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Mitochondrial electron transport chain. Complex I (NADH dehydrogenase), Complex III (cytochrome b–c1 complex), Complex IV (cytochrome c oxidase), and Complex V (ATP synthase) span the inner mitochondrial membrane. Complex II is non-membrane spanning. Reduced forms of NADH (complex I) and FAD(2H) (complex II) donate electrons (e⁻) to the transport chain via complex I and/or complex II, respectively, which are sequentially transferred to electron carriers, including the lipid soluble coenzyme Q (CoQ), complex III, cytochrome c (CytC), and complex IV. Complex IV accepts e⁻ from the electron transport chain and reduces molecular oxygen (O2) into water (H2O). As e⁻ pass the electron transfer chain, protons (H⁺) are pumped across the mitochondrial matrix to the inner mitochondrial space (at complexes I, III, and IV; complex II lacks a proton pumping mechanism), responsible for establishing an electrochemical proton gradient at the inner mitochondrial membrane. The creation of the electrochemical proton gradient forces protons back inside the matrix at complex V, which uses the H⁺ gradient energy to regenerate ATP from ADP (and Pi). The electron transport chain couples the rate of ATP regeneration by the electrochemical proton gradient-coupled oxidative phosphorylation. Under physiological conditions, approximately up to 5% of O2 in cells is converted to reactive oxygen species (ROS), with complexes I and III the main sites for ROS production.
Source publication
The normal function of the heart relies on a series of complex metabolic processes orchestrating the proper generation and use of energy. In this context, mitochondria serve a crucial role as a platform for energy transduction by supplying ATP to the varying demand of cardiomyocytes, involving an intricate network of pathways regulating the metabol...
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Despite the enormous progress in the treatment of atrial fibrillation, mainly with the use of invasive techniques, many questions remain unanswered regarding the pathomechanism of the arrhythmia and its prevention methods. The development of atrial fibrillation requires functional changes in the myocardium that result from disturbed ionic fluxes an...
Citations
... [6][7][8][9] Additionally, existing research suggests that prevalent metabolic alterations prompted by mutations in the sarcomere genes in cases of HCM predominantly entail a rise in sensitivity to calcium ions (Ca 2+ ) within the sarcomere and impairments in sarcomere energy metabolism, including suboptimal energy usage, and heightened energy requirements. 10,11 Certain metabolic consequences brought on by these metabolic changes include disruptions in Ca 2+ metabolic disorders, 10,12 malfunctioning of mitochondria, 13,14 and metabolic reconfiguration. 15,16 The European Society of Cardiology (ESC) has classified HCM into two broad categories. ...
Background
With the disappointing results associated with the use of cardiac myosin inhibitors in the treatment of hypertrophic cardiomyopathy (HCM), the development of new therapies in clinical trials for HCM has rapidly increased. We assessed the characteristics of therapeutic intervention in HCM registered on ClinicalTrials.gov and the International Clinical Trials Registry Platform (ICTRP).
Methods
We conducted a cross-sectional, descriptive study of clinical trials for therapeutic intervention in HCM registered on ClinicalTrials.gov and ICTRP.
Results
This study analyzed 137 registered trials. Regarding study designs of these trials, 77.37% were purpose of treatment, 59.12% were randomized, 50.36% were parallel assignment, 45.26% were performed with masking, 48.18% recruited less than 50 participants, and 27.74% were Phase 2 trials. In total, 67 trials were new drug trials, of which 35 drugs were tested in these trials, and 13 trials involved treatment with mavacamten. Of these 67 clinical drug trials, 44.78% of trials involved the study of amines, and 16.42% involved 1-ring heterocyclic compounds. Regarding the NCI Thesaurus Tree, 23.81% of trials involved myosin inhibitors, 23.81% of trials involved drugs belonging to agents affecting the cardiovascular system, and 20.63% were involved in testing cation channel blockers. The drug-target network showed that myosin-7, potassium voltage-gated channel subfamily h member 2, beta-1 adrenergic receptor, carnitine o-palmitoyltransferase 1, and liver isoform were the most targeted pathways of the clinical trials analyzed in the drug-target network.
