Nitrate Tolerance as a Possible Cause of Multidrug-Resistant Coronary Artery Spasm A Case Report and Its Implications

Abstract

SummaryCoronary spasm can usually be controlled by administration of Ca antagonists. However, there are some cases of coronary spasm whose attacks cannot be controlled even with large doses of Ca antagonist and/or its combination with nitrates. Here we describe the case of a 41-year-old man whose attacks of coronary spasm were resistant to the combined administration of nitrates, Ca antagonists, and a statin. The attacks were alleviated and disappeared after withdrawal of nitrates and recurred after readministration of a nitroglycerin patch. The involvement of nitrate tolerance in the pathogenesis of multidrug resistant coronary spasm was revealed and its implication discussed. (Int Heart J 2010; 51: 211-213) Key words: Alcohol, Aldehyde dehydrogenase 2, Coronary spasm, Nitrate tolerance C oronary (artery) spasm plays an important role in the pathogenesis of not only variant angina but also coronary heart disease (CHD) in general, including unstable angina, acute myocardial infarction, and sudden death.1,2) Organic nitrates including glyceryl trinitrate (GTN) or isosorbide dinitrate (ISDN) have been widely used for the treatment of CHD and the attack of coronary spasm is usually promptly relieved by sublingual administration of GTN or ISDN.1) A major therapeutic limitation inherent to organic nitrates, however, is the development of tolerance which occurs during chronic treatment with these drugs. 3,4) Recent studies have shown that mitochondrial aldehyde dehydrogenase (ALDH2) plays a central role in the development of nitrate tolerance.3) Ca antagonists are, therefore, the first choice for the treatment of coronary spasm. 1)There are, however, not a few cases of coronary spasm whose attacks cannot be controlled even with high doses of Ca antagonists or combination of these agents.1) Long-acting nitrates are often added in the management of such cases. We report a case of multidrug resistant coronary spasm whose attack ameliorated on withdrawal of chronic administration of nitrates and deteriorated on continued GTN medication. This report was approved by the ethical committee of our hospital and written informed consent was obtained from the patient. Case ReportA 41-year-old Japanese man was referred to our hospital because of frequent episodes of constriction in the neck in the early morning. His medical history was unremarkable except for an episode of acute alcohol intoxication and the "flushing response" to alcohol. He had smoked 20 cigarettes a day for 25 years until 1 year previously, when an atrial septal defect (ASD) was detected and he had an Amplatzer device placed for closure of ASD. One month thereafter, he noticed the episode of constriction of the neck in the early morning. Ambulatory monitoring of an electrocardiogram (ECG) revealed ST segment elevation on the inferior leads during the attacks and he was put on the Ca antagonist benidipine (8 mg/day) and the statin pravastatin (5 mg/day) at a local hospital. However, the attacks could not be controlled, occurring 3-4 times a week for 2 months. ...

East Asian Variant of Aldehyde Dehydrogenase 2 Is Associated With Coronary Spastic Angina

“…ALDH2 also plays an essential role in the bioactivation of GTN used widely for the treatment of ischemic heart disease. 18,32,41 However, continued administration of GTN leads to tolerance 18,32,41,42 or even cardiac events 43 through inactivation of the ALDH2 enzyme and an increased ROS. 18,32,41,42 Accordingly, the carriers of ALDH2*2 genotypes are less responsive to GTN and are also susceptible to GTN tolerance and ROS.…”

“…18,32,41 However, continued administration of GTN leads to tolerance 18,32,41,42 or even cardiac events 43 through inactivation of the ALDH2 enzyme and an increased ROS. 18,32,41,42 Accordingly, the carriers of ALDH2*2 genotypes are less responsive to GTN and are also susceptible to GTN tolerance and ROS. 18,32,41,42 It is estimated that >500 million (or 8%) of the world population are carriers of the ALDH2*2 genotype.…”

“…18,32,41,42 Accordingly, the carriers of ALDH2*2 genotypes are less responsive to GTN and are also susceptible to GTN tolerance and ROS. 18,32,41,42 It is estimated that >500 million (or 8%) of the world population are carriers of the ALDH2*2 genotype. 31 However, a considerable number of subjects with the ALDH2*2 genotype or even those with CSA are habitual alcohol drinkers, 6 as shown also in this study.…”

Impact of Cystatin-C Level on the Prevalence and Angiographic Characteristics of Vasospastic Angina in Korean Patients

“…Further studies should be conducted to fully elucidate the interaction between these two pathologies. Although many clinical prognostic factors of VSA have been suggested, 1,2,13,16,24) multivessel spasm has also been reported as an important prognostic factor in VSA. 13,25,26) Patients with multivessel spasm are more likely to have lethal arrhythmias than those with single vessel spasm and occasionally experience sudden cardiac death.…”

Metabolic Planar Imaging Using ¹²³I-<i>β</i>-Methyl-Iodophenyl Pentadecanoic Acid Identifies Myocardial Ischemic Memory After Intracoronary Acetylcholine Provocation Tests in Patients With Vasospastic Angina

“…Compared with atherosclerosis, coronary spasm can assume several forms and unique phenomena such as multiple spasms, repeated chest pain, and silent ischemia. 6,7,9,[20][21][22][23][24] Reduced uptake persists in a specific region, resulting in overlapping or abnormal 123 I-BMIPP uptake in other regions due to repeated spasms. Conventional angiography cannot detect microvascular alterations because of system limitations.…”