Evaluation of exercise-induced cerebrovascular accidents after aortic valve replacement.

To the Editor: Recurrent ischemic events are uncommon in individuals with prosthetic heart valves and are usually due to degeneration of the prosthesis, inadequate anticoagulation, atrial fibrillation, or infection. The prevalence and mechanism of ischemic events with exercise are unknown. We describe a patient with a mechanical aortic valve prosthesis who experienced recurrent ischemic strokes during exercise (Table). TABLE. Summary of Patient's Historya A 43-year-old man presented in 1994 with an idiopathic aneurysm in the ascending aorta but was otherwise asymptomatic and healthy. The aneurysm was repaired with a Bentall procedure, and the aortic valve was replaced with a Medtronic-Hall valve collagen conduit. Subsequently, the patient experienced 3 thromboembolic events, despite absence of risk factors other than a prosthetic valve. For all 3 events, symptoms began during the first minutes of vigorous exercise. Extensive evaluation ruled out prosthetic valvular dysfunction or inadequate anticoagulation as causes. We found no applicable guidance in the literature about management of patients with prosthetic valves and exercise-induced ischemic events; thus, we employed an empirical, stepwise approach to management. The patient underwent studies of platelet activation after the second and third events. Platelet aggregation in response to epinephrine, adenosine diphosphate (ADP), and arachidonic acid was measured and compared with that for 36 historical controls and 42 patients presenting with acute coronary syndrome (Figure). Contrary to expectation, no evidence of aspirin resistance was found. However, in the presence of ADP or epinephrine, aggregation was markedly increased in one study, although this did not occur on a follow-up study. Repeated platelet activation testing in the presence of clopidogrel revealed appropriate suppression in the presence of ADP but no effect on epinephrine-induced platelet activation. We also measured platelet activation immediately before and after exercise and found no evidence of increased platelet activation after exercise on 2 occasions (data not shown). The patient's physicians initiated clopidogrel (in addition to warfarin and aspirin) and instructed the patient to limit his heart rate to 75% of his age-appropriate maximum while exercising. With this regimen, he has remained free of symptoms for 4 years. FIGURE. Agonist-induced platelet aggregation in current patient, those with acute coronary syndrome (ACS), and healthy controls. AA = arachidonic acid; ADP = adenosine diphosphate; Epi = epinephrine. The patient also underwent transcranial Doppler (TCD) examination before and during treadmill exercise. Bilateral, continuous monitoring of the middle cerebral arteries for 20 minutes at rest (before exercise) detected 11 asymptomatic microemboli, consistent with platelet aggregates (or, less likely, gas bubbles). During 10 minutes of exercise on an inclined treadmill in which the patient increased his heart rate to 135 beats/min, TCD recorded 45 microemboli in the middle cerebral arteries. Stroke occurs in patients after aortic valve replacement or combined aortic root and valve replacement at a rate of 0.5% to 0.6% per year,1 but recurrent strokes are highly unusual. The Medtronic-Hall prosthetic valve has a reported 1.3% per year risk of arterial thromboembolism (including cerebrovascular events), a rate that is lower compared with other mechanical valves.2 Butchart et al3 have identified novel risk factors for thromboembolism after valve replacement. On the basis of their schema, our patient had a 0% to 4% risk of thromboembolism at 5 years, consistent with a very low risk. Because his initial event was attributed to a slightly reduced international normalized ratio (INR), monitoring of his INR at home with assessment every 3 days was instituted; however, on the basis of his 2 subsequent ischemic events, it is unlikely that his reduced INR was the cause. Despite an aggressive conventional evaluation, no explanation for the strokes was found. Furthermore, he had no identifiable procoagulant state or aspirin resistance. We hypothesize that platelet aggregation induced by increased valve-associated turbulence and catecholamine stimulation induced by exercise caused his ischemic events. In support of this theory, we demonstrated that exercise was associated with an 8-fold increase in the frequency of asymptomatic microemboli detected by TCD. Recent evidence emphasizes the pivotal role of inappropriate platelet aggregation in acute coronary artery disease, myocardial infarction, unstable angina, and stroke.4 Additionally, agonists such as ADP can amplify platelet aggregation during exercise, working through shear-induced platelet activation pathways.5 Exercise increases thrombin generation, leukocyte activity, and platelet-leukocyte aggregation.6 In the presence of a mechanical valve, exercise-mediated shear stress can result in red cell hemolysis and may contribute to platelet activation that leads to aggregation and microembolus formation. We think that such changes may have played a mechanistic role in the patient's recurrent ischemic attacks. It is unclear whether the apparent rarity of exercise-induced events in patients with prosthetic valves is because such patients rarely exercise intensely or whether the current patient has an unusual and unidentified prothrombotic diathesis that increases risk. Platelet aggregation studies suggest that he may have manifested an increased sensitivity to catecholamines, but using in vitro tests to predict clinical events is controversial. Georgiadis et al7 have reported a high incidence of microemboli from prosthetic valves detectable by TCD. Our patient had 33 microemboli per hour at rest and 270 per hour with exercise. The increase in frequency suggests persistent risk with exercise, requiring aggressive antiplatelet therapy. Further studies that evaluate effects of intense exercise in patients with valve replacement are needed, and clinicians considering valve replacement in young, physically active individuals must weigh the possibility of an increased thromboembolism risk associated with mechanical vs bioprosthetic valves.8 Currently, no guidelines are available for safe exercise parameters for individuals with prosthetic valves. A substantial amount of literature suggests that exercise helps prevent cardiovascular events, but the actual risk-benefit ratio in patients such as ours is unclear. Knowing that exercise is an essential component of a healthy lifestyle motivated our patient to accept a potentially higher risk of recurrent events. To support this decision and manage the risks effectively, his physicians have relied on innovative diagnostic approaches, aggressive anticoagulation and antiplatelet regimens, and heart rate limit during exercise. We hope this regimen will prove effective until further research suggests alternatives.