American Heart Journal
Volume 152, Issue 3 , Pages 469.e9-469.e13, September 2006

Myocardial perfusion in apical ballooning syndrome: Correlate of myocardial injury

Department of Internal Medicine, Division of Cardiovascular Diseases, Mayo Clinic and Mayo Foundation, Rochester, MN

Received 9 February 2006; accepted 16 June 2006.

Article Outline

Background

The pathophysiology of the apical ballooning syndrome (ABS) is poorly understood. This study evaluated myocardial perfusion abnormalities at the time of presentation in patients with ABS and examined whether abnormal microvascular blood flow predicts the extent of myocardial injury.

Methods

We evaluated 42 consecutive patients, all women, with a diagnosis of ABS and technically adequate angiograms for the assessment of the TIMI myocardial perfusion grade (TMPG), an index of myocardial perfusion.

Results

Abnormal myocardial perfusion was present in 29 (69%) patients. There were no differences in age, frequency of conventional coronary atherosclerosis risk factors, left ventricular ejection fraction at either presentation or follow-up, congestive heart failure at presentation, or length of hospital stay between patients with normal versus those with abnormal TMPG. Patients with abnormal TMPG had higher peak troponin level compared with patients with normal TMPG (0.84 ± 0.68 vs 0.42 ± 0.33 ng/mL, P = .047). Similarly, ST elevation or deep T-wave inversion on the electrocardiogram was more common in patients with abnormal perfusion (86% vs 46%, P = .006).

Conclusion

Impaired myocardial perfusion due to abnormal microvascular blood flow is frequently present in patients with ABS and correlates with the extent of myocardial injury. Microvascular dysfunction likely play a pivotal role in the pathogenesis of myocardial stunning in ABS.

 

The apical ballooning syndrome (ABS), also known as Takotsubo cardiomyopathy, stress cardiomyopathy, and “broken heart syndrome,” is a recently described acute cardiac syndrome, typically characterized by transient regional systolic dysfunction involving the left ventricle apex and midventricle with hyperkinesis of the basal segments.1 A key diagnostic point is that the regional wall systolic dysfunction extends beyond the anatomic distribution of a single coronary artery.

There are similarities between ABS and acute coronary syndromes with regard to the symptoms, electrocardiographic changes, and cardiac biomarker elevation that suggest that myocardial ischemia occurs during the initial presentation phase. Multivessel epicardial coronary artery spasm has been proposed as a potential mechanism but has rarely been angiographically documented.1 There are conflicting reports on whether microvascular dysfunction and impaired myocardial perfusion is present in patients with ABS. Prior studies have presented data both to support2, 3 and to refute4 the hypothesis that an abnormal microcirculation contributes to the pathophysiology of the syndrome. The relatively small number of participants in the studies, potential limitations of the methods used to assess for the microcirculatory dysfunction, failure to assess for the microcirculatory dysfunction at the time of the initial presentation,3 and the lack of correlation of observed microvascular function with the extent of myocardial injury precludes any firm conclusions.

The aim of this study was to evaluate whether myocardial perfusion is abnormal at the time of the initial presentation in patients with ABS and correlate the findings with clinical features.

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Methods 

Patients 

Forty-two consecutive patients who were suspected of having an acute coronary syndrome and were subsequently diagnosed with ABS, based on the previously published Mayo criteria,1 and had adequate imaging for unequivocal assessment of TIMI myocardial perfusion grade (TMPG) were included in the study. The diagnostic criteria include the following: (1) transient akinesis or dyskinesis of the left ventricular apical and midventricular segments with regional wall motion abnormalities extending beyond a single epicardial vascular distribution; (2) absence of obstructive coronary disease (≥50% stenosis or angiographic evidence of acute plaque rupture); (3) transient electrocardiographic abnormalities (ST-segment elevation and/or T-wave inversion); and (4) absence of recent significant head trauma, intracranial bleeding, pheochromocytoma, myocarditis, and hypertrophic cardiomyopathy. We evaluated the history, physical examination, 12-lead electrocardiogram (ECG), cardiac biomarkers, and coronary angiogram. ST elevation was defined as >1 mm in amplitude in at least 2 consecutive leads. Deep T-wave inversion was defined as >3 mm in amplitude in at least 3 consecutive leads. The angiograms from a group of 14 patients randomly selected from the cardiac catheterization database served as controls. The patients were matched to those with ABS for age, sex, and ejection fraction; they had no history of coronary atherosclerosis and did not have obstructive coronary artery lesion by angiography (ie, no luminal diameter narrowing ≥50%). The study was approved by the Mayo Clinic Institutional Review Board.

