November 2020

CARDIOVASCULAR

EXPLORING THE RELATIONSHIP BETWEEN INFLAMMATION AND HEART FAILURE

Featuring: Sanjiv Shah, ’00 MD

​​​The presence of inflammatory proteins in the blood was associated with comorbidity burden and abnormal heart function in patients with heart failure with preserved ejection fraction, according to a Northwestern Medicine study published in the journal Circulation.

Heart failure currently effects 6.2 million people in the United States due to a high prevalence of diabetes and obesity. There are two major types of heart failure: heart failure with reduced ejection fraction (HFrEF) — when the heart’s left ventricle is unable to contract normally and pumps less oxygen-rich blood to the body — or heart failure with preserved ejection fraction (HFpEF) — when the left ventricle is unable to relax properly when it fills up with blood, causing blood to back up in the lungs and body.

Another key difference between the two is the availability of proven therapies: while therapies for HFrEF are widely available, therapies for HFpEF are extremely limited, according to Sanjiv Shah, ’00 MD, the Neil J. Stone, MD, Professor of Cardiology and senior author of the study.

“There is a pressing need to determine the underlying pathophysiology and to be able to better target treatments for patients with HFpEF,” said Shah, who is also director of the Center for Deep Phenotyping and Precision Therapeutics and director of research at the Bluhm Cardiovascular Institute.

Previous work suggests that HFpEF is caused by a “constellation” of comorbidities, such as high blood pressure, diabetes and obesity, that induces inflammation in the bloodstream. This, according to Shah, essentially causes small blood vessels on the inner lining of the heart muscle to function poorly, leading to heart failure and the failure of other bodily organs.

Using this knowledge, the investigators aimed to identify circulating proteins in a dataset of previously collected blood samples from patients with HFpEF to determine whether comorbidities are directly correlated with increased inflammation in the bloodstream and abnormal heart structure and function.

The team analyzed 248 unique circulating proteins using two different approaches. In a targeted approach, they analyzed 47 proteins previously known to be involved in inflammation in the bloodstream. In an untargeted or unbiased approach, they performed additional analysis of the 248 proteins which revealed clusters of proteins that were overrepresented in inflammatory pathways.

Through both approaches, inflammation in the bloodstream was associated with both comorbidities and the abnormal heart structure and function. Additionally, inflammation in the bloodstream appeared to be the link mediating the association between comorbidities and worse heart function.

Finally, the team replicated their findings in a separate cohort of 117 participants with HFpEF and 30 comorbidity controls without heart failure. Overall, blood samples from participants with HFpEF showed more inflammation during proteomic analysis compared to the controls, according to the authors.

“Our findings highlight the fact that instead of the heart being the main area of injury, it is inflammation in the bloodstream that appears to be poisoning the heart and the blood vessels in HFpEF,” Shah said.

These specific proteins may be used as targets in anti-inflammatory therapy for HFpEF and in identifying inflammation in patients for prevention of HFpEF. The study also provides a “roadmap” for future studies of cardiovascular syndromes that are resistant to therapies by using comprehensive proteomic analyses that utilize both targeted and unbiased approaches, according to Shah.

“In the future, we want to further validate our findings in other cohorts, both in people who have risk factors and in HFpEF patients who already have the syndrome, and use this data to stimulate basic science studies,” Shah said.

This work was supported by AstraZeneca, the American Heart Association, and the National Institutes of Health.

This article was originally published in the Feinberg School of Medicine News Center on November 30, 2020. 
Sanjiv Shah, ’00 MD, the Neil J. Stone, MD, Professor of Cardiology, was the senior author of the study published in Circulation.

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