Conclusion
The number of clinical trials investigating therapeutic interventions for HCM has increased in recent years. Ultimately, recent HCM therapeutic clinical trials generally did not incorporate either randomized controlled trials or masking and were small studies recruiting fewer than 50 participants. Although recent research has focused on targeting myosin-7, the molecular signaling mechanisms involved in the pathogenesis of HCM have the potential to elucidate novel target pathways.
... Notably, metabolic impairment is vital in heart failure (13, 14). Generally, the heart meets its energy demand by utilizing fatty acids, glucose, amino acid, lactate and ketone bodies, but cardiomyopathies lead to severe metabolic perturbations (15)(16)(17). In cardiovascular research, metabolic explorations have provided new insights (18,19). ...
... In cardiovascular research, metabolic explorations have provided new insights (18,19). The role of metabolic genes and pathways has been explored in several cardiomyopathy studies to understand the pathophysiological changes involved in the progression of cardiomyopathy (15)(16)(17)(20)(21)(22). These studies have reported a metabolic shift in energy sources during disease progression. ...
Introduction
Cardiomyopathies are complex heart diseases with significant prevalence around the world. Among these, primary forms are the major contributors to heart failure and sudden cardiac death. As a high-energy demanding engine, the heart utilizes fatty acids, glucose, amino acid, lactate and ketone bodies for energy to meet its requirement. However, continuous myocardial stress and cardiomyopathies drive towards metabolic impairment that advances heart failure (HF) pathogenesis. So far, metabolic profile correlation across different cardiomyopathies remains poorly understood.
Methods
In this study, we systematically explore metabolic differences amongst primary cardiomyopathies. By assessing the metabolic gene expression of all primary cardiomyopathies, we highlight the significantly shared and distinct metabolic pathways that may represent specialized adaptations to unique cellular demands. We utilized publicly available RNA-seq datasets to profile global changes in the above diseases (|log2FC| ≥ 0.28 and BH adjusted p-val 0.1) and performed gene set analysis (GSA) using the PAGE statistics on KEGG pathways.
Results
Our analysis demonstrates that genes in arachidonic acid metabolism (AA) are significantly perturbed across cardiomyopathies. In particular, the arachidonic acid metabolism gene PLA2G2A interacts with fibroblast marker genes and can potentially influence fibrosis during cardiomyopathy.
Conclusion
The profound significance of AA metabolism within the cardiovascular system renders it a key player in modulating the phenotypes of cardiomyopathies.
... To date, the mechanisms by which sarcomere gene mutations cause myocardial hypertrophy are not fully understood, but knowledge about this topic grew during the last decades and some hypotheses have been proposed [11]. An extensive body of literature strongly supports a direct impact of sarcomere gene variants on cardiac contractility as the central cause of HCM; mutations can be associated with enhanced late sodium current activation, cellular calcium overload, and increased calcium sensitivity of the myofilaments, causing increased contractility and affecting myocardial relaxation and diastolic function [11][12][13][14][15]. Excessive energy consumption, in turn, causes structural and functional impairments of the mitochondria, leading to increased production of reactive oxygen species (ROS) and resulting in glutathione acylation of muscle filaments [16][17][18][19][20]. Moreover, impaired autophagy [18] and accumulation of metabolic end-products [20] may exert a toxic effect on the myocardial contractile apparatus and the cardiomyocyte in general. ...
