Murthy, Vishakantha

This study uncovers a previously unrecognized role for NAV3 in TGF-β1-driven cardiac fibroblast activation. We show that NAV3 facilitates profibrotic remodeling through noncanonical signaling and cell cycle arrest, independently of SMAD2/3. These findings position NAV3 as a novel regulator of fibroblast phenotype and a potential modulator of cardiac fibrosis.

BACKGROUND: Dilated cardiomyopathy (DCM) is a major cause of heart failure and carries a high mortality rate. Myocardial recovery in DCM-related heart failure patients is highly variable, with some patients having little or no response to standard drug therapy. A genome-wide association study may agnostically identify biomarkers and provide novel insight into the biology of myocardial recovery in DCM. METHODS: A genome-wide association study for change in left ventricular ejection fraction was performed in 686 White subjects with recent-onset DCM who received standard pharmacotherapy. Genome-wide association study signals were subsequently functionally validated and studied in relevant cellular models to understand molecular mechanisms that may have contributed to the change in left ventricular ejection fraction. RESULTS: The genome-wide association study identified a highly suggestive locus that mapped to the 5′-flanking region of the CDCP1 (CUB [complement C1r/C1s, Uegf, and Bmp1] domain containing protein 1) gene (rs6773435; P =7.12×10 −7 ). The variant allele was associated with improved cardiac function and decreased CDCP1 transcription. CDCP1 expression was significantly upregulated in human cardiac fibroblasts (HCFs) in response to the PDGF (platelet-derived growth factor) signaling, and knockdown of CDCP1 significantly repressed HCF proliferation and decreased AKT (protein kinase B) phosphorylation. Transcriptomic profiling after CDCP1 knockdown in HCFs supported the conclusion that CDCP1 regulates HCF proliferation and mitosis. In addition, CDCP1 knockdown in HCFs resulted in significantly decreased expression of soluble ST2 (suppression of tumorigenicity-2), a prognostic biomarker for heart failure and inductor of cardiac fibrosis. CONCLUSIONS: CDCP1 may play an important role in myocardial recovery in recent-onset DCM and mediates its effect primarily by attenuating cardiac fibrosis.

Background TAILOR‐PCI (Tailored Antiplatelet Initiation to Lessen Outcomes due to decreased Clopidogrel Response After Percutaneous Coronary Intervention) studied genotype‐guided selection of antiplatelet therapy after percutaneous coronary intervention versus conventional therapy with clopidogrel. The presence of CYP2C19 loss‐of‐function alleles in patients treated with clopidogrel may be associated with increased risk for ischemic events. We report a prespecified sex‐specific analysis of genotyping and associated cardiovascular outcomes from this study. Methods and Results Associations between sex and major adverse cardiac events (MACE: cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia) and Bleeding Academic Research Consortium (BARC) bleeding at 12 months were analyzed using Cox proportional‐hazards models. Among 5276 randomized patients, loss‐of‐function carriers were observed in ≈36% of both sexes, and >80% of carriers were heterozygotes. At 12 months, after adjustment for baseline differences, risks of MACE (HR , 1.28 [0.97 to 1.68]; P =0.088) and BARC bleeding (hazard ratio [HR], 1.36 [0.91 to 2.05]; P =0.14) were comparable among women and men. There were no significant interactions between sex and treatment strategy for MACE interaction P value ( P int =0.59) or BARC bleeding ( P int =0.47) nor for sex and genotype (MACE P int =0.15, and BARC bleeding P int =0.60). Conclusions CYP2C19 loss‐of‐function alleles were present in ≈1 in 3 women and men. Women had similar adjusted risks of MACE and bleeding as men following percutaneous coronary intervention. Genotype‐guided therapy did not significantly reduce the risk of MACE or bleeding relative to conventional therapy for both sexes. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01742117.

Background: The syndrome of thyrotoxicosis typically relies on radioactive iodine scans for establishing its etiology. Alternatively, the determination of thyrotropin (TSH) receptor antibodies (TRAbs) helps to distinguish Graves' disease (GD) from thyrotoxic thyroiditis. Current assays are impacted by limitations in sensitivity and/or turnaround time. Therefore, we decided to test a new assay for the detection of TSH receptor stimulating antibodies (TSAbs) and compare it with the clinically available assays. Methods: We enrolled 110 individuals in 5 cohorts: patients with incident or recurrent GD (cohort 1); patients with thyroiditis, painless or subacute (cohort 2); patients with Graves' orbitopathy/thyroid eye disease (TED) in cohort 3; patients with Hashimoto's thyroiditis (cohort 4), and a control group of normal volunteers (cohort 5). The patients were tested with the two clinically available assays: Roche Elecsys anti-TSHR assay (ROC-TBII) from Roche Diagnostics and Thyretain™ TSI Reporter BioAssay Kit (QUI-TSI) from Quidel. In addition, the samples were tested with the aequorin TSAb assay (OTS-TSI) provided by Otsuka Pharmaceutical Co., Ltd. (Tokyo, Japan). The data were collected in a cross-sectional manner before initiation of therapy. Results: We had 36 cases of GD, 17 cases of thyroiditis, 27 cases of TED, 10 cases of Hashimoto's thyroiditis, and 20 normal volunteers. OTS-TSI had 100% sensitivity and specificity in distinguishing GD from thyroiditis, identical with QUI-TSI but superior to ROC-TBII (sensitivity 86% and specificity 94.1%). OTS-TSI had 93% sensitivity and 100% specificity for the diagnosis of TED, compared with normal controls. QUI-TSI and ROC-TBII performed similarly in this analysis, demonstrating 82% sensitivity and 100% specificity. The range of detectable values for OTS-TSI was 20–29,000 mIU/L and the turnaround time was ≤6 hours, without the need for cell culture equipment. Conclusions: OTS-TSI performed excellently, though similarly to QUI-TSI, for the differential diagnosis of GD vs. thyroiditis, while being superior in that respect to ROC-TBII. Furthermore, OTS-TSI has superior sensitivity to QUI-TSI and ROC-TBII for TED diagnosis, while retaining high specificity. It has a short turnaround time and avoids the need for cell culture and sterility. Larger studies in U.S. populations are needed for its validation.

