Abstract 235: Hypertrophic Cardiomyopathy, a Disease of Altered Cardiac Energetics

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Sara Ranjbarvaziri ◽  
Mathew Ellenberger ◽  
Kristi Kooiker ◽  
Giovanni Fajardo ◽  
Mingming Zhao ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Drug Targets ◽  
Complex Disease ◽  
Citrate Synthase ◽  
Age Of Onset ◽  
High Energy ◽  
Antioxidant Defenses ◽  
Cardiac Energetics ◽  
Septal Myectomy ◽  
Functional Features

Hypertrophic cardiomyopathy (HCM) is a complex disease, the phenotypes of which are only partly explained by the biomechanical effects of individual genetic variants. At the cellular level, HCM sarcomeric mutations generally enhance maximal force production ultimately leading to higher energy demands. Despite significant advances in elucidating sarcomeric structure-function relationships, there is limited knowledge on the link between altered cardiac energetics and HCM phenotypes. In this work, we test the hypothesis that changes in cardiac energetics are a common pathway leading to the clinical pathophysiological phenotypes of HCM. We performed a comprehensive multi-omic study of the molecular, ultrastructural, and functional features of HCM energetics using septal myectomy samples from 27 HCM patients and 13 normal controls (donor hearts). Combined mass spectrometry and RNA-Seq revealed dramatic alterations in multiple metabolic pathways,with major dysregulation in fatty acid metabolism leading to reduced acylcarnitines and accumulation of free fatty acids. Additionally, HCM hearts showed clear signs of global energetic decompensation manifested by a decrease in high energy phosphate metabolites (ATP, ADP, and PCr) and reduction in several mitochondrial genes involved in creatine kinase and ATP synthesis machinery. Quantitative electron microscopy showed a marked increase in severely damaged mitochondria with reduced cristae density, affecting 10-12% of total mitochondria, coinciding with reduced citrate synthase (CS) activity and mitochondrial respiration. These mitochondrial abnormalities were associated with elevated ROS and reduced antioxidant defenses along with insufficient mitophagic clearance. Overall, our findings suggest that perturbed metabolic signaling and mitochondrial dysfunction are common pathogenic mechanisms in HCM. A central role for compromised energetics in HCM could also help explain the delayed age of onset of the clinical phenotype and present novel drug targets for attenuation of the clinical disease through reducing mitochondrial injury and improving function.

scholarly journals Altered Cardiac Energetics and Mitochondrial Dysfunctionin Hypertrophic Cardiomyopathy

Circulation ◽  
2021 ◽  
Author(s):  
Sara Ranjbarvaziri ◽  
Kristina B. Kooiker ◽  
Mathew Ellenberger ◽  
Giovanni Fajardo ◽  
Mingming Zhao ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Drug Targets ◽  
Complex Disease ◽  
Citrate Synthase ◽  
High Energy ◽  
Antioxidant Defenses ◽  
Cardiac Energetics ◽  
Mitochondrial Injury ◽  
Individual Gene ◽  
Functional Components

Background: Hypertrophic cardiomyopathy (HCM) is a complex disease partly explained by the effects of individual gene variants on sarcomeric protein biomechanics. At the cellular level, HCM mutations most commonly enhance force production, leading to higher energy demands. Despite significant advances in elucidating sarcomeric structure-function relationships, there is still much to be learned about the mechanisms that link altered cardiac energetics to HCM phenotypes. In this work, we test the hypothesis that changes in cardiac energetics represent a common pathophysiologic pathway in HCM. Methods: We performed a comprehensive multi-omics profile of the molecular (transcripts, metabolites, and complex lipids), ultrastructural, and functional components of HCM energetics using myocardial samples from 27 HCM patients and 13 normal controls (donor hearts). Results: Integrated omics analysis revealed alterations in a wide array of biochemical pathways with major dysregulation in fatty acid metabolism, reduction of acylcarnitines, and accumulation of free fatty acids. HCM hearts showed evidence of global energetic decompensation manifested by a decrease in high energy phosphate metabolites [ATP, ADP, and phosphocreatine (PCr)] and a reduction in mitochondrial genes involved in creatine kinase and ATP synthesis. Accompanying these metabolic derangements, electron microscopy showed an increased fraction of severely damaged mitochondria with reduced cristae density, coinciding with reduced citrate synthase (CS) activity and mitochondrial oxidative respiration. These mitochondrial abnormalities were associated with elevated reactive oxygen species (ROS) and reduced antioxidant defenses. However, despite significant mitochondrial injury, HCM hearts failed to upregulate mitophagic clearance. Conclusions: Overall, our findings suggest that perturbed metabolic signaling and mitochondrial dysfunction are common pathogenic mechanisms in patients with HCM. These results highlight potential new drug targets for attenuation of the clinical disease through improving metabolic function and reducing mitochondrial injury.