... An extensive body of literature strongly supports a direct impact of sarcomere gene variants on cardiac contractility as the central cause of HCM; mutations can be associated with enhanced late sodium current activation, cellular calcium overload, and increased calcium sensitivity of the myofilaments, causing increased contractility and affecting myocardial relaxation and diastolic function [11][12][13][14][15]. Excessive energy consumption, in turn, causes structural and functional impairments of the mitochondria, leading to increased production of reactive oxygen species (ROS) and resulting in glutathione acylation of muscle filaments [16][17][18][19][20]. Moreover, impaired autophagy [18] and accumulation of metabolic end-products [20] may exert a toxic effect on the myocardial contractile apparatus and the cardiomyocyte in general. The link between sarcomere gene mutation and inflammation is not fully explained yet, but some authors [5] have supposed that cardiomyocyte disarray, sarcomere injury, mitochondrial oxidative stress, and microvascular disease may all trigger early inflammation Content courtesy of Springer Nature, terms of use apply. ...
The hypertrophic cardiomyopathy phenotype encompasses a heterogeneous spectrum of genetic and acquired diseases characterized by the presence of left ventricular hypertrophy in the absence of abnormal cardiac loading conditions. This “umbrella diagnosis” includes the “classic” hypertrophic cardiomyopathy (HCM), due to sarcomere protein gene mutations, and its phenocopies caused by intra‐ or extracellular deposits, such as Fabry disease (FD) and cardiac amyloidosis (CA). All these conditions share a wide phenotypic variability which results from the combination of genetic and environmental factors and whose pathogenic mediators are poorly understood so far. Accumulating evidence suggests that inflammation plays a critical role in a broad spectrum of cardiovascular conditions, including cardiomyopathies. Indeed, inflammation can trigger molecular pathways which contribute to cardiomyocyte hypertrophy and dysfunction, extracellular matrix accumulation, and microvascular dysfunction. Growing evidence suggests that systemic inflammation is a possible key pathophysiologic process potentially involved in the pathogenesis of cardiac disease progression, influencing the severity of the phenotype and clinical outcome, including heart failure. In this review, we summarize current knowledge regarding the prevalence, clinical significance, and potential therapeutic implications of inflammation in HCM and two of its most important phenocopies, FD and CA.
... If this metabolic process is disrupted, heart function or structure is affected. The exact mechanisms of cardiac manifestations are currently unknown; however, they seem to correlate with the accumulation of by-products, toxic effects, and lack of energy [12,[23][24][25]. Cardiac involvement in terms of functional and structural changes in many metabolic diseases has been reported. ...
Glycogen storage disease (GSD) is a hereditary metabolic disorder caused by enzyme deficiency resulting in glycogen accumulation in the liver, muscle, heart, or kidney. GSD types II, III, IV, and IX are associated with cardiac involvement. However, cardiac manifestation in other GSD types is unclear. This study aimed to describe whether energy deprivation and the toxic effects of accumulated glycogen affect the heart of patients with GSD. We evaluated the left ventricle (LV) wall mass, LV systolic and diastolic function and myocardial strain with conventional echocardiography and two-dimensional speckle-tracking echocardiography (2D STE) in 62 patients with GSD type I, III, VI and IX who visited the Wonju Severance Hospital in 2021. Among the GSD patients, the echocardiographic parameters of 55 pediatrics were converted into z-scores and analyzed. Of the patients, 43 (62.3%), 7 (11.3%) and 12 (19.4%) patients were diagnosed with GSD type I, type III, and type IX, respectively. The median age was 9 years (range, 1–36 years), with 55 children under 18 years old and seven adults over 18 years. For the 55 pediatric patients, the echocardiographic parameters were converted into a z-score and analyzed. Multiple linear regression analysis showed that the BMI z-score (p = 0.022) and CK (p = 0.020) predicted increased LV mass z-score, regardless of GSD type. There was no difference in the diastolic and systolic functions according to myocardial thickness; however, 2D STE showed a negative correlation with the LV mass (r = −0.28, p = 0.041). Given that patients with GSD tend to be overweight, serial evaluation with echocardiography might be required for all types of GSD.
