(Stroke. 1995;26:7-13.)
© 1995 American Heart Association, Inc.
Articles |
Risk of Stroke With Mitral Valve Prolapse in Population-Based Cohort Study
From the Departments of Health Sciences Research (A.J.O., D.J.B., J.D.S., W.M.O., J.P.W.) and Neurology (G.W.P.) and the Division of Cardiovascular Diseases and Internal Medicine (B.K.K.), Mayo Clinic and Mayo Foundation, Rochester, Minn; and the Department of Health Sciences Research (J.F.A.), School of Public Health, University of Texas, Houston.
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Abstract |
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Background and Purpose The purpose of this study was to clarify whether mitral valve prolapse increases the subsequent risk of stroke.
Methods A historical cohort study was conducted on 1079 residents of Olmsted County, Minnesota, who had an initial echocardiographic diagnosis of mitral valve prolapse between 1975 and 1989 without prior stroke or transient ischemic attack and who were followed up for first stroke occurrence.
Results There was an overall twofold increase in the incidence of stroke among individuals with mitral valve prolapse relative to the reference population (standardized morbidity ratio, 2.1; 95% confidence interval, 1.3 to 3.2). Sex, duration of follow-up from the diagnosis of mitral valve prolapse, or calendar year of initial diagnosis did not modify the association. Within the cohort of patients who were at least 35 years old at diagnosis of mitral valve prolapse, a time-dependent proportional-hazards multivariate model and a person-years analysis revealed that age, ischemic heart disease, congestive heart failure, and diabetes mellitus were important determinants for stroke when person-years of observation after mitral valve replacement were excluded. Among seven persons with mitral valve replacement, three strokes occurred in 24 person-years of follow-up. For those with an auscultatory diagnosis of mitral valve prolapse only as the indication for echocardiography (44%), the risk of stroke relative to the population was 1.0 (95% confidence interval, 0.2 to 2.9); for those with another cardiac diagnosis, the standardized morbidity ratio was 2.5 (95% confidence interval, 1.5 to 4.0).
Conclusions Individuals with uncomplicated mitral valve prolapse did not have an increased risk of stroke, although a small increase in the risk may not have been detected.
Key Words: echocardiography • mitral valve prolapse • morbidity • risk factors
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Mitral valve prolapse involves a spectrum of structural and functional mitral valve dysfunction. The disease is characterized by a central weakening of the fibrous core tissue, resulting in cusp expansion and elongation.1 Such lesions may lead to thrombus formation, vegetation, and calcification of the mitral valve that may serve as a nidus for thromboembolism. It has been suggested that mitral valve prolapse places an individual at higher risk for several reported complications: cerebral ischemia,2 3 4 infectious endocarditis,5 6 cardiac tachyarrhythmias,7 8 migraine,9 10 11 and mitral valve surgery.12 13
Previous case-control studies,2 3 4 none of which was population-based, have provided conflicting evidence on the magnitude of the relationship between mitral valve prolapse and cerebral ischemia, with reported relative risks ranging from 0.8 to 9.3. However, these studies were limited generally in assessing whether the identification of mitral valve prolapse preceded the stroke occurrence. Thus, the extent of the association of mitral valve prolapse with subsequent development of stroke has been uncertain.
Recent attention has been directed toward the identification of subgroups at high risk for cerebral ischemic events among patients with mitral valve prolapse.14 15 Although these results have not been replicated in other studies, mitral valve prolapse patients with multiple valvular prolapse had a higher frequency of cerebral ischemic events than did those without these characteristics.15
The primary aims of this population-based study were to address the following questions. Is there an increased incidence of an initial stroke among individuals with mitral valve prolapse compared with a population with the same age and sex distribution? Are there factors that may modify the association between mitral valve prolapse and first stroke?
