Inherited and Acquired Rhythm Disturbances in Sick Sinus Syndrome, Brugada Syndrome, and Atrial Fibrillation: Lessons from Preclinical Modeling

Abstract

Rhythm disturbances are life-threatening cardiovascular diseases, accounting for many deaths annually worldwide. Abnormal electrical activity might arise in a structurally normal heart in response to specific triggers or as a consequence of cardiac tissue alterations, in both cases with catastrophic consequences on heart global functioning. Preclinical modeling by recapitulating human pathophysiology of rhythm disturbances is fundamental to increase the comprehension of these diseases and propose effective strategies for their prevention, diagnosis, and clinical management. In silico, in vivo, and in vitro models found variable application to dissect many congenital and acquired rhythm disturbances. In the copious list of rhythm disturbances, diseases of the conduction system, as sick sinus syndrome, Brugada syndrome, and atrial fibrillation, have found extensive preclinical modeling. In addition, the electrical remodeling as a result of other cardiovascular diseases has also been investigated in models of hypertrophic cardiomyopathy, cardiac fibrosis, as well as arrhythmias induced by other non-cardiac pathologies, stress, and drug cardiotoxicity. This review aims to offer a critical overview on the effective ability of in silico bioinformatic tools, in vivo animal studies, in vitro models to provide insights on human heart rhythm pathophysiology in case of sick sinus syndrome, Brugada syndrome, and atrial fibrillation and advance their safe and successful translation into the cardiology arena.

Trends in research on sick sinus syndrome: A bibliometric analysis from 2000 to 2022

“…More than 50% of patients with SSS may develop a brady-tachy arrhythmia syndrome, with tachyarrhythmias, most commonly atrial fibrillation and atrial flutter, leading to an increased risk of embolism and stroke ( 34 ). And anticoagulation therapy had been shown to be beneficial to reduce the risk of embolism and stroke ( 35 ). In addition, secondary sinus node dysfunction was associated with atrial tachyarrhythmias and atrial fibrillation.…”

Electrical Remodelling in Cardiac Disease

“…An in-depth summary of genetic and acquired pathophysiological causes of sick sinus syndrome, Brugada syndrome, and atrial fibrillation reviews preclinical animal and cell models as well as computational simulations for these arrhythmias [27]. In chronic heart failure, both ventricular tachyarrhythmia and atrial fibrillation are common arrhythmias.…”

Structural and Electrical Remodeling of the Sinoatrial Node in Diabetes: New Dimensions and Perspectives

“…Although elevated ROS is a consistent finding in cardiovascular complications of diabetes, data on defined molecular targets and pathways that connect increased oxidation with SAN function are very limited. In sick sinus syndrome, mitochondrial oxidative stress was found to induce HCN4 downregulation ( 128 ). A recent study found that this effect involves the inhibition of mitochondrial thioredoxin-2, an important ROS scavenger that regulates the mitochondrial apoptosis signaling pathway.…”