Materiały źródłowe

• #1 Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Clinical Manifestations, Diagnosis, and Therapy

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5654557/

  Hypertrophic cardiomyopathy (HCM) is a genetic disorder that is characterized by left ventricular hypertrophy unexplained by secondary causes, and a non-dilated left ventricle with preserved or increased ejection fraction. […] The histologic features of HCM include myocyte hypertrophy and disarray, as well as interstitial fibrosis. […] The hypertrophy is also frequently associated with left ventricular diastolic dysfunction. […] Mutations in over a dozen genes encoding sarcomere-associated proteins cause HCM. MYH7 and MYBPC3, encoding -myosin heavy chain and myosin binding protein C, respectively, are the two most common genes involved, together accounting for about 50% of the HCM families. […] The genetic discoveries have enhanced understanding of the molecular pathogenesis of HCM and have stimulated efforts designed to identify new therapeutic agents.

• #1 Mechanisms of disease: hypertrophic cardiomyopathy | Nature Reviews Cardiology

  https://www.nature.com/articles/nrcardio.2011.159

  Hypertrophic cardiomyopathy (HCM) is the most-common monogenically inherited form of heart disease, characterized by thickening of the left ventricular wall, contractile dysfunction, and potentially fatal arrhythmias. […] Much progress has been made in the elucidation of the genetic basis of HCM, resulting in the identification of more than 900 individual mutations in over 20 genes. […] However, the molecular events that ultimately lead to the clinical phenotype of HCM are still unclear. […] We discuss several potential pathways, which include altered calcium cycling and sarcomeric calcium sensitivity, increased fibrosis, disturbed biomechanical stress sensing, and impaired cardiac energy homeostasis. […] The molecular mechanisms of HCM are unclear; potential pathways include altered calcium cycling and sarcomeric calcium sensitivity, increased fibrosis, disturbed biomechanical stress sensing, and impaired cardiac energy homeostasis. […] An improved understanding of the pathological mechanisms involved in HCM should increase the specificity and efficacy of therapy for this condition.

• #2 Mechanisms of disease: hypertrophic cardiomyopathy | Nature Reviews Cardiology

  https://www.nature.com/articles/nrcardio.2011.159

  Hypertrophic cardiomyopathy (HCM) is the most-common monogenically inherited form of heart disease, characterized by thickening of the left ventricular wall, contractile dysfunction, and potentially fatal arrhythmias. […] Much progress has been made in the elucidation of the genetic basis of HCM, resulting in the identification of more than 900 individual mutations in over 20 genes. […] However, the molecular events that ultimately lead to the clinical phenotype of HCM are still unclear. […] We discuss several potential pathways, which include altered calcium cycling and sarcomeric calcium sensitivity, increased fibrosis, disturbed biomechanical stress sensing, and impaired cardiac energy homeostasis. […] The molecular mechanisms of HCM are unclear; potential pathways include altered calcium cycling and sarcomeric calcium sensitivity, increased fibrosis, disturbed biomechanical stress sensing, and impaired cardiac energy homeostasis. […] An improved understanding of the pathological mechanisms involved in HCM should increase the specificity and efficacy of therapy for this condition.

• #2 Hypertrophic Cardiomyopathy: Genes and Mechanisms

  https://www.imrpress.com/journal/FBL/30/2/10.31083/FBL25714/htm

  Hypertrophic cardiomyopathy (HCM) is a hereditary disease of the myocardium characterized by asymmetric hypertrophy (mainly the left ventricle) not caused by pressure or volume load. Most cases of HCM are caused by genetic mutations, particularly in the gene encoding cardiac myosin, such as MYH7, TNNT2, and MYBPC3. These mutations are usually inherited autosomal dominantly. Approximately 30–60% of HCM patients have a family history of similar cases among their immediate relatives. This underscores the significance of genetic factors in the development of HCM. […] The pathogenic genes of HCM mainly involve genes encoding cardiac myofilament proteins, such as MYH7, MYBPC3, etc. These gene mutations lead to abnormal myocardial contractile function, increase the stress load of myofilaments, and ultimately cause myocardial cell hypertrophy, disordered arrangement and fibrosis, which in turn leads to the occurrence and development of HCM.

• #3 Pathogenic Mechanisms of Hypertrophic Cardiomyopathy beyond Sarcomere Dysfunction

  https://www.mdpi.com/1422-0067/22/16/8933

  Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disorder, affecting 1 in 500 people in the general population. […] While HCM is generally accepted as a disease of the sarcomere, variable penetrance in families with identical genetic mutations challenges the monogenic origin of HCM and instead implies a multifactorial cause. […] The etiology of HCM is thus likely multifactorial rather than strictly genetic. […] Mechanistically, at the molecular level, comprehensive characterization of animal models carrying various sarcomere gene mutations demonstrated dysfunctional cardiomyocyte excitation-contraction coupling as a driver of cardiomyocyte hypertrophy. […] However, whether other HCM-associated non-sarcomere gene mutations also promote cardiomyocyte hypertrophy through alteration in excitation-contraction coupling is not fully understood.

• #3 Hypertrophic Cardiomyopathy: Genes and Mechanisms

  https://www.imrpress.com/journal/FBL/30/2/10.31083/FBL25714/htm

  Since the MYBPC3 was recognized by the scientific community as the main causative gene of HCM in 1995, a large number of studies have focused on this gene and its related mutations. To date, more than 600 mutations related to the MYBPC3 have been discovered, and these mutations account for approximately 35% of mutation-positive HCM patients. […] The MYH7 is located on chromosome 14q11.2-q13 and contains 40 exons. It encodes the β-myosin heavy chain (β-MHC), which consists of 1935 amino acids and serves as the core component of ventricular myosin. The protein is composed of two heavy chains and four light chains, forming three functional regions: the head, neck, and tail, which collectively drive muscle contraction. […] The pathogenicity of MYH7 gene mutations is closely related to its key function in cardiomyocytes. These mutations not only affect the contractile function of cardiomyocytes but may also lead to changes in a complex genetic and epigenetic background.

• #4 Hypertrophic Cardiomyopathy: Genes and Mechanisms

  https://www.imrpress.com/journal/FBL/30/2/10.31083/FBL25714/htm

  HCM stands out as the predominant hereditary heart condition, typically passed down through generations in an autosomal dominant manner. It often exhibits incomplete penetrance and a degree of variability, with around 30%–60% of cases showing familial ties. Presently, there’s a prevailing agreement within the medical community to advocate for targeted genetic testing in individuals suspected of HCM. […] The MYBPC3 encodes the cardiac isoform of myosin-binding protein C (cMBP-C). This gene spans a 3.7 kb DNA sequence and contains 34 coding elements, ultimately forming 35 exons. These exons are transcribed to produce a 3824 bp transcript. cMBP-C, a member of the intracellular immunoglobulin superfamily, is encoded by the MYBPC1 and MYBPC2 in skeletal muscle and by the MYBPC3 in the heart. Its structure includes eight immunoglobulin-like domains and three fibronectin type III domains. The core function of cMBP-C is to precisely regulate cross-bridge recycling in cardiomyocytes through phosphorylation and interaction with other factors, thereby contributing to the assembly of myocardial heavy chains. This regulation is crucial for ensuring that the heart muscle contracts and relaxes properly.

• #5 Hypertrophic Cardiomyopathy: Genes and Mechanisms

  https://www.imrpress.com/journal/FBL/30/2/10.31083/FBL25714/htm

  Since the MYBPC3 was recognized by the scientific community as the main causative gene of HCM in 1995, a large number of studies have focused on this gene and its related mutations. To date, more than 600 mutations related to the MYBPC3 have been discovered, and these mutations account for approximately 35% of mutation-positive HCM patients. […] The MYH7 is located on chromosome 14q11.2-q13 and contains 40 exons. It encodes the β-myosin heavy chain (β-MHC), which consists of 1935 amino acids and serves as the core component of ventricular myosin. The protein is composed of two heavy chains and four light chains, forming three functional regions: the head, neck, and tail, which collectively drive muscle contraction. […] The pathogenicity of MYH7 gene mutations is closely related to its key function in cardiomyocytes. These mutations not only affect the contractile function of cardiomyocytes but may also lead to changes in a complex genetic and epigenetic background.

• #6 Hypertrophic Cardiomyopathy: Genes and Mechanisms

  https://www.imrpress.com/journal/FBL/30/2/10.31083/FBL25714/htm

  The GLA is a gene in the human genome and is located on the X chromosome. The coding sequence of the GLA contains 7 exons and 6 introns, with a total length of approximately 13.5 kb. […] In cardiac cells, this deposition leads to organelle dysfunction, intracellular metabolism and energy production are affected, and ultimately leads to cardiomyocyte hypertrophy and hyperplasia. […] The LAMP2 is a gene encoding lysosomal-associated membrane protein 2 (LAMP2). It is located on the X chromosome of the human genome and is also known as a Danon disease-related gene. […] Most cases of HCM are caused by mutations in genes encoding sarcomeric proteins, with less than 3% of pathogenic variants found in the sarcomeric gene ACTC1. […] TNNT2 is located on chromosome 1 (1q32), encoding cardiac troponin T2 (TnT). It mainly regulates actin filament function by binding calcium ions and is crucial for human cardiac muscle contraction and relaxation.

• #7 Hypertrophic Cardiomyopathy: Genes and Mechanisms

  https://www.imrpress.com/journal/FBL/30/2/10.31083/FBL25714/htm

  The GLA is a gene in the human genome and is located on the X chromosome. The coding sequence of the GLA contains 7 exons and 6 introns, with a total length of approximately 13.5 kb. […] In cardiac cells, this deposition leads to organelle dysfunction, intracellular metabolism and energy production are affected, and ultimately leads to cardiomyocyte hypertrophy and hyperplasia. […] The LAMP2 is a gene encoding lysosomal-associated membrane protein 2 (LAMP2). It is located on the X chromosome of the human genome and is also known as a Danon disease-related gene. […] Most cases of HCM are caused by mutations in genes encoding sarcomeric proteins, with less than 3% of pathogenic variants found in the sarcomeric gene ACTC1. […] TNNT2 is located on chromosome 1 (1q32), encoding cardiac troponin T2 (TnT). It mainly regulates actin filament function by binding calcium ions and is crucial for human cardiac muscle contraction and relaxation.

• #8 Hypertrophic Cardiomyopathy: Genes and Mechanisms

  https://www.imrpress.com/journal/FBL/30/2/10.31083/FBL25714/htm

  The GLA is a gene in the human genome and is located on the X chromosome. The coding sequence of the GLA contains 7 exons and 6 introns, with a total length of approximately 13.5 kb. […] In cardiac cells, this deposition leads to organelle dysfunction, intracellular metabolism and energy production are affected, and ultimately leads to cardiomyocyte hypertrophy and hyperplasia. […] The LAMP2 is a gene encoding lysosomal-associated membrane protein 2 (LAMP2). It is located on the X chromosome of the human genome and is also known as a Danon disease-related gene. […] Most cases of HCM are caused by mutations in genes encoding sarcomeric proteins, with less than 3% of pathogenic variants found in the sarcomeric gene ACTC1. […] TNNT2 is located on chromosome 1 (1q32), encoding cardiac troponin T2 (TnT). It mainly regulates actin filament function by binding calcium ions and is crucial for human cardiac muscle contraction and relaxation.

• #9 Pathogenic Mechanisms of Hypertrophic Cardiomyopathy beyond Sarcomere Dysfunction

  https://www.mdpi.com/1422-0067/22/16/8933

  Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disorder, affecting 1 in 500 people in the general population. […] While HCM is generally accepted as a disease of the sarcomere, variable penetrance in families with identical genetic mutations challenges the monogenic origin of HCM and instead implies a multifactorial cause. […] The etiology of HCM is thus likely multifactorial rather than strictly genetic. […] Mechanistically, at the molecular level, comprehensive characterization of animal models carrying various sarcomere gene mutations demonstrated dysfunctional cardiomyocyte excitation-contraction coupling as a driver of cardiomyocyte hypertrophy. […] However, whether other HCM-associated non-sarcomere gene mutations also promote cardiomyocyte hypertrophy through alteration in excitation-contraction coupling is not fully understood.

• #10 Pathogenic Mechanisms of Hypertrophic Cardiomyopathy beyond Sarcomere Dysfunction

  https://www.mdpi.com/1422-0067/22/16/8933

  It is perhaps conceivable that an inciting cellular event, regardless of its genetic or environmental nature, disrupts certain intracellular biological processes with ensuing cardiomyocyte hypertrophy; this in turn alters the extracellular milieu, which subsequently promotes tissue reorganization in an area of otherwise intact cardiomyocytes, culminating in diffuse cardiomyocyte disarray, cardiac fibrosis, and asymmetric septal hypertrophy. […] Collectively, these studies convincingly demonstrated the polygenic nature of HCM pathogenesis and revealed the complex interaction between common variants and modifiable host factors in modulating HCM disease progression. […] Collectively, these findings strongly suggest that a dysregulated autophagy response contributes to HCM pathogenesis in a sarcomere-independent manner.