Coronary angiography 

Coronary angiograms were performed within 24 hours of onset of symptoms in all but one patient, in whom the angiogram was performed 3 days later. TMPG was assessed by a single observer blinded to the clinical characteristics and outcomes of the patients. TIMI myocardial perfusion is a well-validated angiographic surrogate of myocardial perfusion and strongly correlates with outcomes in patients with acute coronary syndromes.5 Analyses were performed in the distribution of all 3 epicardial coronary arteries by using the methodology of Gibson et al.6 The following grades were used: TMPG 0, minimal or no myocardial perfusion; TMPG 1, dye stains the myocardium and the stain persists on the next injection; TMPG 2, dye enters the myocardium but washes out slowly so that dye is strongly persistent at the end of the injection; and TMPG 3, normal entrance and exit of dye in the myocardium.

Statistical analysis 

Data are presented as the mean ± SD or as a frequency (percentage). Continuous variables were compared by using a two-tailed Student t test. Differences between categorical variables were analyzed by χ2 tests. A P value <.05 was considered significant.

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Results 

Baseline characteristics 

All 42 patients were women (mean age, 71 years; range, 42-87 years). There was no difference in age, frequency of conventional coronary atherosclerosis risk factors, left ventricular ejection fraction at presentation or follow-up, presence of congestive heart failure at presentation, or length of hospital stay between patients with normal versus those with abnormal TMPG (Table I). Twenty-eight patients presented with chest pain, 5 with dyspnea, 5 with presyncope or syncope, 2 with cardiac arrest, 1 with confusion, and 1 was asymptomatic. In 12 patients, a significant emotional stressor could be identified (eg, death of a relative, diagnosis of metastatic cancer, divorce of a daughter, death of a pet, heated argument); in 15 patients, a physical stressor in the form of surgery or acute medical illness could be identified (eg, asthmatic attack, hip fracture, acute cholecystitis); and in 15 patients, no compelling precipitating factors could be identified. There were no differences between the 2 groups with regard to the presenting symptom or presence of a stressor (data not shown). None of the patients had spontaneous coronary spasm, embolism, thrombus, or plaque rupture on the angiogram performed during the initial presentation.

Table I. Patients' characteristics according to presence or absence of abnormal TMPG
All patients (N = 42)Normal TMPG (n = 13)Abnormal TMPG (n = 29)P
Age (y)71 ± 1268 ± 1272 ± 12.31
Hypertension, n (%)27 (64)9 (69)18 (62).65
Diabetes mellitus, n (%)5 (12)3 (23)2 (7).15
Hyperlipidemia, n (%)16 (38)5 (38)11 (38).97
Active smoker, n (%)5 (12)2 (15)3 (10).65
CHF (NHYA class III or IV), n (%)11 (26)4 (31)7 (24).65
LVEDP, mm Hg26 ± 729 ± 724 ± 7.09
Presentation EF (%)37 ± 1237 ± 1337 ± 12.93
Follow up EF (%)59 ± 960 ± 1159 ± 8.69
Median time to follow EF (interquartile range) (d)36 (8-70)64 (9-96)29 (8-53).37
Length of hospital stay (d)6 ± 37 ± 46 ± 3.21

P value refers to normal versus abnormal perfusion. CHF, Congestive heart failure; NYHA, New York Heart Association; LVEDP, left ventricular end diastolic pressure; EF, ejection fraction.

The admission ECG showed ST elevation in 16 patients, diffuse deep T-wave inversions in 15 patients, and mild ST-T wave changes in 11 patients. All but 3 patients had an abnormal troponin T level (>0.03 ng/mL) with a median peak level of 0.55 ng/mL (range, 0.01-2.86 ng/mL) (Table II).

