Microvascular arterial disease of the brain and the heart: a shared pathogenesis

Summary

Microvascular arterial disease in the heart manifest as coronary microvascular dysfunction. This condition causes microvascular angina and is associated increased morbidity and mortality. Microvascular arterial disease in the brain is referred to as cerebrovascular small vessel disease. This is responsible for 45% of dementias and 25% of ischaemic strokes. The heart and brain share similar vascular anatomy and common pathogenic risk factors are associated with the development of both coronary microvascular dysfunction and cerebrovascular small vessel disease. Microvascular disease in the heart and brain also appear to share common multisystem pathophysiological mechanisms. Further studies on diagnostic approaches, epidemiology and development of disease-modifying therapy seem warranted.

Introduction

Ischaemic heart disease (IHD), cerebrovascular disease and dementia are the leading causes of mortality and disability worldwide.^1–3 These conditions become more prevalent with increasing age and will therefore continue to have a profound clinical and health economic impact with an ageing global population.

The heart and brain share similar vascular anatomy with conduit arteries distributed over the surface of these organs. These arteries then branch into a microscopic network of penetrating arteries which provide organ perfusion via an end-organ microcirculation. In addition, both organs have common risk factors for arterial disease (e.g. smoking, hypertension, age, diabetes). The pathophysiology and epidemiology of obstructive atherosclerotic cardiovascular disease, including in the heart and brain, have been intensively investigated. However, much less is known about the impact of small vessel disease in the heart and brain, and whether there may be a shared pathophysiological link. This review will focus on the novel impact of small vessel disease in the heart and brain, and the relationship between the two.

Small vessel disease (SVD) in the heart—coronary microvascular dysfunction

IHD includes two major overlapping subgroups—atherosclerotic obstructive epicardial coronary artery disease and myocardial ischaemia with no obstructive coronary arteries. Angina is the most common symptom of chronic IHD, and the management of angina focused on the detection and treatment of flow-limiting atherosclerotic coronary artery disease.⁴ However, most patients referred for an invasive coronary angiogram for the investigation of stable anginal symptoms do not have obstructive coronary artery disease.⁵ Multiple studies have shown that most of these patients have coronary small vessel disease.^6–8 This is a condition referred to as microvascular angina caused by coronary microvascular dysfunction.

The Coronary Vasomotion Disorders International Study group define microvascular angina as symptoms and objective evidence of myocardial ischaemia, with evidence of impaired coronary microvascular function (e.g. impaired coronary flow reserve (CFR <2.0), elevated index of microvascular resistance (IMR >25), coronary microvascular spasm (e.g. during acetylcholine testing), or coronary slow flow phenomenon (TIMI (Thrombolysis in Myocardial Infarction) frame count >25)).⁹

Several methods are diagnostically useful for the assessment of coronary microvascular function (Table 1). The methods include invasive (e.g. functional coronary angiography with acetylcholine testing) and non-invasive (e.g. Stress Cardiovascular Magnetic Resonance Imaging (CMR), Stress PET, Transthoracic doppler echocardiography) modalities. Each technique has strengths and limitations, and contemporary guidelines recommend that the test choice should be guided by local availability and expertise.¹⁰

Table 1.

Methods for assessment of heart and brain SVD

Organ	Method	Diagnostic threshold
Heart	Functional coronary angiography	CFR < 2.0
		IMR > 25
		Microvascular spasm to ACh
	Stress CMR	Global stress MBF < 2.25 ml/g/min
		MPR < 2.2
		MPRENDO < 2.41
	Stress PET	MPR < 2.0
	Transthoracic doppler echo	CFVR < 2.0
Brain	MRI	Presence of:
		White matter hyperintensities, lacunes
		Cerebral microbleeds
		Enlargement of perivascular spaces
		Brain atrophy

ACh, acetylcholine; CFR, coronary flow reserve; CFVR, coronary flow velocity ratio; IMR, index of microvascular resistance; MBF, myocardial blood flow; MPR, myocardial perfusion reserve; MPR_ENDO, endocardial myocardial perfusion reserve.

