Optimal Quantification of Functional Mitral Regurgitation: Comparison of Volumetric and Proximal Isovelocity Surface Area Methods to Predict Outcome.

Background Effective orifice area (EOA) ≥0.2 cm2 or regurgitant volume (Rvol) ≥30 mL predicts prognostic significance in functional mitral regurgitation (FMR). Both volumetric and proximal isovelocity surface area (PISA) methods enable calculation of these metrics. To determine their clinical value, we compared EOA and Rvol derived by volumetric and PISA quantitation upon outcome of patients with FMR. Methods and Results We examined the outcome of patients with left ventricular ejection fraction <35% and moderate to severe FMR. All had a complete echocardiogram including EOA and Rvol by both standard PISA and volumetric quantitation using total stroke volume calculated by left ventricular end-diastolic volume×left ventricular ejection fraction and forward flow by Doppler method: EOA=Rvol/mitral regurgitation velocity time integral. Primary outcome was all-cause mortality or heart transplantation. We examined 177 patients: mean left ventricular ejection fraction 25.2% and 34.5% with ischemic cardiomyopathy. Echo measurements were greater by PISA than volumetric quantitation: EOA (0.18 versus 0.11 cm2), Rvol (24.7 versus 16.9 mL), and regurgitant fraction (61 versus 37 %) respectively (all P value <0.001). During 3.6±2.3 years' follow-up, patients with EOA ≥0.2 cm2 or Rvol ≥30 mL had a worse outcome than those with EOA <0.2 cm2 or Rvol <30 mL only by volumetric (log rank P=0.003 and 0.004) but not PISA quantitation (log rank P=0.984 and 0.544), respectively. Conclusions Volumetric and PISA methods yield different measurements of EOA and Rvol in FMR; volumetric values exhibit greater prognostic significance. The echo method of quantifying FMR may affect the management of this disorder.

Systematic Assessment of the Impact of Ultrasound-Enhancing Agents upon Measurements of Cardiac Size and Function by Echocardiography.

BACKGROUND: Echocardiography with an ultrasound-enhancing contrast agent (CON) is a powerful tool for identifying the endocardial border. However, the precise relationship of measurements obtained from CON to the reference values of two-dimensional unenhanced echocardiography (BASL) remains undefined, especially regarding wall thickness. The aim of this study was to systematically determine the differences between unenhanced and enhanced images for a broad range of left ventricular (LV) measurements and to define reference values for the relationship between the two methods. METHODS: We examined the echocardiograms of 624 consecutive patients in whom CON was performed for clinical indications. We excluded 192 patients in whom studies were technically difficult for measurement by either or both methods. Echocardiograms were from standard parasternal and apical views according to American Society of Echocardiography guidelines. Recordings were measured for wall thickness and chamber dimension in 343 patients and for LV volumes and ejection fraction in 212 patients. RESULTS: LV wall thickness measurements were systematically reduced with a bias of 0.2 cm with limits of agreement (LOA) from -0.5 to 0.16 cm in interventricular septal thickness, and from -0.46 to 0.13 cm in posterior wall thickness in CON. LV dimensions and volumes systematically increased with a bias of 0.2 cm (LOA, -0.19 to 0.58 cm) and 14 to 16 mL (LOA, -11.9 to 42.8 mL), respectively. LV ejection fraction systematically decreased with a bias of 3.4% (LOA, -13.5% to 6.8%) in CON compared to BASL. All differences showed normal distribution in the Kolmogorov-Smirnov test. CONCLUSION: CON yields significantly different measurements of cardiac size and function compared to unenhanced imaging. These data define the systematic differences in measurements between CON and BASL images; the range of differences is narrow. These differences may influence management when the measurement value is a borderline.

Predictive Factors for Progression of Mitral Regurgitation in Asymptomatic Patients With Mitral Valve Prolapse.

