subtype-specific-optical-action-potential-recordings-human-induced

Subtype-specific Optical Action Potential Recordings in Human Induced Pluripotent Stem Cell-derived Ventricular Cardiomyocytes

Cardiomyocytes generated from human induced pluripotent stem cells (iPSC-CMs) are an emerging tool in cardiovascular research. Rather than being a ...

Technical University of Munich

German Centre for Cardiovascular Research (DZHK), Munich Heart Alliance

Long-QT syndromes are heritable diseases associated with prolongation of the QT interval on an electrocardiogram and a high risk of sudden cardiac death due to ventricular tachyarrhythmia. In long-QT syndrome type 1, mutations occur in the KCNQ1 gene, which encodes the repolarizing potassium channel mediating the delayed rectifier I(Ks) current.

Patient-specific induced pluripotent stem-cell models for long-QT syndrome.

The discovery that somatic cells can be reprogrammed to induced pluripotent stem cells (iPSC) by overexpression of a combination of transcription factors bears the potential to spawn a wealth of new applications in both preclinical and clinical cardiovascular research. Disease modeling, which is accomplished by deriving iPSC lines from patients affected by heritable diseases and then studying the pathophysiology of the diseases in somatic cells differentiated from these patient-specific iPSC lines, is the so far most advanced of these applications. Long-QT syndrome and catecholaminergic polymorphic ventricular tachycardia are two heart rhythm disorders that have been already successfully modeled by several groups using this approach, which will likely serve to model other mono- or polygenetic cardiovascular disorders in the future. Test systems based on cells derived from iPSC might prove beneficial to screen for novel cardiovascular drugs or unwanted drug side effects and to individualize medical therapy. The application of iPSC for cell therapy of cardiovascular disorders, albeit promising, will only become feasible if the problem of biological safety of these cells will be mastered.

Induced pluripotent stem cells in cardiovascular research.

The generation of induced pluripotent stem cells (iPSC) from human somatic cells bears the possibility to generate patient-specific stem cell lines which can serve as a theoretically unlimited source of somatic cells carrying the genotype of the patients. Different types of the long-QT syndrome have been studied by analyzing the phenotype of cardiomyocytes generated from patient-specific iPSC lines. Major aspects of the pathophysiology of long-QT syndrome, like prolonged action potentials, arrhythmia, and the effects of pro- and antiarrhythmic drugs could be recapitulated in these cells. In the future, patient-specific iPSC-derived cardiomyocytes might be used to screen for new drugs, to avoid unwanted drug side effects, and to deepen our understanding on the pathophysiology of long-QT syndromes.

Modeling long-QT syndromes with iPS cells.

Membrane potentials display the cellular status of non-excitable cells and mediate communication between excitable cells via action potentials. The use of genetically encoded biosensors employing fluorescent proteins allows a non-invasive biocompatible way to read out the membrane potential in cardiac myocytes and other cells of the circulation system. Although the approaches to design such biosensors date back to the time when the first fluorescent-protein based Förster Resonance Energy Transfer (FRET) sensors were constructed, it took 15 years before reliable sensors became readily available. Here, we review different developments of genetically encoded membrane potential sensors. Furthermore, it is shown how such sensors can be used in pharmacological screening applications as well as in circulation related basic biomedical research. Potentials and limitations will be discussed and perspectives of possible future developments will be provided. 

Genetically Encoded Voltage Indicators in Circulation Research.

For more than 100 years physicians have observed that heartbeats following extrasystolic beats are characterised by augmented myocardial contractility. This phenomenon was termed post-extrasystolic potentiation (PESP). In the 1970s it was first noted that PESP measured at the blood pressure level is typically pronounced in heart failure patients. Only recently, it was shown that PESP measured non-invasively as post-extrasystolic blood pressure potentiation was a strong and independent predictor of death in survivors of myocardial infarction and in patients with chronic heart failure. A similar parameter (PESPAfib) can be also assessed in patients with atrial fibrillation. PESP and PESPAfib can be understood as non-invasive parameters that indicate myocardial dysfunction. They have the potential to improve risk stratification strategies for cardiac patients. 

Article	Year
Patient-specific induced pluripotent stem-cell models for long-QT syndrome. The New England journal of medicine\| PubMed ID: 20660394	2010
Induced pluripotent stem cells in cardiovascular research. Reviews of physiology, biochemistry and pharmacology\| PubMed ID: 22447279	2012
Modeling long-QT syndromes with iPS cells. Journal of cardiovascular translational research\| PubMed ID: 23076501	2013
Genetically Encoded Voltage Indicators in Circulation Research. International journal of molecular sciences\| PubMed ID: 26370981	2015
Post-extrasystolic Blood Pressure Potentiation as a Risk Predictor in Cardiac Patients. Arrhythmia & electrophysiology review\| PubMed ID: 27403290	2016
Cardiac regeneration using HLA-matched induced pluripotent stem cells-no monkey business, but still a long and winding road ahead. Journal of thoracic disease\| PubMed ID: 28449453	2017

Daniel Sinnecker

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