Gender Differences in Takotsubo Syndrome

Luca Arcari, MD; Iván J. Núñez-Gil, MD, PHD; Thomas Stiermaier, MD; Ibrahim El-Battrawy, MD; Federico Guerra, MD; Giuseppina Novo, MD, PHD; Beatrice Musumeci, MD; Luca Cacciotti, MD, PHD; Enrica Mariano, MD, PHD; Pasquale Caldarola, MD; Giuseppe Parisi, MD; Roberta Montisci, MD; Enrica Vitale, MD; Matteo Sclafani, MD; Massimo Volpe, MD; Miguel Corbì-Pasqual, MD; Manuel Martinez-Selles, MD; Manuel Almendro-Delia, MD, PHD; Alessandro Sionis, MD, PHD; Aitor Uribarri, MD; Ibrahim Akin, MD; Holger Thiele, MD; Natale Daniele Brunetti, MD, PHD; Ingo Eitel, MD; Francesco Santoro, MD, PHD

Disclosures

J Am Coll Cardiol. 2022;79(21):2085-2093.

Abstract and Introduction

Abstract

Background: Male sex in takotsubo syndrome (TTS) has a low incidence and it is still not well characterized.

Objectives: The aim of the present study is to describe TTS sex differences.

Methods: TTS patients enrolled in the international multicenter GEIST (GErman Italian Spanish Takotsubo) registry were analyzed. Comparisons between sexes were performed within the overall cohort and using an adjusted analysis with 1:1 propensity score matching for age, comorbidities, and kind of trigger.

Results: In total, 286 (11%) of 2,492 TTS patients were men. Male patients were younger (age 69 ± 13 years vs 71 ± 11 years; P = 0.005), with higher prevalence of comorbid conditions (diabetes mellitus 25% vs 19%; P = 0.01; pulmonary diseases 21% vs 15%; P = 0.006; malignancies 25% vs 13%; P < 0.001) and physical trigger (55 vs 32% P < 0.01). Propensity-score matching yielded 207 patients from each group. After 1:1 propensity matching, male patients had higher rates of cardiogenic shock and in-hospital mortality (16% vs 6% and 8% vs 3%, respectively; both P < 0.05). Long-term mortality rate was 4.3% per patient-year (men 10%, women 3.8%). Survival analysis showed higher mortality rate in men during the acute phase in both cohorts (overall: P < 0.001; matched: P = 0.001); mortality rate after 60 days was higher in men in the overall (P = 0.002) but not in the matched cohort (P = 0.541). Within the overall population, male sex remained independently associated with both in-hospital (OR: 2.26; 95% CI: 1.16–4.40) and long-term mortality (HR: 1.83; 95% CI: 1.32–2.52).

Conclusions: Male TTS is featured by a distinct high-risk phenotype requiring close in-hospital monitoring and long-term follow-up.

Introduction

Takotsubo syndrome (TTS) is an acute heart failure condition characterized by substantially reversible cardiac dysfunction and a not trivial rate of short- and long-term morbidity and mortality.^[1]

Increased catecholaminergic signaling plays a central role in the onset of the syndrome, leading to acute inflammation and metabolic lipid dysregulation at cardiac level together with negative inotropic and chronotropic effects.^[2]

From earlier reports, a preponderance of women, and particularly postmenopausal women, among affected individuals has been observed,^[3] although reasons for such a predisposition are still not fully clear.^[4] Recently, data from multicenter registries identified male sex as a factor associated with worse prognosis.^[5–8] However, the male subgroup is under-reported and understudied,^[4] because only few relatively small observational studies or larger analyses using national inpatient samples with less detailed data were specifically targeted to the characterization of male TTS. In these reports, male patients were described as having higher prevalence of physical factors triggering the syndrome, larger comorbidity burden and higher rates of adverse outcomes as compared with women.^[9–12] Given the uncommon occurrence of TTS in men, the limitations of previous research include small sample sizes and demographic disproportion between groups, for which sex differences in patients with TTS still remain to be clarified.^[13] The aim of the present study is to undertake an analysis of male TTS patients included in the large, multicentric, and international GEIST (GErman Italian Spanish Takotsubo; NCT04361994) registry, to provide a more comprehensive description of disease characteristics and outcomes in this subset of patients.

