Pathophysiology, Classification, and MRI Parallels in Microvascular Disease of the Heart and Brain

Abstract

Diagnostic imaging technology in vascular disease has long focused on large vessels and the pathologic processes that impact them. With improved diagnostic techniques, investigators are now able to uncover many underlying mechanisms and prognostic factors for microvascular disease. In the heart and brain, these pathologic entities include coronary microvascular disease and cerebral small vessel disease, both of which have significant impact on patients, causing angina, myocardial infarction, heart failure, stroke and dementia. In the current paper we will discuss parallels in pathophysiology, classification, and diagnostic modalities, with a focus on the role of magnetic resonance imaging in microvascular disease of the heart and brain. Novel approaches for streamlined imaging of the cardiac and central nervous systems including the use of intravascular contrast agents such as ferumoxytol are presented and unmet research gaps in diagnostics are summarized.

Introduction

Small vessel disease of the brain and the heart has far reaching clinical implications, with healthcare costs totaling billions each year.^1–3 Though a lack of consensus in the classification of small vessel disease exists, the pathophysiologic features implicate damage to small end arteries, arterioles, venules and capillaries, resulting in chronic end organ hypoperfusion.⁴ In the brain, hypoperfusion can contribute to cognitive decline, gait disturbance, dementia, and stroke; in the heart, hypoperfusion can result in angina, coronary syndromes, and debilitating heart failure.⁴ Cardiac and cerebral small vessel disease likely represent variations of the same systemic, pathologic process. Despite similarities in pathogenesis, divergent diagnostic and therapeutic approaches currently exist. In the current paper, we will discuss the parallels between cardiac and cerebral small vessel disease and highlight diagnostic magnetic resonance imaging (MRI) techniques. We will additionally summarize unmet needs and propose an alternative strategy for the diagnosis and monitoring of small vessel disease along the brain-cardiac axis.

Small Vessels, Large Problems: Epidemiology and Cost

Small vessel disease in the heart is also known as coronary microvascular disease (CMD) and affects approximately 3–4 million patients in the United States.⁵ Among patients with chronic angina, 10 to 30% do not have significant coronary artery disease (CAD) on invasive angiography;⁶ approximately 60% of these patients may have microvascular disease.⁷ CMD has five distinct clinical scenarios: primary CMD without myocardial disease or obstructive epicardial CAD (Type 1), CMD in the setting of myocardial disease such as hypertrophic cardiomyopathy or hypertensive heart disease (Type 2), CMD in the setting of obstructive epicardial CAD or structural heart disease (Type 3), iatrogenic CMD in the setting of revascularization (Type 4), and CMD after transplantation (Type 5).⁸ Even in the absence of obstructive epicardial CAD, patients with CMD have increased risk of major adverse cardiovascular events (MACE)⁹ and the projected lifetime cost among women with nonobstructive CAD is $767,288.² Because a key diagnostic criterion of CMD has inconsistent threshold variations across age, gender, and modality used,⁹ there is an underappreciation of the true epidemiologic and economic impact of CMD.

Much like the cardiac circulation, the brain is perfused by large, named vessels giving rise to perforating and progressively smaller branches. Although cerebral small vessel disease (CSVD) has debilitating consequences of similar magnitude and acuity as obstructive CAD, despite advances in diagnostic imaging and therapeutic strategies, multiple challenges remain, including a lack of cohesive diagnostic criteria. These challenges are further compounded by a paucity of research into small vessel strokes.¹⁰ Overall, stroke is a $34 billion problem annually, and CSVD is viewed as the primary cause of lacunar strokes, comprising approximately 25% of all strokes.^1,11 Moreover, CSVD is believed to contribute significantly to the development of vascular dementia, which comprises ~20% of all types of dementia.³ The overall estimated cost for all types of dementia vary between $157 and $215 billion annually.

Mechanistic Underpinnings: Shared Signaling

A number of biochemical and histologic changes occur in the vessels of patients with CMD and CSVD, though the sequence of events leading to clinical pathology remains unclear.^8,12 A summary of potential mechanistic pathways is shown Figure 1. Histologically, the diseases share alterations in vascular smooth muscle cells, with hypertrophy present in CMD and loss of smooth muscle in CSVD. Both also have increased collagen deposition in vessel walls, which, together with alterations in smooth muscle, leads to vessel wall thickening. Some have also implicated arteriolosclerosis in the impaired ability of small vessels to modulate blood flow, resulting in downstream, sub-clinical ischemia.¹²

Figure 1:

Mirrored Mechanisms for Coronary Microvascular and Cerebral Small Vessel Disease.

Of the various mechanisms, endothelial dysfunction seems particularly crucial to both CMD and CSVD. The endothelium plays a pivotal role in regulating vascular blood flow via complex autoregulatory processes,¹³ mediating smooth muscle relaxation and constriction within the microcirculation through molecules such as nitric oxide (NO), prostacyclins, thromboxane A1, and endothelin-1 (ET-1).¹³ Impairment in the ability to modulate the balance between constriction and relaxation may tip the scales in favor of vasoconstriction, ultimately resulting in downstream ischemia and tissue damage. Although the precise mechanism for this shift toward vasoconstriction remains unclear, levels of ET-1 are often elevated among patients with ischemia and no obstructive coronary artery disease (INOCA).¹⁴ In the canine heart, infusion of ET-1 produces resting myocardial perfusion defects in the absence of flow limiting stenoses, similar to those seen in INOCA.¹⁵ In the rat brain, stereotactic ET-1 injection results in white matter infarctions, again highlighting the capability of ET-1 to cause perfusion abnormalities.¹⁶ Showcasing the diffuse nature of small vessel disease is the observation of increased peripheral small artery contractility to ET-1 from gluteal biopsy samples in patients with microvascular angina.¹⁷ The fact that this molecule induces perfusion abnormalities systemically points to a potential shared physiologic underpinning reliant on ET-1 for disease progression.

In addition to ET-1, low levels of NO may also play a key role in the pathogenesis of small vessel disease. Several properties of NO may inhibit the development of small vessel disease, including anti-platelet, anti-smooth muscle cell, and anti-inflammatory features. Among patients with cardiac syndrome X, an older term that encompasses CMD, significantly lower levels of NO have been observed when compared to healthy controls.¹⁸ While ET-1 infusion has been shown to produce perfusion abnormalities, infusion of L-arginine, a precursor to NO, reversed microvascular dysfunction during acetylcholine challenge in patients with CMD.¹⁹ In the brain, distinct haplotypes of endothelial nitric oxide synthase have been identified as protective against the development of CSVD,²⁰ further supporting this hypothesis.

