Background: Takotsubo syndrome is usually triggered by a stressful event. The type of trigger seems to influence the outcome and should therefore be considered separately. Methods and Results: Patients included in the GEIST (German‐Italian‐Spanish Takotsubo) registry were categorized according to physical trigger (PT), emotional trigger (ET), and no trigger (NT) of Takotsubo syndrome. Clinical characteristics as well as outcome predictors were analyzed. Overall, 2482 patients were included. ET was detected in 910 patients (36.7%), PT in 885 patients (34.4%), and NT was observed in 717 patients (28.9%). Compared with patients with PT or NT, patients with ET were younger, less frequently men, and had a lower prevalence of comorbidities. Adverse in‐hospital events (NT: 18.8% versus PT: 27.1% versus ET: 12.1%, P <0.001) and long‐term mortality rates (NT: 14.4% versus PT: 21.6% versus ET: 8.5%, P <0.001) were significantly lower in patients with ET. Increasing age ( P <0.001), male sex ( P =0.007), diabetes ( P <0.001), malignancy ( P =0.002), and a neurological disorder ( P <0.001) were associated with a higher risk of long‐term mortality, while chest pain ( P =0.035) and treatment with angiotensin‐converting enzyme inhibitor/angiotensin receptor blocker ( P =0.027) were confirmed as independent predictors for a lower risk of long‐term mortality. Conclusions: Patients with ET have better clinical conditions and a lower mortality rate. Increasing age, male sex, malignancy, a neurological disorder, chest pain, angiotensin‐converting enzyme inhibitor/angiotensin receptor blocker, and diabetes were confirmed as predictors of long‐term mortality.

Background: Neurological disorders as a risk factor for Takotsubo syndrome (TTS) are not well characterized. The aim of the study was to evaluate TTS‐associated neurological phenotypes and outcome. Methods and Results: Patients with TTS enrolled in the international multicenter GEIST (German Italian Spanish Takotsubo) registry were analyzed. Prevalence, clinical characteristics, and short‐ and long‐term outcomes of patients with TTS were recorded. A subgroup analysis of the 5 most represented neurological disorders was performed. In total, 400 (17%) of 2301 patients had neurological disorders. The most represented neurological conditions were previous cerebrovascular events (39%), followed by neurodegenerative disorders (30.7%), migraine (10%), epilepsy (9.5%), and brain tumors (5%). During hospitalization, patients with neurological disorders had longer in‐hospital stay (8 [interquartile range, 5–12] versus 6 [interquartile range, 5–9] days; P <0.01) and more often experienced in‐hospital complications (27% versus 16%; P =0.01) mainly driven by cardiogenic shock and in‐hospital death (12% versus 7.6% and 6.5% versus 2.8%, respectively; both P <0.01). Survival analysis showed a higher mortality rate in neurological patients both at 60 days and long‐term (8.8% versus 3.4% and 23.5% versus 10.1%, respectively; both P <0.01). Neurological disorder was an independent predictor of both the 60‐day and long‐term mortality rate (odds ratio, 1.78 [95% CI, 1.07–2.97]; P =0.02; hazard ratio, 1.72 [95% CI, 1.33–2.22]; both P <0.001). Patients with neurodegenerative disorders had the worst prognosis among the neurological disease subgroups, whereas patients with TTS with migraine had a favorable prognosis (long‐term mortality rates, 29.2% and 9.7%, respectively). Conclusions: Neurological disorders identify a high‐risk TTS subgroup for enhanced short‐ and long‐term mortality rate. Careful recognition of neurological disorders and phenotype is therefore needed.

Takotsubo Syndrome (TTS) is a transient left ventricular systolic dysfunction that mimics acute coronary syndrome (ACS) with unclear pathophysiology. This study aims to evaluate blood cell subtypes in TTS and ACS on admission and their impact on outcome. Admission hemograms of 466 consecutive TTS patients from the German Italian Spanish (GEIST) registry were recorded and, after propensity matching, compared with admission hemograms of 280 ACS patients. Hemogram parameters, including neutrophil lymphocyte ratio (NLR) and lymphocyte monocyte ratio (LMR), were recorded. The primary endpoint was long-term all-cause mortality; the secondary endpoint was in-hospital complications (hemodynamic or electrical instability). Higher monocyte levels and lower LMR were found in TTS compared with ACS patients (0.63 ± 0.3 vs 0.51 ± 0.24 10³/μL, p < 0.001; 2.7 (IQR 1.8-3.9) vs 3.2 (IQR 2.2-4.4), p < 0.01). One hundred thirty-three out of 466 (28.5 %) TTS patients experienced in-hospital complications. In multivariate analysis, LVEF (OR 0.92, 95 %CI 0.90-0.95, p < 0.001), physical triggers (OR 2.59, 95 %CI 1.47-4.55, p < 0.01), and NLR (OR 1.06, 95 %CI 1.03-1.09, p < 0.001) were independently associated with in-hospital complications. At multivariate analysis, including age, gender, physical trigger, admission LVEF, hemoglobin levels and NLR (model 1) or LMR (model 2), NLR (OR 1.02, 95 %CI 1.01-1.03, p < 0.01) or LMR (OR = 0.89, 95 %CI 0.81-0.99, p < 0.04) were independent predictors of long-term mortality. NLR levels above the median value and LMR levels below the median value were associated with poor survival in TTS patients (log-rank p < 0.01). TTS is featured by higher levels of monocytes and lower LMR than ACS during hospital admission. NLR and LMR are independent predictors of long-term mortality in TTS.