Risk factors predicting progression from low grade to severe mitral regurgitation (MR), which is a guideline criterion for surgical intervention, remain unknown. We hypothesized that abnormalities of cardiac structure and function may predict progression in MR severity. We followed 82 asymptomatic mitral valve prolapse (MVP) patients (65 ± 12 years, 51% men) with mild or moderate MR (36 mild, 46 moderate, mean LVEF: 62%), without significant co-morbidities. We examined clinical findings and 13 echo measurements. The primary end point was progression to severe MR. In a mean follow-up period of 4.5 ± 2.7 years, mortality and heart failure development were similar for mild and moderate MR. No mild MR patient progressed to severe, but 23 moderate MR patients (50.0%) progressed to severe with 9 patients (39.1%) who underwent surgery. No clinical variables were predictive for progression. Only mean mitral annulus diameter (apical 4 and 2 chamber) was predictive for progression to severe MR (hazards ratio 1.14, 95% confidence interval 1.03 to 1.26, p = 0.01). A cut-off annulus diameter of 39.6 mm had a good accuracy (area under the curve 0.78, sensitivity 100%, and specificity 63.8%) for progression to severe. In conclusion, over a 4.5-year period, 50% of asymptomatic MVP patients with moderate MR, but none with mild, progressed to severe MR. Only mitral annular dimension predicted progression of moderate to severe MR, and values >39.6 mm predicted progression accurately. Mitral annulus diameter may be of value in identifying asymptomatic MVP patients at risk of developing severe MR.

Anagliptin, A Dipeptidyl Peptidase-4 Inhibitor Ameliorates Arterial Stiffness in Association with Reduction of Remnant-Like Particle Cholesterol and Alanine Transaminase Levels in Type 2 Diabetic Patients.

BACKGROUND: Inhibition of dipeptidyl peptidase-4 (DPP-4) has been proposed as a therapeutic target for type 2 diabetes (T2DM). Arterial stiffness, a predictor of future cardiovascular events and all-cause mortality, is augmented in these patients. However, effects of DPP-4 inhibitors on arterial stiffness remain unknown. In this study, we compared effects of anagliptin, an inhibitor of DPP-4 on arterial stiffness evaluated by cardio-ankle vascular index (CAVI) with those of an equipotent glucose-lowering agent, glimepiride in patients with T2DM. METHODS: The study involved 50 consecutive outpatients (33 males and 17 females; mean age of 72.5±9.5 years) who visited our hospitals for a risk-screening test or treatment for T2DM. They underwent complete history and physical examination, and determination of blood chemistry and anthropometric variables, and then were randomized to receive either anagliptin (n=26) or glimepiride (n=24) for 6 months. RESULTS: After 6-months treatment, fasting plasma glucose and HbA1c values were comparably reduced in both groups. Anagliptin, but not glimepiride treatment significantly decreased low-density lipoprotein cholesterol, malondialdehyde-modified LDL, remnant-like particle (RLP) cholesterol, CAVI, alanine transaminase (ALT), γ-glutamyl transferase and visceral fat volume. In multiple regression analysis, absolute changes from baseline of RLP cholesterol and ALT after anagliptin treatment for 6 months (ΔRLP cholesterol and ΔALT) were independently correlated with ΔCAVI (R2=0.445). CONCLUSION: The present study suggests that anagliptin may exert a beneficial effect on arterial stiffness in patients with T2DM, which is independent of its blood glucose-lowering property. Anagliptin may ameliorate arterial stiffness partly via reduction of RLP cholesterol and improvement of liver function.

Disturbance of cardiac gene expression and cardiomyocyte structure predisposes Mecp2-null mice to arrhythmias.