Diagnosing Small Vessel Disease: Cardiac Imaging Standards and Challenges

Clinical diagnosis of CMD requires symptoms and objective evidence of ischemia, absence of obstructive epicardial CAD, and evidence of impaired coronary microvascular function. Measures of coronary microvascular dysfunction include impaired coronary flow reserve (CFR), the presence of coronary microvascular spasm during acetylcholine testing, abnormal coronary index of microvascular resistance (IMR), or evidence of slow flow in the coronaries. Assessment of coronary microvascular spasm during acetylcholine challenge (coronary reactivity testing), IMR, and evidence of slow flow require invasive testing, creating additional barriers to diagnosis. CFR has long been a useful method for demonstrating impaired coronary microvascular function and is calculated by dividing myocardial blood flow (MBF) during maximum stress by MBF during rest. Typically, MBF can be augmented to a value approximately three times higher during stress when compared to rest.²¹ A CFR value between 2.0 and 2.5 is typically accepted as abnormal, depending upon the modality.²²

Because the coronary microcirculation is smaller than the resolution attainable by coronary angiography, alternative non-invasive surrogates for the diagnosis of CMD have been proposed, including cardiac magnetic resonance (CMR) imaging, contrast echocardiography (CE) and positron emission tomography (PET). Each modality offers the ability to obtain MBF values at rest and stress, providing a means to evaluate perfusion. Calculation of MBF values using CE requires gas filled microbubbles at a steady state concentration in the circulation. The inherent instability of these microbubbles when exposed to high intensity acoustic signals allows for determination of myocardial blood volume (MBV) and MBF by modeling the time it takes for replenishment of microbubbles after sonographic destruction to occur, as first shown by Wei et al. in canines.²³ Similar ultrasound-based techniques were subsequently applied to the diagnosis of angiographically significant CAD; adenosine stress perfusion with harmonic power Doppler agreed with single-photon emission computed tomography in 81% (83/103 cases) of cases (κ=0.57).²⁴ CE was also validated against PET to obtain fully quantitative MBF values in humans.²⁵ Though CE has shown promising ability to obtain clinically important values, it is hindered by a reliance on operator skill in maintaining an image plane during microbubble replenishment.²⁶

Cardiac PET is one of the most established and well-studied modalities for quantifying myocardial perfusion. PET can measure CFR and absolute MBF,²⁷ with multiple isotopes,^28,29 and has been validated against microspheres. Decreased CFR values by PET have been found to correlate with increased rates of MACE among patients without CAD (Hazard ratio [HR] 2.25; 95% CI 1.31–3.85; p=0.003),³⁰ and have been used to classify patients with CMD in a large population study examining the gender specific prevalence of CMD;³¹ this study also reinforced the importance of impaired CFR on MACE (HR 0.80, 95% CI 0.75–0.86 per 10% increase in CFR; p<0.0001). Though cardiac PET has been used in large studies for the noninvasive diagnosis of CMD, widespread clinical adoption has been slowed by cost, cyclotron proximity requirements, and concerns regarding radiation doses.

CMR offers several advantages over cardiac PET including the absence of radiation, substantially lower cost, wider availability, and higher resolution.⁸ The ability of stress perfusion CMR to accurately calculate myocardial perfusion reserve indices (MPRI), a surrogate for CFR, was established over 20 years ago, and validated against microsphere flow measurements.³² MPRI is based on first-pass perfusion, obtained from infusion of gadolinium based contrast agents, and was first used to diagnose abnormalities attributable to obstructive epicardial CAD.³³ Recent developments in stress perfusion CMR have enabled absolute blood flow quantification³⁴ and fully-automated MBF pixelwise maps³⁵ with automatic inline perfusion curves³⁶; the latter enables more pragmatic uptake by the clinical community for routine use.

Most recently, there has been rising interest in using perfusion CMR to replace invasive pressure measurements in order to facilitate more widespread diagnosis of CMD. Table 1 summarizes recent clinical CMR investigations in CMD. The overall findings from these studies support the ability of CMR to elicit MPRI thresholds that correlate with invasive measures of CMD including CFR, coronary reactivity testing, and IMR (the invasive reference for CMD diagnosis). As part of the Women’s Ischemia Syndrome Evaluation (WISE) study, 139 patients with INOCA underwent invasive coronary vasoreactivity testing with acetylcholine and subsequent stress first-pass perfusion CMR. When compared to invasive coronary vasoreactivity testing, a CMR-derived MPRI of 1.84 had a sensitivity of 73% and specificity of 74% for diagnosis of CMD.³⁷ This effort was one of the first and largest multicenter attempts at linking non-invasively derived CMR perfusion measures to invasive measures of microvascular dysfunction. Building on these findings, stress perfusion CMR indices were validated against IMR.^38,39 Liu et al. performed gadolinium-enhanced first-pass perfusion CMR and invasive coronary testing on 50 patients with angina. Of the 50 patients included in their study, 28 were identified as having obstructive CAD and 22 were diagnosed with nonobstructive CAD. An MPRI value of 1.4 was capable of detecting impaired perfusion caused by CMD (AUC 0.90, sensitivity 89%, specificity 95%, p<0.001), which was validated against an IMR ≥25 among those with fractional flow reserve (FFR) >0.8.³⁸ Using automated pixel-wise perfusion mapping CMR, preliminary work by Kotecha et al³⁹ found in a study of 27 patients that a global stress MBF <1.82 ml/g/min effectively discriminated between obstructive 3-vessel CAD and CMD (AUC 0.94, p <0.001).

Table 1:

Diagnostic Perfusion Cardiac Magnetic Resonance (CMR) Imaging Studies in Coronary Microvascular Disease (CMD).

