Preventative therapeutic approaches for hypertrophic cardiomyopathy

Solomon, Tanya; Filipovska, Aleksandra; Hool, Livia C.; Viola, Helena M.

doi:10.1113/jp279410

Cited by 8 publications

(10 citation statements)

References 93 publications

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“…However, HCM at earlier stages should be considered as a form of acquired combined channelopathy [137] rather than a structural disease, and should be treated as such, using provoking tests to identify patients at risk and employing targeted pharmacological antiarrhythmic therapies in selected patients. Moreover, considering that Ca 2+ handling dysregulation seems to precede the effective presentation of the structural alterations of the disease, including hypertrophy and fibrosis, a preventative rather than corrective therapeutic approach could represent a major improvement in the therapeutic management of HCM [138]. Considering that SCD due to ventricular fibrillation represents the most unpredictable and devastating consequence of HCM, the fine comprehension of the different pathomechanisms underpinning arrhythmogenesis could help to improve and ameliorate the therapeutic management of HCM patients, through a better selection of high-risk patients to be subjected to aggressive arrhythmia-preventing strategies at early stages, either with drugs or with implantable devices.…”

Section: Conclusion: Different Electrophysiological Changes At Different Disease Stagesmentioning

confidence: 99%

Ion Channel Impairment and Myofilament Ca2+ Sensitization: Two Parallel Mechanisms Underlying Arrhythmogenesis in Hypertrophic Cardiomyopathy

Santini

Coppini

Cerbai

2021

Cells

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Life-threatening ventricular arrhythmias are the main clinical burden in patients with hypertrophic cardiomyopathy (HCM), and frequently occur in young patients with mild structural disease. While massive hypertrophy, fibrosis and microvascular ischemia are the main mechanisms underlying sustained reentry-based ventricular arrhythmias in advanced HCM, cardiomyocyte-based functional arrhythmogenic mechanisms are likely prevalent at earlier stages of the disease. In this review, we will describe studies conducted in human surgical samples from HCM patients, transgenic animal models and human cultured cell lines derived from induced pluripotent stem cells. Current pieces of evidence concur to attribute the increased risk of ventricular arrhythmias in early HCM to different cellular mechanisms. The increase of late sodium current and L-type calcium current is an early observation in HCM, which follows post-translation channel modifications and increases the occurrence of early and delayed afterdepolarizations. Increased myofilament Ca2+ sensitivity, commonly observed in HCM, may promote afterdepolarizations and reentry arrhythmias with direct mechanisms. Decrease of K+-currents due to transcriptional regulation occurs in the advanced disease and contributes to reducing the repolarization-reserve and increasing the early afterdepolarizations (EADs). The presented evidence supports the idea that patients with early-stage HCM should be considered and managed as subjects with an acquired channelopathy rather than with a structural cardiac disease.

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Section: Conclusion: Different Electrophysiological Changes At Different Disease Stagesmentioning

confidence: 99%

Ion Channel Impairment and Myofilament Ca2+ Sensitization: Two Parallel Mechanisms Underlying Arrhythmogenesis in Hypertrophic Cardiomyopathy

Santini

Coppini

Cerbai

2021

Cells

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“…A sarcomere is a repeating building block and contractile unit of striated (cardiac and skeletal) muscles that coordinates muscle contraction [ 26 , 27 , 28 , 29 , 30 ]. HCM is sometimes depicted as a “disease of the sarcomere” [ 3 , 7 , 14 ], indicating that it is most often caused by mutations in genes that encode proteins associated with the cardiac sarcomere [ 16 , 31 , 32 , 33 ].…”

Section: Introductionmentioning

confidence: 99%

Hypertrophic Cardiomyopathy: Genetic Foundations, Outcomes, Interconnections, and Their Modifiers

