Feb 15, 2018 - In view of low prevalence rates, diabetes is discussed as a protective ... prevalence and prognostic relevance of concomitant diabetes in TTS.
Diabetes Care
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Prevalence and Prognostic Impact of Diabetes in Takotsubo Syndrome: Insights From the International, Multicenter GEIST Registry
Thomas Stiermaier,1 Francesco Santoro,2 Ibrahim El-Battrawy,3 Christian M¨oller,1 Tobias Graf,1 Giuseppina Novo,4 Andrea Santangelo,4 Enrica Mariano,5 Francesco Romeo,5 Pasquale Caldarola,6 Mario Fanelli,7 Holger Thiele,8 Natale Daniele Brunetti,2 Ibrahim Akin,3 and Ingo Eitel1
https://doi.org/10.2337/dc17-2609
OBJECTIVE
In view of low prevalence rates, diabetes is discussed as a protective factor for the occurrence of Takotsubo syndrome (TTS). Furthermore, it was associated with improved outcome in a small single-center analysis. Therefore, this study assessed the prevalence and prognostic relevance of concomitant diabetes in TTS. RESEARCH DESIGN AND METHODS
A total of 826 patients with TTS were enrolled in an international, multicenter, registrybased study (eight centers in Italy and Germany). All-cause mortality was compared between patients with diabetes and patients without diabetes, and the independent predictive value of diabetes was evaluated in multivariate regression analysis. RESULTS
CONCLUSIONS
Diabetes is not uncommon in patients with TTS, is associated with increased longerterm mortality rates, and is an independent predictor of adverse outcome irrespective of additional risk factors. Since its first systematic description more than two decades ago, Takotsubo syndrome (TTS) is increasingly recognized worldwide as an important differential diagnosis in patients with suspected acute coronary syndrome. The disease is characterized by typical, distinct ventricular contraction abnormalities that are not related to obstructive coronary artery disease and recover completely within several days to weeks (1–3).
Corresponding author: Ingo Eitel, ingo.eitel@ uksh.de. Received 14 December 2017 and accepted 27 January 2018. © 2018 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals .org/content/license.
Diabetes Care Publish Ahead of Print, published online February 15, 2018
CARDIOVASCULAR AND METABOLIC RISK
The prevalence of diabetes was 21.1% (n = 174). TTS patients with diabetes were older (P < 0.001), were more frequently male (P = 0.003), had a higher prevalence of hypertension (P < 0.001), physical triggers (P = 0.041), and typical apical ballooning (P = 0.010), had a lower left ventricular ejection fraction (P = 0.008), had a higher rate of pulmonary edema (P = 0.032), and had a longer hospital stay (P = 0.009). However, 28-day all-cause mortality did not differ between patients with diabetes and patients without diabetes (6.4% vs. 5.7%; hazard ratio [HR] 1.11 [95% CI 0.55–2.25]; P = 0.772). Longer-term follow-up after a median of 2.5 years revealed a significantly higher mortality among TTS patients with diabetes (31.4% vs. 16.5%; P < 0.001), and multivariate regression analysis identified diabetes as an independent predictor of adverse outcome (HR 1.66 [95% CI 1.16–2.39]; P = 0.006).
1 Cardiology/Angiology/Intensive Care Medicine, Medical Clinic II, University Heart Center L¨ubeck, and German Center for Cardiovascular Research (DZHK), L¨ubeck, Germany 2 Department of Medical and Surgery Sciences, University of Foggia, Foggia, Italy 3 Faculty of Medicine, First Department of Medicine, University Medical Centre Mannheim, University of Heidelberg, and German Center for Cardiovascular Research, Mannheim, Germany 4 Cardiology Unit, Biomedical Department of Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy 5 Division of Cardiology, University of Rome Tor Vergata, Rome, Italy 6 Department of Cardiology, San Paolo Hospital, Bari, Italy 7 Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy 8 Department of Internal Medicine/Cardiology, Heart Center Leipzig – University Hospital, Leipzig, Germany
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Diabetes in TTS
Postmenopausal women are primarily affected from TTS, and the occurrence is frequently triggered by physical or emotional stress (1). Recent studies demonstrated considerable short- and long-term adverse event rates with subsequent reevaluation of the disease (4–6). However, despite the progress achieved, several important aspects of TTS are still unclear and require additional investigations. These pending issues include the elusive pathophysiology of TTS and the identification of predictive factors for adverse outcome to guide monitoring and therapy. Recently, substantial research efforts were directed to the role of diabetes in patients with TTS. Experimental and clinical evidence exists that sympathetic overdrive and catecholamine excess are associated with, or can lead to, TTS (7–9). This explanation is currently the favored pathophysiological theory. Diabetic autonomic neuropathy can ameliorate catecholaminemediated effects to the heart and has therefore been considered protective for the occurrence of TTS (10,11). Data suggesting a low prevalence of diabetes in TTS cohorts compared with the general population were interpreted in support of this concept (12). Furthermore, a previous single center study reported lower adverse event rates in TTS patient with diabetes compared with TTS patients without diabetes (13). This observation was also attributed to a potentially attenuated manifestation of TTS in patients with diabetes. However, other investigations could not confirm a beneficial outcome in TTS patients with diabetes and even reported increased mortality rates (4). In view of these inconsistent findings, the aim of this study was to assess the prevalence and prognostic impact of diabetes in TTS in a large, international, multicenter study.
