Roflupram protects against rotenone-induced neurotoxicity and facilitates α-synuclein degradation in Parkinson's disease models.

We have previously shown that roflupram (ROF) protects against MPP+-induced neuronal damage in models of Parkinson's disease (PD). Since impaired degradation of α-synuclein (α-syn) is one of the key factors that lead to PD, here we investigated whether and how ROF affects the degradation of α-syn in rotenone (ROT)-induced PD models in vivo and in vitro. We showed that pretreatment with ROF (10 µM) significantly attenuated cell apoptosis and reduced the level of α-syn in ROT-treated SH-SY5Y cells. Furthermore, ROF significantly enhanced the lysosomal function, as evidenced by the increased levels of mature cathepsin D (CTSD) and lysosomal-associated membrane protein 1 (LAMP1) through increasing NAD+/NADH and the expression of sirtuin 1 (SIRT1). Pretreatment with an SIRT1 inhibitor selisistat (SELI, 10 µM) attenuated the neuroprotection of ROF, ROF-reduced expression of α-syn, and ROF-increased expression levels of LAMP1 and mature CTSD. Moreover, inhibition of CTSD by pepstatin A (20 µM) attenuated ROF-reduced expression of α-syn. In vivo study was conducted in mice exposed to ROT (10 mg·kg-1·d-1, i.g.) for 6 weeks; then, ROT-treated mice received ROF (0.5, 1, or 2 mg·kg-1·d-1; i.g.) for four weeks. ROF significantly ameliorated motor deficits, which was accompanied by increased expression levels of tyrosine hydroxylase, SIRT1, mature CTSD, and LAMP1, and a reduced level of α-syn in the substantia nigra pars compacta. Taken together, these results demonstrate that ROF exerts a neuroprotective action and reduces the α-syn level in PD models. The mechanisms underlying ROF neuroprotective effects appear to be associated with NAD+/SIRT1-dependent activation of lysosomal function.

Impaired Right Ventricular Mechanics at Rest and During Exercise Are Associated With Exercise Capacity in Patients With Hypertrophic Cardiomyopathy.

Background Impaired right ventricular ( RV ) function indicates RV involvement in patients with hypertrophic cardiomyopathy ( HCM ). We aimed to assess RV function at rest and during exercise in HCM patients and to examine the association between impaired RV mechanics and exercise capacity. Methods and Results A total of 76 HCM patients (48 without and 28 with RV hypertrophy) and 30 age- and sex-matched controls were prospectively recruited. RV function was evaluated at rest and during semisupine bicycle exercise by conventional echocardiography and 2-dimensional speckle-tracking imaging. Exercise capacity was measured by metabolic equivalents. RV functional reserve was calculated as the difference of functional parameters between peak exercise and rest. Compared with controls, HCM patients had significantly higher RV free wall thickness, lower RV global longitudinal strain and RV free wall longitudinal strain at rest and during exercise, and reduced RV systolic functional reserve. Compared with those with HCM without RV hypertrophy, patients with HCM with RV hypertrophy had lower metabolic equivalents. Among HCM patients, an effective correlation was seen between exercise capacity and peak exercise RV global longitudinal strain and peak exercise RV free wall longitudinal strain. A binary logistic regression model revealed several independent predictors of exercise intolerance in HCM patients, but receiver operating characteristic curve analysis indicated exercise RV global longitudinal strain had the highest area under the curve for the prediction of exercise intolerance in HCM patients. Conclusions HCM patients have RV dysfunction and reduced contractile reserve. Exercise RV global longitudinal strain correlates with exercise capacity and can independently predict exercise intolerance. In addition, patients with HCM with RV hypertrophy exhibit more reduced exercise capacity, suggesting more severe disease and poorer prognosis.

Decreased biventricular mechanics and functional reserve in nonobstructive hypertrophic cardiomyopathy patients: implications for exercise capacity.

