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Sex Differences in Stress-Induced (Takotsubo) Cardiomyopathy

Open AccessPublished:November 17, 2022DOI:https://doi.org/10.1016/j.cjco.2022.11.012

      Abstract

      Background

      Takotsubo cardiomyopathy (TC) predominantly affects women. Prior studies have suggested that men might have worse short-term outcomes, but limited data is available regarding long-term outcome. We hypothesized that men with TC have worse short and long-term outcomes when compared to women.

      Methods

      Retrospective study of patients diagnosed with TC between 2005 and 2018 in the Veteran Affairs system was performed. Primary outcomes were in-hospital death, 30-day risk of stroke, death, and long-term mortality.

      Results

      A total of 641 patients were included (444 [69%] men; 197 [31%] women). Men had a higher median age (65 vs 60 years; P < 0.001) and women were more likely to present with chest pain (68.7% vs 44.1%; P < 0.001). Physical triggers were more common in men (68.7% vs 44.1%, P < 0.001). Men had higher in-hospital mortality rate (8.1% vs 1%; P < 0.001). On multivariable regression analysis, female sex was an independent predictor for improved in-hospital mortality when compared to men (OR 0.25 [95% CI 0.06-1.10]; P = 0.04).On 30-day follow-up, there was no difference in a combined outcome of stroke, and death (3.9% vs 1.5%; P = 0.12). On long-term follow-up (3.7 ± 3.1 years), female sex was identified as an independent predictor of lower mortality (HR 0.71 [95% CI 0.51-0.97]; P = 0.032). Women were more likely to have TC recurrence (3.6% vs 1.1%; P = 0.04)

      Conclusions

      In our male pre-dominant study, men had less favorable short and long-term outcomes after TC when compared to women.

      Graphical abstract

      Introduction

      Takotsubo (stress-induced) cardiomyopathy (TC) is characterized by transient left ventricular (LV) dysfunction with distinct regional wall-motion abnormalities that is not due to obstructive coronary artery disease (CAD).
      • Prasad A.
      • Lerman A.
      • Rihal C.S.
      Apical ballooning syndrome (Tako-Tsubo or stress cardiomyopathy): A mimic of acute myocardial infarction.
      Although TC has been recognized for over three decades,

      Sato H, Uchida T, Dote K, Ishihara M. Tako-tsubo-like left ventricular dysfunction due to multivessel coronary spasm. Tokyo Kagakuhyoronsha Publ. 1990:56-64.

      our understanding of this unique disease is still evolving. The pathophysiology of TC is not well understood, but activation of the stress regions in the brain,
      • Suzuki H.
      • Matsumoto Y.
      • Kaneta T.
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      Evidence for brain activation in patients with takotsubo cardiomyopathy.
      excess catecholamines,
      • Akashi Y.J.
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      • Miyake F.
      • Musha H.
      • Sasaka K.
      123I-MIBG myocardial scintigraphy in patients with “takotsubo” cardiomyopathy.
      endothelial dysfunction, and estrogen deficiency may play a role in triggering this condition.
      • Naegele M.
      • Flammer A.J.
      • Enseleit F.
      • et al.
      Endothelial function and sympathetic nervous system activity in patients with Takotsubo syndrome.
      ,
      • Pelliccia F.
      • Kaski J.C.
      • Crea F.
      • Camici P.G.
      Pathophysiology of Takotsubo Syndrome.
      Previous studies have reported that TC predominantly affects women and is commonly preceded by intense emotional or physiological stress.
      • Templin C.
      • Ghadri J.R.
      • Diekmann J.
      • et al.
      Clinical Features and Outcomes of Takotsubo (Stress) Cardiomyopathy.
      ,
      • Bybee K.A.
      • Kara T.
      • Prasad A.
      • et al.
      Systematic review: Transient left ventricular apical ballooning: A syndrome that mimics ST-segment elevation myocardial infarction.
      The results of prior studies comparing outcome in men and women with TC suggest that in-hospital outcomes are worse for men. However, most prior studies were limited by small numbers of men, or the sole use of ICD codes for inclusion without chart review.
      • Templin C.
      • Ghadri J.R.
      • Diekmann J.
      • et al.
      Clinical Features and Outcomes of Takotsubo (Stress) Cardiomyopathy.
      ,
      • Schneider B.
      • Athanasiadis A.
      • Stöllberger C.
      • et al.
      Gender differences in the manifestation of tako-tsubo cardiomyopathy.
      • Agdamag A.C.
      • Patel H.
      • Chandra S.
      • et al.
      Sex Differences in Takotsubo Syndrome: A Narrative Review.
      • Brinjikji W.
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      In-hospital mortality among patients with takotsubo cardiomyopathy: A study of the National Inpatient Sample 2008 to 2009.
      • Khera R.
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      Trends in hospitalization for takotsubo cardiomyopathy in the United States.
      In addition, long term outcome has not been well studied. There is also uncertainty as to whether sex is an independent predictor for in-hospital mortality after adjustment for significant difference in comorbidities between men and women.
      • Templin C.
      • Ghadri J.R.
      • Diekmann J.
      • et al.
      Clinical Features and Outcomes of Takotsubo (Stress) Cardiomyopathy.
      ,
      • Schneider B.
      • Athanasiadis A.
      • Stöllberger C.
      • et al.
      Gender differences in the manifestation of tako-tsubo cardiomyopathy.
      ,
      • Weidner K.J.
      • El-Battrawy I.
      • Behnes M.
      • et al.
      Sex differences of in-hospital outcome and long-term mortality in patients with Takotsubo cardiomyopathy.
      • Murakami T.
      • Yoshikawa T.
      • Maekawa Y.
      • et al.
      Gender differences in patients with takotsubo cardiomyopathy: Multi-center registry from Tokyo CCU Network.
      • Budnik M.
      • Nowak R.
      • Fijałkowski M.
      • et al.
      Sex-dependent differences in clinical characteristics and in-hospital outcomes in patients with takotsubo syndrome.
      The United States Veteran Affairs (VA) system serves mostly male patients.