• #11 Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Clinical Manifestations, Diagnosis, and Therapy

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5654557/

  A diverse array of mechanisms, mirroring the diversity of the causal genes and mutations, are implicated in the pathogenesis of HCM. […] The primary defect is the mutation. Initial or proximal phenotypes are defined as those resulting from the direct effects of the mutations on the structure and function of the sarcomere proteins. […] The intermediary (or secondary) phenotypes include the molecular changes that occur in response to the changes in the sarcomere protein structure and function. […] The tertiary effects are the ensuing histological and pathological phenotypes, which are the consequence of perturbation of a myriad of secondary molecular events in the myocardium, such as activation of the hypertrophic signaling pathways. […] These molecular and histological changes lead to the clinical phenotypes of HCM (quaternary).

• #12 Hypertrophic cardiomyopathy: genetics and clinical perspectives – Wolf – Cardiovascular Diagnosis and Therapy

  https://cdt.amegroups.org/article/view/24557/26222

  The primary defect is the sarcomere mutation, but clinical expression is determined by a complex hierarchy of genetic, epigenetic, and environmental factors. […] First, mutations directly alter the structure and function of the sarcomere proteins and alter biophysical properties of the cardiomyocyte, influence calcium handling, and change cellular energy balance. […] Additionally, mutations can directly initiate other signaling pathways via transcriptional activation; including expression and activation of trophic and mitotic factors, such as calcineurin, mitogen-activated protein kinases, and transforming growth factor beta pathways and stimulate non-cardiac cells, such as fibroblasts. […] The primary and secondary effects of the mutations ultimately lead to the functional pathological phenotypes, such as myocardial hypertrophy and ventricular dysfunction.

• #13 Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Diagnosis, Clinical Course and Therapy | IntechOpen

  https://www.intechopen.com/chapters/75983

  Hypertrophic cardiomyopathy (HCM) is a genetic disorder of cardiac myocytes that is characterized by cardiac hypertrophy, unexplained by the loading conditions, a non-dilated left ventricle and a normal or increased left ventricular ejection fraction (LV-EF). […] The precise mechanisms by which sarcomere variants result in the clinical phenotype have not been fully understood. Mutant sarcomere genes trigger several myocardial changes, leading to hypertrophy and fibrosis, which ultimately result in a small, stiff ventricle with impaired systolic and diastolic performance despite a preserved LV-EF. […] From a metabolic viewpoint, mutations in sarcomeric proteins generally increase myofilament activation and result in myocyte hypercontractility and excessive energy use due to higher (disproportionate) mitochondrial activity. Mitochondrial impairments in the cardiac energy-sensing apparatus as well as alterations in calcium handling result in a stimulation of signaling pathways that contribute to myocyte relaxation abnormalities and growth, with aberrant tissue architecture abnormalities such as myofibrillar disarray and myocardial fibrosis.

• #14 Critical Evaluation of Current Hypotheses for the Pathogenesis of Hypertrophic Cardiomyopathy

  https://www.mdpi.com/1422-0067/23/4/2195

  Hereditary hypertrophic cardiomyopathy (HCM), due to mutations in sarcomere proteins, occurs in more than 1/500 individuals and is the leading cause of sudden cardiac death in young people. […] The identity of the primary mutation-induced changes in sarcomere function and how they trigger debilitating remodeling are poorly understood. Support for the importance of mutation-induced hypercontractility, e.g., increased calcium sensitivity and/or increased power output, has been strengthened in recent years. […] We here critically review three hypotheses for the primary mutation-induced change behind the pathogenesis in HCM. […] A hypothesis that has received appreciable attention recently is the idea that hypercontractility, as a direct consequence of the mutations, is a key initiator of pathologic remodeling.

• #15 Critical Evaluation of Current Hypotheses for the Pathogenesis of Hypertrophic Cardiomyopathy

  https://www.mdpi.com/1422-0067/23/4/2195

  Hereditary hypertrophic cardiomyopathy (HCM), due to mutations in sarcomere proteins, occurs in more than 1/500 individuals and is the leading cause of sudden cardiac death in young people. […] The identity of the primary mutation-induced changes in sarcomere function and how they trigger debilitating remodeling are poorly understood. Support for the importance of mutation-induced hypercontractility, e.g., increased calcium sensitivity and/or increased power output, has been strengthened in recent years. […] We here critically review three hypotheses for the primary mutation-induced change behind the pathogenesis in HCM. […] A hypothesis that has received appreciable attention recently is the idea that hypercontractility, as a direct consequence of the mutations, is a key initiator of pathologic remodeling.

• #16 Revealed: The molecular mechanism underlying hypertrophic cardiomyopathy | News Center

  https://med.stanford.edu/news/all-news/2018/08/the-molecular-mechanism-underlying-hypertrophic-cardiomyopathy.html

  A study led by Stanford Medicine researchers shows why so many mutations associated with hypertrophic cardiomyopathy, a heart disorder, alter a key constituent of muscle cells in a way that makes it work overtime. […] About 1 in every 500 people is born with hypertrophic cardiomyopathy, a genetic disease caused by any one of numerous mutations that, mysteriously, cause heart muscle to contract with too much force. […] Now, researchers have discovered the mechanism behind this workaholic heart. […] Spudich has spent decades studying, at the molecular level, how muscles contract – and, in particular, the workings of myosin, a key constituent of every muscle cell, including the ones composing heart muscle. […] Spudich and his colleagues discovered that many mutations associated with hypertrophic cardiomyopathy, although they occur at different points along the myosin gene’s sequence, often wind up affecting amino acids on the same surface of the folded protein’s outer edge, altering the myosin molecule in ways that coax it out of its sleeping flamingo posture. […] The changed postural preference, in turn, keeps the myosin molecule from spending enough time snoozing on the job, collectively causing constant overdrive in the heart muscle’s power output.

• #17 KEGG DISEASE: Hypertrophic cardiomyopathy

  https://www.genome.jp/entry/H00292

  Hypertrophic cardiomyopathy (HCM/CMH) is a primary myocardial disorder with an autosomal dominant pattern of inheritance that is characterized by hypertrophy of the left ventricles with histological features of myocyte hypertrophy, myofibrillar disarray, and interstitial fibrosis. […] Hundreds of mutations in the genes that encode protein constituents of the sarcomere have been identified in HCM. These mutations increase the Ca2+ sensitivity of cardiac myofilaments. Increased myofilament Ca2+ sensitivity is expected to increase the ATP utilization by actomyosin at submaximal Ca2+ concentrations, which might cause an imbalance in energy supply and demand in the heart under severe stress. The inefficient use of ATP suggests that an inability to maintain normal ATP levels could be the central abnormality.

• #18 New perspectives in the pharmacological treatment of hypertrophic cardiomyopathy | Revista Portuguesa de Cardiologia (English edition)

  https://www.revportcardiol.org/en-new-perspectives-in-pharmacological-treatment-articulo-S2174204920300878

  Diltiazem is a non-dihydropyridine L-type calcium channel blocker indicated as a second-line therapy for symptomatic relief in HCM, since it is less effective than beta-blockers. […] HCM-associated sarcomere mutations are now known to lead to early dysregulation of intracellular Ca2+ homeostasis. […] These mutations increase sarcomeric myofilament sensitivity and affinity for Ca2+, thus preventing its reuptake to the sarcoplasmic reticulum and efflux from the cardiomyocyte during diastole. […] In addition, sarcomere mutations result in increased energy expenditure in the cardiomyocyte, reducing the adenosine triphosphate (ATP) available for the ion pumps that regulate intracellular Ca2+ levels. […] This dysregulation leads to intracellular accumulation of Ca2+, which in addition to preventing cell relaxation, causes diastolic dysfunction and increased risk of arrhythmias, and activates signaling pathways which contribute to the adverse myocardial remodeling that is characteristic of HCM.

• #19 KEGG DISEASE: Hypertrophic cardiomyopathy

  https://www.genome.jp/entry/H00292

  Hypertrophic cardiomyopathy (HCM/CMH) is a primary myocardial disorder with an autosomal dominant pattern of inheritance that is characterized by hypertrophy of the left ventricles with histological features of myocyte hypertrophy, myofibrillar disarray, and interstitial fibrosis. […] Hundreds of mutations in the genes that encode protein constituents of the sarcomere have been identified in HCM. These mutations increase the Ca2+ sensitivity of cardiac myofilaments. Increased myofilament Ca2+ sensitivity is expected to increase the ATP utilization by actomyosin at submaximal Ca2+ concentrations, which might cause an imbalance in energy supply and demand in the heart under severe stress. The inefficient use of ATP suggests that an inability to maintain normal ATP levels could be the central abnormality.

• #20 Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Diagnosis, Clinical Course and Therapy | IntechOpen

  https://www.intechopen.com/chapters/75983

  Hypertrophic cardiomyopathy (HCM) is a genetic disorder of cardiac myocytes that is characterized by cardiac hypertrophy, unexplained by the loading conditions, a non-dilated left ventricle and a normal or increased left ventricular ejection fraction (LV-EF). […] The precise mechanisms by which sarcomere variants result in the clinical phenotype have not been fully understood. Mutant sarcomere genes trigger several myocardial changes, leading to hypertrophy and fibrosis, which ultimately result in a small, stiff ventricle with impaired systolic and diastolic performance despite a preserved LV-EF. […] From a metabolic viewpoint, mutations in sarcomeric proteins generally increase myofilament activation and result in myocyte hypercontractility and excessive energy use due to higher (disproportionate) mitochondrial activity. Mitochondrial impairments in the cardiac energy-sensing apparatus as well as alterations in calcium handling result in a stimulation of signaling pathways that contribute to myocyte relaxation abnormalities and growth, with aberrant tissue architecture abnormalities such as myofibrillar disarray and myocardial fibrosis.

• #21 Critical Evaluation of Current Hypotheses for the Pathogenesis of Hypertrophic Cardiomyopathy

  https://www.mdpi.com/1422-0067/23/4/2195

  The so-called “haplo-insufficiency” or “null-allele” mechanism is mostly associated with mutations in cMyBP-C. […] The primary effect of any sarcomere protein mutation would affect the interaction partners and the production of force within the sarcomere. […] The force production, in turn, affects the entire cardiomyocyte mechanically or by accumulation of metabolites and other changes in the intracellular milieu. […] Overall, the tissue response to cope with the changes caused by a sarcomere mutation over time alters the tissue morphology and function by cardiac remodeling, e.g., hypertrophy in HCM.

• #22 Revealed: The molecular mechanism underlying hypertrophic cardiomyopathy | News Center

  https://med.stanford.edu/news/all-news/2018/08/the-molecular-mechanism-underlying-hypertrophic-cardiomyopathy.html

  A study led by Stanford Medicine researchers shows why so many mutations associated with hypertrophic cardiomyopathy, a heart disorder, alter a key constituent of muscle cells in a way that makes it work overtime. […] About 1 in every 500 people is born with hypertrophic cardiomyopathy, a genetic disease caused by any one of numerous mutations that, mysteriously, cause heart muscle to contract with too much force. […] Now, researchers have discovered the mechanism behind this workaholic heart. […] Spudich has spent decades studying, at the molecular level, how muscles contract – and, in particular, the workings of myosin, a key constituent of every muscle cell, including the ones composing heart muscle. […] Spudich and his colleagues discovered that many mutations associated with hypertrophic cardiomyopathy, although they occur at different points along the myosin gene’s sequence, often wind up affecting amino acids on the same surface of the folded protein’s outer edge, altering the myosin molecule in ways that coax it out of its sleeping flamingo posture. […] The changed postural preference, in turn, keeps the myosin molecule from spending enough time snoozing on the job, collectively causing constant overdrive in the heart muscle’s power output.

• #23 Revealed: The molecular mechanism underlying hypertrophic cardiomyopathy, or

  https://scopeblog.stanford.edu/2018/08/14/revealed-the-molecular-mechanism-underlying-hypertrophic-cardiomyopathy-or-workaholic-heart/

  About one in every 500 of us is born with hypertrophic cardiomyopathy, a genetic disease caused by one of numerous mutations that, mysteriously, cause heart muscle to contract with too much force. […] A preponderance — about 40 percent of them — occur in the gene coding for the particular variety of myosin found in heart muscle, leading Spudich to wonder what those mutations have in common. […] Many hypertrophic cardiomyopathy-associated mutations, although they occur at different points along the myosin gene’s sequence, often wind up affecting amino acids on the same surface of the folded protein’s outer edge, altering the myosin molecule in ways that coax it out of its “sleeping flamingo” posture. The changed postural preference, in turn, keeps a myosin molecule from spending enough time snoozing on the job, collectively causing constant overdrive in heart muscle’s power output.

