News | Hypertension | February 25, 2022

Two Elevated Biomarkers Distinguish Blacks with Resistant Hypertension

Researchers call for a wider study of racial differences in high blood pressure after finding two clinical measures that are significantly greater in Blacks with resistant hypertension

Lou Dell'Italia, M.D.

Lou Dell'Italia, M.D. Credit: UAB


February 25, 2022 – University of Alabama at Birmingham researchers are calling for a wider study of racial differences in high blood pressure after finding two clinical measures that are significantly greater in Blacks with resistant hypertension, as compared to whites with resistant hypertension.

Those clinical biomarkers, seen in blood plasma samples, may be related to the much greater heart disease rates that Blacks face. Black adults in the United States have one of the highest rates of hypertension in the world, and the consequences of that hypertension are severe.

Hypertension is an underlying factor for more than half of Black adults with heart failure. Compared to whites, Black adults have a 50 percent increased incidence of heart failure, and heart failure occurs eight years earlier in Black adults compared to whites.

“Although Black adults have the highest death rate for heart failure, they are consistently underrepresented in clinical trials,” said Louis J. Dell’Italia, M.D., a professor emeritus in the UAB Marnix E. Heersink School of Medicine Division of Cardiovascular Disease and leader of the study. “The greater heart failure burden among Black adults calls for further work to discover effective preventive and therapeutic strategies for this higher-risk population.”

This study, published in the journal Hypertension, is the first to show increased plasma xanthine oxidase activity and more fragments of damaged mitochondrial DNA in Black adults with resistant hypertension, compared to white adults with resistant hypertension. Both groups had significantly higher xanthine oxidase levels and DNA fragments compared to people with normal blood pressure.

Resistant hypertension is high blood pressure that remains above goal levels in people despite taking three high blood pressure drugs of different classes at maximally tolerated doses. The present study that finds racial differences follows previous work by Dell’Italia and colleagues reporting increased plasma xanthine oxidase activity in patients with resistant hypertension.

“Although preliminary, the findings suggest an important underlying cause of increased cardiovascular risk in Black adults with difficult-to-treat hypertension attributable to increased oxidative stress,” said David Calhoun, M.D., a former faculty member in the UAB Department of Medicine Division of Cardiovascular Disease and a co-author in the study. “If confirmed in larger, prospective studies, the findings may allow for earlier identification of at-risk patients and the opportunity for targeted risk modification or even specific pharmaceutical interventions.”   

The current retrospective study included 91 resistant hypertension patients, 44 percent of whom were Black, and 37 controls with normal blood pressures. The resistant hypertension group all had blood pressures above 140/90 mmHg, and all were on four or more medications for their high blood pressure.

Besides the higher levels of xanthine oxidase and broken fragments of mitochondrial DNA in Black resistant hypertension patients, they were also an average of seven years younger and had increased signs of heart disease as measured by wall thickness of the left ventricle and a worse diastolic dysfunction. They also had a higher daily level of urinary sodium.

The researchers also looked at biopsies of quadriceps muscle tissue from Black and white patients with resistant hypertension. Electron microscope images from all showed evidence of metabolic syndrome, a group of conditions that are risk factors for heart disease, diabetes, stroke and other health problems.

So how do the enzyme xanthine oxidase and the increase in damaged mitochondrial DNA possibly relate to greater heart disease?

Xanthine oxidase is a major enzyme that is widely distributed in the heart, liver, gut, lung, kidney and brain, as well as in blood plasma. In its normal metabolic function, it generates oxygen radicals as a byproduct, including hydrogen peroxide and superoxide. These reactive oxygen species can damage DNA.

Mitochondria are small organelles that produce 90 percent of the chemical energy cells need to survive. In heart disease, mitochondrial DNA, or mtDNA, is highly susceptible to oxidative stress and damage. So, the researchers hypothesized that increased xanthine oxidase-derived oxidative stress that causes mtDNA damage should also promote the release of fragments of damaged mtDNA from the mitochondria in patients with resistant hypertension.

They did find this damaged mtDNA, which is known to worsen oxidative stress because the fragments — known as mtDNA Damage-Associated Molecular Patterns, or mtDNA DAMPs — are potent activators of the innate immune response through several pathways, and they can promote pro-inflammatory cytokine release. Black adults were already known to have higher levels of oxidative stress than do whites.

“Thus, xanthine oxidase activation may set up a feed-forward cycle of mitochondrial damage, mitochondrial reactive oxygen species production, mtDNA DAMP release, and inflammation in the pathogenesis of hypertension end-organ injury,” Dell’Italia said. “These results warrant a larger study that includes metabolic syndrome and xanthine oxidase as a potential therapeutic target to reduce mitochondrial damage and attenuate left ventricular diastolic dysfunction in Black adults with resistant hypertension.”

Co-first authors of the study, “Racial differences in xanthine oxidase and mtDNA DAMPS in resistant hypertension,” are Brittany Butts, Ph.D., UAB Department of Medicine Division of Cardiovascular Disease, and Jamelle A. Brown, UAB Department of Pathology.

Other co-authors with Dell’Italia and Calhoun are Thomas S. Denney, Auburn University; Scott Ballinger, UAB Department of Pathology and Center for Free Radical Biology; Steven G. Lloyd and Suzanne Oparil, UAB Department of Medicine Division of Cardiovascular Disease; Paul Sanders, UAB Department of Medicine Division of Nephrology; Tony R. Merriman, Angelo Gaffo and Jasvinder Singh, UAB Department of Medicine Division of Clinical Immunology and Rheumatology; and Eric Kelley, West Virginia University.

Support came from National Institutes of Health grants HL077100, HL051952, HD071866 and NR017322; and the UAB Heersink School of Medicine.


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