Methyl-CpG-binding protein 2 (MeCP2) is an epigenetic regulator of gene expression that is essential for normal brain development. Mutations in MeCP2 lead to disrupted neuronal function and can cause Rett syndrome (RTT), a neurodevelopmental disorder. Previous studies reported cardiac dysfunction, including arrhythmias in both RTT patients and animal models of RTT. In addition, recent studies indicate that MeCP2 may be involved in cardiac development and dysfunction, but its role in the developing and adult heart remains unknown. In this study, we found that Mecp2-null ESCs could differentiate into cardiomyocytes, but the development and further differentiation of cardiovascular progenitors were significantly affected in MeCP2 deficiency. In addition, we revealed that loss of MeCP2 led to dysregulation of endogenous cardiac genes and myocardial structural alterations, although Mecp2-null mice did not exhibit obvious cardiac functional abnormalities. Furthermore, we detected methylation of the CpG islands in the Tbx5 locus, and showed that MeCP2 could target these sequences. Taken together, these results suggest that MeCP2 is an important regulator of the gene-expression program responsible for maintaining normal cardiac development and cardiomyocyte structure.

Serum levels of pigment epithelium-derived factor (PEDF) are inversely associated with circulating levels of dipeptidyl peptidase-4 (DPP-4) in humans.

BACKGROUND: We have previously found that advanced glycation end products (AGEs) stimulate the proteolytic cleavage of dipeptidyl peptidase-4 (DPP-4) from plasma membranes, and circulating AGE levels are independently correlated with serum DPP-4 values. Since pigment epithelium-derived factor (PEDF), one of the adipocytokines, inhibits the AGEs-induced insulin resistance and vascular damage, it is conceivable that besides AGEs, PEDF might also regulate soluble DPP-4 levels. In this study, we addressed the issue. STUDY DESIGN AND METHODS: The study involved 188 subjects (123 males and 65 females; mean age of 61.1±9.2) who visited our hospital for a risk-screening test or treatment for cardiovascular disease. They underwent complete history and physical examinations, and determination of blood chemistry and anthropometric variables, including visceral and subcutaneous fat areas. Serum levels of DPP-4 and PEDF levels were examined by enzyme-linked immunosorbent assay. RESULTS: Median (interquartile range) serum levels of DPP-4 and PEDF were 466.6 (400.2-545.1) ng/mL and 14.0 (10.6-17.0) µg/mL, respectively. Multiple stepwise regression analysis revealed that female (p<0.001), aspartate aminotransferase (p<0.001), glycated hemoglobin (p<0.001) and PEDF (inversely, p=0.020) were independently associated with DPP-4 levels (R(2)=0.267). CONCLUSION: We found here for the first time that serum PEDF levels were one of the independent correlates of circulating DPP-4 levels in humans. Since DPP-4 could impair insulin action and evoke vascular damage, our present study suggests that insulin-sensitizing and atheroprotective properties of PEDF might be ascribed partly to its inhibitory actions on DPP-4.

Function and expression pattern of TRPM8 in bladder afferent neurons associated with bladder outlet obstruction in rats.

We investigated the function and expression pattern of the transient receptor potential melastatin-8 (TRPM8) in urinary bladder afferent neurons from control and bladder outlet obstruction (BOO) rats. BOO was produced and, after six weeks, the effects of intravesical infusion of menthol, the agonist of TRPM8, were investigated using unanesthetized cystometry. The intravesical infusion of menthol produced an increase in the micturition pressure in both sham surgery and BOO rats. In BOO rats, increased basal and threshold pressure and a decreased micturition interval were observed. Next, the population of TRPM8-positive and the co-expression proportion of TRPM8 with neurochemical markers (NF200 or TRPV1) in the bladder afferent neurons were each compared between the control and BOO rats using retrograde tracing and immunohistochemistry. The population of TRPM8-immunoreactive bladder afferent neurons was larger in BOO rats (3.28±0.43%) than in the control rats (1.33±0.18%). However, there were no statistical differences between the control and BOO rats in the co-expression proportion of neither TRPM8-NF200 (84.1±4.3% vs 79.7±2.7%, p=0.41) nor TRPM8-TRPV1 (33.3±3.6% vs 40.8±2.6%, p=0.08) in the bladder afferent neurons. The present results suggest that the neuronal input through TRPM8-positive bladder afferent neurons are augmented after BOO, however, the neurochemical phenotype of the up-regulated TRPM8-positive bladder afferent neurons is not changed after BOO.