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The medical and demographic information for the local residents of Olmsted County, Minnesota, made it possible to conduct a population-based, medical record linkage, historical cohort study. The availability of data resulted from the documentation of every formal medical encounter (inpatient, outpatient, and primary medical care) and its corresponding assembly into a medical dossier, the capability of retrieving demographic and clinical data for Olmsted County residents from the original medical records, the incorporation of every patient diagnosis into computerized database files to facilitate retrieval, and the opportunity for extensive follow-up (eg, residency or survival status ascertainment). The medical care for individuals in this community is largely provided either at the Mayo Clinic with its two hospitals, Rochester Methodist Hospital and St Mary's Hospital, or at another group practice, Olmsted Medical Group, and its affiliated hospital, Olmsted Community Hospital.16 17
The Mayo Clinic and its affiliated hospitals perform echocardiographic procedures for all Olmsted County physicians, including those from the Olmsted Medical Group and the Olmsted Community Hospital. M-mode and two-dimensional echocardiography were introduced in 1970 and 1978, respectively. Doppler ultrasonography and color flow imaging were added to the echocardiography laboratory in 1982 and 1985, respectively. Approximately 1 in 50 residents of Olmsted County, Minnesota, undergoes echocardiography each year for differential diagnostic assessment of cardiovascular-related conditions.18
The target population was defined as residents of Olmsted County, Minnesota, who were at least 15 years of age at the time of newly identified mitral valve prolapse diagnosed by echocardiography from January 1, 1975, through December 31, 1989. Potential patients initially diagnosed as having mitral valve prolapse were not included in the study if they (1) did not meet the criteria for mitral valve prolapse diagnosis, (2) had an initial echocardiographic diagnosis of mitral valve prolapse before 1975, (3) had stroke or transient ischemic attack before or at the time of mitral valve prolapse echocardiographic diagnosis, (4) had mitral valve replacement or mitral valve surgery before or at the time of echocardiographic diagnosis of mitral valve prolapse, or (5) had cardiac transplantation. There was verification that the echocardiographic laboratory data could capture all newly recognized cases of mitral valve prolapse in Olmsted County and that medical institutions outside the county did not provide echocardiographic services to the local population.
A clinical diagnosis of mitral valve prolapse had been made in 44% of the patients before the echocardiogram was made. Among persons in the cohort, 89% had both M-mode and two-dimensional echocardiographic examination at the initial diagnosis. Because Doppler ultrasonography was introduced in 1982, only 57% of the cohort had a combined M-mode, two-dimensional, and Doppler echocardiographic examination. Therefore, only this subgroup could be evaluated for the presence or absence of mitral regurgitation.
Echocardiographic reports were retrieved, and established criteria for M-mode19 20 and two-dimensional echocardiography20 were applied for selection of subjects. Echocardiographic tapes on file were reviewed in situations in which a potential mitral valve prolapse case was probable or uncertain.
For this cohort study, the established M-mode criterion for echocardiographic diagnosis of mitral valve prolapse was late systolic posterior motion (>2 mm) of the anterior, posterior, or both mitral leaflets into the left atrium.21 22 The following findings were not considered to be mitral valve prolapse: (1) midsystolic echoes in the left atrium, (2) multiple cascading echoes posterior to the anterior mitral leaflet in systole, (3) pseudosystolic anterior motion of the anterior mitral leaflet during the first half of systole, (4) increased D wave–E wave excursion, or (5) systolic bowing.
