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(Stroke. 1996;27:847-851.)
© 1996 American Heart Association, Inc.

Articles

Risk of Stroke in a Cohort of 815 Patients With Calcification of the Aortic Valve With or Without Stenosis

Arthur Boon, MD; Jan Lodder, MD; Emile Cheriex, MD Fons Kessels, MD

From the Department of Neurology, St-Anna Hospital, Geldrop (A.B.); Departments of Neurology (J.L.) and Cardiology (E.C.), University Hospital, Maastricht; and Department of Epidemiology, University of Limburg, Maastricht (F.K.), Netherlands.

Correspondence to A. Boon, MD, Department of Neurology, St-Anna Hospital, Postbox 90, 5660 AB, Geldrop, Netherlands.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose We sought to establish the possible role of calcification of the aortic valve with or without stenosis as a risk factor for stroke.

Methods Occurrences of stroke, stroke subtypes, and concomitant cardiovascular risk factors were prospectively analyzed in 300 patients with echocardiographic evidence of aortic valve calcification, 515 patients with calcified aortic valve stenosis, and 562 control subjects.

Results Twenty-four patients with aortic valve calcification, 24 patients with calcified aortic valve stenosis, and 27 control subjects had a stroke during follow-up. Using Cox proportional hazards models, we found that strokes were not significantly associated with aortic valve calcification with or without stenosis, but hypertension and any carotid stenosis were associated. On multiple logistic regression analysis, we did not find any association between one of the two valve lesions and indirect possible indications of cardiogenic embolism such as territorial as opposed to small deep brain infarcts or the presence of silent brain infarcts.

Conclusions Aortic valve calcification with or without stenosis is not a risk factor for stroke.

Key Words: aortic valve • embolism • cerebral infarction • classification • risk factors

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Calcification of an aortic valve results from increased valvular stress and may lead to CAS.¹ Increased valvular stress may be caused by hypertension, congenital bicuspid valves, congenital stenosis, or damage from rheumatic fever or radiation.^{2 3 4 5 6 7} Oxalosis, disturbed calcium metabolism in hemodialysis, and chronic uremia may cause calcium infiltration in aortic valves.^{8 9 10} Neurological sequelae could result from global brain ischemia due to reduced cardiac output in severe aortic valve stenosis and cardiac arrhythmias.^{6 11} An important point is whether AVC and CAS should be considered sources of embolism, with the possible consequence of anticoagulant therapy in AVC and CAS patients. To determine the risk of a minor risk factor, a study with a sufficiently large population, with adjustment for concomitant risk factors for stroke, is required, which has not previously been performed. In three series that did not adjust for cardiovascular risk factors for stroke, no association was found between aortic valve calcification and stroke,^{11 12 13} but case reports provide evidence of brain infarction, retinal ischemia, or peripheral vascular occlusion due to calcific emboli from aortic valves.^{14 15 16 17 18} We questioned whether AVC and CAS are risk factors for stroke or markers of generalized atherosclerosis.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Design
We recruited the study population from 8160 consecutive patients who had 11 924 echocardiograms at the University Hospital of Maastricht (Netherlands) between January 1, 1985, and January 1, 1990, and were registered in a prospective database described elsewhere.¹⁹ Three hundred four patients had echocardiographically detected AVC and 526 additional patients showed CAS, and these patients entered the study. As a reference group, we took a random sample of 568 patients from 7600 patients without AVC or CAS. By mail, we double-checked our own data on stroke occurrence, hospital admissions, and mortality, as judged by the general practitioner. The response was 88%. Four patients with AVC, 11 with CAS, and 6 control subjects were lost to follow-up and for geographic reasons. The cohort therefore consisted of 815 patients with aortic valve calcification (including those with AVC and those with CAS) and 562 patients without aortic valve calcification.