Dystrophin (DMD) gene mutations are associated with skeletal muscle diseases such as Duchenne and Becker Muscular Dystrophy (BMD) and X-linked dilated cardiomyopathy (XL-DCM). To investigate the molecular basis of DCM in a 37-year-old woman. Clinical and genetic investigations were performed. Genetic testing was performed with whole exome sequencing (WES) using the Illumina platform. According to the standard protocol, a variant found by WES was confirmed in all available members of the family by bi-directional capillary Sanger resequencing. The effect of the variant was investigated by using an in silico prediction of pathogenicity. The index case was a 37-year-old woman diagnosed with DCM at the age of 33. A germline heterozygous A>G transversion at nucleotide 10103 in the DMD gene, leading to an aspartic acid–glycine substitution at the amino acid 3368 of the DMD protein (c.10103A>G p.Asp3368Gly), was identified and confirmed by PCR-based Sanger sequencing of the exon 70. In silico prediction suggests that this variant could have a deleterious impact on protein structure and functionality (CADD = 30). The genetic analysis was extended to the first-degree relatives of the proband (mother, father, and sister) and because of the absence of the variant in both parents, the p.Asp3368Gly substitution was considered as occurring de novo. Then, the direct sequencing analysis of her 8-year-old son identified as hemizygous for the same variant. The young patient did not present any signs or symptoms attributable to DCM, but reported asthenia and presented with bilateral calf hypertrophy at clinical examination. Laboratory testing revealed increased levels of creatinine kinase (maximum value of 19,000 IU/L). We report an early presentation of dilated cardiomyopathy in a 33-year-old woman due to a de novo pathogenic variant of the dystrophin (DMD) gene (p.Asp3368Gly). Genetic identification of this variant allowed an early diagnosis of a skeletal muscle disease in her son.

Inherited arrhythmia syndromes include several different diseases, as well as Brugada syndrome (BrS), long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and short QT syndrome (SQTS). They represent, together with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), an important cause of sudden cardiac death in the young. Most arrhythmia syndromes are inherited in an autosomal dominant manner, and genetic studies are suggested.: to report the spectrum of genetic variations and clinical phenotype in an Italian cohort with confirmed inherited arrhythmia syndromes and arrhythmogenic cardiomyopathy using whole-exome sequencing (WES). Patients with confirmed inherited arrhythmia syndromes and hereditary cardiomyopathy were recruited at the Cardiology Unit, University Polyclinic Hospital of Foggia, Italy and were included in this study. Genomic DNA samples were extracted from peripheral blood and conducted for WES. The variants were annotated using BaseSpace Variant Interpreter Annotation Engine 3.15.0.0 (Illumina). Reported variants were investigated using ClinVar, VarSome Franklin and a literature review. They were categorised agreeing to the criteria of the American College of Medical Genetics and Genomics. Overall, 62 patients were enrolled. Most of them had a clinical diagnosis of BrS (n 48, 77%). The remaining patients included in the present study had diagnosis of confirmed LQT (n 7, 11%), AR-DCM (n 4, 6.5%), ARVD (n 2, 3%), and SQT (n 1, 1.6%). Using the WES technique, 22 variants in 15 genes associated with Brugada syndrome were identified in 21 patients (34%). Among these, the SCN5A gene had the highest number of variants (6 variants, 27%), followed by KCNJ5 and CASQ2 (2 variants). Only one variant was identified in the remaining genes. In 27 patients with a clinical diagnosis of BrS, no gene variant was detected. In patients with confirmed LQT, SQT, 10 variants in 9 genes were identified. Among patients with ARVD and AR-DCM, 6 variants in 5 genes were found. Variants found in our cohort were classified as pathogenic (6), likely pathogenic (3), of uncertain significance (26), and benign (1). Two additional gene variants were classified as risk factors. In this study, 13 novel genetic variations were recognized to be associated with inherited arrhythmogenic cardiomyopathies. Our understanding of inherited arrhythmia syndromes continues to progress. The era of next-generation sequencing has advanced quickly, given new genetic evidence including pathogenicity, background genetic noise, and increased discovery of variants of uncertain significance. Although NGS study has some limits in finding the full genetic data of probands, large-scale gene sequencing can promptly be applied in real clinical practices, especially in inherited and possibly fatal arrhythmia syndromes.