The pathophysiology of coronary microvascular dysfunction is incompletely understood and commonly multifactorial. Vascular involvement may involve functional and structural abnormalities. The coronary microvessels are typically <0.5 mm in diameter, and, therefore, standard invasive coronary angiography lacks the necessary spatial resolution to visualize them directly. Structural abnormalities, reflecting microvascular remodelling, include luminal narrowing of arterioles, capillary rarefaction and extracellular matrix remodelling, leading in turn to impaired microvascular perfusion.¹¹ Risk factors for microvascular remodelling include hypertension, diabetes, renal dysfunction and increased left ventricular mass.^12,13

Functional coronary microvascular dysfunction is due to impaired coronary vasodilation and/or abnormal vasoconstriction (microvascular spasm) in response to pharmacological (e.g. acetylcholine, adenosine, ergonovine and substance P²⁴) or physiological (e.g. exercise) stimuli. Both endothelium-dependent and endothelium-independent vascular mechanisms underlie coronary microvascular dysfunction.⁷

In clinical practice, the diagnostic management of angina prioritises anatomical coronary artery imaging by non-invasive CT coronary angiography or invasive coronary angiography. These tests have very high sensitivity for coronary atherosclerosis but the microcirculation (or perfusion) is not resolved. Accordingly, a diagnosis of coronary microvascular dysfunction is commonly not considered or postulated if functional test data are available. Coronary microvascular dysfunction is not benign. It is associated with increased risks of major adverse cardiovascular events,^14,15 persistent anginal symptoms,¹⁶ impaired quality of life¹⁷ and health resource utilization due to recurrent hospitalizations and repeat invasive angiograms.¹⁶ Recent studies have highlighted the benefits of establishing an accurate diagnosis coupled with stratified medical therapy that leads to improvements in angina symptoms, quality of life and patient satisfaction.^8,18 The Coronary Microvascular Angina (CorMicA) trial prospectively enrolled 391 patients who had been referred for invasive coronary angiography for the investigation of chest pain during a 12-month period. Almost half of these patients (n = 185; 47%) had no obstructive coronary artery disease. One hundred and fifty-one of these patients then entered the randomized trial which involved a 1:1 randomized, blinded, sham-controlled, parallel-group, clinical trial of stratified medicine vs. angiography-guided management. Stratified medicine involved adjunctive coronary function and acetylcholine reactivity testing to identify disease endotypes with linked medical therapy. Compared with standard care, the stratified medical therapy was associated with improvement in angina severity, quality of life and treatment satisfaction.

Small vessel disease in the brain—cerebral small vessel disease

Cerebral small vessel disease (CSVD) also increases with age and is ubiquitously present by the age of 90.¹⁹ Clinically CSVD may manifest as cognitive impairment or ischaemic stroke (lacunar). It is responsible for 45% of dementias²⁰ and 25% of ischaemic stroke.²¹ However, the clinical presentation is often varied, and reflects the different underlying pathological mechanisms and disease stages. CSVD may be present as an acute focal neurological deficit due to ischaemic stroke, or progressive cognitive decline, often with executive dysfunction due to subcortical white matter disruption or atrophy. However, a considerable proportion of patients with imaging evidence of CSVD remain asymptomatic, or due to the slow and insidious onset of symptoms, may incorrectly pass unrecognized in relation to the physiological effects of ageing.²² In meta-analyses, MRI evidence of CSVD is associated with increased morbidity, mortality and health care costs.²³

CSVD is a collective term for vascular pathologies affecting the perforating cerebral arterioles, capillaries and venules. The most common form of CSVD is arteriosclerosis, in which there is concentric hyaline thickening of deep penetrating arterioles (diameter <200 µm) with associated fibrosis of the vessel wall and depletion of vascular smooth muscle cells.²⁴ Amyloid-related CSVD is caused by mural deposition of amyloid-beta peptide (Aβ) within small leptomeningeal and cortical arteries. This pathology is strongly related to dementia, occurring in 90% of patients with Alzheimer’s disease.²⁵

CSVD is detected using MRI, particularly T2-weighted sequences. Cardinal features of CSVD include white matter hyperintensities, lacunes, cerebral microbleeds, enlargement of perivascular spaces and demyelination leading to axonal loss and brain atrophy. Each of these CSVD features are associated with vascular risk factors. The presence or absence of these features on cerebrovascular MRI can be used to calculate a CSVD score²⁶ which estimates the burden of CSVD and correlates with the clinical presentation of the patients.²⁷ Cerebrovascular MRI, therefore, provides the possibility of identifying patients with subclinical CSVD who then may be stratified to intensive preventative therapy in advance of developing clinical disease.