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Next Section

Table 1. Baseline Characteristics of Patients Within the Overall and Matched Cohort
	Overall Cohort		P Values	SMD	Matched Cohort		P Values	SMD
	Male TTS (n = 286)	Female TTS (n = 2,206)	P Values	SMD	Male TTS (n = 207)	Female TTS (n = 207)	P Values	SMD
Age, y^a	69 ± 13	71 ± 11	0.005	0.178	70 ± 12	71 ± 12	0.705	0.037
Comorbidities
Hypertension	188/284 (66)	1,501/2,194 (68)	0.451	0.063	137/207 (66)	153/207 (74)	0.086	0.168
Diabetes mellitus^a	71/284 (25)	408/2,194 (19)	0.01	0.162	55/207 (27)	43/207 (21)	0.165	0.136
Dyslipidemia	107/263 (41)	878/2,075 (42)	0.614	0.033	84/191 (44)	73/194 (38)	0.205	0.129
Current smoker^a	95/284 (33)	345/2,194 (16)	<0.001	0.464	54/207 (26)	54/207 (26)	<0.99	<0.001
Pulmonary disease^a	56/260 (21)	287/1,929 (15)	0.006	0.183	40/197 (20)	35/138 (25)	0.274	0.121
Malignancies^a	62/251 (25)	250/1,887 (13)	<0.001	0.324	46/207 (22)	59/207 (28)	0.142	0.144
Coronary artery disease	39/249 (16)	167/1,904 (9)	0.001	0.234	31/181 (17)	13/142 (9)	0.038	0.232
Clinical presentation
Chest pain	120/253 (47)	1,207/1,963 (62)	<0.001	0.286	91/184 (49)	57/125 (46)	0.505	0.077
Dyspnea	106/253 (42)	686/1,961 (35)	0.031	0.144	77/184 (42)	64/125 (51)	0.105	0.187
Stressful trigger	209/285 (73)	1,555/2,197 (71)	0.371	0.056	149/207 (72)	150/207 (72)	0.913	0.011
Emotional^a	53/285 (19)	859/2,197 (39)	<0.001	0.425	46/207 (22)	43/207 (21)	0.720	0.035
Physical^a	158/285 (55)	699/2,197 (32)	<0.001	0.231	103/207 (50)	107/207 (52)	0.694	0.038
Admission electrocardiographic findings
Atrial fibrillation	39/250 (16)	307/1,981 (16)	0.966	0.003	29/184 (16)	33/196 (17)	0.777	0.029
ST-segment changes	198/244 (81)	1,565/1,908 (82)	0.738	0.023	147/182 (81)	94/120 (78)	0.606	0.061
Admission echocardiographic findings
Apical ballooning	241/286 (84)	1,898/2,205 (89)	0.408	0.052	176/207 (85)	150/207 (72)	0.002	0.306
Midventricular ballooning	40/286 (14)	256/2,205 (12)	0.243	0.073	27/207 (13)	54/207 (26)	0.001	0.328
Basal ballooning	3/286 (1)	45/2,205 (2)	0.251	0.072	2/207 (1)	2/207 (1)	>0.99	<0.001
Focal	2/286 (0.7)	6/2,205 (0.3)	0.232	0.075	2/207 (1)	1/207 (1)	>0.99	0.057
LVEF	38 ± 11	40 ± 10	0.001	0.214	39 ± 11	41 ± 11	0.011	0.251
In-hospital course and treatment
In-hospital complications	95/286 (33)	387/2,206 (17)	<0.001	0.432	65/207 (31)	31/207 (15)	<0.001	0.390
Pulmonary edema	29/286 (10)	171/2,206 (8)	0.162	0.087	22/207 (11)	13/207 (6)	0.112	0.156
Cardiogenic shock	54/286 (19)	175/2,206 (8)	<0.001	0.379	33/207 (16)	13/207 (6)	0.002	0.307
Arrhythmias	27/174 (16)	135/1,194 (11)	0.108	0.130	17/127 (13)	17/154 (11)	0.548	0.072
Death	20/286 (7)	51/2,206 (2)	<0.001	0.281	17/207 (8)	7/207 (3)	0.035	0.206
Catecholamine administration	56/286 (20)	160/2,206 (7)	<0.001	0.438	37/194 (19)	12/191 (6)	<0.001	0.383
OTI	47/286 (16)	126/2,206 (6)	<0.001	0.421	29/191 (15)	12/194 (6)	0.004	0.291
In-hospital stay, d	11 ± 13	9 ± 9	<0.001	0.257	10 ± 10	9 ± 8	0.082	0.174
Discharge
Aspirin	144/255 (57)	1,122/1,944 (58)	0.705	0.025	114/185 (62)	115/190 (60)	0.828	0.022
DAPT	30/206 (15)	139/1,425 (10)	0.034	0.157	22/146 (15)	16/160 (10)	0.179	0.153
Anticoagulant	44/245 (18)	312/1,769 (18)	0.901	0.008	31/177 (17)	29/187 (15)	0.606	0.054
Beta-blockers	152/240 (63)	1,354/1,855 (73)	0.002	0.214	121/175 (69)	154/187 (82)	0.003	0.309
ACE inhibitor/ARBs	157/255 (62)	1,380/1,963 (70)	0.004	0.189	122/185 (66)	157/190 (83)	<0.001	0.382
Statin	142/253 (56)	1,005/1,936 (52)	0.207	0.084	110/183 (60)	89/190 (47)	0.010	0.265
TTS recurrence	8/198 (4)	70/1,664 (4)	0.912	0.008	7/149 (5)	10/113 (9)	0.177	0.168

