Hyperintense: Midlife Hypertension and the Brain

NCT ID: NCT06175663

Last Updated: 2023-12-19

Basic Information

• Recruitment Status: RECRUITING
• Total Enrollment: 130 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2021-07-06
• Study Completion Date: 2023-12-31

Brief Summary

Cerebral small vessel disease (SVD) describes a set of pathologies affecting the smallest blood vessels in the brain. SVD contributes to up to a fifth of ischemic and hemorrhagic strokes en is the main vascular cause of dementia. On MRI, SVD is marked by different types of lesions, including white matter abnormalities, and small infarcts and hemorrhages. Recent studies indicate that SVD develops slowly over the years, starting presumably decades before the typical MRI lesions become apparent. High blood pressure plays an important role in the development of SVD MRI lesions. However, it remains unclear exactly how hypertension leads to vascular pathology. To gain more insight into how hypertension leads to SVD it is important to study mechanisms in individuals (largely) free of SVD, that is before midlife.

Therefore, the investigators aim to examine abnormalities in brain (micro) structure and vascular function in young patients with hypertension. Furthermore, the investigators aim to determine the effects of blood pressure increase and subsequent blood pressure reduction during a period of withdrawal and restart of blood pressure lowering drugs on brain (micro)structure and vascular function.

Conditions

Hypertension; Small Vessel Cerebrovascular Disease

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

Cross-sectional study

To examine if there are cerebral abnormalities present following hypertension before MRI markers of SVD have manifested, we will do high-resolution 3T MRI in 100 young (18-40 years) hypertensive adults.

No interventions assigned to this group

Longitudinal study

In a cohort study, we will examine the effects of an increase and decrease in blood pressure on the brain. For this analysis, we will include hypertensive patients that are referred to the Radboudumc Department of Internal Medicine for a diagnostic work up on the cause(s) of their hypertension. The diagnostic procedure entails withdrawal of antihypertensives for approximately four weeks, as per the routine diagnostic protocol to allow for diagnosis of the cause of hypertension, and subsequent restart of treatment until the target blood pressure is reached (normotension). Measurements are performed just before antihypertensive medication is withdrawn (baseline), approximately four weeks after withdrawal (T=1), once patients have reached their target blood pressure and blood pressure is stable, estimated to occur within 2-4 months (T=2) and approximately 1 year after T=2 (T=3).

Antihypertensive medication withdrawal

Intervention Type: DRUG

To determine if high blood pressure is caused by an overproduction of aldosterone in the adrenal gland (i.e. primary hyperaldosteronism), the plasma aldosterone/renin ratio (ARR) can be determined. Because many common hypertensive drugs are known to interfere with this ratio, patients often have to discontinue drugs prior to screening or switch to drugs that are known not to affect ARR (i.e. doxazosin, verapamil, diltiazem, hydralazine). Drugs have to be stopped for at least four weeks (for mineralocorticoid receptor antagonists) or two weeks (for diuretics, Angiotensin Converting Enzyme (ACE) inhibitors, Angiotensin Receptor Blockers (ARBs)). This often leads to a temporary increase in blood pressure. After diagnostics are completed, medication is adjusted accordingly and blood pressure levels drop again.

Interventions

Antihypertensive medication withdrawal

To determine if high blood pressure is caused by an overproduction of aldosterone in the adrenal gland (i.e. primary hyperaldosteronism), the plasma aldosterone/renin ratio (ARR) can be determined. Because many common hypertensive drugs are known to interfere with this ratio, patients often have to discontinue drugs prior to screening or switch to drugs that are known not to affect ARR (i.e. doxazosin, verapamil, diltiazem, hydralazine). Drugs have to be stopped for at least four weeks (for mineralocorticoid receptor antagonists) or two weeks (for diuretics, Angiotensin Converting Enzyme (ACE) inhibitors, Angiotensin Receptor Blockers (ARBs)). This often leads to a temporary increase in blood pressure. After diagnostics are completed, medication is adjusted accordingly and blood pressure levels drop again.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Age 18-40 years
• Blood pressure above 140/90 mmHg, measured within three months prior to study participation

• Age 18-55 years
• Undergoing diagnostic routine of temporary antihypertensive withdrawal for biochemical analysis as part of clinical work-up

Exclusion Criteria

• Pre-existing cerebrovascular disease
• Pregnancy
• Contraindications for 3 T MRI
• Renal function eGFR below 30 ml/min (for Dynamic Contrast Enhanced [DCE]-MRI
• Major risk factors for acute ischemic stroke other than SVD according to the TOAST criteria, including, but not limited to, large-artery atherosclerosis, cardioembolism and vasculitis based on medical history and ultrasound of the carotids collected at baseline or any chronic disease that could lead to brain lesions mimicking SVD
• Major (neurological/psychiatric) disease (e.g. multiple sclerosis)
• Not able to give informed consent

Study 2: longitudinal study

• Pre-existing cerebrovascular disease
• Pregnancy
• Contraindications for 3 T MRI
• Renal function eGFR below 30 ml/min (for Dynamic Contrast Enhanced [DCE]-MRI
• Major risk factors for acute ischemic stroke other than SVD according to the TOAST criteria,22 including, but not limited to, large-artery atherosclerosis, cardioembolism and vasculitis based on medical history and ultrasound of the carotids collected at baseline or any chronic disease that could lead to brain lesions mimicking SVD
• Major (neurological/psychiatric) disease (e.g. multiple sclerosis)
• Not able to give informed consent

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 55 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Radboud University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Frank-Erik de Leeuw

Role: PRINCIPAL_INVESTIGATOR

Radboud University Medical Center

Locations

RadboudUMC

Nijmegen, , Netherlands

Site Status: RECRUITING

Countries

Netherlands

Central Contacts

Esther Janssen

Role: CONTACT

Phone: +31651758279

Email: esther.janssen@radboudumc.nl

Facility Contacts

Esther Janssen

Role: primary

References

Janssen E, de Jong JJA, Verburgt E, Ter Telgte A, van den Berg DTNA, Marques JP, Maas MC, Meijer FJA, Tuladhar A, Riksen NP, Deinum J, Backes WH, de Leeuw FE. Higher Blood-Brain Barrier Permeability in Middle-Aged Adults With Hypertension. Hypertension. 2025 Oct 15. doi: 10.1161/HYPERTENSIONAHA.125.25290. Online ahead of print.

Reference Type: DERIVED

PMID: 41091964 (View on PubMed)

Other Identifiers

NL75003.091.20

Identifier Type: -

Identifier Source: org_study_id