Renin angiotensin system inhibitors and outcome in patients with Takotsubo syndrome: a propensity score analysis of the GEIST registry.

BACKGROUND: Few data are available on long-term drug therapy and its potential prognostic impact after Takotsubo syndrome (TTS). Aim of the study is to evaluate clinical characteristics and long-term outcome of TTS patients on Renin Angiotensin system inhibitors (RASi). METHODS: TTS patients were enrolled in the international multicenter GEIST (GErman Italian Spanish Takotsubo) registry. Median follow-up was 31 (Interquartile range 12-56) months. Comparison of RASi treated vs. untreated patients was performed within the overall population and after 1:1 propensity score matching for age, sex, comorbidities, type of trigger and in-hospital complications. REGISTRATION: clinicaltrials.gov, NCT04361994, https://clinicaltrials.gov/study/NCT04361994 RESULTS: Of the 2453 TTS patients discharged alive, 1683 (68%) received RASi therapy. Patients with RASi were older (age 71±11 vs 69±13 years, p=0.01), with higher prevalence of hypertension (74%vs53%, p<0.01) and diabetes (19%vs15%, p=0.01), higher admission left ventricular ejection fraction (LVEF) (41±11% vs 39±12%, p<0.01) and lower rates of in-hospital complications (18.9% vs 29.6%, p<0.01). At multivariable analysis, RASi therapy at discharge was independently associated with lower mortality (HR 0.63, 95%CI 0.45-0.87, p<0.01). Survival analysis showed that at long term, patients treated with RASi had lower mortality rates in the overall cohort (log-rank p=0.001). However, this benefit was not found among patients treated with RASi in the matched cohort (log-rank p=0.168). Potential survival benefit of RASi were present, both in the overall and matched cohort, in two subgroups: patients with admission LVEF ≤40% (HR 0.54 95%CI 0.38-0.78, p=0.001; HR 0.59, 95%CI 0.37-0.95, p=0.030) and diabetes (HR 0.41, 95%CI 0.23-0.73, p= 0.002; HR 0.41, 95%CI 0.21-0.82, p=0.011). CONCLUSIONS: Long-term therapy with RASi after a TTS episode was not associated with lower mortality rates at propensity score analysis. However, potential survival benefit can be found among patients with admission LVEF ≤40% or diabetes.

Multidisciplinary approach in cardiomyopathies: From genetics to advanced imaging.

Cardiomyopathies are myocardial diseases characterized by mechanical and electrical dysfunction of the heart muscle which could lead to heart failure and life-threatening arrhythmias. Certainly, an accurate anamnesis, a meticulous physical examination, and an ECG are cornerstones in raising the diagnostic suspicion. However, cardiovascular imaging techniques are indispensable to diagnose a specific cardiomyopathy, to stratify the risk related to the disease and even to track the response to the therapy. Echocardiography is often the first exam that the patient undergoes, because of its non-invasiveness, wide availability, and cost-effectiveness. Cardiac magnetic resonance imaging allows to integrate and implement the information obtained with the echography. Furthermore, cardiomyopathies' genetic basis has been investigated over the years and the list of genetic mutations deemed potentially pathogenic is expected to grow further. The aim of this review is to show echocardiographic, cardiac magnetic resonance imaging, and genetic features of several cardiomyopathies: dilated cardiomyopathy (DMC), hypertrophic cardiomyopathy (HCM), arrhythmogenic cardiomyopathy (ACM), left ventricular noncompaction cardiomyopathy (LVNC), myocarditis, and takotsubo cardiomyopathy.

De Novo p.Asp3368Gly Variant of Dystrophin Gene Associated with X-Linked Dilated Cardiomyopathy and Skeletal Myopathy: Clinical Features and In Silico Analysis.

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.

Beta-blockers and renin-angiotensin system inhibitors for Takotsubo syndrome recurrence: a network meta-analysis.

