Reduced kinase function in two ultra-rare TNNI3K variants in families with congenital junctional ectopic tachycardia.

Genetic missense variants in TNNI3K, encoding troponin-I interacting kinase, have been associated with dilated cardiomyopathy (DCM) and observed in families with supraventricular tachycardias (SVT). Previously, a family harboring the TNNI3K-c.1615A > G (p.Thr539Ala) variant presented with congenital junctional ectopic tachycardia (CJET), an arrhythmia that arises from the atrioventricular (AV) node and His bundle. However, this was a relatively small four-generational family with limited genetic testing (N = 3). We here describe a multigenerational family with CJET harboring a novel ultra-rare TNNI3K variant: TNNI3K-c.1729C > T (p.Leu577Phe). Of all 18 variant carriers, 13 individuals presented with CJET, resulting in a genetic penetrance of 72%. In addition, CJET is reported in another small family harboring TNNI3K-c.2225C > T (p.Pro742Leu). Similar to the previously published CJET family, both TNNI3K variants demonstrate a substantial reduction of kinase activity. Our study contributes novel evidence supporting the involvement of TNNI3K genetic variants as significant contributors to CJET, shedding light on potential mechanisms underlying this cardiac arrhythmia.

Genetic Burden of TNNI3K in Diagnostic Testing of Patients With Dilated Cardiomyopathy and Supraventricular Arrhythmias.

BACKGROUND: Genetic variants in TNNI3K (troponin-I interacting kinase) have previously been associated with dilated cardiomyopathy (DCM), cardiac conduction disease, and supraventricular tachycardias. However, the link between TNNI3K variants and these cardiac phenotypes shows a lack of consensus concerning phenotype and protein function. METHODS: We describe a systematic retrospective study of a cohort of patients undergoing genetic testing for cardiac arrhythmias and cardiomyopathy including TNNI3K. We further performed burden testing of TNNI3K in the UK Biobank. For 2 novel TNNI3K variants, we tested cosegregation. TNNI3K kinase function was estimated by TNNI3K autophosphorylation assays. RESULTS: We demonstrate enrichment of rare coding TNNI3K variants in DCM patients in the Amsterdam cohort. In the UK Biobank, we observed an association between TNNI3K missense (but not loss-of-function) variants and DCM and atrial fibrillation. Furthermore, we demonstrate genetic segregation for 2 rare variants, TNNI3K-p.Ile512Thr and TNNI3K-p.His592Tyr, with phenotypes consisting of DCM, cardiac conduction disease, and supraventricular tachycardia, together with increased autophosphorylation. In contrast, TNNI3K-p.Arg556_Asn590del, a likely benign variant, demonstrated depleted autophosphorylation. CONCLUSIONS: Our findings demonstrate an increased burden of rare coding TNNI3K variants in cardiac patients with DCM. Furthermore, we present 2 novel likely pathogenic TNNI3K variants with increased autophosphorylation, suggesting that enhanced autophosphorylation is likely to drive pathogenicity.

Retrospective Review on the Safety and Efficacy of Nitrofurantoin for the Treatment of Cystitis in the Veteran Population With or Without Renal Insufficiency.

BACKGROUND: The emergence of antimicrobial resistance in uropathogens has generated interest in the use of nitrofurantoin in controversial populations, such as in males and those with renal dysfunction. The purpose of this study was to compare the efficacy and safety of nitrofurantoin for the treatment of cystitis in males and females with variable degrees of renal dysfunction. METHODS: A retrospective chart review was conducted in adult patients who received nitrofurantoin for acute cystitis in the outpatient setting. The primary outcome was clinical cure compared between males and females and across various renal function groups (creatinine clearances [CrCl] >60 mL/min, 30-60 mL/min, and <30 mL/min) following nitrofurantoin treatment. The secondary outcome was adverse events. RESULTS: A total of 446 patients were included, with 278 females and 168 males. The overall clinical cure rate was 86.5% (95% CI, 83.0%-89.4%; n = 386). The clinical cure rate did not vary between genders (odds ratio [OR], 0.6; 95% CI 0.35-1.04; P = .085) or between patients with a CrCl >60 mL/min compared with those with CrCl 30-60 mL/min (OR, 1.01; 95% CI, 0.40-2.44; P = 1). The 1 patient with a CrCl <30 mL/min was not included in the analysis. A history of benign prostatic hyperplasia (OR, 0.5; 95% CI, 0.26-0.99; P = .045) or cirrhosis (OR, 0.21; 95% CI, 0.06-0.82; P = .025) was associated with decreased odds of clinical cure. Adverse events occurred in 2% (n = 9) of patients. CONCLUSIONS: There was no statistically significant difference in clinical cure with nitrofurantoin between genders or various renal functions.

The Diverse Roles of TNNI3K in Cardiac Disease and Potential for Treatment.