• #24 New perspectives in the pharmacological treatment of hypertrophic cardiomyopathy | Revista Portuguesa de Cardiologia (English edition)

  https://www.revportcardiol.org/en-new-perspectives-in-pharmacological-treatment-articulo-S2174204920300878

  Diltiazem is a non-dihydropyridine L-type calcium channel blocker indicated as a second-line therapy for symptomatic relief in HCM, since it is less effective than beta-blockers. […] HCM-associated sarcomere mutations are now known to lead to early dysregulation of intracellular Ca2+ homeostasis. […] These mutations increase sarcomeric myofilament sensitivity and affinity for Ca2+, thus preventing its reuptake to the sarcoplasmic reticulum and efflux from the cardiomyocyte during diastole. […] In addition, sarcomere mutations result in increased energy expenditure in the cardiomyocyte, reducing the adenosine triphosphate (ATP) available for the ion pumps that regulate intracellular Ca2+ levels. […] This dysregulation leads to intracellular accumulation of Ca2+, which in addition to preventing cell relaxation, causes diastolic dysfunction and increased risk of arrhythmias, and activates signaling pathways which contribute to the adverse myocardial remodeling that is characteristic of HCM.

• #25 New perspectives in the pharmacological treatment of hypertrophic cardiomyopathy | Revista Portuguesa de Cardiologia (English edition)

  https://www.revportcardiol.org/en-new-perspectives-in-pharmacological-treatment-articulo-S2174204920300878

  Diltiazem is a non-dihydropyridine L-type calcium channel blocker indicated as a second-line therapy for symptomatic relief in HCM, since it is less effective than beta-blockers. […] HCM-associated sarcomere mutations are now known to lead to early dysregulation of intracellular Ca2+ homeostasis. […] These mutations increase sarcomeric myofilament sensitivity and affinity for Ca2+, thus preventing its reuptake to the sarcoplasmic reticulum and efflux from the cardiomyocyte during diastole. […] In addition, sarcomere mutations result in increased energy expenditure in the cardiomyocyte, reducing the adenosine triphosphate (ATP) available for the ion pumps that regulate intracellular Ca2+ levels. […] This dysregulation leads to intracellular accumulation of Ca2+, which in addition to preventing cell relaxation, causes diastolic dysfunction and increased risk of arrhythmias, and activates signaling pathways which contribute to the adverse myocardial remodeling that is characteristic of HCM.

• #26 New perspectives in the pharmacological treatment of hypertrophic cardiomyopathy | Revista Portuguesa de Cardiologia (English edition)

  https://www.revportcardiol.org/en-new-perspectives-in-pharmacological-treatment-articulo-S2174204920300878

  Diltiazem is a non-dihydropyridine L-type calcium channel blocker indicated as a second-line therapy for symptomatic relief in HCM, since it is less effective than beta-blockers. […] HCM-associated sarcomere mutations are now known to lead to early dysregulation of intracellular Ca2+ homeostasis. […] These mutations increase sarcomeric myofilament sensitivity and affinity for Ca2+, thus preventing its reuptake to the sarcoplasmic reticulum and efflux from the cardiomyocyte during diastole. […] In addition, sarcomere mutations result in increased energy expenditure in the cardiomyocyte, reducing the adenosine triphosphate (ATP) available for the ion pumps that regulate intracellular Ca2+ levels. […] This dysregulation leads to intracellular accumulation of Ca2+, which in addition to preventing cell relaxation, causes diastolic dysfunction and increased risk of arrhythmias, and activates signaling pathways which contribute to the adverse myocardial remodeling that is characteristic of HCM.

• #27 New perspectives in the pharmacological treatment of hypertrophic cardiomyopathy | Revista Portuguesa de Cardiologia (English edition)

  https://www.revportcardiol.org/en-new-perspectives-in-pharmacological-treatment-articulo-S2174204920300878

  Diltiazem is a non-dihydropyridine L-type calcium channel blocker indicated as a second-line therapy for symptomatic relief in HCM, since it is less effective than beta-blockers. […] HCM-associated sarcomere mutations are now known to lead to early dysregulation of intracellular Ca2+ homeostasis. […] These mutations increase sarcomeric myofilament sensitivity and affinity for Ca2+, thus preventing its reuptake to the sarcoplasmic reticulum and efflux from the cardiomyocyte during diastole. […] In addition, sarcomere mutations result in increased energy expenditure in the cardiomyocyte, reducing the adenosine triphosphate (ATP) available for the ion pumps that regulate intracellular Ca2+ levels. […] This dysregulation leads to intracellular accumulation of Ca2+, which in addition to preventing cell relaxation, causes diastolic dysfunction and increased risk of arrhythmias, and activates signaling pathways which contribute to the adverse myocardial remodeling that is characteristic of HCM.

• #28 Mechanism-driven therapies for hypertrophic cardiomyopathy – Browse Articles – Conditioning Medicine

  http://www.conditionmed.org/Data/View/14835

  Several approaches have been undertaken to target various pathological features of HCM. This section focuses on therapies designed to attenuate myocardial fibrosis, oxidative stress, impaired myocardial energetics, and hypercontractility. […] Myocardial fibrosis is an independent predictor of adverse outcomes in HCM patients; and hence, it is not surprising that attempts have been made to prevent the development of fibrosis in the setting of HCM. […] The occurrence of LVH and fibrosis are considered secondary to the activation of numerous mitotic pathways, including those mediated by oxidative stress. […] Impaired myocardial energetics is considered an early and common driver of HCM independent of family history, clinical status, and patient genotype. […] Hypercontractility is another pathological feature of HCM, which is attributed to the destabilization of the myosin super-relaxed (SRX) state. […] Mechanistically, mavacamten is thought to decrease force production, inhibit myosin ATPase activity, and accelerate cross-bridge detachment rate, but as to how this agent attenuates LVH, fibrosis, and diastolic dysfunction warrants further investigation.

• #29 Mechanism-driven therapies for hypertrophic cardiomyopathy – Browse Articles – Conditioning Medicine

  http://www.conditionmed.org/Data/View/14835

  Several approaches have been undertaken to target various pathological features of HCM. This section focuses on therapies designed to attenuate myocardial fibrosis, oxidative stress, impaired myocardial energetics, and hypercontractility. […] Myocardial fibrosis is an independent predictor of adverse outcomes in HCM patients; and hence, it is not surprising that attempts have been made to prevent the development of fibrosis in the setting of HCM. […] The occurrence of LVH and fibrosis are considered secondary to the activation of numerous mitotic pathways, including those mediated by oxidative stress. […] Impaired myocardial energetics is considered an early and common driver of HCM independent of family history, clinical status, and patient genotype. […] Hypercontractility is another pathological feature of HCM, which is attributed to the destabilization of the myosin super-relaxed (SRX) state. […] Mechanistically, mavacamten is thought to decrease force production, inhibit myosin ATPase activity, and accelerate cross-bridge detachment rate, but as to how this agent attenuates LVH, fibrosis, and diastolic dysfunction warrants further investigation.

• #30 Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Diagnosis, Clinical Course and Therapy | IntechOpen

  https://www.intechopen.com/chapters/75983

  Hypertrophic cardiomyopathy (HCM) is a genetic disorder of cardiac myocytes that is characterized by cardiac hypertrophy, unexplained by the loading conditions, a non-dilated left ventricle and a normal or increased left ventricular ejection fraction (LV-EF). […] The precise mechanisms by which sarcomere variants result in the clinical phenotype have not been fully understood. Mutant sarcomere genes trigger several myocardial changes, leading to hypertrophy and fibrosis, which ultimately result in a small, stiff ventricle with impaired systolic and diastolic performance despite a preserved LV-EF. […] From a metabolic viewpoint, mutations in sarcomeric proteins generally increase myofilament activation and result in myocyte hypercontractility and excessive energy use due to higher (disproportionate) mitochondrial activity. Mitochondrial impairments in the cardiac energy-sensing apparatus as well as alterations in calcium handling result in a stimulation of signaling pathways that contribute to myocyte relaxation abnormalities and growth, with aberrant tissue architecture abnormalities such as myofibrillar disarray and myocardial fibrosis.

• #31 Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Clinical Manifestations, Diagnosis, and Therapy

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5654557/

  A diverse array of mechanisms, mirroring the diversity of the causal genes and mutations, are implicated in the pathogenesis of HCM. […] The primary defect is the mutation. Initial or proximal phenotypes are defined as those resulting from the direct effects of the mutations on the structure and function of the sarcomere proteins. […] The intermediary (or secondary) phenotypes include the molecular changes that occur in response to the changes in the sarcomere protein structure and function. […] The tertiary effects are the ensuing histological and pathological phenotypes, which are the consequence of perturbation of a myriad of secondary molecular events in the myocardium, such as activation of the hypertrophic signaling pathways. […] These molecular and histological changes lead to the clinical phenotypes of HCM (quaternary).

• #32 Hypertrophic cardiomyopathy: genetics and clinical perspectives – Wolf – Cardiovascular Diagnosis and Therapy

  https://cdt.amegroups.org/article/view/24557/26222

  The primary defect is the sarcomere mutation, but clinical expression is determined by a complex hierarchy of genetic, epigenetic, and environmental factors. […] First, mutations directly alter the structure and function of the sarcomere proteins and alter biophysical properties of the cardiomyocyte, influence calcium handling, and change cellular energy balance. […] Additionally, mutations can directly initiate other signaling pathways via transcriptional activation; including expression and activation of trophic and mitotic factors, such as calcineurin, mitogen-activated protein kinases, and transforming growth factor beta pathways and stimulate non-cardiac cells, such as fibroblasts. […] The primary and secondary effects of the mutations ultimately lead to the functional pathological phenotypes, such as myocardial hypertrophy and ventricular dysfunction.

• #33 New perspectives in the pharmacological treatment of hypertrophic cardiomyopathy | Revista Portuguesa de Cardiologia (English edition)

  https://revportcardiol.org/en-new-perspectives-in-pharmacological-treatment-articulo-S2174204920300878

  Gene therapy has the potential to help prevent disease development in HCM. […] These approaches are targeted at key events early in the development of HCM. […] Unlike the drugs currently recommended for the treatment of HCM, which seek to alleviate symptoms or prevent complications, these new strategies may mitigate or delay the development of the disease phenotype or even prevent disease onset.

• #34 Hypertrophic cardiomyopathy: genetics and clinical perspectives – Wolf – Cardiovascular Diagnosis and Therapy

  https://cdt.amegroups.org/article/view/24557/26222

  The primary defect is the sarcomere mutation, but clinical expression is determined by a complex hierarchy of genetic, epigenetic, and environmental factors. […] First, mutations directly alter the structure and function of the sarcomere proteins and alter biophysical properties of the cardiomyocyte, influence calcium handling, and change cellular energy balance. […] Additionally, mutations can directly initiate other signaling pathways via transcriptional activation; including expression and activation of trophic and mitotic factors, such as calcineurin, mitogen-activated protein kinases, and transforming growth factor beta pathways and stimulate non-cardiac cells, such as fibroblasts. […] The primary and secondary effects of the mutations ultimately lead to the functional pathological phenotypes, such as myocardial hypertrophy and ventricular dysfunction.

• #35 33 Hypertrophic cardiomyopathy: pathogenesis, therapies and disease modulation | Heart Asia

  https://heartasia.bmj.com/content/11/Suppl_1/A14

  Hypertrophic cardiomyopathy (HCM) is a prevalent heritable cardiac disorder, characterised by unexplained left ventricular hypertrophy (LVH) with the triad of myocyte hypertrophy, disarray, and interstitial fibrosis. Such pathological hallmarks impact diastolic function and contribute to adverse clinical outcomes: arrhythmias, progressive heart failure and sudden cardiac death. To date, none of the available armamentaria has been shown to fundamentally modify disease progression, or to benefit genotype-positive, phenotype-negative or preclinical HCM patients. Multiple genetic studies have identified considerable numbers of HCM-causing mutations in human sarcomere protein genes, and mice engineered to carry such human mutations recapitulated key phenotypes of HCM. This has provided remarkable opportunities to identify the novel therapeutics at the molecular levels, and allowed us to integrate gene-based diagnostics into clinical management of preclinical HCM. Studies in HCM mouse models have illustrated the importance of activated transforming growth factor beta (TGF-) pathway in the early development of HCM. Treatment with either TGF- neutralising antibodies or with angiotensin II type 1 receptor antagonist, losartan, was shown to retard and prevent HCM development in mouse models. Lately, MYK-461, the first allosteric inhibitor of the cardiac myosin adenosine triphosphate (ATPase), has been shown to reduce left ventricular contractility and attenuate HCM development in mouse models of HCM. Clinical trials are currently underway to evaluate and investigate these two promising disease-modifying therapies in HCM patients.

• #36 New perspectives in the pharmacological treatment of hypertrophic cardiomyopathy | Revista Portuguesa de Cardiologia (English edition)

  https://www.revportcardiol.org/en-new-perspectives-in-pharmacological-treatment-articulo-S2174204920300878

  Disruption of intracellular sodium homeostasis may contribute to the pathophysiology of HCM, as raised sodium levels in the cardiomyocyte worsen the dysregulation of intracellular Ca2+ homeostasis which, as mentioned previously, is a key feature of the disease’s pathogenesis. […] The antioxidant effect of NAC may thus play an important role in the treatment of HCM. […] Reactive oxygen species (ROS) levels are known to rise in HCM and oxidative stress plays a major role in the pathophysiology of the disease. […] Oxidative stress contributes to the HCM phenotype by stimulating and activating hypertrophy-inducing signaling kinases and transcription factors. […] Gene therapy has the potential to help prevent disease development in HCM. […] Recently, efforts have been made to correct HCM by inducing the expression of a functional sarcomere protein which replaces the endogenous mutated form.