Authors	Patient population (n)	Imaging Characteristics (Field strength, contrast agent, stress agent).	Study Goal	Results
Wilke et al.32 (1997)	Chest pain and without hemodynamically significant coronary artery lesions (8).	1.5T Gadopentetate dimeglumine Adenosine (140ug/kg*min)	Demonstrate ability of CMR to obtain myocardial perfusion reserve index values, validated against ICD coronary flow reserve measurements.	Regional MPRI matched the coronary flow reserve (linear regression slope 1.02 ± 0.09, r=0.80).
Jerosch-Herold et al.113 (1998)	Suspected microvascular disease/syndrome X and no hemodynamically significant lesions on angiogram (9).	1.5T Gadopentetate dimeglumine Adenosine (140ug/kg*min)	Demonstrate ability of CMR obtained MPRI to mirror ICD ultrasound obtained flow reserves.	MPRI obtained via CMR modeling correlate linearly with intracoronary flow reserves obtained via Doppler ultrasound in the LAD (r=0.84).
Wöhrle et al.114 (2006)	Sinus rhythm, typical angina pectoris and angiographic exclusion of CAD (12).	1.5T Gadolinium-DTPA Adenosine (140ug/kg*min)/Acetylcholine	Demonstrate association between MPRI and CMD and serum level markers of inflammation or endothelial activation.	Coronary blood flow reserve obtained via ICD correlated with MPRI on both adenosine and acetylcholine challenges (r=0.75, p=0.033, r=0.65, p=0.022, respectively). Soluble CD40 ligand and tumor necrosis factor-α were associated with decreased MPRI (p<0.001 and p<0.011, respectively).
Lanza et al.115 (2008)	Cardiac syndrome X (defined as history of effort angina, ST depressions during exercise stress test, angiographically normal epicardial arteries) (18), healthy controls (10).	1.5T Gadolinium Dobutamine (40ug/kg*min) (MRI)/Adenosine (140ug/kg*min) (Doppler/coronary flow response (CFR) calculations)	Demonstrate relationship between perfusion defects detected by CMR and impaired coronary microvascular dilatory function.	Correlation between CFR to adenosine and perfusion defect score identified on CMR in the LAD territory (r= −0.45, p=0.019). Cardiac syndrome X patients with dobutamine induced CMR perfusion defects had lower CFR than those without (1.69 ± 0.5 vs. 2.31 ± 0.6, respectively, p=0.01).
Yilmaz et al.116 (2010)	Unstable angina pectoris and exclusion of significant CAD (42).	1.5T Gadolinium Adenosine (140ug/kg*min)	To evaluate whether myocardial perfusion CMR in patients with angina and without CAD is related to epicardial or microvascular dysfunction.	91% of patients with a reversible stress induced perfusion defect on CMR had a pathological microvascular reaction during intracoronary Ach testing, compared to 50% without a defect (p<0.01).
Thomson et al.37 (2015)	Women with signs/symptoms of ischemia and no obstructive coronary disease (118), asymptomatic control (21).	1.5T Gadolinium Adenosine (140ug/kg*min)	To evaluate whether noninvasive stress imaging with cardiac CMR is able to detect CMD in the study population.	MPRI threshold of 1.84 is capable of predicting abnormal CRT (sensitivity 73%, specificity 74%). Lower MPRI was predictive of abnormalities among CRT variables (OR 0.78, 95% CI 0.70–0.88).
Ahn et al.117 (2016)	Severe aortic stenosis, angina, and normal epicardial coronary arteries (117, 20 normal control).	1.5T Gadobutrol Adenosine (140ug/kg*min)	To evaluate whether microvascular dysfunction is responsible for angina in severe aortic stenosis patients with normal coronary arteries via cardiac stress CMR.	MPRI values were lowest in severe aortic stenosis patients with angina when compared to severe aortic stenosis patients without angina (0.74 ± 0.25; 1.08 ± 0.28, respectively. p<0.001).
Liu et al.38 (2018)	Angina (28 with obstructive CAD, 22 with nonobstructive coronary artery disease).	1.5T and 3T Gadolinium Adenosine (140ug/kg*min)	To evaluate CMR as a modality for the diagnosis of CMD in patients without obstructive coronary disease, determine whether CMR measures can correlate with the index of microcirculatory index.	An MPRI of 1.4 was able to detect impaired perfusion related to CMD (IMR≥25; FFR>0.8, with specificity of 95% and sensitivity of 89%; p<0.001; AUC: 0.90).
Liu et al.76 (2018)	Angina (60), and healthy controls (30).	1.5T and 3T No contrast Adenosine (140ug/kg*min)	Validation of stress T1 mapping against invasive measures of obstructive coronary disease and coronary microvascular dysfunction.	A ΔT1 of 1.5% could detect obstructive CAD (sensitivity 93%, specificity 95%, p<0.001), while a ΔT1 of 4.0 was able to detect CMD (sensitivity 94%, specificity 94%, p<0.001).
Shaw et al.118 (2018)	Female patients with ischemia and no obstructive CAD (22), reference controls (12).	1.5T No contrast No stress protocol.	Determine whether native T1 values in INOCA patients are associated with reduced MPRI.	Native T1 was significantly elevated in INOCA patients when compared to controls (1040.1±29.3ms vs 1003.8±18.5ms, p<0.001). Increased T1 had a significant inverse correlation with MPRI (r=−0.481, p=0.004).

CAD, coronary artery disease; CFR, coronary flow reserve; CMD, coronary microvascular disease CMR, cardiac magnetic resonance; CRT, coronary reactivity testing; ICD, intracoronary Doppler; INOCA, ischemia and no obstructive coronary artery disease; MPRI, myocardial perfusion reserve index

To further establish a relationship between quantitative CMR-derived MBF and invasive coronary measurements for the diagnosis of CMD, investigators in the United Kingdom have designed the Coronary Microvascular Angina Cardiac Magnetic Resonance Imaging (CorCMR)⁴⁰ sub-study of the Stratified Medical Therapy Using Invasive Coronary Function Testing in Angina (CorMicA, ClinicalTrials.gov NCT03193294) parent trial. The CorCMR sub-study seeks to compare invasive data from the CorMicA study with CMR-derived MBF data among patients with angina and no obstructive CAD.⁴⁰ To date, the CorMicA trial has shown improved angina and quality of life scores among CMD patients who underwent medical management based upon invasive coronary measurements, highlighting the important unmet need for accurate, noninvasive imaging surrogates.⁴¹ Although early findings are promising, correlations among quantitative non-invasive imaging surrogates, IMR, and coronary vasoreactivity testing, in larger, multicenter, CMD patient cohorts will be crucial for further development of noninvasive imaging standards.

Diagnosing Small Vessel Disease: Neurologic Imaging Standards and Challenges

As in the cardiac circulation, PET provided an early means to obtain relevant information relating to perfusion in the form of cerebral oxygen extraction fraction (OEF), cerebral metabolic rate of oxygen (CMRO₂), cerebral blood volume (CBV) and cerebral blood flow (CBF) via inhalation and injection-based ¹⁵O PET studies.⁴² Adding to the utility of this modality is the finding that inter-individual variation among these values is typically within 20%, even across multiple centers, allowing for potential development of a normalized cerebral hemodynamic values database.⁴³ There is a large body of literature relating to the utility of ¹⁵O PET in the cerebral circulation that is beyond the scope of this review. We refer the reader to the excellent review⁴⁴ by Ito et al. for further information.

Diagnostic challenges to accurately characterize CSVD parallel difficulties faced in CMD. The changes seen on neurologic imaging associated with CSVD are numerous and varied, including subcortical and deep gray or white matter lacunar infarcts, white and deep gray matter T2 hyperintensities, microbleeds, diffuse volume loss, and enlarged perivascular spaces.¹² Compounding the diagnostic challenges in CSVD is the non-specific nature of some imaging findings, which can manifest as a result of other biological processes,⁴⁵ as well as inconsistencies in image acquisition protocols, interpretation, and reporting.

