With $650K Grant, Canty Explores Molecular Remodeling in VF

The most serious cardiac rhythm disturbance, VF is a lethal public health problem, accounting for half of sudden cardiac deaths.

VF leads to death within minutes unless treated quickly and properly. Surviving an attack outside the hospital is rare, occurring in fewer than 5 percent of cases, by some estimates.

Most people with the condition have no history of heart disease, making it difficult for clinicians to stratify one’s risk.

“Many people who develop a lethal arrhythmia do so as their first manifestation of heart disease, with no prior cardiac symptoms,” says Canty, chief of the Division of Cardiovascular Medicine.

“When we look at their heart with tests performed after an event and exam their prior health records, the majority don’t have heart failure and have never had a heart attack.”

Although autopsy results of people who die of sudden cardiac arrest reveal coronary artery narrowings, the link between these abnormalities and the development of the arrhythmia “remains elusive” Canty says, “because they aren’t always related to an acute heart attack, and the narrowings can develop asymptomatically.”

Canty and his co-investigators will explore whether ischemia-induced adaptations resulting from a coronary stenosis cause molecular remodeling of the heart that makes a patient more vulnerable to VF.

“The changes that occur in the heart muscle cells allow the heart to adapt to periods when there’s inadequate blood flow, but it’s a double-edged sword,” he says.

“These adaptations prevent cells from dying, but they can set people up for developing arrhythmias.”

Using an implantable cardiac defibrillator, the researchers will abort sudden cardiac arrest in a novel pig model with hibernating myocardium, allowing them to identify whether particular biomarkers become elevated in the animals that develop VF compared with survivors.

“Our goal is to identify biomarkers elevated at the time the cardiac arrhythmia develops that may be indicative of molecular tissue remodeling,” Canty says.

“If we can then demonstrate that the same biomarkers are elevated in the days or weeks before ventricular fibrillation develops, we can use this to identify a patient at risk and try to intervene to prevent the lethal arrhythmias from occurring,” he adds.

While many cardiologists have considered VF to arise from acute reductions in blood flow to the heart — such as those arising from a heart attack — the preponderance of evidence doesn’t support that hypothesis in the majority of patients, Canty says.

“We do treadmill stress tests in people who have narrowed coronary arteries and inadequate blood flow to the heart during exercise, but rarely do we see ventricular fibrillation develop during exercise,” he notes.

For decades, researchers focused on warning arrhythmias to predict sudden cardiac arrest, but while strongly correlated, that theory did not hold up, he adds.

Collecting routine blood samples from the animal models over a period of time will allow Canty’s team to determine not only whether a biomarker is elevated in those that develop VF, but for how long it’s elevated before the onset of a cardiac event. If successful, this could help better identify who may be at highest risk of developing the condition.

“Out-of-hospital sudden cardiac arrest remains a major clinical problem in cardiology and an area of research where we haven’t made substantial advances despite intense study by many investigators,” Canty says.

“Currently, the best thing we can offer is rapid treatment after VF develops — immediate bystander CPR, applying an automatic external defibrillator and, hopefully, successful resuscitation before there’s irreversible damage,” he says. 

“Unfortunately, most people who develop sudden cardiac arrest won’t get that far,” he adds. “We therefore need better ways to predict who’s at risk so therapies like implantable defibrillators can be used in those at highest risk before an event occurs.”

Canty is conducting the research with James A. Fallavollita, MD, professor of medicine, and Jun Qu, associate professor of pharmaceutical sciences and director of the proteomics core and chief scientist in bioanalysis at UB’s New York State Center of Excellence in Bioinformatics and Life Sciences.

The VA merit review awards support investigator-initiated research by eligible VA investigators.

Canty’s grant is administered through the VA Western New York Healthcare System.