Values are mean ± SD, or n/N (%). ^aVariables that were used to calculate the propensity score for matching.
ACE = angiotensin-converting enzyme; ARB = angiotensin II receptor blocker; DAPT = dual antiplatelet therapy; LVEF = left ventricular ejection fraction; OTI = oro-tracheal intubation; SMD = standardized mean difference; TTS = takotsubo syndrome.

Table 2. Univariable and Multivariable Analysis for Factors Associated With Male Sex
	Univariable		Multivariable
	OR (95% CI)	P Value	OR (95% CI)	P Value
Age (per 5-y increase)	0.93 (0.88–0.98)	0.004	NS	NS
Hypertension	0.90 (0.70–1.12)	0.451	—	—
Dyslipidemia	0.93 (0.72–1.21)	0.614	—	—
Diabetes	1.46 (1.09–1.95)	0.01	NS	NS
Current smoking	2.70 (2.00–3.54)	<0.001	2.77 (1.99- 3.84)	<0.001
Pulmonary disease	1.57 (1.14–2.16)	0.006	NS	NS
Malignancies	2.15 (1.57–2.95)	<0.001	2.11 (1.48–3.00)	<0.001
Physical trigger	2.67 (2.08–4.42)	<0.001	2.46 (1.85–3.29)	<0.001
LVEF (per 5-point increase)	0.90 (0.85–0.96)	0.001	0.92 (0.86–0.99)	0.02
Apical ballooning	0.87 (0.62–1.22)	0.408	—	—

LVEF = left ventricular ejection fraction; NS = nonsignificant.

Table 3. Univariable and Multivariable Analysis for Factors Associated With In-Hospital and Long-Term Mortality
	Univariable		Multivariable
	OR (95% CI)	P Value	OR (95% CI)	P Value
In-hospital mortality
Age (per 5-y increase)	1.27 (1.13–1.43)	<0.001	1.38 (1.19–1.61)	<0.001
Male	3.12 (1.86–5.41)	<0.001	2.26 (1.16–4.40)	0.016
Hypertension	1.17 (0.69–1.98)	0.552	—	—
Dyslipidemia	1.05 (0.63–1.76)	0.848	—	—
Diabetes	2.39 (1.45–3.94)	0.001	NS	NS
Current smoking	0.77 (0.39–1.51)	0.442	—	—
Pulmonary disease	2.04 (1.16–3.6)	0.014	NS	NS
Malignancies	2.18 (1.24–3.85)	0.007	NS	NS
Physical trigger	2.52 (1.56–4-05)	<0.001	NS	NS
LVEF (per 5-point increase)	0.62 (0.55–0.71)	<0.001	0.72 (0.61–0.84)	<0.001
Apical ballooning	2.20 (0.88–5.52)	0.09	NS	NS
Cardiogenic shock	11.16 (6.85–18.2)	<0.001	10.69 (5.85- 19.53)	<0.001
Long-term mortality
Age (per 5-y increase)	1.35 (1.28–1.44)	<0.001	1.38 (1.28–1.48)	<0.001
Male	2.27 (1.72–2.99)	<0.001	1.83 (1.32–2.52)	<0.001
Hypertension	1.33 (1.04–1.71)	0.025	NS	NS
Dyslipidemia	0.99 (0.79–1.25)	0.958	—	—
Diabetes	2.19 (1.74–2.76)	<0.001	2.06 (1.59–2.66)	<0.001
Current smoking	0.78 (0.58–1.04)	0.093	NS	NS
Pulmonary disease	2.13 (1.63–2.79)	<0.001	1.63 (1.22–2.17)	0.001
Malignancies	2.40 (1.84–3.12)	<0.001	2.05 (1.53–2.76)	<0.001
Physical trigger	2.35 (1.89–2.91)	<0.001	1.91 (1.48–2.47)	<0.001
LVEF (per 5-point increase)	0.79 (0.75–0.83)	<0.001	0.84 (0.79–0.89)	<0.001
Apical ballooning	1.67 (1.18–2.35)	0.003	NS	NS
Cardiogenic shock	3.97 (3.10–5.09)	<0.001	3.44 (2.56–4.62)	<0.001

