Effect of blood pressure-lowering agents on microvascular function in people with small vessel diseases (TREAT-SVDs): a multicentre, open-label, randomised, crossover trial

Kopczak, Anna; Stringer, Michael S; van den Brink, Hilde; Kerkhofs, Danielle; Blair, Gordon W; van Dinther, Maud; Reyes, Carmen Arteaga; Garcia, Daniela Jaime; Onkenhout, Laurien; Wartolowska, Karolina A; Thrippleton, Michael J; Kampaite, Agniete; Duering, Marco; Staals, Julie; Lesnik-Oberstein, Saskia; Muir, Keith W; Middeke, Martin; Norrving, Bo; Bousser, Marie-Germaine; Mansmann, Ulrich; Rothwell, Peter M; Doubal, Fergus N; van Oostenbrugge, Robert; Biessels, Geert Jan; Webb, Alastair J S; Wardlaw, Joanna M; Dichgans, Martin; Kopczak, Anna; Stringer, Michael S.; van den Brink, Hilde; Kerkhofs, Danielle; Blair, Gordon W.; van Dinther, Maud; Arteaga Reyes, Carmen; Jaime Garcia, Daniela; Onkenhout, Laurien; Wartolowska, Karolina A.; Thrippleton, Michael J.; Kampaite, Agniete; Duering, Marco; Staals, Julie; Lesnik-Oberstein, Saskia; Muir, Keith; Middeke, Martin; Norrving, Bo; Bousser, Marie-Germaine; Mansmann, Ulrich; Rothwell, Peter M.; Doubal, Fergus N.; van Oostenbrugge, Robert; Biessels, Geert Jan; Webb, Alastair J.S.; Wardlaw, Joanna; Dichgans, Martin; André, Elisabeth; Kääb, Stefan; Anders, Hans-Joachim; Hack, Remco; Kaffe, Maria; Dewenter, Anna; Malik, Rainer

doi:10.1016/s1474-4422(23)00293-4

Cited by 11 publications

(8 citation statements)

References 42 publications

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“…Emerging evidence suggests drug-class-specific effects in reducing BPV, especially in the context of sporadic SVD, though more research is needed to confirm these findings. 17,46 Given that the CAA-related pathophysiological cascade starts decades before the onset of cognitive decline, 37 targeting the interventions at the earliest stages of the disease will be essential.…”

Section: Discussionmentioning

confidence: 99%

Association of Long-Term Blood Pressure Variability with Cerebral Amyloid Angiopathy-related Brain Injury and Cognitive Decline

Sveikata,

Zotin,

Schoemaker

et al. 2024

Preprint

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Introduction: Long-term systolic blood pressure variability (BPV) has been proposed as a novel risk factor for dementia, but the underlying mechanisms are largely unknown. We aimed to investigate the association between long-term blood pressure variability (BPV), brain injury, and cognitive decline in patients with mild cognitive symptoms and cerebral amyloid angiopathy (CAA), a well-characterized small-vessel disease that causes cognitive decline in older adults. Methods: Using a prospective memory clinic cohort, we enrolled 102 participants, of whom 52 with probable CAA. All underwent a 3-tesla research MRI at baseline and annual neuropsychological evaluation over 2 years, for which standardized z-scores for four cognitive domains were calculated. BPV was assessed using a coefficient of variation derived from serial outpatient BP measurements (median 12) over five years. We measured the peak width of skeletonized mean diffusivity (PSMD) as a marker of white matter integrity, and other neuroimaging markers of CAA, including lacunes and cortical cerebral microinfarcts. Using regression models, we evaluated the association of BPV with microstructural brain injury and whether CAA modified this association. We also examined the association of BPV with subsequent cognitive decline. Results: Systolic BPV was dose-dependently associated with PSMD (estimate=0.22, 95% CI: 0.06, 0.39, p=0.010), independent of age, sex, mean BP, common vascular risk factors, brain atrophy, and CAA severity. The presence of probable CAA strengthened the association between BPV and PSMD (estimate=9.33, 95% CI: 1.32, 17.34, p for interaction = 0.023). Higher BPV correlated with greater ischemic injury (lobar lacunes and cortical cerebral microinfarcts) and a decline in global cognition and processing speed (estimate=-0.30, 95% CI: -0.55, -0.04, p=0.022). Discussion: Long-term BPV has a dose-dependent association with alterations in white matter integrity, lobar lacunes, and cortical cerebral microinfarcts, and predicts cognitive decline. Controlling BPV is a potential strategic approach to prevent cognitive decline, especially in early-stage CAA.

