Genetic Mutations and Mitochondrial Redox Signaling as Modulating Factors in Hypertrophic Cardiomyopathy: A Scoping Review

Abstract

Hypertrophic cardiomyopathy (HCM) is a heart condition characterized by cellular and metabolic dysfunction, with mitochondrial dysfunction playing a crucial role. Although the direct relationship between genetic mutations and mitochondrial dysfunction remains unclear, targeting mitochondrial dysfunction presents promising opportunities for treatment, as there are currently no effective treatments available for HCM. This review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Extension for Scoping Reviews guidelines. Searches were conducted in databases such as PubMed, Embase, and Scopus up to September 2023 using "MESH terms". Bibliographic references from pertinent articles were also included. Hypertrophic cardiomyopathy (HCM) is influenced by ionic homeostasis, cardiac tissue remodeling, metabolic balance, genetic mutations, reactive oxygen species regulation, and mitochondrial dysfunction. The latter is a common factor regardless of the cause and is linked to intracellular calcium handling, energetic and oxidative stress, and HCM-induced hypertrophy. Hypertrophic cardiomyopathy treatments focus on symptom management and complication prevention. Targeted therapeutic approaches, such as improving mitochondrial bioenergetics, are being explored. This includes coenzyme Q and elamipretide therapies and metabolic strategies like therapeutic ketosis. Understanding the biomolecular, genetic, and mitochondrial mechanisms underlying HCM is crucial for developing new therapeutic modalities.

Keywords: hypertrophic cardiomyopathy; metabolism; mitochondrial dysfunction; mitochondrial redox signaling.

Figure 1

PRISMA flowchart of the reviewed articles.

Figure 3

Metabolic redox integration in cardiomyocytes. Legends: HCM = Hypertrophic Cardiomyopathy, FFAs = Free Fatty Acids, NAD = Nicotinamide Adenine Dinucleotide, NADH = Nicotinamide Adenine Dinucleotide Hidrogenado, ADP = Adenosine Diphosphate, ATP = Adenosine Triphosphate, GSH = Glutathione, GSSG = Oxidized Glutathione, ROS = Reactive Oxygen Species.

Figure 2

Genetic and non-genetic causes of hypertrophic cardiomyopathy. Legends: MELAS = mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; MERRF = myoclonic epilepsy with ragged red fibers; MYBPC3 = myosin-binding protein C, cardiac-type; MYH7 = myosin, heavy chain 7; TNNI3 = troponin I, cardiac; TNNT2 = troponin T, cardiac.

Figure 4

Metabolic fluxes under high ATP demand in hypertrophic cardiomyopathy. Legends: ATP = adenosine triphosphate, and ATPase = enzyme.

Figure 5

Mitochondrial electron transport chain and ROS generation. Legends: NADH = adenine dinucleotide; NAD⁺ = nicotinamide adenine dinucleotide; PH = potential of hydrogen; SOD = superoxide dismutase; CAT = catalase; GSH = glutathione; GSSG = oxidized glutathione; ADP = adenosine diphosphate; ATP = adenosine triphosphate; Complex I = NADH dehydrogenase; Complex II = Succinate dehydrogenase; Complex III = Cytochrome b-c1; Complex IV = Cytochrome oxidase; Complex V = ATP synthase.

Figure 6

Ongoing pharmacological strategies to treat HCM. Legends: EGCG = epigallocatechin-3-gallate, LTCC = L-type calcium channel, NCX = Sodium-Calcium Exchanger, β-AR = beta-adrenergic receptor, RYR2 = ryanodine receptor type 2, SR = sarcoplasmic reticulum.