Tadalafil may improve cerebral perfusion in small-vessel occlusion stroke—a pilot study

Abstract

New treatments for cerebral small-vessel disease are needed to reduce the risk of small-vessel occlusion stroke and vascular cognitive impairment. We investigated an approach targeted to the signalling molecule cyclic guanosine monophosphate, using the phosphodiesterase 5 inhibitor tadalafil, to explore if it improves cerebral blood flow and endothelial function in patients with cerebral small-vessel disease and stroke. In a randomized, double-blinded, placebo-controlled, cross-over pilot trial (NCT02801032), we included patients who had a previous (>6 months) small-vessel occlusion stroke. They received a single dose of either 20 mg tadalafil or placebo on 2 separate days at least 1 week apart. We measured the following: baseline MRI for lesion load, repeated measurements of blood flow velocity in the middle cerebral artery by transcranial Doppler, blood oxygen saturation in the cortical microvasculature by near-infrared spectroscopy, peripheral endothelial response by EndoPAT and endothelial-specific blood biomarkers. Twenty patients with cerebral small-vessel disease stroke (3 women, 17 men), mean age 67.1 ± 9.6, were included. The baseline mean values ± standard deviations were as follows: blood flow velocity in the middle cerebral artery, 57.4 ± 10.8 cm/s; blood oxygen saturation in the cortical microvasculature, 67.0 ± 8.2%; systolic blood pressure, 145.8 ± 19.5 mmHg; and diastolic blood pressure, 81.3 ± 9.1 mmHg. We found that tadalafil significantly increased blood oxygen saturation in the cortical microvasculature at 180 min post-administration with a mean difference of 1.57 ± 3.02%. However, we saw no significant differences in transcranial Doppler measurements over time. Tadalafil had no effects on peripheral endothelial function assessed by EndoPAT and endothelial biomarker results conflicted. Our findings suggest that tadalafil may improve vascular parameters in patients with cerebral small-vessel disease stroke, although the effect size was small. Increased oxygenation of cerebral microvasculature during tadalafil treatment indicated improved perfusion in the cerebral microvasculature, theoretically presenting an attractive new therapeutic target in cerebral small-vessel disease. Future studies of the effect of long-term tadalafil treatment on cerebrovascular reactivity and endothelial function are needed to evaluate general microvascular changes and effects in cerebral small-vessel disease and stroke.

A single dose of exenatide had no effect on blood flow velocity in the middle cerebral artery in elderly healthy volunteers: Randomized, placebo-controlled, double-blind clinical trial

“…We found no effect of exenatide on peripheral arterial function measured with EndoPAT. We have previously shown a substantial consistency on day-to-day measurements with EndoPAT but less consistency on same-day measurements, which may be reflected in our findings of no change (Hansen et al, 2017;Ölmestig et al, 2020). ABI is used to estimate peripheral artery disease with analysis of the systolic blood pressure in the ankle divided by the systolic blood pressure in the arm.…”

“…A time-averaged mean of V MCA was recorded bilaterally by TCD (2 MHz, Multidop X Doppler, DWL; Lübech and Sipplingen, Sipplingen, Germany) using handheld probes according to previously published methods ( Ölmestig et al, 2020 ). The average of four measurements was calculated over a 30 s time interval.…”

“…Endothelial function and arterial stiffness were assessed non-invasively by finger plethysmography (EndoPAT2000; Itamar Medical Ltd., Caesarea, Israel) in accordance with our previously published methods ( Hansen et al, 2017 ; Butt et al, 2018 ; Ölmestig et al, 2020 ). Measurements were done after 30 min rest, and included a 6-min baseline, 5-min occlusion, and 4-min reactive hyperemia phase.…”

“…We accepted a coefficient of variation (CV) value cut-off of 25% (Butt et al, 2018;Ölmestig et al, 2020).…”

Association between Blood Pressure, Blood Pressure Variability, and Post-Stroke Cognitive Impairment

“…The Perindopril pROtection aGainst REcurrent Stroke Study (PROGRESS) showed a positive effect in cognitive function maintenance in a poststroke patient with a combination of ACEIs and indapamide that reduced the overall risk of PSCI by one-third [208]. In addition to ordinary antihypertensive medications, one study reported that tadalafil improved cerebral perfusion in patients with small vessel occlusion (SVO) [209]. However, there was no evaluation of cognition.…”