Melissa Walton-Shirley, MD

Disclosures

August 31, 2016

How many times have we been "fooled," even disappointed that the ACS patient with a positive troponin had seemingly normal coronary arteries? During my 20     years in the cath lab, I confess there was a sense of relief when there was nothing more to be done. In the small lab where I first started my private     angiography career, that meant not having to arrange for transport. After PCI without surgery on site was finally approved in Kentucky, clear arteries     meant the table was open for another case. It was disconcerting, though, when the look on my patient's face lying on the table, sheet tucked around their     neck for warmth, changed from a look of anticipation to confusion. It was my habit to unbuckle and temporarily discard my lead suit, then turn the monitor     in the patient's direction so they could actually see their coronary arteries. Proving their vessels were large, smooth, and unobstructed and in many cases     accompanied by a normal LV gram would surely reassure them. These were not the takotsubo patients, though. Those gals got far more attention     because at least they had "something." Their heart muscle didn't work, so their family, friends, and neighbors would validate the need for the ambulance     ride. The guys? They were tough enough to survive a heart attack but luckily didn't have to have a stent. As for the girls going out the door with no real     diagnosis, a bottle of aspirin, and nitro, "just in case it was spasm," well, you know, they overreacted.

Over the past 20 years, patients with MI without obstructive CAD, of whom women outnumber men by 2:1, have finally gotten their own acronym. They are     labeled as MINOCA (MI-No-Coronary-Atherosclerosis) patients. Even that acronym is a misnomer because optical coherence tomography (OCT) and intravascular     ultrasound (IVUS) will often uncover sneaky plaque ruptures and hematomas. At least we've started to promote the malady as a syndrome, but we don't have a     lot of data. The workup is usually based on a hypothesis, driven by gut feelings and laced with a heavy dose of common sense. There is no     one-size-fits-all treatment because the etiologies are highly variable.

In a session on "Acute myocardial infarction with no obstructive coronary atherosclerosis" at the European Society of Cardiology (ESC) 2016 Congress, Dr Hiroaki Shimokawa (Tohoku University, Sendai, Japan) gave an overview of the pathogenesis. He flashed a slide[1] that lumped cardiac etiologies into three categories: myocardial, including     takotsubo, dilated and hypertrophic cardiomyopathy; coronary disorders, including concealed coronary dissection, sympathomimetic induced spasm, epicardial     spasm, microvascular spasm, microvascular dysfunction, slow–flow phenomenon, plaque disruption/coronary thrombosis, and coronary emboli; and thrombotic     disorders, including Factor V Leiden and protein C and S deficiency. An audience member would later step to the microphone and add anticardiolipin antibody     that can promote both venous and arterial clot. The presenter pointed out the additional need to screen for cocaine use. There were slides of highly     offended coronary arteries choking from an acetylcholine challenge then rescued by nitro, and then there was the most fascinating point of Dr Shimokawa's     lecture.

Researchers looked at evidence of sustained brain activation in patients suffering from presumed microvascular dysfunction. Plasma serotonin levels were     elevated in many patients at >9.55 nmol/L (P<0.007). In the acute phase of takotsubo syndrome, brain activation was distinctly increased in     the hippocampus and the basal ganglia. The prefrontal cortex and the brainstem were also more activated in the acute phase (up to 4 days) than in the     chronic phase (days 28–39). Even a layperson could see the varying shades of blue, green, yellow, and red that dotted the slides.

The presenter would conclude his talk by reminding us that 14% of MINOCA patients would have thrombophilia. Nearly 11% of patients with a first cryptogenic     cerebral ischemic event will also have a subclinical MI due to the presence of a patent foramen ovale (PFO). A slide of a glistening red wormlike thrombus     stretched across a light blue drape to make his point. A clip from a transesophageal echocardiogram (TEE) demonstrated a clot straddling the atrial septum,     caught red-handed with a dual destination of both the coronary and cerebral circulation. He concluded with a slide of the Japanese Coronary Spasm     Association that included 85 institutions. I didn't even know there was a coronary spasm institution anywhere.

Next, Dr Giampaolo Niccoli (Catholic University of the Sacred Heart             ,      Rome, Italy) presented information on the recommended workup. First, he reemphasized the diagnostic criteria published in 2016[2]. The diagnosis can be made only  by a coronary angiography finding of less than 50% obstruction. The     AMI criteria includes "a positive biomarker, preferably troponin, with at least one value above the 99th percentile of the upper reference limit," plus one     of the following: symptoms, new ECG changes, a new wall-motion abnormality, or an intracoronary thrombus on angiography or at autopsy.

