Yael Peled

Titin Mutation in Familial Restrictive Cardiomyopathy

BACKGROUNDnFamilial restrictive cardiomyopathy (RCM) caused by a single gene mutation is the least common of the inherited cardiomyopathies. Only a few RCM-causing mutations have been described. Most mutations causing RCM are located in sarcomere protein genes which also cause hypertrophic cardiomyopathy (HCM). Other genes associated with RCM include the desmin and familial amyloidosis genes. In the present study we describe familial RCM with severe heart failure triggered by a de novo mutation in TTN, encoding the huge muscle filament protein titin.nnnMETHODS AND RESULTSnFamily members underwent physical examination, ECG and Doppler echocardiogram studies. The family comprised 6 affected individuals aged 12-35 years. Linkage to candidate loci was performed, followed by gene sequencing. Candidate loci/gene analysis excluded 18 candidate genes but showed segregation with a common haplotype surrounding the TTN locus. Sequence analysis identified a de novo mutation within exon 266 of the TTN gene, resulting in the replacement of tyrosine by cysteine. p.Y7621C affects a highly conserved region in the protein within a fibronectin-3 domain, belonging to the A/I junction region of titin. No other disease-causing mutation was identified in cardiomyopathy genes by whole exome sequencing.nnnCONCLUSIONSnOur study shows, for the first time, that mutations in TTN can cause restrictive cardiomyopathy. The giant filament titin is considered to be a determinant of a resting tension of the sarcomere and this report provides genetic evidence of its crucial role in diastolic function.

Feelings of indebtedness and guilt toward donor and immunosuppressive medication adherence among heart transplant (HTx) patients, as assessed in a cross‐sectional study with the Basel Assessment of Adherence to Immunosuppressive Medications Scale (BAASIS)

Nonadherence (NA) to immunosuppressive (IS) medications after organ transplant is a major risk factor for transplant failure, morbidity, and treatment costs. This study examined the association between feelings of indebtedness and guilt toward the donor, and IS medication adherence among HTx patients.

Metformin therapy reduces the risk of malignancy after heart transplantation

BACKGROUNDnMalignancy and diabetes mellitus (DM) cause significant morbidity and mortality after heart transplantation (HTx). Metformin, one of the most commonly used anti-diabetic drugs worldwide, has also been shown to exhibit anti-tumor activity. We therefore investigated the association between metformin therapy and malignancy after HTx.nnnMETHODSnThe study population comprised 237 patients who underwent HTx between 1991 and 2016 and were prospectively followed-up. Clinical data were recorded on prospectively designed forms. The primary outcome was any cancer recorded during 15 years of follow-up. Treatment with metformin and the development of DM after HTx were assessed as time-dependent factors in the analyses.nnnRESULTSnOf the 237 study patients, 85 (36%) had diabetes. Of the DM patients, 48 (56%) were treated with metformin. Kaplan-Meier survival analysis showed that, at 15 years after HTx, malignancy rate was 4% for DM patients treated with metformin, 62% for those who did not receive metformin and 27% for non-DM patients (log-rank test, p < 0.0001). Consistently, multivariate analysis showed that for DM patients, metformin therapy was independently associated with a significant 90% reduction (hazard ratio = 0.10; 95% confidence interval 0.02 to 0.40; p = 0.001) in the risk of the development of a malignancy. DM patients who were treated with metformin had a markedly lower risk (65%; p = 0.001) for the development of a malignancy or death after HTx as compared with non-DM patients.nnnCONCLUSIONSnOur findings suggest that metformin therapy is independently associated with a significant reduction in the risk of malignancy after HTx.

Quality of life and long‐term mortality in patients with advanced chronic heart failure treated with intermittent low‐dose intravenous inotropes in an outpatient setting

There are limited data on the effect of low‐dose, intermittent inotropic therapy in an outpatient setting on the quality of life (QOL) in patients with advanced refractory heart failure (HF) symptoms. We aimed to analyse the effect of this treatment modality on QOL and subsequent survival.

Sinus tachycardia is associated with impaired exercise tolerance following heart transplantation

Sinus tachycardia often presents in heart transplantation (HTx) recipients, but data on its effect on exercise performance are limited.

Differentiating Takotsubo cardiomyopathy from ST-segment elevation myocardial infarction