Table II. Troponin value and ECG abnormalities according to myocardial perfusion status
Total population (N = 42)Normal TMPG (n = 13)Abnormal TMPG (n = 29)P
Peak troponin level (ng/mL)0.71 ± 0.620.42 ± 0.330.84 ± 0.68.047
ECG .006
Nonspecific ST-T wave changes, n (%)11 (26)7 (54)4 (14)
Deep T-wave inversions, n (%)15 (36)5 (38)10 (34)
ST elevation, n (%)16 (38)1 (8)15 (52)

TIMI myocardial perfusion grade 

Normal TMPG was present in 13 patients and abnormal TMPG in 29 patients. Eighteen had abnormal perfusion in all 3 coronary artery territories, 7 had involvement of the myocardium in 2 coronary artery territories, and 4 had involvement of the myocardium in 1 coronary artery distribution. Of the 29 patients with abnormal TMPG, 2 had TMPG 0, 9 had TMPG 1, and 18 had TMPG 2 (Figure 1). When present, abnormal perfusion appeared to be limited to apical and midventricular regions in all patients.

All 14 patients in the control group were women with a mean age of 66 ± 10 years (vs 71 ± 12 years for study patients, P = .16) and a mean ejection fraction of 39% ± 5% (vs 37% ± 12% for study patients, P = .51). All control patients had a normal (TMPG 3) myocardial perfusion.

Relationship between TMPG, peak troponin level, and ECG abnormalities 

Patients with abnormal TMPG had a higher peak troponin level compared with patients with normal TMPG (0.84 ± 0.68 vs 0.42 ± 0.33 ng/mL, P = .047). Similarly, significant ECG abnormalities were more prevalent in patients with abnormal perfusion, with 86% versus 46% having either ST elevation or deep T-wave inversion (P = .006) (Table II). The relationship between TMPG and peak troponin level and frequency of ECG abnormalities are illustrated in Figure 2, Figure 3, respectively. Of note, both patients with TMPG 0 had ST elevation on their ECG despite a normal TIMI grade 3 flow in the epicardial vessels.

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Discussion 

This study is one of the largest case series of patients with angiographically documented ABS and reports several new findings, namely: (1) angiographic evidence of abnormal myocardial perfusion can be detected in approximately two thirds of patients with ABS, (2) the perfusion abnormality involves multiple coronary territories in most (86%) patients, and (3) the severity of perfusion defect correlates with the extent of myocardial injury.

Our study demonstrates that there is diffuse impairment of coronary microvascular function at the time of hospital presentation in many patients with ABS, detected as abnormal myocardial perfusion despite normal epicardial blood flow. This observation provides novel insights into the pathophysiology of ABS, and a potential mechanism by which myocardial stunning and injury could coexist. The findings are consistent with our previous study and the reports by Kurisu et al3 and Bybee et al7 in which coronary blood flow was assessed by using TIMI frame counts. In both studies, counts were increased compared with controls and the abnormality was frequently present in all 3 coronary distributions. However, TIMI frame count is modified by the heart rate, nitrate therapy, phase of the cardiac cycle during which contrast is injected, and vasomotor tone. Frame count appears to, at least partly, reflect epicardial blood flow.8, 9 On the other hand, the TIMI myocardial perfusion grade has been validated against measurement of microvascular blood flow by using the Doppler Flowire (Volcano Inc., Rancho Cordova, CA).10 Our findings are further supported by a recent study of 8 patients with ABS in which invasive coronary assessment showed decreased coronary flow reserve and short diastolic deceleration time.2 Nuclear perfusion imaging studies have reported apical defects on thallium single-photon emission computed tomography when performed at a mean duration of 5 days after hospitalization; the condition improved over several weeks.3 Thus, the emerging data suggests that this unique, transient cardiomyopathy is associated with acute reversible microvascular dysfunction or “stunning” that recovers slowly, together with the contractile function.

