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Researchers at UTHealth Houston have uncovered a molecular mechanism explaining the varying severity of heart attacks based on the time of day, a breakthrough that could lead to new therapeutic approaches aligned with the body’s natural circadian rhythms.
The study, published in Nature, sheds light on the established observation that heart damage following an acute myocardial infarction—commonly known as a heart attack—differs by time of occurrence, with morning attacks causing more severe damage and poor outcomes.
“If you experience a heart attack in the morning, the risk of fatal arrhythmias, heart failure, and mortality increases significantly. Our inquiry focused on understanding why this is the case,” stated Holger Eltzschig, MD, PhD, the study’s senior author and the chair of the Department of Anesthesiology, Critical Care and Pain Medicine at McGovern Medical School.
The researchers identified an interaction between two proteins, BMAL1 and HIF2A, as instrumental in explaining day-time discrepancies in heart injury severity post-heart attack. BMAL1 is integral to circadian rhythms, influencing various biological functions such as sleep, metabolism, and hormone release. In contrast, HIF2A assists the body in responding to low oxygen levels—also known as hypoxia—by promoting red blood cell production, new blood vessel growth, and enhanced cell survival in oxygen-poor conditions.
Heart attacks occur when blood flow is obstructed to the heart, leading to oxygen deprivation and subsequent muscle damage. This study revealed that the BMAL1-HIF2A interaction affected how heart cells in mice cope with low oxygen levels after a heart attack, thereby affecting the heart’s injury response.
In their preclinical study, the researchers noted that heart attacks occurring around 3 a.m. led to more significant heart damage, characterized by increased infarct size and heightened risks of heart failure. Conversely, heart attacks occurring at 3 p.m. were associated with less severity, as the heart exhibited a greater capacity to adapt to reduced oxygen levels and facilitate healing.
The research further indicated that the proteins BMAL1 and HIF2A influence a specific gene, amphiregulin (AREG), which plays a crucial role in determining heart damage levels throughout the day. The scientists discovered that manipulating the BMAL1 and HIF2A-AREG pathway with pharmacological agents significantly protects the heart, particularly if the timing of drug administration coincides with the circadian rhythm.
According to Eltzschig, forthcoming clinical trials should investigate the benefits of timing treatments in accordance with the body’s internal clock to improve patient outcomes. “This finding opens new pathways for treating heart attacks by taking into account the optimal timing for drug delivery,” Eltzschig commented. “Targeting specific proteins to mitigate heart attack severity can lead to significant advancements in patient care. Additionally, individuals undergoing cardiac surgeries could benefit from such therapeutics, like the hypoxia-inducible factor activator vadadustat, when strategically administered prior to their procedures.”
The research team included Kuang-Lei Tsai, PhD, an assistant professor, and Tao Li, PhD, a postdoctoral researcher and co-first author, both from the Department of Biochemistry and Molecular Biology at McGovern Medical School. Their use of high-resolution cryo-electron microscopy facilitated the visualization of the structural interactions between BMAL1 and HIF2A, supporting prospective drug development targeting their interaction. According to Eltzschig, this work provides robust molecular evidence that can guide the creation of innovative therapeutic strategies.
Wei Ruan, MD, PhD, assistant professor of anesthesiology, critical care, and pain medicine at McGovern Medical School, served as the first and corresponding author for this pivotal research.
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