ABSTRACT Inactivating mutations of the ENPP1 gene are associated with generalized arterial calcification of infancy (GACI) and less often autosomal-recessive hypophosphatemic rickets type 2 (ARHR2). We aimed to investigate the spectrum of phenotypes in a family with monoallelic and biallelic mutations of ENPP1 after identification through whole exome sequencing of a 54-year-old female with biallelic mutation of ENPP1, c.323G > T; p.Cys108Phe and c.1441C > T; p.Arg481Trp. Including the proband, 2 subjects had biallelic mutations, 5 had monoallelic mutations, and 2 had no mutation of ENPP1. The maternal mutation, a known pathogenic variant associated with GACI, was found in 3 subjects with monoallelic mutations, while the paternal mutation, which was not previously reported, was present in 2 subjects with monoallelic mutations. Both subjects with biallelic mutations had bowing of bilateral femurs, periarticular mineral deposition, normocalcemic primary hyperparathyroidism with multigland parathyroidectomy, increased carotid intima-media thickness, and enthesopathy was also noted in one subject. Intact FGF23 was elevated in both subjects with biallelic mutations, while C-terminal FGF23 was only elevated in one and PPi was reduced in one. Subjects with monoallelic mutations did not have periarticular calcifications or bone deformities. To conclude, patients with biallelic GACI causing mutations can survive well into adulthood, and despite the same biallelic ENPP1 pathogenic variants, clinical and biochemical manifestations can significantly differ, and include enthesopathy and primary hyperparathyroidism, which have not been previously described. Although carriers of monoallelic ENPP1 variants appear unaffected by classic disease manifestations, there may be subtle biochemical and clinical findings that warrant further investigation. © 2019 American Society for Bone and Mineral Research.

Background and Aims: Aging population is a major demographic trend worldwide. Globally, 50% of all the elderly individuals are estimated to undergo atleast one surgical procedure and post-operative cognitive dysfunction (POCD) is one of the most common and often poorly understood post-operative complications in this section of the population. This randomised prospective study was conducted to assess the post-operative cognitive status in the elderly undergoing non-cardiac surgery, evaluate the cognitive parameters affected, evaluate the potential risk factors and thereby analyse the potential for implementation of preventive strategies. Methods: This study was conducted on 200 patients aged 60 years or older scheduled for elective non-cardiac surgeries. The baseline cognitive status of the patients was assessed 2 days prior to the date of the surgery. The post-operative cognitive status was assessed on the 3 rd day, 7 th day and after 1 month. Statistical analysis was performed using SAS and SPSS. Results: The incidence of POCD showed a gradual decline from postoperative day 3 to 30. Females were found to be at significant risk in developing POCD. Advancing age and level of education emerged as dominant factors, while type of anaesthesia, duration of surgery, and presence of coexisting comorbidities had no influence on the incidence of cognitive dysfunction. Conclusion: POCD is a definite complication after surgery and anaesthesia in the elderly population. Gender emerged as a significant risk factor with increasing age as a dominating factor contributing to POCD.

Abstract Objectives Adults who develop type 2 diabetes (T2D) at later stages are at a higher risk of developing Alzheimer's disease (AD). Pharmacological agents such as dipeptidyl peptidase-4 (DPP-4) inhibitors that increase the levels of glucagon-like peptide-1 (GLP-1) and ameliorate T2D have also become promising candidates as disease-modifying agents in the treatment of AD. The present study investigates the efficacy of vildagliptin, a DPP-4 inhibitor in a streptozotocin (STZ)-induced rat model of AD. Methods Three months following the induction of AD by intracerebral injection of STZ, animals were orally administered with vildagliptin (2.5, 5 and 10 mg/kg) for 30 days. Dose-dependent and time-course effects of vildagliptin on memory retention were investigated during the course of treatment. Following treatment, the animals were sacrificed, and brain tissues were used to evaluate the effects of vildagliptin on hippocampal and cortical GLP-1 levels, amyloid beta (Aβ) burden, tau phosphorylation and inflammatory markers. Key findings The results reveal a time-dependent improvement in memory retention and a dose-dependent attenuation of Aβ, tau phosphorylation and inflammatory markers and increased GLP-1 levels. Conclusions These robust therapeutic effects of vildagliptin demonstrate a unique mechanism for Aβ and tau clearance and reverse the cognitive deficits and pathology observed in AD.