... Although the model effectively predicts the variations of signaling pathways that lead to familial HCM and DCM, it has some limitations. The cardiac metabolic network plays a significant role in mediating genotype to phenotype in familial cardiomyopathies, especially in their progression to heart failure [111]. In DCM, truncating mutations in the TTN gene were associated with a reduced rate of O 2 consumption, significant ROS production, and transcriptional upregulation of mitochondrial oxidative phosphorylation system [112,113]. ...
Familial cardiomyopathy is a precursor of heart failure and sudden cardiac death. Over the past several decades, researchers have discovered numerous gene mutations primarily in sarcomeric and cytoskeletal proteins causing two different disease phenotypes: hypertrophic (HCM) and dilated (DCM) cardiomyopathies. However, molecular mechanisms linking genotype to phenotype remain unclear. Here, we employ a systems approach by integrating experimental findings from preclinical studies (e.g., murine data) into a cohesive signaling network to scrutinize genotype to phenotype mechanisms. We developed an HCM/DCM signaling network model utilizing a logic-based differential equations approach and evaluated model performance in predicting experimental data from four contexts (HCM, DCM, pressure overload, and volume overload). The model has an overall prediction accuracy of 83.8%, with higher accuracy in the HCM context (90%) than DCM (75%). Global sensitivity analysis identifies key signaling reactions, with calcium-mediated myofilament force development and calcium-calmodulin kinase signaling ranking the highest. A structural revision analysis indicates potential missing interactions that primarily control calcium regulatory proteins, increasing model prediction accuracy. Combination pharmacotherapy analysis suggests that downregulation of signaling components such as calcium, titin and its associated proteins, growth factor receptors, ERK1/2, and PI3K-AKT could inhibit myocyte growth in HCM. In experiments with patient-specific iPSC-derived cardiomyocytes (MLP-W4R;MYH7-R723C iPSC-CMs), combined inhibition of ERK1/2 and PI3K-AKT rescued the HCM phenotype, as predicted by the model. In DCM, PI3K-AKT-NFAT downregulation combined with upregulation of Ras/ERK1/2 or titin or Gq protein could ameliorate cardiomyocyte morphology. The model results suggest that HCM mutations that increase active force through elevated calcium sensitivity could increase ERK activity and decrease eccentricity through parallel growth factors, Gq-mediated, and titin pathways. Moreover, the model simulated the influence of existing medications on cardiac growth in HCM and DCM contexts. This HCM/DCM signaling model demonstrates utility in investigating genotype to phenotype mechanisms in familial cardiomyopathy.
... These two transport proteins are the primary steps in the utilization of their respective substrate for metabolism in the heart. FAT/CD36 is responsible for the uptake of long chain fatty acids into the myocardium, this accounts for about 70% of the energy generated in the healthy heart, while GLUT4 is responsible for the uptake of glucose into the myocardium and accounts for about 20% of the energy generated in the healthy heart [8]. Indeed, the heart is known to be a metabolic omnivore as it can use fatty acids, glucose, lactate and ketone bodies as substrate for energy generation [9]. ...
Background
Altered substrate transport protein expression is central to the effect of insulin resistance on cardiac metabolism. The present study was thus designed to investigate the comparative effects of high fat, high sucrose and salt-induced IR on cardiac expression of fatty acid transporter (FATP) and glucose transporter (GLUT4) in rats.
Results
Rats fed with high fat, high sucrose and salt diets developed impaired glucose tolerance ( p > 0.05) and hyperinsulinemia ( p < 0.05) compared with control group. Myocardial glucose transporter expression was significantly increased ( p < 0.001 for salt-induced IR; p < 0.01 for sucrose-induced IR; p < 0.01 for fat-induced IR) across all IR groups compared with control. Fatty acid transporter expression was also increased ( p < 0.001) in high salt diet-induced IR rats, and high fat diet-induced IR rats ( p < 0.05).
