© 2015, Wiley Periodicals, Inc. DOI: 10.1111/echo.12949

Echocardiography

ORIGINAL INVESTIGATIONS

Determinants of Secondary Pulmonary Hypertension in Patients with Takotsubo Cardiomyopathy Masaki Izumo, M.D., Ph.D.,* Maiko Shiota, M.D.,† Smruti Nalawadi, M.D.,* Jayanta R. Das, M.D.,* Sohail Dohad, M.D.,* Eiji Kuwahara, M.D., Ph.D.,* Yoko Fukuoka, M.D.,* Robert J. Siegel, M.D.,* and Takahiro Shiota, M.D., Ph.D.* *The Heart Institute at Cedars-Sinai Medical Center, Los Angeles, California; and †Stanford University Medical Center, Stanford, California

Background: Although takotsubo cardiomyopathy (TTC) has been reported to have a favorable outcome, many complications may occur in the acute phase. Heart failure is the most common clinical complication in patients with TTC. We aimed to investigate determinants of secondary pulmonary hypertension (PH) in patients with TTC. Methods: This study consisted of 55 patients with TTC. Detailed echocardiographic measurements were taken, including pulmonary artery systolic pressure (PASP). PH was identified PASP >35 mmHg. The severity of mitral regurgitation (MR) was evaluated by measuring effective regurgitant orifice area (EROA). Follow-up echocardiography was performed in 45 patients (81.8%) within 4 weeks after initial presentation. Results: All patients were stratified into PH or no PH (NPH) group (average PASP: 46.2
6.7 vs. 29.8
3.3 mmHg, P < 0.001); 25 patients (45.5%) were categorized into the PH group. Left ventricular (LV) volume, LV ejection fraction, and troponin I levels did not significantly differ between the two groups. Age and EROA were significantly greater in PH group than NPH group (age; 74.6
9.1 vs. 63.5
17.7, EROA; 0.22
0.17 vs. 0.03
0.05 cm2, all P < 0.01). The multivariate analysis revealed that age and EROA were independent predictors for PH in patients with TTC (all P < 0.001). PASP was significantly improved at follow-up compared to those at initial presentation (35.8
8.4 vs. 30.3
7.9 mmHg, P < 0.01). Conclusion: Age and the severity of MR were independent predictors for secondary PH in patients with TTC. (Echocardiography 2015;32:1608–1613) Key words: takotsubo cardiomyopathy, pulmonary hypertension, echocardiography Takotsubo cardiomyopathy (TTC), which is also called apical ballooning syndrome or stress cardiomyopathy, is recognized as transient left ventricular (LV) apical ballooning and electrocardiographic changes that have been recently recognized as an important consideration in the differential diagnosis of acute coronary syndrome.1–3 This syndrome generally has a favorable outcome; however, some complications may occur in the acute phase. Management of TTC with complications remains difficult.3–7 Heart failure with or without pulmonary edema is the most common clinical complication.8 To date, an association between TTC and secondary pulmonary hypertension (PH) has not been fully elucidated. The aim of this study was to investigate determinants of secondary PH in patients with TTC.

Address for correspondence and reprint requests: Takahiro Shiota, M.D., Ph.D., The Heart Institute at Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048. Fax: +1(310)-423-8571; E-mail: [email protected]

1608

Methods: Study Population: This study reviewed consecutive 55 patients with chest pain or dyspnea and changes on electrocardiograms who underwent coronary angiography and left ventriculography to confirm TTC in the Cedars-Sinai Medical Center between October 2006 and July 2010. The inclusion criteria were as follows: (1) balloon-like LV with apical akinesis or dyskinesis on initial left ventriculography or echocardiogram; (2) ST-segment or T-wave abnormalities on electrocardiogram and increases in blood concentrations of cardiac troponin level; (3) no significant coronary artery stenosis confirmed by coronary angiography; and (4) the absence of pheochromocytoma and myocarditis.9 All patients were diagnosed as having TTC by the consensus of 2 experienced cardiologists. This study was approved by the institutional review board of Cedars-Sinai Medical Center. Cardiac Catheterization and Blood Test: All patients underwent coronary angiography and left ventriculography within 24 hours after