2023

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Hypertrophic cardiomyopathy (HCM) is the most prevalent heritable cardiomyopathy. HCM is considered to be caused by mutations in cardiac sarcomeric protein genes. Recent research suggests that the genetic foundation of HCM is much more complex than originally postulated. The clinical presentations of HCM are very variable. Some mutation carriers remain asymptomatic, while others develop severe HCM, terminal heart failure, or sudden cardiac death. Heterogeneity regarding both genetic mutations and the clinical course of HCM hinders the establishment of universal genotype–phenotype correlations. However, some trends have been identified. The presence of a mutation in some genes encoding sarcomeric proteins is associated with earlier HCM onset, more severe left ventricular hypertrophy, and worse clinical outcomes. There is a diversity in the mechanisms implicated in the pathogenesis of HCM. They may be classified into groups, but they are interrelated. The lack of known supplementary elements that control the progression of HCM indicates that molecular mechanisms that exist between genotype and clinical presentations may be crucial. Secondary molecular changes in pathways implicated in HCM pathogenesis, post-translational protein modifications, and epigenetic factors affect HCM phenotypes. Cardiac loading conditions, exercise, hypertension, diet, alcohol consumption, microbial infection, obstructive sleep apnea, obesity, and environmental factors are non-molecular aspects that change the HCM phenotype. Many mechanisms are implicated in the course of HCM. They are mostly interconnected and contribute to some extent to final outcomes.

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“…Pharmacological therapies, surgical interventions including septal reduction and implantable cardioverter-defibrillators are the main treatment for HCM at present (3). The most widely used medicine for HCM include β-adrenergic receptor blockers and Ca 2+ channel blockers (4), and the surgical interventions is only applicable to severe cases.…”

Section: Introductionmentioning

confidence: 99%

Differences in clinical features of hypertrophic cardiomyopathy with or without left ventricular enlargement

et al. 2021

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Background: Few studies have focused on the clinical features of hypertrophic cardiomyopathy (HCM) with enlarged left ventricle (ELV).Methods: In this study, participants were patients with HCM (n=170), who were divided into two groups [ELV and normal left ventricle (NLV)] according to left ventricle size. Age at diagnosis, sex, complications, electrocardiogram (ECG), symptoms, drug treatment, and echocardiographic parameters were compared between the NLV (n=153) and ELV (n=17) groups.Results: The incidence of end-stage HCM (ES-HCM) among all HCM patients was 5.29%, while that of ELV was 10.0%. For all patients with HCM and those with asymmetric septal HCM (ASHCM), there were more males with ELV than NLV. Of the patients with HCM and ASHCM, left ventricular ejection fraction (LVEF) was significantly lower in the ELV group than the NLV group; accordingly, the rates of diuretics use in the ELV group were higher than those in the NLV group. Among apical HCM (ApHCM) patients, the left atrial diameter (LAd), incidence of atrial fibrillation (Af) or ST-T change, and rate of angiotensin converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) use were all higher in the ELV group compared to the NLV group.Conclusions: These findings suggest that the prevalence of ES-HCM in HCM patients with ELV was higher than those with NLV. Additionally, ELV is more common in men than women and there are differences in the clinical features of different types of HCM with ELV.

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Preventative therapeutic approaches for hypertrophic cardiomyopathy

Abstract: Sarcomeric gene mutations are associated with the development of hypertrophic cardiomyopathy (HCM). Current drug therapeutics for HCM patients are effective in relieving symptoms, but do not prevent or reverse disease progression. Moreover, due to heterogeneity in

Cited by 8 publications

References 93 publications

Ion Channel Impairment and Myofilament Ca2+ Sensitization: Two Parallel Mechanisms Underlying Arrhythmogenesis in Hypertrophic Cardiomyopathy

Ion Channel Impairment and Myofilament Ca2+ Sensitization: Two Parallel Mechanisms Underlying Arrhythmogenesis in Hypertrophic Cardiomyopathy

Hypertrophic Cardiomyopathy: Genetic Foundations, Outcomes, Interconnections, and Their Modifiers

Differences in clinical features of hypertrophic cardiomyopathy with or without left ventricular enlargement

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