Conclusions
Our results demonstrate that salt and not caloric excess has a potential role in IR alteration of myocardial substrate transport protein expression in the rat.
... If this metabolic process is disrupted, heart function or structure is affected. The exact mechanisms of cardiac manifestations are currently unknown, but they seem to correlate with the accumulation of by-products, toxic effects, and lack of energy [11,[22][23][24]. Cardiac involvement in terms of functional and structural changes in many metabolic diseases has been reported. ...
Purpose
Glycogen storage disease (GSD) is a hereditary metabolic disorder caused by enzyme deficiency resulting in glycogen accumulation in the liver, muscle, heart, or kidney. GSD types II, III, IV, and IX are associated with cardiac involvement. However, cardiac manifestation of other GSD types is unclear. This study aimed to describe whether energy deprivation and the toxic effects of accumulated glycogen affect the heart of patients with GSD.
Methods
We evaluated LV wall mass, LV systolic and diastolic function and myocardial strain in 64 patients with GSD type I, III, VI and IX who visited Wonju Severance Hospital in 2021, by conventional echocardiography and two-dimensional speckle-tracking echocardiography (2D STE). Among the GSD patients, the echocardiographic parameters of 55 pediatrics were converted into z-scores and analyzed.
Results
Of the patients, 43(62.3%), 7(11.3%) and 12(19.4%) were diagnosed with GSD type 1, type 3 and type 9, respectively. The median age was 9 years (range, 1–36years), 55 children under 18 years old and 7 adults over 18 years old. Multiple linear regression analysis showed that BMI z-score (p = 0.022) and CK (p = 0.020) predicted increased LV mass z-score, regardless of GSD type. There was no difference in the diastolic and systolic functions according to myocardial thickness, but 2D STE shows a negative correlation with LV mass (r=-0.28, p = 0.041).
Conclusion
Given that GSD patients tend to be overweight. As well as laboratory tests and abdomen ultrasounds of the liver and muscles in patients with GSD are needed, but it is also thought that serial heart evaluation with echocardiography is required.
... В связи с возникающим системным дефектом энергетического метаболизма поражаются в различной комбинации наиболее энергозависимые ткани и органы мишени (миокард и скелетные мышцы, центральная нервная система), что обусловливает выраженный полиморфизм клинических симптомов, мультисистемный характер поражения и прогрессирующее течение [6,[9][10][11]. Гипертрофия миокарда при митохондриальных болезнях имеет динамичный характер: в процессе течения заболевания может произойти как ее уменьшение, так и молниеносное прогрессирование во время эпизодов метаболической декомпенсации [12]. В ряде случаев при прогрессировании заболевания происходит смена фенотипа с формированием дилатации полостей сердца и развитием в последующем систолической дисфункции [13,14]. ...
The few foreign papers of the last decade have shown the relationship of various pathogenic variants of the ELAC2 gene to heterogeneous phenotypic manifestations, for which the unfavorable prognosis is common, caused by severe cardiomyopathy in the first year of life. The article presents the first clinical observation of a rare variant of the hypertrophic phenotype cardiomyopathy with a fatal outcome in the first year of life, and variants c.887T>C, p.L296P and c.1979A>T, p.K660I of the ELAC2 gene in Russia.
The purpose of the work is to present clinical observation of a child with an early manifestation of a hypertrophic phenotype of cardiomyopathy caused by pathogenic variants of the ELAC2 gene.
... In addition, increased oxygen consumption has been reported in preclinical sarcomere mutation carriers before the development of hypertrophy, followed by a decrease in oxygen consumption in the hearts of patients with advanced HCM [29,63]. Changes in energetic status and metabolism are thus present at early and advanced HCM disease stages in sarcomere mutation carriers and are considered as a possible therapeutic target [73,88]. ...
