Abstract P397: MTCH2 As A Modifier Of Cardiomyopathy

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Julie A Fischer ◽  
Megan Puckelwartz ◽  
Matthew Wolf ◽  
Mattia Quattrocelli ◽  
Lorenzo Pesce ◽  
...  
Keyword(s):  
Heart Failure ◽  
Genetic Variation ◽  
Oxygen Consumption ◽  
Genetic Modifier ◽  
Significant Risk ◽  
Hek293 Cells ◽  
Energy Deficit ◽  
Dependent Manner ◽  
Genetic Modifiers ◽  
Heart Tube

Background: Cardiomyopathy is a highly heritable disorder that carries a significant risk for heart failure and arrhythmias. Most inherited cardiomyopathies are characterized by variable penetrance and expressivity, which in part arises from additional genetic variation, known as genetic modifiers. Methods and Results: Genomic profiling of human cardiomyopathy cases identified enriched genetic variation in the gene MTCH2. Specifically, a truncating variant was found to be overrepresented in patients with cardiomyopathy compared to controls. MTCH2 encodes a mitochondrial carrier protein that has a role in regulating oxidative phosphorylation. To investigate fundamental mechanisms by which MTCH2 contributes to cardiac and metabolic phenotypes, we generated a knockdown model of the Drosophila MTCH2 ortholog, Mtch. We found that cardiac-specific Mtch reduction in flies produced heart tube dilation and reduced function as well as a shortened life span, documenting a clear role Mtch in the myocardium. Metabolomic profiling demonstrated cardiac deficiency of Mtch lowered the flux of glucose-derived metabolites to the citric acid cycle associated with reduced downstream oxygen consumption and ATP synthesis, causing an energy deficit. We generated a deletion of MTCH2 using gene editing in HEK293 cells. Similar to the fly model, these cells demonstrated reduced oxygen consumption in the presence of glucose, but not fatty acids, and had a higher level of inhibitory phosphorylation of pyruvate dehydrogenase, a critical regulator of glucose metabolism. These data suggest MTCH2 influences the efficiency of glucose oxidation and substrate usage, an important mode of cardiac energy generation, especially in the setting of heart failure. Conclusions: We identified MTCH2 as a modifier of the cardiomyopathy phenotype in humans. Reduction of MTCH2 resulted in impaired cardiac function with reduced oxygen consumption and increased glycolysis in a substrate dependent manner. Since failed hearts are more dependent on glycolysis, these data support that reduction of MTCH2 promotes heart failure and provides a mechanism by which MTCH2 acts as a deleterious genetic modifier in heart failure.

Abstract 261: Evaluating MTCH2 as a Modifier of Cardiomyopathy

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Julie A Fischer ◽  
Mattia Quattrocelli ◽  
Megan Puckelwartz ◽  
Matthew Wolf ◽  
Elizabeth M McNally
Keyword(s):  
Heart Failure ◽  
Genetic Variation ◽  
Oxygen Consumption ◽  
Metabolic Regulation ◽  
Critical Role ◽  
Genetic Modifier ◽  
Significant Risk ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Heart Tube

Background: Cardiomyopathy is a highly heritable disorder that carries a significant risk for heart failure and arrhythmias. The onset, severity, and progression of cardiomyopathy is influenced by genetic variation, with the most common form of inheritance in familial cases being autosomal dominant. All inherited cardiomyopathies are characterized by variable penetrance and expressivity, which in part arises from additional genetic variation, known as genetic modifiers. Methods and Results: Broad genomic profiling of human cardiomyopathy cases identified enriched genetic variation in the gene MTCH2. Specifically, a loss of function variant was found to be enriched in patients with cardiomyopathy. MTCH2 single nucleotide polymorphisms have also been linked to obesity, underscoring a critical role for MTCH2 in metabolic regulation. MTCH2 encodes a mitochondrial carrier protein that has a role in regulating oxidative phosphorylation. In order to investigate fundamental mechanisms by which MTCH2 contributes to cardiac and metabolic phenotypes, we generated a knockdown model of the Drosophila MTCH2 ortholog, Mtch. This knockdown model mimics what is seen in human carriers with the heterozygous loss of function allele. In the Drosophila model, Mtch RNA was reduced by approximately half. We found that cardiac-specific Mtch deficiency in flies produced heart tube dilated and reduced function as well as a shortened life span, documenting a clear role for cardiac Mtch. Cardiac deficiency of Mtch increased circulating lactate levels in flies. Oxygen consumption was reduced in cardiac Mtch deficiency flies in the presence of glucose, but not palmitate. Thus, loss of Mtch2 alters oxygen consumption in a substrate dependent manner. Conclusions: We identified MTCH2 as a modifier of the cardiomyopathy phenotype in humans. Reduction of Mtch in flies resulted in impaired cardiac function and reduced oxygen consumption under certain metabolic condition. As failed hearts are more dependent on glycolysis, these data support that reduction of MTCH2 promotes heart failure and provides a mechanism by which MTCH2 acts as a deleterious genetic modifier in heart failure.

