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

Author:

Ölmestig Joakim1,Marlet Ida R1,Hansen Rasmus H2,Rehman Shazia2,Krawcyk Rikke Steen13,Rostrup Egill4,Lambertsen Kate L567,Kruuse Christina18ORCID

Affiliation:

1. Department of Neurology, Neurovascular Research Unit, Herlev Gentofte Hospital, University of Copenhagen, Herlev 2730, Denmark

2. Department of Radiology, Herlev Gentofte Hospital, Herlev 2730, Denmark

3. Department of Physiotherapy and Occupational Therapy, Herlev Gentofte Hospital, Herlev 2730, Denmark

4. Center for Neuropsychiatric Schizophrenia Research, Mental Health Center Glostrup, Capital Region Psychiatry, Glostrup 2600, Denmark

5. Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense 5000, Denmark

6. Department of Neurology, Odense University Hospital, Odense 5000, Denmark

7. BRIDGE—Brain Research Inter-Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, Odense 5000, Denmark

8. Institute for Clinical Medicine, University of Copenhagen, 2200 Copenhagen N, Denmark

Abstract

AbstractNew 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.

Funder

University of Copenhagen

AP Møller Foundation for the Advancement of Medical Sciences

Foundation for Neurological Research. C.K.

Borregaard Stipend

Novo Nordic Foundation

Publisher

Oxford University Press (OUP)

Subject

General Earth and Planetary Sciences,General Environmental Science

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