• #37 Reconstruction and analysis of potential biomarkers for hypertrophic cardiomyopathy based on a competing endogenous RNA network | BMC Cardiovascular Disorders | Full Text

  https://bmccardiovascdisord.biomedcentral.com/articles/10.1186/s12872-022-02862-9

  The results on KEGG analysis showed that downregulated DEGs of the subnetwork and LINC00310 were enriched in the cGMP-PKG signaling pathway. […] The role of LINC00310 in HCM has not been previously reported. […] This study could unravel the pathogenesis of HCM and provide potential target genes of HCM pathogenesis.

• #38 Pathogenic Mechanisms of Hypertrophic Cardiomyopathy beyond Sarcomere Dysfunction

  https://www.mdpi.com/1422-0067/22/16/8933

  It is perhaps conceivable that an inciting cellular event, regardless of its genetic or environmental nature, disrupts certain intracellular biological processes with ensuing cardiomyocyte hypertrophy; this in turn alters the extracellular milieu, which subsequently promotes tissue reorganization in an area of otherwise intact cardiomyocytes, culminating in diffuse cardiomyocyte disarray, cardiac fibrosis, and asymmetric septal hypertrophy. […] Collectively, these studies convincingly demonstrated the polygenic nature of HCM pathogenesis and revealed the complex interaction between common variants and modifiable host factors in modulating HCM disease progression. […] Collectively, these findings strongly suggest that a dysregulated autophagy response contributes to HCM pathogenesis in a sarcomere-independent manner.

• #39

  https://journals.lww.com/cardiologyinreview/fulltext/2025/05000/mechanism_of_ion_channel_impairment_in_the.12.aspx

  Sudden cardiac death is the most unpredictable and devastating consequence of hypertrophic cardiomyopathy, most often caused by persistent ventricular tachycardia or ventricular fibrillation. […] Although myocardial hypertrophy, fibrosis, and microvascular disorders are the main mechanisms of persistent reentrant ventricular arrhythmias in patients with advanced hypertrophic cardiomyopathy, the cardiomyocyte mechanism based on ion channel abnormalities may play an important role in the early stages of the disease. […] In recent years, research on ion channels in arrhythmias in HCM patients has drawn increasing attention to the role of ion channel impairment in the occurrence of arrhythmias in HCM patients. […] Evidence has shown that nearly every AP-related current is abnormal in HCM cardiomyocytes with electrophysiological impairments, resulting in significant abnormalities in AP dynamics and duration.

• #40

  https://journals.lww.com/cardiologyinreview/fulltext/9900/mechanism_of_ion_channel_impairment_in_the.161.aspx

  Evidence has shown that nearly every AP-related current is abnormal in HCM cardiomyocytes with electrophysiological impairments, resulting in significant abnormalities in AP dynamics and duration. […] These studies highlight the complex remodeling process of the HCM myocardium and a series of specific electrophysiological functional changes, and these changes play an important role in the link between HCM and arrhythmia. […] The increased ionic current causes intracellular Na+ and Ca2+ concentrations to be higher than those in the control group via several complex mechanisms, resulting in an increased frequency of EADs or delayed after depolarizations and thus induced arrhythmias. […] Notably, the extent of APD prolongation in cardiomyocytes from HCM patients is independent of the presence and location of muscle cell mutations.

• #41

  https://journals.lww.com/cardiologyinreview/fulltext/2025/05000/mechanism_of_ion_channel_impairment_in_the.12.aspx

  The increased ionic current causes intracellular Na+ and Ca2+ concentrations to be higher than those in the control group via several complex mechanisms, resulting in an increased frequency of EADs or delayed after depolarizations and thus induced arrhythmias. […] Notably, the extent of APD prolongation in cardiomyocytes from HCM patients is independent of the presence and location of muscle cell mutations. […] This observation suggests that the prolongation of APD is not the direct result of the induced mutation but rather the result of a complex hypertrophic remodeling process involving multiple signaling pathways and genetic modifications. […] The process by which increased Ca2+ activates the sarcoplasmic reticulum Ca2+ release channel Ryanodine receptor 2 is called calcium-induced calcium release, and the increase in intracellular Ca2+ mainly depends on this process.

• #42

  https://journals.lww.com/cardiologyinreview/fulltext/9900/mechanism_of_ion_channel_impairment_in_the.161.aspx

  Evidence has shown that nearly every AP-related current is abnormal in HCM cardiomyocytes with electrophysiological impairments, resulting in significant abnormalities in AP dynamics and duration. […] These studies highlight the complex remodeling process of the HCM myocardium and a series of specific electrophysiological functional changes, and these changes play an important role in the link between HCM and arrhythmia. […] The increased ionic current causes intracellular Na+ and Ca2+ concentrations to be higher than those in the control group via several complex mechanisms, resulting in an increased frequency of EADs or delayed after depolarizations and thus induced arrhythmias. […] Notably, the extent of APD prolongation in cardiomyocytes from HCM patients is independent of the presence and location of muscle cell mutations.

• #43

  https://journals.lww.com/cardiologyinreview/fulltext/2025/05000/mechanism_of_ion_channel_impairment_in_the.12.aspx

  Observations from these studies suggest that alterations in CaMKII activity may be a bridge between HCM gene mutations and electrophysiological abnormalities in cardiomyocytes. […] CaMKII-induced increased ion channel phosphorylation results in increased intracellular Na+ and Ca2+ levels, which is an electrophysiological abnormality event at the cellular level. […] The frequency of EADs and the extent of prolonged APD are closely related to the incidence of ventricular arrhythmias. […] By correcting or inhibiting the intracellular triggers of these events, namely, abnormalities in Na+, K+, and Ca2+ channels and currents, APD can be shortened, and the occurrence of EADs can be reduced. […] Therefore, arrhythmia in HCM appears to be more akin to channelopathies than general cardiomyopathy. […] The occurrence of arrhythmias in HCM patients is driven by functional alterations at the cellular and molecular levels, which may be a new target for innovative treatments.

• #44

  https://journals.lww.com/cardiologyinreview/fulltext/9900/mechanism_of_ion_channel_impairment_in_the.161.aspx

  This observation suggests that the prolongation of APD is not the direct result of the induced mutation but rather the result of a complex hypertrophic remodeling process involving multiple signaling pathways and genetic modifications. […] Observations from these studies suggest that alterations in CaMKII activity may be a bridge between HCM gene mutations and electrophysiological abnormalities in cardiomyocytes. […] CaMKII-induced increased ion channel phosphorylation results in increased intracellular Na+ and Ca2+ levels, which is an electrophysiological abnormality event at the cellular level. […] The occurrence of arrhythmias in HCM patients is driven by functional alterations at the cellular and molecular levels, which may be a new target for innovative treatments.

• #45

  https://journals.lww.com/cardiologyinreview/fulltext/2025/05000/mechanism_of_ion_channel_impairment_in_the.12.aspx

  The increased ionic current causes intracellular Na+ and Ca2+ concentrations to be higher than those in the control group via several complex mechanisms, resulting in an increased frequency of EADs or delayed after depolarizations and thus induced arrhythmias. […] Notably, the extent of APD prolongation in cardiomyocytes from HCM patients is independent of the presence and location of muscle cell mutations. […] This observation suggests that the prolongation of APD is not the direct result of the induced mutation but rather the result of a complex hypertrophic remodeling process involving multiple signaling pathways and genetic modifications. […] The process by which increased Ca2+ activates the sarcoplasmic reticulum Ca2+ release channel Ryanodine receptor 2 is called calcium-induced calcium release, and the increase in intracellular Ca2+ mainly depends on this process.

• #46

  https://journals.lww.com/cardiologyinreview/fulltext/9900/mechanism_of_ion_channel_impairment_in_the.161.aspx

  Evidence has shown that nearly every AP-related current is abnormal in HCM cardiomyocytes with electrophysiological impairments, resulting in significant abnormalities in AP dynamics and duration. […] These studies highlight the complex remodeling process of the HCM myocardium and a series of specific electrophysiological functional changes, and these changes play an important role in the link between HCM and arrhythmia. […] The increased ionic current causes intracellular Na+ and Ca2+ concentrations to be higher than those in the control group via several complex mechanisms, resulting in an increased frequency of EADs or delayed after depolarizations and thus induced arrhythmias. […] Notably, the extent of APD prolongation in cardiomyocytes from HCM patients is independent of the presence and location of muscle cell mutations.

• #47 Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Clinical Manifestations, Diagnosis, and Therapy

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5654557/

  A diverse array of mechanisms, mirroring the diversity of the causal genes and mutations, are implicated in the pathogenesis of HCM. […] The primary defect is the mutation. Initial or proximal phenotypes are defined as those resulting from the direct effects of the mutations on the structure and function of the sarcomere proteins. […] The intermediary (or secondary) phenotypes include the molecular changes that occur in response to the changes in the sarcomere protein structure and function. […] The tertiary effects are the ensuing histological and pathological phenotypes, which are the consequence of perturbation of a myriad of secondary molecular events in the myocardium, such as activation of the hypertrophic signaling pathways. […] These molecular and histological changes lead to the clinical phenotypes of HCM (quaternary).

• #48 Histopathological Changes and Clinical Implications in Patients with Hypertrophic Cardiomyopathy | ECR Journal

  https://www.ecrjournal.com/articles/histopathological-changes-and-clinical-implications-patients-hypertrophic-cardiomyopathy?language_content_entity=en

  Hypertrophic cardiomyopathy (HCM) is a familial disease with a disease-causing mutation in the genes encoding structural components of the cardiac muscle sarcomere in about 60% of cases. The histopathological hallmarks of HCM are general myocyte hypertrophy, regions of myocyte disarray, different types of fibrosis and small-vessel disease. To better understand the disease development and the aetiology of the electrical instability leading to serious arrhythmias and sudden cardiac death (SCD) in these patients, it is important to explore the relationship between histopathological features and clinical findings and outcome in patients with HCM. […] The histopathological hallmarks of HCM with general myocyte hypertrophy, i.e. regions of myocyte disarray, different types of fibrosis and small-vessel disease, originate from several autopsy and transplant studies from HCM patients who suffered sudden cardiac death (SCD) or progression to end-stage heart failure. Myocyte disarray is characterised by regions of architectural disorganisation of hypertrophied myocytes and distinct nuclear changes. This architectural disorganisation of the myocytes has been found, although to a lesser extent, in patients with dilated CM, alcoholic CM, various congenital heart diseases and cardiovascular diseases (systemic hypertension, coronary artery disease and cor pulmonale) and in normal hearts.

• #49 Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Clinical Manifestations, Diagnosis, and Therapy

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5654557/

  Hypertrophic cardiomyopathy (HCM) is a genetic disorder that is characterized by left ventricular hypertrophy unexplained by secondary causes, and a non-dilated left ventricle with preserved or increased ejection fraction. […] The histologic features of HCM include myocyte hypertrophy and disarray, as well as interstitial fibrosis. […] The hypertrophy is also frequently associated with left ventricular diastolic dysfunction. […] Mutations in over a dozen genes encoding sarcomere-associated proteins cause HCM. MYH7 and MYBPC3, encoding -myosin heavy chain and myosin binding protein C, respectively, are the two most common genes involved, together accounting for about 50% of the HCM families. […] The genetic discoveries have enhanced understanding of the molecular pathogenesis of HCM and have stimulated efforts designed to identify new therapeutic agents.

• #50 Histopathological Changes and Clinical Implications in Patients with Hypertrophic Cardiomyopathy | ECR Journal

  https://www.ecrjournal.com/articles/histopathological-changes-and-clinical-implications-patients-hypertrophic-cardiomyopathy?language_content_entity=en

  Hypertrophic cardiomyopathy (HCM) is a familial disease with a disease-causing mutation in the genes encoding structural components of the cardiac muscle sarcomere in about 60% of cases. The histopathological hallmarks of HCM are general myocyte hypertrophy, regions of myocyte disarray, different types of fibrosis and small-vessel disease. To better understand the disease development and the aetiology of the electrical instability leading to serious arrhythmias and sudden cardiac death (SCD) in these patients, it is important to explore the relationship between histopathological features and clinical findings and outcome in patients with HCM. […] The histopathological hallmarks of HCM with general myocyte hypertrophy, i.e. regions of myocyte disarray, different types of fibrosis and small-vessel disease, originate from several autopsy and transplant studies from HCM patients who suffered sudden cardiac death (SCD) or progression to end-stage heart failure. Myocyte disarray is characterised by regions of architectural disorganisation of hypertrophied myocytes and distinct nuclear changes. This architectural disorganisation of the myocytes has been found, although to a lesser extent, in patients with dilated CM, alcoholic CM, various congenital heart diseases and cardiovascular diseases (systemic hypertension, coronary artery disease and cor pulmonale) and in normal hearts.

