Background—: We sought to assess the utility of left ventricular global longitudinal strain (LV-GLS) in predicting mortality in moderate to severe and paradoxical severe aortic stenosis (AS) patients with preserved ejection fraction. Methods and Results—: We studied 395 AS patients (70±14 years, 57% men) with aortic valve area <1.3 cm ² evaluated between January to June 2008 (excluding severe other valve disease and LV ejection fraction <50%). Clinical and echocardiographic data were recorded. LV-GLS was analyzed using Velocity Vector Imaging. AS patients were classified as (a) moderate–severe (n=93; aortic valve area, 1.1–1.3 cm ² ), (b) standard severe (n=161; aortic valve area, ≤1 cm2; mean gradient ≥40 mm Hg), and (c) paradoxical severe (n=141; aortic valve area, ≤1 cm2 and mean gradient <40 mm Hg). Additive Euroscore was 7±3. The association of LV-GLS with all-cause mortality was assessed after risk-adjustment using Cox proportional hazards models. Median LV-GLS was −14.8% (interquartile range, −17.2%, −12.1%). At 4.4±1.4 years, there were 92 (23%) deaths. On multivariable Cox analysis, additive Euroscore (hazard ratio, 1.19; 1.13–1.27; P <0.001), New York Heart Association class (hazard ratio, 1.44; 1.11–1.87; P <0.001), AV surgery with time-dependent covariate analysis (hazard ratio, 0.29; 0.19–0.45; P <0.001), and LV-GLS (hazard ratio, 1.05; 1.03–1.07; P <0.001) were independent predictors of mortality. LV-GLS <−12.1% (4th quartile) was associated with significantly reduced survival. Addition of LV-GLS to clinical parameters (additive Euroscore+New York Heart Association class) led to significant improvement in prediction of mortality (χ ² increased from 48 to 58; P <0.01). Conclusions—: LV-GLS independently predicts mortality in moderate–severe and severe AS patients with preserved LV ejection fraction, providing incremental prognostic utility, in addition to standard clinical and echocardiographic parameters.

It is unknown whether canagliflozin, a selective sodium glucose co-transporter 2 inhibitor, reduces epicardial adipose tissue (EAT) thickness, which is associated with insulin resistance and is a risk factor for coronary artery disease. We administered 100 mg of canagliflozin for 6 months to 13 patients with type 2 diabetes mellitus. We evaluated glycemic control, visceral adipose tissue (VAT) area and subcutaneous adipose tissue (SAT) area, and skeletal muscle mass by using impedance methods, and EAT thickness by using echocardiography. Canagliflozin treatment for 6 months decreased hemoglobin A1c level from 7.1 ± 0.5% to 6.7 ± 0.6% (P < 0.05) and decreased EAT thickness from 9.3 ± 2.5 to 7.3 ± 2.0 mm (P < 0.001), along with a trend of decreasing VAT and SAT area. No association was found between any of these changes. Canagliflozin reduced EAT thickness in patients with type 2 diabetes mellitus independent of its effect on lowering blood glucose, suggesting that canagliflozin may have an effect in preventing cardiovascular events in these patients (UMIN000021327).

Lifestyle-related diseases promote atherosclerosis, a chronic inflammatory disease; however, the molecular mechanism remains largely unknown. Endogenous DNA fragments released under over-nutrient condition provoke sterile inflammation through the recognition by DNA sensors. Here, we investigated the role of stimulator of interferon genes (STING), a cytosolic DNA sensor, in atherogenesis. Apolipoprotein E-deficient (Apoe^−/−) mice fed a western-type diet (WTD), a hypercholesterolaemic mouse model, showed higher STING expression and markers for DNA damage such as γH2AX, p53, and single-stranded DNA (ssDNA) accumulation in macrophages in the aorta compared with wild-type (WT) mice. The level of cGAMP, a STING agonist, in the aorta was higher in Apoe^−/− mice. Genetic deletion of Sting in Apoe^−/− mice reduced atherosclerotic lesions in the aortic arch, lipid, and macrophage accumulation in plaques, and inflammatory molecule expression in the aorta compared with the control. Pharmacological blockade of STING using a specific inhibitor, C-176, ameliorated atherogenesis in Apoe^−/− mice. In contrast, bone marrow-specific STING expression in Apoe^−/− mice stimulated atherogenesis. Expression or deletion of STING did not affect metabolic parameters and blood pressure. In vitro studies revealed that STING activation by cGAMP or mitochondrial DNA accelerated inflammatory molecule expression (e.g. TNF-α or IFN-β) in mouse and human macrophages. Activation of nuclear factor-κB and TANK binding kinase 1 was involved in STING-associated vascular inflammation and macrophage activation. Furthermore, human atherosclerotic lesions in the carotid arteries expressed STING and cGAMP. Stimulator of interferon genes stimulates pro-inflammatory activation of macrophages, leading to the development of atherosclerosis. Stimulator of interferon genes signalling may serve as a potential therapeutic target for atherosclerosis. STING signalling, originally associated with innate immune system, may provide a novel mechanism of atherogenesis by linking lifestyle-related diseases to chronic inflammatory disease and serve as a potential therapeutic target for atherosclerosis.

