□ CASE REPORT □

Refractory Vasospasms of the due to Multiple Factors: An Autopsy Case

Kentaro Arakawa 1,HideoHimeno1, Toshikazu Gondo 2, Jin Kirigaya 1, Fumie Otomo 1, Kensuke Matsushita 1, Hidefumi Nakahashi 1, Satoru Shimizu 1, Manabu Nitta 1, Hideto Yano 1, Mitsuaki Endo 1, Kazuo Kimura 3 and Satoshi Umemura 4

Abstract

A 41-year-old man was admitted with decompensated . Mechanical ventilation was maintained with a large dose of propofol. On day 4, significant ST elevation with complete was noted, which subsequently induced cardiopulmonary arrest. Treatment with percutaneous cardiopulmonary support and therapeutic hypothermia was initiated. Emergent cardiac showed simultaneous mul- tivessel coronary spasms. Although nitroglycerin and nicorandil were ineffective, the intracoronary admin- istration of fasudil, a Rho-kinase inhibitor, successfully resolved the vasospasms. However, during rewarming, the coronary vasospasms recurred, and the patient died of cardiogenic shock. In addition to hypertrophy, the autopsied heart demonstrated the accumulation of inflammatory cells in the pericardium and adventitia of the coronary arteries.

Key words: coronary artery spasm, inflammation, hypertrophic

(Intern Med 53: 963-967, 2014) (DOI: 10.2169/internalmedicine.53.1900)

nous congestion were evident on a chest roentgenogram. Introduction and the laboratory data showed no evi- dence of myocardial (Fig. 1). An echocardiogram Variant , first described by Prinzmetal and col- demonstrated concentric hypertrophy and a reduced systolic leagues in 1959, is caused by severe coronary vasospasms function of the left ventricle (Fig. 2A, B). Mechanical venti- associated with transmural myocardial ischemia (1). Most lation was induced and maintained with a large dose of in- patients respond to nitrates or calcium channel blockers. travenous propofol. To treat the acute decompensated heart However, in some cases, medical treatment-resistant vaso- failure, a continuous infusion of carperitide and nitroglycerin spasms have been reported. We herein present an autopsy was administered in addition to diuretics. On day 4, signifi- case of vasospastic angina refractory to conventional ther- cant ST elevation was noted on the telemetry monitor. Sub- apy. Multiple factors are associated with the occurrence of sequent electrocardiography revealed ST elevation in leads coronary vasospasms that cannot be relieved with medical II, III and aVF with complete atrioventricular block, which management. subsequently induced cardiopulmonary arrest (Fig. 3). The patient received prolonged cardiopulmonary resuscitation Case Report and percutaneous cardiopulmonary support with therapeutic hypothermia. Emergent cardiac angiography showed diffuse A 41-year-old man was admitted to our hospital with severe narrowing of the right coronary artery (RCA) and to- dyspnea and . and pulmonary ve- tal occlusion of the mid left anterior descending artery

１Division of Cardiology, Fujisawa City Hospital, Japan, ２Division of Pathology, Fujisawa City Hospital, Japan, ３Division of Cardiology, Yoko- hama City University Medical Center, Japan and ４Department of Medical Science and Cardiorenal Medicine, Yokohama City University, School of Medicine, Japan Received for publication October 9, 2013; Accepted for publication November 24, 2013 Correspondence to Dr. Kentaro Arakawa, [email protected]

963 Intern Med 53: 963-967, 2014 DOI: 10.2169/internalmedicine.53.1900

Figure 1. A chest X-ray and electrocardiogram obtained on admission. A: A decubitus anteropos- terior chest X-ray showing cardiomegaly and pleural effusion. B: A 12-lead electrocardiogram show- ing sinus , biatrial enlargement and left .

Figure 2. A transthoracic echocardiogram obtained on admission showing concentric hypertrophy with a reduced systolic function of the left ventricle (A: long-axis view; B: M-mode).

lesions with negative arterial remodeling in both the LAD and RCA, which suggested that the angiographic appearance was due to multivessel coronary vasospasms (Fig. 4A-D). However, the repeated intracoronary administration of nitro- glycerin and nicorandil was ineffective in resolving the spasms. Therefore, we administered fasudil, a Rho-kinase inhibitor, into the spastic arteries, which successfully re- solved the spasms with resolution of the inferior ST eleva- tion and an improvement in the myocardial ischemia (Fig. 4E, F). We discontinued the propofol and initiated the continuous intravenous administration of fasudil. However, on day 6, during rewarming following treatment with thera- peutic hypothermia, the ST elevation in the inferior leads and complete atrioventricular block recurred. The intrave- Figure 3. An electrocardiogram obtained immediately prior nous infusion of hydrocortisone and was ineffec- to cardiopulmonary arrest in the intensive care unit. Marked tive in resolving the myocardial ischemia. The patient’s va- ST-elevation in the inferior leads and complete atrioventricu- sopressor requirements increased, and he died of cardiogenic lar block were evident. shock six hours later. An autopsy was carried out 24 hours after his death. At autopsy, the heart weighted 980 g. Con- centric hypertrophy of the left ventricle was observed with (LAD). Intravascular ultrasound demonstrated a myocardial extensive myocardial necrosis in the inferior wall. A small bridge in the LAD and non-calcified mildly atherosclerotic abscess was noted in the pericardial sac. Multiple transverse

