Hypercapnic Responses Uncover Regional Cerebrovascular Dysfunction and A Varying Role of Cyclooxygenase in Young Adults with Metabolic Syndrome

Background Individuals with metabolic syndrome (MetSyn) have an increased risk of cerebrovascular diseases even if the condition does not progress to diabetes. Cerebrovascular reactivity (CVR) to a hypercapnic stimulus in a middle cerebral artery (MCA) is a common test used to assess clinical risk for cerebrovascular disease and stroke. Therefore, we tested the hypothesis that MetSyn impairs cerebral dilation to a clinically relevant hypercapnic stimulus, due to reduced vasodilator signals from the enzyme Cyclooxygenase (COX). Methods 6 healthy controls (Con, 27±1 yrs) and 8 MetSyn patients (38±8 yrs) completed two hypercapnic trials under either placebo (PLA) or COX inhibition (INDO, 100mg indomethacin) in a randomized, single‐blind, cross‐over design. Subjects breathed a hypercapnic mixture (Fi CO 2 =0.03, 5 min steady state) to induce mild increases in CO 2 levels similar to clinical conditions like sleep apnea (Δ P et CO 2 3.7±0.4mmHg). Macroscopic cerebral blood flow (CBF) was measured with a novel 4D Flow MRI approach at 3T using radial undersampling. Blood pressure, O 2 Saturation (SaO 2 ), end‐tidal CO 2 (P et CO 2 ) was also measured. To quantify regional vasodilation, Cerebral Vascular Conductance (CVC=CBF/blood pressure*100mmHg) and reactivity (CVR = ΔCVC/Δ P et CO 2 mmHg) were calculated for five intracranial arteries: MCA x2, Anterior [ACA] x2, and Basilar [BA]. Results Results are means ± SE. Basal CVC was ~46% lower in MetSyn (715±96 Con vs. 384±44 MetSyn, p=0.02). During PLA, CVR to hypercapnia was greater in Con (Con = 34±10 vs. MetSyn = 5.1±5.4, p = 0.01). CVR differed by region: The MCA's (Con 2.4±1.4, MetSyn 2.2±1.2, p = 0.4) and BA (Con = 4±3, MetSyn 0.06±1.7, p = 0.1) had similar CVR, however, Con displayed greater CVR in the ACA's (Con = 10±6, MetSyn, = 0.1±1, p = 0.02). INDO dramatically reduced basal CVC in both groups (Con = Δ −404±65 vs. MetSyn = Δ‐197±36, p=0.01), however, these represented similar relative decrease (~53%, p=0.3) indicating similar effectiveness of COX inhibition between the groups. INDO decreased basal CVC more in BA of Con (Con = −54± 5 %, MetSyn 39±5, %, p = 0.03). Interestingly, INDO did not affect total CVR in MetSyn (INDO = 5.1±5.2, p =0.9) nor in Con despite ~ 34% decrease compared to PLA (Con INDO = 23±23, p = 0.3). Regionally, INDO only reduced CVR in the BA of Con (PLA = 4±3, INDO = −0.7±2, p= 0.045) but not in MetSyn (p=0.2). Summary/Conclusion MetSyn exhibit ~46% lower basal CVC. In response to clinically relevant levels of hypercapnia, total CVR was lower in MetSyn, but effects were regionally distinct. Specifically, CVR was preserved in MCA but abolished in ACA and BA of MetSyn patients. Additionally, INDO did not alter total or regional CVR in MetSyn, indicating a loss of prostaglandin contribution to hypercapnic vasodilation. These data add new insight suggesting younger adults (<45 years) with MetSyn have greater basal total vascular resistance and display regional cerebrovascular dysfunction of vessels down stream of anterior cerebral and basilar arteries. Support or Funding Information Grant support provided by the American Diabetes association ADA 1‐12‐IN‐39. J. Mikhail Kellawan is supported by the American Heart Association 15POST23100020