1. Acute Heart Failure in Apical Ballooning Syndrome (Takotsubo/Stress Cardiomyopathy) Clinical Correlates and Mayo Clinic Risk Score Malini Madhavan, MBBS; Charanjit S. Rihal, MD, FACC; Amir Lerman MD, FACC; Abhiram Prasad, MD, FRCP, FACC Division of Cardiovascular Diseases Mayo Clinic, Rochester No relevant author disclosures J. Am. Coll. Cardiol. 2011;57;1400-1401

2. Background Apical ballooning syndrome (ABS) is characterized by transient regional systolic dysfunction of the left ventricle in the absence of obstructive coronary artery disease Apical ballooning syndrome (ABS) is characterized by transient regional systolic dysfunction of the left ventricle in the absence of obstructive coronary artery disease Acute heart failure (HF) is the most common complication Acute heart failure (HF) is the most common complication Acute HF can cause significant morbidity in ABS Acute HF can cause significant morbidity in ABS

3. Aims To examine the frequency and prognosis of patients with acute HF complicating ABS To examine the frequency and prognosis of patients with acute HF complicating ABS To identify the risk factors for acute HF in ABS To identify the risk factors for acute HF in ABS

4. Methods Study Population Study cohort Study cohort 118 consecutive ABS patients identified between January 2002 and January 2008 118 consecutive ABS patients identified between January 2002 and January 2008 Validation cohort Validation cohort 52 consecutive ABS patients identified between Feb 2008 and December 2009 52 consecutive ABS patients identified between Feb 2008 and December 2009

5. Methods Mayo diagnostic criteria for ABS Transient akinesis, hypokinesis or dyskinesis of the left ventricular mid segments with or without apical involvement. The regional wall motion abnormalities extend beyond a single epicardial vascular distribution Transient akinesis, hypokinesis or dyskinesis of the left ventricular mid segments with or without apical involvement. The regional wall motion abnormalities extend beyond a single epicardial vascular distribution Absence of obstructive coronary disease or angiographic evidence of acute plaque rupture, Absence of obstructive coronary disease or angiographic evidence of acute plaque rupture, New ECG abnormalities (either ST-segment elevation and/or T wave inversion) or elevated cardiac troponin, New ECG abnormalities (either ST-segment elevation and/or T wave inversion) or elevated cardiac troponin, The absence of pheochromocytoma or myocarditis The absence of pheochromocytoma or myocarditis Prasad et al. Am Heart J 155(3):408-17

6. Methods: Definitions Acute heart failure New onset symptoms such as dyspnea, and New onset symptoms such as dyspnea, and At least 2 of the following physical signs - pulmonary rales, elevated central venous pressure, and the presence of a third heart sound At least 2 of the following physical signs - pulmonary rales, elevated central venous pressure, and the presence of a third heart sound Cardiogenic shock Systolic blood pressure of <90 mm Hg for greater than 1 hour secondary to cardiac dysfunction associated with signs of hypoperfusion Systolic blood pressure of <90 mm Hg for greater than 1 hour secondary to cardiac dysfunction associated with signs of hypoperfusion Patients with systolic blood pressure increase to >90 mm Hg within 1 hour after administration of inotropic agents, who met other criteria for cardiogenic shock Patients with systolic blood pressure increase to >90 mm Hg within 1 hour after administration of inotropic agents, who met other criteria for cardiogenic shock

7. Clinical Characteristics Variable Variable No Acute HF (N=65) Acute HF (N=53)p-value Age (years) Age (years) 67 (12) 73 (12) 0.02 Female gender Female gender 63 (97%) 52 (98%) 0.7 Presenting symptom Presenting symptom Chest Pain Chest Pain Dyspnea Dyspnea 51 (78%) 26 (40%) 23 (43%) 35 (66%) <0.00010.005 Precipitating factor Precipitating factor Emotional stress Emotional stress Physical stress Physical stress 19 (30%) 23 (35%) 11 (21%) 37 (70%) 0.0003 Electrocardiogram Electrocardiogram ST-segment elevation ST-segment elevation Deep T wave inversion Deep T wave inversion 23 (36%) 39 (60%) 31 (58%) 26 (49%) 0.010.2

