Evaluation of Microvascular Rarefaction in Vascular Cognitive Impairment and Heart Failure (CRUCIAL): Study Protocol for an Observational Study

Abstract

Introduction: Microvascular rarefaction, the functional reduction in perfused microvessels and structural reduction of microvascular density, seems to be an important mechanism in the pathophysiology of small blood vessel-related disorders including vascular cognitive impairment (VCI) due to cerebral small vessel disease and heart failure with preserved ejection fraction (HFpEF). Both diseases share common risk factors including hypertension, diabetes mellitus, obesity, and ageing; in turn, these comorbidities are associated with microvascular rarefaction. Our consortium aims to investigate novel non-invasive tools to quantify microvascular health and rarefaction in both organs, as well as surrogate biomarkers for cerebral and/or cardiac rarefaction (via sublingual capillary health, vascular density of the retina, and RNA content of circulating extracellular vesicles), and to determine whether microvascular density relates to disease severity.

Methods: The clinical research program of CRUCIAL consists of four observational cohort studies. We aim to recruit 75 VCI patients, 60 HFpEF patients, 60 patients with severe aortic stenosis (AS) undergoing surgical aortic valve replacement as a pressure overload HFpEF model, and 200 elderly participants with mixed comorbidities to serve as controls. Data collected will include medical history, physical examination, cognitive testing, advanced brain and cardiac MRI, ECG, echocardiography, sublingual capillary health, optical coherence tomography angiography (OCTa), extracellular vesicles RNA analysis, and myocardial remodelling-related serum biomarkers. The AS cohort undergoing surgery will also have myocardial biopsy for histological microvascular assessment.

Discussion: CRUCIAL will examine the pathophysiological role of microvascular rarefaction in VCI and HFpEF using advanced brain and cardiac MRI techniques. Furthermore, we will investigate surrogate biomarkers for non-invasive, faster, easier, and cheaper assessment of microvascular density since these are more likely to be disseminated into widespread clinical practice. If microvascular rarefaction is an early marker of developing small vessel diseases, then measuring rarefaction may allow preclinical diagnosis, with implications for screening, risk stratification, and prevention. Further knowledge of the relevance of microvascular rarefaction and its underlying mechanisms may provide new avenues for research and therapeutic targets.

Keywords: Heart failure with preserved ejection fraction; Microvascular disease; Microvascular rarefaction; Vascular cognitive impairment.

Fig. 1.

CRUCIAL study overview.

Fig. 2.

Example of T1-weighted MR image of the brain and ASL (arterial spin labelling) map displaying cerebral blood flow (CBF) for a vascular cognitive impairment patient.

Fig. 3.

Example of a FLAIR (fluid-attenuated inversion recovery) MR image of the brain displaying white matter hyperintensities and IVIM (intravoxel incoherent motion) maps of parenchymal diffusivity D and the perfusion fraction f for a vascular cognitive impairment patient.

Fig. 4.

Example of CMR stress (top) and rest (bottom) perfusion maps with myocardial blood flow mapping in a participant with severe aortic stenosis with quality assurance outcomes.

Fig. 5.

OCTa images of the multiple layers of the retina in a participant with severe aortic stenosis.

Fig. 6.

Still image of the sublingual blood vessels obtained by the GlycoCheck system.