To reduce wide variation in terminology used for defining the imaging characteristics of CSVD, investigators from an international working group established the Standards for Reporting Vascular Changes On Neuroimaging (STRIVE). They cited a lack of consistency in terminology and definitions as a barrier to research and recommended that the following common classifications be used to describe features on neuroimaging:¹⁰ recent small subcortical infarct, lacune of presumed vascular origin, white matter hyperintensity of presumed vascular origin, perivascular space, cerebral microbleed, and brain atrophy. Representative examples of these findings are shown in Figure 2, with additional examples from clinical cases shown in Figure 3. The STRIVE position statement recommended ‘minimum essential sequences’ for diagnosis of CSVD in clinical or epidemiological studies, which included T1- and T2-weighted sequences, diffusion weighted imaging (DWI), T2-weighted FLuid-Attenuated Inversion Recovery (T2-FLAIR) sequence, and T2*-weighted gradient echo (GRE) sequences.¹⁰ In many recent studies (Table 2), the total MRI burden of CSVD is estimated using an ordinal scale from 0–4, with 1 point provided for the presence of lacune, white matter hyperintensities, cerebral microbleeds and enlarged perivascular spaces, respectively. This has resulted in a streamlined way to quantify the severity of CSVD in routine MRI reporting. The scale’s simplicity has allowed for wider application to a spectrum of disease processes, with clinically impactful findings that correlate total CSVD burden such as dementia⁴⁶ and post-stroke cognitive decline,⁴⁷ as well as unexpected mechanisms and conditions such as subclinical hypothyroidism, decreased 25-hydroxyvitamin D levels, and post-stroke depression.

Figure 2:

Representative magnetic resonance imaging (MRI) examples used for characterizing the spectrum of cerebral small vessel disease (CSVD) and expected findings on various MRI pulse sequences. MRI characteristics for a spectrum of CSVD. MRI features related to small vessel disease are shown in the sample image and as a schematic representation. Characteristics of each CSVD subset and their signal behavior on commonly used MRI pulse sequences are shown in the lower portion of the figure. Reprinted from The Lancet Neurology, Vol. 12, Wardlaw et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration, Pages No 822–838., Copyright (2013), with permission from Elsevier.

Figure 3:

Representative images of cerebral small vessel disease (CSVD) from a 73-year-old male with hypertension who presented to the emergency department with acute left upper extremity weakness secondary to a focal, acute, lacunar infarct (A-E) and an 86 year old male demonstrating diffuse cerebral volume loss (F). Axial Diffusion Weighted Image (DWI) (A), Apparent Diffusion Coefficient (ADC) map (B), T2 (C), T2-FLAIR (Fluid Attenuated Inversion Recovery) (D) and Gradient Echo (GRE) (E) images of the brain demonstrate a focal acute lacunar infarct in the right corona radiata region corresponding to T2 prolongation and T2-FLAIR hyper-intensity, explaining his clinical symptoms. GRE images (E) demonstrate multiple microbleeds in the region of basal ganglia and thalami most compatible with hypertensive vasculopathy and severe CSVD. Additional findings of CSVD, including periventricular and deep white matter T2-FLAIR hyperintensities (D), enlarged Virchow-Robin spaces, and cerebral volume loss are also evident in this patient. These findings can be seen in (F), and are also known as the ‘swiss cheese striatum’ or ‘état criblé’.

Table 2:

Association of Total MRI Burden of Cerebral Small Vessel Disease (CSVD) with Clinical Parameters.

Authors	Population (n)	Imaging Characteristics on MRI*	Association Studied	Findings
Klarenbeek et al119 (2013)	First ever lacunar stroke (122)	Asymptomatic lacunar infarcts, white matter lesions, cerebral microbleeds, enlarged perivascular spaces	Ambulatory blood pressure with burden of CSVD.	Increasing 24 hour systolic (OR 1.25; 95% CI 1.02–1.52 per 10mm Hg) and diastolic blood pressure (OR 1.32 95% CI 1.12–1.56 per 5mm Hg) were associated with increased total CSVD burden.
Huijts et al120 (2013)	Patients at risk for CSVD (112 hypertensive and 77 first ever lacunar stroke).	Asymptomatic lacunar infarcts, white matter lesions, brain microbleeds, enlarged perivascular spaces	Overall cognitive function with burden of CSVD.	With increasing MRI burden of CSVD, information processing speed and overall cognition decrease (r=−0.181, p=0.013 and r=−0.178, p=0.017 respectively).
Xiao et al121 (2015)	First ever lacunar stroke (413)	Asymptomatic lacunar infarcts, white matter lesions, cerebral microbleeds, enlarged perivascular spaces	Markers of chronic kidney disease with burden of CSVD.	Proteinuria and low estimated GFR were associated with total CSVD burden (OR=2.13; 95% CI 1.10–4.14 and OR= 5.59 95% CI 2.58–12.08, respectively).
Yang et al122 (2017)	First ever lacunar stroke (210)	Asymptomatic lacunar infarcts, white matter lesions, cerebral microbleeds, enlarged perivascular spaces	Levels of serum cystatin C with burden of CSVD.	Elevated levels of cystatin C, impaired eGFR and presence of proteinuria all correlated with total MRI burden of CSVD (OR 2.633 95% CI 1.284–5.403; OR 2.442, 95% CI 1.213–4.918; and OR 2.151, 95% CI 1.162–3.983, respectively).
Zhang et al123 (2017)	First ever lacunar stroke (374)	Asymptomatic lacunar infarcts, white matter lesions, cerebral microbleeds, enlarged perivascular spaces	Post-stroke depression and burden of CSVD.	Higher total MRI CSVD burden was an independent predictor for post-stroke depression (OR 4.577, 95% CI 2.400–8.728 among patients with 3–4 potential CSVD markers).
Song et al124 (2017)	Acute ischemic stroke (1096)	Cerebral microbleeds, high grade white matter hyperintensities, high grade perivascular spaces, and asymptomatic lacunar infarctions	Long-term outcomes (death, ischemic stroke, hemorrhagic stroke, fatal cardiovascular events) and burden of CSVD	Total CSVD score associated with death (HR 1.18 per point, 95% CI 1.07–1.30), ischemic stroke (HR 1.20 per point, 95% CI 1.01–1.42), and hemorrhagic stroke (HR 2.05 per point, 95% CI 1.30–3.22) but not fatal cardiovascular events (HR 1.17, 95% CI 0.82–1.67).
Zhang et al125 (2017)	Patients with minor stroke/TIA and diagnosis of subclinical hypothyroidism (43).	Silent lacunar infarcts, white matter lesions, cerebral microbleeds and enlarged perivascular spaces	Presence of subclinical hypothyroidism and CSVD burden.	Subclinical hypothyroidism was associated with increasing total burden of CSVD on MRI (OR 1.905, 95% CI 1.019–3.597).
Li et al.126 (2018)	First ever acute ischemic stroke or transient ischemic attack. (278)	Asymptomatic lacunar infarcts, white matter lesions, cerebral microbleeds, enlarged perivascular spaces	Procalcitonin levels and CSVD burden.	Patients with procalcitonin levels in the top quartile (compared to lowest quartile) were more likely to have increased total MRI CSVD burden (OR 3.743, 95% CI 1.998–7.008).
Li et al106 (2018)	Consecutive patients referred for neurology evaluation, excluding history of symptomatic stroke, carotid stenosis>50%, or brain tumor. (99)	Asymptomatic lacunar infarcts, white matter lesions, cerebral microbleeds, enlarged perivascular spaces	Compromised Blood-Brain Barrier Integrity and CSVD burden	Blood-brain barrier leakage rate was positively associated with total MRI CSVD burden in normal appearing white matter, white matter hyperintensities, cortical gray matter, and deep gray matter (p<0.01).
Feng et al.127 (2019)	First-ever minor ischemic stroke or transient ischemic attack (234).	Silent lacunar infarcts, white matter lesions, cerebral microbleeds and enlarged perivascular spaces	25-hydroxyvitamin D levels and CSVD burden.	Patients with first quartile levels of 25-hydroxyvitamin D, when compared to fourth quartile patients, were more likely to have increasing total MRI CSVD burden (OR 3.00, 95% CI 1.36–6.53).
Jiang et al.128 (2019)	Patients with single, small subcortical strokes. (160).	Lacunes, white matter hyperintensities, cerebral microbleeds and enlarged perivascular spaces	Progression of neurological deterioration following single, small subcortical stroke and CSVD burden.	Total CSVD score was associated with progression (defined as worsening by ≥1 point on the National Institutes of Health Stroke Scale motor score within 72 hours of stroke onset) of neurological deterioration (OR 3.359, 95% CI 2.016–5.599).
Lu et al.129 (2019)	Patients with ischemic stroke of suspected small or large artery origin. (221).	Lacunar infarction, white matter hyperintensities, cerebral microbleeds, and enlarged perivascular spaces	Relationship between extracranial artery stenosis and CSVD burden.	Increasingly severe extracranial artery stenosis was more common with increasing CSVD score (OR 1.76, 95% CI 1.16–2.69).