Relationship between heart and brain SVD

The vascular anatomy of the heart and brain is similar. In addition, common pathogenic risk factors have been identified for the development of both coronary microvascular dysfunction and CSVD, e.g. diabetes, hypertension and increasing age. Furthermore, shared pathophysiological mechanisms such as atherosclerosis, inflammation, neurohormonal dysfunction, vasospasm and microemboli, contribute to small vessel disease in both organs.

Dysregulation of the endothelin system, based on genetic and/or acquired factors, is one potential common pathophysiological mechanism,²⁸ and this possibility is being intensively investigated, not least because of the availability of endothelin receptor antagonists which have potential for microvascular disease prevention, if confirmed by future randomized, controlled, clinical trials.

The Cerebral-Coronary Connection (C3) study was a prospective blinded investigation of the prevalence of coronary microvascular dysfunction in patients with coronary artery disease and its association with CSVD and cognitive function. Sixty-seven patients underwent functional assessment of coronary and cerebral large arteries and microvasculature. Coronary microvascular function was assessed by the measurement of CFR and hyperaemic microvascular resistance. Participants also underwent brain MRI, transcranial doppler (TCD) and extensive neurocognitive examinations. Patients with coronary microvascular dysfunction, as demonstrated by an abnormal CFR (<2.0), had higher burden of white matter hyperintensities, lower grey matter volume and white matter microstructural damage in diffusion-tensor imaging. Abnormal CFR was also associated with higher resistive and pulsatility values on TCD, and worse neurocognitive test scores. The C3 study, therefore, adds to the growing body of evidence that small vessel disease in the heart and brain share a common pathophysiological process.

Several clinical studies have investigated cerebral blood flow in patient with coronary microvascular dysfunction. Most of these studies have used brain single photon emission tomography (SPECT) to measure cerebral flow and detect cerebral perfusion abnormalities. Pai et al.²⁹ used technetium-99m ethyl cysteinate dimer brain SPECT to investigate abnormal cerebral blood flow in 30 patients with coronary microvascular dysfunction. They demonstrated that there was a high incidence of hypoperfusion lesions in the brains of patients with coronary microvascular dysfunction (21/30), and that this was strongly associated with myocardial perfusion SPECT abnormalities. Similar results were shown by Sun et al.,³⁰ in a case control study. Using brain SPECT imaging, they showed that 23/25 patients with coronary microvascular dysfunction had multiple hypoperfusion areas in the brain versus 2/15 patients with normal coronary microvascular function. In the largest of these case series, Weidmann et al.³¹ performed brain SPECT examination in 95 patients with coronary microvascular dysfunction. They found that 72/95 (76%) had findings suggestive of cerebral perfusion abnormalities. However, an earlier case control study of 16 patients with coronary microvascular dysfunction and 16 normal controls showed no difference in cerebral blood flow and cerebrovascular vasodilator reserve when measured by the 133Xe inhalation method.³² Therefore, the evidence arising from these small studies is inconclusive.

There have also been several neuropathology studies of the relationship between coronary and CSVD. In a clinico-pathological study of 175 patients with dementia, Andin et al.³³ demonstrated that cardiovascular pathologies were more common in patients with small vessel dementia compared with other dementia subtypes. In addition, Thore et al.³⁴ investigated anatomical changes associated with CSVD. They performed computerized morphometry to analyse brain sections from 55 subjects from a broad age range (from 23 weeks to 102 years) to determine if there was an association between cerebral arteriolar tortuosity and leukoaraiosis (focal white matter lesions seen in CSVD). They found that cerebral arteriolar tortuosity increased with age, and that the presence of atherosclerotic coronary artery disease or cerebrovascular disease correlated with the extent of arteriolar tortuosity. Nonetheless, this study is susceptible to confounding factors, such as age, which also associates with these traits.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare, inherited form of CSVD which is caused by mutations in the NOTCH3 gene. Whilst CADASIL typically affects brain vessels leading to stroke and cognitive impairment at an early age, it is a systemic microangiopathy, and several studies have demonstrated cardiac involvement. In a case control study of 17 patients with genetically confirmed CADASIL and 15 healthy controls, Argiro et al.³⁵ demonstrated that CADASIL patients have reduced coronary flow reserved due to coronary microvascular dysfunction compared with healthy controls. In another study,³⁶ 25% of CADASIL mutation carriers from a group of 15 families had ECG evidence of myocardial infarction, whilst none of the non-mutation carriers had ECG changes.

