Modeling Hypertrophic Cardiomyopathy: Mechanistic Insights and Pharmacological Intervention

Mosqueira, Diogo; Smith, James G W; Bhagwan, Jamie R.; Denning, Chris

doi:10.1016/j.molmed.2019.06.005

Cited by 47 publications

(46 citation statements)

References 128 publications

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“…To achieve a deeper understanding of pathological mechanisms of HCM, several models of disease have been developed, ranging from preparations of scarcely available human heart tissue biopsies to whole animals [ 39 ]. Recent technological advances have resulted in the application of hPSC-CMs for disease modeling, advantageous relative to previous models due to the ability to provide an unlimited source of cardiomyocytes and recapture patient genetic makeup [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial DNA: Hotspot for Potential Gene Modifiers Regulating Hypertrophic Cardiomyopathy

Kargaran

Evans

Bodbin

et al. 2020

JCM

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Hypertrophic cardiomyopathy (HCM) is a prevalent and untreatable cardiovascular disease with a highly complex clinical and genetic causation. HCM patients bearing similar sarcomeric mutations display variable clinical outcomes, implying the involvement of gene modifiers that regulate disease progression. As individuals exhibiting mutations in mitochondrial DNA (mtDNA) present cardiac phenotypes, the mitochondrial genome is a promising candidate to harbor gene modifiers of HCM. Herein, we sequenced the mtDNA of isogenic pluripotent stem cell-cardiomyocyte models of HCM focusing on two sarcomeric mutations. This approach was extended to unrelated patient families totaling 52 cell lines. By correlating cellular and clinical phenotypes with mtDNA sequencing, potentially HCM-protective or -aggravator mtDNA variants were identified. These novel mutations were mostly located in the non-coding control region of the mtDNA and did not overlap with those of other mitochondrial diseases. Analysis of unrelated patients highlighted family-specific mtDNA variants, while others were common in particular population haplogroups. Further validation of mtDNA variants as gene modifiers is warranted but limited by the technically challenging methods of editing the mitochondrial genome. Future molecular characterization of these mtDNA variants in the context of HCM may identify novel treatments and facilitate genetic screening in cardiomyopathy patients towards more efficient treatment options.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial DNA: Hotspot for Potential Gene Modifiers Regulating Hypertrophic Cardiomyopathy

Kargaran

Evans

Bodbin

et al. 2020

JCM

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“…As a particular feature of the present study, all participants are offered comprehensive genetic testing for mutations in genes associated with HCM. Due to variable penetrance and expression, the phenotypic characteristics of HCM are multifaceted and may be influenced by other factors beyond single pathogenic mutations . The complex genotype‐phenotype characteristics of HCM were potentially under‐recognized in the past, which may have resulted in an unsatisfactory efficacy of drug management .…”

Section: Discussionmentioning

confidence: 99%

“…Due to variable penetrance and expression, the phenotypic characteristics of HCM are multifaceted and may be influenced by other factors beyond single pathogenic mutations . The complex genotype‐phenotype characteristics of HCM were potentially under‐recognized in the past, which may have resulted in an unsatisfactory efficacy of drug management . Therefore, our clinical trial may contribute to a better understanding of the association between sarcomere mutations and phenotype characteristics and disease severity as well as its impact on treatment response.…”

Section: Discussionmentioning

confidence: 99%

Design of the SILICOFCM study: Effect of sacubitril/valsartan vs lifestyle intervention on functional capacity in patients with hypertrophic cardiomyopathy