The present study investigated the changes of biventricular mechanics at rest and during exercise and examined the association between exercise capacity and biventricular mechanics and functional reserve in nonobstructive hypertrophic cardiomyopathy (NHCM) patients. A total of 50 NHCM patients and 25 controls were consecutively recruited for this study. Using echocardiography and two-dimensional speckle-tracking imaging, an experienced echocardiographer determined the following indices: RV free wall longitudinal strain (RVFWLS), LV global longitudinal strain (LVGLS), strain rate (SR), and functional reserve of strain values. We also investigated the relationships between biventricular mechanics and exercise capacity using metabolic equivalents (METs). NHCM patients had lower RVFWLS, LVGLS, systolic SR, early diastolic SR, and systolic and diastolic reserve during exercise compared to controls. An association of biventricular mechanics (LVGLS, RVFWLS) with exercise capacity at rest and during exercise was established. Multivariable logistic regression revealed that RVFWLS and LVE/e' during exercise (RVFWLS-exe, E/e'-exe) were independent predictors of exercise intolerance. Receiver operating characteristic curve analysis indicated that LVE/e'-exe had a higher area under the curve for predicting exercise intolerance in NHCM patients. In hierarchical analysis, RVFWLS-exe provided an incremental predictive value of exercise intolerance over LVGLS during exercise (LVGLS-exe) and LVE/e'-exe. LVE/e'-exe also changed incrementally compared to LVGLS-exe and RVFWLS-exe. NHCM patients have decreased biventricular mechanics at rest and during exercise and impaired biventricular functional reserve, and biventricular mechanics are associated with functional capacity. We propose that simultaneous evaluation of biventricular function should provide incremental predictive value for exercise intolerance.

Impaired left ventricular mechanics and functional reserve are associated with reduced exercise capacity in patients with hypertrophic cardiomyopathy.

BACKGROUND: Reduced metabolic equivalents (METs) are an indicator of exercise intolerance, which predicts poor prognosis in hypertrophic cardiomyopathy (HCM) patients. We sought to evaluate the changes in left ventricular (LV) mechanics and functional reserves, as well as their association with functional capacity in HCM patients. METHODS: Seventy HCM patients and thirty controls were included in this study. LV mechanics were evaluated at rest and during exercise by echocardiography and two-dimensional speckle-tracking imaging to obtain parameters of functional reserve, LV global longitudinal strain (LVGLS), strain rate (SR), and circumferential strain. RESULTS: Hypertrophic cardiomyopathy (HCM) patients had lower LVGLS, systolic SR, early and late diastolic SR at rest and during exercise, and reduced absolute and relative systolic and diastolic reserve compared to controls. LV circumferential strain was significantly higher at rest but lower during exercise in HCM patients. Exercise capacity was markedly reduced in HCM patients, and peak exercise LVGLS (LVGLS-exe) significantly correlated with exercise capacity. Multivariate regression analyses showed that LVGLS-exe, LV filling pressure during exercise (E/e'-exe), and LV mass index (LVMI) were independent predictors of exercise capacity. Moreover, LVGLS-exe displayed incremental predictive value over E/e'-exe and LVMI for exercise intolerance. Receiver operating characteristic curve analysis showed LVGLS-exe had optimal accuracy for predicting exercise intolerance in HCM patients. CONCLUSIONS: Hypertrophic cardiomyopathy (HCM) patients have reduced LV mechanics at rest and during exercise and impaired mechanical reserve. LVGLS-exe is associated with exercise capacity and is an optimal predictive value for reduced exercise capacity in HCM patients.

Effects of nonvalvular atrial fibrillation on the structure and function of mitral valves (a STROBE-compliant article).

