Response to Letter Regarding Article, “Mechanisms of Coronary Artery Spasm”
We very much appreciate the comments of Yasue et al on our review about coronary artery spasm (CAS).1 In our article, we questioned that endothelial dysfunction (ED) can by itself be the main pathophysiological substrate for CAS in the clinical setting for 2 main reasons: (1) the discrepancy between the high prevalence of ED and the low prevalence of vasospastic angina; (2) the lack of any significant relation between most cardiovascular risk factors (CVRFs) known to cause ED and CAS.
In their letter, instead, Yasue et al propose that ED is the central abnormality in the mechanisms of CAS; specifically, they propose that smooth muscle cell (SMC) hyperreactivity, ultimately responsible for CAS, is caused by chronic ED.
Yasue et al speculate that the reason why chronic ED does not frequently cause CAS in Western countries, despite its large diffusion, depends on the fact that the high prevalence of dyslipidemia in these populations also results in the frequent development of atherosclerotic coronary plaques, which would constitute an inadequate milieu for the development of SMC hyperreactivity. In contrast, in Japanese people, the low prevalence of dyslipidemia would result in a low prevalence of coronary plaques, whereas the high prevalence of smoking would induce a chronic ED that, in the absence of dyslipidemia-related coronary plaques, would result in SMC hyperreactivity and CAS.
This hypothesis of a different phenotypic coronary manifestation of ED depending on specific CVRFs is intriguing. Epidemiological studies, however, showed that all CVRFs, including smoking, are associated both with ED and coronary atherosclerosis.2 Of note, a large number of patients do not develop coronary plaques despite the presence of CVRFs and ED. Accordingly, if chronic ED were the key factor for CAS in the absence of coronary plaques, it is not clear why, in this subset of subjects, smoking only shows a significant association with CAS, whereas other classical CVRFs (dyslipidemia, hypertension, and diabetes mellitus) do not.3
In fact, the peculiar association of smoking with CAS rather suggests that, besides and beyond ED, and differently from other known CVRFs, smoking may have direct effects on SMCs resulting in SMC hyperreactivity, as suggested by in vitro experimental studies.4 Of note, the possibility to induce CAS by direct modifications of SMCs is confirmed by experimental models.5
Importantly, the evidence of ED in patients with CAS deriving from the studies cited by Yasue et al, although showing an association between the 2 abnormal findings, does not prove a causal relation.
Finally, we respectfully disagree with Yasue et al that CAS does not occur in the presence of atherosclerotic plaques. CAS in the early studies on vasospastic angina was indeed mainly described in patients with angiographically evident coronary atherosclerosis, and CAS inducibility at the level of atherosclerotic lesions has been reported in several studies.3
In summary, although the notion that ED may favor CAS occurrence is shareable, we believe that current experimental, epidemiological, and clinical evidence suggests that endothelium-independent modifications of SMCs are responsible for SMC hyperreactivity and CAS in patients with vasospastic angina.
Gaetano Antonio Lanza, MD
Giulia Careri, MD
Filippo Crea, MD
Department of Cardiovascular Medicine
Catholic University of Sacred Heart
- © 2012 American Heart Association, Inc.