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Section: Discussionmentioning

confidence: 99%

Association of Long-Term Blood Pressure Variability with Cerebral Amyloid Angiopathy-related Brain Injury and Cognitive Decline

Sveikata,

Zotin,

Schoemaker

et al. 2024

Preprint

Self Cite

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“…Although an earlier meta-analysis involving >50 000 participants (27 observational studies and RCTs) found no difference in the effects according to the class of drug, 85,86 a more recent meta-analysis involving more participants (n=649 790) that adopted a network analysis found that use of calcium channel blockers or angiotensin II receptor blockers was associated with reduced risk of dementia. 87 Few studies also investigated the effects of BP lowering on the progression of cSVD.…”

Section: Hypertension and Antihypertensivesmentioning

confidence: 97%

“…97 From the perspective of drug class, the SPRINT-MIND study suggested that angiotensinconverting enzyme inhibitors and calcium channel blockers were associated with reduced WMH progression independent of BP control and age compared with β-blockers, 98 while an RCT showed that 4 weeks of treatment with amlodipine, losartan, or atenolol did not differ in their effects on cerebrovascular reactivity in cSVD. 86 In addition to an absolute BP target, emerging observational evidence suggested that BP variability may also independently contribute to the risk of dementia. For instance, a recent cohort study showed that higher systolic BP variability was associated with an increased risk of dementia in later life over a median follow-up duration of 10 years, 99 especially among participants not taking calcium channel blockers.…”

Section: Hypertension and Antihypertensivesmentioning

confidence: 99%

Current and Future Treatments of Vascular Cognitive Impairment

Ip,

Ko,

Lam

et al. 2024

Stroke

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Nonamyloid sporadic cSVD is considered the most prevalent cause or pathological substrate of VCI. 20,21 It refers to diseased microscopic perforating cerebral arterioles, capillaries, and venules giving rise to abnormalities in the cerebral white and deep gray matter. 5 Driven by arteriosclerosis and fibrinoid necrosis, the arteriolar wall can be stenosed, occluded, dilated, or ruptured, which may result in lacunar infarcts or deep microparenchymal/macroparenchymal hemorrhages. 22 In addition, recent studies suggested that cSVD is a dynamic process that affects the whole brain, beginning at the cellular level that involves the components of neurovascular units, including endothelial cells, pericytes, vascular smooth muscle cells, glia, neurons, immune cells, and extracellular matrix. 23,24 These units regulate cerebral blood flow, endothelial function, BBB integrity, and neuroinflammation. 5,23,25 Endothelial dysfunction, astrocytopathy, and BBB leakage may occur when components of neurovascular units are diseased or damaged due to aging, vascular risk factors (eg, hypertension, hyperlipidemia, hyperhomocysteinemia, diabetes, smoking), 26,27 increase in pulsatile flow being transmitted to the cerebral small vessels secondary to aortic stiffness, 28 and genetic factors. 5,24,29,30 These pathological changes may lead to compromised cerebral

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“…62 Cerebrovascular reactivity (the ability of vessels to increase blood supply in response to brain activity) is a sensitive measure of vascular impairment and sufficiently developed to be a primary outcome in multicenter clinical trials. 64 Blood-brain barrier leakage is a key underlying pathology in SVD, 65 possibly occurring in active disease. 66 Quantification of blood-brain barrier leakage, using intravenous gadolinium and dynamic contrast-enhanced MRI, the most established technique, 67 has been used successfully in multicenter studies, 68 to assess vascular function and predict disease progression and intervention response.…”

Section: Quantitative Including Subvisible Vci-related Features Diffu...mentioning

confidence: 99%

Section: Quantitative Including Subvisible Vci-related Featuresmentioning

confidence: 99%

Imaging Biomarkers of VCI: A Focused Update

Clancy,

Kancheva,

Valdés Hernández

et al. 2024

Stroke

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Vascular cognitive impairment is common after stroke, in memory clinics, medicine for the elderly services, and undiagnosed in the community. Vascular disease is said to be the second most common cause of dementia after Alzheimer disease, yet vascular dysfunction is now known to predate cognitive decline in Alzheimer disease, and most dementias at older ages are mixed. Neuroimaging has a major role in identifying the proportion of vascular versus other likely pathologies in patients with cognitive impairment. Here, we aim to provide a pragmatic but evidence-based summary of the current state of potential imaging biomarkers, focusing on magnetic resonance imaging and computed tomography, which are relevant to diagnosing, estimating prognosis, monitoring vascular cognitive impairment, and incorporating our own experiences. We focus on markers that are well-established, with a known profile of association with cognitive measures, but also consider more recently described, including quantitative tissue markers of vascular injury. We highlight the gaps in accessibility and translation to more routine clinical practice.

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Effect of blood pressure-lowering agents on microvascular function in people with small vessel diseases (TREAT-SVDs): a multicentre, open-label, randomised, crossover trial

Cited by 11 publications

References 42 publications

Association of Long-Term Blood Pressure Variability with Cerebral Amyloid Angiopathy-related Brain Injury and Cognitive Decline

Association of Long-Term Blood Pressure Variability with Cerebral Amyloid Angiopathy-related Brain Injury and Cognitive Decline

Current and Future Treatments of Vascular Cognitive Impairment

Imaging Biomarkers of VCI: A Focused Update

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