Background—: The role of exercise-induced pulmonary hypertension in decision making regarding surgical timing for asymptomatic chronic mitral regurgitation is controversial. We reasoned that the exercise-induced pulmonary hypertension response could not be interpreted without knowledge of right ventricular (RV) function. The aim of this study was to assess the role of RV measures at rest and during exercise as predictors of prognosis in asymptomatic mitral regurgitation. Methods and Results—: Comprehensive resting and exercise echocardiography was performed in 196 consecutive patients (56±13 years; 64% male) with isolated moderate to severe mitral regurgitation (effective regurgitant orifice area, 38±18 mm ² ) and preserved left ventricular function in whom initial management was expectant. Left ventricular and RV longitudinal strain were analyzed at rest using velocity vector imaging. Tricuspid annular plane systolic excursion and systolic pulmonary arterial pressure were measured at rest and during exercise. Valve surgery was performed in 88 patients (45%) over 27±15 months. After adjustment for age and sex in a Cox proportional-hazards model, exercise tricuspid annular plane systolic excursion (hazard ratio, 0.26; P <0.001), was associated with valve surgery-free survival, independent of resting left ventricular strain (hazard ratio, 1.09; P =0.027), exercise systolic pulmonary arterial pressure (hazard ratio, 1.03; P <0.001), and resting RV strain (hazard ratio, 1.10; P =0.004). In sequential Cox models, a model based on clinical data and left ventricular strain (χ ² , 15.9) was improved by RV strain and RV chamber size (χ ² , 28.8; P =0.003) and exercise systolic pulmonary arterial pressure (χ ² , 40.1; P =0.002) and further increased by exercise tricuspid annular plane systolic excursion (χ ² , 52.2; P =0.002). Conclusions—: Exercise-induced RV dysfunction provides important incremental prognostic value in the management of asymptomatic mitral regurgitation.

Objective Cardiac amyloidosis (CA) is a rapidly progressive disease that portends poor prognosis. Our objective was to evaluate the prognostic impact of relative regional strain ratio (RRSR, a measure of the relative apical sparing of longitudinal strain (LS)) in CA. Methods This is a retrospective study evaluating 97 patients with CA from 2004 to 2013. Patients were included if they met criteria for CA based on endomyocardial biopsy or advanced imaging criteria coupled with either extracardiac biopsy or genetic analysis. Baseline clinical and imaging data were collected and compared between light-chain amyloidosis (AL) (n=59) and transthyretin amyloidosis (ATTR) (n=38) subtypes. RRSR was defined as the average apical LS divided by the sum of the average mid and basal LS values. A Cox proportional hazards model was used to assess the effects of clinical and echocardiographic characteristics, including RRSR, on the outcome of time to death or heart transplantation. Results Despite younger age, the AL subtype had a statistically significant association with the composite outcome as compared with ATTR (p=0.022). Log-transformed RRSR was independently associated with the composite outcome at 5 years (HR 2.45 (1.36 to 4.40), p=0.003). Patients with low ejection fraction and high RRSR had the worst prognosis. In multivariable analysis, RRSR remained predictive of the primary outcome (p=0.018). Addition of covariates related to systolic function (global LS and ejection fraction) to the model attenuated this effect. Conclusions High RRSR is adversely prognostic in patients with cardiac amyloid. This novel tool is both diagnostic and prognostic and may have implications in management and suitability for treatment.