• #51 Histopathological Changes and Clinical Implications in Patients with Hypertrophic Cardiomyopathy | ECR Journal

  https://www.ecrjournal.com/articles/histopathological-changes-and-clinical-implications-patients-hypertrophic-cardiomyopathy?language_content_entity=en

  Hypertrophic cardiomyopathy (HCM) is a familial disease with a disease-causing mutation in the genes encoding structural components of the cardiac muscle sarcomere in about 60% of cases. The histopathological hallmarks of HCM are general myocyte hypertrophy, regions of myocyte disarray, different types of fibrosis and small-vessel disease. To better understand the disease development and the aetiology of the electrical instability leading to serious arrhythmias and sudden cardiac death (SCD) in these patients, it is important to explore the relationship between histopathological features and clinical findings and outcome in patients with HCM. […] The histopathological hallmarks of HCM with general myocyte hypertrophy, i.e. regions of myocyte disarray, different types of fibrosis and small-vessel disease, originate from several autopsy and transplant studies from HCM patients who suffered sudden cardiac death (SCD) or progression to end-stage heart failure. Myocyte disarray is characterised by regions of architectural disorganisation of hypertrophied myocytes and distinct nuclear changes. This architectural disorganisation of the myocytes has been found, although to a lesser extent, in patients with dilated CM, alcoholic CM, various congenital heart diseases and cardiovascular diseases (systemic hypertension, coronary artery disease and cor pulmonale) and in normal hearts.

• #52 Histopathological Changes and Clinical Implications in Patients with Hypertrophic Cardiomyopathy | ECR Journal

  https://www.ecrjournal.com/articles/histopathological-changes-and-clinical-implications-patients-hypertrophic-cardiomyopathy?language_content_entity=en

  Hypertrophic cardiomyopathy (HCM) is a familial disease with a disease-causing mutation in the genes encoding structural components of the cardiac muscle sarcomere in about 60% of cases. The histopathological hallmarks of HCM are general myocyte hypertrophy, regions of myocyte disarray, different types of fibrosis and small-vessel disease. To better understand the disease development and the aetiology of the electrical instability leading to serious arrhythmias and sudden cardiac death (SCD) in these patients, it is important to explore the relationship between histopathological features and clinical findings and outcome in patients with HCM. […] The histopathological hallmarks of HCM with general myocyte hypertrophy, i.e. regions of myocyte disarray, different types of fibrosis and small-vessel disease, originate from several autopsy and transplant studies from HCM patients who suffered sudden cardiac death (SCD) or progression to end-stage heart failure. Myocyte disarray is characterised by regions of architectural disorganisation of hypertrophied myocytes and distinct nuclear changes. This architectural disorganisation of the myocytes has been found, although to a lesser extent, in patients with dilated CM, alcoholic CM, various congenital heart diseases and cardiovascular diseases (systemic hypertension, coronary artery disease and cor pulmonale) and in normal hearts.

• #53 Histopathological Changes and Clinical Implications in Patients with Hypertrophic Cardiomyopathy | ECR Journal

  https://www.ecrjournal.com/articles/histopathological-changes-and-clinical-implications-patients-hypertrophic-cardiomyopathy?language_content_entity=en

  There are indications that increasing amounts of fibrosis and ischaemia occur in the natural history of HCM. The amount of fibrosis is associated with small-vessel disease, increasing septal thickness, cardiac mass, increasing age, progression to end-stage heart failure and SCD. The aetiology of the electrical instability leading to malignant arrhythmias and SCD in HCM patients is still unknown. Myocyte disarray, acute or subacute ischaemia leading to scarring and different types of fibrosis may play an important role.

• #54 Hypertrophic Cardiomyopathy – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK430788/

  Dynamic LVOTO: Obstruction can occur either at rest or with exercise. […] The likelihood of obstruction is typically determined by the pattern of hypertrophy in the left ventricle, with classical asymmetric left ventricular hypertrophy (LVH) most commonly affecting the basal interventricular septum. […] LVOTO in HCM can be attributed to 2 main causes. The first is an increase in septal thickness, which narrows the LVOT and leads to abnormal movement of the mitral valve leaflets. […] The second cause is alterations in the structure of the mitral valve, such as elongated leaflets and displacement of the papillary muscles and valve apparatus towards the anterior region. […] Myocardial Ischemia: Common findings in HCM include myocardial hypertrophy, microvascular dysfunction, impaired coronary flow reserve, and medial and intimal hypertrophy of intramural arterioles.

• #55 Myocardial Fibrosis in the Pathogenesis, Diagnosis, and Treatment of Hypertrophic Cardiomyopathy – ScienceOpen

  https://www.scienceopen.com/hosted-document?doi=10.15212/CVIA.2021.0008

  Hypertrophic cardiomyopathy (HCM) is a type of hereditary cardiomyopathy caused by gene mutation. Its histological features include cardiomyocyte hypertrophy and disarray as well as myocardial fibrosis. Gene mutation, abnormal signal transduction, and abnormal energy metabolism are considered the main mechanisms of myocardial fibrosis. […] There is a strong correlation between myocardial fibrosis and the occurrence, development, and prognosis of HCM. […] The mechanism of myocardial fibrosis in HCM is still unclear. […] The presence of myocardial fibrosis might be the primary defect of sarcomere gene mutations. […] Increased myocardial fibrosis not only impairs cardiac diastolic function but also increases the propensity of heart failure and ventricular arrhythmias. […] Myocardial fibrosis is the basis of heart failure and arrhythmia in patients with HCM. We now know that gene mutation, abnormal signal transduction, and energy metabolism are all involved in the occurrence of fibrosis.

• #56 Myocardial Fibrosis in the Pathogenesis, Diagnosis, and Treatment of Hypertrophic Cardiomyopathy – ScienceOpen

  https://www.scienceopen.com/hosted-document?doi=10.15212/CVIA.2021.0008

  Hypertrophic cardiomyopathy (HCM) is a type of hereditary cardiomyopathy caused by gene mutation. Its histological features include cardiomyocyte hypertrophy and disarray as well as myocardial fibrosis. Gene mutation, abnormal signal transduction, and abnormal energy metabolism are considered the main mechanisms of myocardial fibrosis. […] There is a strong correlation between myocardial fibrosis and the occurrence, development, and prognosis of HCM. […] The mechanism of myocardial fibrosis in HCM is still unclear. […] The presence of myocardial fibrosis might be the primary defect of sarcomere gene mutations. […] Increased myocardial fibrosis not only impairs cardiac diastolic function but also increases the propensity of heart failure and ventricular arrhythmias. […] Myocardial fibrosis is the basis of heart failure and arrhythmia in patients with HCM. We now know that gene mutation, abnormal signal transduction, and energy metabolism are all involved in the occurrence of fibrosis.

• #57 Myocardial Fibrosis in the Pathogenesis, Diagnosis, and Treatment of Hypertrophic Cardiomyopathy – ScienceOpen

  https://www.scienceopen.com/hosted-document?doi=10.15212/CVIA.2021.0008

  Hypertrophic cardiomyopathy (HCM) is a type of hereditary cardiomyopathy caused by gene mutation. Its histological features include cardiomyocyte hypertrophy and disarray as well as myocardial fibrosis. Gene mutation, abnormal signal transduction, and abnormal energy metabolism are considered the main mechanisms of myocardial fibrosis. […] There is a strong correlation between myocardial fibrosis and the occurrence, development, and prognosis of HCM. […] The mechanism of myocardial fibrosis in HCM is still unclear. […] The presence of myocardial fibrosis might be the primary defect of sarcomere gene mutations. […] Increased myocardial fibrosis not only impairs cardiac diastolic function but also increases the propensity of heart failure and ventricular arrhythmias. […] Myocardial fibrosis is the basis of heart failure and arrhythmia in patients with HCM. We now know that gene mutation, abnormal signal transduction, and energy metabolism are all involved in the occurrence of fibrosis.

• #58 Myocardial Fibrosis in the Pathogenesis, Diagnosis, and Treatment of Hypertrophic Cardiomyopathy – ScienceOpen

  https://www.scienceopen.com/hosted-document?doi=10.15212/CVIA.2021.0008

  Hypertrophic cardiomyopathy (HCM) is a type of hereditary cardiomyopathy caused by gene mutation. Its histological features include cardiomyocyte hypertrophy and disarray as well as myocardial fibrosis. Gene mutation, abnormal signal transduction, and abnormal energy metabolism are considered the main mechanisms of myocardial fibrosis. […] There is a strong correlation between myocardial fibrosis and the occurrence, development, and prognosis of HCM. […] The mechanism of myocardial fibrosis in HCM is still unclear. […] The presence of myocardial fibrosis might be the primary defect of sarcomere gene mutations. […] Increased myocardial fibrosis not only impairs cardiac diastolic function but also increases the propensity of heart failure and ventricular arrhythmias. […] Myocardial fibrosis is the basis of heart failure and arrhythmia in patients with HCM. We now know that gene mutation, abnormal signal transduction, and energy metabolism are all involved in the occurrence of fibrosis.

• #59 Inline perfusion mapping provides insights into the disease mechanism in hypertrophic cardiomyopathy | Heart

  https://heart.bmj.com/content/106/11/824

  CMR has demonstrated evidence of coronary microvascular flow impairment, finding inverse correlations between perfusion and both hypertrophy and fibrosis. […] However, the quantification techniques used in these studies have been highly labour intensive in terms of both image acquisition and analysis. […] Our results support the previous literature of perfusion in HCM using different modalities over decades. […] The perfusion abnormalities are not explained by epicardial coronary disease or conventional cardiovascular risk factors, and only partly explained by LGE and hypertrophy, occurring even in the absence of both. […] A striking finding was that stress flow in HCM could be paradoxically lower than rest in HCM. […] There are multiple possible explanations for perfusion falling during vasodilator stress.

• #60 Inline perfusion mapping provides insights into the disease mechanism in hypertrophic cardiomyopathy | Heart

  https://heart.bmj.com/content/106/11/824

  In patients with hypertrophic cardiomyopathy (HCM), the role of small vessel disease and myocardial perfusion remains incompletely understood and data on absolute myocardial blood flow (MBF, mL/g/min) are scarce. […] Microvascular dysfunction is common in HCM and associated with hypertrophy and LGE. […] Perfusion can fall during vasodilator stress and is abnormal even in apparently normal myocardium suggesting it may be an early disease marker. […] The histological features are myocyte disarray, left (right) ventricular hypertrophy (LVH), small vessel disease and fibrosis, but how these features develop and relate to adverse outcomes is poorly understood. […] Ischaemia in HCM is likely a key disease pathway. […] Several mechanisms may contribute to ischaemia in HCM including small vessel abnormalities, demand-supply mismatch due to hypertrophy, reduced perfusion pressure related to shortened diastolic time, high diastolic pressure, left ventricular outflow tract (LVOT) obstruction and possibly myocardial bridging.

• #61 Inline perfusion mapping provides insights into the disease mechanism in hypertrophic cardiomyopathy | Heart

  https://heart.bmj.com/content/106/11/824

  In patients with hypertrophic cardiomyopathy (HCM), the role of small vessel disease and myocardial perfusion remains incompletely understood and data on absolute myocardial blood flow (MBF, mL/g/min) are scarce. […] Microvascular dysfunction is common in HCM and associated with hypertrophy and LGE. […] Perfusion can fall during vasodilator stress and is abnormal even in apparently normal myocardium suggesting it may be an early disease marker. […] The histological features are myocyte disarray, left (right) ventricular hypertrophy (LVH), small vessel disease and fibrosis, but how these features develop and relate to adverse outcomes is poorly understood. […] Ischaemia in HCM is likely a key disease pathway. […] Several mechanisms may contribute to ischaemia in HCM including small vessel abnormalities, demand-supply mismatch due to hypertrophy, reduced perfusion pressure related to shortened diastolic time, high diastolic pressure, left ventricular outflow tract (LVOT) obstruction and possibly myocardial bridging.

• #62 Inline perfusion mapping provides insights into the disease mechanism in hypertrophic cardiomyopathy | Heart

  https://heart.bmj.com/content/106/11/824

  CMR has demonstrated evidence of coronary microvascular flow impairment, finding inverse correlations between perfusion and both hypertrophy and fibrosis. […] However, the quantification techniques used in these studies have been highly labour intensive in terms of both image acquisition and analysis. […] Our results support the previous literature of perfusion in HCM using different modalities over decades. […] The perfusion abnormalities are not explained by epicardial coronary disease or conventional cardiovascular risk factors, and only partly explained by LGE and hypertrophy, occurring even in the absence of both. […] A striking finding was that stress flow in HCM could be paradoxically lower than rest in HCM. […] There are multiple possible explanations for perfusion falling during vasodilator stress.