^*Imaging characteristics on MRI are quantified to generate a total CSVD burden, where one point is given per category of imaging characteristic

CI, confidence interval; CSVD, cerebral small vessel disease; eGFR, estimated glomerular filtration rate GFR, glomerular filtration rate; HR, hazard ratio; MRI, magnetic resonance imaging; OR, odds ratio; TIA, transient ischemic attack

One MRI technique in CSVD research that merits discussion is diffusion tensor imaging (DTI). As an imaging biomarker for tissue integrity and architecture, DTI measures both the magnitude and direction of water diffusivity within a tissue of interest. Scalar measures often derived from the diffusion tensor include: 1) mean diffusivity (MD), which reflects the average diffusivity in all directions; 2) fractional anisotropy (FA), which is a measure of the directional coherence of water; 3) axial diffusivity (λ_‖), a scalar index representing the component of water diffusion parallel to the axonal tract; and 4) radial diffusivity (λ_⊥), the component of the scalar index perpendicular to the axonal tract.⁴⁸ Although white matter damage is not specific to CSVD, changes in white matter structural integrity result in alterations of the aforementioned scalar parameters, which may serve as early surrogates for physiologic impairment before symptomatic clinical consequences are manifested. DTI has been used to identify areas that are prone to white matter hyperintensity development⁴⁹ and was able to predict eventual development of dementia among a cohort of patients with CSVD.⁵⁰ Alterations in axial diffusivity and radial diffusivity were first linked to axonal damage and demyelination, respectively, in a mouse model of retinal ischemia.⁵¹ More recent work however, has demonstrated a correlation between changes in radial diffusivity and impaired cognition among patients with CSVD.⁵² Thus, DTI, via generation of the above parameters, represents a promising non-invasive means of assessing tissue architecture and integrity; we refer the reader to existing publications for detailed descriptions on axial and radial diffusivity.⁴⁸ These early imaging surrogates are of substantial clinical relevance because interventions such as exercise therapy have been shown to reduce progression of vascular dementia.⁵³

Results from two studies call attention to the impact of CSVD on morbidity and mortality, and the key role of MRI in illuminating these relationships. One large study investigating outcomes and associations among patients with CSVD, the Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Imaging Cohort (RUN-DMC) has found that imaging changes of CSVD were associated with an increased 8-year risk of mortality. Of note, change in magnetic resonance diffusion imaging was the characteristic noted to be most closely linked with risk of mortality.⁵⁴ Additionally, in the Second Manifestations of ARTerial disease-Magnetic Resonance (SMART-MR) study, CSVD was found to increase the risk of both death and ischemic stroke in patients with atherosclerotic disease, regardless of prior history of cerebrovascular disease.⁵⁵

Shared Diagnostic Dilemma

At its core, small vessel disease is characterized by perturbations in supply and demand of oxygen delivery to tissue. The microscopic nature of this disease has resulted in a number of similar research gaps across organ systems, summarized in Table 3. Particularly relevant to our discussion are the suboptimal noninvasive imaging modalities currently available to synchronously map both disease processes before clinical signs or symptoms occur. Given the limited spatial resolution for clinical depiction of the microvasculature, functional imaging may offer the best means of reliably diagnosing these abnormalities in their earliest stage. In particular, a promising contrast agent, ferumoxytol, combined with relaxation rate mapping sequences, may offer unique steady-state applications for both cardiac and neurologic imaging of small vessel disease.

Table 3:

Current Research Gaps in Cardiac and Neurologic Small Vessel Disease.

Cardiac small vessel disease

Lack of well-matched animal model of disease. Lack of large studies evaluating outcomes and prognosis. Suboptimal noninvasive imaging modalities for identification of disease. Poor understanding of genetic and comorbid risk factors. Lack of data assessing treatment and disease modifying therapy.

Cerebral small vessel disease

Lack of well-matched animal model of disease. Inability to separate imaging findings indicative of aging and other forms of dementia with disease process changes. Incomplete understanding of risk factors and their impact on disease. Lack of large, prognostic studies. Lack of noninvasive, functional imaging modality to identify disease progression and guide treatment before end stage. Lack of therapeutic options.