Abbreviations as in Table 2.

Authors and Disclosures

Luca Arcari, MD^a,*, Iván J. Núñez-Gil, MD, PHD^b,*, Thomas Stiermaier, MD^c, Ibrahim El-Battrawy, MD^d,e, Federico Guerra, MD^f, Giuseppina Novo, MD, PHD^g, Beatrice Musumeci, MD^h, Luca Cacciotti, MD, PHD^a, Enrica Mariano, MD, PHDⁱ, Pasquale Caldarola, MD^j, Giuseppe Parisi, MD^j, Roberta Montisci, MD^k, Enrica Vitale, MD^l, Matteo Sclafani, MD^h, Massimo Volpe, MD^h, Miguel Corbì-Pasqual, MD^m, Manuel Martinez-Selles, MDⁿ, Manuel Almendro-Delia, MD, PHD^o, Alessandro Sionis, MD, PHD^p, Aitor Uribarri, MD^q, Ibrahim Akin, MD^d, Holger Thiele, MD^r, Natale Daniele Brunetti, MD, PHD^l, Ingo Eitel, MD^c,† and Francesco Santoro, MD, PHD^l,†

^aInstitute of Cardiology, Madre Giuseppina Vannini Hospital, Rome, Italy; ^bInterventional Cardiology, Cardiovascular Institute, Hospital Clínico Universitario San Carlos, Madrid, Spain; ^cUniversity Heart Center Lübeck, Medical Clinic II (Cardiology/Angiology/Intensive Care Medicine) and German Center for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Lübeck, Lübeck, Germany; ^dDepartment of Cardiology, University of Mannheim, Mannheim, Germany; ^eDepartment of Cardiology and Angiology, Bergmannsheil University Hospitals, Ruhr University of Bochum, Bochum, Germany; ^fCardiology and Arrhythmology Clinic, Marche Polytechnic University, University Hospital "Umberto I – Lancisi – Salesi", Ancona, Italy; ^gDepartment of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, Cardiology Unit, University of Palermo, University Hospital P. Giaccone, Palermo, Italy; ^hCardiology, Clinical and Molecular Medicine Department, Faculty of Medicine and Psychology, Sapienza University of Rome, Rome, Italy; ⁱDivision of Cardiology, University of Rome Tor Vergata, Rome, Italy; ^jDepartment of Cardiology, San Paolo Hospital, Bari, Italy; ^kClinical Cardiology, Department of Medical Science and Public Health, University of Cagliari, Cagliari, Italy; ^lUniversity of Foggia, Department of Medical and Surgical Sciences, Foggia, Italy; ^mDepartment of Cardiology, Complejo Hospitalario de Albacete, Albacete, Spain; ⁿDepartment of Cardiology, Hospital General Universitario Gregorio Marañon, CIBERCV, and Universidad Europea, Universidad Complutense, Madrid, Spain; ^oServicio de Cardiología, Hospital Virgen de la Macarena, Sevilla, Spain; ^pUnidad de Cuidados Intensivos Cardiológicos, Servicio de Cardiología, Hospital de Sant Pau, Instituto de Investigación Biomédica Sant Pau (IIB Sant Pau), Barcelona, Spain; ^qDepartment of Cardiology, Hospital vall d'hebron, Barcelona, Spain; and the ^rHeart Center Leipzig at University of Leipzig and Leipzig Heart Institute, Department of Internal Medicine/Cardiology, Leipzig, Germany. *Drs Arcari and Núñez-Gil contributed equally to this work as first authors. †Drs Eitel and Santoro contributed equally to this work as senior authors.

Address for Correspondence
Prof Natale Daniele Brunetti, University of Foggia, Department of Medical and Surgical Sciences, Viale Pinto n.1, 71122 Foggia, Italy. E-mail: natale.brunetti@unifg.it.

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