 Hello, I'm David Fish. I'm here to talk about an entity that has received some attention more recently. And it's called minocca, which is sort of a nifty acronym for myocardial infarction with non-obstructive coronary arteries. I have no relevant disclosures for this. So minocca is sort of a complex subject, and we're going to address these issues. I'm going to remind ourselves about oxygen transport and blood, coronary blood flow. What is actually the issue in coronary artery disease? What causes myocardial infarction? What is myocardial infarction by definition? And then what is minocca? Diagnosis and management of minocca, we're going to look at the outcomes. And then some interesting work combining optical coherence tomography of the coronary arteries with cardiac MRI in minocca. So first, let's look at oxygen transport in the blood. This is going to be relevant to our understanding of myocardial infarction. As you may recall, there are, in the hemoglobin molecule, there are four binding sites for oxygen. And this results in a biochemical result called co-operativity, where in the binding of subsequent oxygens after the first, alters the binding curve. And here, on the right, you'll see the oxyhemoglobin dissociation curve. At the right, you'll see, at the red arrows, the content of oxygen in the blood, as it's carried, in the arterial blood. And then the content of oxygen in the venous blood. So on average, as sampled in the pulmonary artery, the body and total uses about a quarter of the oxygen bound to hemoglobin. In other words, it takes one out of the four bound oxygens, which has the characteristic of being bound and unbound at relatively low transition pressures. This is quite different from the heart in particular. The heart, on the other hand, uses as much as three quarters, that is three out of four of the bound oxygens. And it can operate between about 50% and 25% saturation. And it turns out that 25% saturation occurs at a pressure that is not physiologically relevant. In other words, myocardium can use 100% of the blood, 100% of the time. So that means that oxygen delivery in the myocardium is constitutively regulated by coronary blood flow. The only way to get more oxygen is to increase the flow of blood, and therefore the content of oxygen flowing by. I also want to remind us about the function of the coronary arteries. They are conduit arteries. And here you'll see sample arteriograms showing the dark blush of contrast that proceeds from the coronary artery into the myocardial blood vessels. What is coronary artery disease? First, it's a process that causes structural changes. And we treat this condition by treatment for lipids and risk factors. There's inflammation of the artery wall, plaque formation, medial degeneration, stenosis, and ectasia that can develop. It's also a process that causes instability of the thrombotic system. And for this, we treat with platelets suppressants. These unstable events can involve plaque rupture, plaque erosion, and secondary thrombosis that may be occlusive. What causes myocardial infarction? Well, I'm going to paraphrase Dr. Robert Cloner's work looking at the coronary artery of a canine. And after about a couple of minutes of occlusion, you'll see mitochondrial changes that correct promptly if the occlusion is released. But between two to five minutes of occlusion, there are mitochondrial changes that take hours to days to correct. And after about five minutes, there are irreversible mitochondrial changes. And therefore, myocardial necrosis begins. I point this out to say that the time sensitivity of the threshold for myocardial injury means that many of the processes that affect coronary blood flow and or myocardial oxygen demand, including non-cardiac processes, can result in myocardial infarction. What is myocardial infarction? Well, this is from the fourth universal definition of myocardial infarction published from the writing group in 2018. This is an extremely comprehensive and thoughtful document. And I would encourage everyone who has the opportunity to read this. It points out the criteria for myocardial infarction. Clinical definition denotes the presence of acute myocardial injury detected by abnormal cardiac biomarkers in the setting of evidence of acute ischemia. The criteria for myocardial injury is detection of an elevated cardiac troponin value above the 99th percentile of the upper limit. And this is defined as myocardial injury. The injury is considered acute if there is a rise and fall of the cardiac troponin values. This produces a spectrum of myocardial injury. And here in this bullet diagram, you can see on the outer circle an injury leading to infarction on the inner circle and the overlapping potential complicated factors, including heart failure, anemia, hypoxemia, hypotension, and kidney disease. So what's new in this universal definition? There are large parts of this document are reinforced from the previous third universal definition document. But among the things that is pointed out is the use of cardiovascular magnetic resonance imaging to define etiology. And we'll be seeing more of this. Updated concepts include the refinement of the type 1 and type 2 