Precision and genomic medicine for dilated and hypertrophic cardiomyopathy

Nomura, Seitaro; Ōno, Minoru

doi:10.3389/fcvm.2023.1137498

Cited by 3 publications

(2 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Clinical determinations of within the micro-environment are close to reality with emerging high-resolution time resolved approaches including fourdimensional flow cardiac magnetic resonance imaging (CMR), diffusion tensor imaging (DTI), and hybrid positron-emission tomography-MRI [118]. Moreover, clinical workflows for precision medicine in genetic cardiomyopathy remain a work in progress with some papers outlining the needs in the field in the general population [119] and in ethnic racial groups [120].…”

Section: Future Directions and Concluding Remarksmentioning

confidence: 99%

Emerging Concepts of Mechanisms Controlling Cardiac Tension: Focus on Familial Dilated Cardiomyopathy (DCM) and Sarcomere-Directed Therapies

Solaro,

Goldspink,

Wolska

2024

Preprint

View full text Add to dashboard Cite

Novel therapies for treatment of familial dilated cardiomyopathy (DCM) are lacking. Triggers for the progression of the disorder commonly occur due to specific gene variants that affect the production of sarcomeric/cytoskeletal proteins. Generally these variants cause a decrease in tension by the myofilaments, resulting in signaling abnormalities within the micro-environment which over time result in structural and functional maladaptations leading to heart failure (HF). Current concepts support the hypothesis that the mutant sarcomere proteins induce a causal depression in the tension time integral (TTI) of linear preparations of cardiac muscle. However, molecular mechanisms underlying tension generation particularly in relation to mutant proteins and their impact on sarcomere molecular signaling, are currently the subject of controversy. Thus, there is a need for clarification as to how mutant proteins affect sarcomere molecular signaling in the etiology and progression of DCM. A main topic in this controversy is the control of the number of tension generating myosin heads reacting with the thin filament. One line of investigation proposes that this number is determined by changes in the ratio of myosin heads in a sequestered super-relaxed state (SRX) or in a disordered relaxed state (DRX) poised for force generation upon Ca-activation of the thin filament. Contrasting evidence from nanometer–micrometer-scale x-ray diffraction in intact trabeculae indicates that the SRX/DRX states may have a lesser role. Instead, the proposal is that myosin heads are in a basal OFF state in relaxation then transfer to an ON state through a mechano-sensing mechanism induced during early thin filament activation and increasing thick filament strain. Recent evidence about the modulation of these mechanisms by protein phosphorylation has also introduced a need for reconsidering control of tension. We discuss these mechanisms that lead to different ideas related to how tension is controlled and disturbed by mutant sarcomere proteins linked to DCM including cardiac myosin, myosin-binding protein C, titin filaments, and thin filaments. Resolving the various mechanisms and incorporating them into a unified concept is crucial for gaining a comprehensive understanding of DCM. This deeper understanding is not only important for diagnosis and treatment strategies with small molecules, but also for understanding the reciprocal signaling processes that occur between cardiac myocytes and their micro-environment. By unraveling these complexities, we can pave the way for improved therapeutic interventions for managing DCM.

show abstract

Section: Future Directions and Concluding Remarksmentioning

confidence: 99%

Emerging Concepts of Mechanisms Controlling Cardiac Tension: Focus on Familial Dilated Cardiomyopathy (DCM) and Sarcomere-Directed Therapies

Solaro,

Goldspink,

Wolska

2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Clinical determinations within the micro-environment are close to reality with the use of emerging high-resolution time-resolved approaches including four-dimensional flow cardiac magnetic resonance imaging (CMR), diffusion tensor imaging (DTI), and hybrid positron-emission tomography-MRI [123]. Moreover, clinical workflows for precision medicine in genetic cardiomyopathy remain a work in progress with some papers outlining the needs in the field in the general population [124] and in ethnic racial groups [125]. There are also the important issues in the broad spectrum of DCM including sex-related pathologies and lifestyles such as alcohol consumption [126][127][128].…”

Section: Future Directions and Concluding Remarksmentioning

confidence: 99%

Emerging Concepts of Mechanisms Controlling Cardiac Tension: Focus on Familial Dilated Cardiomyopathy (DCM) and Sarcomere-Directed Therapies

Solaro,

Goldspink,

Wolska

2024

Biomedicines

View full text Add to dashboard Cite

Novel therapies for the treatment of familial dilated cardiomyopathy (DCM) are lacking. Shaping research directions to clinical needs is critical. Triggers for the progression of the disorder commonly occur due to specific gene variants that affect the production of sarcomeric/cytoskeletal proteins. Generally, these variants cause a decrease in tension by the myofilaments, resulting in signaling abnormalities within the micro-environment, which over time result in structural and functional maladaptations, leading to heart failure (HF). Current concepts support the hypothesis that the mutant sarcomere proteins induce a causal depression in the tension-time integral (TTI) of linear preparations of cardiac muscle. However, molecular mechanisms underlying tension generation particularly concerning mutant proteins and their impact on sarcomere molecular signaling are currently controversial. Thus, there is a need for clarification as to how mutant proteins affect sarcomere molecular signaling in the etiology and progression of DCM. A main topic in this controversy is the control of the number of tension-generating myosin heads reacting with the thin filament. One line of investigation proposes that this number is determined by changes in the ratio of myosin heads in a sequestered super-relaxed state (SRX) or in a disordered relaxed state (DRX) poised for force generation upon the Ca2+ activation of the thin filament. Contrasting evidence from nanometer–micrometer-scale X-ray diffraction in intact trabeculae indicates that the SRX/DRX states may have a lesser role. Instead, the proposal is that myosin heads are in a basal OFF state in relaxation then transfer to an ON state through a mechano-sensing mechanism induced during early thin filament activation and increasing thick filament strain. Recent evidence about the modulation of these mechanisms by protein phosphorylation has also introduced a need for reconsidering the control of tension. We discuss these mechanisms that lead to different ideas related to how tension is disturbed by levels of mutant sarcomere proteins linked to the expression of gene variants in the complex landscape of DCM. Resolving the various mechanisms and incorporating them into a unified concept is crucial for gaining a comprehensive understanding of DCM. This deeper understanding is not only important for diagnosis and treatment strategies with small molecules, but also for understanding the reciprocal signaling processes that occur between cardiac myocytes and their micro-environment. By unraveling these complexities, we can pave the way for improved therapeutic interventions for managing DCM.

show abstract

Mavacamten in hypertrophic obstructive cardiomyopathy: Prospects for AI integration and mitigating healthcare disparities

Sulaiman,

Saeed,

Khatib

et al. 2024

Current Problems in Cardiology

View full text Add to dashboard Cite

Precision and genomic medicine for dilated and hypertrophic cardiomyopathy

Cited by 3 publications

References 49 publications

Emerging Concepts of Mechanisms Controlling Cardiac Tension: Focus on Familial Dilated Cardiomyopathy (DCM) and Sarcomere-Directed Therapies

Emerging Concepts of Mechanisms Controlling Cardiac Tension: Focus on Familial Dilated Cardiomyopathy (DCM) and Sarcomere-Directed Therapies

Emerging Concepts of Mechanisms Controlling Cardiac Tension: Focus on Familial Dilated Cardiomyopathy (DCM) and Sarcomere-Directed Therapies

Mavacamten in hypertrophic obstructive cardiomyopathy: Prospects for AI integration and mitigating healthcare disparities

Contact Info

Product

Resources

About