an-intact-pericardium-ischemic-rodent-model

An Intact Pericardium Ischemic Rodent Model

This protocol has shown that the pericardium and its contents play an essential anti-fibrotic role in the ischemic rodent model (coronary ligation to ...

Cumming School of Medicine

Cecal microbiota from type 2 diabetic (db/db) and control (db/(+)) mice was obtained following 6 weeks of sedentary or exercise activity. qPCR analysis revealed a main effect of exercise, with greater abundance of select Firmicutes species and lower Bacteroides/Prevotella spp. in both normal and diabetic exercised mice compared with sedentary counterparts. Conversely, Bifidobacterium spp. was greater in exercised normal but not diabetic mice (exercise × diabetes interaction). How exercise influences gut microbiota requires further investigation. 

Exercise training modifies gut microbiota in normal and diabetic mice.

Structural cardiac remodeling after ischemic injury can induce a transition to heart failure from progressive loss of cardiac function. Cellular regenerative therapies are promising but face significant translational hurdles. Tissue extracellular matrix (ECM) holds the necessary environmental cues to stimulate cell-based endogenous myocardial repair pathways and promote adaptive remodeling toward functional recovery. Heart epicardium has emerged as an important anatomic niche for endogenous repair pathways including vasculogenesis and cardiogenesis. We show that acellular ECM scaffolds surgically implanted on the epicardium following myocardial infarction (MI) can attenuate structural cardiac remodeling and improve functional recovery. We assessed the efficacy of this strategy on post-MI functional recovery by comparing intact bioactive scaffolds with biologically inactivated ECM scaffolds. We confirm that bioactive properties within the acellular ECM biomaterial are essential for the observed functional benefits. We show that interaction of human cardiac fibroblasts with bioactive ECM can induce a robust cell-mediated vasculogenic paracrine response capable of functional blood vessel assembly. Fibroblast growth factor-2 is uncovered as a critical regulator of this novel bioinductive effect. Acellular bioactive ECM scaffolds surgically implanted on the epicardium post-MI can reprogram resident fibroblasts and stimulate adaptive pro-reparative pathways enhancing functional recovery. We introduce a novel surgical strategy for tissue repair that can be performed as an adjunct to conventional surgical revascularization with minimal translational challenges.

Bioactive Extracellular Matrix Scaffold Promotes Adaptive Cardiac Remodeling and Repair.

Atrial fibrillation (AF) is prevalent in hypertension and elevated angiotensin II (Ang II); however, the mechanisms by which Ang II leads to AF are poorly understood. Here, we investigated the basis for this in mice treated with Ang II or saline for 3 weeks. Ang II treatment increased susceptibility to AF compared to saline controls in association with increases in P wave duration and atrial effective refractory period, as well as reductions in right and left atrial conduction velocity. Patch-clamp studies demonstrate that action potential (AP) duration was prolonged in right atrial myocytes from Ang II treated mice in association with a reduction in repolarizing K currents. In contrast, APs in left atrial myocytes from Ang II treated mice showed reductions in upstroke velocity and overshoot, as well as greater prolongations in AP duration. Ang II reduced Na current (I) in the left, but not the right atrium. This reduction in I was reversible following inhibition of protein kinase C (PKC) and PKCα expression was increased selectively in the left atrium in Ang II treated mice. The transient outward K current (I) showed larger reductions in the left atrium in association with a shift in the voltage dependence of activation. Finally, Ang II caused fibrosis throughout the atria in association with changes in collagen expression and regulators of the extracellular matrix. This study demonstrates that hypertension and elevated Ang II cause distinct patterns of electrical and structural remodeling in the right and left atria that collectively create a substrate for AF.

Distinct patterns of atrial electrical and structural remodeling in angiotensin II mediated atrial fibrillation.

Fluoroquinolone (FQ) antibiotics are associated with adverse aortic clinical events. We assessed human aortic myofibroblast-mediated extracellular matrix (ECM) dysregulation as a possible cellular mechanism underlying FQ-associated aortopathy.

Induction of human aortic myofibroblast-mediated extracellular matrix dysregulation: A potential mechanism of fluoroquinolone-associated aortopathy.

Empagliflozin, an SGLT2 inhibitor, has shown remarkable reductions in cardiovascular mortality and heart failure admissions (EMPA-REG OUTCOME). However, the mechanism underlying the heart failure protective effects of empagliflozin remains largely unknown. Cardiac fibroblasts play an integral role in the progression of structural cardiac remodelling and heart failure, in part, by regulating extracellular matrix (ECM) homeostasis. The objective of this study was to determine if empagliflozin has a direct effect on human cardiac myofibroblast-mediated ECM remodelling.

Direct Effects of Empagliflozin on Extracellular Matrix Remodelling in Human Cardiac Myofibroblasts: Novel Translational Clues to Explain EMPA-REG OUTCOME Results.