definitions. We won't address type 3, type 4, or 5 today. Type 1 is myocardial infarction with the emphasis on the causal relationship of plaque disruption in the coronary atherothrombosis model. Type 2 includes settings with oxygen demand and supply imbalance unrelated to acute coronary atherothrombosis. I have some general disagreements with the approach taken in these definitions, and I'll refer to these shortly. Finally, among new sections in the definition, there is Takotsubo syndrome. Minoka, our subject today, the role of chronic kidney disease, atrial fibrillation, and silent or unrecognized myocardial infarction. The criteria ultimately involves a demonstration of myocardial injury as measured by the troponin values, clinical symptoms of myocardial ischemia, electrocardiographic changes, including the possible development of pathological q-waves and other imaging evidence of the loss of viable myocardium, or the identification of coronary thrombus biarteriography. Myocardial injury related to acute myocardial ischemia because of oxygen supply demand and balance may involve spasm, embolism, dissection, bradyarhythmia, hypotension or shock, respiratory failure, or severe anemia. So summing up the clinical classification of myocardial infarction, Type 1 is mainly about the atherothorombotic coronary artery disease form of infarction. This is usually precipitated by atherosclerotic plaque disruption. The burden of atherosclerosis and thrombosis in the culprit lesion may vary greatly. The dynamic thrombotic component may lead to distal coronary embolization, also resulting in myocyte necrosis. And plaque rupture may not only be complicated by intralerminal thrombosis, but also by hemorrhage into the plaque through the disrupted surface. And here, summarized on the left are the criteria. And I've provided these notations to remind us that plaque hemorrhage may develop and that the dynamic thrombotic component may lead to distal coronary embolization. Type 2, myocardial infarction, highlights the mismatch between oxygen supply and demand. By definition, atherosclerotic plaque disruption is not a feature of Type 2 MI. However, this is my note, such acute structural change to the coronary artery that reduces coronary blood flow may be a cult and may have resolved and it may have occurred by other mechanisms such as spontaneous dissection and would still be, while it shares a pathophysiologic consequence of Type 1 MI, is here classified as Type 2 MI. Type 2 has a higher frequency in women. The short and long-term mortality rates for patients with Type 2 are generally higher than for Type 1 due to an increased prevalence of comorbid conditions. Coronary disease is still a common finding in Type 2 patients. In general, these patients have a worse prognosis than those without coronary disease. Coronary embolism caused by thrombi, calcium or vegetation from the atria or ventricles or acute aortic dissection may result in a Type 2 MI. And spontaneous coronary artery dissection with or without intramural hematoma is another non-atherosclerotic condition that may occur, especially in young women, but it does have the same consequence as atherosclerotic conclusion of the coronary. So in that sense, it maps pathophysiologically to very similar to Type 1 MI. So I find these definitions a little inconsistent. Type 2 is defined not to include atherosclerotic plaque disruption, but such disruption that it results in transient or occult occlusion may be included. Other structural or other acute obstructions such as embolized thrombus, spontaneous coronary dissection, so-called SCAD, are also classified with Type 2 MI, but they are isomorphic to myocardial infarction due to coronary disease in effect. The prognosis derives separately from myocardial injury and persistent risk posed by coronary artery disease. Combining myocardial infarction due to some forms of acute structural change of the coronary artery that reduce coronary blood flow with coronary blood flow demand-based causes of ischemia and injury, I feel complicates this definition and also as you will see, the definition of monoca. Here is the recapitulated on the left, the criteria for Type 2 MI, but here also depicted on the right is an example of non-atherosclerotic coronary artery dissection, but this is still an acute structural change to the coronary artery that obstructs blood flow. Monoca has a number of features. I will say at the outset that monoca is a clinical diagnosis, and therefore it does not ultimately necessarily have a consistent set of pathophysiologic definitions. Myocardial infarction patients with no angiographic obstructive coronary disease is one of the criteria. As in myocardial infarction, it indicates there's an ischemic mechanism responsible for the injury. The diagnosis of monoca necessitates that obstructive coronary disease has not been inadvertently overlooked, such as spontaneous coronary artery dissection. Atherosclerotic plaque disruption and coronary thrombosis may be a cause of monoca, that is Type 1 MI. However, coronary spasm and spontaneous coronary dissection may also be involved. That is a Type 2 MI, along with other possible causes. The prevalence of monoca is estimated to