Myocardial and Cerebral Blood Volume

The MBV represents the fractional blood volume of the intravascular space (including arterioles, venules and capillaries) within the unit volume of myocardium. Both MBF and MBV are tightly controlled by dynamic autoregulation of the epicardial and intramyocardial coronary vasculature.^26,56 Within a wide range of coronary perfusion pressures, autoregulatory mechanisms, through vasodilation of arterioles and capillary recruitment, maintain rest perfusion. At high levels of O₂ demand, the MBV expands.²⁶ Due to this adaption, severely ischemic myocardium has a blunted MBV response at peak stress compared to healthy myocardium. This is because at rest, a portion of the MBV reserve has been recruited; with additional excess O₂ demand, there is less “reserve” or ability to “expand.”⁵⁷ As MBV has been found to have a predictable relationship to perfusion, using MBV as a means to quantify perfusion has a strong scientific basis because increases in MBV may correlate more closely with increased oxygen demand than MBF.⁵⁸

The brain also relies on the close coupling between CBV, CBF, and capacitance vessel diameter changes, with the added complexity of a fixed intracranial volume.⁵⁹ As in the cardiac circulation, CBF is maintained within a relatively constant and narrow window to ensure adequate brain perfusion, even while wide variations in blood pressure may be occurring. Physiologic manipulation of the PaO₂ and PaCO₂ within the circulation can cause alterations in CBF that are otherwise difficult to induce. Measuring CBV proves particularly useful in the cerebral circulation for similar reasons as in the cardiac circulation. In rhesus monkeys, regional CBV has been found to increase linearly as mean arterial pressure decreases, highlighting CBV’s role in maintaining constant CBF despite systemic hemodynamic perturbations.⁶⁰ Imaging techniques capable of identifying increased CBV may prove helpful in conditions where chronic hypoperfusion is present, such as CSVD, potentially allowing for early detection of perfusion abnormalities. It is important to note that the relationship of CBV and CBF is relatively complicated. CBV increases to maintain CBF in the setting of “compensated” decreased mean arterial pressure. If mean arterial pressure is decreased substantially, both CBV and CBF eventually decrease, leading to decompensation and eventual infarct.^61,62 One parameter in dynamic-susceptibility contrast-enhanced MRI that require additional study in CSVD is the time to peak (TTP), which reflects the time required for a contrast bolus to achieve maximum concentration after arrival at the tissue of interest. TTP has been used predominantly in acute, large vessel stroke to assess perfusion-diffusion mismatch.⁶³ In a canine model of acute stroke, Harris et al. found that decreases in CBF and increases in TTP did not always occur at coincident time points, as would be expected.⁶⁴ The authors theorized that this time variance may reflect both recruitment and subsequent loss of adequate collateral blood flow. In a small study involving 50 patients with CSVD, increased TTP has also been linked with white matter hyperintensity burden; however, a subgroup of patients had alterations in TTP parameters, but did not have significant white matter burden. These findings raise the possibility of using TTP prolongation for earlier detection of CSVD.⁶⁵

Why T1?

T1, or longitudinal relaxation time, is an MRI parameter representing the time constant associated with relaxation of bulk magnetization along the z-axis toward equilibrium following radiofrequency excitation. As an imaging parameter, T1 is significantly impacted by changes in mobile water within tissues.⁶⁶ Application of a cardiac stressor has shown strong ability to induce changes in MBV, resulting in up to 60% increases in canines.⁶⁷ CBV, much like MBV, is capable of large increases when stressed or activated: capillary CBV alone can increase by almost 20% during functional stimulation in rodents.⁶⁸ The increase in MBV and CBV by a stressor supports the potential use of a T1 technique. Stress-induced increases in blood volume are theorized to result in a direct change in measured T1 within different tissues. Regions supplied by vessels with microvascular disease would have less robust or lower vasoreactivity, reflected by T1 measurements, as they would be unable to match the blood volume delivered by healthy circulation. Comparing a map of myocardial or cerebral T1 values obtained before and after the application of a stressor allows quantification of vasoreactivity response related to inducible blood volume changes. An example of T1 stress mapping is shown in Figure 4. In regions of capillary loss or microvascular pruning, it is conceivable that abnormal T1 may be detectable at rest and have minimal to no response with a stressor. Beyond T1, T2 or T2* quantification may be another means of assessing ischemia, via its ability to detect changes in the concentration of deoxygenated hemoglobin. This property has already been applied to acute stroke, which showed decreased T2* among areas of hypoperfusion, likely secondary to higher levels of deoxygenated hemoglobin.⁶⁹

Figure 4:

Native (non-contrast) and ferumoxytol-enhanced myocardial T1 maps (3.0T, MOLLI) from a male patient with end-stage renal disease on dialysis, diabetes, and non-obstructive coronary artery disease on cardiac catheterization. Native myocardial T1 maps of the left ventricular short-axis are shown in the upper panel and ferumoxytol-enhanced T1 maps at rest and peak adenosine-stress (140mcg/kg/min, 4 minute infusion) are shown in the middle and lower panels, respectively. Because ferumoxytol is a true intravascular MR contrast agent, the difference in myocardial T1 before and after administration of ferumoxytol relates to the fractional blood volume in the voxel of interest. On average, ferumoxytol shortened the myocardial T1 by 45–46% at baseline. The FE T1 reactivity, defined as the percent difference between myocardial T1 at rest and peak vasodilator stress is blunted (septum= −1.7%, lateral wall= −1.5%).

T1 Stress Mapping: Demonstrated Clinical Utility in CMD

Recent work using native T1 stress mapping demonstrated utility among patients with aortic stenosis and those with epicardial CAD⁷⁰ as well as the effect of adenosine vasodilation on myocardial T1, T2, MBV, and extracellular volume measurements during normal physiology.⁷¹ However, given the ability of T1 mapping to detect alterations in MBV, it may allow for the earlier detection and treatment of patients with CMD. Several myocardial T1 mapping sequences exist⁷² including the Modified Look-Locker Inversion Recovery (MOLLI), Shortened Modified Look-Locker Inversion recovery (ShMOLLI), and Saturation recovery Single-shot acquisition-(SASHA).

