High Incidence of Focal Left Ventricular Wall Motion Abnormalities and Normal Coronary Arteries in Patients with Myocardial Infa

Myocardial infarction with angiographically normal coronary arteries (MINCA) is a well-documented syndrome.¹ The incidence of MINCA among all patients with myocardial infarctions is thought to be low, ranging from 1–5%,^2–4 as reported from older and often incomplete studies. Recent studies^5,6 of patients with MINCA have reported groups, but not the incidence, of patients with an unusual left ventricular wall motion abnormality (LVWMA) called Takotsubo cardiomyopathy,⁷ a rare condition that was first described in Japan and has been documented more recently in the United States.⁸ Takotsubo cardiomyopathy is found predominantly in females. They usually present with chest pain and electrocardiographic (ECG) findings of an acute myocardial infarction in the setting of emotional or physical stress, with elevated cardiac enzymes, normal coronary arteries and a distinctive cardiomyopathy. The appearance of the left ventricle is likened to a Japanese octopus pot called a takotsubo. It has been our impression over the past several years at Marin General Hospital that the incidence of patients with Takotsubo cardiomyopathy has been unusually high. Even more surprising is the high incidence of focal anterior and inferior LVWMAs in our MINCA patients, suggestive of typical anterior and inferior myocardial infarctions. The purpose of this study is to document, in a consecutive series of patients, the incidence of MINCA and these unusual LVWMAs and to describe the characteristics of patients who are at risk for presenting with this syndrome. Methods Study patients. Marin General Hospital is a 180-bed community hospital located north of San Francisco, California, in Marin County. In this study, data were retrospectively collected on 409 consecutive patients with myocardial infarctions who were admitted to Marin General Hospital between June 1, 2002 and October 31, 2004. These patients were divided into two groups: those with ST-elevation myocardial infarctions (STEMI), and those with non-ST-elevation myocardial infarctions (NSTEMI) (Figure 1). To be classified as STEMI, patients had to have cardiac symptoms (usually chest pain) and ST-segment elevation in at least two leads (anterior, lateral or inferior) and elevated troponins. Our STEMI protocol is for all patients to go directly to angiography for possible primary angioplasty. To be classified as NSTEMI, patients had to have elevated troponins and symptoms. Not all NSTEMI patients at our hospital underwent catheterization. Only those patients with NSTEMI who underwent catheterization were included in our study. Angiography. All patients in this study received coronary and left ventricular angiography. Coronary angiograms were assessed visually by two angiographers and by computerized quantification software (Siemens Medical, Mountain View, California) and considered normal if no significant irregularities were noted. Left ventriculograms were assessed for ejection fraction utilizing computerized quantification (Siemens) and for wall motion abnormalities by visual evaluation by two angiographers. Statistical analysis. All continuous variables with normal distributions are displayed as mean values plus or minus the standard deviation. Continuous variables with skewed distributions are displayed as median values with lower and upper range limits. Categorical variables are displayed as percentages. Chi-square tests of significance were used to compare differences in proportions within patient categories. A p-value Results Clinical characteristics. There were 165 patients (114 males and 51 females) with STEMI (Figure 1). Seventeen (11 females and 6 males) of the 165 patients with STEMI had MINCA and underwent early catheterization within a median time of 2 hours and 52 minutes from presentation (25 minutes – 51 hours and 52 minutes). Fifteen patients presented to either Marin General Hospital or the emergency department of another local hospital, while 2 patients developed STEMI during hospitalization for other medical conditions. As all of the 165 consecutive patients with STEMI underwent catheterization, we know that 10.3% of all patients, 21.6% of all females, and 5.3% of all males presenting with STEMI had normal coronary arteries. There were 244 patients (145 males and 99 females) with NSTEMI who underwent catheterization (Figure 1). This number does not represent all patients at MGH with NSTEMI as we do not routinely perform catheterization on all patients with NSTEMI. Fifteen patients (12 females and 3 males) from this group of NSTEMI had MINCA and underwent catheterization within a median time of 16 hours and 16 minutes from presentation (1 hour 17 minutes – 115 hours 49 minutes). As some patients with NSTEMI were not catheterized, we do not know the true incidence