Background: Takotsubo cardiomyopathy affects between 1.7% and 2.2% of patients hospitalized with suspected acute coronary syndromes. Characterized by chest pain, electrocardiogram changes, and transient left ventricular apical wall motion abnormality, it is under-recognized and often misdiagnosed. Objectives: In order to better differentiate between St-segment myocardial infarction and Takotsubo cardiomyopathy, we developed a scoring system. Methods: Of the 82 patients enrolled with Takotsubo cardiomyopathy, 67 had ST-segment elevation on electrocardiogram and were compared with 79 ST-elevation myocardial infarction patients. A multi-variant logistic regression model was used to find factors independently associated with Takotsubo cardiomyopathy. The Platelets and Thrombosis in Sheba (PLATIS)-Takotsubo cardiomyopathy is based on a 10-point scoring system: stressful events (3), females (2), no history of diabetes mellitus (2), estimated left ventricular ejection fractionu2009≤u200940% on admission echo (1), positive troponin on admission (1), and no smoking (1). Patients with Takotsubo cardiomyopathy were older (66u2009±u200911 vs 60u2009±u200911u2009years, pu2009<u20090.001), predominantly female (90% vs 15%, pu2009<u20090.001), with a lower incidence of diabetes mellitus, dyslipidemia, and smoking. Nevertheless, in-hospital mortality was similar in both groups. Results: In a multivariate logistic regression analysis, the average Platelets and Thrombosis in Sheba-Takotsubo cardiomyopathy scoring was significantly higher in Takotsubo cardiomyopathy compared with ST-elevation myocardial infarction patients (8.35u2009±u20091.7 vs 3.42u2009±u20091.6, pu2009<u20090.001). With an overall score ofu2009≥7, the receiver-operating characteristic curve was 0.82 with a sensitivity of 75% and a specificity of 89% (positive predictive valueu2009=u200985% and negative predictive valueu2009=u200980%). Conclusion: The Takotsubo cardiomyopathy scoring system is a simple, reliable tool that can assist in diagnosing and differentiating between patients with Takotsubo cardiomyopathy and those with ST-elevation myocardial infarction.

Donor-recipient ethnic mismatching impacts short- and long-term results of heart transplantation

The impact of donor‐recipient ethnic matching on heart transplantation (HT) has been poorly studied with inconclusive results. We aimed to investigate the impact of ethnic matching on HT outcomes in Israeli multiethnic patients.

Intrapatient variability in tacrolimus trough levels after solid organ transplantation varies at different postoperative time periods

We thank Lemaitre et al1 for their letter regarding our manuscript describing the association between intrapatient variability (IPV) of tacrolimus (TAC) trough levels and long-term outcomes in heart transplant (HTx) patients. Indeed, in our study2 we found that high TAC through level variability at 3-12 months post-HTx was associated with higher rates of graft rejection at odds ratio (OR) of 8.52. However, we wish to clarify that due to the wide 95% confidence interval (1.63-44.53), the minimum odds might also be 1.63 and hence prefer not to define the risk of high TAC through level variability as tremendous1 . This article is protected by copyright. All rights reserved.

High tacrolimus trough level variability is associated with rejections after heart transplant

Tacrolimus, the major immunosuppressant after heart transplant (HTx) therapy, is a narrow therapeutic index drug. Hence, achieving stable therapeutic steady state plasma concentrations is essential to ensure efficacy while avoiding toxicity. Whether high variability in steady state concentrations is associated with poor outcomes is unknown. We investigated the association between tacrolimus trough level variability during the first year post‐HTx and outcomes during and beyond the first postoperative year. Overall, 72 patients were analyzed for mortality, of whom 65 and 61 were available for rejection analysis during and beyond the first year post‐HTx, respectively. Patients were divided into high (median >28.8%) and low tacrolimus level variability (<28.8%) groups. Mean tacrolimus levels did not differ between the groups (12.7 ± 3.4 ng/mL vs 12.8 ± 2.4 ng/mL, P = .930). Patients in the high variability group exhibited higher long‐term rejection rate (median total rejection score: 0.33 vs 0, P = .04) with no difference in rejection scores within the first year post‐HTx. Multivariate analysis showed that high tacrolimus trough level variability was associated with >8‐fold increased risk for any rejection beyond the first year post‐HTx (P = .011). Mortality was associated only with cardiovascular complications (P = .018), with no effect of tacrolimus through level variability.

Relation of Atrial Premature Complexes During Exercise Stress Testing to the Risk for the Development of Atrial Fibrillation in Patients Undergoing Cardiac Rehabilitation

Atrial fibrillation (AF) is associated with increased morbidity and mortality. We sought to determine whether atrial premature complexes (APCs) detected during a standard exercise stress test (EST) in patients undergoing cardiac rehabilitation (CR) are associated with an increased risk of AF. The present study population comprised 6,523 consecutive patients without prior AF who participated in a CR program in a tertiary medical center in years 2009 to 2016. Multivariate analysis was used to identify the association between APCs during the baseline EST at CR and the risk for the development of AF over a mean follow-up period of 2.5xa0years. A total of 213 (3.7%) patients had APCs during their EST. Despite being older (mean age 63 ± 13xa0years old vs 58 ± 13; p <0.001, respectively), no other statistically significant differences were documented. Kaplan-Meier survival analysis showed that the rate of AF development during follow-up was significantly higher in patients with APCs at baseline EST (11%) as compared with those without APCs (5%; log-rank p <0.001 for the overall difference during follow-up). Consistently, multivariate analysis showed that patients with APCs showed >twofold increase risk for AF compared with those without APCs (hazard ratio 2.1; 95% confidence interval 1.36 to 3.25; p <0.001). In conclusion, our findings suggest that APCs detected during EST in patients participating in the CR program independently predict AF and can be used to improve risk stratification in this population.