be six to eight percent among patients diagnosed with myocardial infarction, more common in women than men, more common in patients presenting with N-stemi compared to those presenting with ST elevation of myocardial infarction. Additional coronary imaging and functional testing methods may be useful to elucidate the multiple mechanisms of ischemia in monoca. A monoca event may include Type 1 or Type 2 MI. It's mechanistically diverse, and that causes the characterization of etiology, treatment and prognosis to be difficult, and perhaps renders the entity itself pathophysiologically incoherent. This paper is from a consensus statement from the AHA concerning the entity of monoca, and I also would encourage people to read this. It is a very good position paper. In this document, monoca is addressed by definition. It's the myocardial infarction in the absence of obstructive coronary disease. It was first documented as long as 75 years ago when autopsy reports detailed myocardial necrosis in the absence of a significant coronary atherosclerosis. The prevalence of non-obstructive coronary disease in five to six to percent, up to 15% depending on the population of patients with acute myocardial infarction, may be in the monoca population. So the current focus is to address the misperception by some clinicians who still suppose that the absence of obstructive coronary disease excludes the possibility of an acute myocardial infarction. Acute myocardial infarction from the fourth universal definition. Again, detection of a rise or fall of troponin, a corroborative clinical evidence of infarction, non-obstructive coronary arteries on angiography, and no specific alternate diagnosis for the clinical presentation. These are the criteria for monoca. There are some epidemiologic observations of interest. Monoca patients are usually younger than those with coronary disease. Women make up close to 50% of the monoca population, but only about 25% of the population with acute infarction due to coronary disease. Women with acute myocardial infarction twice as likely as men to have monoca. Monoca is also more likely to occur in patients of black, Maori, or Pacific race and Hispanic ethnicity. Traditional risk factors such as hypertension, diabetes, tobacco abuse, and a family history of myocardial infarction may be less frequent in monoca patients. So there are some key issues in defining monoca. Patients with monoca generally have better prognosis than patients with coronary disease and acute infarction. Multiple atherosclerotic and non-atherosclerotic causes with heterogeneous pathophysiologic mechanisms can cause monoca. Unlike coronary disease causing acute myocardial infarction, there's a paucity of dedicated studies examining it and therefore a lack of evidence-based therapies. Monocas should be reserved. This term should be reserved for patients in whom there is an ischemic basis for their clinical presentation. The MI and monoca does, after all, stand for myocardial infarction. There are also key exclusions. Despite the absence of obstructive coronary disease, it's imperative to exclude clinically overt causes for the elevated troponin, such as sepsis or pulmonary embolism. Clinically overlooked obstructive disease, such as complete occlusion of a small artery. Clinically subtle non-aschemic mechanisms of myocyte injury that can mimic myocardial infarction, such as myocarditis. And if coronary arteriography is performed and FFR, fractional flow reserve, is interrogated, a significant flow limiting stenosis by the definition of 0.80 cannot exist. This is a general flow diagram re-emphasizing the clinical diagnosis and the diagnosis of exclusion that is posed by monoca. Following the flow chart on the left, down to the exclusion of coronary disease and other forms of myocardial injury. At the bottom, the flow diagram terminates in the diagnosis of monoca, which is a clinical characterization. Subsequent investigation of the monoca cases may lead to specific diagnoses in the lower right corner, including plaque disruption due to spontaneous coronary dissection, an entity that was in the excluded forms of diagnosis higher up in the flow diagram. This emphasizes that the specific pathophysiologic findings that are ultimately associated to the diagnosis of monoca do not form a coherent definition of monoca. Rather, monoca is a diagnosis of exclusion. It's a working diagnosis that has to be assigned when the earlier forms or causes of myocardial infarction are excluded. So in any case, the patient does need to have the underlying cause responsible for monoca, identified and treated. It is myocardial infarction and cardio protector therapies must be patient-specific. Antiplatelet therapy is indicated if it's a type I myocardial infarction. It's uncertain of uncertain value for a type II myocardial infarction. The prognosis depends on underlying cause. Most studies have shown that monoca patients have a better outcomes than those with coronary disease. Approximately 25% of patients with monoca will experience angina in the subsequent 12 months. This is similar to the frequency reported in patients with coronary disease and infarction. Some meta-analysis studies show a