Experimental Models of Hypertrophic Cardiomyopathy

Figures

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  Figure 1. PRISMA Flow Diagram of the Literature Screening Process PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

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  Central Illustration. Experimental HCM Models, Highlighting Mouse and iPSC Models Reporting Disease Hallmarks The methods illustration shows the PRISMA flow diagram of the literature screening process. The results illustrate the distribution of animal and cell-based models in HCM studies, with “n-numbers” indicating the studies that describe the use of specific models. Additionally, the number of studies is normalized to the total number of studies per 5-year period, highlighting the increasing trend of cell-based studies compared to animal models over time. The “Mouse Models” and “iPSC Models” illustrations display the number of publications published over time, the number of hallmarks described per paper, and how many papers studied the same hallmark. ∗Until April. ESC = embryonic stem cell; ESC-CM = embryonic stem cell–derived cardiomyocytes; HCM = hypertrophic cardiomyopathy; iPSC = induced pluripotent stem cell; iPSC-CMs, induced pluripotent stem cell–derived cardiomyocyte.

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  Figure 2. Number of Studies per Model (A) Distribution of animal and cell-based models in hypertrophic cardiomyopathy studies. Numbers indicate the studies that describe the use of the specific model. (B) Hypertrophic cardiomyopathy models over time (per 5-year period) specified by model type. (C) Number of studies normalized to the total number of studies per 5-year period. Increasing trend of cell-based studies compared with animal models over time. ESC = embryonic stem cell; ESC-CM = embryonic stem cell–derived cardiomyocytes; iPSC = induced pluripotent stem cell; iPSC-CMs, induced pluripotent stem cell–derived cardiomyocyte.

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  Figure 3. General Information on Mouse Studies (A) The numbers of mouse studies published per 5-year period. (B) Geographical distribution of research on mouse models based on the country of corresponding author. Each country is shaded according to the percentage of total mouse model publications. (C) Distribution of gene mutations in which each segment represents the percentage of studies on a specific gene in their mouse model. All genes that translate to sarcomere proteins are grouped as “other sarcomere” except for Myh6/MYH7, Mybpc3, Tnnc1, Tnnt2, Tnni3, and Tpm1. Genes not translating to sarcomere proteins are grouped as “non-sarcomere.” (D) Overview of zygosity, in which categorization of mouse models is based on their zygosity in relation to sarcomere mutations, non-sarcomere mutations, and compound heterozygous mutations.

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  Figure 4. HCM Hallmarks in Mouse Models (A-F) The numbers are based on the extracted data related to hypertrophic cardiomyopathy (HCM) hallmarks including hypertrophy, impaired relaxation, fibrosis, sarcomere disarray, cardiomyocyte (CM) hypertrophy, and ventricular arrhythmias. An HCM hallmark is identified as “yes” when a significant difference between HCM model and control model is observed. If no significant difference is found, the HCM hallmark is marked as “no,” indicating that it was investigated but not identified. A single study may investigate multiple models (eg, strain, sex, or age), allowing it to contribute to both “yes" and “no.” Additionally, different genetic backgrounds studied in 1 paper can result in contributions multiple gene groups.

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  Figure 5. General Information on Cat Studies (A) The numbers of cat studies published per 5-year period. The genetic background was either reported (yellow) or not reported (green). (B) Geographical distribution of research on cat models based on the country of corresponding author. Each country is shaded according to the percentage of total cat model publications. (C) Overview of the cat breeds, the number of studies using specific breeds. (D) Distribution of gene mutations, each segment of the inner circle represents the percentage of studies on a specific gene. The outer circle categorizes these specific mutation based on zygosity.

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  Figure 6. HCM Hallmarks in Cat Models (A-F) The numbers are based on the extracted data related to HCM hallmarks including hypertrophy, impaired relaxation, fibrosis, sarcomere disarray, CM hypertrophy, and ventricular arrhythmias. An HCM hallmark is identified as “yes” when a significant difference between HCM model and control model is observed. If no significant difference is found, the HCM hallmark is marked as “no,” indicating that it was investigated but not identified. A single study may investigate multiple breeds allowing it to contribute to multiple breeds. Abbreviations as in Figure 4.

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  Figure 7. General Information on hiPSC-CM Studies (A) The numbers of human induced pluripotent stem cell (hiPSC)/human induced pluripotent stem cell–derived cardiomyocyte (hiPSC-CM) studies, including reports on the generation of hiPSCs, and generated mutant lines published. ∗Until April. (B) Geographical distribution of research on hiPSC/hiPSC-CM studies based on the country of corresponding author. Each country is shaded according to the percentage of total cat model publications. (C) Distribution of gene mutations, each segment represents percentage of studies investigating a specific gene. All genes that translate to sarcomere proteins are grouped as “other-sarcomere” except for MYH7, MYBPC3, TNNT2, TNNI3, and TPM1. Genes not translating to sarcomere proteins are grouped as “non-sarcomere.” (D) Overview of zygosity, categorization of hiPSC models based on their zygosity in relation to sarcomere mutations, non-sarcomere mutations, and compound heterozygous mutations.

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  Figure 8. Origin of Cell Lines and Age of hiPSC-CMs (A) The percentage of hiPSC lines categorized by their origin, specifically by sex and method used generate them. (B) The percentage of studies that conducted experiments with hiPSC-CMs at different age ranges. Abbreviations as in Figure 7.

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  Figure 9. Quality Assessment (A, B) Assessment of study quality of all studies reporting on findings in animals and in cell models, based on the CAMARADES checklist and the RIVER recommendations. Questions could be answered with “yes;” “yes in reference,” when descriptive data could be found in referenced publications; and “no.” For the animal models, models could be generated via transgene approach, spontaneous, or healthy. For some studies, the sample size could not be calculated, as they were retrospective studies, prospective studies, or case reports.

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  Figure 10. Risk-of-Bias Assessment (A, B) Assessment of the risk of bias in all studies reporting on findings in animals and in cell models, based on SYRCLE’s tool for risk-of-bias assessment. Questions could be answered with “yes,” “no,” or “unclear.” For some of the studies, the animals were not housed in-house, so additional options “client/breeder-owned,” “colony,” or “shelter” were available.