In the two decades since the discovery of TNNI3K it has been implicated in multiple cardiac phenotypes and physiological processes. TNNI3K is an understudied kinase, which is mainly expressed in the heart. Human genetic variants in TNNI3K are associated with supraventricular arrhythmias, conduction disease, and cardiomyopathy. Furthermore, studies in mice implicate the gene in cardiac hypertrophy, cardiac regeneration, and recovery after ischemia/reperfusion injury. Several new papers on TNNI3K have been published since the last overview, broadening the clinical perspective of TNNI3K variants and our understanding of the underlying molecular biology. We here provide an overview of the role of TNNI3K in cardiomyopathy and arrhythmia covering both a clinical perspective and basic science advancements. In addition, we review the potential of TNNI3K as a target for clinical treatments in different cardiac diseases.

Retrospective Review on the Safety and Efficacy of Direct Oral Anticoagulants Compared With Warfarin in Patients With Cirrhosis.

PURPOSE: Patients with cirrhosis needing anticoagulation therapy have historically been prescribed warfarin. New retrospective research has concluded that in patients with cirrhosis direct oral anticoagulants (DOACs) have similar or lower bleeding rates compared with that of warfarin. This study compares the safety and efficacy of DOACs with that of warfarin in patients with cirrhosis. METHODS: A retrospective chart review was conducted in adult patients with cirrhosis taking either apixaban, dabigatran, edoxaban, rivaroxaban, or warfarin. Exclusion criteria consisted of patients prescribed triple antithrombotic therapy (dual antiplatelet therapy plus an anticoagulant) and indications other than nonvalvular atrial fibrillation (NVAF) and venous thromboembolism (VTE). The primary endpoint was all-cause bleeding, and the secondary endpoints were failed efficacy and major bleeding as defined by the International Society on Thrombosis and Haemostasis in 2005. Failed efficacy was a combination endpoint including the development of VTE, stroke, myocardial infarction and/or death. Patient data were collected from the Computerized Patient Record System from October 31, 2014 to October 31, 2018. RESULTS: The study included 42 patients in the DOAC group and 37 patients in the warfarin group. Baseline characteristics were not significantly different between groups except for the Child-Turcotte-Pugh score, Model for End-Stage Liver Disease score, international normalized ratio, and number of days on anticoagulation therapy. The rate of all-cause bleeding in the DOAC group was 16.7% (n = 7) vs 21.6% (n = 8) in the warfarin group (P = .7). The rate of major bleeding in the DOAC group was 2.4% (n = 1) vs 5.4% (n = 2) in the warfarin group (P = .6). The rate of failed efficacy in the DOAC group was 7.1% (n = 3) compared with 8.1% (n = 3) in the warfarin group (P = .9). Subgroup analysis of allcause bleeding did not identify any significant trends between groups. CONCLUSIONS: There were no statistically significant differences identified between the rates of all-cause bleeding, major bleeding, and failed efficacy between the DOACs and warfarin groups. DOACs may be a safe alternative to warfarin in patients with cirrhosis requiring anticoagulation for NVAF or VTE, but large randomized trials are required to confirm these results.

Surgical outcomes associated with a sutureless drainage valve implantation procedure in patients with refractory glaucoma.

PURPOSE: To evaluate the safety and efficacy profile of a sutureless procedure for drainage valve implantation with combined cataract removal and/or endoscopic cyclophotocoagulation (ECP). MATERIALS AND METHODS: A retrospective case series study of consecutive surgeries for Ahmed glaucoma valve (AGV; New World Medical) implantation in a 1-year period was analyzed. The surgery was performed using a Tisseel fibrin sealant (Baxter Healthcare Corporation) in place of sutures. Some subsets within the case series also included a cataract extraction with intraocular lens (CEIOL) insertion and/or ECP (Endo Optiks) within the same procedure. Primary outcomes for this study including efficacy (IOP change, reduction in medications) and safety (complications and reoperations) were measured out to 3 years. Comparisons between subsets were made using ANOVA with post hoc Tukey's pairwise tests. RESULTS: One hundred twenty-two eyes of 99 patients underwent sutureless AGV implantation surgery. Of the 122, 18 had an AGV implantation only, 46 had an AGV + CEIOL, 35 had an AGV + ECP, and 23 had an AGV + CEIOL + ECP. In total, there was a significant decrease in IOP (P<0.0001) and number of glaucoma medications (P≤0.0054) at each postoperative visit. In a one-way ANOVA, there were no significant differences in mean IOP between the different subsets of surgeries (P>0.05); 10.7% and 14.8% of eyes required a reoperation either for a complication or for uncontrolled glaucoma, respectively. CONCLUSION: Sutureless valve implantation is associated with a significant reduction in IOP percentage and medication use after the procedure with a safety profile comparable with other glaucoma surgeries.