scholarly journals Increasing mitochondrial ATP synthesis with butyrate normalizes ADP and contractile function in metabolic heart disease

2020 ◽  
Vol 33 (5) ◽  
Author(s):  
Marcello Panagia ◽  
Huamei He ◽  
Tomas Baka ◽  
David R. Pimentel ◽  
Dominique Croteau ◽  
...  
Keyword(s):  
Heart Disease ◽  
Contractile Function ◽  
Atp Synthesis ◽  
Metabolic Heart Disease

Abstract 15315: SGLT2 Inhibitor Ertugliflozin Decreases Elevated Intracellular Sodium, Improves Myocardial Energetics and Enhances Function in Metabolic Heart Disease

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Dominique Croteau ◽  
Tomas Baka ◽  
Sara Young ◽  
Huamei He ◽  
David R Pimentel ◽  
...  
Keyword(s):  
Heart Failure ◽  
Heart Disease ◽  
Contractile Function ◽  
Control Diet ◽  
Sglt2 Inhibitor ◽  
Atp Synthesis ◽  
Intracellular Sodium ◽  
Contractile Reserve ◽  
Isolated Hearts ◽  
Metabolic Heart Disease

Background: Sodium-glucose co-transporter 2 (SGLT2) inhibitors are antidiabetic drugs of great interest in cardiology due to their improvement of heart failure outcomes independent of diabetes. As SGLT2 is not expressed in cardiomyocytes, the mechanism of such benefit remains unclear. Elevated myocardial intracellular sodium [Na + ] i has been found in heart failure and SGLT2 inhibition lowers [Na + ] i in isolated cardiomyocytes. Elevated [Na + ] i was shown to decrease mitochondrial calcium via mitochondrial Na/Ca exchanger (NCx MITO ), resulting in decreased mitochondrial ATP synthesis. We have previously shown that mice fed a diet high in fat and sugar (HFHS) develop metabolic heart disease (MHD) characterized by decreased mitochondrial ATP synthesis with decreased phosphocreatine (PCr), worsened diastolic function and contractile reserve. We hypothesize that the SGLT2 inhibitor ertugliflozin (ERTU) decreases the elevated [Na + ] i to improve energetics and contractile function in MHD. Methods and Results: Isolated hearts from mice after 6 months of HFHS vs. control diet (CD), +/- ERTU in the last month, were studied using 31 P and 23 Na NMR spectroscopy to measure PCr/ATP ratio and [Na + ] i , respectively. As expected, HFHS hearts showed lower PCr/ATP, diastolic dysfunction (↑LVEDP) and lack of contractile reserve (↓RPP) during high work protocol compared to CD hearts. Myocardial [Na + ] i was elevated more than 2-fold in HFHS compared to CD. One month of ERTU treatment decreased [Na + ] i and improved energetics and contractile function in HFHS to levels similar to or better than CD. Perfusion with CGP 37157, which inhibits NCx MITO , improved PCr/ATP in HFHS hearts. Conclusion: Lowering of myocardial [Na + ] i by ertugliflozin contributes to improved energetics and function in MHD. These results suggest targeting [Na + ] i as an effective strategy to improve cardiac dysfunction in MHD and other forms of heart disease associated with elevated myocardial [Na + ] i.

scholarly journals Chronic Perinatal Hypoxia Delays Cardiac Maturation in a Mouse Model for Cyanotic Congenital Heart Disease

2020 ◽  
Author(s):  
Jennifer Romanowicz ◽  
Zaenab Dhari ◽  
Devon Guerrelli ◽  
Colm Mulvany ◽  
Marissa Reilly ◽  
...  
Keyword(s):  
Gene Expression ◽  
Congenital Heart Disease ◽  
Heart Disease ◽  
Congenital Heart ◽  
Chronic Hypoxia ◽  
Cardiac Development ◽  
Contractile Function ◽  
Adverse Outcomes ◽  
Perinatal Hypoxia ◽  
Postnatal Environment