      National Center for Veterans Analysis and Statistics. Profile of Veterans: 2017.; 2019. http://www.census.gov/acs/www/.

      This dominant male population provides sufficient numbers of men for comparison of clinical characteristics and outcome in a disease that predominantly affects women. We hypothesized that men with TC have worse short and long-term outcomes when compared to women.

      Methods

      Data source and study population:

      Using data from Compensation and Pension Record Interchange (CAPRI) system, we identified patients who had the diagnosis of TC between January 2005 and January 2018 across all hospitals in the VA healthcare system in the United States. CAPRI is an electronic health record system that contains national data and allows electronic search as well as review of notes, procedures, imaging reports, and lab results across various VA hospitals. We initially narrowed our search by identifying patients with the following ICD codes: Takotsubo syndrome, ICD 10 code: I51. 81, ICD 9 code 429.83. We used a combination of electronic data searching (using ICD codes) and manual verification to identify demographic data and baseline clinical variables at the time of diagnosis. We then removed any duplicate charts. We manually reviewed each medical record. Patients who did not meet the revised Mayo Clinic criteria and International Takotsubo diagnostic criteria were excluded.
      • Prasad A.
      • Lerman A.
      • Rihal C.S.
      Apical ballooning syndrome (Tako-Tsubo or stress cardiomyopathy): A mimic of acute myocardial infarction.
      ,
      • Ghadri J.-R.
      • Wittstein I.S.
      • Prasad A.
      • et al.
      International Expert Consensus Document on Takotsubo Syndrome (Part I): Clinical Characteristics, Diagnostic Criteria, and Pathophysiology.
      . All patients were required to have a coronary angiography performed unless the procedure was deemed unnecessary by the treating cardiologist and with the reviewers’ agreement (if characteristic echocardiography changes, recent coronary angiography, the risks of coronary angiography were deemed higher than the benefits, no ST abnormalities suggestive of injury, and/or no typical pattern of troponin elevation). Patient data were individually collected by at least 2 investigators. If there was any disagreement about the diagnosis between the reviewers, then consensus was reached with the rest of the investigational team. Patients with no echocardiogram or ventriculography consistent with TC were excluded.
      The following information was collected: demographic data, comorbidities, medications, trigger factor, presenting symptoms, electrocardiography results, echocardiogram results (at presentation and serial echocardiography), left heart catheterization, type of TC, in-hospital events, 30-day events, and long-term outcomes (up to July 2020, which would give us about 2.5 years of follow up for last patients included in our study). In patients with missing data from echocardiogram report, diagnosis was based on ventriculography data obtained from heart catheterization. The Central Arkansas VA Health System’s institutional review board approved the study.
      We categorized trigger factors as physical or emotional. Physical trigger factors included acute medical/surgical illness, accidents, physical altercations, trauma, and others.

      Types of TC:

      Based on previously described types, TC was classified as apical, mid-ventricular, basal, or focal.
      • Templin C.
      • Ghadri J.R.
      • Diekmann J.
      • et al.
      Clinical Features and Outcomes of Takotsubo (Stress) Cardiomyopathy.
      The type of TC was decided based on the description of wall motion abnormality in echocardiography or angiography reports.

      Outcomes:

      We collected data for in-hospital complications, including cardiogenic shock, arrythmias, cardiac arrest, respiratory failure, and death. We also collected data on the use of vasopressor/inotropic drugs, LV assist devices, and invasive and non-invasive ventilation. Primary outcomes of interest were: (a) in hospital mortality; (b) 30-day risk of stroke, and death; and (c) long-term mortality.

