Improving Cerebral Blood Flow and Cognition in Patients with Cerebral Small Vessel Disease. the ETLAS-2 Trial

Inclusion Criteria:

1. MRI/computed tomography (CT) evidence of small vessel occlusion stroke(s)/lacunarstroke(s) (involving ≤2 cm in the acute phase and ≤1.5cm in the late phase) and/orconfluent deep white matter hyperintensities (≥ grade 2 on Fazekas's scale).

2. Clinical evidence of cerebral small vessel disease can be: a) small vessel occlusionstroke (lacunar stroke) syndrome with symptoms lasting > 24 hours, occurring < 5years ago; OR b) transient ischemic attack (TIA) with symptoms lasting < 24 hoursAND with MR-DWI imaging performed acutely showing small vessel occlusion stroke,occurring < 5 years ago; OR c) TIA with symptoms lasting < 24 hours AND no acuteMRI-DWI lesion but MRI/CT evidence of CSVD with old small vessel occlusion stroke(s) (involving ≤1.5cm) and/or confluent deep white matter hyperintensities (≥ grade 2 onFazekas's scale).

3. Age ≥ 50 years.

Exclusion Criteria:

1. Known diagnosis of dementia, medically treated dementia, or under investigation fordementia

2. Pregnancy or nursing

3. Women of childbearing age not taking contraception

4. Known cortical infarction (> 1.5 cm maximum diameter)

5. Known carotid artery stenosis ≥ 50 % with Doppler ultrasound, CT angiography, or MRIangiography diagnosed within the last five years

6. Known carotid or vertebral dissection as a cause of stroke

7. Stroke after carotid or heart surgery

8. Known hypercoagulable disease

9. Systolic BP < 90 and/or diastolic BP < 50

10. Known severe renal impairment (eGFR < 30ml/min)

11. Known severe hepatic impairment (Child-Pugh > B)

12. History of non-arthritic anterior ischemic optic neuropathy

13. Concomitant use of PDE5 inhibitors e.g. sildenafil, tadalafil, and vardenafil duringtrial period

14. Patients receiving nicorandil and nitrates e.g. isosorbide mononitrate, isosorbidedinitrate, glyceryl trinitrate

15. History of acute myocardial infarction in the last three months before trialintervention

16. Body weight > 130kg

17. Known cardiac failure (NYHA ≥ II)

18. Known persistent or paroxysmal atrial fibrillation/flutter

19. History of "sick sinus syndrome" or other supraventricular cardiac conductionconditions such as sinoatrial or atrioventricular block (2nd of 3rd degree)

20. Other known cardiogenic cause of stroke

21. Contraindication to CO2 challenge, eg severe respiratory disease

22. MRI not tolerated or contraindicated

23. Known monogenic causes of stroke i.e. CADASIL

24. Unable to provide informed consent

25. The participant does not wish to be informed about results from the MRI