scholarly journals A Method for Predicting the Main Indicators of Cardiopulmonary Stress Testing for Patients with Chronic Heart Failure

2020 ◽  
Vol 23 (1) ◽  
pp. 96-104
Author(s):  
A. S. Krasichkov ◽  
E. Mbazumutima ◽  
F. Shikama ◽  
E. M. Nifontov
Keyword(s):  
Heart Failure ◽  
Oxygen Consumption ◽  
Chronic Heart Failure ◽  
Stress Testing ◽  
Stress Test ◽  
Significant Risk ◽  
Exercise Stress Test ◽  
Exercise Stress ◽  
Peak Oxygen Consumption ◽  
Prognostic Information

Introduction. Cardiopulmonary stress test provides significant diagnostic and prognostic information of the condition of patients with cardiovascular and pulmonary diseases. There is a serious problem, that final phase of stress testing is a physically difficult exercise for a person. There is a significant risk of occurrence and development of pathological conditions of the patient's cardiovascular system. One of the solutions is the development of methods for assessing the biological parameters of the patients at the end of a load protocol based on data from the initial stages of the test.Aim. Development of a method for finding an estimate of the maximum heart rate (HR) and of the peak oxygen consumption (OC) for the patients with chronic heart failure at the end of a cardiorespiratory exercise stress test, based on the results of the study obtained at the first initial stages of the test.Materials and methods. For the study, 149 anonymized records of rhythmograms and data of changes in the oxygen consumption of the patients with chronic heart failure were used. The patients underwent a cardiopulmonary stress test by a bicycle ergometer using step-by-step load protocol (the load power increase at each stage was 10 W, the duration of the load stage was 1 min)Results. Based on the analysis of the data obtained, a method for assessing the peak values of HR and of PC of the patients with chronic heart failure was developed.Conclusion. The relative error of the proposed estimate of the HR peak in most cases was no more than 10 %, which allows it to be used for practical purposes. It was established that when performing 70 % of the stress protocol, the error of the proposed estimate of the OC peak in most cases did not exceed 20 %. More research is needed to improve the accuracy of the assessment for using in medical applications aimed to the modernization of methods and equipment for stress testing of the patients.

Prolonged Kinetics of Recovery of Oxygen Consumption After Maximal Graded Exercise in Patients With Chronic Heart Failure

Circulation ◽  
1995 ◽  
Vol 91 (12) ◽  
pp. 2924-2932 ◽  
Author(s):  
Alain Cohen-Solal ◽  
Thierry Laperche ◽  
Daniel Morvan ◽  
Michel Geneves ◽  
Bernard Caviezel ◽  
...  
Keyword(s):  
Heart Failure ◽  
Oxygen Consumption ◽  
Chronic Heart Failure ◽  
Graded Exercise ◽  
Kinetics Of

scholarly journals THU0442 GOUT AND HEART FAILURE IN THE US: A NATIONAL PERSPECTIVE

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 458.2-458
Author(s):  
G. Singh ◽  
M. Sehgal ◽  
A. Mithal
Keyword(s):  
Risk Factors ◽  
Heart Failure ◽  
Confidence Intervals ◽  
Burden Of Illness ◽  
Average Length ◽  
Private Insurance ◽  
Significant Risk ◽  
Case Fatality ◽  
The United States ◽  
The Us