The potential diagnostic use of stress native (non-contrast) T1 mapping for CMD has been reported among patients with known pathologic contributors to CMD. Levelt et al. evaluated native (non-contrast) T1 reactivity among patients with type 2 diabetes mellitus (T2DM) without obstructive CAD.⁷³ T1 reactivity was defined as the percent difference in myocardial T1 between peak stress and rest. In their study, patients with T2DM and no significant CAD were compared to matched, healthy controls. Stress T1 mapping results were obtained, as were first-pass perfusion and late gadolinium enhanced images. While both diabetic patients and healthy controls demonstrated adenosine-induced T1 reactivity, the response in patients with T2DM was blunted (ΔT1= 4.1 ± 2.9% in T2DM, ΔT1= 6.6 ± 2.9% in controls, p=0.007; ShMOLLI sequence performed at 3.0T). Of note, MPRI was also found to be significantly reduced in T2DM patients when compared to controls (T2DM MPRI, 1.60 ± 0.44, control MPRI 2.01 ± 0.42, p=0.008). The authors attributed the blunted response to CMD in patients with T2DM, highlighting the potential of stress native T1 mapping as a non-invasive diagnostic modality. However, the dynamic range in native T1 mapping is narrow and differences between diseased and normal tissue are relatively small, albeit statistically significant. In addition to diabetes, cardiovascular disease in patients with chronic kidney disease (CKD) can result in significant morbidity and mortality. Moreover, the use of gadolinium-based contrast agents is not desirable in CKD patients,⁷⁴ making traditional perfusion MR imaging techniques more challenging. Shah et al. applied stress T1 mapping to a cohort of 20 CKD patients, some of whom also had CAD.⁷⁵ Native stress T1 mapping was able to differentiate between remote, ischemic and infarcted myocardium, with ΔT1 values of 4.7 ± 4.5%, 1.0 ± 4.1% and −1.1 ± 6.1%, respectively. Notably, these studies did not have invasive reference measures of IMR or FFR for validation. Liu et al. however, sought to validate stress native T1 mapping with invasive coronary measurements in 90 patients, and defined CMD as having an FFR≥0.8 and index of microcirculatory resistance (IMR) ≥25U).⁷⁶ They showed that a ΔT1 cutoff of 1.5% performed well in delineating between obstructive and non-obstructive CAD (based upon FFR), with an area under the receiver curve of 0.97 ± 0.02 (p<0.001). This method (AUC: 0.97 ± 0.02, p<0.001) was superior to a gadolinium-based first-pass perfusion study when visual (AUC: 0.85 ± 0.04, p<0.001) semi-quantitative (AUC: 0.87 ± 0.04, p<0.001) and even fully quantitative (AUC: 0.91 ± 0.03, p<0.001) analyses were performed. In patients with a FFR ≥ 0.8, T1 reactivity had discriminatory power to accurately depict IMR thresholds (ΔT1 3.0 ± 0.9% vs. 5.0 ± 0.9%, p<0.001 for IMR ≥25 U and IMR <25, respectively). Using a ΔT1 threshold of 4.0% allowed for the generation of an AUC of 0.95 ± 0.03 (p<0.001) for differentiation between patients with or without CMD with FFR ≥ 0.8.

Stressing the Brain

While stress imaging has allowed for easier detection of CMD in the heart, many of the current imaging standards for diagnosis of CSVD rely on identification of macroscopic markers of damage that may reflect end-stage disease.⁷⁷ Attempts to visualize and quantify changes in cerebral flow to stress, or cerebrovascular reactivity (CVR) may enable early identification of CSVD, where interventions could alter downstream outcomes or mitigate progression of disease.

Common means of stress testing the brain include acetazolamide,⁷⁸ and respiratory manipulation to alter PaCO₂.⁷⁹ Acetazolamide dilates the cerebral arteries, mimicking increased cerebral perfusion demand. Gadolinium-enhanced MRI perfusion technique allows for calculation of CBV and CBF pre and post administration of acetazolamide, and enables quantification of CVR. While measurements of CVR are well established with transcranial doppler ultrasound, MRI measures have not been widely applied to CSVD. Early studies using transcranial methods of calculating CVR showed promising results. Molina et al., in a case control series of first ever lacunar stroke, found significantly reduced CVR among patients who developed a lacunar infarction compared to controls (50.0 ± 12.7% vs 65.2 ± 12.4, respectively; p<0.0001).⁸⁰ The authors additionally found that patients who suffered multiple lacunar infarctions had a significantly lower CVR than those who only had one. Additional studies during this time period investigated the utility of CBF alone, and reported decreased flow among vascular dementia patients and the ability to correlate declining neuropsychologic scores with flow values.^81,82 A study using PET to evaluate lacunar stroke patients did not find differences in CVR based upon white matter lesion (WML) severity (48.6 ± 22.6% vs 42.5 ± 17.2; p=0.524 for severe and mild WML severity, respectively). The researchers however, did find statistically significant differences in CBF, OEF, and CMRO₂ between the two groups.⁸³ Based on published reports, flow and reactivity appear to be linked to disease progression or severity, though sonographic measurements suffered from an inability to obtain localized flow data, and reliance on data from a single artery.⁷⁹

To date, MRI CVR studies in CSVD have predominantly relied on blood oxygen level dependent (BOLD) and arterial spin labeling (ASL) MRI. A recent systematic review of MRI based CVR in CSVD identified only five studies, inclusive of 155 CSVD patients addressing this topic.⁷⁹ It was not clear whether CVR in CSVD as assessed by MRI results in meaningful clinical data, as these studies lacked uniform criteria for imaging and administration of vaso-reactive challenge.

Multiple MRI techniques have been used and are being developed to study CSVD. Among these are dynamic susceptibility gadolinium-enhanced MRI perfusion⁷⁸ and permeability⁸⁴, ASL,⁸⁵ vesselness filter-based segmentation of cerebrovascular morphology (vessel density, caliber, tortuosity) on MR angiography,⁸⁶ susceptibility weighted imaging and quantitative susceptibility mapping,⁸⁷ BOLD imaging,⁸⁸ vessel size imaging,⁸⁹ and intravoxel incoherent motion (IVIM).⁹⁰ Vessel size imaging exploits T2 and T2* changes resulting from magnetic susceptibility gradients created by the presence of intravascular contrast agents such as gadolinium or ferumoxytol, to reveal information about diameter, density, distribution, and reactivity of small vessels.⁸⁹ IVIM is of particular interest given its ability to calculate parameters reflective of both diffusion (D or D*, diffusion or pseudodiffusion coefficients, respectively) and perfusion (f, a metric reflecting the percent of a voxel’s volume which is occupied by capillaries). Of particular interest in CSVD are findings of increased f values in the normal appearing white matter of CSVD patients⁹¹ and a demonstrated ability to detect perfusion changes induced via carbon dioxide inhalation;⁹² both reflect a role for IVIM in assessing CVR.

Ferumoxytol, the Heart, and the Brain: Imaging of the Neuro-cardiac Axis

The use of ultra-small superparamagnetic iron oxide (USPIO) contrast agents to improve MRI has been a long-standing area of research. These agents, with half-lives far longer than typical contrast agents, provide a means to image tissue in steady state while improving contrast to noise ratios.⁹³ These molecules were initially used as negative contrast agents due to high T2 relaxivity; however, they were quickly adapted for use in T1 weighted imaging.⁹⁴ These contrast agents also improve image quality and definition when used in both spin and gradient echo pulse sequences.⁹⁵

One particular USPIO that is available clinically is ferumoxytol (Feraheme, AMAG Pharmaceuticals) and has been used off-label by several groups for vascular imaging.^96–99 Ferumoxytol received U.S. FDA approval in 2009 as an iron replacement therapy for adult patients with anemia secondary to CKD; the clinical indication was expanded in 2018 to include iron deficiency anemia refractory to oral iron repletion. Using ferumoxytol as an off-label MR contrast agent avoids any risk of nephrogenic systemic fibrosis⁷⁴ and more importantly, obviates concerns about gadolinium accumulation in brain tissues,¹⁰⁰ which may occur even in the setting of normal renal function.¹⁰¹ Although ferumoxytol carries an FDA black-box warning related to its potential for fatal anaphylaxis based on safety data from therapeutic use, recent multicenter safety registry data in >3000 patients report no severe, life-threatening adverse events with dosing that is modified for diagnostic MRI.¹⁰²

