Research News

Imagine you go on a hiking trip, climbing several thousand feet. You start feeling dizzy, confused and weaker than normal – this is more than just being tired from walking. Your blood oxygen is reduced because of the high altitudes, but you push through for a full day or more.   

This is one scenario where hypoxia, or lack of oxygen to your tissues, could cause heart remodeling – changes in the heart’s function or physical properties as a result of injury – in as little as 18 hours. A Cleveland Clinic study recently published in Circulation Research showed how hypoxia desensitizes receptors in the heart. This dysfunction affects how the heart responds to adrenaline and can potentially lead to heart failure and stroke. 

The research is a collaboration between the labs of Sathyamangla Prasad, PhD, Staff in Cardiovascular and Metabolic Sciences and Serpil Erzurum, MD, Cleveland Clinic’s Chief Research and Academic Officer and a practicing pulmonologist. 

Heart failure and stroke are extremely common, but further research into hypoxia is providing more insight on how these potentially deadly conditions happen, says Dr. Prasad, senior author on the paper.   

Dr. Prasad’s lab focuses on beta-adrenergic receptors (beta-ARs), critical to maintaining homeostasis in the heart and nervous system. When the body enters “fight or flight,” hormones like adrenaline release in response to stress. Typically, the heart senses these hormones and pumps faster, sending more blood and oxygen throughout the body. 

This research found that hypoxia leads to activation of a molecule called PI3Kγ (phosphoinositide 3-kinase γ) which turns off the receptor, reducing the number of receptors available for adrenergic response. The cardiac remodeling from hypoxia impairs the heart’s ability to respond to stress, potentially predisposing a person to stroke, Dr. Prasad says. 

“What was surprising is how little time it can take for the heart to remodel in response to hypoxia, with harmful implications for patients with ongoing cardiovascular disease,” he says.  

These findings are a starting point for research into other conditions associated with hypoxia and heightened cardiovascular event risk, including chronic obstructive pulmonary disease (COPD), sleep apnea, asthma and infections like COVID-19.  

“Understanding the heart functions in times of low oxygen availability is important for all patients who are critically ill, in particular in patients with underlying heart and lung diseases,” says Dr. Erzurum. “This research is a gateway to more comprehensive, proactive care to secure the best outcome in times of serious illness.”  
 

Turning this receptor back on or not allowing it to shut off in the first place could provide therapeutic opportunities for people suffering from cardiovascular disease. For example, after a stroke, there is a three-hour window between the event and patient reaching the hospital for care. Typically, stroke victims are given beta-blockers to manage their heart rate and reduce the recurrence of stroke.  

Drs. Prasad and Erzurum’s teams are working on developing a small-molecule drug that would target the PI3Kγ-mediated pathways to combat cardiac dysregulation.  

“If you already have a heightened risk of heart failure, including people with diabetes, obesity, pulmonary hypertension and COPD, acute hypoxia would potentially pre-dispose you to stroke risk,” says Dr. Prasad. “This finding gives us new research opportunities to develop therapeutics that could potentially prevent these life-altering events.”