For two-dimensional echocardiographic examination, criteria included (1) marked superior systolic displacement or billowing of one or both mitral leaflets across the saddle-shaped mitral annular plane in the parasternal long-axis view and (2) displacement of the mitral valve leaflet in the apical long-axis view. Either Doppler or color flow imaging was used to detect and determine semiquantitatively the presence of mitral regurgitation.23 24 25 Systolic bowing of one or both mitral leaflets in the apical four-chamber view only was not considered evidence of mitral valve prolapse.25
Patients were followed up until the occurrence of stroke, death, migration out of Olmsted County, or the conclusion of the study (July 1, 1990). The neurological end points for the study included initial cerebral infarction or intracerebral hemorrhage, designated hereafter as initial stroke. The stroke criteria noted below are identical to the criteria for the ascertainment of stroke in Rochester, Minnesota, for generating the expected stroke incidence rates.26
Ischemic stroke was defined as the acute onset (minutes to hours) of a focal neurological deficit persisting for more than 24 hours, with or without computed tomographic (CT) or magnetic resonance imaging documentation, and caused by altered circulation to a limited region of the cerebral hemispheres, brain stem, or cerebellum. Patients who had only persistent sensory symptoms or mild impairment of dexterity with preservation of normal muscle strength were included if the patient was aware of such symptoms being present for more than 24 hours. None of the stroke patients in the present study had positive findings on CT scans without clinical neurological manifestations. Infarction of the retina, cochlea, or labyrinth was excluded because there were no standardized incidence rates available for these conditions in Rochester for comparison.
Intracerebral hemorrhage with or without subarachnoid blood was defined as the acute onset of a focal neurological deficit associated with some or all of the following: headache, vomiting, altered level of consciousness, signs of meningeal irritation, or blood-stained cerebrospinal fluid. If performed, CT, magnetic resonance imaging, or autopsy demonstrated a parenchymal hemorrhage. The following cases were also excluded: traumatic intracerebral hemorrhage, intracerebral hemorrhage into an area affected by a disease process such as tumor (primary or secondary) or encephalitis, and intracerebral hemorrhage occurring in the presence of a significant hematologic disorder.
Standardized morbidity ratios (SMRs) were estimated by using the age- and sex-specific incidence rates of an initial stroke for the population of Rochester, Minnesota, in 1980 through 1984. These rates were applied to the age- and sex-specific person-years of follow-up for subjects in the mitral valve prolapse study cohort to generate the expected number of stroke cases. Age- and sex-specific incidence rates for initial stroke events in the cohort were then determined. SMRs were also determined by stratifying for the duration of follow-up after mitral valve prolapse diagnosis and for the calendar period of echocardiographic diagnosis of mitral valve prolapse.
The objective of the internal comparison analysis was to identify subgroups of patients with mitral valve prolapse who might have a greater risk of developing stroke than the group as a whole.
The youngest person with mitral valve prolapse who had a stroke was 47 years of age at first stroke. Therefore, in modeling stroke events for those who had mitral valve prolapse, the analysis was restricted to patients 35 years and older at the initial diagnosis of mitral valve prolapse (n=612).
Models were developed with the time-dependent proportional-hazards (Cox) model,27 28 censoring at the time of surgical replacement of the mitral valve. The model coefficients and their standard errors were estimated, and the corresponding hazards ratios and 95% confidence intervals (CIs) were calculated. The Cox model27 assumes that the hazards ratios are constant over time. The following characteristics were assessed at baseline examination and as they occurred during the follow-up period: diabetes, ischemic heart disease (myocardial infarction or angina pectoris), congestive heart failure, hypertension, and atrial fibrillation. Persons with mitral valve replacement at baseline were not included. When mitral valve replacement occurred after baseline, patient follow-up was censored at that point. The following attributes, measured only at mitral valve prolapse diagnosis, were available: sex, cigarette smoking, aortic valve disease, tricuspid valve disease, moderate-to-severe mitral regurgitation, thickened mitral valve, calcified mitral valve, myxomatous mitral valve, redundant mitral valve, and body mass index (kilograms per meters squared).
To identify attributes that could increase the risk of a stroke, each variable was assessed univariately and then simultaneously, adjusting for the presence of other variables in multivariate models. For the multivariate analyses, the time-dependent proportional-hazards model was used to account for pertinent covariates at baseline and those that developed during the follow-up period.