Potential mechanistic links

In addition to sharing similar vascular anatomy, the heart and brain are unique in that the microcirculation of both organs regulate perfusion depending on the metabolic demands of the myocardium and brain parenchyma. Therefore, impairment of microvascular function in both organs can have a profound impact. SVD in both organs can be due to common pathological mechanisms such as endothelial dysfunction, atherosclerosis, thrombosis, capillary rarefaction and arteriolar remodelling.³⁷ In addition, shared cardiovascular risk factors (e.g. smoking, hypertension, dyslipidaemia, diabetes) contribute to endothelial dysfunction which leads to microvessel alterations, resulting in functional impairment and adverse vascular remodelling.

The hypothesis that endothelial dysfunction contributes to multisystem small vessel disease was tested in the CorMicA study.³⁸ Using peripheral arterioles isolated from glutaeal biopsies of patients with coronary microvascular dysfunction and controls, impaired coronary microvascular function measured invasively in vivo was associated with peripheral endothelial dysfunction and enhanced vasoconstriction in vitro. Furthermore, in patients with CSVD secondary to hypertension, endothelial activation (measured by serum markers) is associated with impaired cognitive function.³⁹

Endothelin-1 (ET-1) dysregulation is implicated in multisystem SVD. ET-1 is a small peptide released by endothelial cells. It is a potent vasoconstrictor, and its effects are mediated via ET_A receptor activation, which are found on vascular smooth muscle cells. Coronary microvascular dysfunction is associated with elevated circulating concentrations of ET-1⁴⁰ and enhanced peripheral vasoconstriction in response to exposure to ET-1 in vitro.³⁸ In animal models, ET-1 released by dysfunctional endothelial cells can cause pathological vasoconstriction in the brain, potentially contributing to CSVD.⁴¹

Heart–brain axis

The Heart–Brain axis consists of the effects of cardiovascular disease on the nervous system (e.g. embolic stroke in atrial fibrillation), and the effects of neurological disorders on the cardiovascular system (e.g. stress cardiomyopathy after subarachnoid haemorrhage).⁴² This is controlled by a complex network of several physiological and neurohormonal circuits, and the interactions between the two go beyond the shared risk factors.

Cardiac complications underlie morbidity after ischaemic stroke. Stroke–Heart syndrome⁴³ occurs in 10–20% of patients following ischaemic stroke and may manifest as ECG changes, arrhythmia, myocardial injury, acute coronary syndrome, heart failure, Takotsubo (stress) cardiomyopathy, or sudden cardiac death. Stroke–Heart syndrome is associated with a 2–3-fold increase in short-term mortality and 1.5–2-fold increased risk of major adverse cardiovascular event at 1 year. Both clinical studies and animal models have elucidated pathophysiological mechanisms. These include the release of local cerebral and systemic mediators which lead to autonomic dysfunction and an inflammatory response, which in turn results coronary microvascular dysfunction, cardiomyocyte injury and macrophage dysfunction.

Future perspectives

Small vessel disease is a prevalent underpinning mechanism of IHD, vascular dementia and lacunar stroke. Prior studies have limitations, e.g. small sample size, and further investigation is required.

Simultaneous assessment of heart and brain SVD in clinical research protocols seems warranted, wherever feasible. MRI is diagnostically useful for both coronary microvascular dysfunction and CSVD, and is safe, non-invasive and repeatable. Advances in cardiovascular MRI including the development of fully automatic, pixel-wise quantitative mapping of myocardial perfusion which automatically generates pixel-encoded maps of myocardial blood flow (ml/min/g tissue) which are acquired during vasodilator (hyperaemic) stress and resting conditions. This allows for accurate, non-invasive diagnosis of coronary microvascular dysfunction. Quantitative assessments of atherosclerotic coronary artery disease, myocardial blood flow and cerebral SVD are being implemented in the British Heart Foundation CorCMR trial (NCT04805814). The primary objective is to assess the clinical utility of quantitative stress perfusion CMR for the diagnosis of coronary microvascular dysfunction and then determine whether stratified medical therapy guided by the results of the stress perfusion CMR improves symptoms, well-being, cardiovascular risk and health and economic outcomes. The study participants will also undergo brain MRI at 1.5 Tesla, and neurocognitive testing, to assess the relationship between coronary microvascular dysfunction, CSVD and cognitive function (Figure 1).