Atrial fibrillation (AF) is prevalent in diabetes mellitus (DM); however, the basis for this is unknown. This study investigated AF susceptibility and atrial electrophysiology in type 1 diabetic Akita mice using in vivo intracardiac electrophysiology, high-resolution optical mapping in atrial preparations, and patch clamping in isolated atrial myocytes. qPCR and western blotting were used to assess ion channel expression. Akita mice were highly susceptible to AF in association with increased P-wave duration and slowed atrial conduction velocity. In a second model of type 1 DM, mice treated with streptozotocin (STZ) showed a similar increase in susceptibility to AF. Chronic insulin treatment reduced susceptibility and duration of AF and shortened P-wave duration in Akita mice. Atrial action potential (AP) morphology was altered in Akita mice due to a reduction in upstroke velocity and increases in AP duration. In Akita mice, atrial Na current (I) and repolarizing K current (I) carried by voltage gated K (K1.5) channels were reduced. The reduction in I occurred in association with reduced expression of  and voltage gated Na (Na1.5) channels as well as a shift in I activation kinetics. Insulin potently and selectively increased I in Akita mice without affecting I Chronic insulin treatment increased I in association with increased expression of Na1.5. Acute insulin also increased I, although to a smaller extent, due to enhanced insulin signaling via phosphatidylinositol 3,4,5-triphosphate (PIP). Our study reveals a critical, selective role for insulin in regulating atrial I, which impacts susceptibility to AF in type 1 DM.

Loss of insulin signaling may contribute to atrial fibrillation and atrial electrical remodeling in type 1 diabetes.

Coronary heart disease is a leading cause of death. Tissue remodeling and fibrosis results in cardiac pump dysfunction and ischemic heart failure. Cardiac fibroblasts may rebuild damaged tissues when prompted by suitable environmental cues. Here, we use acellular biologic extracellular matrix scaffolds (bioscaffolds) to stimulate pathways of muscle repair and restore tissue function. We show that acellular bioscaffolds with bioinductive properties can redirect cardiac fibroblasts to rebuild microvascular networks and avoid tissue fibrosis. Specifically, when human cardiac fibroblasts are combined with bioactive scaffolds, gene expression is upregulated and paracrine mediators are released that promote vasculogenesis and prevent scarring. We assess these properties in rodents with myocardial infarction and observe bioscaffolds to redirect fibroblasts, reduce tissue fibrosis and prevent maladaptive structural remodeling. Our preclinical data confirms that acellular bioscaffold therapy provides an appropriate microenvironment to stimulate pathways of functional repair. We translate our observations to patients with coronary heart disease by conducting a first-in-human observational cohort study. We show that bioscaffold therapy is associated with improved perfusion of infarcted myocardium, reduced myocardial scar burden, and reverse structural remodeling. We establish that clinical use of acellular bioscaffolds is feasible and offers a new frontier to enhance surgical revascularization of ischemic heart muscle.

Acellular bioscaffolds redirect cardiac fibroblasts and promote functional tissue repair in rodents and humans with myocardial injury.

Atrial fibrillation (AF) is highly prevalent in diabetes mellitus (DM), yet the basis for this finding is poorly understood. Type 2 DM may be associated with unique patterns of atrial electrical and structural remodeling; however, this has not been investigated in detail.

Electrical and structural remodeling contribute to atrial fibrillation in type 2 diabetic db/db mice.

Heart rate (HR) is a critical indicator of cardiac performance that is determined by sinoatrial node (SAN) function and regulation. Natriuretic peptides, including C-type NP (CNP) have been shown to modulate ion channel function in the SAN when applied exogenously. CNP is the only NP that acts as a ligand for natriuretic peptide receptor-B (NPR-B). Despite these properties, the ability of CNP and NPR-B to regulate HR and intrinsic SAN automaticity in vivo, and the mechanisms by which it does so, are incompletely understood. Thus, the objective of this study was to determine the role of NPR-B signaling in regulating HR and SAN function.

Article	Year
Exercise training modifies gut microbiota in normal and diabetic mice. Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme\| PubMed ID: 25962839	2015
Bioactive Extracellular Matrix Scaffold Promotes Adaptive Cardiac Remodeling and Repair. JACC. Basic to translational science\| PubMed ID: 30062163	2017
Distinct patterns of atrial electrical and structural remodeling in angiotensin II mediated atrial fibrillation. Journal of molecular and cellular cardiology\| PubMed ID: 30273558	2018
Induction of human aortic myofibroblast-mediated extracellular matrix dysregulation: A potential mechanism of fluoroquinolone-associated aortopathy. The Journal of thoracic and cardiovascular surgery\| PubMed ID: 30528439	2019
Direct Effects of Empagliflozin on Extracellular Matrix Remodelling in Human Cardiac Myofibroblasts: Novel Translational Clues to Explain EMPA-REG OUTCOME Results. The Canadian journal of cardiology\| PubMed ID: 31837891	2020
Loss of insulin signaling may contribute to atrial fibrillation and atrial electrical remodeling in type 1 diabetes. Proceedings of the National Academy of Sciences of the United States of America\| PubMed ID: 32198206	2020
Acellular bioscaffolds redirect cardiac fibroblasts and promote functional tissue repair in rodents and humans with myocardial injury. Scientific reports\| PubMed ID: 32528051	2020
Electrical and structural remodeling contribute to atrial fibrillation in type 2 diabetic db/db mice. Heart rhythm\| PubMed ID: 32911049	2021
Natriuretic peptide receptor B maintains heart rate and sinoatrial node function via cyclic GMP-mediated signaling. Cardiovascular research\| PubMed ID: 34273155	2021

Darrell D. Belke

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