Clinical Risk Factors at the Start of the Follow-up
We recorded the following: age, sex, hypertension (known hypertension treated with antihypertensive medication, two or more blood pressure recordings >160/90 mm Hg), diabetes mellitus (known diabetes treated with diet and/or medication, or either a fasting serum glucose >7 mmol/L or a postprandial serum glucose level >11 mmol/L measured on at least two separate occasions), history of ischemic heart disease (myocardial infarction, angina pectoris), history of coronary artery bypass grafting, use of oral anticoagulants or salicylates, prior stroke or transient ischemic attack, serum cholesterol (the mean of all available measurements with or without treatment), history of hypercholesterolemia, peripheral arterial disease, atrial fibrillation, and date and type of any cardiac valve replacement.

Echocardiographic Parameters at the Start of Follow-up
Echocardiographic readings were on-line prospective evaluations by one observer. AVC was defined as bright dense echoes on one or more cusps >1 mm (and in general decreasing the mobility of the cusp). Determination of CAS was semiquantitative. Continuous Doppler velocity <2 m/s was regarded as normal, more than that as stenosis. CAS (defined as a maximal pressure gradient >16 mm Hg) and other echocardiographic parameters that might influence cardioembolic potential were registered: mitral annulus calcification (defined as bright echoes in mitral annulus on two-dimensional echocardiogram with "stone-shadow"); mitral stenosis (defined as rheumatic mitral stenosis with increased velocities over the valve and a mitral valve area 2.5 cm², or nonrheumatic valvular disease if mitral annulus calcification and fibrosis of the mitral valve apparatus caused a more than physiological gradient and a mitral valve orifice 2.5 cm²); grade of mitral regurgitation; enlarged left atrium (diameter 45 mm); atrial septal aneurysm and atrial septal defect; cardiac valve prosthesis or bioprosthesis; infarct location; apical aneurysm; intracardiac thrombus; dilated cardiomyopathy; left ventricular ejection fraction 40%; fractional shortening 28%; wall motion score; and left ventricular wall mass in patients without anterior wall myocardial infarction and with successive cut points of 175, 200, and 225 g for men and 165, 190, and 215 g for women.²⁰ In patients without cardiomyopathy, asymmetrical hypertrophy was incorporated in left ventricular wall mass.

Wall motion score was a semiquantitative measure of left ventricular wall motion. For this purpose, the left ventricle was divided into 13 segments. Wall motion in each segment was scored from 0 to 4 (normokinesis, hypokinesis, hypokinesis to akinesis, akinesis, and dyskinesis). A wall motion score of >12 was regarded as the cutoff point between small and larger asynergy of the left ventricle. Fractional shortening was defined as the difference between left ventricular end-diastolic and end-systolic diameters. All diameters used were measured according to the recommendations of the American Society of Echocardiography.^{21 22 23}

Outcome Definitions
Stroke was defined as a brain infarct or intracerebral hematoma. A brain infarct was defined as rapidly developing clinical signs of focal disturbance of cerebral function, lasting longer than 24 hours or leading to death, with no apparent cause other than that of vascular origin, while CT scan showed an area of low attenuation compatible with the clinical signs and symptoms or was without specific lesion. CT had been performed in 92% of patients with stroke. For symptomatic infarcts, when no CT was available, we applied the Guy's Hospital Stroke Diagnostic Score (Allen Score).²⁴

We divided symptomatic infarcts into small deep and territorial infarcts. We defined a small deep infarct as a CT lesion compatible with the occlusion of a single perforating artery, ie, a subcortical, small, sharply marginated hypodense lesion with a diameter <20 mm, or as a clinically demonstrated lacunar syndrome if no specific lesion was visible on CT. A territorial infarct was defined as a CT lesion compatible with infarction involving the cortex or as a clinically demonstrated cortical syndrome if no specific lesion was visible on CT. Patients with a large subcortical infarct were included in this group.²⁵ Territorial infarcts were divided into two groups by presumed cause: cardioembolic and remaining infarcts. We defined a cardioembolic infarct as a territorial infarct in the presence of one or more of the following cardiac sources of embolism: chronic and paroxysmal atrial fibrillation, anterior myocardial infarction less than 6 weeks before, prosthetic aortic or mitral valve, endocarditis, dilated cardiomyopathy, mitral stenosis, left ventricular aneurysm, and intraventricular thrombus. AVC and CAS were not considered potential cardioembolic sources.