• #63 Mitral Regurgitation in Hypertrophic Cardiomyopathy: A Narrative Review of Mechanism and Current Management

  https://clinmedjournals.org/articles/ijcc/international-journal-of-clinical-cardiology-ijcc-9-248.php?jid=ijcc

  Intrinsic MR (SAM-independent): Significant MR due to MV abnormalities may occur in up to 10% to 20% of patients with HCM who carry a genetic mutation for HCM but have not manifested septal hypertrophy or LVOTO. […] SAM-independent MR is usually directed anteriorly or centrally into the left atrium and is usually holosystolic. […] The true prevalence of mitral abnormalities in HCM is difficult to assess, as many abnormalities are poorly appreciated and often not documented. […] It is known that up to 59% of patients with HCM have at least one abnormality of the MV apparatus as a direct effect of genetic mutations. […] MV abnormalities may be present in any component of the mitral apparatus (Leaflets, subvalvular apparatus and annulus) and thus numerous abnormalities have been described with wide variability among patients with both obstructive and non-obstructive types of HCM.

• #64 Mitral Regurgitation in Hypertrophic Cardiomyopathy: A Narrative Review of Mechanism and Current Management

  https://clinmedjournals.org/articles/ijcc/international-journal-of-clinical-cardiology-ijcc-9-248.php?jid=ijcc

  Excessive leaflet elongation and increased leaflet area are present in about 50% of patients and can involve one or both MV leaflets. […] Leaflet elongation is a unique finding of HCM. […] However, the leaflet size is more related to chamber geometry and hypertrophy pattern rather than genetic factors within overt HCM. […] The anterior leaflet averages 34 mm in HCM versus 24 mm in normal hearts. […] An increased ratio of anterior leaflet length to LVOT diameter is associated with resting and provocable obstruction. […] The mechanism of valve thickening and calcification is unknown, but the traumatic fibrosis from repetitive septal contact may result in retraction, and MR. […] In patients with restricted, calcified, and thickening leaflets with resting SAM, it is difficult to determine whether the MR is caused solely by SAM of the MV or is related in part to intrinsic MV disease.

• #65 Mitral Regurgitation in Hypertrophic Cardiomyopathy: A Narrative Review of Mechanism and Current Management

  https://clinmedjournals.org/articles/ijcc/international-journal-of-clinical-cardiology-ijcc-9-248.php?jid=ijcc

  Subvalvular abnormalities are described in more than 50% of HCM patients. […] Anterior and apically displaced papillary muscle that shifts the MV leaflets anteriorly toward the LV outflow and leads to chordal and leaflet laxity. […] Changes in size, shape, and angulation of the MV annulus in HCM are less appreciated. […] It was shown that mitral annulus area is enlarged in both obstructive and non-obstructive HCM patients compared to normal as detected by 3D echocardiography and MRI. […] Given the stressful hemodynamic loading conditions in HCM, marked mitral annular calcification may be seen. […] The treatment strategies of HCM are based upon observational data and clinical experience. […] The approach of treatment has largely been limited to symptomatic patient with obstructive HCM.

• #66 Mitral Regurgitation in Hypertrophic Cardiomyopathy: A Narrative Review of Mechanism and Current Management

  https://clinmedjournals.org/articles/ijcc/international-journal-of-clinical-cardiology-ijcc-9-248.php?jid=ijcc

  Subvalvular abnormalities are described in more than 50% of HCM patients. […] Anterior and apically displaced papillary muscle that shifts the MV leaflets anteriorly toward the LV outflow and leads to chordal and leaflet laxity. […] Changes in size, shape, and angulation of the MV annulus in HCM are less appreciated. […] It was shown that mitral annulus area is enlarged in both obstructive and non-obstructive HCM patients compared to normal as detected by 3D echocardiography and MRI. […] Given the stressful hemodynamic loading conditions in HCM, marked mitral annular calcification may be seen. […] The treatment strategies of HCM are based upon observational data and clinical experience. […] The approach of treatment has largely been limited to symptomatic patient with obstructive HCM.

• #67 Hypertrophic Cardiomyopathy – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK430788/

  Hypertrophic cardiomyopathy (HCM) is an autosomal dominant cardiac myocyte disease caused by mutations in sarcomere protein genes encoding for elements of the contractile machinery of the heart. Characteristic cardiac structural changes include increased left ventricular wall thickness causing dynamic left ventricular outflow obstruction, diastolic dysfunction, myocardial ischemia, arrhythmias, autonomic dysfunction, and mitral regurgitation. […] The underlying mechanisms and genetic basis of HCM, including the molecular pathways involved in disease progression, are explored, and the diverse clinical presentations and diagnostic modalities of HCM are reviewed. […] Five mechanisms contribute to the development of HCM: dynamic LVOTO, mitral regurgitation, diastolic dysfunction, myocardial ischemia, and autonomic dysfunction.

• #68 Hypertrophic Cardiomyopathy – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK430788/

  Dynamic LVOTO: Obstruction can occur either at rest or with exercise. […] The likelihood of obstruction is typically determined by the pattern of hypertrophy in the left ventricle, with classical asymmetric left ventricular hypertrophy (LVH) most commonly affecting the basal interventricular septum. […] LVOTO in HCM can be attributed to 2 main causes. The first is an increase in septal thickness, which narrows the LVOT and leads to abnormal movement of the mitral valve leaflets. […] The second cause is alterations in the structure of the mitral valve, such as elongated leaflets and displacement of the papillary muscles and valve apparatus towards the anterior region. […] Myocardial Ischemia: Common findings in HCM include myocardial hypertrophy, microvascular dysfunction, impaired coronary flow reserve, and medial and intimal hypertrophy of intramural arterioles.

• #69 Hypertrophic Cardiomyopathy – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK430788/

  Dynamic LVOTO: Obstruction can occur either at rest or with exercise. […] The likelihood of obstruction is typically determined by the pattern of hypertrophy in the left ventricle, with classical asymmetric left ventricular hypertrophy (LVH) most commonly affecting the basal interventricular septum. […] LVOTO in HCM can be attributed to 2 main causes. The first is an increase in septal thickness, which narrows the LVOT and leads to abnormal movement of the mitral valve leaflets. […] The second cause is alterations in the structure of the mitral valve, such as elongated leaflets and displacement of the papillary muscles and valve apparatus towards the anterior region. […] Myocardial Ischemia: Common findings in HCM include myocardial hypertrophy, microvascular dysfunction, impaired coronary flow reserve, and medial and intimal hypertrophy of intramural arterioles.

• #70 Hypertrophic Cardiomyopathy – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK430788/

  Dynamic LVOTO: Obstruction can occur either at rest or with exercise. […] The likelihood of obstruction is typically determined by the pattern of hypertrophy in the left ventricle, with classical asymmetric left ventricular hypertrophy (LVH) most commonly affecting the basal interventricular septum. […] LVOTO in HCM can be attributed to 2 main causes. The first is an increase in septal thickness, which narrows the LVOT and leads to abnormal movement of the mitral valve leaflets. […] The second cause is alterations in the structure of the mitral valve, such as elongated leaflets and displacement of the papillary muscles and valve apparatus towards the anterior region. […] Myocardial Ischemia: Common findings in HCM include myocardial hypertrophy, microvascular dysfunction, impaired coronary flow reserve, and medial and intimal hypertrophy of intramural arterioles.

• #71 Hypertrophic cardiomyopathy – Wikipedia

  https://en.wikipedia.org/wiki/Hypertrophic_cardiomyopathy

  Ventricular hypertrophy causes a dynamic pressure gradient across the left ventricular outflow tract (LVOT), which is associated with further narrowing of the outflow during systole. Pulling of the mitral valve leaflets towards the septum contributes to the outflow obstruction. This pulling is thought to occur by several proposed mechanisms, including that the flow of blood through the narrowed outflow tract results in it having a higher velocity, and less pressure through the Venturi effect. This low pressure then causes the anterior leaflet of the mitral valve to be pulled into the outflow tract, resulting in further obstruction.

• #72 Mitral Regurgitation in Hypertrophic Cardiomyopathy: A Narrative Review of Mechanism and Current Management

  https://clinmedjournals.org/articles/ijcc/international-journal-of-clinical-cardiology-ijcc-9-248.php?jid=ijcc

  Significant mitral regurgitation (MR) is frequent in patients with hypertrophic cardiomyopathy (HCM) either obstructive or non-obstructive. […] Many studies described that significant MR is associated with poor long-term outcome of HCM patients, which indicate the importance of an adequate MR assessment including detailed evaluation of the mitral valve (MV) anatomy. […] Complete understanding the mechanism of MR and accurate quantification can guide towards the selection of therapeutic modality. […] This review will focus on the abnormalities of the MV apparatus for understanding the mechanism MR in HCM with a discussion of the value of multimodality imaging approach to diagnosis and quantification. […] LVOTO is frequently associated with significant mitral regurgitation (MR) because of systolic anterior motion (SAM) of mitral leaflets (SAM-dependent MR).

• #73 Mitral Regurgitation in Hypertrophic Cardiomyopathy: A Narrative Review of Mechanism and Current Management

  https://clinmedjournals.org/articles/ijcc/international-journal-of-clinical-cardiology-ijcc-9-248.php?jid=ijcc

  Significant MR may occur in up to 10% to 20% of HCM patients without SAM (SAM-independent MR) and is due to intrinsic mitral valve (MV) abnormalities. […] SAM-dependent MR: In most patients with obstructive HCM, the MR that is dependent on SAM peaks in mid and late systole. […] Anterior displacement of the papillary muscles shifts the MV leaflets anteriorly toward the LVOT and leads to chordal and leaflet laxity. […] As drag forces generated by the LV pull the anteriorly displaced and elongated leaflets into the outflow tract in early systole, the distal one half to one third of the leaflets form an angle anteriorly into the LVOT, creating a „funnel” composed of both leaflets. […] The degree of MR relates to the extent of mismatch of anterior to posterior leaflet length and the decreased mobility of the posterior leaflet to move anteriorly which can be significant (moderate or greater depending on the extent of the gap).

• #74 Mitral Regurgitation in Hypertrophic Cardiomyopathy: A Narrative Review of Mechanism and Current Management

  https://clinmedjournals.org/articles/ijcc/international-journal-of-clinical-cardiology-ijcc-9-248.php?jid=ijcc

  Significant MR may occur in up to 10% to 20% of HCM patients without SAM (SAM-independent MR) and is due to intrinsic mitral valve (MV) abnormalities. […] SAM-dependent MR: In most patients with obstructive HCM, the MR that is dependent on SAM peaks in mid and late systole. […] Anterior displacement of the papillary muscles shifts the MV leaflets anteriorly toward the LVOT and leads to chordal and leaflet laxity. […] As drag forces generated by the LV pull the anteriorly displaced and elongated leaflets into the outflow tract in early systole, the distal one half to one third of the leaflets form an angle anteriorly into the LVOT, creating a „funnel” composed of both leaflets. […] The degree of MR relates to the extent of mismatch of anterior to posterior leaflet length and the decreased mobility of the posterior leaflet to move anteriorly which can be significant (moderate or greater depending on the extent of the gap).

• #75 Mitral Regurgitation in Hypertrophic Cardiomyopathy: A Narrative Review of Mechanism and Current Management

  https://clinmedjournals.org/articles/ijcc/international-journal-of-clinical-cardiology-ijcc-9-248.php?jid=ijcc

  Intrinsic MR (SAM-independent): Significant MR due to MV abnormalities may occur in up to 10% to 20% of patients with HCM who carry a genetic mutation for HCM but have not manifested septal hypertrophy or LVOTO. […] SAM-independent MR is usually directed anteriorly or centrally into the left atrium and is usually holosystolic. […] The true prevalence of mitral abnormalities in HCM is difficult to assess, as many abnormalities are poorly appreciated and often not documented. […] It is known that up to 59% of patients with HCM have at least one abnormality of the MV apparatus as a direct effect of genetic mutations. […] MV abnormalities may be present in any component of the mitral apparatus (Leaflets, subvalvular apparatus and annulus) and thus numerous abnormalities have been described with wide variability among patients with both obstructive and non-obstructive types of HCM.

• #76 Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Clinical Manifestations, Diagnosis, and Therapy

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5654557/

  Hypertrophic cardiomyopathy (HCM) is a genetic disorder that is characterized by left ventricular hypertrophy unexplained by secondary causes, and a non-dilated left ventricle with preserved or increased ejection fraction. […] The histologic features of HCM include myocyte hypertrophy and disarray, as well as interstitial fibrosis. […] The hypertrophy is also frequently associated with left ventricular diastolic dysfunction. […] Mutations in over a dozen genes encoding sarcomere-associated proteins cause HCM. MYH7 and MYBPC3, encoding -myosin heavy chain and myosin binding protein C, respectively, are the two most common genes involved, together accounting for about 50% of the HCM families. […] The genetic discoveries have enhanced understanding of the molecular pathogenesis of HCM and have stimulated efforts designed to identify new therapeutic agents.

