Pathophysiology of myocardial infarction with non-obstructive coronary arteries and Takotsubo syndrome

Sammanfattning: Introduction: The working diagnosis myocardial infarction with non-obstructive coronary arteries (MINOCA), with the subgroup myocardial infarction with normal coronary arteries (MINCA), encompasses conditions of diverse aetiological origin. One of them is Takotsubo syndrome (TTS), a reversible and often stress-induced condition of acute heart failure, predominantly affecting postmenopausal women. Both MINOCA and TTS are associated with substantial morbidity and mortality, yet evidence-based treatment is lacking. The overall aim of this thesis was to expand the knowledge on pathophysiological mechanisms of MINOCA and TTS, with a view to guide future clinical management. The study specific aims were I) to characterise MINCA patients regarding risk factors and markers for endothelial function and atherosclerosis, II) to improve the diagnostics of MINOCA, III) to study if coronary microvascular dysfunction (CMD) is a prominent feature of acute TTS, and whether CMD in TTS is associated with clinical parameters, and IV) to determine whether sympathetic activity and reactivity are enhanced in the early recovery phase of TTS. Methods and results: In study I, the first Stockholm Myocardial Infarction with Normal Coronaries (SMINC) study, we included 100 MINCA patients together with two age- and sexmatched control groups of MI patients with coronary heart disease, respectively healthy volunteers. Endothelial function was evaluated with peripheral arterial tonometry measuring reactive hyperaemia index. Atherosclerosis was evaluated with carotid ultrasound measuring intima-media thickness. MINCA was associated with many established cardiovascular risk factors and female sex. Measures of endothelial function and atherosclerosis did not differ between study groups. One out of four MINCA patients received a clinical diagnosis of TTS. In study II, the SMINC-2 study, 148 MINOCA patients were examined by comprehensive cardiovascular magnetic resonance (CMR) imaging at median 3 days after admission. 150 patients from the screening phase of the SMINC-1 study, examined by standard CMR imaging at median 12 days after admission, served as historical controls. The underlying diagnosis was identified in 77% of patients in the SMINC-2 study, compared to 47% of patients in SMINC-1. The improved diagnostic yield was mainly due to increased detection of myocarditis and TTS. In study III, the Sympathetic And vascular Function in Takotsubo syndrome (SAFT) study, we included 27 female TTS patients together with age- and sexmatched controls with ischemia and no obstructive coronary arteries (INOCA). CMD was assessed invasively with thermodilution technique during index coronary angiography. Cardiac function was determined by echocardiography and CMR imaging in TTS patients. CMD was more common in TTS patients than in INOCA controls (78% vs. 44%). CMD was related to left ventricular function in TTS and more pronounced in the apical than midventricular phenotype. In study IV, muscle sympathetic nerve activity (MSNA) was determined by microneurography of the peroneal nerve at rest and during stress in 18 TTS patients from the SAFT study together with 13 age- and sex-matched healthy controls. Cardiac specific sympathetic activity was depicted by 123Imetaiodobenzylguanidine scintigraphy in 10 TTS patients. Despite signs of increased cardiac sympathetic activity in TTS, MSNA at rest and in response to stress did not differ between TTS patients and controls. Conclusions: MINCA is associated with many cardiovascular risk factors, female sex, and TTS, but not with markers of endothelial function and atherosclerosis. Early and comprehensive CMR imaging significantly improves the diagnostic yield in MINOCA and is therefore strongly suggested as a standard diagnostic tool. CMD is highly prevalent in the acute phase of TTS, associated with left ventricular function, and thus proposed as a key mediator in TTS pathophysiology. An altered cardiac response to sympathetic activation, rather than an underlying sympathetic hyperactivity or hyperreactivity, is likely central for TTS development.