AbstractBackgroundCompared to acyanotic congenital heart disease (CHD), cyanotic CHD has an increased risk of lifelong mortality and morbidity. These adverse outcomes may be attributed to delayed cardiomyocyte maturation, since the transition from a hypoxic fetal milieu to oxygen rich postnatal environment is disrupted. We established a rodent model to replicate hypoxic myocardial conditions spanning perinatal development, and tested the hypothesis that chronic hypoxia impairs cardiac development.MethodsMouse dams were housed in hypoxia beginning at embryonic day 16. Pups stayed in hypoxia until postnatal day (P)8 when cardiac development is nearly complete. Global gene expression was quantified at P8 and at P30, after recovering in normoxia. Phenotypic testing included electrocardiogram, echocardiogram, and ex-vivo electrophysiology study.ResultsHypoxic animals were 48% smaller than controls. Gene expression was grossly altered by hypoxia at P8 (1427 genes affected), but normalized after recovery (P30). Electrocardiograms revealed bradycardia and slowed conduction velocity in hypoxic animals at P8, which resolved after recovery (P30). Notable differences that persisted after recovery (P30) included a 65% prolongation in ventricular effective refractory period, sinus node dysfunction, and a 24% reduction in contractile function in animals exposed to hypoxia.ConclusionsWe investigated the impact of chronic hypoxia on the developing heart. Perinatal hypoxia was associated with changes in gene expression and cardiac function. Persistent changes to the electrophysiologic substrate and contractile function warrant further investigation, and may contribute to adverse outcomes observed in the cyanotic CHD population.

scholarly journals Differential Effects of Sacubitril/Valsartan on Diastolic Function in Mice With Obesity-Related Metabolic Heart Disease

2020 ◽  
Vol 5 (9) ◽  
pp. 916-927
Author(s):  
Dominique Croteau ◽  
Fuzhong Qin ◽  
Jordan M. Chambers ◽  
Ethan Kallick ◽  
Ivan Luptak ◽  
...  
Keyword(s):  
Heart Disease ◽  
Diastolic Function ◽  
Differential Effects ◽  
Metabolic Heart Disease

scholarly journals Impaired Myocardial Energetics Causes Mechanical Dysfunction in Decompensated Failing Hearts

Function ◽  
2020 ◽  
Vol 1 (2) ◽  
Author(s):  
Rachel Lopez ◽  
Bahador Marzban ◽  
Xin Gao ◽  
Ellen Lauinger ◽  
Françoise Van den Bergh ◽  
...  
Keyword(s):  
Heart Failure ◽  
Free Energy ◽  
Inorganic Phosphate ◽  
Contractile Function ◽  
Adenine Nucleotides ◽  
Pressure Overload ◽  
Atp Synthesis ◽  
Whole Body ◽  
Metabolic Dysfunction ◽  
Mechanical Function

Abstract Cardiac mechanical function is supported by ATP hydrolysis, which provides the chemical-free energy to drive the molecular processes underlying cardiac pumping. Physiological rates of myocardial ATP consumption require the heart to resynthesize its entire ATP pool several times per minute. In the failing heart, cardiomyocyte metabolic dysfunction leads to a reduction in the capacity for ATP synthesis and associated free energy to drive cellular processes. Yet it remains unclear if and how metabolic/energetic dysfunction that occurs during heart failure affects mechanical function of the heart. We hypothesize that changes in phosphate metabolite concentrations (ATP, ADP, inorganic phosphate) that are associated with decompensation and failure have direct roles in impeding contractile function of the myocardium in heart failure, contributing to the whole-body phenotype. To test this hypothesis, a transverse aortic constriction (TAC) rat model of pressure overload, hypertrophy, and decompensation was used to assess relationships between metrics of whole-organ pump function and myocardial energetic state. A multiscale computational model of cardiac mechanoenergetic coupling was used to identify and quantify the contribution of metabolic dysfunction to observed mechanical dysfunction. Results show an overall reduction in capacity for oxidative ATP synthesis fueled by either fatty acid or carbohydrate substrates as well as a reduction in total levels of adenine nucleotides and creatine in myocardium from TAC animals compared to sham-operated controls. Changes in phosphate metabolite levels in the TAC rats are correlated with impaired mechanical function, consistent with the overall hypothesis. Furthermore, computational analysis of myocardial metabolism and contractile dynamics predicts that increased levels of inorganic phosphate in TAC compared to control animals kinetically impair the myosin ATPase crossbridge cycle in decompensated hypertrophy/heart failure.