scholarly journals Clinical Features and Echocardiographic Findings in Children with Hypertrophic Cardiomyopathy

2013 ◽  
Vol 59 (6) ◽  
pp. 285-288
Author(s):  
Blesneac Cristina ◽  
Benedek Theodora ◽  
Togănel Rodica ◽  
Benedek I
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Age Of Onset ◽  
Adult Population ◽  
Systemic Disease ◽  
Ventricular Outflow Tract ◽  
Left Ventricular ◽  
Septal Myectomy ◽  
Sarcomeric Protein ◽  
Asymptomatic Patients ◽  
Left Ventricular Outflow

Abstract Background: Hypertrophic cardiomyopathy, one of the most common inherited cardiomyopathies, is a heterogeneous disease resulting from sarcomeric protein mutations, with an incidence in the adult population of 1:500. Current information on the epidemiology and outcomes of this disease in children is limited. Methods: Thirty-four children diagnosed with hypertrophic cardiomyopathy in the Pediatric Cardiology Department from Tîrgu Mureș were evaluated concerning familial and personal history, clinical, paraclinical and therapeutic aspects. Hypertrophic cardiomyopathy was defined by the presence of a hypertrophied, non-dilated ventricle, in the absence of a cardiac or systemic disease that could produce ventricular hypertrophy. Results: The youngest diagnosed child was a neonate, a total of 10 patients being diagnosed until 1 year of age. In 6 cases a positive familial history was found. Noonan syndrome was found in 2 cases. Only 21 patients were symptomatic, the predominant symptoms being shortness of breath on exertion with exercise limitations. Left ventricular outflow tract obstruction was present in 21 cases (61.7%). Twenty-four patients were on β-blocking therapy, while 4 patients underwent septal myectomy. Conclusions: Hypertrophic cardiomyopathy is a heterogeneous disorder in terms of evolution, age of onset, type and extent of hypertrophy, and the risk of sudden death. It can affect children of any age. There is a need for a complex evaluation, including familial and personal anamnesis, clinical examination, electrocardiogram and echocardiography of all patients. It is highly important to develop screening strategies, including genetic testing, for an early diagnosis, especially in asymptomatic patients with a positive familial background

scholarly journals Metabolic and Proteomic Defects in Human Hypertrophic Cardiomyopathy

2021 ◽  
Author(s):  
Michael Previs ◽  
Thomas O'Leary ◽  
Neil Wood ◽  
Michael Morley ◽  
Brad Palmer ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Hypertrophic Cardiomyopathy ◽  
Fatty Acid Oxidation ◽  
Cardiac Metabolism ◽  
Acid Oxidation ◽  
Cardiac Energetics ◽  
Intermediary Metabolites ◽  
Energy Depletion ◽  
Septal Myectomy ◽  
Alternate Fuel

Rationale: Impaired cardiac energetics in hypertrophic cardiomyopathy (HCM) is thought to result from increased ATP utilization at the sarcomere and is believed to be central to pathophysiology. However, the precise defects in cardiac metabolism and substrate availability in human HCM have not been defined. Objective: The purpose of this study is to define major disease pathways and determine the pool sizes of intermediary metabolites in human HCM. Methods and Results: We conducted paired proteomic and metabolomic analyses of septal myectomy samples from patients with HCM and compared results to non-failing control human hearts. Increased abundance of extracellular matrix and intermediate filament / Z-disc proteins, and decreased abundance of proteins involved in fatty acid oxidation and cardiac energetics was evident in HCM compared to controls. Acyl carnitines, byproducts of fatty acid oxidation, were markedly depleted in HCM samples. Conversely, the ketone body 3-hydroxybutyrate, lactate, and the 3 branched chain amino acids, were all significantly increased in HCM hearts, suggesting that they may serve as alternate fuel sources for the production of ATP. ATP, nicotinamide adenine dinucleotide (NADH), NADP and NADPH, and acetyl CoA were also severely depleted in HCM hearts. Based on measurements from human skinned muscle fibers, the magnitude of observed reduction in ATP content in the HCM hearts would be expected to decrease the rate of cross-bridge detachment, implying a direct effect of energy depletion on myofilament function that could contribute to diastolic dysfunction. Conclusions: HCM hearts display profound deficits in cardiac energetics, marked by depletion of fatty acid derivatives and compensatory increases in other metabolites that could serve as alternate fuel sources. These results lend support to the paradigm that energy depletion contributes to the pathophysiology of HCM and also have important therapeutic implications for the future design of metabolic modulators to treat HCM.

