Glucagon-like peptide-1 protects against ischemic left ventricular dysfunction during hyperglycemia in patients with coronary artery disease and type 2 diabetes mellitus.

BACKGROUND: Enhancement of myocardial glucose uptake may reduce fatty acid oxidation and improve tolerance to ischemia. Hyperglycemia, in association with hyperinsulinemia, stimulates this metabolic change but may have deleterious effects on left ventricular (LV) function. The incretin hormone, glucagon-like peptide-1 (GLP-1), also has favorable cardiovascular effects, and has emerged as an alternative method of altering myocardial substrate utilization. In patients with coronary artery disease (CAD), we investigated: (1) the effect of a hyperinsulinemic hyperglycemic clamp (HHC) on myocardial performance during dobutamine stress echocardiography (DSE), and (2) whether an infusion of GLP-1(7-36) at the time of HHC protects against ischemic LV dysfunction during DSE in patients with type 2 diabetes mellitus (T2DM). METHODS: In study 1, twelve patients underwent two DSEs with tissue Doppler imaging (TDI)-one during the steady-state phase of a HHC. In study 2, ten patients with T2DM underwent two DSEs with TDI during the steady-state phase of a HHC. GLP-1(7-36) was infused intravenously at 1.2 pmol/kg/min during one of the scans. In both studies, global LV function was assessed by ejection fraction and mitral annular systolic velocity, and regional wall LV function was assessed using peak systolic velocity, strain and strain rate from 12 paired non-apical segments. RESULTS: In study 1, the HHC (compared with control) increased glucose (13.0 ± 1.9 versus 4.8 ± 0.5 mmol/l, p < 0.0001) and insulin (1,212 ± 514 versus 114 ± 47 pmol/l, p = 0.01) concentrations, and reduced FFA levels (249 ± 175 versus 1,001 ± 333 μmol/l, p < 0.0001), but had no net effect on either global or regional LV function. In study 2, GLP-1 enhanced both global (ejection fraction, 77.5 ± 5.0 versus 71.3 ± 4.3%, p = 0.004) and regional (peak systolic strain -18.1 ± 6.6 versus -15.5 ± 5.4%, p < 0.0001) myocardial performance at peak stress and at 30 min recovery. These effects were predominantly driven by a reduction in contractile dysfunction in regions subject to demand ischemia. CONCLUSIONS: In patients with CAD, hyperinsulinemic hyperglycemia has a neutral effect on LV function during DSE. However, GLP-1 at the time of hyperglycemia improves myocardial tolerance to demand ischemia in patients with T2DM. TRIAL REGISTRATION: http://www.isrctn.org . Unique identifier ISRCTN69686930

Left Atrial Function Is Associated with Earlier Need for Cardiac Surgery in Moderate to Severe Mitral Regurgitation: Usefulness in Targeting for Early Surgery

BACKGROUND: The aim of this study was to determine whether assessment of left atrial (LA) function helps identify patients at risk for early deterioration during follow-up with mitral valve prolapse and mitral regurgitation. METHODS: Patients with moderate to severe mitral regurgitation but no guideline-based indications for surgery were retrospectively identified from a dedicated clinical database. Maximal and minimal LA volumes were used to derive total LA emptying fraction ([maximal LA volume - minimal LA volume]/maximal L volume × 100%). Average values of peak contractile, conduit, and reservoir strain were obtained using two-dimensional speckle-tracking imaging. The study outcome was time to mitral surgery. RESULTS: One hundred seventeen patients were included; median follow-up was 18 months. Sixty-eight patients underwent surgery. Receiver operating characteristic curves were used to derive optimal cutoffs for TLAEF (>50.7%) and strain (reservoir, >28.5%; contractile, >12.5%). Using Cox analysis, TLAEF and contractile, reservoir, and conduit strain were univariate predictors of time to event. After multivariate analysis, TLAEF (hazard ratio, 2.59; P = .001), reservoir strain (hazard ratio, 3.06; P < .001), and contractile strain (hazard ratio, 2.01; P = .022) remained independently associated with events, but conduit strain did not. Using Kaplan-Meier curves, event-free survival was considerably improved in patients with values above the derived thresholds (TLAEF: 1-year survival, 78 ± 5% vs 28 ± 8%; 3-year survival, 68 ± 6% vs 13 ± 5%; P < .001 for both; reservoir strain: 1-year survival, 79 ± 5% vs 29 ± 7%; 3-year survival, 67 ± 6% vs 15 ± 6%; P < .001 for both; contractile strain: 1-year survival, 80 ± 5% vs 41 ± 7%; 3-year survival, 69 ± 6% vs 24 ± 6%; P < .001 for both). CONCLUSION: LA function is independently associated with surgery-free survival in patients with mitral valve prolapse and moderate to severe mitral regurgitation. Quantitative assessment of LA function may have clinical utility in guiding early surgical intervention in these patients

Atrial fibrillation in embolic stroke of undetermined source: Role of advanced imaging of left atrial function

