Ölmestig Joakim, Marlet Ida R, Hansen Rasmus H, Rehman Shazia, Krawcyk Rikke Steen, Rostrup Egill, Lambertsen Kate L, Kruuse Christina
Department of Neurology, Neurovascular Research Unit, Herlev Gentofte Hospital, University of Copenhagen, Herlev 2730, Denmark.
Department of Radiology, Herlev Gentofte Hospital, Herlev 2730, Denmark.
Brain Commun. 2020 Feb 20;2(1):fcaa020. doi: 10.1093/braincomms/fcaa020. eCollection 2020.
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.
需要新的脑小血管疾病治疗方法来降低小血管闭塞性中风和血管性认知障碍的风险。我们研究了一种针对信号分子环磷酸鸟苷的方法，使用磷酸二酯酶5抑制剂他达拉非，以探索其是否能改善脑小血管疾病和中风患者的脑血流量和内皮功能。在一项随机、双盲、安慰剂对照、交叉试验（NCT02801032）中，我们纳入了既往（>6个月）有小血管闭塞性中风的患者。他们在至少相隔1周的2个不同日期分别接受一剂20mg他达拉非或安慰剂。我们测量了以下指标：用于评估病变负荷的基线磁共振成像（MRI）、经颅多普勒对大脑中动脉血流速度的重复测量、近红外光谱法对皮质微血管血氧饱和度的测量、EndoPAT对外周内皮反应的测量以及内皮特异性血液生物标志物。纳入了20例脑小血管疾病中风患者（3名女性，17名男性），平均年龄67.1±9.6岁。基线平均值±标准差如下：大脑中动脉血流速度为57.4±10.8cm/s；皮质微血管血氧饱和度为67.0±8.2%；收缩压为145.8±19.5mmHg；舒张压为81.3±9.1mmHg。我们发现，他达拉非在给药后180分钟时显著提高了皮质微血管的血氧饱和度，平均差异为1.57±3.02%。然而，随着时间推移，经颅多普勒测量结果并无显著差异。他达拉非对通过EndoPAT评估的外周内皮功能没有影响，且内皮生物标志物结果相互矛盾。我们的研究结果表明，他达拉非可能改善脑小血管疾病中风患者的血管参数，尽管效应大小较小。他达拉非治疗期间脑微血管氧合增加表明脑微血管灌注改善，理论上为脑小血管疾病提供了一个有吸引力的新治疗靶点。需要进一步研究长期使用他达拉非治疗对脑血管反应性和内皮功能的影响，以评估脑小血管疾病和中风中的一般微血管变化及效应。