Tafelmeier

Baessler

Wagner

et al. 2020

Clinical Cardiology

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Background: Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disease with a broad spectrum of disease severity. HCM ranges from a benign course to a progressive disorder characterized by angina, heart failure, malignant arrhythmia, syncope, or sudden cardiac death. So far, no medical treatment has reliably shown to halt or reverse progression of HCM or to alleviate its symptoms.While the angiotensin receptor neprilysin inhibitor sacubitril/valsartan has shown to reduce mortality and hospitalization in heart failure with reduced ejection fraction, data on its effect on HCM are sparse.Hypothesis: A 4-month pharmacological (sacubitril/valsartan) or lifestyle intervention will significantly improve exercise tolerance (ie, peak oxygen consumption) in patients with nonobstructive HCM compared to the optimal standard therapy (control group).Methods: SILICOFCM is a prospective, multicenter, open-label, randomized, controlled, three-arm clinical trial (NCT03832660) that will recruit 240 adult patients with a confirmed diagnosis of nonobstructive HCM. Eligible patients are randomized to sacubitril/valsartan, lifestyle intervention (physical activity and dietary supplementation with inorganic nitrate), or optimal standard therapy alone (control group). The primary endpoint is the change in functional capacity (ie, peak oxygen consumption). Secondary endpoints include: (a) Change in cardiac structure and function as assessed by transthoracic echocardiography and cardiac magnetic resonance (MRI imaging), (b) change in biomarkers (ie, CK, CKMB, and NT-proBNP), (c) physical activity, and (d) quality of life.Results: Until December 2019, a total of 41 patients were recruited into the ongoing SILICOFCM study and were allocated to the study groups and the control group. Lars S. Maier and Djordje G. Jakovljevic contributed equally to this study.

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“…Efficient transfection methods can greatly support disease modelling research to clarify genetic causation and disrupt pathological signalling pathways. Despite accounting for 31% of global deaths worldwide in 2017 [ 8 ], the disease mechanisms of many cardiac disorders are poorly understood, especially those in the cardiomyopathies [ 9 ]. At present, human pluripotent stem cell (hPSC) derived cardiomyocytes (CM) might be one of the best resources to promote cardiac repair [ 10 , 11 ] and model cardiac disorders, complementing preceding in vivo models [ 9 , 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

“…Despite accounting for 31% of global deaths worldwide in 2017 [ 8 ], the disease mechanisms of many cardiac disorders are poorly understood, especially those in the cardiomyopathies [ 9 ]. At present, human pluripotent stem cell (hPSC) derived cardiomyocytes (CM) might be one of the best resources to promote cardiac repair [ 10 , 11 ] and model cardiac disorders, complementing preceding in vivo models [ 9 , 12 , 13 ]. Transfection of hPSC-CMs provides further mechanistic insight into these diseases, towards the development of improved and effective treatments, which are still elusive in several cardiac disorders such as cardiomyopathies [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Transfection of hPSC-Cardiomyocytes Using Viafect™ Transfection Reagent

Bodbin

Denning

Mosqueira

2020

MPs

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Twenty years since their first derivation, human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have shown promise in disease modelling research, while their potential for cardiac repair is being investigated. However, low transfection efficiency is a barrier to wider realisation of the potential this model system has to offer. We endeavoured to produce a protocol for improved transfection of hPSC-CMs using the ViafectTM reagent by Promega. Through optimisation of four essential parameters: (i) serum supplementation, (ii) time between replating and transfection, (iii) reagent to DNA ratio and (iv) cell density, we were able to successfully transfect hPSC-CMs to ~95% efficiencies. Transfected hPSC-CMs retained high purity and structural integrity despite a mild reduction in viability, and preserved compatibility with phenotyping assays of hypertrophy. This protocol greatly adds value to the field by overcoming limited transfection efficiencies of hPSC-CMs in a simple and quick approach that ensures sustained expression of transfected genes for at least 14 days, opening new opportunities in mechanistic discovery for cardiac-related diseases.

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Modeling Hypertrophic Cardiomyopathy: Mechanistic Insights and Pharmacological Intervention

Cited by 47 publications

References 128 publications

Mitochondrial DNA: Hotspot for Potential Gene Modifiers Regulating Hypertrophic Cardiomyopathy

Mitochondrial DNA: Hotspot for Potential Gene Modifiers Regulating Hypertrophic Cardiomyopathy

Design of the SILICOFCM study: Effect of sacubitril/valsartan vs lifestyle intervention on functional capacity in patients with hypertrophic cardiomyopathy

Transfection of hPSC-Cardiomyocytes Using Viafect™ Transfection Reagent

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