Background: Atrial fibrillation (AF) is detected in over 30% of patients following an embolic stroke of undetermined source (ESUS) when monitored with an implantable loop recorder (ILR). Identifying AF in ESUS survivors has significant therapeutic implications and AF risk is essential to guide screening with long-term monitoring. The present study aimed to establish the role of Left Atrial (LA) function in subsequent AF identification and develop a risk model for AF in ESUS. Methods: We conducted a single-centre retrospective case-control study including all patients with ESUS referred to our institution for ILR implantation from December 2009 to September 2019. We recorded clinical variables at baseline and analyzed transthoracic echocardiograms in sinus rhythm. Univariate and multivariable analyses were performed to inform variables associated with AF. Lasso regression analysis was used to develop a risk prediction model for AF. The risk model was internally validated using bootstrapping. Results: Three hundred and twenty-three patients with ESUS underwent ILR implantation. In the ESUS population, 293 had a stroke, whereas 30 had suffered a TIA as adjudicated by a senior stroke physician. AF of any duration was detected in 47.1%. Mean follow-up was 710 days. Following lasso regression with backward elimination, we combined increasing lateral PA (the time interval from the beginning of p wave on surface electrocardiogram to the beginning of A’ wave on pulsed wave tissue Doppler of the lateral mitral annulus) (OR 1.011), increasing Age (OR 1.035), higher diastolic blood pressure (DBP) (OR 1.027) and abnormal LA reservoir Strain (OR 0.973) into a new PADS score. The probability of identifying AF can be estimated using the formula: Model discrimination was good (AUC 0.72). The PADS score was internally validated using bootstrapping with 1000 samples of 150 patients showing consistent results with an AUC of 0.73. Conclusions: The novel PADS score can identify the risk of AF on prolonged monitoring with ILR following ESUS and should be considered a dedicated risk-stratification tool for decision-making regarding the screening strategy for AF in stroke

Editing independent effects of ADARs on the miRNA/siRNA pathways

Adenosine deaminases acting on RNA (ADARs) are best known for altering the coding sequences of mRNA through RNA editing, as in the GluR-B Q/R site. ADARs have also been shown to affect RNA interference (RNAi) and microRNA processing by deamination of specific adenosines to inosine. Here, we show that ADAR proteins can affect RNA processing independently of their enzymatic activity. We show that ADAR2 can modulate the processing of mir-376a2 independently of catalytic RNA editing activity. In addition, in a Drosophila assay for RNAi deaminase-inactive ADAR1 inhibits RNAi through the siRNA pathway. These results imply that ADAR1 and ADAR2 have biological functions as RNA-binding proteins that extend beyond editing per se and that even genomically encoded ADARs that are catalytically inactive may have such functions

Prognostic Value of Cardiac Magnetic Resonance Feature Tracking Strain in Aortic Stenosis

Background: Recent data have suggested that global longitudinal strain (GLS) could be useful for risk stratification of patients with severe aortic stenosis (AS). In this study, we aimed to investigate the prognostic role of GLS in patients with AS and also its incremental value in relation to left ventricular ejection fraction (LVEF) and late gadolinium enhancement (LGE). Methods: We analysed all consecutive patients with AS and LGE-CMR in our institution. Survival data were obtained from office of national statistics, a national body where all deaths in England are registered by law. Death certificates were obtained from the general register office. Results: Some 194 consecutive patients with aortic stenosis were investigated with CMR at baseline and followed up for 7.3 ± 4 years. On multivariate Cox regression analysis, only increasing age remained significant for both all-cause and cardiac mortality, while LGE (any pattern) retained significance for all-cause mortality and had a trend to significance for cardiac mortality. Kaplan–Meier survival analysis demonstrated that patients in the best and middle GLS tertiles had significantly better mortality compared to patients in the worst GLS tertiles. Importantly though, sequential Cox proportional-hazard analysis demonstrated that GLS did not have significant incremental prognostic value for all-cause mortality or cardiac mortality in addition to LVEF and LGE. Conclusions: Our study has demonstrated that age and LGE but not GLS are significant poor prognostic indicators in patients with moderate and severe AS

Echocardiographic assessment of aortic stenosis: a practical guideline from the British Society of Echocardiography.

The guideline provides a practical step-by-step guide in order to facilitate high-quality echocardiographic studies of patients with aortic stenosis. In addition, it addresses commonly encountered yet challenging clinical scenarios and covers the use of advanced echocardiographic techniques, including TOE and Dobutamine stress echocardiography in the assessment of aortic stenosis

Management of asymptomatic severe aortic stenosis: a systematic review and meta-analysis.

Funder: National Institute for Health Research (NIHR)OBJECTIVES: The management of severe aortic stenosis mandates consideration of aortic valve intervention for symptomatic patients. However, for asymptomatic patients with severe aortic stenosis, recent randomised trials supported earlier intervention. We conducted a systematic review and meta-analysis to evaluate all the available data comparing the two management strategies. METHODS: PubMed, Cochrane and Web of Science databases were systematically searched from inception until 10 January 2022. The search key terms were 'asymptomatic', 'severe aortic stenosis' and 'intervention'. RESULTS: Meta-analysis of two published randomised trials, AVATAR and RECOVERY, included 302 patients and showed that early intervention resulted in 55% reduction in all-cause mortality (HR=0.45, 95% CI 0.24 to 0.86; I2 0%) and 79% reduction in risk of hospitalisation for heart failure (HR=0.21, 95% CI 0.05 to 0.96; I2 15%). There was no difference in risk of cardiovascular death between the two groups (HR=0.36, 95% CI 0.03 to 3.78; I2 78%). Additionally, meta-analysis of eight observational studies showed improved mortality in patients treated with early intervention (HR=0.38, 95% CI 0.26 to 0.56; I2 77%). CONCLUSION: This meta-analysis provides evidence that, in patients with severe asymptomatic aortic stenosis, early intervention reduces all-cause mortality and improves outcomes compared with conservative management. While this is very encouraging, further randomised controlled studies are needed to draw firm conclusions and identify the optimal timing of intervention. PROSPERO REGISTRATION NUMBER: CRD42022301037