The Effect of Spironolactone on Cerebral Blood Flow and Cognition

Abstract

Hypertension and arterial stiffness are associated with structural and functional changes in cerebral circulation and cognitive function, but based on existing evidence the effects are potentially reversible by spironolactone (Spiro) reducing blood pressure (BP) and arterial stiffness. This thesis consisted of a double-blind, controlled trial with older hypertensive adults (OA) who were receiving stable treatment with centrally acting angiotensin converting enzyme inhibitors randomly assigned to Spiro or placebo to test the hypothesis that reductions in BP and arterial stiffness would be associated with improved anterior cerebral blood flow (aCBF) and cognitive function. Secondary objectives were to investigate how Spiro would affect cerebrovascular autoregulation and to conduct a supplementary experimental study in younger adults (YA) comparing blood pressure and arterial stiffness to OA; and to determine how induced acute small changes in BP could impact interpretation of the chronic changes in BP and arterial stiffness associated with Spiro therapy.

The pooled data from the randomized, controlled trial (RCT) in OA (n=18) showed that age, mean arterial pressure (MAP), systolic (SBP), diastolic (DBP) and pulse pressure (PP) were 65±3 years, 97±9 mmHg, 142±16 mmHg, 75±8 mmHg, and 66±13 mmHg respectively. There was a significant association between age and carotid distensibility coefficient (r= - 0.51, P<0.05). Six months of Spiro significantly reduced SBP and PP by 14±14 mmHg and 12±14 mmHg respectively. However arterial stiffness estimated by regional indicator carotid-femoral pulse wave velocity (cfPWV), or local indicators carotid distensibility coefficient and β-stiffness index, remained unchanged. Spiro did not significantly improve aCBF or cognitive function scores. Cerebrovascular autoregulation response to standing upright remained unchanged after Spiro compared to placebo. Mean adherence to study-drug was at least 95% for both groups. The calculated Cohen’s d effect size for Spiro was 0.3 from this thesis RCT data; much smaller than the desired Cohen’s d effect size of 1.0 that was derived from observational data used to calculate sample size for the RCT. The supplementary experimental study in YA (n=14) demonstrated that OA in the RCT had greater MAP (97±9 mmHg vs 86±9 mmHg, P<0.01), SBP (142±16 mmHg vs 124±12 mmHg, P<0.01), DBP (75±8 mmHg vs 67±9 mmHg, P<0.05), PP (66±13 mmHg vs 57±7 mmHg, P<0.05), and arterial stiffness was greater as indicated by faster cfPWV (7.22±1.09 m/s vs 5.43±1.13 m/s, P<0.001), smaller carotid distensibility coefficient (0.0014±0.0006 mmHg-1 vs 0.0031±0.0008, P<0.001), and greater β-stiffness index (8.78±3.53 a.u. vs 3.74±0.91, P<0.001). Application of lower body negative pressure to induce acute hemodynamic changes in these YA reduced stroke volume (P<0.001) and cardiac output (P<0.001); and increased total peripheral resistance (P<0.001) while MAP remained unchanged. There were also small acute decreases in both SBP (P<0.05) and PP (P<0.001) in these YA that were concurrent with a non-significant increase in arterial stiffness (cfPWV increase, carotid distensibility coefficient decrease, β-stiffness index increase). Transit times from R-peak of QRS complex to foot of aortic velocity pulse, carotid artery, or finger artery significantly increased with progressively increasing LBNP as a consequence of longer pre-ejection period (P<0.001).

In conclusion for the main thesis objective, Spiro safely and effectively reduced BP while arterial stiffness, aCBF, cognitive function, and cerebrovascular autoregulation remained unchanged. OA, compared to YA, had greater blood pressure and arterial stiffness for all measures. In YA, acute reductions in systolic and pulse pressure affected stiffness indicators, in contrast to unchanged stiffness indicators observed in OA. These limited data should be interpreted with caution given the small sample size in the RCT, small effect size of Spiro and that acute reductions in SBP and PP may affect arterial stiffness.