Background:Heart failure (HF) is the eighth leading cause of death in the US, with a 38% increase in the number of deaths due to HF from 2011 to 2017 (1). Gout and hyperuricemia have previously been recognized as significant risk factors for heart failure (2), but there is little nationwide data on the clinical and economic consequences of these comorbidities.Objectives:To study heart failure hospitalizations in patients with gout in the United States (US) and estimate their clinical and economic impact.Methods:The Nationwide Inpatient Sample (NIS) is a stratified random sample of all US community hospitals. It is the only US national hospital database with information on all patients, regardless of payer, including persons covered by Medicare, Medicaid, private insurance, and the uninsured. We examined all inpatient hospitalizations in the NIS in 2017, the most recent year of available data, with a primary or secondary diagnosis of gout and heart failure. Over 69,800 ICD 10 diagnoses were collapsed into a smaller number of clinically meaningful categories, consistent with the CDC Clinical Classification Software.Results:There were 35.8 million all-cause hospitalizations in patients in the US in 2017. Of these, 351,735 hospitalizations occurred for acute and/or chronic heart failure in patients with gout. These patients had a mean age of 73.3 years (95% confidence intervals 73.1 – 73.5 years) and were more likely to be male (63.4%). The average length of hospitalization was 6.1 days (95% confidence intervals 6.0 to 6.2 days) with a case fatality rate of 3.5% (95% confidence intervals 3.4% – 3.7%). The average cost of each hospitalization was $63,992 (95% confidence intervals $61,908 - $66,075), with a total annual national cost estimate of $22.8 billion (95% confidence intervals $21.7 billion - $24.0 billion).Conclusion:While gout and hyperuricemia have long been recognized as potential risk factors for heart failure, the aging of the US population is projected to significantly increase the burden of illness and costs of care of these comorbidities (1). This calls for an increased awareness and management of serious co-morbid conditions in patients with gout.References:[1]Sidney, S., Go, A. S., Jaffe, M. G., Solomon, M. D., Ambrosy, A. P., & Rana, J. S. (2019). Association Between Aging of the US Population and Heart Disease Mortality From 2011 to 2017. JAMA Cardiology. doi:10.1001/jamacardio.2019.4187[2]Krishnan E. Gout and the risk for incident heart failure and systolic dysfunction. BMJ Open 2012;2:e000282.doi:10.1136/bmjopen-2011-000282Disclosure of Interests: :Gurkirpal Singh Grant/research support from: Horizon Therapeutics, Maanek Sehgal: None declared, Alka Mithal: None declared

scholarly journals The Novel ALG-2 Target Protein CDIP1 Promotes Cell Death by Interacting with ESCRT-I and VAPA/B

2021 ◽  
Vol 22 (3) ◽  
pp. 1175
Author(s):  
Ryuta Inukai ◽  
Kanako Mori ◽  
Keiko Kuwata ◽  
Chihiro Suzuki ◽  
Masatoshi Maki ◽  
...  
Keyword(s):  
Cell Death ◽  
Essential Gene ◽  
Susceptibility Gene ◽  
Target Protein ◽  
Hek293 Cells ◽  
Dependent Manner ◽  
Gene Encoding ◽  
Endosomal Sorting ◽  
Cell Death Pathways ◽  
Apoptotic Protein