... FAs come from the plasma as free FAs bound to albumin or from stored triglycerides and are broken down for energy production by β-oxidation (fatty acid oxidation (FAO)) [81]. FAs move into the cell through the transporter fatty acid translocase/cluster of differentiation 36 (FAT/CD36), are esterified into acyl-CoA in the cytosol, and subsequently enter the mitochondria using the carnitine shuttle comprised of carnitine palmitoyltransferase 1 (CPT1), carnitine-acylcarnitine translocase (CACT) and carnitine palmitoyltransferase 2 (CPT2) [73]. Exogenous glucose enters the cell via the insulin-dependent GLUT4-transporter and, to a lesser extent, the GLUT-1 transporter or is derived from stored glycogen. ...
Background
Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have emerged as a powerful tool for disease modeling, though their immature nature currently limits translation into clinical practice. Maturation strategies increasingly pay attention to cardiac metabolism because of its pivotal role in cardiomyocyte development and function. Moreover, aberrances in cardiac metabolism are central to the pathogenesis of cardiac disease. Thus, proper modeling of human cardiac disease warrants careful characterization of the metabolic properties of iPSC-CMs.
Methods
Here, we examined the effect of maturation protocols on healthy iPSC-CMs applied in 23 studies and compared fold changes in functional metabolic characteristics to assess the level of maturation. In addition, pathological metabolic remodeling was assessed in 13 iPSC-CM studies that focus on hypertrophic cardiomyopathy (HCM), which is characterized by abnormalities in metabolism.
Results
Matured iPSC-CMs were characterized by mitochondrial maturation, increased oxidative capacity and enhanced fatty acid use for energy production. HCM iPSC-CMs presented varying degrees of metabolic remodeling ranging from compensatory to energy depletion stages, likely due to the different types of mutations and clinical phenotypes modeled. HCM further displayed early onset hypertrophy, independent of the type of mutation or disease stage.
Conclusions
Maturation strategies improve the metabolic characteristics of iPSC-CMs, but not to the level of the adult heart. Therefore, a combination of maturation strategies might prove to be more effective. Due to early onset hypertrophy, HCM iPSC-CMs may be less suitable to detect early disease modifiers in HCM and might prove more useful to examine the effects of gene editing and new drugs in advanced disease stages. With this review, we provide an overview of the assays used for characterization of cardiac metabolism in iPSC-CMs and advise on which metabolic assays to include in future maturation and disease modeling studies.
... Early in the 21st century, different studies investigated the capability of statins to reduce LV hypertrophy in HCM models. Since the presence of oxidative stress was demonstrated in HCM cardiomyocytes through different models of disease [137], it became a target of interest, and statins were tested for their antioxidant effects [138][139][140]. Marian and coworkers investigated the antioxidant capability of atorvastatin in a transgenic rabbit model of HCM carrying a mutation on the β-myosin heavy chain (R403Q). ...
Hypertrophic cardiomyopathy (HCM), the most common inherited heart disease, is still orphan of a specific drug treatment. The erroneous consideration of HCM as a rare disease has hampered the design and conduct of large, randomized trials in the last 50 years, and most of the indications in the current guidelines are derived from small non-randomized studies, case series, or simply from the consensus of experts. Guideline-directed therapy of HCM includes non-selective drugs such as disopyramide, non-dihydropyridine calcium channel blockers, or β-adrenergic receptor blockers, mainly used in patients with symptomatic obstruction of the outflow tract. Following promising preclinical studies, several drugs acting on potential HCM-specific targets were tested in patients. Despite the huge efforts, none of these studies was able to change clinical practice for HCM patients, because tested drugs were proven to be scarcely effective or hardly tolerated in patients. However, novel compounds have been developed in recent years specifically for HCM, addressing myocardial hypercontractility and altered energetics in a direct manner, through allosteric inhibition of myosin. In this paper, we will critically review the use of different classes of drugs in HCM patients, starting from "old" established agents up to novel selective drugs that have been recently trialed in patients.