hospital mortality rate of about 0.9% and a 12-month mortality of about 4.7%. One registry in New Zealand indicated that death or recurrent MIA occurred in 4.6% over two years compared with only 2.2% of age and sex-matched subjects without coronary disease or diabetes. So there's some additional prognosis risk for the diagnosis of monoca. The largest study that is outlined in this paper is the sweetheart registry and included more than 9,000 patients with the diagnosis of monoca and a mean follow-up of 4.1 years. They took the opportunity to evaluate the outcomes relating to the use of statins, ACE inhibitors and ARBs, beta blockers and dual anti-platelet therapy, using the composite of all-cause mortality or hospitalization for re-infarction, heart failure, or stroke. They did find that there was a significantly lower event rate associated to the use of statins with a 23% relative risk reduction, 18% risk reduction with ACE inhibitors and ARBs, a trend for a possible lower event rate with the use of beta blockers. And however, dual anti-platelet agents was not associated with the lower event rate. In follow-up, there was a 13, over 4.1 years, there was a 13.4% mortality, which is less than half of the mortality was classified as cardiovascular mortality. 7.1% had recurrent myocardial infarction, 4% stroke, 6% hospitalization for heart failure, 3.6% hospitalization for pleading, and 1.7% one-year mortality in young patients. So the predictors of in-hospital mortality in Menocra are similar to those in AMI-CAD, that is age, higher troponal level, renal dysfunction, heart rate, blood pressure and peripheral arterial disease, SD segment elevation on electrocardiogram and presentation with heart failure or shock were more strongly predictive in-hospital death among patients with Menocra than among those with acute infarction due to coronary disease. Here are the plots showing the advantage in the composite endpoint for statins on the upper left, for RAS inhibitors on the right, for beta blockers on the lower left, and the lack of discernible benefit for dual antiplatelet therapy. This is a very important paper that examined in this registry the reinfaction events in patients who had original diagnosis of Menocra. There were 570 patients in the sweetheart registry, about 6.3%, who had a new MI in follow-up. They tended to be older with more diabetes and hypertension and previous MI and a higher creatinine. On angiography, however, interestingly, a high proportion of the patients had recurring Menocra, about half of them. The survival plots are a little discouraging. This is survival to 120 months, so this is very useful and well-done cohort. But on the left here, you can see that if the patient is treated conservatively, and specifically if they are not investigated by coronary arteriography, their prognosis is substantially worse. On the right panel, you can see that late survival, if the patient has recurrent Menocra, and that was 50% of the patients, their prognosis is also worse than if they had a second myocardial infarction on the basis of coronary artery disease. Management, therefore, that's suggested, is that primary management of Menocra should include the treatment of coronary risk factors. Coronary arteriography must be strongly considered in patients who are readmitted with myocardial infarction after Menocra. Those who do not receive coronary arteriography have a worse prognosis. And finally, recurrent Menocra has a worse prognosis than recurrent MI due to coronary disease. The prognosis in terms of all-cause death in patients with previous Menocra readmitted is poor. The adverse prognosis is most pronounced in patients selected for a conservative strategy. Prognosis after the new MI did not differ between patients with MI and obstructive catin and new Menocra. There are currently no randomized trials aiming at improving the prognosis for patients for the Menocra, so these are really needed. At present, intense treatment for a traditional risk factor seems like a reasonable approach because the predictors for adverse outcome are most similar after Menocra asked for MI with obstructive coronary disease. There is some observational study in the sweetheart registry that suggests beneficial effects of statins and Renan angiotensin system receptor blockers. More recently, to investigate the various pathophysiologic causes of Menocra, OCT, that is optical coherence tomography of the coronary arteries and cardiac MRI, have been employed to help us understand the entity further. This is hard to read this flow diagram essentially out of about 5,000 patients. There were, who had acute myocardial infarction, a number of patients, about 260 were identified who had Menocra, and then in the flow diagram, ultimately in this particular study, about 40 out of about 80 eligible patients were ultimately studied. They included patients like this one, a 41-year-old woman who had apical lateral non-ST elevation myocardial infarction, patient at proximal coronary arteries that were patent, a somewhat small distal LAD, and adorapical wall motion abnormality. Optical coherence tomography of the coronary showed an innermal tear of the LAD and mural hematoma. A cardiac