Microvascular dysfunction and ABS 

Our study is the first to report that the severity of myocardial injury, as measured by peak troponin level and ECG abnormalities, correlates with the severity of microvascular dysfunction. Both patients with absent myocardial perfusion (TMPG grade 0) had ST elevation, and approximately 50% of the patients with impaired myocardial perfusion (TMPG 1 and 2) had ST elevation (Figure 3). Almost all the patients with absent or impaired TMPG had either ST elevation or deep T-wave inversion on their ECG. This observation allows us to speculate that microvascular dysfunction may be directly responsible for inducing myocardial ischemia and subsequent myocardial stunning in ABS. Thirteen (31%) patients with similar baseline characteristics to those with abnormal TMPG had normal myocardial perfusion. Although ST elevation was rarely seen in patients with normal perfusion, T-wave inversion was often present. These patients may not have had abnormal perfusion at any time or had a very brief period of microvascular dysfunction that normalized by the time the coronary angiogram was performed, or the magnitude of vascular injury was not severe enough to be detected by the angiographic technique. The range of myocardial perfusion abnormality detected is consistent with the facts that there is heterogeneity in the severity of the clinical features and ventricular dysfunction in ABS, and that the magnitude of troponin elevation was significantly less in the patients with normal TMPG.

An alternative explanation for the association between the perfusion abnormality and myocardial injury is that abnormal microvascular function is secondary to the cardiomyopathy and elevated filling pressures. However, this is not supported by the observations that myocardial perfusion was normal in all patients in the control group who had a similar magnitude of left ventricular systolic dysfunction, and left ventricular end diastolic pressure was lower in ABS patients with abnormal perfusion. Interestingly, the presence of abnormal perfusion was not associated with worse clinical outcomes, as measured by length of hospitalization, and left ventricular ejection fraction at follow-up. This is similar to the report that brain natriuretic peptide levels do not predict outcomes in ABS.11 Taken together, these data indicate that ABS has a distinct pathophysiology from acute coronary syndromes in which both abnormal myocardial perfusion and brain natriuretic peptide level are markers for adverse outcomes.

Stress, microvascular function, and ABS 

A stress response appears to play a role in the pathophysiology of ABS,1 as suggested by the frequent antecedent emotional or physical trigger.7 In addition, severely elevated plasma catecholamine levels have been reported in patients with ABS,11, 12 although this has not been a consistent finding.13 Acute psychological stress has been shown to induce endothelial injury via β-1 adrenoreceptors in cynomolgus monkeys,14 and this phenomenon has also been observed in humans.15 Furthermore, transient hemodynamic changes, such as those that may accompany a catecholamine surge, have been shown to induce endothelial stunning.16 Thus, we speculate that catecholamine-mediated endothelial stunning may be responsible for the microvascular dysfunction observed in patients with ABS.

Limitations 

This is a retrospective analysis that is subject to the limitations of such analyses, and does not allow us to establish whether microvascular dysfunction contributes to the pathophysiology of ABS. The time from symptom onset to coronary angiography was not recorded; hence, we cannot comment on the impact of this variable on myocardial perfusion. Excessive release of catecholamines has been implicated in the pathogenesis of left ventricular dysfunction in patients with intracranial hemorrhage in the absence of myocardial perfusion abnormalities.17 We, however, have not measured plasma catecholamine levels and could not determine any association between catecholamines excess and myocardial impairment in patients with ABS.

Conclusion and implications 

Impaired myocardial perfusion due to abnormal microvascular blood flow is frequently present in patients with ABS and correlates with the extent of myocardial injury. Microvascular dysfunction may play a pivotal role in the pathogenesis of myocardial stunning in ABS. Further studies are required to investigate microvascular function in patients with ABS, specifically to address whether there is abnormal resting microvascular function or an abnormal response to mental stress. Studies with therapeutic interventions that modify microvascular blood flow would also be of interest to establish whether myocardial functional recovery can be accelerated.

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References 

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PII: S0002-8703(06)00555-2

doi:10.1016/j.ahj.2006.06.007

American Heart Journal
Volume 152, Issue 3 , Pages 469.e9-469.e13, September 2006

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