      Statistical analysis:

      Patients were classified into 2 groups: men and women. Categorical variables were reported as counts and percentages; differences were assessed with chi-square test. Continuous variables were presented as medians with interquartile range (IQR); and differences were compared with Mann-Whitney test. Kaplan-Meier analysis was used to compare all-cause mortality for the unadjusted data.
      We performed univariate analysis for gender, comorbidities, clinical characteristics, trigger factor, labs at the time of diagnosis (hemoglobin, WBC, GFR, Troponin, BNP), ejection fraction, admission medications (beta blockers, ACE-I/ARB, antiplatelets/anticoagulants, statin), medical treatment, the presence of cardiogenic shock, and respiratory failure requiring ventilatory support to evaluate in-hospital morality. We subsequently performed multivariate logistic regression analysis on variables with a P value < 0.05 to identify independent variables that predicted in-hospital mortality. Similarly, we performed univariable analysis then multivariate analysis for 30 days combined death and stroke. We used the discharge medications instead of the admission medications.
      For long-term follow-up, we performed univariable analysis for the above variables except for using discharge medications instead of admission medications. We then performed Cox regression analysis to adjust for baseline variables and calculate the adjusted hazard ratios for mortality on long-term follow-up. A two-sided P value < 0.05 was considered significant. Analysis was performed using Medcalc (ver 18.11, Ostend, Belgium).

      Patient and public involvement:

      Patients or the public were not involved in the design, or conduct, or reporting, or dissemination plans of our research

      Results:

      Baseline characteristics:

      A total of 641 patients with the diagnosis of TC were included in our analysis, 444 of whom (69%) were men and 197 (31%) were women. Table 1 compares baseline characteristics between the two groups. Men were significantly older than women (median [IQR] 65 [60-72.5] vs 60 [55-66] years; P < 0.001), with a higher prevalence of CAD (18.7% vs 11.2%; P = 0.02), chronic kidney disease (16.9% vs 7.1%, P = 0.001), chronic obstructive pulmonary disease (48% vs 38.1%, P = 0.02), and history of malignancy (19.8% vs 8.1%; P < 0.001). In addition, men had a higher prevalence of reported alcohol use (39.9% vs 19.8%; P < 0.001). Women had higher median body mass index (26 vs 24.8 kg/m2; P = 0.01) and were more likely to have bipolar disease (12.7% vs 6.1%; P = 0.005) and fibromyalgia (20.8% vs 10.6%; P < 0.001). There was no significant difference in baseline medications at presentation between the two groups.
      Table 1Differences in baseline characteristics between men and women
      Demographic VariableMen (N=444)Women (N=197)P Value
      Age, median (IQR), y65 (60-72.5)60 (55-66)<0.001
      Diabetes, no. (%)142 (32)55 (27.9)0.3
      Hypertension, no. (%)266 (59.9)108 (54.8)0.23
      Hyperlipidemia, no. (%)289 (65.1)140 (71.1)0.14
      CKD, no. (%)75 (16.9)14 (7.1)0.001
      COPD, no. (%)213 (48)75 (38.1)0.02
      CAD, no. (%)83 (18.7)22 (11.2)0.02
      PVD, no. (%)57 (12.8)7 (3.6)<0.001
      CHF, no. (%)47 (10.6)16 (8.1)0.33
      Atrial fibrillation, no. (%)41 (9.2)12 (6.1)0.18
      History of malignancy, no. (%)88 (19.8)16 (8.1)<0.001
      CVA, no. (%)96 (21.6)30 (15.2)0.06
      Bipolar disease, no. (%)27 (6.1)25 (12.7)0.005
      Smoking history, no. (%)270 (60.8)101 (51.3)0.02
      White race, no. (%)340 (81.3)151 (83.9)0.42
      Black race, no. (%)69 (15.5)22 (11.2)0.14
      Medications on admission
      Beta Blocker, no. (%)148 (33.8)59 (30.3)0.38
      ACE-I/ARB, no. (%)174 (39.7)76 (39)0.86
      Antiplatelets, no. (%)199 (45.4)74 (37.9)0.08
      Anticoagulation, no. (%)40 (9.1)16 (8.2)0.71
      Statin, no. (%)191 (43.6)83 (42.6)0.81
      Calcium Channel Blocker, no. (%)74 (16.9)28 (14.4)0.42
      Trigger Factor
      Emotional Trigger, no. (%)33 (8.1)40 (22.6)<0.001
      Physical Trigger, no. (%)281 (68.7)78 (44.1)<0.001
      No Trigger Factor Identified, no. (%)95 (23.2)59 (33.3)0.01
      Location
      Initial admission for TC, no. (%)280 (65.1)161 (83)<0.001
      Already admitted to Inpatient general ward, no. (%)87 (20.2)20 (10.3)<0.001
      Already admitted to ICU, no. (%)57 (13.3)7 (3.6)<0.001
      Operating room, no. (%)6 (1.4)6 (3.1)0.15
      Abbreviations: ACE-I: Angiotensin converting enzyme inhibitors; ARB: Angiotensin II receptor blocker; CAD: coronary artery disease; CHF: congestive heart failure; CKD: chronic kidney disease; COPD: chronic obstructive pulmonary disease; CVA: cerebrovascular accident; ICU: intensive care unit; PVD: peripheral vascular disease; TC: Takotsubo Cardiomyopathy

      Trigger factor and presenting symptoms:

      Physical stress was a more common trigger factor in men than in women (68.7% vs 44.1%; P < 0.001), while typical emotional stress was more likely in women than in men (22.6% vs 8.1%; P < 0.001). In our cohort, 26.2% had no evident trigger and was more common in women than in men (33.3% vs 23.2%; P = 0.01).
      Chest pain was the most common presenting symptom in both groups but was more common in women (60.3% vs 40.5%; P < 0.001). Compared to women, men were more likely to present with shortness of breath (18.8% vs 10.9%; P = 0.02), weakness (6.7% vs 2.2%; P = 0.02), and respiratory failure or pulmonary edema (3.9% vs 0.5%; P = 0.02). Women were more likely to have TC as a primary diagnosis at presentation to the hospital (83% vs 65.1%; P < 0.001).