scholarly journals Cardiac microtubules in health and heart disease

2019 ◽  
Vol 244 (15) ◽  
pp. 1255-1272 ◽  
Author(s):  
Matthew A Caporizzo ◽  
Christina Yingxian Chen ◽  
Benjamin L Prosser
Keyword(s):  
Heart Disease ◽  
Intermediate Filaments ◽  
Cardiac Remodeling ◽  
Translational Regulation ◽  
Contractile Function ◽  
Super Resolution ◽  
Post Translational Modification ◽  
Filamentous Actin ◽  
Microtubule Network ◽  
Cytoskeletal Networks

Cardiomyocytes are large (∼40,000 µm3), rod-shaped muscle cells that provide the working force behind each heartbeat. These highly structured cells are packed with dense cytoskeletal networks that can be divided into two groups—the contractile (i.e. sarcomeric) cytoskeleton that consists of filamentous actin-myosin arrays organized into myofibrils, and the non-sarcomeric cytoskeleton, which is composed of β- and γ-actin, microtubules, and intermediate filaments. Together, microtubules and intermediate filaments form a cross-linked scaffold, and these networks are responsible for the delivery of intracellular cargo, the transmission of mechanical signals, the shaping of membrane systems, and the organization of myofibrils and organelles. Microtubules are extensively altered as part of both adaptive and pathological cardiac remodeling, which has diverse ramifications for the structure and function of the cardiomyocyte. In heart failure, the proliferation and post-translational modification of the microtubule network is linked to a number of maladaptive processes, including the mechanical impediment of cardiomyocyte contraction and relaxation. This raises the possibility that reversing microtubule alterations could improve cardiac performance, yet therapeutic efforts will strongly benefit from a deeper understanding of basic microtubule biology in the heart. The aim of this review is to summarize the known physiological roles of the cardiomyocyte microtubule network, the consequences of its pathological remodeling, and to highlight the open and intriguing questions regarding cardiac microtubules. Impact statement Advancements in cell biological and biophysical approaches and super-resolution imaging have greatly broadened our view of tubulin biology over the last decade. In the heart, microtubules and microtubule-based transport help to organize and maintain key structures within the cardiomyocyte, including the sarcomere, intercalated disc, protein clearance machinery and transverse-tubule and sarcoplasmic reticulum membranes. It has become increasingly clear that post translational regulation of microtubules is a key determinant of their sub-cellular functionality. Alterations in microtubule network density, stability, and post-translational modifications are hallmarks of pathological cardiac remodeling, and modified microtubules can directly impede cardiomyocyte contractile function in various forms of heart disease. This review summarizes the functional roles and multi-leveled regulation of the cardiac microtubule cytoskeleton and highlights how refined experimental techniques are shedding mechanistic clarity on the regionally specified roles of microtubules in cardiac physiology and pathophysiology.

Abnormalities in Skeletal Muscle Metabolism in Cyanotic Patients with Congenital Heart Disease: A 31P Nuclear Magnetic Resonance Spectroscopy Study

1993 ◽  
Vol 85 (1) ◽  
pp. 105-109 ◽  
Author(s):  
I. Adatia ◽  
G. J. Kemp ◽  
D. J. Taylor ◽  
G. K. Radda ◽  
B. Rajagopalan ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Congenital Heart ◽  
Haemoglobin Concentration ◽  
Muscle Metabolism ◽  
Atp Synthesis ◽  
Resonance Spectroscopy ◽  
Cytosolic Ph ◽  
Control Subjects ◽  
Resting Muscle

1. Exercise tolerance is impaired in congenital heart disease. To examine the possible contribution of abnormalities in skeletal muscle bioenergetics, we used 31P nuclear magnetic resonance spectroscopy to investigate muscle metabolism in 10 subjects with congenital heart disease with cyanosis (median age 17.3 years) and in eight healthy age-matched control subjects. Spectra were collected from the gastrocnemius muscle at rest and during exercise and recovery. 2. In resting muscle there were significant elevations in cytosolic pH and in the cytosolic concentration of inorganic phosphate in the patients, and a strong positive correlation between cytosolic pH and blood haemoglobin concentration in all subjects. 3. During plantar flexion exercise the patients showed increased phosphocreatine depletion and cytosolic acidification over a shorter duration of exercise. The rise in calculated cytosolic ADP concentration was similar in both groups. 4. After cessation of exercise, the recovery half-times of phosphocreatine, ADP and phosphate were two to three times longer in the patients, and the initial rate of phosphocreatine resynthesis (a measure of the rate of mitochondrial ATP synthesis) was half the control value, consistent with a reduction in the effective maximum rate of oxidative ATP synthesis (expressed per volume of muscle). Also, recovery was faster in the young control subjects than in our earlier studies of older healthy control subjects. 5. The high phosphate concentration in resting muscle and the abnormalities found in exercise and recovery are consistent with a decrease in oxidative ATP synthesis due to reduced oxygen delivery by the blood in chronic hypoxaemia. The correlation between cytosolic pH and haemoglobin concentration remains to be explained.