Ferumoxytol has a molecular weight of 750 kDa and a hydrodynamic diameter of ~23 nm, is not cleared by the renal system, and relies on macrophage-driven phagocytosis for clearance from the bloodstream.⁹⁶ These features contribute to a prolonged intravascular half-life of 14–15 hours⁹⁶ enabling unique applications in MRI. A high r1 of 15mM/s at 1.5T permits use of ferumoxytol in bright blood imaging.⁹⁶ As a pure and potent intravascular MRI contrast agent, ferumoxytol can also sensitize the myocardial T1 signal to changes in the MBV and substantially amplify the T1 reactivity. Indeed, a proof-of-concept study has already highlighted the impact that ferumoxytol enhanced stress T1 mapping can have on the amplitude and ranges of ΔT1.¹⁰³ A pre and post contrast ferumoxytol enhanced cardiac image is shown in Figure 4, highlighting its ability to alter T1 values.

For neuroimaging applications, ferumoxytol has enjoyed earlier adoption.¹⁰⁴ A large body of work has focused on ferumoxytol-enhanced MRI of neurologic malignancies, where determination of pseudoprogression, and subsequent treatment decisions for tumors are based on CBV and CBF.¹⁰⁵ Ferumoxytol’s intravascular profile is useful for perfusion imaging because gadolinium agents often extravasate out of the vasculature due to the leaky blood brain barrier that may accompany neurologic malignancies, resulting in under- or overestimation of CBV and CBF. Similar to neurologic malignancies, patients with CSVD may suffer from impaired blood brain barrier function, perhaps contributing to suboptimal studies using gadolinium-enhancement for CBV or CBF quantification.¹⁰⁶ Ferumoxytol has additional advantages for CBV imaging: 1) steady-state ferumoxytol-enhanced CBV maps with high SNR may obviate the need for fast, dynamic imaging,^107,108 and 2) high resolution R2* mapping at high-field magnet strengths may be possible for generation of CBV maps.¹⁰⁹ An example of ferumoxytol enhanced CBV mapping using MRI is shown in Figure 5. In addition, recent work examining USPIO contrast agents in the setting of CSVD has noted measurable changes in relaxation rate,¹¹⁰ which may be clinically useful in the near future. The reader is referred to cited references for detailed description of other techniques.

Figure 5:

Impact of ferumoxytol-enhancement (FE) on relaxometry behavior and cerebral blood volume maps. On the left, pre- and post-FE signal intensity in the cortex and sagittal sinus across a spectrum of echo time (TE) is shown. On the right, gradient echo (GRE, A) and parametric maps (B-F) from a single healthy patient are shown. Because ferumoxytol is a true intravascular MR contrast agent, the ΔR2* map proportionally reflects the CBV and is obtained by subtraction of the pre-FE R2* map (C) from the post-FE R2* map (E). Adapted from NeuroImage, Vol 83, D’Arceuil et al. Ferumoxytol enhanced resting state fMRI and relative cerebral blood volume mapping in normal human brain. Pages 200–209, Copyright (2013), with permission from Elsevier.

The relationship between ferumoxytol concentration and T1 /T2 weighted signal intensity appears to be dose-dependent. On T2-weighted scans, signal loss occurs at high ferumoxytol concentration (≥2.1 mM), while increased signal intensity is achievable with lower concentration of ferumoxytol on T1-weighted scans.¹¹¹ For T1 imaging, a typical dose of 0.07 mM/kg yields a steady-state blood concentration of ~1.16 mM (75 kg person, 4.5 L total blood volume). Although ex vivo data suggest that a ferumoxytol dose of 2.5 mM (~8.4 mg/kg)¹¹¹ optimizes signal to noise at steady-state, this dose is impractical due to cost implications. Thus, combined use of CBV measurements with T1 and T2-weighted imaging may enable unique characterization of tissue pathology. While early work with ferumoxytol-enhanced MRI has been promising for characterization of CSVD,¹¹⁰ more extensive investigations are necessary.

Ferumoxytol enhanced MRI offers the potential for multi-station imaging and has been leveraged by investigators for vascular mapping.^98,112 As evidence accumulates that small vessel disease represents a systemic process rather than multiple separate entities,⁴ ongoing work by these investigators to facilitate imaging of both cardiac and cerebral small vessels may enable new insights into disease mechanisms, pathophysiology, risk factors, and treatment that are not currently available.

Conclusions

Disease of the small vessels in the heart and brain represents a pathology that until recently is underrecognized and under-investigated. This has been, in part, due to the diagnostic difficulties posed by unsatisfactory surrogates of disease within these vessels. While the current imaging standards for CMD and CSVD are not without limitations, recent advances, particularly in the realm of MRI, offer the promise of improved identification of disease. Use of ferumoxytol, in combination with innovative stress mapping sequences that rely on physiologic alterations of fractional blood volume, may enhance our ability to diagnose small vessel disease in both the heart and brain.

List of Abbreviations:

ASL

Arterial spin labeling

BOLD

Blood oxygen level dependent

CMR

Cardiac Magnetic Resonance

CSVD

Cerebral small vessel disease

CBF

Cerebral blood flow

CBV

Cerebral blood volume

CMRO₂

Cerebral metabolic rate of oxygen

CVR

Cerebrovascular reactivity

CKD

Chronic kidney disease

CE

Contrast echocardiography

CAD

Coronary artery disease

CFR

Coronary flow reserve

CorCMR

Coronary Microvascular Angina Cardiac Magnetic Resonance Imaging

CMD

Coronary microvascular disease

DTI

Diffusion tensor imaging

ET-1

Endothelin-1

FLAIR

Fluid-Attenuated Inversion Recovery

FA

Fractional anisotropy

FFR

Fractional flow reserve

GRE

Gradient echo

HR

Hazard ratio

IMR

Index of microvascular resistance

INOCA

Ischemia and no obstructive coronary artery disease

MRI

Magnetic resonance imaging

MACE

Major adverse cardiovascular event

MD

Mean diffusivity

MBF

Myocardial blood flow

MBV

Myocardial blood volume

MPRI

Myocardial perfusion reserve indices

NO

Nitric oxide

OEF

Oxygen extraction fraction

PET

Positron emission tomography

RUN-DMC

Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Imaging Cohort

SMART-MR

Second Manifestations of Arterial disease-Magnetic Resonance

STRIVE

Standards for Reporting Vascular Changes on Neuroimaging

CorMicA

Stratified Medical Therapy Using Invasive Coronary Function Testing in Angina

T2DM

Type 2 diabetes mellitus

USPIO

Ultra-small superparamagnetic iron oxide

WML

White matter lesion

WISE

Women’s Ischemia Syndrome Evaluation