      Electrocardiogram, Echocardiogram and Coronary angiogram on admission:

      As shown in Table 2, there were no significant differences between the groups in ST-T changes by electrocardiogram. Men were more likely to present with atrial fibrillation or atrial flutter (8.9% vs 1.5%; P = 0.004).
      Table 2Differences in clinical presentation between men and women
      Presentation/SymptomsMen (N=444)Women (N=197)P Value
      Chest pain, no. (%)168 (40.5)111 (60.3)<0.001
      Shortness of Breath, no. (%)78 (18.8)20 (10.9)0.02
      Cough, no. (%)48 (11.6)8 (4.3)0.005
      Gastrointestinal, no. (%)8 (1.9)6 (3.3)0.31
      Weakness, no. (%)28 (6.7)4 (2.2)0.022
      Respiratory failure/pulmonary edema, no. (%)16 (3.9)1 (0.5)0.02
      Arrythmia, no. (%)14 (3.4)5 (2.7)0.67
      Shock, no. (%)15 (3.6)4 (2.2)0.35
      Cardiac Arrest, no. (%)24 (5.8)10 (5.4)0.92
      ECG on Presentation
      ST-segment elevation, no. (%)131 (39.5)46 (36.5)0.56
      ST-segment depression, no. (%)25 (7.5)12 (9.5)0.48
      T wave changes, no. (%)99 (31.9)44 (37.9)0.24
      Lab Tests, median (IQR)
      WBC, cells/μL9.9 (7.2-13.9)9.2 (7-12.3)0.41
      Hemoglobin, g/dL12.4 (10.4-14.6)13.3 (11.3-14.4)0.22
      Troponin I, ng/mL1.7 (0.6-4.4)1.6 (0.7-3.8)0.81
      BNP, pg/mL622.5 (187-1654)615 (370-1246)0.98
      GFR, ml/min60 (58-92.5)64 (55-81)0.62
      Echo on presentation
      EF <=35, no. (%)231 (63.5)83 (54.6)0.06
      EF, median (IQR), % [no.]32 (30-35) [364]35 (32-40) [152]0.03
      Coronary Angiography done, no. (%)318 (71.6)161 (81.7)0.007
      LVEDP, median (IQR), mm Hg [no.]20 (15-26) [76]21.5 (16-26) [36]0.82
      Type of TC
      Apical, no. (%)301 (95)137 (98.6)0.07
      Mid-Ventricular, no. (%)5 (1.6)00.33
      Basal, no. (%)11 (3.5)2 (1.4)0.23
      Abbreviations: BNP: brain natriuretic peptide; ECG: electrocardiogram; EF: ejection fraction; GFR: glomerular filtration rate; LVEDP: left ventricular end diastolic pressure; TC: Takotsubo Cardiomyopathy; WBC: white blood cell
      On the admission echocardiogram, men had lower median (IQR) ejection fraction (32% [25-40] vs 35% [25-45]; P = 0.03). The most common type of TC identified was apical in both groups (94.7% in men vs 98.4% in women; P = 0.08).
      Coronary angiogram was more likely to be performed in women than in men (81.7% vs 71.6%; P = 0.007). All patients who presented after a cardiac arrest underwent coronary angiography.

      In-Hospital course/outcomes:

      As shown in Table 3, men were more likely to require invasive or non-invasive ventilation (30.2% vs 14.6%; P = 0.001) and vasopressors/inotropes (17.2% vs 8.4%; P = 0.01). Men also had higher median (IQR) length of stay (7 [3-14] vs 4 [2-8] days; P <0.001) and were more likely to sustain cardiac arrest (12.4% vs 4.9%; P = 0.01).
      Table 3In-hospital events in men and women with Takotsubo cardiomyopathy
      In-Hospital EventsMen (N=444)Women (N=197)P value
      Cardiogenic Shock, no. (%)55 (15)16 (11.2)0.26
      Invasive/noninvasive positive pressure ventilation, no. (%)112 (30.2)21 (14.6)0.001
      Mechanical circulatory support (IABP/Impella), no. (%)11 (3)4 (2.8)0.95
      Pharmacological inotrope/vasopressor support, no. (%)62 (17.2)12 (8.4)0.01
      LOS, median (IQR), days7 (3-14)4 (2-8)<0.001
      In hospital death, no. (%)36 (8.1)2 (1)<0.001
      Cardiac arrest, no. (%)46 (12.4)7 (4.9)0.01
      Combined Cardiac arrest/respiratory failure/cardiogenic shock, no. (%)141 (36.4)31 (20.1)<0.001
      IABP: intra-aortic balloon pump; LOS: length of stay
      Men were more likely to die during initial admission (8.1% vs 1%; P = 0.001).
      In the total study population, patients who were already being admitted for another medical/surgical reason had higher mortality rates compared to patients who were diagnosed with TC on presentation to the hospital (12.6% vs 3.2%; P < 0.001).
      Age, male sex, presence of physical stress as trigger factor, and the use of Intubation/Non-invasive ventilation were independently associated with in-hospital mortality (Table 4). Chronic obstructive pulmonary disease, atrial fibrillation, and chronic kidney disease showed trends toward increased mortality but didn’t reach statistical significance.
      Table 4Multivariate regression for in-hospital mortality
      VariableOdd Ratios95% CIP Value
      Age1.041.00 to 1.090.01
      Female sex0.250.06 to 1.100.04
      Diabetes Mellitus0.800.37 to 1.760.69
      Chronic kidney disease0.330.10 to 1.100.07
      Chronic obstructive pulmonary disease0.480.23 to 1.040.06
      Coronary artery disease0.900.35 to 2.370.91
      Peripheral vascular disease1.260.42 to 3.760.80
      Atrial Fibrillation2.350.80 to 6.940.07
      History of Malignancy1.610.73 to 3.590.24
      Physical stress4.691.51 to 14.600.004
      Intubation/Non-invasive ventilation3.791.72 to 8.36<0.001
      Cardiogenic shock1.980.86 to 4.540.19
      Ejection Fraction <35%1.680.75 to 3.790.17

      30 days outcomes:

      At 30-day follow-up (Table 5), there was no significant difference in readmission, or a combined outcome of stroke, and death between the two groups (3.9% vs 1.5%; P = 0.12). Men had higher rate of arrhythmias (2.7% vs 0; P = 0.02
      Table 5Events at 30 days after discharge of men and women with Takotsubo cardiomyopathy
      30-days eventsMen (N=408) no. (%)Women (N=193) no. (%)P Value
      Stroke3 (0.7)1 (0.5)0.75
      Arrythmia11 (2.7)00.02
      Death13 (3.2)2 (1)0.12
      Combined Stroke/ Death16 (3.9)3 (1.5)0.12
      Readmission87 (21.3)32 (16.6)0.17
      MI: myocardial infarction
      Patients who had TC while admitted for medical/surgical illness had higher mortality rates at 30 days after hospital discharge than patients who were diagnosed with TC on presentation to the hospital (5.7% vs 1.2%; P = 0.002). Older age at diagnosis of TC, chronic kidney disease, chronic obstructive pulmonary disease, peripheral vascular disease, and need for intubation/non-invasive ventilation were all independent predictors for 30 days combined outcomes of stroke and death (Table 6).
      Table 6Multivariate regression for mortality and stroke at 30 days
      CovariateOdd Ratios95% CIP
      Age at diagnosis1.071.03 to 1.11<0.001
      Female sex0.520.14 to 1.910.32
      Diabetes Mellitus0.670.28 to 1.620.38
      Chronic kidney disease2.931.23 to 7.000.02
      Chronic obstructive pulmonary disease0.400.18 to 0.920.03
      Coronary artery disease1.150.45 to 2.940.78
      Peripheral vascular disease3.081.17 to 8.090.02
      Atrial Fibrillation1.710.52 to 5.620.38
      History of Malignancy1.610.67 to 3.870.29
      Ejection fraction<35%1.080.47 to 2.520.85
      Physical stress as a trigger factor1.880.72 to 4.880.20
      Intubation/Non-invasive ventilation4.221.71 to 10.430.002
      Cardiogenic shock1.140.35 to 3.700.83
      ACE-I: Angiotensin converting enzyme inhibitors; ARB: Angiotensin II receptor blocker

      Long-term outcomes:

      After median ± SD follow-up of 3.7±3.1 years, mortality was higher among men than women (HR 1.99 [95% CI 1.54-2.6] p<0.001. Figure 1).
      Figure thumbnail gr1
      Figure 1Long Term Mortality in Men and Women with Takotsubo Cardiomyopathy. Kaplan-Meir analysis for mortality on long-term follow up. On median±SD follow up of 3.7±3.1 years, men were found to have significantly higher mortality rates (HR 1.99 [95% CI 1.54-2.6] p<0.001).
      Age at diagnosis of TC, male sex, diabetes mellitus, chronic kidney disease, chronic obstructive pulmonary disease, peripheral vascular disease, history of malignancy, physical stress as a trigger factor, and receiving intubation/non-invasive ventilation were all independently associated with increased mortality on long-term follow-up (Table 7).
      Table 7Cox regression analysis of factors affecting long-term all-cause mortality of patients with Takotsubo cardiomyopathy
      CovariateHazard ratio95% CIP
      Age at diagnosis1.031.02 to 1.04<0.001
      Female sex0.710.51 to 0.970.03
      Diabetes Mellitus1.381.05 to 1.830.02
      Chronic kidney disease1.471.06 to 2.040.02
      Chronic obstructive pulmonary disease1.441.11 to 1.860.006
      Coronary artery disease1.300.94 to 1.800.12
      Peripheral vascular disease1.481.03 to 2.130.03
      Atrial Fibrillation1.120.72 to 1.750.60
      History of Malignancy2.051.52 to 2.75<0.001
      Ejection fraction<35%1.110.85 to 1.440.44
      Physical stress as a trigger factor1.751.33 to 2.31<0.001
      Intubation/Non-invasive ventilation1.661.14 to 2.110.006
      Cardiac arrest1.160.35 to 3.810.81
      ACE-I/ARB on discharge0.900.70 to 1.160.42
      ACE-I: Angiotensin converting enzyme inhibitors; ARB: Angiotensin II receptor blocker
      Patients who were discharged on ACE-I/ARB had lower mortality rates (HT 0.5[95% CI 0.57-0.98] p=0.03). However, on cox regression, discharging patients on ACE-I/ARB did not predict improved outcome during long term follow-up. There was no significant difference in mortality between patients who were discharged on beta blockers compared to those without beta blockers. The overall incidence of recurrent TC was 1.8%. Men were less likely to have recurrence than women (1.1% vs 3.6%; P = 0.04).

      Discussion:

      The major findings in this large retrospective study of patients in a VA healthcare system are the following: (a) men had higher in-hospital mortality than women; (b) there was no significant difference in the combined outcome of stroke and death or readmission rate in men at 30 days after discharge than in women; and (c) men had worse all-cause mortality but less recurrence in long-term follow-up than women.
      To our knowledge this study includes the largest cohort of men with TC (n=444).
      • Templin C.
      • Ghadri J.R.
      • Diekmann J.
      • et al.
      Clinical Features and Outcomes of Takotsubo (Stress) Cardiomyopathy.
      ,
      • Schneider B.
      • Athanasiadis A.
      • Stöllberger C.
      • et al.
      Gender differences in the manifestation of tako-tsubo cardiomyopathy.
      ,
      • Agdamag A.C.
      • Patel H.
      • Chandra S.
      • et al.
      Sex Differences in Takotsubo Syndrome: A Narrative Review.
      ,
      • Tsuchihashi K.
      • Ueshima K.
      • Uchida T.
      • et al.
      Transient left ventricular apical ballooning without coronary artery stenosis: A novel heart syndrome mimicking acute myocardial infarction.
      • Wittstein I.S.
      • Thiemann D.R.
      • Lima J.A.C.
      • et al.
      Neurohumoral Features of Myocardial Stunning Due to Sudden Emotional Stress.
      • Ghadri J.R.
      • Kato K.
      • Cammann V.L.
      • et al.
      Long-Term Prognosis of Patients With Takotsubo Syndrome.
      • Arcari L.
      • Núñez-Gil I.J.
      • Stiermaier T.
      • et al.
      Gender Differences in Takotsubo Syndrome.

      Clinical characteristics/trigger factors:

      In our cohort, the men were older and had higher rates of medical comorbidities on presentation, including CAD, which is consistent with previous studies.
      • Templin C.
      • Ghadri J.R.
      • Diekmann J.
      • et al.
      Clinical Features and Outcomes of Takotsubo (Stress) Cardiomyopathy.
      ,
      • Agdamag A.C.
      • Patel H.
      • Chandra S.
      • et al.
      Sex Differences in Takotsubo Syndrome: A Narrative Review.
      There were also significant differences in trigger factors between men and women. Previous studies have shown conflicting results regarding the predominant trigger factor in patients diagnosed with TC.
      • Templin C.
      • Ghadri J.R.
      • Diekmann J.
      • et al.
      Clinical Features and Outcomes of Takotsubo (Stress) Cardiomyopathy.
      ,
      • Schneider B.
      • Athanasiadis A.
      • Stöllberger C.
      • et al.
      Gender differences in the manifestation of tako-tsubo cardiomyopathy.
      ,
      • Agdamag A.C.
      • Patel H.
      • Chandra S.
      • et al.
      Sex Differences in Takotsubo Syndrome: A Narrative Review.
      ,
      • Wittstein I.S.
      • Thiemann D.R.
      • Lima J.A.C.
      • et al.
      Neurohumoral Features of Myocardial Stunning Due to Sudden Emotional Stress.
      In our study, physical stress was more commonly identified as the trigger factor in both men and women but it was more common in men. The reason is unclear, but in previous studies physical trigger was associated with higher levels of norepinephrine in patients with Takotsubo, which might play a role in the pathophysiology of the disease.
      • Sobue Y.
      • Watanabe E.
      • Ichikawa T.
      • et al.
      Physically triggered Takotsubo cardiomyopathy has a higher in-hospital mortality rate.
      We also observed a high proportion of patients in both groups with no identifiable trigger factor, which is consistent with previous reports.
      • Templin C.
      • Ghadri J.R.
      • Diekmann J.
      • et al.
      Clinical Features and Outcomes of Takotsubo (Stress) Cardiomyopathy.
      Similar results were obtained when we compared men above the age of 51 to women of similar age group (above the median age of menopause). More than 60% of the men in our study presented with symptoms other than chest pain; this is contrary to previous studies that showed chest pain as the presenting symptom in men in 57%-100% of patients.
      • Templin C.
      • Ghadri J.R.
      • Diekmann J.
      • et al.
      Clinical Features and Outcomes of Takotsubo (Stress) Cardiomyopathy.
      ,
      • Schneider B.
      • Athanasiadis A.
      • Stöllberger C.
      • et al.
      Gender differences in the manifestation of tako-tsubo cardiomyopathy.
      ,
      • Wittstein I.S.
      • Thiemann D.R.
      • Lima J.A.C.
      • et al.
      Neurohumoral Features of Myocardial Stunning Due to Sudden Emotional Stress.
      This is likely because more men developed TC in the midst of other medical or surgical illness where symptoms elicitation is challenging. However, a true sex difference cannot be ruled out. This was consistent with a previous study that showed low rates of chest pain as the presenting symptom in patients with exacerbated underlying disorder or procedure.
      • Tsuchihashi K.
      • Ueshima K.
      • Uchida T.
      • et al.
      Transient left ventricular apical ballooning without coronary artery stenosis: A novel heart syndrome mimicking acute myocardial infarction.
      Patients with an emotional or no trigger factor were more likely to present with chest pain than patients with a physical trigger, and this finding was similar for men and women in our study.