INTRODUCTION: Takotsubo syndrome (TTS) is an acute heart failure syndrome, featured by transient left ventricular systolic dysfunction. Recurrences of TTS are not infrequent and there is no standard preventive therapy. The aim of this study was to evaluate in a network meta-analysis if beta-blockers (BB) and ACE inhibitors/angiotensin receptor blockers (ACEi/ARBs), in combination or not, can effectively prevent TTS recurrences. METHODS: We performed a systematic network meta-analysis, using MEDLINE/EMBASE and the Cochrane Central Register of Controlled Trials for clinical studies published between January 2010 and September 2022. We considered all those studies including patients receiving medical therapy with BB, ACEi/ARBs. The primary outcome was TTS recurrence. RESULTS: We identified 6 clinical studies encompassing a total of 3407 patients with TTS. At 40±10 months follow-up, TTS recurrence was reported in 160 (4.7%) out of 3407 patients. Mean age was 69.8±2 years and 394 patients (11.5%) out of 3407 were male. There were no differences in terms of TTS recurrence when comparing ACEi/ARBs versus control (OR 0.83; 95% CI 0.47 to 1.47, p=0.52); BB versus control (OR 1.01; 95% CI 0.63 to 1.61, p=0.96) and ACEi/ARBs versus BB (OR 0.88; 95% CI 0.51 to 1.53, p=0.65).Combination of BB and ACEi/ARBs was also not effective in reducing the risk of recurrence versus control (OR 0.91; 95% CI 0.58 to 1.43, p=0.68) vs ACEi/ARBs (OR 0.79; 95% CI 0.46 to 1.34, p=0.38)) and vs BB (OR 0.77; 95% CI 0.49 to 1.21, p=0.26). CONCLUSIONS: Our study did not find sufficient statistical evidence regarding combination therapy with BB and ACEi/ARBs in reduction of TTS recurrence.

Impact of Frailty on Outcome of Older Patients With Non-ST Elevation Acute Myocardial Infarction Who Undergo Percutaneous Coronary Intervention.

Frailty status is linked with a poorer clinical outcome, and patients with frailty are often less revascularized, even with percutaneous coronary intervention (PCI). We therefore sought to assess the impact of frailty on the clinical outcome of older patients with non-ST elevation acute myocardial infarction (NSTEMI) who underwent PCI. We prospectively enrolled 141 consecutive older patients (>75 years) admitted for NSTEMI; 104 patients underwent PCI (35 with frailty, 69 without frailty), and 37 were not revascularized (22 with frailty, 15 without). Patients with frailty were older, less frequently male, more affected by dementia and severe left ventricular dysfunction, and less treated with PCI; patients treated with PCI were younger and less affected by dementia. Thirty-day mortality rates were proportionally higher, from 3% in patients without frailty treated with PCI, to 7% in patients without frailty not treated with PCI, 17% in patients with frailty treated with PCI, and 48% in patients with frailty not treated with PCI (p <0.05). Similarly, 6-month mortality rates were proportionally higher (12%, 29%, 37%, and 71%). At multivariable analysis, frail status was associated to a sixfold increased risk of mortality at 30 days; at 6 months, frail status was associated to a 3.4-fold risk of death (p <0.01), but PCI was also associated to a lower risk of mortality (odds ratio 0.2, p <0.01). In an observational study in older patients with NSTEMI, frail status is associated to a poorer outcome, whereas PCI is associated to a better long-term outcome. A careful selection of patient suitable for revascularization by PCI may be useful in improving outcomes of older patients with frailty with NSTEMI.

Investigation of a Large Kindred Reveals Cardiac Calsequestrin (CASQ2) as a Cause of Brugada Syndrome.

BACKGROUND: Brugada syndrome (BrS) is an inherited primary channelopathy syndrome associated with the risk of ventricular fibrillation (VF) and sudden cardiac death in a structurally normal heart. AIM OF THE STUDY: The aim of this study was to clinically and genetically evaluate a large family with severe autosomal dominant Brugada syndrome. METHODS: Clinical and genetic studies were performed. Genetic analysis was conducted with NGS technologies (WES) using the Illumina instrument. According to the standard procedure, variants found by WES were confirmed in all available families by Sanger sequencing. The effect of the variants was studied by using in silico prediction of pathogenicity. RESULTS: The proband was a 52-year-old man who was admitted to the emergency department for syncope at rest. WES of the index case identified a heterozygous VUS CASQ2, c.532T>C, p.(Tyr178His). We studied the segregation of the variation in all pedigree members. All the patients were heterozygous for the variation CASQ2 p.(Tyr178His), whereas the remaining healthy individuals in the family were homozygous for the normal allele. Structural analysis of CASQ2 p.(Tyr178His) was performed and revealed an important effect of the missense variation on monomer stability. The CASQ2 Tyr180 residue is located inside the sarcoplasmic reticulum (SR) junctional face membrane interaction domain and is predicted to disrupt filamentation. CONCLUSIONS: Our data suggest that the p.Tyr178His substitution is associated with BrS in the family investigated, affecting the stability of the protein, disrupting filamentation at the interdimer interface, and affecting the subsequent formation of tetramers and polymers that contain calcium-binding sites.

