Protecting the vascular endothelial barrier – a novel approach to treating atrial fibrillation

A new pharmacologic modality for treating AFib.

Atrial fibrillation (AF) is the most common form of irregular cardiac rhythm (arrhythmia), affecting approximately 3% of the US population. It is a significant risk factor for heart failure, ischemic stroke, and sudden cardiac death. The AF mortality rate is growing globally, and risk factors known to increase the incidence of new onset AF include hypertension, diabetes, myocardial infarction, cardiac surgery, and COVID-19.

The Need

The mechanisms underlying AF are not well understood. As a consequence, development of new antiarrhythmic drugs has been minimal and current treatments are limited to managing this progressive disease, rather than arresting the underlying pathology. Emphasis has been on invasive techniques for radiofrequency or cryo ablation, with a 60%-70% success rate (and frequent need for repeated procedures), as well as new anticoagulant drugs. AF is associated with inflammation and vascular dysfunction. Consideration of vascular tissue can reveal novel arrhythmia mechanisms and encourage development of new drugs that effectively target these mechanisms.

The Technology

This invention is a method for treating AF or other cardiac arrhythmias induced by inflammation-induced vascular leak. It comprises administering to the patient a gap junction hemichannel or pannexin channel inhibitor to preserve endothelial barrier function.

AFib patients have elevated levels of vascular endothelial growth factor A (VEGF-A), which promotes vascular leak and edema. The inventors have previously identified disruption of cardiac sodium channel (NaV1.5) –rich intercalated disk (ID) nanodomains as a novel arrhythmia mechanism. They hypothesized that (i) elevated VEGF-A levels promote AF by disrupting ID nanodomains and slowing atrial impulse propagation, and (ii) protection of the vascular barrier can prevent these arrhythmias. As an example, they demonstrated that treatment with multiple peptide and small molecule agents targeting gap junction hemichannels and pannexin channels decreased both incidence and duration of VEGF-A-induced arrhythmias. These results highlighted VEGFA–induced vascular leak as a novel atrial arrhythmia mechanism and suggest vascular barrier protection as an anti-arrhythmic therapy.

Commercial Applications

Prevention of paroxysmal AFib

Benefits/Advantages

Arrests the underlying pathology of AFib

Patents

Pending patent applications in US and Europe

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