      In-hospital outcomes:

      Men with TC required higher rates of using invasive and non-invasive ventilation and catecholamines. Length of stay was longer for men, and they were more likely to sustain a cardiac arrest or die in the hospital. This is consistent with the previous large multicenter study by Templin et al.
      • Templin C.
      • Ghadri J.R.
      • Diekmann J.
      • et al.
      Clinical Features and Outcomes of Takotsubo (Stress) Cardiomyopathy.
      A very recent published study by Arcari et al also found higher in-hospital mortality, increased frequency of cardiogenic shock, and longer length of stay in men compared to women.
      • Arcari L.
      • Núñez-Gil I.J.
      • Stiermaier T.
      • et al.
      Gender Differences in Takotsubo Syndrome.
      In addition, patients with TC who developed cardiac arrest were more likely to be men in a previous study.
      • Gili S.
      • Cammann V.L.
      • Schlossbauer S.A.
      • et al.
      Cardiac arrest in takotsubo syndrome: Results from the InterTAK Registry.
      Though the reason is unclear, higher medical comorbidities in men might be a contributing factor. In a previous small study of patients diagnosed with TC in the intensive care unit, half of the patients were men.
      • Haghi D.
      • Fluechter S.
      • Suselbeck T.
      • et al.
      Takotsubo cardiomyopathy (acute left ventricular apical ballooning syndrome) occurring in the intensive care unit.
      Interestingly, men were less likely to receive coronary angiography during their hospitalization, we think it might been related to the aversion of come clinicians to perform invasive procedures in patients who are more acutely ill at diagnosis such as the men in our cohort. In addition, male sex was a predictor of in-hospital mortality on multivariate analysis in our study. Prior studies have conflicting results regarding in-hospital mortality. Weidner et al and Schneider et al showed no difference for in-hospital mortality between men vs women, neither studies evaluated for independent predictors for in-hospital mortality.
      • Schneider B.
      • Athanasiadis A.
      • Stöllberger C.
      • et al.
      Gender differences in the manifestation of tako-tsubo cardiomyopathy.
      ,
      • Weidner K.J.
      • El-Battrawy I.
      • Behnes M.
      • et al.
      Sex differences of in-hospital outcome and long-term mortality in patients with Takotsubo cardiomyopathy.
      Murakami et al found male sex was independent predictor of in-hospital composite cardiac events while Budnik et al found sex was not a predictor of in-hospital complications on univariate analysis,
      • Murakami T.
      • Yoshikawa T.
      • Maekawa Y.
      • et al.
      Gender differences in patients with takotsubo cardiomyopathy: Multi-center registry from Tokyo CCU Network.
      ,
      • Budnik M.
      • Nowak R.
      • Fijałkowski M.
      • et al.
      Sex-dependent differences in clinical characteristics and in-hospital outcomes in patients with takotsubo syndrome.
      . Brinjikji el al identified male sex as an independent predictor of in-hospital mortality, but patients included in the study and outcomes were based on chart coding only.
      • Brinjikji W.
      • El-Sayed A.M.
      • Salka S.
      In-hospital mortality among patients with takotsubo cardiomyopathy: A study of the National Inpatient Sample 2008 to 2009.
      Templin et al reported male sex, physical trigger as predictors for composite endpoint (catecholamine use, cardiogenic shock, invasive/non-invasive ventilation, cardiopulmonary resuscitation, and death). But male sex was not an independent predictor on multivariate analysis. Interestingly age, above 70 was found to be an independent predictor of better outcomes in the same study.
      • Templin C.
      • Ghadri J.R.
      • Diekmann J.
      • et al.
      Clinical Features and Outcomes of Takotsubo (Stress) Cardiomyopathy.
      Male sex was identified as an independent predictor of in-hospital mortality on multivariate analysis in the GEIST (German Italian Spanish Takotsubo) registry.
      • Arcari L.
      • Núñez-Gil I.J.
      • Stiermaier T.
      • et al.
      Gender Differences in Takotsubo Syndrome.

