Small-Vessel Disease in the Heart and Brain: Current Knowledge, Unmet Therapeutic Need, and Future Directions

Colin Berry, Novalia Sidik, Anthony C Pereira, Thomas J Ford, Rhian M Touyz, Juan-Carlos Kaski, Atticus H Hainsworth, Colin Berry, Novalia Sidik, Anthony C Pereira, Thomas J Ford, Rhian M Touyz, Juan-Carlos Kaski, Atticus H Hainsworth

No abstract available

Keywords: angina; cerebrovascular disease; endothelin‐1; magnetic resonance imaging; microvascular dysfunction.

Figures

Figure 1
Figure 1
Microvascular disease as a multisystem disorder.
Figure 2
Figure 2
Two clinical cases of patients with microvascular angina who experienced an acute ischemic stroke within 12 months of diagnosis. A, A 69‐year‐old woman with background of hypertension and treated dyslipidemia underwent invasive angiography for the investigation of typical angina. She was enrolled in the CorMicA clinical trial (ClinicalTrials.gov Identifier: NCT03193294). Her coronary angiogram was normal and as per the trial protocol she underwent blinded assessment of coronary artery function. Endothelial function was grossly abnormal using an acetylcholine probe (10‐6 ‐ 10‐4 mol/L infused for 2 minutes). A, During acetylcholine, the patient has transient loss of flow in the left coronary artery despite no gross epicardial coronary diameter change. This represents intense microvascular vasoconstriction with absence of contrast in the lumen. There were associated dynamic ST‐segment changes on ECG with reproduction of angina. B, After GTN the flow returns to normal with prompt ECG and symptom resolution. Six months later she presented with generalized headache and bilateral visual disturbance and was found to have a right homonymous hemianopia. C and D, The MRI brain scan shows a left posterior circulation infarct involving the temporal and occipital lobes. B, A 67‐year‐old man underwent invasive coronary angiography for severe angina (CCS IV). His background history included myocardial infarction with nonobstructive coronary disease (MINOCA), hypertension, paroxysmal atrial fibrillation with previous stroke, stage III chronic kidney disease, obesity, and moderate left ventricular impairment. Invasive coronary angiography showed nonobstructive coronary disease confirmed with pressure wire (yellow arrow) physiological assessment of the left anterior descending artery (LAD fractional flow reserve 0.84). Indices of coronary microvascular function using adenosine as an endothelial independent probe were profoundly abnormal. The index of microvascular resistance measured in the LAD coronary artery was 49 (abnormal >25) and the coronary flow reserve in the same artery was 1.7 (abnormal < 2.0). Endothelial function testing with acetylcholine provoked slow flow (Thrombolysis in Myocardial Infarction (TIMI) grade 0) (A), which represents intense inappropriate microvascular constriction during 10‐4 mol/L acetylcholine infusion. Reproduction of angina and ECG changes ensued in keeping with microvascular spasm–induced ischemia. Changes promptly resolved with GTN (B). An MRI brain (C) scan is shown after his previous stroke, which was attributed to atrial fibrillation. The scan shows no evidence of intracranial mass lesions, abnormal enhancement, or signs of raised intracranial pressure. There is marked dilatation of the lateral and third ventricles with right frontal and right parietal cortical malacia and underlying gliosis in keeping with infarcts. The FLAIR sequence (D) shows periventricular white matter changes and multifocal punctate white matter hyperintensities that are typical of SVD affecting the brain. CCS indicates Canadian Cardiovascular Society; GTN, Glyceryl Trinitrate; MINOCA, Myocardial Infarction with No Obstructive Coronary Artery disease; MRI, magnetic resonance imaging.
Figure 3
Figure 3
Endothelial function and harmony of the vascular endothelin system. There is complex homeostatic interplay between endothelial (dys)function and the effects of ET‐1 on vascular tone and atherogenic milieu. Endothelial dysfunction causes coronary and systemic (peripheral) microvascular disease and the underlying mechanisms involve dysregulation of the endothelin‐1 (ET‐1) system. EDN1 gene transcription in vascular endothelial cells produces pre‐pro ET‐1, which is cleaved to big ET‐1 and subsequently to ET‐1. Around 80% of ET‐1 secretion occurs abluminally, where it binds to ET A and ET B are G‐protein coupled receptors that are expressed on the vascular smooth muscle cell surface mediating constrictor and mitogenic effects. In healthy endothelial cells, luminal ET‐1 binds to and activates ET B receptors, providing a crucial homeostatic role. Endothelial ET B activation leads to eNOS activation and PGI2 and nitric oxide (NO) production. Endothelial dysfunction is associated with reductions in NO, prostacyclin, and endothelium‐derived hyperpolarizing factor and a preponderance of oxidants, ET‐1, and other vasoconstrictor and mitogenic substances within the vascular wall. ROS indicates reactive oxygen species.

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