for this group of patients. While acknowledging this limitation, in those patients with NSTEMI who received angiography, 6.1% of all patients, 12.1% of all females and 2.6% of all males had normal coronary arteries. Combining our patients with STEMI and NSTEMI, 7.8% of all patients, 15.3% of all females and 3.5% of all males with myocardial infarctions had normal coronary arteries. The mean age of the 32 patients with MINCA was 57 years (22–88) with 84% presenting with chest pain. There were 28 Caucasians, 1 African-American, 1 Persian, 1 Hispanic and 1 Burmese. The mean age of the 17 STEMI patients was 57 years, and the mean age of the 15 NSTEMI patients was 54 years. Of our patients with MINCA, 71.8% were females and 28.2% were males. Females were more likely to present with MINCA than males, both for STEMI (21.6% vs. 5.3%; p Electrocardiography. The patients with STEMI had at least 1 mm ST-elevation in 11 cases and 0.5 mm ST-elevation in 6 cases in at least 2 inferior, anterior or lateral leads. All patients with NSTEMIs had abnormal ECGs with nonspecific ST- and T-wave changes. Four of the 8 patients with anterior LVWMA had precordial ST-elevation, while 1 of 2 patients with inferior LVWMA had inferior ST-elevation. Six of our 7 patients with Takotsubo had ST-elevation, with 3 showing anterior and 3 showing inferior changes. The ECG pattern did not appear to predict the type of LVWMA. Cardiac markers. The median peak troponin I was 14.6 ng/ml (range 3.2–265; abnormal > 2.0) and was elevated in all patients. The CK-MB/total CK index was obtained in 72% of the cases and found to be elevated in 96% of the cases for which it was tested, with a median peak index of 10.9 (range 2.9–16.5; abnormal > 5). The timing of the blood draws varied, with STEMI patients having immediate and serial measurements per protocol, while the timing of NSTEMI measurements was more variable. The peak troponins did not correlate with the LVEF or type of LVWMA. Most patients had the typical immediate rise in troponins, suggesting an acute event. Coronary angiography. The coronary angiograms appeared to be completely normal in 29 cases (90.7%), with the other 3 cases (9.3 %) having noncritical stenosis (14%, 28% and 33% diameters). The plaques that were present appeared to be smooth, not associated with reduced coronary flow, were not thought to be culprit lesions and were not associated with any particular LVWMA. Coronary artery flow was graded by TIMI classification.⁹ There was reduced TIMI 2 coronary artery flow in 9 patients (28.1%), all of whom had normal-appearing coronary arteries. The slow flow was in the left anterior descending alone in 5 cases, the left anterior descending and left circumflex in 3 cases and the right coronary artery in 1 case, and did not correlate with any particular LVWMA. Left ventriculography. The median LVEF for all 32 patients was 45% (13–77%). The 32 patients could be subdivided into 5 groups (Table 1). There were 8 patients, 7 females and 1 male, who had a focal anterior LVWMA (Figure 2). The median EF for these patients was 40% (26–53%), with 4 STEMI and 4 NSTEMI. There were 2 patients, 1 male and 1 female, with a focal inferior LVWMA (Figure 3) with LVEFs of 40% and 54%, with 1 STEMI and 1 NSTEMI. Seven patients had Takotsubo *cardiomyopathy (Figure 4) with the typical left ventricular appearance of an octopus pot with preservation of the basal constrictors and a ballooning of the anterior, apical and inferior walls during systole. The median LVEF was 34% (29–40%), all females, with 6 STEMI and 1 NSTEMI. There were *9 patients with a diffusely hypokinetic LVWMA, with a median LVEF of 47% (13–50%), 3 females and 6 males, with 4 STEMI and 5 NSTEMI. There were 6 patients with a normal LVEF with a median EF of 58.5% (57–77%), 2 males and 4 females, with 2 STEMI and 4 NSTEMI. Follow-up echocardiograms. There were 26 patients with abnormal left ventricular angiograms. Fourteen of these patients received follow-up echocardiograms, with 13 having normal left ventricular function, and 1 with no change in the ejection fraction. Included in the follow-up echocardiograms were 5 of the 7 patients with Takotsubo, and all of these echocardiograms showed a return to normal LVEF. Discussion The current study is the first to describe a consecutive series of patients presenting with MINCA in a community hospital. By performing this study in a community hospital, we avoid the referral bias inherent in tertiary centers. As reported in other recent papers,^5,6 there was a high incidence of Takotsubo cardiomyopathy, particularly in females with stress. A new finding in our study is the even higher incidence of focal anterior and inferior LVWMAs. Our series contains a unique group of patients with focal anterior and inferior LVWMAs, suggesting myocardial damage in the distribution of a single coronary artery. Eight patients had focal anterior hypokinesis in the distribution of the left anterior descending coronary artery and 2 had focal inferior hypokinesis in the distribution of the right coronary artery. This finding expands the range of patients reported by Wittstein et al⁵ and Sharkey et al.