium-dependent vasodilatation: mechanisms of acetylcholine effects on coronary flow and arterial diameter in patients with nonstenotic coronary arteries.Circulation1989;79,1043-1051. [PubMed]
 
Ludmer, PL, Selwyn, AP, Shook, TL, et al Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary artery.N Engl J Med1986;315,1046-1051. [PubMed]
 
Yasue, H, Matsuyama, K, Matsuyama, K, et al Responses of angiographically normal human coronary arteries to intracoronary injection of acetylcholine by age and segment: possible role of early coronary atherosclerosis.Circulation1990;81,482-490. [PubMed]
 

Figures

Tables

References

Kodama-Takahashi, K, Shigematsu, Y, Hamada, M, et al (2001) Coronary vasospasm in hypertrophic cardiomyopathy.Chest119,1290-1291
 
Zeiher, AM, Drexler, H, Wollschlager, H, et al Modulation of coronary vasomotor tone in humans: progressive endothelial dysfunction with different early stages of coronary atherosclerosis.Circulation1991;83,391-401. [PubMed] [CrossRef]
 
Cannon, RO, III, Curiel, RV, Prasad, A, et al Comparison of coronary endothelial dynamics with electrocardiographic and left ventricular contractile response to stress in the absence of coronary artery disease.Am J Cardiol1998;82,710-714. [PubMed]
 
Maseri, A, Davies, C, Hackett, D, et al Coronary artery spasm and vasoconstriction: the case for distinction.Circulation1990;81,1983-1991. [PubMed]
 
Kodama, K, Shigematsu, Y, Hamada, M, et al The effect of coronary vasospasm on the direction of ST-segment deviation in patients with both hypertrophic cardiomyopathy and vasospastic angina.Chest2000;117,1300-1308. [PubMed]
 
Hodgson, JM, Marshall, JJ, et al Direct vasoconstriction and endothelium-dependent vasodilatation: mechanisms of acetylcholine effects on coronary flow and arterial diameter in patients with nonstenotic coronary arteries.Circulation1989;79,1034-1051
 
Kodama, K, Hamada, M, Kazatani, Y, et al Clinical characteristics in Japanese patients with coexistent hypertrophic cardiomyopathy and coronary vasospasm.Angiology1998;49,849-855. [PubMed]
 
Kodama, K, Hamada, M, Kazatani, Y, et al Clinical characteristics in Japanese patients with coexistent hypertrophic cardiomyopathy and coronary vasospasm.Angiology1998;49,849-855. [PubMed] [CrossRef]
 
Kodama, K, Shigematsu, Y, Hamada, M, et al The effect of coronary vasospasm on the direction of ST-segment deviation in patients with both hypertrophic cardiomyopathy and vasospastic angina.Chest2000;117,1300-1308. [PubMed]
 
Kodama-Takahashi, K, Shigematsu, Y, Hamada, M, et al Coronary vasospasm in hypertrophic cardiomyopathy.Chest2001;119,1290-1291
 
Dimitrow, PP, Krzanowski, M, Nizankowski, R, et al Verapamil improves the response of coronary vasomotion to cold pressor test in asymptomatic and mildly symptomatic patients with hypertrophic cardiomyopathy.Cardiovasc Drugs Ther1999;13,259-264. [PubMed]
 
Dimitrow, PP, Krzanowski, M, Nizankowski, R, et al Comparison of the effect of verapamil and propranolol on response of coronary vasomotion to cold pressor test in symptomatic patients with hypertrophic cardiomyopathy.Cardiovasc Drugs Ther2000;14,643-650. [PubMed]
 
Sueda, S, Ochi, N, Kawada, H, et al Frequency of provoked coronary vasospasm in patients undergoing coronary arteriography with spasm provocation test of acetylcholine.Am J Cardiol1999;83,1186-1190. [PubMed]
 
Sueda, S, Saeki, H, Otani, T, et al Major complications during spasm provocation tests with an intracoronary injection of acetylcholine.Am J Cardiol2000;85,391-394. [PubMed]
 
Hodgson, JM, Marshall, JJ Direct vasoconstriction and endothelium-dependent vasodilatation: mechanisms of acetylcholine effects on coronary flow and arterial diameter in patients with nonstenotic coronary arteries.Circulation1989;79,1043-1051. [PubMed]
 
Ludmer, PL, Selwyn, AP, Shook, TL, et al Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary artery.N Engl J Med1986;315,1046-1051. [PubMed]
 
Yasue, H, Matsuyama, K, Matsuyama, K, et al Responses of angiographically normal human coronary arteries to intracoronary injection of acetylcholine by age and segment: possible role of early coronary atherosclerosis.Circulation1990;81,482-490. [PubMed]
 
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