To further support the proportional-hazards models, we performed person-years analyses for each significant factor, including age, censoring again at the time of mitral valve replacement. For each risk factor, those patients with the factor present at diagnosis of mitral valve prolapse contributed only to risk-factor person-years, which were accumulated from the diagnosis of mitral valve prolapse to the last follow-up (or stroke). Those who never developed the risk factor contributed only to no-risk-factor person-years, which were also accumulated from mitral valve prolapse diagnosis to last follow-up. Those patients who did not have the risk factor at mitral valve prolapse diagnosis but developed it during follow-up contributed to the no-risk-factor person-years from mitral valve prolapse diagnosis until the risk factor occurred and then to the risk-factor person-years from the occurrence of the risk factor until last follow-up. For these analyses, all person-years were subdivided into two groups: ages 35 through 79 years and 80 years and older.29
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Results |
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The mean age at initial echocardiographic diagnosis of mitral valve prolapse (n=1079) was 44 years: 49 years for men and 42 years for women. Prevalent comorbid characteristics for the entire cohort, measured at baseline, are noted in Table 1
for the whole
cohort over 15 years of age and also for those aged 35 years and
older.
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The mean age at initial stroke among patients with mitral valve prolapse was 78 years: 75 years for men and 81 years for women. The majority of the infarcts involved, but were not necessarily limited to, the cerebral cortex (57%). Other sites included the internal capsule, basal ganglia, deep hemispheric white matter, and cerebellum.
The 1079 persons aged 15 years or older with mitral valve prolapse were
followed up for a total of 4819 person-years after diagnosis of mitral
valve prolapse; during this time 22 patients had a stroke, whereas 10.4
strokes would have been expected (SMR, 2.1; 95% CI, 1.3 to 3.2). Among
the 22 persons with stroke, 21 had a cerebral infarct, and 1 had an
intracerebral hemorrhage. All but one stroke was confirmed by CT scan
or magnetic resonance imaging. This twofold increase was observed in
men and women (Table 2). There were 1726 person-years of
observation in those younger than 35 years with no strokes. Because
there were no strokes in those younger than 35 years and very few in
the population at that age, the SMR in Table 2 would be essentially the
same if the estimates had been made for those older than 35 years.
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The duration of follow-up after the diagnosis of mitral valve prolapse may potentially affect the association between mitral valve prolapse and stroke. To assess its impact, the duration of follow-up was partitioned into two sequential 5-year periods. The risk of stroke was not different for the first 5 years of follow-up compared with the next 5 years (rate ratio, 1.33; 95% CI, 0.5 to 3.3). The calendar period at mitral valve prolapse diagnosis did not show a difference in the association between mitral valve prolapse and a subsequent first stroke over the three quinquennia 1975 through 1979, 1980 through 1984, and 1985 through 1989.
The indication for echocardiography was an auscultatory diagnosis of mitral valve prolapse in 44% of patients and another cardiac diagnosis in 56%. For those with an auscultatory diagnosis of mitral valve prolapse only, there were 2245 person-years of observation with a risk of stroke relative to the population of 1.0 (95% CI, 0.2 to 2.9). For those with another cardiac diagnosis, there were 2574 person-years with an SMR of 2.5 (95% CI, 1.5 to 4.0).
Anticoagulant therapy is not likely to have influenced the results. Only 6% of those with an auscultatory diagnosis of mitral valve prolapse and 16% of those with another cardiac diagnosis as the indication for echocardiography were receiving anticoagulants after the mitral valve prolapse diagnosis. Also, 14 of the 22 persons with stroke were receiving anticoagulants at the time of the stroke.
Of the 612 patients older than 35 years, 7 had their mitral valve replaced and were followed up for 24 person-years after the mitral valve replacement; during this time, 3 of them experienced a stroke at 5 days, 1 month, and 11 years after the surgical replacement. Because of this extraordinarily high risk, all subsequent analyses were performed excluding the person-years of follow-up subsequent to a mitral valve replacement.
