Ventricular Pressure

BackgroundLiraglutide is an antidiabetic agent with cardioprotective effect. The purpose of this study is to test efficacy of liraglutide to improve diabetic cardiomyopathy in patients with diabetes mellitus type 2 (DM2) without cardiovascular disease.MethodsPatients with DM2 were randomly assigned to receive liraglutide 1.8 mg/day or placebo in this double-blind trial of 26 weeks. Primary outcome measures were LV diastolic function (early (E) and late (A) transmitral peak flow rate, E/A ratio, early deceleration peak (Edec), early peak mitral annular septal tissue velocity (Ea) and estimated LV filling pressure (E/Ea), and systolic function (stroke volume, ejection fraction, cardiac output, cardiac index and peak ejection rate) assessed with CMR. Intention-to-treat analysis of between-group differences was performed using ANCOVA. Mean estimated treatment differences (95% confidence intervals) are reported.Results23 patients were randomized to liraglutide and 26 to placebo. As compared with placebo, liraglutide significantly reduced E (- 56 mL/s (- 91 to - 21)), E/A ratio (- 0.17 (- 0.27 to - 0.06)), Edec (- 0.9 mL/s2 * 10-3 (- 1.3 to - 0.2)) and E/Ea (- 1.8 (- 3.0 to - 0.6)), without affecting A (3 mL/s (- 35 to 41)) and Ea (0.4 cm/s (- 0.9 to 1.4)). Liraglutide reduced stroke volume (- 9 mL (- 16 to - 2)) and ejection fraction (- 3% (- 6 to - 0.1)), but did not change cardiac output (- 0.4 L/min (- 0.9 to 0.2)), cardiac index (- 0.1 L/min/m2 (- 0.4 to 0.1)) and peak ejection rate (- 46 mL/s (- 95 to 3)).ConclusionsLiraglutide reduced early LV diastolic filling and LV filling pressure, thereby unloading the left ventricle. LV systolic function reduced and remained within normal range. Future studies are needed to investigate if liraglutide-induced left ventricular unloading slows progression of diabetic cardiomyopathy into symptomatic stages. Trial registration ClinicalTrials.gov: NCT01761318.

Despite the existing association of gut dysbiosis and T cell inflammation in heart failure (HF), whether and how gut microbes contribute to T cell immune responses, cardiac fibrosis and dysfunction in HF remains largely unexplored. Our objective was to investigate whether gut dysbiosis is induced by cardiac pressure overload, and its effect in T cell activation, adverse cardiac remodeling, and cardiac dysfunction. We used 16S rRNA sequencing of fecal samples and discovered that cardiac pressure overload-induced by transverse aortic constriction (TAC) results in gut dysbiosis, characterized by a reduction of tryptophan and short-chain fatty acids producing bacteria in WT mice, but not in T cell-deficient mice (Tcra-/- ) mice. These changes did not result in T cell activation in the gut or gut barrier disruption. Strikingly, microbiota depletion in WT mice resulted in decreased heart T cell infiltration, decreased cardiac fibrosis, and protection from systolic dysfunction in response to TAC. Spontaneous reconstitution of the microbiota partially reversed these effects. We observed decreased cardiac expression of the Aryl hydrocarbon receptor (AhR) and enzymes associated with tryptophan metabolism in WT mice, but not in Tcra-/- mice, or in mice depleted of the microbiota. These findings demonstrate that cardiac pressure overload induced gut dysbiosis and T cell immune responses contribute to adverse cardiac remodeling, and identify the potential contribution of tryptophan metabolites and the AhR to protection from adverse cardiac remodeling and systolic dysfunction in HF.

Activating transcription factor 3 (ATF3), which is encoded by an adaptive-response gene induced by various stimuli, plays an important role in the cardiovascular system. However, the effect of ATF3 on cardiac hypertrophy induced by a pathological stimulus has not been determined. Here, we investigated the effects of ATF3 deficiency on cardiac hypertrophy using in vitro and in vivo models. Aortic banding (AB) was performed to induce cardiac hypertrophy in mice. Cardiac hypertrophy was estimated by echocardiographic and hemodynamic measurements and by pathological and molecular analysis. ATF3 deficiency promoted cardiac hypertrophy, dysfunction and fibrosis after 4 weeks of AB compared to the wild type (WT) mice. Furthermore, enhanced activation of the MEK-ERK1/2 and JNK pathways was found in ATF3-knockout (KO) mice compared to WT mice. In vitro studies performed in cultured neonatal mouse cardiomyocytes confirmed that ATF3 deficiency promotes cardiomyocyte hypertrophy induced by angiotensin II, which was associated with the amplification of MEK-ERK1/2 and JNK signaling. Our results suggested that ATF3 plays a crucial role in the development of cardiac hypertrophy via negative regulation of the MEK-ERK1/2 and JNK pathways.

BackgroundRight heart catheterization (RHC) with pulmonary capillary wedge pressure (PCWP) assessment is the reference standard for diagnosis of heart failure with preserved ejection fraction (HFpEF), but remains largely underused. Different approaches for non-invasive PCWP calculation have been proposed. However, as left atrial strain (LA Es) and end-systolic volume index (ESVi) emerge as key criteria in HFpEF, we sought to investigate them for PCWP calculation.MethodsThe derivation population consisted of patients referred to RHC and cardiovascular magnetic resonance (CMR) imaging who were enrolled in a prospective monocentric registry. Patients were classified by RHC according to current guideline recommendations. The external validation population consisted of patients included in the HFpEF-Stress trial who underwent exercise-stress RHC and CMR with follow-up after 4 years for hospitalized cardiovascular events. Performance of strain-derived PCWP was compared to a published LA volume (LAV) and left ventricular mass (LVM) derived method.ResultsThe derivation population consisted of n = 209 patients, n = 123 underwent exercise-stress RHC (n = 55 without pulmonary hypertension [PH], n = 72 pre-capillary, n = 27 combined post- and pre-capillary pulmonary hypertension [CpcPH], n = 15 isolated post-capillary pulmonary hypertension [IpcPH], n = 34 exercise, and n = 6 unclassified PH). Linear regression models identified the following formulae for functional PCWPrest 10.304 - 0.095 * Es + 0.098 * ESVi and functional PCWPstress 24.666 - 0.251 * Es + 0.056 * ESVi calculation. The validation population consisted of n = 74 patients (n = 15 without, n = 5 pre-capillary, n = 8 CpcPH, n = 10 IpcPH, and n = 32 exercise PH with n = 4 remaining unclassified). Functional PCWPrest (11.8) and RHC-derived PCWPrest (11 mmHg) were statistically similar (p = 0.285) and showed moderate correlation (r = 0.53, p ConclusionFunctional PCWP may aid in the identification of post-capillary involvement in PH and HFpEF superiorly compared to morphology-derived PCWP and shows prognostic implications.