scholarly journals Living with hypertrophic cardiomyopathy: the patient’s perspective

2021 ◽  
Author(s):  
Wendy Borsari ◽  
Lindsay Davis ◽  
Eric Meiers ◽  
Lisa Salberg ◽  
Barbara McDonough
Keyword(s):  
Quality Of Life ◽  
Hypertrophic Cardiomyopathy ◽  
Complex Disease ◽  
Symptomatic Relief ◽  
Disease Diagnosis ◽  
Implantable Cardioverter Defibrillator Therapy ◽  
Septal Myectomy ◽  
Potential Impact ◽  
Humanistic Burden

Hypertrophic cardiomyopathy (HCM) is a complex disease characterized by thickening of the cardiac muscle. Common symptoms include chest pain, shortness of breath, palpitations, fatigue and syncope (fainting), which are often confused for other conditions. Clinical treatment focuses on the relief of symptoms with medical therapies, which provide adequate to more variable symptomatic relief. Patients may experience more severe complications that require surgical intervention, such as implantable cardioverter-defibrillator therapy or septal myectomy. Despite the potential impact on quality of life, the humanistic burden of HCM is not well established. Here, we present four patient testimonials that highlight challenges faced by patients and clinicians in diagnosing HCM and managing symptoms. These testimonials provide valuable information on the spectrum and expression of HCM across generations. Such testimonials can better inform disease diagnosis and monitoring, maximizing quality of life and improving disease outcome.

RF42 LONG TERM RESULTS OF SEPTAL MYECTOMY IN OBSTRUCTIVE HYPERTROPHIC CARDIOMYOPATHY

2018 ◽  
Vol 19 ◽  
pp. e76-00
Author(s):  
G. Saitto ◽  
F. Grimaldi ◽  
A. Varrica ◽  
A. Biondi ◽  
A. Garatti ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Long Term Results ◽  
Septal Myectomy ◽  
Obstructive Hypertrophic Cardiomyopathy

Genetic and Epigenetic Modulation of Drug Resistance in Cancer: Challenges and Opportunities

2020 ◽  
Vol 20 (14) ◽  
pp. 1114-1131 ◽  
Author(s):  
Kanisha Shah ◽  
Rakesh M. Rawal
Keyword(s):  
Drug Resistance ◽  
Drug Targets ◽  
Complex Disease ◽  
Cancer Therapies ◽  
Altered Expression ◽  
Acquired Drug Resistance ◽  
Challenges And Opportunities ◽  
Chemotherapeutic Treatment ◽  
Epigenetic Modulation ◽  
Targeted Drug Therapies

Cancer is a complex disease that has the ability to develop resistance to traditional therapies. The current chemotherapeutic treatment has become increasingly sophisticated, yet it is not 100% effective against disseminated tumours. Anticancer drugs resistance is an intricate process that ascends from modifications in the drug targets suggesting the need for better targeted therapies in the therapeutic arsenal. Advances in the modern techniques such as DNA microarray, proteomics along with the development of newer targeted drug therapies might provide better strategies to overcome drug resistance. This drug resistance in tumours can be attributed to an individual’s genetic differences, especially in tumoral somatic cells but acquired drug resistance is due to different mechanisms, such as cell death inhibition (apoptosis suppression) altered expression of drug transporters, alteration in drug metabolism epigenetic and drug targets, enhancing DNA repair and gene amplification. This review also focusses on the epigenetic modifications and microRNAs, which induce drug resistance and contributes to the formation of tumour progenitor cells that are not destroyed by conventional cancer therapies. Lastly, this review highlights different means to prevent the formation of drug resistant tumours and provides future directions for better treatment of these resistant tumours.

