Kattman, S. | bioRxiv Science

bioRxiv2024

Transcriptional Variabilities in Human hiPSC-derived Cardiomyocytes: All Genes Are Not Equal and Their Robustness May Foretell Donor's Disease Susceptibility

Human induced pluripotent stem cells (hiPSCs) are frequently used to study disease-associated variations. We characterized transcriptional variability from a hiPSC-derived cardiomyocyte (hiPSC-CM) study of left ventricular hypertrophy (LVH) using donor samples from the HyperGEN study. Multiple hiPSC-CM differentiations over reprogramming events (iPSC generation) across 7 donors were used to assess variabilities from reprogramming, differentiation, and donor LVH status. Variability arising from pathological alterations was assessed using a cardiac stimulant applied to the hiPSC-CMs to trigger hypertrophic responses. We found that for most genes (73.3%[~]85.5%), technical variability was smaller than biological variability. Further, we identified and characterized lists of "noise" genes showing greater technical variability and "signal" genes showing greater biological variability. Together, they support a "genetic robustness" hypothesis of disease-modeling whereby cellular response to relevant stimuli in hiPSC-derived somatic cells from diseased donors tends to show more transcriptional variability. Our findings suggest that hiPSC-CMs can provide a valid model for cardiac hypertrophy and distinguish between technical and disease-relevant transcriptional changes.

genetics↗

bioRxiv2021

Pharmacologic Therapy for Engraftment Arrhythmia Induced by Transplantation of Human Cardiomyocytes

BackgroundEngraftment arrhythmias (EAs) are observed in large animal studies of intramyocardial transplantation of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) for myocardial infarction. Although transient, the risk posed by EA presents a barrier to clinical translation. ObjectivesWe hypothesized that clinically approved antiarrhythmic drugs can prevent EA-related mortality as well as suppress tachycardia and arrhythmia burden. MethodshPSC-CM were transplanted into the infarcted porcine heart by surgical or percutaneous delivery to induce EA. Following a screen of antiarrhythmic agents, a prospective study was conducted to determine the effectiveness of amiodarone plus ivabradine in preventing cardiac death and suppressing EA. ResultsEA was observed in all subjects, and amiodarone-ivabradine treatment was well-tolerated. None of the treated subjects experienced the primary endpoint of cardiac death, unstable EA or heart failure compared to 5/8 (62.5%) in the control cohort (hazard ratio 0.00; 95% confidence interval, 0-0.297; p = 0.002). Overall survival including two deaths in the treated cohort from immunosuppression-related infection showed borderline improvement with treatment (hazard ratio 0.21; 95% confidence interval, 0.03-1.01; p = 0.05). Without treatment, peak heart rate averaged 305 {+/-} 29 beats per min (bpm), whereas in treated subjects peak daily heart rate was significantly restricted to 185{+/-}9 bpm (p = 0.006). Similarly, treatment reduced peak daily EA burden from 96.8 {+/-} 2.9% to 76.5 {+/-} 7.9% (p = 0.003). Antiarrhythmic treatment was safely discontinued after approximately one-month of treatment without recrudescence of arrhythmia. ConclusionsThe risk of engraftment arrhythmia following hPSC-CM transplantation can be reduced significantly by combined amiodarone and ivabradine drug therapy. Condensed AbstractEngraftment arrhythmia (EA) is a transient but serious complication of cardiac remuscularization therapy. Using a porcine model of cardiac remuscularization and EA, ivabradine and amiodarone were independently effective in suppressing tachycardia and arrhythmia, respectively. Baseline amiodarone combined with adjunctive ivabradine successfully prevented cardiac death, unstable EA and heart failure (hazard ratio 0.00; 95% confidence interval, 0-0.297; p = 0.002) and significantly suppressed peak daily heart rate and arrhythmia burden (p=0.006 and 0.003, respectively). Antiarrhythmic treatment was successfully discontinued after one-month without recrudescence of arrhythmia. We conclude that EA can be suppressed by combined amiodarone and ivabradine drug therapy.

pharmacology and toxicology↗