PH in Takotsubo Cardiomyopathy

symptom onset. Left ventriculography was used to calculate LV ejection fraction (EF) and LV volume using Simpson’s method. Venous blood was collected every 3 hours to measure the troponin I concentration in the acute phase and continued until a peak value was observed. Echocardiographic Examination: All patients with TTC underwent two-dimensional echocardiographic and Doppler examinations using an iE33 system (Philips Medical Systems, Andover, MA, USA) within 24 hours of admission. Follow-up echocardiography was performed within 4 weeks (range 1 to 4 weeks) after initial presentation. With continuous-wave Doppler, the maximum peak tricuspid regurgitant velocity recorded from any view was used to determine the pulmonary artery systolic pressure (PASP) with the simplified Bernoulli’s equation [PASP = 4* (peak velocity)2 + mean right atrial pressure]10; mean right atrial pressure was estimated based on the most recent ASE recommendation.11 PH was considered present if the Doppler echocardiography estimated PASP exceeded 35 mmHg.12 The transmitral flow velocity profile was recorded in the apical fourchamber view with the sample volume positioned in the direction of antegrade flow at the level of the mitral valve tips in diastole. The early diastolic tissue (E0 ) velocity was recorded in the same view with the sample volume (5 mm) positioned at the septal mitral annulus.13 Mitral regurgitation (MR) was quantitated by proximal isovelocity surface area method acquired from magnified apical 4-chamber, 2-chamber, and long axis view. Effective regurgitant orifice area (EROA) was calculated using the formula: EROA = 2p 9 R2 9 Valiasing/Vmax, where R was the maximal proximal isovelocity surface area radius (cm), Valiasing was aliasing velocity of the proximal flow convergence (cm/s), and Vmax was maximal velocity of continuous-wave Doppler MR signal (cm/s).14 We measured the mitral annular (MA) area, which was estimated by the product of MA diameters in the apical 4-chamber and 2-chamber views.15,16 Left ventricular outflow tract (LVOT) pressure gradients were measured by continuous-wave Doppler through the LVOT. The LV wall motion score index (WMSI) was calculated on a basis of the 16-segment model recommended by the American Society of Echocardiography.17 Statistical Analysis: All values were expressed as mean
SD. An unpaired t-test was used to compare the continuous variables, and the chi-square and Fisher’s exact test were used for the categorical variables. A paired t-test was used to compare initial and

follow-up measurements. Univariate logistic regression was used to relate clinical and echocardiographic variables to prevalence of PH. Multivariate logistic regression was performed to identify factors associated with PH. Significant variables on univariate analysis entered into models were age, E, E/E0 , and EROA on clinical and echocardiographic parameters in patients with TTC. Differences were considered significant if P < 0.05. Statistical analyses were performed using SPSS 17.0 (SPSS, Inc, Chicago, IL, USA). Results: Baseline characteristics are shown in Table I. Of the 55 patients of this study, 49 patients (89.1%) were female, and the mean age was 69
15 years (range 28 to 87 years). The mean LV end-diastolic volume, end-systolic volume, and EF were 85.5
17.9 mL, 51.3
14.2 mL, and 39.4
11.6%, respectively. Physical stressors, such as pneumonia, asthma attack, traffic accident, hematemesis, and overwork, were identified in 25 patients (45.5%), and emotional stressors were also identified in 11 patients (20.0%). On electrocardiograms, ST segment elevation was present in 28 patients (50.9%), ST depression in 7 patients (12.7%), and T-wave inversion in 20 patients (36.4%). In this study, 25 patients had PH on presentation (45.4%, PH group; average PASP, 48.4
6.3 mmHg) and the remaining 30 patients (54.6%) without PH were categorized into the no PH (NPH) group (average PASP, 31.8
2.9 mmHg). Comparison of clinical and echocardiographic characteristics between the PH group and the NPH group is listed in Table I. Gender, troponin I levels, LV volume, and LVEF did not significantly differ between the two groups. Age, E, E/A, E/E0 , and EROA were significantly greater in the PH group than the NPH group (Table I). The ratio of patients with TTC who presented with shortness of breath on admission was also greater in the PH group than the NPH group (56.0% vs. 20.0%, P < 0.001). PASP was well correlated with age (r2 = 0.236) and EROA (r2 = 0.322), respectively (Fig. 1). The univariate analysis demonstrated that PASP was significantly associated with age, E, E/E0 , and EROA, respectively, in all patients (Table II). Multivariate logistic regression analysis revealed that age and EROA independently predicted PASP (Table II). Using receiver-operating characteristic curves, we found that the sensitivity and specificity in predicting acute secondary PH were 71.5% and 65.5% for age >72 years (area under the curve = 0.73), and 76.0% and 86.2% for EROA >0.1 cm2 (area under the curve = 0.85) (Table III and Fig. 2). Follow-up echocardiography was performed in 45 patients (81.8%) with TTC within 4 weeks after initial presenta1609

Izumo, et al.

TABLE I Clinical Characteristics and Echocardiographic Data All (n = 55) 69
49 (89.1) 4.3
132.6
76.4
39.4
85.5
51.3
42.7
123.5
86.1
86.3
1.0
7.5
12.2
0.12
27.2
39.5


Age (years) Female (%) Troponin I (lg/L) Systolic BP (mmHg) Diastolic BP (mmHg) LV EF (%) LV EDV (mL) LV ESV (mL) LA volume (mL) LV mass (g) E (cm/s) A (cm/s) E/A Septal E0 (cm/s) E/E0 EROA (cm2) MA dimension (mm) PASP (mmHg)

15 4.9 28.2 14.2 11.6 17.9 14.2 14.1 45.1 21.5 24.4 0.4 1.8 4.3 0.15 3.9 9.6

PH (n = 25)

NPH (n = 30)

P-Value

76
22 (88) 4.0
133.8
78.1
37.2
83.1
50.8
44.8
117.1
93.4
85.6
1.2
7.0
14.0
0.22
28.1
48.4


64
27 (90) 4.5
131.8
75.0
41.7
88.3
51.9
40.9
132.9
77.7
87.1
0.93
8.1
10.0
0.03
25.8
31.8


0.001 0.849 0.695 0.724 0.612 0.171 0.332 0.798 0.142 0.459 0.018 0.854 0.024 0.366 0.002