¹⁰ Wittstein et al reported on 19 patients presenting with congestive heart failure and MINCA. Sharkey et al reported on 22 patients presenting with chest pain and MINCA. Wittstein et al and Sharkey et al combined involved 41 patients with Takotsubo cardiomyopathy, and all but 1 were females, while only 21.9% of our patients had Takotsubo cardiomyopathy, and only 71.9% were females. The distribution of the LVWMAs is interesting, as it may provide some insight into the pathophysiology of myocardial infarctions in general. Wachsman et al¹⁰ have postulated that Takotsubo cardiomyopathy may be a reflection of a diffuse process such as spasm associated with stress affecting multiple coronary vessels, given that the extent of the apical dyskinesis does not fit into the distribution of only one major coronary artery. Our high incidence of focal anterior and inferior wall motion abnormalities suggests that MINCA is part of a continuous process that may affect single as well as multiple coronary arteries. This *observation may provide insight into the role of stress causing a myocardial infarction in the larger population of patients with atherosclerotic coronary artery disease. If stress can cause a myocardial infarction in the distribution of a single normal coronary artery, then the consequences of stress on a diseased coronary artery might be more significant than currently believed. Another interesting finding is that 6 of our patients with MINCA had normal left ventricular function in spite of ECG changes and elevated troponins. This observation shows the spectrum of MINCA ranging from Takotsubo cardiomyopathy to normal-appearing left ventricular wall motion. The degree and pattern of left ventricular dysfunction may be related to the number and susceptibility of the vessels involved, the duration of the process and the lapsed time to study that might affect the recovery of myocardial function. In our series of patients, we could not find any relationship between time from symptoms to catheterization and the type of wall motion abnormality. **Strunk4_Tako_systole.jpg*There is definitely a gender preference associated with the type of LVWMA with MINCA. Only 1 out of our 17 (5.9%) patients with Takotsubo or focal anterior or inferior LVWMA is male. However, 7 out of 15 patients (46.7%) with diffuse LVWMA or normal left ventricular function are males. In our study we also found a previously unreported observation of slow TIMI 2 coronary artery blood flow in 9 (28.1%) of our 32 patients, 3 with Takotsubo, 4 with diffuse and 2 with anterior LVWMAs. There was no correlation between the involved vessels and type of LVWMA. This observation supports the idea of some obstruction downstream from the epicardial coronary arteries causing the slow coronary blood flow, but does not discriminate between possible catecholamine-induced vascular spasm or myocardial necrosis. Previous reports3–5 have shown a low incidence (1–5%) of patients with myocardial infarction having MINCA. Sharfi et al3 reviewed 1,124 angiograms of patients with myocardial infarction and found a 1% incidence. Betriu et al2 studied 259 out of 300 patients and found a 3% incidence. Kereiakes et al4 looked at 799 STEMI patients who underwent thrombolysis as part of the TAMI protocols and found a 5.5% incidence of patients who had 7,11 Fifty percent of our patients had a significant stressful event within hours before their MINCA. One patient woke up in bed to find her husband dead. One woman witnessed a jogger struck by an automobile. A young male athlete on the day of his MINCA had just received a major league baseball contract. Unfortunately, our stress evaluation was retrospective and we do not have a comparison with the non-MINCA patients. Takotsubo cardiomyopathy recently has become a popular example of a stress cardiomyopathy, or “broken heart” syndrome.⁵ Seven (21.8%) of our patients with MINCA, all females, had Takotsubo cardiomyopathy, with 6 having a STEMI and 4 having a significant stressful event. Recently, Wittstein et al⁵ have emphasized the role of stress and associated elevated catecholamine levels and possibly coronary artery spasm in patients presenting with the acute onset of severe congestive heart failure with normal coronary arteries. The major contribution of Wittstein et al’s report to the understanding of the pathogenesis of MINCA is the demonstration of an elevation of catecholamine levels in association with Takotsubo cardiomyopathy. While these data do not prove a causal relationship among MINCA, stress and catecholamines, they do suggest a possible explanation, as elevated catecholamine levels have been associated with coronary artery spasm^12,13 as well as myocardial injury.