Dr Niccoli discussed briefly the standardized international COVADIS criteria for the diagnosis of coronary vasomotor disorders.[3] It includes     the following: nitrate-responsive angina, transient ischemic ECG changes, and documented coronary artery spasm. He pointed out that multislice CT is not     adequate and that OCT and also IVUS in some cases are necessary. He prefers acetylcholine (ACH) testing over ergotamine and then demonstrated various trials     depicting the low complication rate with testing. In a trial of 921 patients, microvascular spasm was demonstrated in 24% and epicardial spasm in 33% while     the remainder yielded an inconclusive or uneventful ACH test.[4]

As for takotsubo patients, he added the important caveat to consider the rare pheochromocytoma in patients who had severe hypertension or persistent     tachycardia. He then demonstrated the accepted four variants of acute LV dysfunction in takotsubo. He urged us to look up the diagnostic criteria for     myocarditis[5] and emphasized the necessity of cardiac magnetic resonance (CMR) in suspected cases. He notes that 14% of MINOCA patients are     hypercoagulable. In a study published in 2015,[6] 12% had factor V Leiden mutations, 2.6% demonstrated protein C or S deficiency, and another     2.5% had factor XII deficiency. I looked at the bottom right-hand corner of the slide and saw the total number of patients studied was only 356. There is     so much cardiac hematology that will never be known in my lifetime.

In addition to the obligatory angiogram the workup generally includes an acetylcholine challenge in suspected vasospasm, IVUS and OCT for eccentric plaque     assessment, ventriculography CMR for takotsubo patients, and assessment for parvo B 19 virus, then CMR with endomyocardial biopsy (EMB) to assess for myocarditis. We should perform     a TEE in appropriate cases where a PFO is suspected.

Dr Eva Prescott (Bispebjerg University Hospital, Copenhagen, Denmark) then addressed short- and long-term prognosis. She pointed out that studies have not     found a correlation between troponin I level and outcomes. Of 4900 patients in CRUSADE, complications were low, but 4.4% would develop heart failure, 3.7%     would require transfusion postangiography, and 1.7% would die or reinfarct[7]. Pooled data from 26 studies demonstrated that 21% would have a     subendocardial infarction, 29% myocarditis, 23% hypertrophic cardiomyopathy, and 16% takotsubo syndrome; 6% would be from "other causes."[6]     There was a frustrating 2% that will have a completely normal CMR. In-hospitality mortality ranged from 1.1% to 3.2% in some trials, and 12-month mortality,     although lower than in patients with fixed obstruction, ranges from 3.5% to 6.7%. Dr Prescott then pointed out that in takotsubo patients 3.0% will develop     ventricular tachycardia, 1.3% a ventricular thrombus, and 0.2% ventricular rupture.

Finally we heard from Dr Juan-Carlos Kaski (St George's University, London, UK) regarding treatment. He pointed out that therapy depends upon the etiology.     MINOCA patients usually receive the standard AMI therapy with aspirin, a P2Y12-receptor antagonist, low-molecular-weight heparin, and perhaps a     beta-blocker. He also notes that after a "normal coronary angiogram, most therapies are stopped, adding that "we don't know if this is right or wrong." He     also touts the need for CMR. He listed around 50 known triggers for takotsubo and the need to stop drugs with sympathomimetic action such as inotropes,     catecholamines, and beta 2 agonists. If there is left ventricular outflow tract obstruction he advised the consideration of a beta-blocker (unless there is     evidence of a pheochromocytoma) or an alpha one agonist. He mentioned the use of levosimendan for cardiogenic shock if there is no mechanical support     available.

After the presentation, he said, "All patients with evidence of myocarditis need to be assessed for spasm and then treated with calcium-channel blockers if     present." I then asked how he approaches patients who have received anticoagulation prior to the opportunity to test for thrombophilia. Like the rest of     us cardiologists, he prefers to punt that question to the hematologists.

Throughout the presentation, my mind drifted to many MINOCA patients and of course I asked myself the obvious question, "Should I have done something     different?" I recall the devastating double tragedy of a mother who presented directly from her son's funeral in cardiogenic shock. She is the one and only     MICONA patient I've ever lost. I cathed her, put in a temporary pacer, and an intra-aortic balloon pump (IABP). Her coronaries demonstrated a 50%     obstruction in the LAD with brisk TIMI flow. I could never support her pressure for very long and packaged her for transport to a tertiary center for an     LVAD or extracorporeal membrane oxygenation (ECMO). Twenty minutes later, the helicopter sat back down on the landing pad. My patient had died. Oddly, her     son had succumbed to fixed obstruction and was reportedly buried clutching a pack of cigarettes in his hand. My other notable patient has hit a troponin I     level of 5 twice. She has ongoing chest pain, a normal cath x 3, and a normal IVUS. I've never obtained an MRI or an acetylcholine challenge. I've     treated her with calcium-channel blockers, nitrates, antiplatelet agents plus aspirin and she still cycles into several weeks' worth of angina quelled by     an almost daily requirement for nitroglycerin. I wonder what I should do differently for her? Will an additional workup change anything?

I'm encouraged that we at least have an acronym for this syndrome. It's hopeful that we no longer label these patients as hysterical, and we have a plan     with active enrollment into trials to develop appropriate workup and therapies. Twenty years ago, I cared for my first MINOCA patient, a 40-year smoker     that I left in my training hospital awaiting a heart transplant. I'm happy that most of the world understands them better now and especially that after a     "normal" cath, indeed we are just getting started.

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