Aortic Plaques and Stroke: Cardiovascular Therapy of Retrograde Embolization Risk

Stroke is a leading cause of morbidity and mortality in Western industrialized societies. Despite advances in the detection of embolic sources of stroke with attendant changes in patient management, approximately 25% of acute strokes remain undetermined (cryptogenic). However, the identification of the underlying source of stroke is paramount for therapy planning and prevention of secondary events. It is well understood that aortic stiffening can lead to atherosclerosis and subsequently the development of complex aortic plaques (thickness ≥4mm), which act as potential sources for embolic stroke. The incidence of complex plaques is highest in the descending aorta (DAo) but because the DAo is distal to the left subclavian artery and retrograde embolization was thought to be unlikely, these plaques have not been traditionally considered a source of stroke. Recent studies, however, have shown that marked diastolic flow reversal in the DAo is frequently found in patients with aortic atherosclerosis, even in the absence of aortic valve insufficiency. Ruptured and detached DAo plaques can thus travel retrogradely into the carotid (or vertebral) arteries and cause cerebral embolism as a previously overlooked mechanism of stroke. The root cause of elevated flow reversal in the DAo is increased aortic stiffness (quantified by pulse wave velocity, PWV) as recently demonstrated in a study with 296 patients. These data suggest the structural and dynamic changes associated with aortic stiffening can thus lead to the concurrent development of aortic plaques and flow reversal, thus enhancing the risk for retrograde DAo plaque embolization and stroke. Further, a large body of literature shows that first-line post-stroke pharmacological therapies, including Diuretics and ACE inhibitors for antihypertensive therapy, have been implicated in arterial stiffness diminishment but vary in their degree of effect. A primary objective of this proposal is, thus, to quantify the relationship between DAo plaques and retrograde embolization and test the preliminary efficacy of two classes of anti-hypertensive therapy on central flow dynamics and their potential to reduce DAo flow reversal. The aims of this proposal are to establish a comprehensive MRI protocol for the detection of characterization aortic plaques and 3D hemodynamics by 3D T1-contrast MRI and k-t accelerated 4D flow MRI. In a prospective study with n=50 patients with cryptogenic stroke and aortic atheroma in the DAo, comprehensive aortic MRI will will be employed. Flow connectivity mapping will score the probability of the reversed blood flow to reach the brain-supplying artery matching the territory affected by embolic infarction (i.e. embolization risk). The impact of medical therapy on aortic flow reversal will be evaluated by randomizing 50 patients recruited in aim 2 in either of two treatment arms (ACE inhibitors vs. diuretics). The aim is to investigate if standard-of-care first-line clinical management can reduce can reduce aortic stiffness, flow reversal, and degree of retrograde embolization at follow-up 4D flow MRI at six months.