scholarly journals Twelve years of GWAS discoveries for osteoporosis and related traits: advances, challenges and applications

Bone Research ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Xiaowei Zhu ◽  
Weiyang Bai ◽  
Houfeng Zheng
Keyword(s):  
Drug Targets ◽  
Complex Disease ◽  
Association Studies ◽  
Osteoporotic Fractures ◽  
Disease Prediction ◽  
Genome Wide Association Studies ◽  
Mineral Density ◽  
Small Effect Size ◽  
Endocrine Status ◽  
Meta Analyses

AbstractOsteoporosis is a common skeletal disease, affecting ~200 million people around the world. As a complex disease, osteoporosis is influenced by many factors, including diet (e.g. calcium and protein intake), physical activity, endocrine status, coexisting diseases and genetic factors. In this review, we first summarize the discovery from genome-wide association studies (GWASs) in the bone field in the last 12 years. To date, GWASs and meta-analyses have discovered hundreds of loci that are associated with bone mineral density (BMD), osteoporosis, and osteoporotic fractures. However, the GWAS approach has sometimes been criticized because of the small effect size of the discovered variants and the mystery of missing heritability, these two questions could be partially explained by the newly raised conceptual models, such as omnigenic model and natural selection. Finally, we introduce the clinical use of GWAS findings in the bone field, such as the identification of causal clinical risk factors, the development of drug targets and disease prediction. Despite the fruitful GWAS discoveries in the bone field, most of these GWAS participants were of European descent, and more genetic studies should be carried out in other ethnic populations to benefit disease prediction in the corresponding population.

scholarly journals SEPTAL MYECTOMY OR ALCOHOL ABLATION FOR HYPERTROPHIC CARDIOMYOPATHY: A NATIONWIDE INPATIENT SAMPLE (NIS) DATABASE ANALYSIS

2021 ◽  
Vol 77 (18) ◽  
pp. 1111
Author(s):  
Waqas Ullah ◽  
Nishanth Thalambedu ◽  
Salman Zahid ◽  
Sameer Saleem ◽  
Drew Johnson ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Nationwide Inpatient Sample ◽  
Database Analysis ◽  
Alcohol Ablation ◽  
Septal Myectomy

Oxidized low-density lipoprotein and 15-deoxy-Δ12,14-PGJ2 increase mitochondrial complex I activity in endothelial cells

2003 ◽  
Vol 285 (6) ◽  
pp. H2298-H2308 ◽  
Author(s):  
Erin K. Ceaser ◽  
Anup Ramachandran ◽  
Anna-Liisa Levonen ◽  
Victor M. Darley-Usmar
Keyword(s):  
Endothelial Cells ◽  
Complex I ◽  
Citrate Synthase ◽  
Umbilical Vein ◽  
Oxidized Ldl ◽  
Antioxidant Defenses ◽  
Oxidized Lipids ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Complex I Activity

Oxidized lipids are capable of initiating diverse cellular responses through both receptor-mediated mechanisms and direct posttranslational modification of proteins. Typically, exposure of cells to low concentrations of oxidized lipids induces cytoprotective pathways, whereas high concentrations result in apoptosis. Interestingly, mitochondria can contribute to processes that result in either cytoprotection or cell death. The role of antioxidant defenses such as glutathione in adaptation to stress has been established, but the potential interaction with mitochondrial function is unknown and is examined in this article. Human umbilical vein endothelial cells (HUVEC) were exposed to oxidized LDL (oxLDL) or the electrophilic cyclopentenone 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2). We demonstrate that complex I activity, but not citrate synthase or cytochrome- c oxidase, is significantly induced by oxLDL and 15d-PGJ2. The mechanism is not clear at present but is independent of the induction of GSH, peroxisome proliferator-activated receptor (PPAR)-γ, and PPAR-α. This response is dependent on the induction of oxidative stress in the cells because it can be prevented by nitric oxide, probucol, and the SOD mimetic manganese(III) tetrakis(4-benzoic acid) porphyrin chloride. This increased complex I activity appears to contribute to protection against apoptosis induced by 4-hydroxynonenal.

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