• #77 Hypertrophic Cardiomyopathy – Cardiovascular Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/cardiovascular-disorders/cardiomyopathies/hypertrophic-cardiomyopathy

  Most cases of hypertrophic cardiomyopathy are inherited. At least 1,500 different mutations that are inherited in an autosomally dominant pattern have been identified; spontaneous mutations can also occur. […] The myocardium is abnormal with cellular and myofibrillar disarray, although this finding is not specific for hypertrophic cardiomyopathy. […] About two thirds of patients exhibit obstructive physiology at rest or during exercise. Obstruction is the result of mechanical impedance to LV outflow during systole due to systolic anterior motion (SAM) of the mitral valve. […] Hypertrophy results in a stiff, noncompliant chamber (usually the left ventricle) that resists diastolic filling, elevating end-diastolic pressure and thus increasing pulmonary venous pressure. […] Coronary blood flow may be impaired, causing angina pectoris, syncope, or arrhythmias in the absence of epicardial coronary artery disease (CAD).

• #78 KEGG DISEASE: Hypertrophic cardiomyopathy

  https://www.genome.jp/dbget-bin/www_bget?ds:H00292

  Hypertrophic cardiomyopathy (HCM/CMH) is a primary myocardial disorder with an autosomal dominant pattern of inheritance that is characterized by hypertrophy of the left ventricles with histological features of myocyte hypertrophy, myofibrillar disarray, and interstitial fibrosis. […] Hundreds of mutations in the genes that encode protein constituents of the sarcomere have been identified in HCM. These mutations increase the Ca2+ sensitivity of cardiac myofilaments. Increased myofilament Ca2+ sensitivity is expected to increase the ATP utilization by actomyosin at submaximal Ca2+ concentrations, which might cause an imbalance in energy supply and demand in the heart under severe stress. […] The inefficient use of ATP suggests that an inability to maintain normal ATP levels could be the central abnormality. This theory might be supported by the discovery of the role of a mutant PRKAG2 gene in HCM, which in active form acts as a central sensing mechanism protecting cells from depletion of ATP supplies.

• #79 Hypertrophic Cardiomyopathy – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK430788/

  Dynamic LVOTO: Obstruction can occur either at rest or with exercise. […] The likelihood of obstruction is typically determined by the pattern of hypertrophy in the left ventricle, with classical asymmetric left ventricular hypertrophy (LVH) most commonly affecting the basal interventricular septum. […] LVOTO in HCM can be attributed to 2 main causes. The first is an increase in septal thickness, which narrows the LVOT and leads to abnormal movement of the mitral valve leaflets. […] The second cause is alterations in the structure of the mitral valve, such as elongated leaflets and displacement of the papillary muscles and valve apparatus towards the anterior region. […] Myocardial Ischemia: Common findings in HCM include myocardial hypertrophy, microvascular dysfunction, impaired coronary flow reserve, and medial and intimal hypertrophy of intramural arterioles.

• #80 Hypertrophic Cardiomyopathy – Cardiovascular Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/cardiovascular-disorders/cardiomyopathies/hypertrophic-cardiomyopathy

  Most cases of hypertrophic cardiomyopathy are inherited. At least 1,500 different mutations that are inherited in an autosomally dominant pattern have been identified; spontaneous mutations can also occur. […] The myocardium is abnormal with cellular and myofibrillar disarray, although this finding is not specific for hypertrophic cardiomyopathy. […] About two thirds of patients exhibit obstructive physiology at rest or during exercise. Obstruction is the result of mechanical impedance to LV outflow during systole due to systolic anterior motion (SAM) of the mitral valve. […] Hypertrophy results in a stiff, noncompliant chamber (usually the left ventricle) that resists diastolic filling, elevating end-diastolic pressure and thus increasing pulmonary venous pressure. […] Coronary blood flow may be impaired, causing angina pectoris, syncope, or arrhythmias in the absence of epicardial coronary artery disease (CAD).

• #81 Hypertrophic Cardiomyopathy – Cardiovascular Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/cardiovascular-disorders/cardiomyopathies/hypertrophic-cardiomyopathy

  In some cases, myocytes gradually die, probably because capillary/myocyte imbalance causes chronic diffuse ischemia. As myocytes die, they are replaced by diffuse fibrosis. Then, the hypertrophied ventricle with diastolic dysfunction gradually dilates and systolic dysfunction develops. […] Hypertrophic cardiomyopathy is usually due to one of numerous genetic mutations that cause various types of ventricular hypertrophy that restrict filling (ie, cause diastolic dysfunction) and sometimes obstruct LV outflow. […] Mavacamten, an oral cardiac myosin inhibitor that reduces actin-myosin cross-bridge formation, relieves symptoms, reduces left ventricular outflow tract (LVOT) obstruction, and increases exercise tolerance in patients with hypertrophic cardiomyopathy.

• #82 Hypertrophic Cardiomyopathy – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK430788/

  Autonomic Dysfunction: Autonomic dysfunction in HCM is defined as an abnormal blood pressure response to exercise specifically, a failure to increase systolic blood pressure by at least 20 mm Hg or a drop in systolic blood pressure during exercise of more than 20 mm Hg from the peak value is associated with poor prognosis. […] The most common arrhythmia in HCM is atrial fibrillation, present in about 25% of patients, which is 4- to 6-fold higher than in the general population. […] Atrial fibrillation is poorly tolerated in patients with HCM.

• #83 Hypertrophic Cardiomyopathy – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK430788/

  Autonomic Dysfunction: Autonomic dysfunction in HCM is defined as an abnormal blood pressure response to exercise specifically, a failure to increase systolic blood pressure by at least 20 mm Hg or a drop in systolic blood pressure during exercise of more than 20 mm Hg from the peak value is associated with poor prognosis. […] The most common arrhythmia in HCM is atrial fibrillation, present in about 25% of patients, which is 4- to 6-fold higher than in the general population. […] Atrial fibrillation is poorly tolerated in patients with HCM.

• #84 New perspectives in the pharmacological treatment of hypertrophic cardiomyopathy | Revista Portuguesa de Cardiologia (English edition)

  https://revportcardiol.org/en-new-perspectives-in-pharmacological-treatment-articulo-S2174204920300878

  Changes in Ca2+ homeostasis and in late sodium current in hypertrophic cardiomyopathy and mechanism of action of diltiazem and ranolazine. […] Disruption of intracellular sodium homeostasis may contribute to the pathophysiology of HCM, as raised sodium levels in the cardiomyocyte worsen the dysregulation of intracellular Ca2+ homeostasis which, as mentioned previously, is a key feature of the disease’s pathogenesis. […] The antioxidant effect of NAC may thus play an important role in the treatment of HCM. […] Despite these promising initial results, a recent clinical trial in 35 patients with obstructive HCM was discontinued prematurely as perhexiline showed no demonstrable efficacy in symptom improvement and oxygen consumption in HCM patients. […] Overall, despite their theoretical beneficial effect on the pathophysiology of HCM, metabolic modulators have not demonstrated efficacy in improving symptoms for patients with the disease.

• #85 Mechanism-driven therapies for hypertrophic cardiomyopathy – Browse Articles – Conditioning Medicine

  http://www.conditionmed.org/Data/View/14835

  Several approaches have been undertaken to target various pathological features of HCM. This section focuses on therapies designed to attenuate myocardial fibrosis, oxidative stress, impaired myocardial energetics, and hypercontractility. […] Myocardial fibrosis is an independent predictor of adverse outcomes in HCM patients; and hence, it is not surprising that attempts have been made to prevent the development of fibrosis in the setting of HCM. […] The occurrence of LVH and fibrosis are considered secondary to the activation of numerous mitotic pathways, including those mediated by oxidative stress. […] Impaired myocardial energetics is considered an early and common driver of HCM independent of family history, clinical status, and patient genotype. […] Hypercontractility is another pathological feature of HCM, which is attributed to the destabilization of the myosin super-relaxed (SRX) state. […] Mechanistically, mavacamten is thought to decrease force production, inhibit myosin ATPase activity, and accelerate cross-bridge detachment rate, but as to how this agent attenuates LVH, fibrosis, and diastolic dysfunction warrants further investigation.

• #86 Mechanism-driven therapies for hypertrophic cardiomyopathy – Browse Articles – Conditioning Medicine

  http://www.conditionmed.org/Data/View/14835

  Several approaches have been undertaken to target various pathological features of HCM. This section focuses on therapies designed to attenuate myocardial fibrosis, oxidative stress, impaired myocardial energetics, and hypercontractility. […] Myocardial fibrosis is an independent predictor of adverse outcomes in HCM patients; and hence, it is not surprising that attempts have been made to prevent the development of fibrosis in the setting of HCM. […] The occurrence of LVH and fibrosis are considered secondary to the activation of numerous mitotic pathways, including those mediated by oxidative stress. […] Impaired myocardial energetics is considered an early and common driver of HCM independent of family history, clinical status, and patient genotype. […] Hypercontractility is another pathological feature of HCM, which is attributed to the destabilization of the myosin super-relaxed (SRX) state. […] Mechanistically, mavacamten is thought to decrease force production, inhibit myosin ATPase activity, and accelerate cross-bridge detachment rate, but as to how this agent attenuates LVH, fibrosis, and diastolic dysfunction warrants further investigation.

• #87 Mechanism-driven therapies for hypertrophic cardiomyopathy – Browse Articles – Conditioning Medicine

  http://www.conditionmed.org/Data/View/14835

  Several approaches have been undertaken to target various pathological features of HCM. This section focuses on therapies designed to attenuate myocardial fibrosis, oxidative stress, impaired myocardial energetics, and hypercontractility. […] Myocardial fibrosis is an independent predictor of adverse outcomes in HCM patients; and hence, it is not surprising that attempts have been made to prevent the development of fibrosis in the setting of HCM. […] The occurrence of LVH and fibrosis are considered secondary to the activation of numerous mitotic pathways, including those mediated by oxidative stress. […] Impaired myocardial energetics is considered an early and common driver of HCM independent of family history, clinical status, and patient genotype. […] Hypercontractility is another pathological feature of HCM, which is attributed to the destabilization of the myosin super-relaxed (SRX) state. […] Mechanistically, mavacamten is thought to decrease force production, inhibit myosin ATPase activity, and accelerate cross-bridge detachment rate, but as to how this agent attenuates LVH, fibrosis, and diastolic dysfunction warrants further investigation.

• #88 Mechanism-driven therapies for hypertrophic cardiomyopathy – Browse Articles – Conditioning Medicine

  http://www.conditionmed.org/Data/View/14835

  Several approaches have been undertaken to target various pathological features of HCM. This section focuses on therapies designed to attenuate myocardial fibrosis, oxidative stress, impaired myocardial energetics, and hypercontractility. […] Myocardial fibrosis is an independent predictor of adverse outcomes in HCM patients; and hence, it is not surprising that attempts have been made to prevent the development of fibrosis in the setting of HCM. […] The occurrence of LVH and fibrosis are considered secondary to the activation of numerous mitotic pathways, including those mediated by oxidative stress. […] Impaired myocardial energetics is considered an early and common driver of HCM independent of family history, clinical status, and patient genotype. […] Hypercontractility is another pathological feature of HCM, which is attributed to the destabilization of the myosin super-relaxed (SRX) state. […] Mechanistically, mavacamten is thought to decrease force production, inhibit myosin ATPase activity, and accelerate cross-bridge detachment rate, but as to how this agent attenuates LVH, fibrosis, and diastolic dysfunction warrants further investigation.

• #89 New perspectives in the pharmacological treatment of hypertrophic cardiomyopathy | Revista Portuguesa de Cardiologia (English edition)

  https://www.revportcardiol.org/en-new-perspectives-in-pharmacological-treatment-articulo-S2174204920300878

  Disruption of intracellular sodium homeostasis may contribute to the pathophysiology of HCM, as raised sodium levels in the cardiomyocyte worsen the dysregulation of intracellular Ca2+ homeostasis which, as mentioned previously, is a key feature of the disease’s pathogenesis. […] The antioxidant effect of NAC may thus play an important role in the treatment of HCM. […] Reactive oxygen species (ROS) levels are known to rise in HCM and oxidative stress plays a major role in the pathophysiology of the disease. […] Oxidative stress contributes to the HCM phenotype by stimulating and activating hypertrophy-inducing signaling kinases and transcription factors. […] Gene therapy has the potential to help prevent disease development in HCM. […] Recently, efforts have been made to correct HCM by inducing the expression of a functional sarcomere protein which replaces the endogenous mutated form.

• #90 Mechanism-driven therapies for hypertrophic cardiomyopathy – Browse Articles – Conditioning Medicine

  http://www.conditionmed.org/Data/View/14835

  Several approaches have been undertaken to target various pathological features of HCM. This section focuses on therapies designed to attenuate myocardial fibrosis, oxidative stress, impaired myocardial energetics, and hypercontractility. […] Myocardial fibrosis is an independent predictor of adverse outcomes in HCM patients; and hence, it is not surprising that attempts have been made to prevent the development of fibrosis in the setting of HCM. […] The occurrence of LVH and fibrosis are considered secondary to the activation of numerous mitotic pathways, including those mediated by oxidative stress. […] Impaired myocardial energetics is considered an early and common driver of HCM independent of family history, clinical status, and patient genotype. […] Hypercontractility is another pathological feature of HCM, which is attributed to the destabilization of the myosin super-relaxed (SRX) state. […] Mechanistically, mavacamten is thought to decrease force production, inhibit myosin ATPase activity, and accelerate cross-bridge detachment rate, but as to how this agent attenuates LVH, fibrosis, and diastolic dysfunction warrants further investigation.

