Human atrial engineered heart muscle as a new patient specific model for atrial fibrillation

• Applicant: Professor Dr. Wolfgang Niels Voigt
• Subject Area: Pharmacology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 455580345

More than two million people in Germany suffer from atrial fibrillation (AF), the most common sustained arrhythmia in the clinical setting. AF is associated with increased mortality and morbidity. Although during the last decades a great deal has been achieved in investigating the molecular mechanisms underlying the arrhythmia, current pharmacological treatment options are largely based on classical antiarrhythmic drugs, which have insufficient efficacy and exert severe side effects. Translation of new antiarrhythmic concepts into clinical practice appears difficult (“translational gap”). This is thought to be due to the fact that pathophysiological mechanisms studied in animal models only partially represent the complexity found in patients with AF. In addition, recent studies suggest that the arrhythmogenic substrate, promoting the development and maintenance of AF, differs between patients. Therefore, identifying and targeting patient-specific arrhythmic mechanisms is crucial for the successful treatment of AF.Development of engineered heart muscle (EHM) based on atrial cardiomyocytes derived from human induced pluripotent stem cells (iPSC-CM) may be key to bridging this gap. Therefore, we aim to develop atrial EHM models of AF and computational models that may allow prediction of individual-specific electrophysiology, based on atrial EHMs generated from the respective patient.First we will investigate the impact of electrical (tachypacing) and mechanical (chronic stretch) stimulation on cellular electrophysiology and calcium homeostasis of atrial EHMs. We will compare these results with similar data obtained in atrial biopsies from patients with AF and heart failure, respectively. In addition, we will generate and characterize atrial EHMs from patients with genetic alterations predisposing to AF development. We propose to investigate the arrhythmogenic substrate and inducibility of arrhythmias in atrial EHMs using simultaneous optical voltage and calcium mapping techniques. Finally, we will obtain atrial biopsies from patients undergoing open-heart surgery and also generate atrial EHMs from these patients. Building on electrophysiological characterization of both samples, we will develop computational models that will allow one to predict the electrophysiological phenotype of individuals, based on each individual’s generated atrial EHM.The models developed in the proposed project will allow direct investigation of arrhythmic mechanisms in human atrial tissue, thereby narrowing the translational gap between basic science and clinical practice. In addition, atrial EHMs will allow for the diagnosis of patient-specific arrhythmogenic substrates and the application of patient-tailored therapeutic concepts.

• DFG Programme: Research Grants