The aim of this study was to explore the effects of nonvalvular atrial fibrillation (NVAF) on the structure and function of mitral valve and analyze independent risk factors of moderate to severe mitral regurgitation (MR) by quantitative measurement of mitral parameters using real-time 3-dimensional transesophageal echocardiography.This study included 30 subjects with sinus rhythm group, and 65 patients with NVAF. The 65 patients with NVAF were divided into 35 with paroxysmal atrial fibrillation group and 30 with persistent atrial fibrillation. According to MR degree, the patients with NVAF were again divided into no or mild MR group (n = 44) and moderate to severe MR group (n = 21).There were significant differences in anterolateral-to-posteromedial diameter (DAlPm), anterior-to-posterior diameter, 3-dimensional circumference (C3D), 2-dimensional area (A2D), mitral leaflet surface area in late systolic phase, the index of mitral valve coaptation and left atrial internal diameter (LAID) between different cardiac rhythm groups (all P < .05). The DAlPm, C3D, A2D, nonplanar angle (θNPA), and LAID were greater but the mitral valve coaptation index was smaller in the moderate to severe MR group than in the no or mild MR group (all P < .05). Logistic regression analysis indicated that DAlPm and LAID were independent risk factors of moderate to severe MR in the patients with NVAF (OR > 1, P < .05).DAlPm and LAID are independent risk factors of moderate to severe MR in the patients with NVAF. NVAF can change the structure and function of mitral valve, which leads to MR.

Evaluation of the left atrial appendage by real time three-dimensional transesophageal echocardiography online.

OBJECTIVE: The objective of this study was to evaluate the feasibility of online real time three-dimensional transesophageal echocardiography (RT3DTEE) in the measurement of left atrial appendage (LAA) orifice size. We also analyzed the correlation between LAA ejection fraction (EF) and its peak empty velocity (PEV). METHODS: There were 91 subjects enrolled in this study, with 46 patients with AF and 45 individuals with sinus rhythm (SR). RT3DTEE was performed by four methods including iSlice and iCrop online and QLAB software 3DQ and GI-3DQ off-line which were used to measure LAA orifice area, long diameter, short diameter, depth in the largest LAA, and number of LAA lobes. These LAA parameters achieved by the four methods were compared, respectively. GI-3DQ off-line was used to measure LAA end-diastolic and end-systolic volumes to calculate EF of LAA. Two-dimensional (2D) TEE was applied to measure PEV of LAA. The correlation between EF and PEV was analyzed. RESULTS: There were no significant differences in all LAA parameters between any two RT3DTEE methods (All P > .05). There was a significant and positive correlation between PEV and EF (r = .423, P = .000). There were statistical differences in LAA EF and PEV between patients with AF and SR individuals (0.38 ± 0.12 vs 0.61 ± 0.07, 35.7 ± 12.1 vs 49.5 ± 10.0 cm/s, P = .000). CONCLUSION: Using online RT3DTEE for measuring LAA orifice size is feasible, and online RT3DTEE is more convenient than offline RT3DTEE. EF is positively correlated with PEV. LAA function is significantly decreased in patients with AF.

Whole exome sequencing identifies novel mutation in eight Chinese children with isolated tetralogy of Fallot.

BACKGROUND: Tetralogy of Fallot is the most common cyanotic congenital heart disease. However, its pathogenesis remains to be clarified. The purpose of this study was to identify the genetic variants in Tetralogy of Fallot by whole exome sequencing. METHODS: Whole exome sequencing was performed among eight small families with Tetralogy of Fallot. Differential single nucleotide polymorphisms and small InDels were found by alignment within families and between families and then were verified by Sanger sequencing. Tetralogy of Fallot-related genes were determined by analysis using Gene Ontology /pathway, Online Mendelian Inheritance in Man, PubMed and other databases. RESULTS: A total of sixteen differential single nucleotide polymorphisms loci and eight differential small InDels were discovered. The sixteen differential single nucleotide polymorphisms loci were located on Chr 1, 2, 4, 5, 11, 12, 15, 22 and X. Among the sixteen single nucleotide polymorphisms loci, six has not been reported. The eight differential small InDels were located on Chr 2, 4, 9, 12, 17, 19 and X, whereas of the eight differential small InDels, two has not been reported. Analysis using Gene Ontology /pathway, Online Mendelian Inheritance in Man, PubMed and other databases revealed that PEX5, NACA, ATXN2, CELA1, PCDHB4 and CTBP1 were associated with Tetralogy of Fallot. CONCLUSIONS: Our findings identify PEX5, NACA, ATXN2, CELA1, PCDHB4 and CTBP1 mutations as underlying genetic causes of isolated tetralogy of Fallot.