Thus, for the analysis, the 612 patients with mitral valve prolapse were followed up for 2706 person-years, during which time 19 first strokes occurred. The assessment of potential risk factors in this mitral valve prolapse cohort with only 19 strokes observed has limited power, and combinations of risk factors must be assessed with great care. For this reason, both Cox proportional-hazards models (with time-dependent covariates) and person-years analyses are presented in reference to the four variables that appear in the "final" model.
Table 3 contains summaries of Cox model assessments of
each putative risk factor, with each model containing only the risk
factor and age as a continuous variable. Except for sex, smoking
status, body mass index, and echocardiographically determined
variables, the status of risk factors could change during follow-up,
making them time-dependent. These "age-adjusted" hazards ratios
are almost all smaller than the univariate ratios without adjusting for
age (not presented), indicating that the prevalence of many of the
risk factors increases with age and that their impact may be at least
partially explained by this age relationship. The hazards ratios
estimated from the Cox models indicate the magnitude of the increase in
risk of stroke for those with the risk factor relative to those without
the factor.
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Three risk factors (diagnoses) in addition to age were identified as having independent impacts on the rate of stroke occurrence from multivariate Cox models. These were ischemic heart disease, congestive heart failure, and diabetes mellitus.
Table 4 summarizes the person-years analysis of each
of these three risk factors jointly with age. These analyses of the
three risk factors are equivalent, in a general sense, to the
proportional-hazards analyses summarized in Table 3
, except that age is
treated continuously in the proportional-hazards analysis and is
dichotomized in the analyses summarized in Table 4. In these
person-years analyses, the generalized linear model is used with a
log-link function, which effectively models the logarithm of the
incidence rates as a function of the main effects of age and the
associated risk factor. The estimation of these main effects
corresponds to the logarithm of the ratio of the incidence rates
associated with the presence and absence of the risk factor. Thus, the
incidence rate ratios quoted in Table 4 (7.3 for ischemic heart
disease, 6.4 for congestive heart failure, 4.5 for diabetes) are
comparable to the corresponding hazards ratios from Table 3 (4.3, 3.0,
and 6.0, respectively).
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A comprehensive analysis of the joint influence of these
three risk factors (diagnoses) and age requires a multivariate approach
either through the proportional-hazards model or through the
generalized linear model. The data are extremely sparse, limiting the
utility of such analyses and certainly prohibiting any discussion of
the possibility that the risk factors might act synergistically with
each other or with age. Thus, the models summarized hierarchically in
terms of hazards and incidence rate ratios in Table 5
are "main effects" models only. This means, for example, that the
proportionate increase in risk of stroke between patients with and
without congestive heart failure is assumed to be the same whether or
not the patient also has ischemic heart disease.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Several reports of case series indicated that patients with mitral valve prolapse in young to early middle-age are at particularly increased risk of stroke.30 31 32 33 34 35 36 However, in this population-based study, the age at first stroke of individuals with mitral valve prolapse was similar to that reported in an unselected population,26 and no strokes occurred in 4169 person-years in persons younger than 45 years.
Among 7 patients who had mitral valve replacement, there were 3 who had stroke in only 24 person-years of follow-up after replacement, two of which occurred within 1 month. Excluding those person-years, the prominent variables in the models found to be associated independently with a first stroke in persons with mitral valve prolapse were older age, ischemic heart disease, congestive heart failure, and diabetes mellitus. At least one of these attributes in the model, other than age, was present in 13 of the 19 patients (68%) who had a first stroke.
A referral-based study comparing individuals with thickening and redundancy of the mitral valve leaflets with persons without leaflet thickening showed a high prevalence in the former group of infective endocarditis, moderate-to-severe mitral regurgitation, and the need for mitral valve replacement. There was no difference in the frequency of stroke between these two groups.14 The present study also showed that leaflet thickening or calcified or myxomatous mitral valves did not affect the frequency of stroke.