Figure 1.

Two clinical cases with angina and ‘heart-brain’ imaging. Top: Normal heart and brain MRI scans. A 42-year-old man with a history of multiple hospital attendances for chest pain underwent coronary angiography for investigation of coronary artery disease. The angiogram was normal. He then gave informed consent to take part in the CorCMR clinical trial. (A) Pharmacological stress imaging during intravenous infusion of adenosine, a drug which causes tachycardia and vasodilatation and an increase in blood flow in the heart. The images are calibrated hence absolute blood flow can be quantified in ml/min/g tissue, within the whole heart or in segments. In this case, there is normal augmentation of blood flow (bright orange, arrow) and no perfusion defects (i.e. no residual blue colour). (B) Cardiac MRI reveals normal myocardial blood flow at rest (uniform dark blue, arrow). (C) Normal MRI brain scan, axial T2 turbo spin echo scan, with no evidence of small vessel disease. Bottom: Small vessel disease in the heart and brain. A 59-year-old woman with a history of chest pain underwent coronary angiography for the investigation of coronary artery disease. The angiogram was normal. She then gave informed consent to take part in the CorCMR clinical trial. (A) Pharmacological stress MRI was undertaken to assess the capacity for blood flow augmentation achieved by infusion of intravenous adenosine which stimulates tachycardia and vasodilatation. The scan revealed a circumferential subendocardial perfusion defect (dark blue, arrow) that contrasts with the hyperaemia (bright orange) elsewhere in the heart. This feature is diagnostic of microvascular dysfunction within the sub-endocardium, supporting a clinical diagnosis of microvascular angina. (B) Cardiac MRI reveals normal blood flow at rest (upper panel—dark blue, arrow). (C) Brain MRI showing extensive periventricular and subcortical high T2-weighted white matter signal change (examples shown by blue arrows) in keeping with small vessel ischaemic damage. Furthermore, prominent cerebrospinal fluid (CSF) spaces in keeping with brain volume loss (atrophy) for age were noted. In summary, this patient has microvascular angina and brain imaging features of small vessel disease and early atrophy that portend a future risk of stroke and vascular dementia.

Currently, there are no evidence-based, disease-modifying therapies for CSVD or coronary microvascular dysfunction, and the current therapy focuses on modification of risk factors and empirical control of symptoms. However, several randomized controlled trials are investigating new pharmacological treatments. The Precision Medicine with Zibotentan in Microvascular Angina (PRIZE) trial (NCT04097314)⁴⁴ is investigating the use of ET_A antagonist in patients with coronary microvascular dysfunction. Other studies are investigating phosphodiesterase inhibitor 3 (NCT03855332), phosphodiesterase inhibitor 5 (NCT04097314) and cilostazol (NCT01932203) in CSVD.

Conclusions

The heart and brain share similar vascular anatomy, disease risk factors and pathophysiological mechanisms of disease. IHD, vascular dementia and stroke together present the leading global causes of non-communicable disease.

Microvascular disease in the heart and brain appears to share common multisystem pathophysiological mechanisms. Further studies on diagnostic approaches, epidemiology and development of disease-modifying therapy seem warranted.

Author contributions

Conor Bradley (Writing—original draft [equal]).

Funding

The authors are supported by funding from the British Heart Foundation grant (RE/18/6134217, PG/18/52/33892) and Medical Research Council (MR/S018905/1).

Conflict of interest

C.P.B. and C.B. are employed by the University of Glasgow, which holds consultancy and research agreements with companies that have commercial interests in the diagnosis and management of angina, including Abbott Vascular, AstraZeneca, Boehringer Ingelheim, GSK, Heartflow, Menarini Pharmaceuticals, Neovasc, Siemens Healthcare and Valo Health. The authors received no support from any of these organisations for the submitted work.