Diabetes Care
Paolo Hospital, Bari, Italy (n = 36); University Hospital of Palermo, Italy (n = 79); and University of Tor Vergata General Hospital, Rome, Italy (n = 79). The prospective inclusion of patients in the registry was performed according to recommended diagnostic criteria for TTS consisting of 1) transient regional wall motion abnormalities of the left or right ventricle, which are frequently preceded by a stressful trigger and usually extend beyond a single epicardial vascular distribution; 2) absence of culprit atherosclerotic coronary artery disease; 3) new and reversible electrocardiography abnormalities; 4) elevated cardiac troponin and serum natriuretic peptide levels; and 5) recovery of ventricular systolic function at followup (2,3). Exemplary images of the three most common contraction patterns are provided in Fig. 1. Recovery of left ventricular (LV) systolic function was documented 3–6 months after the acute event in all surviving patients. Diabetes was defined as preexisting disease on admission, which was treated by either diet and lifestyle measures alone or the additional use of oral glucoselowering medication and insulin, or newly diagnosed diabetes during the hospital stay for the TTS episode (fasting plasma glucose level $7.0 mmol/L [126 mg/dL], plasma glucose 2 h after a 75-g glucose load $11.1 mmol/L [200 mg/dL],
or glycated hemoglobin $6.5%). The prognostic implications of diabetes were evaluated regarding all-cause mortality, which was assessed during regular outpatient visits or scheduled telephone contact with the patients, relatives, and treating physicians. All events were verified via medical records and evaluated by a clinical events committee. The study was approved by the local ethics committees of the participating study centers, and all patients gave written informed consent before inclusion. Statistical Analysis
Categorical variables are presented as number (percentage) of patients and were compared with the x2 test. Continuous data were tested for normal distribution with the Shapiro-Wilk test. Since all continuous variables were nonnormally distributed, they are reported as median (interquartile range [IQR]) and were compared with the Mann-Whitney U test. Baseline characteristics and outcome were compared between TTS patients with diabetes and TTS patients without diabetes. Mortality rates were illustrated with the Kaplan-Meier method and compared with log-rank testing. Univariate and stepwise multivariate Cox regression analysis was performed to obtain hazard ratios (HRs) and 95% CIs. Multivariate testing included only variables with a
RESEARCH DESIGN AND METHODS Study Design and Population
This study included 836 consecutive patients with TTS enrolled in the international, multicenter GErman Italian STress cardiomyopathy (GEIST) registry, which involves eight centers: University Heart Center L¨ubeck, Germany (n = 108); Heart Center Leipzig – University Hospital, Germany (n = 178); University Medical Center Mannheim, Germany (n = 141); University Hospital of Foggia, Italy (n = 185); Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy (n = 30); San
Figure 1—Contraction patterns in patients with TTS. End-diastolic (top row) and end-systolic (bottom row) images in cardiac magnetic resonance. A: Apical ballooning with akinesia of apical and mid-LV segments with preserved basal function (four-chamber view). B: Mid-ventricular ballooning with akinesia of mid-LV segments with normal apical and basal function (two-chamber view). C: Basal ballooning with akinesia of basal LV segments with preserved mid and apical function (four chamber view). In addition, rare cases of focal LV ballooning or isolated right ventricular ballooning have been reported.
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significant P value in univariate analysis. Statistical analyses were performed with SPSS (version 17.0; SPSS, Chicago, IL). A two-sided P value #0.05 was considered statistically significant. RESULTS
Of the 836 consecutive patients included in the GEIST registry, 10 (1.2%) did not have diabetes status available, resulting in a final study population of 826 patients with TTS for the present analysis. The baseline clinical characteristics provided in Table 1 reflect a typical TTS cohort, with a predominance of postmenopausal women. The acute event was frequently preceded by a stressful trigger, and apical ballooning was the most prevalent contraction pattern. LV ejection fraction was moderately impaired at acute presentation and recovered during follow-up. The prevalence of diabetes was 21.1% (n = 174), and all cases of diabetes were type 2 diabetes. Clinical Characteristics According to the Presence of Diabetes
TTS patients with diabetes were older (P , 0.001), with a higher prevalence of hypertension (P , 0.001) and physical triggers (P = 0.041), and the proportion of patients who were male among TTS patients with diabetes was higher (P = 0.003), compared with patients without
diabetes (Table 1). Furthermore, typical apical ballooning was observed more frequently among patients with diabetes (P = 0.010), which resulted in a more severely impaired LV ejection fraction (P = 0.008), a higher rate of pulmonary edema (P = 0.032), and, consequently, a longer hospital stay (P = 0.009). Recovery of systolic LV function was similar in both groups and not affected by diabetes status (P = 0.198). Outcome According to the Presence of Diabetes
Follow-up data were available in 755 patients (91.4%) after a median of 2.5 years (IQR 0.5–4.9) and showed an all-cause mortality of 19.6% (n = 148). Stratification according to the presence of diabetes revealed significantly higher mortality rates in TTS patients with diabetes compared with TTS patients without diabetes (31.4% vs. 16.5%; HR 2.02 [95% CI 1.43– 2.84]; P , 0.001). As illustrated in the Kaplan-Meier plot (Fig. 2), survival curves initially show a parallel course before starting to diverge several months after the initial event, which results in a significant difference .1 year after the acute TTS episode. Accordingly, 28-day mortality did not differ significantly between groups (6.4% vs. 5.7%; HR 1.11 [95% CI 0.55–2.25]; P = 0.772).
Table 1—Baseline clinical characteristics Variable Age (years)
All patients (n = 826) Diabetes (n = 174) No diabetes (n = 652)
P
