Heart Disease on a Dish

Disheet Shah

    Research output: Book/ReportDoctoral thesisCollection of Articles


    Cardiac diseases represent one of the most frequent causes of death globally. Genetic mutations are often the basis of cardiac diseases that may cause structural, mechanical, or electrical changes, affecting the normal function of the heart and can even be fatal. Modeling diseases helps to understand disease pathophysiology and to test therapeutic options. Disease modeling with human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) offers a unique opportunity for studying human cardiac diseases in vitro. This model is more advantageous over animal models and cellular expression systems in certain aspects that it provides an opportunity to study human diseases using human physiology. Different cardiac diseases have been modeled using hiPSC-CMs and subjected to detailed analysis to study the diseases.

    Finland, due to its geographical location and history, has a unique genetic identity where disease mutations have enriched. These mutations give a unique clinical phenotype for the diseases, which may require unique treatment options. An additional challenge in treating patients with these disease mutations is that they express a variable disease penetrance and a dissimilar clinical phenotype. Many carriers of the mutation may not present clinical symptoms but retain a higher risk of death. These Finnish founder mutations have been studied well; clinically and genetically, however there is a need for models to aid in studying their pathophysiology at cellular level.

    This dissertation work includes modeling of cardiac diseases with Finnish founder mutations for dilated cardiomyopathy (DCM) and long QT syndrome (LQTS) affecting the mechanical and electrical function of the heart, respectively. A mutation causing DCM (p.S143P in the LMNA gene encoding the Lamin A/C gene) and causing LQT2 (p.L552S in the KCNH2 gene encoding the α-subunit of the HERG channel) were studied. Patient skin fibroblasts were reprogramed to hiPSCs and differentiated to cardiomyocytes. The effects of these mutations on the structure and electrophysiological function were studied. The results of this work demonstrate that with our in-vitro hiPSC-CM models, we can recapitulate the hallmarks of these
    diseases, including characteristic arrhythmias reproduced at cellular level. More pronounced presentations of the phenotype were observed on stimulation by pharmacological compounds or under stress in both DCM and LQTS. Differences between hiPSC-CMs from asymptomatic and symptomatic carriers of the LQTS mutation, were detected at the hiPSC-CM aggregate level, but not at the single-cell level.

    Models from hiPSC-CMs are increasingly used to study diseases, drug toxicity screening, and therapy. Though hiPSC-CMs offer a considerable advantage in providing a model with human cellular physiology, the hiPSC-CMs are immature and have a variable phenotype. In this regard, the third study in this dissertation includes a comparison of the time-series of the beating rhythm of healthy human hearts and field potentials of hiPSC-CMs aggregates. Scaling properties showed remarkable similarities between the ECG and hiPSC-CM data.

    In conclusion, the findings from the studies in this dissertation show that 1) hiPSC-CMs from disease models may show morphological changes, 2) hiPSC-CMs from disease models may show pronounced differences under stress or stimulation,
    3) hypoxia reduces or arrests the beating rate, while oxygen-reperfusion restores the functionality in control hiPSC-CMs, the restoration of function may be limited in the hiPSC-CMs from the disease model, 4) hiPSC-CMs can be used to model clinically varied phenotype of genetic cardiac diseases, 5) disease phenotype was observed more evidently at cell aggregate level rather than at the single cell level, 6) hiPSC-CMs can reproduce disease-specific arrhythmias at cellular level and can also be used to study the effects of drugs, 7) detrended fluctuation analysis revealed notable similarities in the beating patterns and scaling exponents from the RR-QT intervals from ECG data and IBI-FPD intervals from hiPSC-CM cardiac aggregates. These findings encourage a further study of the mechanisms of the disease, drug development, and assist in the translation of findings from basic research to benefit patients in clinical practice.
    Original languageEnglish
    Place of PublicationTampere
    PublisherTampere University
    ISBN (Electronic)978-952-03-1759-1
    ISBN (Print)978-952-03-1758-4
    Publication statusPublished - 2020
    Publication typeG5 Doctoral dissertation (articles)

    Publication series

    NameTampere University Dissertations - Tampereen yliopiston väitöskirjat
    ISSN (Print)2489-9860
    ISSN (Electronic)2490-0028


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