Y. Peled

A Novel Titin Mutation in Adult-Onset Familial Dilated Cardiomyopathy

Familial dilated cardiomyopathy is a major cause of advanced heart failure and heart transplantation. In most families, the disease-causing mutation is unknown, and relatives should therefore undergo periodic screening to facilitate early diagnosis and therapy. In the present study, we describe a novel titin truncation mutation causing adult-onset familial dilated cardiomyopathy in an Israeli Arab family. The family members underwent physical examination, electrocardiography, and Doppler echocardiography. Linkage to candidate loci was performed, followed by gene sequencing. We identified 13 clinically affected family members (8 men and 5 women, mean age 47 ± 12 years). Compared with their healthy first-degree relatives, the affected relatives had a larger end-diastolic left ventricular dimension (60 ± 10 vs 49 ± 4 mm, p <0.001), lower ejection fraction (43 ± 11% vs 60 ± 6%, p <0.001), and markedly higher end-systolic volume indexes but no difference in wall thickness or diastolic function. The linkage studies or direct sequencing excluded LMNA, MYH7, TNNT2, TNNI3, SCN5A, DES, SGCD, ACTC, PLN, and MYH6 but established linkage to the TTN locus at chromosome 2q31, yielding a maximum (2-point) LOD score of 3.44. Sequence analysis identified an insertion (c.58880insA), causing protein truncation after 19,628 amino acids (p.S19628IfsX1). No founder effect was found among the Israeli Arabs. In conclusion, titin is a giant protein with a key role in sarcomere assembly, force transmission, and maintenance of resting tension. Although some mutations result in skeletal myopathy, others cause isolated, maturity-onset cardiomyopathy.

The impact of gender mismatching on early and late outcomes following heart transplantation: Gender mismatching impacts heart transplantation outcomes

The role of donor/recipient gender matching on the long‐term rejection process and clinical outcomes following heart transplantation (HT) outcomes is still controversial. We aim to investigate the impact of gender matching on early and long‐term outcome HT.

Elevated Admission Potassium Levels and 1-Year and 10-Year Mortality Among Patients With Heart Failure

Background: Limited, contradictory data exist regarding the effect of hyperkalemia on both short‐ and long‐term all‐cause mortality among hospitalized patients with heart failure (HF). Methods: We analyzed 4,031 patients who were enrolled in the Heart Failure Survey in Israel. The study patients were grouped into 3 different potassium (K) categories. Multivariate analysis was used to determine the association of potassium levels as well as 1‐ and 10‐year all‐cause mortality. Results: A total of 3,349 patients (83%) had K < 5 mEq/L, whereas 461 patients (11%) had serum K ≥ 5 mEq/L but≤ 5.5 mEq/L and 221 patients (6%) had K > 5.5 mEq/L. Survival analysis showed that 1‐year mortality rates were significantly higher among patients with K > 5.5 mEq/L (40%) and those with serum K ≥ 5 mEq/L but ≤ 5.5 mEq/L (34%) compared to those with K < 5 mEq/L (27%); (all log rank P < 0.01). Similarly, 10‐year mortality rates among those with K > 5.5 mEq/L were 92%, whereas among those with serum K ≥ 5 mEq/L but ≤ 5.5 mEq/L rates were 88%, and in those with K < 5 mEq/L rates were 82%; (all log rank P < 0.001). Consistently, multivariate analysis showed that compared to patients with K < 5 mEq/L, patients with K > 5.5 mEq/L had an independently 51% and 31% higher mortality risk at 1 year and 10 years, respectively (1‐year hazard ratio = 1.51, 95% CI: 1.04‐2.2; 10‐years hazard ratio = 1.31, 95% CI: 1.035‐1.66), whereas patients with serum K ≥ 5 mEq/L but ≤ 5.5 mEq/L had comparable adjusted mortality risk to patients with K < 5 mEq/L at 1 and 10 years. Conclusions: Among hospitalized patients with HF, admission K > 5.5 mEq/L was independently associated with increased short‐ and long‐term mortality, whereas serum K ≥ 5 mEq/L but ≤ 5.5 mEq/L was not independently associated with worse outcomes.