scholarly journals The Polyphenols Resveratrol and S17834 Prevent the Structural and Functional Sequelae of Diet-Induced Metabolic Heart Disease in Mice

Circulation ◽  
2012 ◽  
Vol 125 (14) ◽  
pp. 1757-1764 ◽  
Author(s):  
Fuzhong Qin ◽  
Deborah A. Siwik ◽  
Ivan Luptak ◽  
Xiuyun Hou ◽  
Lei Wang ◽  
...  
Keyword(s):  
Heart Disease ◽  
Metabolic Heart Disease

scholarly journals Galectin‐3 Is Associated With Stage B Metabolic Heart Disease and Pulmonary Hypertension in Young Obese Patients

2019 ◽  
Vol 8 (7) ◽  
Author(s):  
Deepa M. Gopal ◽  
Nir Ayalon ◽  
Yi‐Chih Wang ◽  
Deborah Siwik ◽  
Aaron Sverdlov ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Heart Disease ◽  
Obese Patients ◽  
Galectin 3 ◽  
Metabolic Heart Disease

Abstract P150: Association Of Leisure Time Physical Activity (LTPA) With Left Atrial Function In Older Adults: The Atherosclerosis Risk In Communities (ARIC) Study

Circulation ◽  
2021 ◽  
Vol 143 (Suppl_1) ◽  
Author(s):  
Romil Parikh ◽  
Riccardo M Inciardi ◽  
Wendy Wang ◽  
Sheila M Hegde ◽  
Faye L Norby ◽  
...  
Keyword(s):  
Risk Factors ◽  
Heart Disease ◽  
Diastolic Function ◽  
Left Atrial ◽  
Contractile Function ◽  
Left Ventricular ◽  
Volume Index ◽  
Aric Study ◽  
Lv Diastolic Function ◽  
Conduit Function

Introduction: Prior research indicates that higher LTPA is associated with better left ventricular (LV) diastolic function, but not with left atrial volume index (LAVI). Left atrial (LA) strain is a more sensitive marker of LA pathology. Hence, we evaluated association of LTPA with LA strain in the ARIC study, a community-based cohort study. Hypothesis: Higher LTPA is associated with better LA reservoir, conduit and contractile function. Methods: We included 4005 participants (mean age 75 years, 63% female, 21% black) with 2D echocardiographic (2DE) LA % strain data, LTPA data, and without prevalent coronary heart disease, valvular heart disease, heart failure, atrial fibrillation, and stroke at Visit 5 (V5, 2011-13). We estimated LTPA as metabolic equivalent-minutes per week from validated Baecke questionnaire and categorized it as poor, intermediate, or ideal as per AHA recommendation. We categorized change in LTPA from V3 (1993-95) to V5 as persistently poor (referent), decreasing, increasing, or persistently active. LA reservoir, conduit, and contractile % strain were measured from speckle-tracking 2DE. Linear regression was used to evaluate association of LTPA with LA function. We modeled LTPA (1) cross-sectionally at V5 as a continuous variable and (2) change from V3 to V5, as continuous and categorical variables (referent- persistently poor). Results: Higher LTPA at V5 (Table) and persistently high (vs poor) LTPA from V3 to 5 (β estimate -0.89, 95% CI -1.40, -0.38) were significantly associated with better LA conduit function after adjusting for CV risk factors, LV function, and LAVI. The same associations with LA reservoir function were no longer significant after adjusting for CV risk factors. LTPA was not associated with LA contractile function (Table). Conclusions: Consistent with LTPA’s salutary effect on LV diastolic function, higher LTPA is associated with better LA conduit function. Maintaining high LTPA from midlife to late-life may be beneficial in mitigating age-related changes in cardiac function.

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