964 Intern Med 53: 963-967, 2014 DOI: 10.2169/internalmedicine.53.1900

Figure 4. Coronary angiogram and intravascular ultrasound findings. A, B: Initial angiograms showing diffuse severe narrowing of the right coronary artery (RCA) and total occlusion of the mid left anterior descending artery (LAD). C, D: Intravascular ultrasound images obtained following the intracoronary administration of nitroglycerin demonstrating non-calcified mildly atherosclerotic le- sions with negative arterial remodeling in the RCA (black arrows) and a large myocardial bridge with a myocardial band overlying a segment of the LAD (white arrows). E, F: Final angiograms showing fasudil-induced dilatation with residual fixed narrowing. sections of the coronary arteries exhibited luminal narrowing tions are often used to relieve the vasospasms (2). due to the presence of atherosclerotic plaques in 25% to In the present case, even fasudil was only transiently ef- 75% of the cross-sections, including the area involved in the fective. Several factors are associated with the occurrence of spasms; however, no occlusion was observed. A histological coronary vasospasms refractory to conventional medications. examination demonstrated marked hypertrophied and bizarre First, in patients with hypertrophic cardiomyopathy, an myocytes with disarray in addition to the accumulation of impaired sympathetic nerve function and the genetic variants inflammatory cells in the pericardium and adventitia of the of the delta-sarcoglycan and the endothelial nitric oxide syn- coronary arteries at the site of the vasospasms, even inside thase are associated with increased vasomotor activity (3-5). the perivascular nerve tissue (Fig. 5A-F). The infiltrating Additionally, mechanical stimulation at the myocardial cells in the epineurium and endoneurium were primarily bridge site of the mid LAD induces endothelial dysfunction lymphocytes. and enhanced local susceptibility to vasoconstrictor stim- uli (6). Discussion Second, the continuous infusion of large doses of propo- fol can result in autonomic imbalances and lipid metabolic Simultaneous multivessel coronary spasms, one of the disorders, including the presence of remnant-like particles most severe forms of coronary spastic angina due to the associated with an upregulated Rho-kinase expression in presence of severe and extensive myocardial ischemia, are coronary vascular smooth muscle cells and a markedly en- often associated with refractory angina and multiple medica- hanced coronary vasospastic activity (7).

965 Intern Med 53: 963-967, 2014 DOI: 10.2169/internalmedicine.53.1900

Figure 5. Photomicrographs of the autopsied heart. A: Subserial ventricular myocardial sections of the autopsied heart showing marked diffuse thickening of the left ventricular walls. There is suben- docardial hyperemia (arrowheads) within a nearly transmural inferior myocardial infarct. B: Histo- logical appearance of the left ventricle (non-infarct area). Marked hypertrophied and bizarre myo- cytes with disarray were observed. C: Histological appearance of the pericardium showing the accumulation of inflammatory cells, primarily lymphocytes and macrophages. D: A transverse sec- tion of the right coronary artery at the site of the spasms. Although no coronary thrombi were found, luminal narrowing due to atherosclerotic plaque was evident and the coronary arterial adventitia was thickened with collagen. E, F: Higher magnification views of the areas #1 and #2 in D. Many inflam- matory cells, primarily lymphocytes, were clustered in the adventitia around and even inside the perivascular nerve tissue.

Third, rewarming following treatment with therapeutic hy- The coronary adventitia is richly innervated with automatic pothermia can trigger the recurrence of vasospasms. Experi- fibers that form a network around the entire length of each mental studies of isolated human middle cerebral arteries coronary vessel. The degeneration of these autonomic ner- have shown that human arteries dilate only slightly with vous fibers due to irritation by inflammatory cells induces cooling and undergo a more profound constrictor response irregularities in the sympathetic activity, including the vaso- upon rewarming (8). Both an increase in metabolic demands motor activity (12). Moreover, chronic inflammation of the and ventilator requirements and the massive reproduction of adventitia is reported to induce alterations in smooth muscle cytokines and oxygen free radicals can occur during re- phenotypes toward dedifferentiation (13). In this way, the warming (9). smooth muscle cells of the coronary arterial media are Fourth, inflammation associated with intense stimulated directly by chemical mediators secreted by in- may spread to the adventitia of atherosclerotic coronary ar- flammatory cells or indirectly by irritated autonomic ner- teries. Recently, enhanced inflammation in perivascular fat vous fibers involved in the inflammatory process. has been reported to influence vascular homeostasis and the In conclusion, we herein described an autopsy case of re- development of atherosclerosis in coronary arteries (10, 11). fractory vasospasms of the coronary arteries due to multiple

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