Takotsubo syndrome outcomes predicted by thyroid hormone signature: insights from cluster analysis of a multicentre registry.

BACKGROUND: Recently, abnormal thyroid function was shown to be common in patients with Takotsubo syndrome (TTS), being classified into "endocrine-type" and "stress-type" responses. The aim of this study was to investigate the association between thyroid homeostasis and TTS in a larger international registry. METHODS: In total 288 patients with TTS were enrolled through the GEIST multicentre registry from Germany, Italy and Spain. Thyrotropin (TSH), free T4 (FT4) and free T3 (FT3) concentrations were analysed at admission. Data were collected both retrospectively and prospectively from 2017 onwards. Primary endpoints included in-hospital and all-cause fatality, determined by cluster analysis using an unsupervised machine learning algorithm (k-medoids). FINDINGS: Three clusters were identified, classifying TTS with low (TSLT), high (TSHT) and normal (TSNT) thyroid output, based on TSH and FT4 levels in relation to the median thyroid's secretory capacity (SPINA-GT). Although TSH and FT4 concentrations were similar among survivors and non-survivors, these clusters were significantly associated with patient outcomes. In the longitudinal Kaplan-Meier analysis including in- and out-of-hospital survival, the prognosis related to concentrations of TSH, FT4, and FT3 as well as SPINA-GT, deiodinase activity (SPINA-GD) and clusters. Patients in the TSHT cluster and with cardiogenic shock had a lower initial left ventricular ejection fraction (LVEF). INTERPRETATION: This study suggests that thyroid hormones may impact the evolution and prognosis of TTS. The findings indicate that thyroid-derived biomarkers may help identify high-risk patients and pave the way for novel personalized and preventive therapeutic options. FUNDING: This research was not funded by any public, commercial, or not-for-profit agencies.

Neurological Disorders in Takotsubo Syndrome: Clinical Phenotypes and Outcomes.

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.

A Novel DLG1 Variant in a Family with Brugada Syndrome: Clinical Characteristics and In Silico Analysis.

BACKGROUND: Brugada syndrome (BrS) is an inherited primary channelopathy syndrome associated to sudden cardiac death. Overall, variants have been identified in eighteen genes encoding for ion channel subunits and seven genes for regulatory proteins. Recently, a missense variant in DLG1 has been found within a BrS phenotype-positive patient. DLG1 encodes for synapse associated protein 97 (SAP97), a protein characterized by the presence of multiple domains for protein-protein interactions including PDZ domains. In cardiomyocytes, SAP97 interacts with Nav1.5, a PDZ binding motif of SCN5A and others potassium channel subunits. AIM OF THE STUDY: To characterize the phenotype of an Italian family with BrS syndrome carrying a DLG1 variant. METHODS: 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 members of the family by bi-directional capillary Sanger resequencing. The effect of the variant was investigated by using in silico prediction of pathogenicity. RESULTS: The index case was a 74-year-old man with spontaneous type 1 BrS ECG pattern that experienced syncope and underwent ICD implantation. WES of the index case, performed assuming a dominant mode of inheritance, identified a heterozygous variant, c.1556G>A (p.R519H), in the exon 15 of the DLG1 gene. In the pedigree investigation, 6 out of 12 family members had the variant. Carriers of the gene variant all had BrS ECG type 1 drug induced and showed heterogeneous cardiac phenotypes with two patients experiencing syncope during exercise and fever, respectively. The amino acid residue #519 lies near a PDZ domain and in silico analysis suggested a causal role for the variant. Modelling of the resulting protein structure predicted that the variant disrupts an H-bond and a likelihood of being pathogenic. As a consequence, it is likely that a conformational change affects protein functionality and the modulating role on ion channels. CONCLUSIONS: A DLG1 gene variant identified was associated with BrS. The variant could modify the formation of multichannel protein complexes, affecting ion channels to specific compartments in cardiomyocytes.

Trigger-Associated Clinical Implications and Outcomes in Takotsubo Syndrome: Results From the Multicenter GEIST Registry.

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.