Metabolic Remodeling in the Pressure‐Loaded Right Ventricle: Shifts in Glucose and Fatty Acid Metabolism—A Systematic Review and Meta‐Analysis

Abstract

BackgroundRight ventricular (RV) failure because of chronic pressure load is an important determinant of outcome in pulmonary hypertension. Progression towards RV failure is characterized by diastolic dysfunction, fibrosis and metabolic dysregulation. Metabolic modulation has been suggested as therapeutic option, yet, metabolic dysregulation may have various faces in different experimental models and disease severity. In this systematic review and meta‐analysis, we aimed to identify metabolic changes in the pressure loaded RV and formulate recommendations required to optimize translation between animal models and human disease.Methods and ResultsMedline and EMBASE were searched to identify original studies describing cardiac metabolic variables in the pressure loaded RV. We identified mostly rat‐models, inducing pressure load by hypoxia, Sugen‐hypoxia, monocrotaline (MCT), pulmonary artery banding (PAB) or strain (fawn hooded rats, FHR), and human studies. Meta‐analysis revealed increased Hedges’ g (effect size) of the gene expression of GLUT1 and HK1 and glycolytic flux. The expression of MCAD was uniformly decreased. Mitochondrial respiratory capacity and fatty acid uptake varied considerably between studies, yet there was a model effect in carbohydrate respiratory capacity in MCT‐rats.ConclusionsThis systematic review and meta‐analysis on metabolic remodeling in the pressure‐loaded RV showed a consistent increase in glucose uptake and glycolysis, strongly suggest a downregulation of beta‐oxidation, and showed divergent and model‐specific changes regarding fatty acid uptake and oxidative metabolism. To translate metabolic results from animal models to human disease, more extensive characterization, including function, and uniformity in methodology and studied variables, will be required.

Right versus left ventricular remodeling in heart failure due to chronic volume overload

“…These changes were demonstrated in both ventricles. Similar pattern of metabolic gene transcription program was observed previously in pressure-overloaded ventricles, including RV 21 . In summary, metabolic response to stress resembles a reactivation of fetal gene expression program and is uniform in terms of chamber (RV vs LV) or overload etiology 21 .…”

“…Upregulation of fetal isoform (PKM2) was previously observed in failing RV due to PH 57 . In parallel, we observed downregulation of α and β subunits of trifunctional enzyme of β-oxidation of fatty acids ( HADHA, HADHB ), more pronounced in volume-overloaded RV than in LV, consistent with switch in myocardial metabolic preference typical to fetal or failing heart 21 , 39 . Downregulation of mitochondrial 2,4-dienoyl-CoA reductase, an enzyme of β-oxidation of unsaturated fatty acids, was also observed in both VO ventricles.…”

“…To identify chamber-specific responses to VO, we correlated individual hemodynamic parameters with sensitive gene expression markers of myocardial stress response ( Myh7/6 ratio ) 13 , 15 and myocardial substrate metabolism ( Glut1/4 ratio ) 21 (Fig. 3 c, Table 3 ).…”

Right versus left ventricular remodeling in heart failure due to chronic volume overload: pressure-volume and proteome analysis

“…was previously observed in failing RV due to PH 57 . In parallel, we observed downregulation of α and β subunits of trifunctional enzyme of β-oxidation of fatty acids (HADHA, HADHB), more pronounced in volume-overloaded RV than in LV, consistent with switch in myocardial metabolic preference typical to fetal or failing heart 33,39 . Downregulation of mitochondrial 2,4-dienoyl-CoA reductase, an enzyme of β-oxidation of unsaturated fatty acids, was also observed in both VO ventricles.…”

Characteristics of Blood Metabolic Profile in Coronary Heart Disease, Dilated Cardiomyopathy and Valvular Heart Disease Induced Heart Failure

“…A considerable body of evidence suggests that myocardial substrate and energy metabolism play a key role in affecting the development and prognosis of HF ( 10 , 11 , 13 ). Additionally, the metabolic state of the heart is closely related to the intricate signaling network and transcription factors controlling gene expression ( 14 , 15 ). Various studies have explored the plasma metabolites of HF patients as potential biomarkers ( 7 , 16 – 18 ), but few focused on the metabolic profile differences among CHD, DCM, and VHD, which may be vital for effective disease management.…”