• #91 Mechanism-driven therapies for hypertrophic cardiomyopathy – Browse Articles – Conditioning Medicine

  http://www.conditionmed.org/Data/View/14835

  Several approaches have been undertaken to target various pathological features of HCM. This section focuses on therapies designed to attenuate myocardial fibrosis, oxidative stress, impaired myocardial energetics, and hypercontractility. […] Myocardial fibrosis is an independent predictor of adverse outcomes in HCM patients; and hence, it is not surprising that attempts have been made to prevent the development of fibrosis in the setting of HCM. […] The occurrence of LVH and fibrosis are considered secondary to the activation of numerous mitotic pathways, including those mediated by oxidative stress. […] Impaired myocardial energetics is considered an early and common driver of HCM independent of family history, clinical status, and patient genotype. […] Hypercontractility is another pathological feature of HCM, which is attributed to the destabilization of the myosin super-relaxed (SRX) state. […] Mechanistically, mavacamten is thought to decrease force production, inhibit myosin ATPase activity, and accelerate cross-bridge detachment rate, but as to how this agent attenuates LVH, fibrosis, and diastolic dysfunction warrants further investigation.

• #92 Hypertrophic Cardiomyopathy: a Review | USC Journal

  https://www.uscjournal.com/articles/hypertrophic-cardiomyopathy-form-heart-failure-preserved-ejection-fraction-diagnosis-drugs?language_content_entity=en

  SAM of the MV is characterized by abnormal movement of the MV leaflets into the LVOT, leading to or accentuating the LVOTO. […] The primary mechanism involves drag forces on the anterior mitral valve leaflet pulling it toward the LVOT. […] The 2024 AHA/ACC HCM guidelines recommend the use of CMI, disopyramide and septal reduction therapy (SRT) in patients with persistent symptoms despite first-line therapy. […] CMIs are a novel class of drugs that act by blocking myosin ATPase, which reduces the availability of myosin heads for engagement in cross-bridge formation with actin filaments. […] This leads to a reduction in myocardial hypercontractility, relieving LVOT obstruction, decreasing wall stress and improving the rate of myocardial relaxation. […] Mavacamten is the first-in-class CMI approved for treatment of obstructive HCM.

• #93 Hypertrophic Cardiomyopathy: a Review | USC Journal

  https://www.uscjournal.com/articles/hypertrophic-cardiomyopathy-form-heart-failure-preserved-ejection-fraction-diagnosis-drugs?language_content_entity=en

  SAM of the MV is characterized by abnormal movement of the MV leaflets into the LVOT, leading to or accentuating the LVOTO. […] The primary mechanism involves drag forces on the anterior mitral valve leaflet pulling it toward the LVOT. […] The 2024 AHA/ACC HCM guidelines recommend the use of CMI, disopyramide and septal reduction therapy (SRT) in patients with persistent symptoms despite first-line therapy. […] CMIs are a novel class of drugs that act by blocking myosin ATPase, which reduces the availability of myosin heads for engagement in cross-bridge formation with actin filaments. […] This leads to a reduction in myocardial hypercontractility, relieving LVOT obstruction, decreasing wall stress and improving the rate of myocardial relaxation. […] Mavacamten is the first-in-class CMI approved for treatment of obstructive HCM.

• #94 Mechanism-driven therapies for hypertrophic cardiomyopathy – Browse Articles – Conditioning Medicine

  http://www.conditionmed.org/Data/View/14835

  Several approaches have been undertaken to target various pathological features of HCM. This section focuses on therapies designed to attenuate myocardial fibrosis, oxidative stress, impaired myocardial energetics, and hypercontractility. […] Myocardial fibrosis is an independent predictor of adverse outcomes in HCM patients; and hence, it is not surprising that attempts have been made to prevent the development of fibrosis in the setting of HCM. […] The occurrence of LVH and fibrosis are considered secondary to the activation of numerous mitotic pathways, including those mediated by oxidative stress. […] Impaired myocardial energetics is considered an early and common driver of HCM independent of family history, clinical status, and patient genotype. […] Hypercontractility is another pathological feature of HCM, which is attributed to the destabilization of the myosin super-relaxed (SRX) state. […] Mechanistically, mavacamten is thought to decrease force production, inhibit myosin ATPase activity, and accelerate cross-bridge detachment rate, but as to how this agent attenuates LVH, fibrosis, and diastolic dysfunction warrants further investigation.

• #95 New perspectives in the pharmacological treatment of hypertrophic cardiomyopathy | Revista Portuguesa de Cardiologia (English edition)

  https://revportcardiol.org/en-new-perspectives-in-pharmacological-treatment-articulo-S2174204920300878

  Gene therapy has the potential to help prevent disease development in HCM. […] These approaches are targeted at key events early in the development of HCM. […] Unlike the drugs currently recommended for the treatment of HCM, which seek to alleviate symptoms or prevent complications, these new strategies may mitigate or delay the development of the disease phenotype or even prevent disease onset.

• #96 New perspectives in the pharmacological treatment of hypertrophic cardiomyopathy | Revista Portuguesa de Cardiologia (English edition)

  https://www.revportcardiol.org/en-new-perspectives-in-pharmacological-treatment-articulo-S2174204920300878

  Disruption of intracellular sodium homeostasis may contribute to the pathophysiology of HCM, as raised sodium levels in the cardiomyocyte worsen the dysregulation of intracellular Ca2+ homeostasis which, as mentioned previously, is a key feature of the disease’s pathogenesis. […] The antioxidant effect of NAC may thus play an important role in the treatment of HCM. […] Reactive oxygen species (ROS) levels are known to rise in HCM and oxidative stress plays a major role in the pathophysiology of the disease. […] Oxidative stress contributes to the HCM phenotype by stimulating and activating hypertrophy-inducing signaling kinases and transcription factors. […] Gene therapy has the potential to help prevent disease development in HCM. […] Recently, efforts have been made to correct HCM by inducing the expression of a functional sarcomere protein which replaces the endogenous mutated form.

• #97 New perspectives in the pharmacological treatment of hypertrophic cardiomyopathy | Revista Portuguesa de Cardiologia (English edition)

  https://revportcardiol.org/en-new-perspectives-in-pharmacological-treatment-articulo-S2174204920300878

  Gene therapy has the potential to help prevent disease development in HCM. […] These approaches are targeted at key events early in the development of HCM. […] Unlike the drugs currently recommended for the treatment of HCM, which seek to alleviate symptoms or prevent complications, these new strategies may mitigate or delay the development of the disease phenotype or even prevent disease onset.

• #98 New perspectives in the pharmacological treatment of hypertrophic cardiomyopathy | Revista Portuguesa de Cardiologia (English edition)

  https://www.revportcardiol.org/en-new-perspectives-in-pharmacological-treatment-articulo-S2174204920300878

  These approaches are targeted at key events early in the development of HCM. […] Unlike the drugs currently recommended for the treatment of HCM, which seek to alleviate symptoms or prevent complications, these new strategies may mitigate or delay the development of the disease phenotype or even prevent disease onset.

• #99 Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Clinical Manifestations, Diagnosis, and Therapy

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5654557/

  A diverse array of mechanisms, mirroring the diversity of the causal genes and mutations, are implicated in the pathogenesis of HCM. […] The primary defect is the mutation. Initial or proximal phenotypes are defined as those resulting from the direct effects of the mutations on the structure and function of the sarcomere proteins. […] The intermediary (or secondary) phenotypes include the molecular changes that occur in response to the changes in the sarcomere protein structure and function. […] The tertiary effects are the ensuing histological and pathological phenotypes, which are the consequence of perturbation of a myriad of secondary molecular events in the myocardium, such as activation of the hypertrophic signaling pathways. […] These molecular and histological changes lead to the clinical phenotypes of HCM (quaternary).

• #100 Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Diagnosis, Clinical Course and Therapy | IntechOpen

  https://www.intechopen.com/chapters/75983

  Hypertrophic cardiomyopathy (HCM) is a genetic disorder of cardiac myocytes that is characterized by cardiac hypertrophy, unexplained by the loading conditions, a non-dilated left ventricle and a normal or increased left ventricular ejection fraction (LV-EF). […] The precise mechanisms by which sarcomere variants result in the clinical phenotype have not been fully understood. Mutant sarcomere genes trigger several myocardial changes, leading to hypertrophy and fibrosis, which ultimately result in a small, stiff ventricle with impaired systolic and diastolic performance despite a preserved LV-EF. […] From a metabolic viewpoint, mutations in sarcomeric proteins generally increase myofilament activation and result in myocyte hypercontractility and excessive energy use due to higher (disproportionate) mitochondrial activity. Mitochondrial impairments in the cardiac energy-sensing apparatus as well as alterations in calcium handling result in a stimulation of signaling pathways that contribute to myocyte relaxation abnormalities and growth, with aberrant tissue architecture abnormalities such as myofibrillar disarray and myocardial fibrosis.

• #101 Hypertrophic cardiomyopathy: genetics and clinical perspectives – Wolf – Cardiovascular Diagnosis and Therapy

  https://cdt.amegroups.org/article/view/24557/26222

  The primary defect is the sarcomere mutation, but clinical expression is determined by a complex hierarchy of genetic, epigenetic, and environmental factors. […] First, mutations directly alter the structure and function of the sarcomere proteins and alter biophysical properties of the cardiomyocyte, influence calcium handling, and change cellular energy balance. […] Additionally, mutations can directly initiate other signaling pathways via transcriptional activation; including expression and activation of trophic and mitotic factors, such as calcineurin, mitogen-activated protein kinases, and transforming growth factor beta pathways and stimulate non-cardiac cells, such as fibroblasts. […] The primary and secondary effects of the mutations ultimately lead to the functional pathological phenotypes, such as myocardial hypertrophy and ventricular dysfunction.

• #102 New perspectives in the pharmacological treatment of hypertrophic cardiomyopathy | Revista Portuguesa de Cardiologia (English edition)

  https://revportcardiol.org/en-new-perspectives-in-pharmacological-treatment-articulo-S2174204920300878

  Gene therapy has the potential to help prevent disease development in HCM. […] These approaches are targeted at key events early in the development of HCM. […] Unlike the drugs currently recommended for the treatment of HCM, which seek to alleviate symptoms or prevent complications, these new strategies may mitigate or delay the development of the disease phenotype or even prevent disease onset.

• #103 Mechanism-driven therapies for hypertrophic cardiomyopathy – Browse Articles – Conditioning Medicine

  http://www.conditionmed.org/Data/View/14835

  Several approaches have been undertaken to target various pathological features of HCM. This section focuses on therapies designed to attenuate myocardial fibrosis, oxidative stress, impaired myocardial energetics, and hypercontractility. […] Myocardial fibrosis is an independent predictor of adverse outcomes in HCM patients; and hence, it is not surprising that attempts have been made to prevent the development of fibrosis in the setting of HCM. […] The occurrence of LVH and fibrosis are considered secondary to the activation of numerous mitotic pathways, including those mediated by oxidative stress. […] Impaired myocardial energetics is considered an early and common driver of HCM independent of family history, clinical status, and patient genotype. […] Hypercontractility is another pathological feature of HCM, which is attributed to the destabilization of the myosin super-relaxed (SRX) state. […] Mechanistically, mavacamten is thought to decrease force production, inhibit myosin ATPase activity, and accelerate cross-bridge detachment rate, but as to how this agent attenuates LVH, fibrosis, and diastolic dysfunction warrants further investigation.

• #104 33 Hypertrophic cardiomyopathy: pathogenesis, therapies and disease modulation | Heart Asia

  https://heartasia.bmj.com/content/11/Suppl_1/A14

  Hypertrophic cardiomyopathy (HCM) is a prevalent heritable cardiac disorder, characterised by unexplained left ventricular hypertrophy (LVH) with the triad of myocyte hypertrophy, disarray, and interstitial fibrosis. Such pathological hallmarks impact diastolic function and contribute to adverse clinical outcomes: arrhythmias, progressive heart failure and sudden cardiac death. To date, none of the available armamentaria has been shown to fundamentally modify disease progression, or to benefit genotype-positive, phenotype-negative or preclinical HCM patients. Multiple genetic studies have identified considerable numbers of HCM-causing mutations in human sarcomere protein genes, and mice engineered to carry such human mutations recapitulated key phenotypes of HCM. This has provided remarkable opportunities to identify the novel therapeutics at the molecular levels, and allowed us to integrate gene-based diagnostics into clinical management of preclinical HCM. Studies in HCM mouse models have illustrated the importance of activated transforming growth factor beta (TGF-) pathway in the early development of HCM. Treatment with either TGF- neutralising antibodies or with angiotensin II type 1 receptor antagonist, losartan, was shown to retard and prevent HCM development in mouse models. Lately, MYK-461, the first allosteric inhibitor of the cardiac myosin adenosine triphosphate (ATPase), has been shown to reduce left ventricular contractility and attenuate HCM development in mouse models of HCM. Clinical trials are currently underway to evaluate and investigate these two promising disease-modifying therapies in HCM patients.

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