Racial Differences in XO (Xanthine Oxidase) and Mitochondrial DNA Damage-Associated Molecular Patterns in Resistant Hypertension

Abstract

Background: We previously reported increased plasma XO (xanthine oxidase) activity in patients with resistant hypertension. Increased XO can cause mitochondrial DNA damage and promote release of fragments called mitochondrial DNA damage-associated molecular patterns (mtDNA DAMPs). Here, we report racial differences in XO activity and mtDNA DAMPs in Black and White adults with resistant hypertension.

Methods: This retrospective study includes 91 resistant hypertension patients (44% Black, 47% female) with blood pressure >140/90 mm Hg on ≥4 medications and 37 normotensive controls (30% Black, 54% female) with plasma XO activity, mtDNA DAMPs, and magnetic resonance imaging of left ventricular morphology and function.

Results: Black-resistant hypertension patients were younger (mean age 52±10 versus 59±10 years; P=0.001), with higher XO activity and left ventricular wall thickness, and worse diastolic dysfunction than White resistant hypertension patients. Urinary sodium excretion (mg/24 hour per kg) was positively related to left ventricular end-diastolic volume (r=0.527, P=0.001) and left ventricular mass (r=0.394, P=0.02) among Black but not White resistant hypertension patients. Patients with resistant hypertension had increased mtDNA DAMPs versus controls (P<0.001), with Black mtDNA DAMPS greater than Whites (P<0.001). Transmission electron microscopy of skeletal muscle biopsies in resistant hypertension patients demonstrates mitochondria cristae lysis, myofibrillar loss, large lipid droplets, and glycogen accumulation.

Conclusions: These data warrant a large study to examine the role of XO and mitochondrial mtDNA DAMPs in cardiac remodeling and heart failure in Black adults with resistant hypertension.

Keywords: biopsy; blood pressure; hypertension; mitochondria; xanthine oxidase.

Figure 1.. Box plots presenting quantitative mitochondrial DNA damage-associated molecular patterns (mtDNA DAMP) levels in plasma samples from control and resistant hypertension (RHTN) patients.

Cell-free DNA was extracted from plasma samples, and levels of mtDNA DAMPs from the NADH dehydrogenase subunit 1 (ND1) and NADH dehydrogenase subunit 1 (ND6) regions of the mtDNA were quantitatively determined. A and B, mtDNA DAMP levels of controls and RHTN patients from the ND1 and ND6 regions, respectively. C and D, mtDNA DAMP levels of controls and RHTN patients segregated by race for the ND1 and ND6 regions, respectively.

Figure 2.. Transmission electron microscopy images of skeletal muscle biopsies from 5 patients with resistant hypertension and one normal subject at 8000X (left) and 16 000X (right).

RHTN Patient 01: 35-y-old Black female with numerous interfibrillar large lipid droplets (LDs) surrounded by large accumulations of glycogen (Gly) and clusters of small, disorganized mitochondria within glycogen. RHTN Patient 04: 48-y-old Black male with large subsarcolemmal lipid droplets and evidence of glycophagy (white box). RHTN Patient 05: 74-y-old White female with myofibrillar breakdown (arrows) and multiple small mitochondria (mt) in disarray with lysis of cristae (box). RHTN Patient 08: 70-y-old Black female with large increases in glycogen (Gly) amidst numerous LDs and many multiple sized mitochondria (mt) in areas of myofibril lysis. RHTN Patient 10 has large accumulations of subsarcolemmal glycogen and large lipid droplets. Interfibrillar areas have numerous mitochondria (mt) with cristae lysis. The skeletal muscle biopsy from the Normotensive control subject (HTN20), a 35-y-old White female showed none of these pathological changes.

Figure 3.. Scenario that connects hypertension, dietary salt indiscretion, and aldosterone to a combined pressure and volume overload as demonstrated by a dilated concentric hypertrophy.

However, in Black adults, stretch on the heart and vascular endothelium perpetuates a more aggressive vicious cycle of XO (xanthine oxidase), and mitochondrial DNA damage-associated molecular patterns (mtDNA DAMPs).