From the Guidelines
Cardiomyopathy is primarily caused by mutations in genes encoding protein components of the cardiac sarcomere, leading to abnormal calcium handling, mitochondrial dysfunction, and altered cell signaling, with the most significant pathways being related to the sarcomere and its components, as identified in the study by 1. The cellular pathways involved in cardiomyopathy are complex and multifaceted, with various forms of the disease, including hypertrophic, dilated, restrictive, and arrhythmogenic cardiomyopathy, each having distinct underlying mechanisms.
- The study by 1 highlights the importance of genetic mutations in the development of hypertrophic cardiomyopathy, with mutations in genes such as beta-myosin heavy chain, myosin-binding protein C, and cardiac troponin-T being common causes.
- The World Health Organization and International Society and Federation of Cardiology Task Force recognize five basic forms of cardiomyopathy, including dilated, hypertrophic, restrictive, arrhythmogenic, and unclassified cardiomyopathies, as noted in the study by 1.
- The classification of cardiomyopathies has evolved over time, with the American Heart Association proposing a classification based on genomics, and the European Society of Cardiology using a clinically oriented classification, as discussed in the study by 1.
- The study by 1 provides insight into the pathophysiology of hypertrophic cardiomyopathy, including the role of diastolic dysfunction, myocardial ischemia, and outflow obstruction in the development of symptoms.
- Overall, the cellular pathways involved in cardiomyopathy are complex and involve multiple mechanisms, including abnormal calcium handling, mitochondrial dysfunction, and altered cell signaling, with the specific pathways varying depending on the type of cardiomyopathy, as noted in the studies by 1.
From the Research
Cellular Pathway Involved in Cardiomyopathy
The cellular pathway involved in cardiomyopathy is complex and multifaceted. Key aspects include:
- Sarcomere mutations: Mutations in sarcomere proteins, the contractile building blocks of the heart, are a primary cause of hypertrophic cardiomyopathy (HCM) 2, 3, 4.
- Energy depletion and metabolic alterations: Mutations can lead to energy depletion, altering cellular metabolism with increased mitochondrial work, and triggering secondary disease modifiers that worsen the disease 2, 5.
- Mitochondrial dysfunction: HCM hearts show evidence of global energetic decompensation, decreased high-energy phosphate metabolites, and reduced mitochondrial genes involved in creatine kinase and ATP synthesis 5.
- Reactive oxygen species (ROS) imbalance: Excessive cellular ROS in HCM patients and animal models contribute to disease progression, with oxidative stress markers increased in the heart and serum of HCM patients 2, 5.
- Altered cardiac energetics: Changes in cardiac energetics represent a common pathophysiologic pathway in HCM, with alterations in fatty acid metabolism, reduction of acylcarnitines, and accumulation of free fatty acids 5.
Molecular Mechanisms
Molecular mechanisms underlying cardiomyopathy include:
- Genetic and molecular abnormalities: Unique to and shared between primary cardiomyopathies, such as increased myosin heavy chain (MHC) binding and ATP utilization in HCM, and abnormal protein-protein interaction and impaired Ca2+ flux in dilated cardiomyopathy (DCM) 6.
- Signal transduction and cellular constituents: Activation of multiple cellular constituents, including signal transducers, contributes to the clinical phenotype of HCM 3.
Potential Therapeutic Approaches
Potential therapeutic approaches for cardiomyopathy include:
- Restoring metabolism and mitochondrial function: Interventions aimed at improving metabolic function, reducing mitochondrial injury, and restoring ROS balance may be promising therapeutic approaches 2, 5.
- Targeting sarcomeric proteins and signal transduction: Therapies targeting sarcomeric proteins and signal transduction pathways may help attenuate the clinical disease 3, 4.