A novel AGK splicing mutation in a patient with Sengers syndrome and left ventricular non-compaction cardiomyopathy.

BACKGROUND: Sengers syndrome characterized by hypertrophic cardiomyopathy is an extremely rare genetic disorder. Sengers syndrome associated with left ventricular non-compaction (LVNC) has not been described. METHODS: Genetic testing was used to identify candidate AGK variants in the proband. The predicted molecular structures were constructed by protein modeling. Exon skipping caused by the identified splicing mutations was verified by in silico analyses and in vitro assays. The genotypic and phenotypic features of patients with AGK splicing mutations were extracted by a systematic review. RESULTS: The proband was characterized by Sengers syndrome and LVNC and caused by a novel compound heterozygous AGK splicing mutation. This compound mutation simultaneously perturbed the protein sequences and spatial conformation of the acylglycerol kinase protein. In silico and in vitro analyses demonstrated skipping of exons 7 and 8 and premature truncation as a result of exon 8 skipping. The systematic review indicated that patients with an AGK splicing mutation may have milder phenotypes of Sengers syndrome. CONCLUSIONS: The genotypic and phenotypic spectrums of Sengers syndrome have been expanded, which will provide essential information for genetic counseling. The molecular mechanism in AGK mutations can offer insights into the potential targets for treatment. IMPACT: First description of a child with Sengers syndrome and left ventricular non-compaction cardiomyopathy. A novel pathogenic compound heterozygous splicing mutation in AGK for Sengers syndrome was identified. The identified mutations led to exons skipping by in silico analyses and in vitro assays.

C-reactive protein as a predictor of malignant ventricular arrhythmias in non-ST elevation myocardial infarction.

OBJECTIVE: To investigate whether C-reactive protein (CRP) is a biomarker of malignant ventricular arrhythmias (MVA) occurring in non-ST elevation myocardial infarction (NSTEMI) patients with Global Registry of Acute Coronary events (GRACE) scores < 140. METHODS: A total of 1450 NSTEMI patients were included in this study. Hs-CRP blood levels were measured via a turbidimetric immunoassay after confirming the diagnosis of NSTEMI with GRACE scores < 140. RESULTS: Consistent with prior studies, the MVA occurrence rate in our cohort was 6.7%, and patients with MVA exhibited a reduced left ventricular ejection fraction (46.1% ± 6.9% vs. 61.5% ± 8.7%, P = 0.032), a higher incidence of Killip classification > 1 (34.1% vs. 24.2%, P < 0.001), an increased surgical revascularization rate (34.1% vs. 9.7%, P < 0.001), and increased mortality (16.5% vs. 5.8%, P < 0.001). Serum hs-CRP levels were higher (P = 0.003) in NSTEMI patients with MVA, and this increase appeared unrelated to other clinical parameters. The C-statistic to discriminate MVA was 0.82 (95% CI: 0.74-0.89). Using receiver operating characteristics analysis, we optimized a cutoff point of 16 mL/L, and the sensitivity and specificity were 95% and 61%, respectively; the positive predictive value was 20% and the negative predictive value was 99%. CONCLUSIONS: An hs-CRP assay is a potential MVA biomarker in low-risk NSTEMI patients with GRACE scores < 140. If validated in prospective studies, hs-CRP may offer a low-cost supplementary strategy for risk stratification for NSTEMI patients.

Activation of ATP-sensitive potassium channels protects vascular endothelial cells from hypertension and renal injury induced by hyperuricemia.

BACKGROUND AND OBJECTIVES: It has been demonstrated that hyperuricemia induces reno-cardiovascular damage resulting in hypertension and renal injury because of vascular endothelial dysfunction. The pathogenesis of hyperuricemia, endothelial dysfunction, hypertension, and renal injury is progressive, and develops into a vicious cycle. It is reasonable to suggest that an antihypertensive drug with endothelial protection may block this vicious cycle. Iptakalim, a novel antihypertensive drug undergoing phase-three clinical trials, is a new ATP-sensitive potassium channel opener and can ameliorate endothelial dysfunction. We hypothesized that iptakalim could prevent hypertension and retard the pathogenesis of endothelial dysfunction and renal injury in hyperuricemic rats. METHODS AND RESULTS: In rats with hyperuricemia induced by 2% oxonic acid and 0.1 mmol/l uric acid, iptakalim prevented increases in systolic blood pressure, reduced the impairment of endothelial vasodilator function, and attenuated renal dysfunction and pathological changes in glomerular and renal interstitial tissue at 0.5, 1.5, and 4.5 mg/kg orally daily for 4 weeks. Serum levels of nitric oxide and prostacyclin, and gene expression of endothelial nitric oxide synthase in the aortic and intrarenal tissue, were increased, whereas the serum levels of endothelin-1 and gene expression of endothelin-1 in aortic and intrarenal tissue were decreased. However, serum levels of angiotensin II and renin remained unchanged in the hyperuricemic rats treated with iptakalim. In cultured rat aortic endothelial cells, amelioration of endothelial dysfunction by iptakalim was suggested by inhibition of the overexpression of intercellular adhesive molecule-1, vascular cell adhesive molecule-1, and monocyte chemoattractant protein-1 mRNA induced by uric acid, and reversal of the inhibitory effects of uric acid on nitric oxide release in a concentration-dependent manner, which could be abolished by pretreatment with glibenclamide, an ATP-sensitive potassium channel blocker. Iptakalim ameliorated hyperuricemia in this rat model by decreasing renal damage through its antihypertensive and endothelial protective properties, and it had no direct effects on anabolism, catabolism and excretion of uric acid. CONCLUSION: These findings suggest that the activation of ATP-sensitive potassium channels by iptakalim can protect endothelial function against hypertension and renal injury induced by hyperuricemia. Iptakalim is suitable for use in hypertensive individuals with hyperuricemia.