“Apical Ballooning” — What Is the Cause?

ABSTRACT: The pathophysiology of takotsubo cardiomyopathy remains enigmatic. Here we attempted to define the link between the coronary arteries and the histopathological involvement of the left ven- tricle. We observed similarities and discrepancies between patients. All patients experienced stress prior to the event. We found a reduced coronary flow reserve in all patients and signs of hibernating my- ocardium on biopsy specimen. This raises a strong suspicion of stress- induced endothelial dysfunction with hibernating myocardium in the pathogenesis of this cardiomyopathy. J INVASIVE CARDIOL 2008;20:599–602 Case 1 A 73-year-old female was admitted with pneumonia and developed sudden dyspnea and hypotension. Her medical illness was her inciting stress factor. Her electrocardiogram (ECG) showed ST-segment elevations in the anterior leads. Anterior akinesia was documented echocardiographically. She was referred for primary percutaneous intervention with an anterior wall myocardial infarction (MI) and a systolic pressure of 60 mmHg on vasoactive medications and mechanical ventilation. She had a known case of large-cell carcinoma of the lung with a history of a left-upper lobectomy and radiation therapy 8 years previously when she underwent pericardial fenestration. She also had undergone radiofrequency ablation to treat atrioventricular nodal re-entrant tachycardia. Left ventricular (LV) angiography showed classic LV apical ballooning in systole (Figures 1A and B). The angiogram revealed normal coronary arteries (Figures 1C and D). The ECG with ST-segment elevations in anterior leads, normal coronary arteries and classic features of apical ballooning on LV angiography fulfilled the three criteria as proposed by the Modified Mayo Clinic for LV apical ballooning syndrome (ABS), or takotsubo cardiomyopathy.3,9 Since the pathogenesis of ABS is not clear,9 we investigated further. The patient’s endothelial function was determined using a Flow-wire (Volcano Corp., San Diego, California), and flow responses were documented to acetylcholine, nitroglycerin and adenosine. Intracoronary acetylcholine (Ach, 10-5M) did not cause a significant change in average peak velocity (APV) and remained unchanged in response to intracoronary nitroglycerin and adenosine, which resulted in a blunted coronary flow reserve of 1.4. Intravascular ultrasound (IVUS) performed with a recorder (Volcano Corp.), and no relevant plaques were documented. LV biopsy (done from the apex) showed an accumulation of periodic-acid Schiff stain (PAS)-positive material. Case 2 A 54-year-old female was admitted with dyspnea and chest pain. She had psychological stress due to interpersonal conflict with her husband. The patient had a previous invasive investigation which revealed a dilated cardiomyopathy. The LV angio of the present admission revealed an akinesia of the apical and inferior areas with sparing of the basal area (Figures 2A and B). The left coronary angiogram showed a plaque in the proximal left anterior descending (LAD) (Figures 2C and D). The LAD was not a wraparound LAD that normally extends beyond the apex (shown in Figure 4). The other vessels were normal. We considered the possibility of a variant of takotsubo cardiomyopathy. The Doppler assessment showed severe endothelial dysfunction (APV baseline 36), with no response to acetylcholine, nitroglycerin or adenosine. IVUS showed a plaque burden of 62%. In light of the IVUS findings and the patient’s clinical presentation, we performed primary stenting of the LAD plaque. Biopsies from the apex and base of the LV were performed and compared to the case described above. The histological findings of both biopsies showed moderate signs of myocardial hypertrophy, as well as interstitial and perivascular fibrosis (Figures 4 and 5). Some cardiomyocytes contained accumulations of diastase-PAS-positive material, which corresponded to a particular glycogen on electron microscopy. The findings were compatible with dilated cardiomyopathy. Neither acute ischemic changes nor a myocarditis was present. Case 3 A 63-year-old female presented with chest pain and ECG changes in the anterior territory. Her brother had recently passed away and she was psychologically stressed after this incident. The LV presented as a mid-ventricular ballooning pattern (Figures 3A and B) and the coronary arteries were normal (Figure 