8. Clinical Characteristics Variable Variable No Acute HF (N=65) Acute HF (N=53) p- value Biomarkers Biomarkers Admission Troponin T (ng/ml) Admission Troponin T (ng/ml) Peak Troponin T (ng/ml) Peak Troponin T (ng/ml) BNP (pg/ml) (N=48) BNP (pg/ml) (N=48) 0.37 (0.42) 0.55 (0.56) 783 (753) 0.71 (0.85) 0.93 (0.90) 1161 (1010) 0.0090.010.1 Angiography Angiography Ejection fraction (%) Ejection fraction (%) LVEDP (mm Hg) LVEDP (mm Hg) Grade 3 or 4 MR Grade 3 or 4 MR 46 (11) 23 (7) 5 (10%) 35 (13) 28 (7) 8 (21%) 0.00010.0010.08 Admission Echocardiogram Admission Echocardiogram Ejection fraction (%) Ejection fraction (%) Wall motion score index Wall motion score index 44 (13) 1.74 (0.41) 36 (13) 2.05 (0.47) 0.0040.0006

9. Independent Predictors of Acute HF Multivariate Analysis Predictor Odds Ratio* 95% confidence interval P value Age (years)1.061.02 - 1.110.001 Physical stress trigger4.011.64 – 10.360.002 Admission Troponin T2.431.05 – 6.590.04 LV Ejection fraction0.960.92 - 0.990.01 ST-segment elevation1.340.5 – 3.520.7 *Per unit change in variable

10. Troponin T Stratified by Severity of HF

11. Mayo Clinic Risk Score for Acute HF in ABS One point was assigned to each of the following independent risk factors: One point was assigned to each of the following independent risk factors: Age > 70 years Age > 70 years Presence of physical stressor Presence of physical stressor Ejection fraction < 40% Ejection fraction < 40% Troponin T was not included due to heterogeneity in assay and cut-off value used at different institutions Troponin T was not included due to heterogeneity in assay and cut-off value used at different institutions

12. Mayo Clinic Risk Score for Acute HF in ABS Significant positive correlation between the frequency of acute HF and the risk score in the: Significant positive correlation between the frequency of acute HF and the risk score in the: Development cohort – C statistic 0.77, p<0.001 Development cohort – C statistic 0.77, p<0.001 Validation cohort – C statistic 0.77, p=0.002 Validation cohort – C statistic 0.77, p=0.002

13. Acute HF Stratified by Mayo Risk Score Development cohortValidation cohort

14. Outcome in ABS No acute HF (N=65) Acute HF (N=53) P value Cardiogenic shockN/A25 (47%)N/A Cardio respiratory support Inotrope use Intra-aortic balloon pump use Mechanical ventilation 0 3 (5%) 20 (38%) 9 (17%) 15 (28%) <0.001 Duration of hospitalization (days)5.4 (8.7)11.2 (5.4)0.0004 Outcome at discharge Residual HF Death in hospital N/A 0 (0%) 6 (11%) 3 (6%) N/A 0.09 Discharge medications Beta blocking agent ACE inhibitor/ ARB Furosemide 49 (77%) 39 (61%) 6 (9%) 41 (82%) 37 (74%) 20 (40%) 0.5 0.1 0.0001 Follow-up echocardiogram Time from presentation (days) Ejection fraction (%) Wall motion score index 74 (148) 62 (6) 1.08 (0.21) 78 (120) 60 (10) 1.13 (0.29) 0.9 0.3 0.4

15. Conclusions Heart Failure is a common complication of ABS Heart Failure is a common complication of ABS Approximately 50% developed HF Approximately 50% developed HF One in five developed cardiogenic shock One in five developed cardiogenic shock Patients who developed acute HF had, Patients who developed acute HF had, Greater myocardial injury and stunning Greater myocardial injury and stunning Greater morbidity and longer hospitalization Greater morbidity and longer hospitalization Prognosis is good with resolution of HF with supportive management in the majority of patients Prognosis is good with resolution of HF with supportive management in the majority of patients Mortality secondary to cardiogenic shock occurred in 3 patients Mortality secondary to cardiogenic shock occurred in 3 patients

16. Conclusions The Mayo Clinic risk score is predictive of acute HF in patients with ABS The Mayo Clinic risk score is predictive of acute HF in patients with ABS Risk stratification using the Mayo Clinic risk score may: Risk stratification using the Mayo Clinic risk score may: Assist in triaging high risk patients to an intensive care unit for management Assist in triaging high risk patients to an intensive care unit for management Allow physicians to identify patients in whom early initiation of beta-adrenergic blockers may be harmful Allow physicians to identify patients in whom early initiation of beta-adrenergic blockers may be harmful