Apoptosis-linked gene 2 (ALG-2, also known as PDCD6) is a member of the penta-EF-hand (PEF) family of Ca2+-binding proteins. The murine gene encoding ALG-2 was originally reported to be an essential gene for apoptosis. However, the role of ALG-2 in cell death pathways has remained elusive. In the present study, we found that cell death-inducing p53 target protein 1 (CDIP1), a pro-apoptotic protein, interacts with ALG-2 in a Ca2+-dependent manner. Co-immunoprecipitation analysis of GFP-fused CDIP1 (GFP-CDIP1) revealed that GFP-CDIP1 associates with tumor susceptibility gene 101 (TSG101), a known target of ALG-2 and a subunit of endosomal sorting complex required for transport-I (ESCRT-I). ESCRT-I is a heterotetrameric complex composed of TSG101, VPS28, VPS37 and MVB12/UBAP1. Of diverse ESCRT-I species originating from four VPS37 isoforms (A, B, C, and D), CDIP1 preferentially associates with ESCRT-I containing VPS37B or VPS37C in part through the adaptor function of ALG-2. Overexpression of GFP-CDIP1 in HEK293 cells caused caspase-3/7-mediated cell death. In addition, the cell death was enhanced by co-expression of ALG-2 and ESCRT-I, indicating that ALG-2 likely promotes CDIP1-induced cell death by promoting the association between CDIP1 and ESCRT-I. We also found that CDIP1 binds to vesicle-associated membrane protein-associated protein (VAP)A and VAPB through the two phenylalanines in an acidic tract (FFAT)-like motif in the C-terminal region of CDIP1, mutations of which resulted in reduction of CDIP1-induced cell death. Therefore, our findings suggest that different expression levels of ALG-2, ESCRT-I subunits, VAPA and VAPB may have an impact on sensitivity of anticancer drugs associated with CDIP1 expression.

scholarly journals Heart Failure and PAHs, OHPAHs, and Trace Elements Levels in Human Serum: Results from a Preliminary Pilot Study in Greek Population and the Possible Impact of Air Pollution

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3207
Author(s):  
Eirini Chrysochou ◽  
Panagiotis Georgios Kanellopoulos ◽  
Konstantinos G. Koukoulakis ◽  
Aikaterini Sakellari ◽  
Sotirios Karavoltsos ◽  
...  
Keyword(s):  
Heart Failure ◽  
Trace Elements ◽  
Human Serum ◽  
Demographic Data ◽  
Smoking Habit ◽  
Environmental Pollutants ◽  
Significant Risk ◽  
Direct Determination ◽  
Healthy Donors ◽  
Polycyclic Aromatic

Cardiovascular diseases (CVDs) have been associated with environmental pollutants. The scope of this study is to assess any potential relation of polycyclic aromatic hydrocarbons (PAHs), their hydroxylated derivatives, and trace elements with heart failure via their direct determination in human serum of Greek citizens residing in different areas. Therefore, we analyzed 131 samples including cases (heart failure patients) and controls (healthy donors), and the respective demographic data were collected. Significantly higher concentrations (p < 0.05) were observed in cases’ serum regarding most of the examined PAHs and their derivatives with phenanthrene, fluorene, and fluoranthene being the most abundant (median of >50 μg L−1). Among the examined trace elements, As, Cd, Cu, Hg, Ni, and Pb were measured at statistically higher concentrations (p < 0.05) in cases’ samples, with only Cr being significantly higher in controls. The potential impact of environmental factors such as smoking and area of residence has been evaluated. Specific PAHs and trace elements could be possibly related with heart failure development. Atmospheric degradation and smoking habit appeared to have a significant impact on the analytes’ serum concentrations. PCA–logistic regression analysis could possibly reveal common mechanisms among the analytes enhancing the hypothesis that they may pose a significant risk for CVD development.

Genetic Modifiers of Tauopathy in Drosophila

Genetics ◽  
2003 ◽  
Vol 165 (3) ◽  
pp. 1233-1242
Author(s):  
Joshua M Shulman ◽  
Mel B Feany
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Genetic Modifier ◽  
Genetic Modifiers ◽  
Protein Tau ◽  
Major Class ◽  
Drosophila Model ◽  
Tau Kinases

Abstract In Alzheimer's disease and related disorders, the microtubule-associated protein Tau is abnormally hyperphosphorylated and aggregated into neurofibrillary tangles. Mutations in the tau gene cause familial frontotemporal dementia. To investigate the molecular mechanisms responsible for Tau-induced neurodegeneration, we conducted a genetic modifier screen in a Drosophila model of tauopathy. Kinases and phosphatases comprised the major class of modifiers recovered, and several candidate Tau kinases were similarly shown to enhance Tau toxicity in vivo. Despite some clinical and pathological similarities among neurodegenerative disorders, a direct comparison of modifiers between different Drosophila disease models revealed that the genetic pathways controlling Tau and polyglutamine toxicity are largely distinct. Our results demonstrate that kinases and phosphatases control Tau-induced neurodegeneration and have important implications for the development of therapies in Alzheimer's disease and related disorders.

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