Pharmacokinetics and Immune Reconstitution Following Discontinuation of Thiopurine Analogues: Implications for Drug Withdrawal Strategies

Background and Aims Discontinuation of thiopurine analogues is common prior to live vaccines, during infection or when de-escalating therapy. Data regarding clearance of active metabolites and immune re-constitution is scant. We aimed to determine drug elimination and immune re-constitution following thiopurine cessation. Methods The elimination kinetics of 6-thioguanine nucleotides (6-TGN) were determined in nine inflammatory bowel disease [IBD] patients discontinuing thiopurines. Immune reconstitution was evaluated by toxic shock syndrome toxin 1 [TSST1] or anti-CD3 [OKT3]-induced CD4+ T-cell proliferation, following an initial exposure to TSST1 and 6-mercaptopurine [6MP], separately or combined. Results All patients discontinuing thiopurines displayed first-order elimination kinetics of 6-TGN, with a median elimination half-life of 6.8 days [interquartile range 5.9-8.4]. Resting CD4+ T-cells exposed to 6MP preserved their response to subsequent polyclonal or Vβ2+-preferential stimulation. By contrast, exposure of TSST1-activated CD4+ T-cells to 6MP inhibited their subsequent Vβ2+clonal response to further stimulation [p = 0.008], whereas overall response to further non-Vβ2-selective stimulation with OKT3 was unaltered [p = 0.9]. Conclusions Upon 6MP/azathioprine discontinuation, a 6-TGN elimination half-life of less than 10 days is expected in most patients. Immune reconstitution, however, may take longer for T-cell clones exposed to stimulation during thiopurine treatment. These findings may be useful when considering thiopurine cessation.

The Association of Body Mass Index and 20-Year All-Cause Mortality Among Patients With Stable Coronary Artery Disease

BACKGROUND Limited data exist regarding the long-term association of body mass index (BMI) and all-cause mortality among patients with stable coronary artery disease (CAD). Accordingly, the aim of this study is to explore the association between BMI and long-term all-cause mortality among patients with stable CAD. METHODS Our study included 15,357 patients with stable CAD who were enrolled in the Bezafibrate Infarction Prevention (BIP) registry between February, 1990 and October1992, and subsequently followed-up through December 2014. RESULTS 5,051 (33%) patients were classified as normal weight (BMI 18.5-24.99kg/m2), while 7,841 (51%) patients were classified as overweight (BMI 25-29.99kg/m2), and 2,465 (16%) as obese (BMI≥30). Kaplan-Meier survival analysis showed that at 20 years of follow-up the rate of all-cause mortality was significantly higher among obese patients (67%) compared to overweight (61%) and normal weight (61%); log rank p-value for the overall difference <0.001. Multivariable analysis showed that obese patients had an independently 12% greater mortality risk compared to normal weight patients (HR=1.12; 95% CI 1.02-1.23; p=0.02), whereas, overweight patients experienced a similar mortality risk as normal weight patients (HR=0.99; 95% CI 0.92-1.06; p=0.76). The mortality risk associated with obesity was pronounced among patients younger than 65 years (p-value for interaction<0.05). CONCLUSIONS Our findings indicate that obesity is independently associated with increased risk for long-term mortality among patients with stable coronary artery disease, whereas overweight does not appear to confer an additional risk in this population.

Risk of Early, Intermediate, and Late Rejection Following Heart Transplantation: Trends Over the Past 25 Years and Relation to Changes in Medical Management Tertiary Center Experience: The Sheba Heart Transplantation Registry

To explore the trends in the risk for rejection following heart transplantation (HT) over the past 25 years, and their relation to changes in medical management.