      Short-term Outcomes:

      On 30-day follow up, male sex was not an independent predictor of mortality in our study. Previous studies have conflicting data. Increased mortality rates in the matched cohort of men at 60 days compared to women was reported in the GEIST registry.
      • Arcari L.
      • Núñez-Gil I.J.
      • Stiermaier T.
      • et al.
      Gender Differences in Takotsubo Syndrome.
      While male sex was not an independent predictor in the international takotsubo registry at 30-days.
      • Ghadri J.R.
      • Kato K.
      • Cammann V.L.
      • et al.
      Long-Term Prognosis of Patients With Takotsubo Syndrome.

      Long-term outcomes:

      In our study, men were less likely to have recurrence than women on long term follow up (1.1% vs 3.6%; P = 0.04). Previous studies have shown conflicting data regarding recurrence rate between men and women. There was no difference in recurrence rate between men and women in the GEIST registry and in the international takotsubo registry (0.8% vs 1.9%; P=0.22)
      • Templin C.
      • Ghadri J.R.
      • Diekmann J.
      • et al.
      Clinical Features and Outcomes of Takotsubo (Stress) Cardiomyopathy.
      ,
      • Arcari L.
      • Núñez-Gil I.J.
      • Stiermaier T.
      • et al.
      Gender Differences in Takotsubo Syndrome.
      , while in a meta-analysis nearly all cases of recurrence occurred in women on 72 months followup.
      • Singh K.
      • Carson K.
      • Usmani Z.
      • Sawhney G.
      • Shah R.
      • Horowitz J.
      Systematic review and meta-analysis of incidence and correlates of recurrence of takotsubo cardiomyopathy.
      An explanation might be the repetitive nature of emotional stress that might trigger recurrent episodes in women.
      There are limited studies on long-term outcomes in patients with TC. In our study, men had higher overall mortality than women. Other independent predictors of mortality in our study, beside male sex, were age at diagnosis of TC, diabetes mellitus, chronic kidney disease, chronic obstructive pulmonary disease, peripheral vascular disease, history of malignancy, physical stress as a trigger factor, and receiving intubation/non-invasive ventilation during the hospital admission of the TC diagnosis. Weidner et al assessed long-term mortality in patients with TC and male sex and EF<35% were identified as an independent predictor for all-cause mortality, but the study had small number of men (n=16). In our study, EF <35% at diagnosis was not an independent predictor of mortality. In the recent published study involving patients in the GEIST registry, male sex, age, diabetes, pulmonary disease, malignancies, physical trigger, low EF, and cardiogenic shock were identified as independent predictors of long-term mortality.
      • Arcari L.
      • Núñez-Gil I.J.
      • Stiermaier T.
      • et al.
      Gender Differences in Takotsubo Syndrome.
      Long-term mortality rate was higher in our study when compared to the GEIST registry. This could be due to the higher number of significant lung disease and physical triggers in our study. The independent predictors of long-term mortality in the international takotsubo registry were male sex, age > 70, malignancies, EF < 45%, physical triggers, and no triggers.
      • Ghadri J.R.
      • Kato K.
      • Cammann V.L.
      • et al.
      Long-Term Prognosis of Patients With Takotsubo Syndrome.

      Limitations:

      Despite its large size and multicenter cohort, our study was based on retrospective record review and thus is prone to bias. ICD codes were used to identify cases, so not all cases may have been identified. However, this limitation affects both groups and is, therefore, unlikely to affect the results. Compared to studies that used ICD codes for adjudicating outcomes, patient level data and outcomes were manually extracted. This manual review allowed us to identify outcomes when patients were admitted outside the VA system since we had access to scanned records and collect follow-up data due to the ability of tracking individual patients across the healthcare system even when they moved to a different city. However, some events could have been missed. Multivariate analysis for inpatient mortality was underpowered due to the low number of events compared to the number of variables included.
      In addition, due to the male predominate population at the VA, the study cohort might not be representative of general population.
      Patients were only included if they met the latest criteria for diagnosis TC, however cases of coronary spasm and myocardial infarction with non-obstructive coronary arteries (MINOCA) could have been included due to the limitation of the criteria.

      Conclusion:

      Men diagnosed with TC are more likely to have a physical trigger, become more acutely ill, have a more complicated hospital course, and have higher mortality rates on long-term follow-up than women. However, women were more likely to have recurrent TC and were more likely to present with chest pain. Future prospective studies should focus on the mechanisms of these differences to elucidate how sex affects the TC clinical course, which may help physicians make better treatment decisions and more accurate prognoses.

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