Association of the P441L KCNQ1 variant with severity of long QT syndrome and risk of cardiac events.

Dysfunction of potassium voltage-gated channel subfamily Q member 1 (KCNQ1) is a primary cause of long QT syndrome type 1 (LQT1). Here, we report a missense mutation P441L in KCNQ1 C-terminus of a 37-year-old woman with severe LQT1 phenotype. Variant P441L transporting to the plasma membrane and interacting with KCNE1 were both markedly decreased, leading to potassium efflux disorder and eventually LQT1. Mutations between the C-terminal helix A and helix B of KCNQ1 have linked with low cardiac event risk, however, we firstly find variant P441L causing a severe LQT1 phenotype with a high risk of cardiac events.

Cholecystokinin-mediated pharmacological preconditioning effects on ischemic rat hearts: Possible signaling pathways.

BACKGROUND: Cholecystokinin (CCK-8) has been shown to exhibit pharmacological preconditioning and cardioprotective effects. However, the molecular mechanisms involved in CCK-8-induced pharmacological preconditioning have not yet been clarified. OBJECTIVES: The current study explored the molecular mechanisms involved in CCK-8-mediated pharmacological preconditioning effects on ischemic rat hearts. MATERIAL AND METHODS: Pharmacological preconditioning was induced in male Wistar rats by administration of CCK-8 (20 µg/kg) 24 h before heart isolation. The PI3K inhibitor LY294002 (10 mg/kg and 20 mg/kg) and the HIF-1α inhibitor YC-1 (1 mg/kg and 2 mg/kg) were administered 30 min before the administration of CCK-8. The hearts were subjected to ischemia-reperfusion (IR) injury using a Langendorff apparatus. Myocardial injury was quantified by measuring the release of LDH-1, CK-MB and cTnT. The levels of HIF-1α and p-Akt expression and the ratio of p-GSK-3ß/GSK-3ß, were assessed in the heart homogenates. RESULTS: Pharmacological preconditioning with CCK-8 reduced IR-induced increases in the release of LDH, CK-MB and cTnT. Moreover, it restored the expression of HIF-1α and p-Akt, and the p-GSK-3ß/GSK-3ß ratio. However, administration of LY294002 or YC-1 with CCK-8 significantly abolished the cardioprotective effects of pharmacological preconditioning. The PI3K and HIF-1α inhibitors also abolished the effects of CCK-8 preconditioning on HIF-1α, p-Akt and p-GSK-3ß/GSK-3ß. CONCLUSIONS: Based on these findings, it may be concluded that the molecular mechanisms participating in CCK-8-induced pharmacological preconditioning involve HIF-1α, PI3K, Akt, and GSK-3ß signaling pathways.

Prognostic Usefulness of Serum Cholesterol Efflux Capacity in Patients With Coronary Artery Disease.

Cholesterol efflux capacity has been shown to have an inverse relation with coronary artery disease (CAD) and may overcome the limitations of high-density lipoprotein (HDL) cholesterol levels as a predictor for CAD risks. We investigated the predictive value of cholesterol efflux capacity for the prognosis of CAD. Serum cholesterol efflux capacity in 313 patients newly diagnosed with CAD by coronary angiography was measured, and all patients completed a 3-year follow-up. The primary clinical end points were nonfatal myocardial infarction, nonfatal stroke, and cardiovascular mortality. The secondary clinical end points were class IV heart failure requiring hospitalization and coronary artery revascularization. Cholesterol efflux capacity was lower in patients with CAD compared with control group, and decreased cholesterol efflux capacity was associated with an increased risk of acute coronary syndrome (odds ratios, 0.25; 95% confidence interval, 0.14 to 0.46; p <0.01). There was no association between cholesterol efflux capacity and serum HDL cholesterol levels. Follow-up data showed that patients with CAD with lower cholesterol efflux capacity had higher primary clinical end point events (26 of 158 vs 8 of 155, p <0.01). Cox regression and Kaplan-Meier analysis further showed that a decreased cholesterol efflux capacity was associated with an increased risk of the primary end point events regardless of adjustment. There was no association between cholesterol efflux capacity and the secondary end point events. In conclusion, the results provide the important clinical evidence that cholesterol efflux capacity is a predictive index for plaque stability and the prognosis of CAD, independent of HDL cholesterol levels.

Sphingomyelin in erythrocyte membranes increases the total cholesterol content of erythrocyte membranes in patients with acute coronary syndrome.

OBJECTIVES: To investigate whether the sphingomyelin content of erythrocyte membranes (SEM) is changed in patients with acute coronary syndrome (ACS) and determine the correlation between SEM and the total cholesterol content of erythrocyte membranes (CEM). METHODS: The SEM and CEM levels were measured in 354 patients undergoing coronary artery angiography in three different groups: ACS patients (n=199), patients with stable angina pectoris (SAP) (n=82), and controls (n=73). RESULTS: The SEM levels in the ACS group were significantly higher than those of the SAP group. The SEM levels were correlated positively with the CEM levels in patients with coronary artery disease. Multivariable logistic regression analysis showed that patients with higher levels of both SEM and CEM had an 8.569-fold greater risk of developing ACS than other patients, after adjusting for all potential confounding variables. CONCLUSION: Elevated SEM and CEM levels showed both independent and combined correlations with the occurrence of ACS and were positively correlated with each other in patients with coronary artery disease. These data suggest that the increased levels of SEM may play a role in the progression to plaque instability in ACS and may be the mechanisms underlying elevated levels of CEM in patients with ACS.

[The predictive value of mild renal insufficiency on the prognosis of patients with acute coronary syndrome].

OBJECTIVE: To investigate the predictive value of mild renal insufficiency on the endpoint events in patients with acute coronary syndrome (ACS). METHODS: A total of 552 patients with ACS were enrolled in the present study. According to the levels of estimated glomerular filtration rate (eGFR), patients were divided into two groups, normal renal function (eGFR ≥ 90 ml×min(-1)×1.73 m(-2)) and mild renal insufficiency (60 ≤ eGFR<90 ml×min(-1)×1.73 m(-2)). The primary and secondary events were collected and analyzed through the present prospective follow-up study. RESULTS: The patients in mild renal insufficiency group had a higher incidence of the primary endpoint events than normal renal function group [31 cases (12.6%) vs 15 cases (4.9%), P = 0.001]. There was no difference of the secondary endpoint events incidence in the two groups. The incidence rate of all-cause mortality [8.9% (22 cases) vs 2.2% (7 cases), P < 0.001] and cardiac death [6.5% (16 cases) vs 1.3% (4 cases), P = 0.001] was higher in mild renal insufficiency group, but there was no statistical difference of incidence rate of no fatal stroke and myocardial infarction in the two groups. The results of COX regression analysis showed that the incidence of primary endpoint events in patients with mild renal dysfunction was 2.265 folds (95%CI 1.076-4.771, P = 0.031) of patients with normal renal function. Further analysis indicated that the predictive value of mild renal insufficiency was only for all-cause mortality (HR 3.118, 95%CI 1.197-8.125, P = 0.020), not for heart failure and revascularization. According to the Kaplan-Meier curves results, the incidences of the primary endpoint events (P = 0.004) and all-cause mortality (P = 0.001) were higher in mild renal insufficiency group than in normal renal function group. CONCLUSION: Mild renal insufficiency has important predictive value for primary endpoint events in patients with ACS.