Brain CT scan of patients with a stroke sometimes showed signs of prior unperceived (silent) brain infarcts, defined as a low-density area on CT compatible with an infarct but without a history of stroke. We distinguished silent small deep lesions and silent territorial infarcts.

At the time of stroke, in addition to age and sex the following risk factors were recorded: hypertension present before stroke or at least 1 week after stroke, diabetes mellitus not measured in the acute phase of stroke (the first 72 hours), a history of ischemic heart disease, and symptomatic or asymptomatic carotid stenosis 50%. Noninvasive carotid studies were done by continuous-wave Doppler or duplex scanning.

Patient Selection and Analysis
Patients were considered out of risk in the primary analysis when they had a stroke earlier than an arbitrary number of 70 days before the index echocardiogram, or from the date of a first stroke after the index echocardiogram, or for patients with AVC or CAS from the date of aortic valve replacement, or at the last follow-up. Follow-up was continued for each patient until the last date for which we could determine the absence or presence of stroke or a clinical risk factor. We did not match for covariates, but results were adjusted.

Statistical Analysis
First-ever strokes during follow-up were primary end points, but analysis was done with and without previous stroke and any transient ischemic attack. We determined the association of AVC or CAS with stroke by proportional hazards analysis. We performed crude analysis with incidence density ratios and 95% CIs and used hazard ratios for analysis of different subsets of the registered risk factors. We used multivariate logistic regression analysis with ORs to determine the association of AVC or CAS with symptomatic or silent small deep, territorial, and multiple silent cerebral infarcts as dependent variables.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Baseline Data
Baseline data are presented in Table 1 and therapy data in Table 2. Left ventricular wall mass and ejection fraction were determined in 764 and 644 patients and 473 and 354 control subjects, respectively. Four patients with AVC and 85 with CAS had aortic valve replacement. Two patients with CAS, still at risk after heart surgery, had a territorial stroke within 8 days after surgery.

View this table: [in this window] [in a new window]   Table 1. Baseline Data in Patients With Calcification of the Aortic Valve With and Without Stenosis and in Control Subjects

View this table: [in this window] [in a new window]   Table 2. Aspirin and Anticoagulant Use

Outcome
Twenty-four patients (8%) with AVC, 24 (5%) with CAS, and 27 control subjects (5%) had a stroke during follow-up. Seven had prior stroke (4 with AVC, 2 with CAS, and 1 control), and 1 control subject had prior transient ischemic attack. Mean delay until CT was 8 days (range, 0 to 87 days).

Strokes among patients with AVC comprised 18 (75%) territorial, 4 (17%) small deep infarcts, 1 (4%) unspecified supratentorial infarct, and 1 (4%) intracerebral hematoma. In the CAS group, 12 strokes (50%) were territorial, 4 (17%) small deep infarcts, 3 (12%) unspecified supratentorial infarcts, 4 (17%) infratentorial infarcts, and 1 (4%) intracerebral hematoma. Among control subjects, there were 13 (48%) territorial, 5 (19%) small deep infarcts, 4 (15%) unspecified infarcts, 1 infratentorial infarct, 3 (11%) intracerebral hematomas, and 1 (4%) unspecified.

Mean follow-up was 833 days for patients with AVC, 831 with CAS, and 687 for control subjects. Of patients with AVC, 47 (16%) died after a mean follow-up of 547 days, 64 (12%) with CAS died after a mean follow-up of 504 days, and 77 (14%) of the control subjects died after a mean follow-up of 524 days. The most common cause of death was heart failure (47%, 68%, and 33%, respectively).

Risk Factors for Stroke
Crude analysis, adjusted for duration of follow-up, showed no significant association of AVC or CAS with stroke (incidence density ratio, 0.7; 95% CI, 0.31 to 1.40; P=.28; and incidence density ratio, 0.87; 95% CI, 0.44 to 1.70; P=.08, respectively). Results were similar with Cox analysis, in which only hypertension and symptomatic or asymptomatic carotid stenosis were strongly associated with stroke (Table 3 and Figure).