3C). There was no vasospastic response to acetylcholine, nitrogylcerin and adenosine testing, indicating a highly dysfunctional and unresponsive endothelium. No significant plaque was documented by IVUS. Biopsy of the akinetic LV showed ischemic subendocardial fibrosis and myocardial hypertrophy, as well as a unifocal, sparse, mixed lymphohistiocytic and granulocytic infiltrate. Nested polymerase chain reaction (PCR) examination revealed persistent parvovirus B19, but no evidence of active myocarditis. Some cardiomyocytes showed an intracellular accumulation of PAS-positive material (Figure 6). Discussion The apical ballooning syndrome was first described by Dote et al,1 who proposed the term “takotsubo”, meaning an octopus trap in Japanese. Since this description, many causative mechanisms have been proposed.2–4 Psychological stress or even a triggering of stress by accidents, surgery, natural calamities (after earthquakes in Japan, for example) have been proposed.2 These have been postulated by their mere presence, but the exact pathophysiology remains unknown. All of our patients experienced stress, one in the form of medical illness (pneumonia), and the other two had family stress triggers. Early measurement of catecholamine levels is reported in many patients following stress cardiomyopathy as a causative mechanism.5,8 This catecholamine surge causes characteristic contraction band necroses, focal mononuclear inflammatory infiltrates and areas of fibrosis as described in a recent histopathological report on 7 patients.7 Fibrosis and lymphohistiocytic infiltrates were observed in our third patient. However, PCR examination revealed the presence of parvovirus B19 as a possible cause of the observed histopathologic changes. Focal contraction band necroses are a common artefact due to the biopsy procedure and cannot be reliably differentiated from necroses caused by catecholamines. They were also present in our biopsy specimens. In accordance with the above mentioned publication,7 we found increased amounts of PAS-positive intracytoplasmic glycogen confirmed by electron microscopy in the biopsies of our patients. Our histopathological findings do question the pathophysiologic explanations for stress-initiated cardiomyopathy. A case series of 5 patients who underwent IVUS showed coronary plaque rupture, and all these patients had a wraparound, long LAD.6 In our 3 cases, the LAD was short, and 1 patient had a plaque burden which on IVUS was not suggestive of a ruptured plaque. Hence, the possibility of an atherosclerotic narrowing of the LAD as an etiology is low on the list in our patients. We performed the Ach test, and none of our patients had significant vasospasm. The presence of abnormal endothelial function (low coronary flow reserve) in all patients led us to consider endothelial dysfunction resulting in ischemia as a possible causative factor. Furthermore, it is in concordance with the study by Sadamatsu et al.10 We measured flow only in the LAD, but we think abnormal endothelial function exists in all the vessels, causing a mixed area of involvement. Recently, a rodent model demonstrated an increased density of the beta adrenoceptor as well as modulation in the apical region of the LV.8 There have been descriptions of right ventricular biopsies, and fewer from the LV.7 We obtained biopsies from the LV apex and the base with the aim of exploring the possibility of a unique histopathological correlation. The results of the biopsies did not reveal a specific pattern, however. There was typical accumulation of PAS stain-positive material in our specimens. The presence of this material indicates a hibernating myocardium. Hibernating cardiomyocytes are reversibly hypocontractile and switch in primary substrate utilization from fatty acids to glucose. Hibernating myocardium also contains increased amounts of glycogen. Takotsubo cardiomyopathy may be similar to myocardial hibernation secondary to endothelial dysfunction stimulated by stress factors. One of our patients with mid-ventricular atypical takotsubo had associated parvovirus B19 without myocarditis. We attribute this to a mere association, as there was no clinical precedent or histopathological correlation to this finding. Study limitations. This is a small series of patients and will require a larger study to further delineate our concept.

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