¹⁴ Our series differs from that of Wittstein et al in that our cases consist of typical patients presenting to the local emergency department with chest pain, while Wittstein et al looked specifically and only for patients with congestive heart failure and a recent stressful event in a referral university hospital. It is difficult to explain why the patients in Wittstein’s series had a lower, and often normal, level of cardiac laboratory markers, or why only 2 of their 19 patients had ST-segment elevation, while 17 of our 32 patients had ST-segment elevation and all had significantly elevated troponins. On the other hand, Sharkey et al6 reported 22 patients more like our group, presenting with chest pain. All of their patients had a recent stressful event and Takotsubo cardiomyopathy, with 59% having ST-segment elevation and 68% having elevated troponins. Together, these 3 groups of patients are probably part of the continuous spectrum of stress-induced myocardial infarctions. While the initial reports⁷ of Takotsubo cardiomyopathy were from Japan and emphasized the preponderance of Asians, our study, and others⁸ as well, shows that MINCA is a universal disease. Among our patients, 87.5% with MINCA were Caucasian. We were only able to obtain follow-up echocardiograms on 54.6% of the patients who initially had left ventricular dysfunction. Of these follow-up echocardiograms, 92.9% were normal, which agrees with the previously reported high incidence of return of normal left ventricular function with MINCA.^5,6 We did not exclude myocarditis as a possible cause of MINCA since we did not perform endomyocardial biopsies on our patients. Wittstein et al⁵ did perform biopsies on 5 of their 19 patients and found no evidence of myocarditis. Sharkey et al⁶ did not perform biopsies on any of their 22 patients. Almost all of our patients presented with chest pain and, by definition, all of our STEMI patients had ST-elevation. While acute myocarditis can present in this way, it would be unusual for a group of patients of this size to present in such a short period of time with this diagnosis to our hospital. The early mortality rate for patients with MINCA is reportedly low,^3,7,10,15 and none of our patients died during their hospitalization. However, since our report, we had our first mortality due to MINCA in the case of an elderly woman, admitted shortly after her husband’s death, who developed a Takotsubo cardiomyopathy complicated by mitral regurgitation. Study limitations. Our assessment of stress was not performed systematically across all patients. We did not systematically question our patients about recent stressful events, nor did we administer any psychological testing, so we may be incorrectly estimating the role of stress in the incidence of MINCA. It was not possible to include an age-matched group for comparing stress associated with MINCA with stress associated with myocardial infarctions from coronary artery occlusion. We did not perform angiography on all patients with NSTEMI who presented to our hospital, therefore introducing a possible bias into our analysis. We did not perform intravascular ultrasound or computed tomography angiography of the coronary arteries to completely exclude artherosclerosis that was not visible angiographically, which may result in an artificially high estimate of the incidence of MINCA. And finally, myocarditis was not excluded with an endomyocardial biopsy. Conclusion This study is the first to document the incidence of MINCA and Takotsubo cardiomyopathy in a series of consecutive patients presenting to a community hospital with myocardial infarction. We also describe a new phenomenon of focal anterior and inferior wall motion abnormalities in patients with MINCA. There was an unexpected high incidence of MINCA in females, especially those with STEMI, as well as a strong association with stress. Whether this higher than previously reported incidence is unique to Marin County, California, or is applicable to larger populations may be elucidated by further studies in other communities. Further studies of patients with MINCA are warranted to help clarify the pathophysiology involved with MINCA, mechanisms that may also play an important role in causing myocardial infarction in the patients with a significant atherosclerotic burden. Stress may well be a prominent factor, but future studies should include psychological questionnaires, autonomic nervous system testing and catecholamine levels to verify its role in this syndrome. Acknowledgments. The skillful help of catheterization laboratory assistants Greg Lee, Jim Whitlock, Margaret Roberts and Sandra Augustus, the editing assistance of my son, Adam Strunk, MD, and the transcription assistance of Barbara Nelson are gratefully acknowledged.

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