Background: Resistant hypertension (RHTN) is defined as consistent blood pressure above 130/80 mmHg despite being on three or more antihypertensive medications. RHTN carries higher cardiovascular morbidity and mortality than those with hypertension (HTN), even when adjusted for blood pressure. RHTN is usually associated with increased arterial stiffness (AS), a direct consequence of chronic inflammation. An inflammatory response develops from the innate upregulation of several proinflammatory mediators (PiMs) in response to stressors, followed by resolution. The resolution process is complex, but specialized pro-resolving mediators (SPMs) play an active role. It has been shown that in obesity, an inefficient SPM response and elevated PiMs lead to a persistent low-grade proinflammatory state. This causes dysregulation in the inflammation-resolution process, leading to impaired vascular repair and increased AS, subsequently predisposing to RHTN. Herein, we assess the role of PiMs and SPMs in the development of AS among non-diabetic patients with obesity-related RHTN.

Methods: Patients seen in the University of Alabama at Birmingham Hypertension Referral Clinic underwent AS measurement and analysis of PiMs and SPMs. AS was measured via carotid-femoral pulse wave velocity (SphygmoCor). PiMs and SPMs were measured by targeted lipidomics analysis by LC/MS in combination with quantification of the lipid mediators. Plasma from 15 individuals was included in the final results. Healthy normotensive patients served as control.

Results: We analyzed 40 bioactive lipid mediators as potential PiMs and SPMs contributing to AS. In this cohort of 15 individuals, the mean age of the hypertensive group was 57.5±3.5 years, BMI was 34.85±2.7 kg/m2, blood pressure was 146.39±8.7/88.9±5.8 mmHg, and AS was 10.7±1.9 m/s (p =0.0031). LC/MS analysis showed PiMs such as prostaglandin F1(PGF1)-alpha was significantly higher among the obesity-related HTN group with increased AS compared to the control group (p=0.01), and PGF2-alpha was also higher when compared to the control group (p=0.06). SPMs such as Resolvin-D1 did not show a significant difference between the two groups, indicating a possible complex dysequilibrium in the resolution of chronic inflammation in the vasculature.

Conclusion: Our study shows that PiMs play a significant role in AS in obesity-related RHTN, and dysregulation in the SPM pathway leads to continued low-grade inflammation in the vasculature. Further studies with a larger patient population can help us target the inflammation-resolution pathway for novel therapies to reduce AS and subsequently prevent RHTN and cardiovascular disease.