View this table: [in this window] [in a new window]   Table 3. AVC, CAS, and Cofactors and Risk of Stroke by Proportional Hazards Analysis

View larger version (21K): [in this window] [in a new window]   Figure 1. AVC, CAS, and covariates as risk factors for stroke (proportional hazards model). perph. indicates peripheral; regurg., regurgitation; lv, left ventricular; tia, transient ischemic attack, and HR, hazard ratio. Shown is the lowest category of left ventricular wall mass (see text); results were similar for other categories.

AVC and CAS were not associated with all-time stroke, ie, any stroke before or during follow-up (OR, 1.14; 95% CI, 0.76 to 1.69; P=.5; and OR, 0.67; 95% CI, 0.44 to 1.00; P=.05, respectively). Combining AVC and CAS gave similar results.

Risk Factors Associated With Stroke Subtypes
AVC and CAS were not significantly more strongly associated with territorial than small deep infarcts (OR, 0.39; 95% CI, 0.06 to 2.5; and OR, 1.33; 95% CI, 0.13 to 14.2, respectively), adjusted among others for any carotid stenosis and the presence of a potential cardioembolic source. Although included in the overall analysis of strokes, there were too few hematomas, hemorrhagic infarcts, and infratentorial infarcts for this analysis.

Risk Factors Associated With Silent Brain Infarcts
AVC and CAS were not significantly associated with silent cerebral infarcts (OR, 1.26; 95% CI, 0.27 to 5.84; P=.7; and OR, 1.01; 95% CI, 0.127 to 8.08; P=.9, respectively), silent small deep infarcts (OR, 0.88; 95% CI, 0.14 to 5.55; P=.8; and OR, 1.95; 95% CI, 0.18 to 20.8; P=.5, respectively), or silent territorial infarcts (AVC: OR, 1.27; 95% CI, 0.11 to 14.8; P=.8; CAS patients had too few silent territorial infarcts for analysis).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We determined from this study that AVC and CAS are not risk factors for stroke; however, hypertension and any carotid stenosis were strongly associated with stroke of any type. This indicates that stroke in patients with aortic valve calcification (either AVC or CAS) is due to atherosclerosis caused by vascular risk factors rather than cardioembolism.

Evidence that an ischemic stroke in a patient with aortic valve calcification is cardioembolic may be suggested indirectly from an association of aortic valve calcification with territorial rather than small deep infarcts, because small deep infarcts are unlikely to be caused by cardiogenic embolism.^{26 27} However, there was no significant association of aortic valve calcification with territorial infarcts and no negative association with small deep infarcts. This supports the theory that any symptomatic ischemic stroke in patients with aortic valve calcification is unlikely to be due to embolism from the valve.

Although strongly questioned,^{28 29} an argument in favor of cardiac embolism could come from the finding of silent brain infarcts in patients with aortic valve calcification.^{27 30 31 32 33 34 35 36 37 38 39 40 41 42 43} However, the lack of any association with silent infarcts in our study supports the idea that aortic valve calcification is not a potential stroke source.

Patient selection, namely, cardiology referral, might lead to underestimation of stroke risk due to AVC and CAS. Although the powers were 62%, 82%, and 91% to detect hazard ratios of 2, 2.5, and 3, respectively, the narrow CIs are more informative in this respect. Confounding cannot be avoided by design if aortic valve calcification is strongly correlated with cardiovascular disease. Any bias resulting from differences in mean age between patients and control subjects would have led to an overestimation of stroke risk due to AVC and CAS and therefore would not influence our conclusions.

In conclusion, our study indicates that AVC and CAS are not risk factors for stroke but merely markers of generalized cardiovascular disease.

	Selected Abbreviations and Acronyms

 

AVC = aortic valve calcification without stenosis CAS = calcified aortic stenosis CI = confidence interval OR = odds ratio

Received September 7, 1994; revision received January 15, 1996; accepted January 18, 1996.

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