MRI confirmed wall motion abnormality, but no late gadolinium enhancement. The authors state that in this study, optical coherence tomography, coupled with MRI, it provided a clear substrate and or diagnosis in all patients presenting with Menocca, including electrocardiographic features of ischemia associated with corresponding wall motion abnormalities. The specific question of the mechanisms that may be unique to women was undertaken in a collaborative study and reported by Harmony Reynolds in circulation. These subsequent slides are taken from Dr. Reynolds' presentation to the AHEA in 2020, the HARP investigators. Again, to remind us, Menocca was defined in this study as MI meeting the universal definition, less than 50% stenosis in major epicardial arteries on angiography, normal appearance or mild to moderate atherosclerosis, no specific alternate diagnosis. It occurs in six to 15% of MI, disproportionately affecting women. There is a four year rate of late adverse event. I have 24% and five year mortality of about 11%. Pathogenesis is varied, leading to uncertainty about treatment. And in this particular research program, patients were referred with the intent to perform cath or PCI as indicated. They underwent OCT if eligible and cardiac MRI if available. Of 301 women in 16 sites, 170 were found to have Menocca. Of all these, 145 underwent OCT and 116 had cardiac MRI. And a number of features are worth noting here. ST elevation by cardioparticle infarction was in a small minority, 3.5%. Segmental wall motion abnormality was identified on echocardiogram in about 44%. Coronary arteriography was reported as normal by the investigation site in 54%. OCT findings identified a culprit lesion in 46%, including plaque rupture, thrombosis without plaque rupture, layered plaque and enamel bump, including spasm, for example, and one case of spontaneous coronary dissection. MRI findings included infarction, specific findings of infarction in 33%, regional injury in 21%, non-eschemic causes were found in 21%. And interestingly, myocarditis was identified in 15%. In some other papers, this was even higher. Overall, the MRI was normal in about a quarter of the patients. Integrating these two, a cause was identified in 85% of patients, no cause in 15%. There was OCT culprit with cardiac MRI, evidence of infarction or regional ischemia in 69%. So, putting it together, of course, multimodality imaging with both OCT and cardiac MRI in these women with menoka identified a cause in 85%. This is a sample case that was provided in the paper showing 44-year-old women without cardiac risk factors who had chest pain and heavy menstrual bleeding. The hemoglobin of seven had a peak troponin of 3.25, nanograms per milliliter, and OCT identified LED plaque rupture with a thin cap fibroethyroma. And there was a small transmural infarction at the end of the LAD identified on cardiac MRI. So there are limitations to this study with a small sample size. There was no control group, no spasm testing, and of not all subjects had three-vessel OCT and MRI, only about half. It was limited to women. However, it provides useful diagnostic information. Cardiac MRI findings correlated well with OCT culprit lesions, demonstrating that non-obstructive culprit lesions frequently cause menoka. Coronary artery spasm or thrombolymbalism is likely caused by MI or regional ischemic injury in cases without OCT culprit. Mechanisms of menoka and women are often similar to mechanisms of myocardial infarction and coronary disease, atherothrombosis with possible contribution of coronary spasm. And this goes to what I mentioned earlier that on investigation of menoka, which has arrived at by exclusion, that causes can be identified that are specifically excluded investigation of the patient prior to the conclusion of menoka. There is a study that is intended to provide us a randomized prospective control view of therapy for menoka using beta blockers and ACE inhibitors in a two by two factorial trial. They intend to randomize quite a few patients, about 3,500. And last report, my understanding, the progress has been slow, but this will be important work for our conclusions. So some notes, final notes. Menoka is a diagnosis of exclusion. The more you exclude, the less diverse the mechanisms are included in menoka. Menoka reminds us that in the presence of criteria for acute MI, the absence of high-grade obstructive coronary disease does not exclude MI. Menoka cohorts include a disproportionately high number of women, 50% as compared to MI with coronary disease at 25%. The approach to treating menoka should include suppression of risk factors, including treatment of statins and harass inhibitors, beta blockers and dual anti-platelet therapy are as yet of unproven benefit. However, these conclusions are drawn from retrospective study. We do not yet have prospective data to confirm these. OCT and MRI are together very sensitive and specific for the diagnosis of the mechanisms of menoka. Recurrent MI after menoka and especially recurrent menoka has a poor prognosis. Thank you very much for your attention. I appreciate it. This is a difficult subject and I think that we will learn more about this in the future.