In a hospital-based study of mitral valve prolapse in patients (mean age, 38 years) with cerebral ischemia, a higher prevalence of aortic valve prolapse, myxomatous degeneration and aortic valve prolapse, or multiple valve prolapse was found compared with that in mitral valve prolapse patients without cerebral ischemia.15 The cross-sectional nature of these studies14 15 with highly selected study populations makes it difficult to determine whether the identification of the mitral valve lesion preceded or was concurrent with the stroke complication.37
Hypertension and atrial fibrillation each have been judged to be independent risk factors for stroke.38 39 However, neither was shown to be a contributing factor to strokes that occurred in this cohort. This is a reflection of the patients referred for echocardiography for this cohort.
For this population-based historical cohort study, selection bias is relevant only from the standpoint of how patients were selected for echocardiography. For those with only an auscultatory diagnosis of mitral valve prolapse, there was no increase in risk of stroke relative to the population, but for those with another cardiac diagnosis there was an increase in the SMR.
Because the prevalence of mitral valve prolapse in Rochester, Minnesota (ie, the reference standard), is low,40 the impact of contamination of the population by unidentified mitral valve prolapse cases on the overall association between mitral valve prolapse and stroke is inconsequential. If much contamination was present, the estimate of the magnitude of the association between mitral valve prolapse and stroke would be biased toward the null effect.
The adoption of standardized criteria for stroke diagnosis in the mitral valve prolapse cohort that was identical to the criteria for stroke used since 1950 in the long-term incidence survey for the population of Rochester, Minnesota, makes misclassification of stroke diagnosis unlikely.
Certain limitations exist with the use of echocardiography. Although the echocardiographers serving the population of Olmsted County, Minnesota, are well trained, there may be interobserver variability in the findings. The majority of individuals in the present study underwent two-dimensional echocardiography; however, the technology continued to evolve with higher-resolution devices. The echocardiographer potentially could have missed findings related to the mitral valve in earlier evaluations compared with later ones. Such nondifferential misclassification diminishing over time could have been detected in our data by a declining relative risk over the period of stroke associated with mitral valve prolapse. Although limited in power by the number of patients experiencing strokes during follow-up, the analysis showed no change over time in the association between mitral valve prolapse and subsequent first stroke. Finally, the valve thickness was measured by a semiquantitative process.
If auscultatory criteria for mitral valve prolapse had been used for this historical cohort study, misclassification bias and its direction would not be predictable. In screening for mitral valve prolapse by auscultation, it has been shown that the physician's ability to discriminate varies by practice setting and by specialty.41
Because all patients in the cohort had mitral valve prolapse,
confounding could only be assessed indirectly by comparing the
prevalence of selected established risk factors for stroke in the
mitral valve prolapse cohort with that of the age- and sex-adjusted
prevalence in the community.40 42 Although the prevalence
of ischemic heart disease, hypertension, and cigarette smoking was not
much different in the mitral valve prolapse cases from that in the
general population, diabetes was 60% as prevalent, atrial fibrillation
was more than three times more prevalent, and congestive heart failure
more than four times more prevalent in the mitral valve prolapse cohort
than in the general population (Table 6). The prevalence
of "none of these factors" was similar to that for the general
population.
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The increased risk of stroke in this cohort was attributed to mitral valve replacement and comorbidity of ischemic heart disease, congestive heart failure, and diabetes mellitus. In the absence of these conditions, there was no increase in the risk of stroke compared with the general population, but the 95% CI indicates that a small increase in risk may not have been detected.
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Acknowledgments |
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This study was supported in part by research grants NS-06663 and AR-30582 from the National Institutes of Health. The authors thank Susanne L. Daood and Jon L. Kosanke for programming assistance; C. Mary Beard, LaVonne A. Gates, and Judy K. Stancl of the Rochester Epidemiology Project; and Darcy Jacobson and Marilyn M. Goodman for manuscript preparation.
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Footnotes |
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Reprint requests to Jack P. Whisnant, MD, Department of Health Sciences Research, Mayo Clinic, 200 First St SW, Rochester, MN 55905.
Received August 18, 1994; revision received October 12, 1994; accepted October 12, 1994.
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