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National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham; Massachusetts, USADivision of Preventive Medicine, Boston University School of Medicine, Boston, Massachusetts, USADepartment of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham; Massachusetts, USADivision of Preventive Medicine, Boston University School of Medicine, Boston, Massachusetts, USA
National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham; Massachusetts, USANational Heart, Lung and Blood Institute, Bethesda, Maryland, USA; Divisions ofDivision of Preventive Medicine, Boston University School of Medicine, Boston, Massachusetts, USADivisions of Cardiology and Clinical Epidemiology, Beth Israel Hospital, Boston, Massachusetts, USA
National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham; Massachusetts, USADivision of Preventive Medicine, Boston University School of Medicine, Boston, Massachusetts, USA
National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham; Massachusetts, USADivision of Preventive Medicine, Boston University School of Medicine, Boston, Massachusetts, USA
National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham; Massachusetts, USADivision of Preventive Medicine, Boston University School of Medicine, Boston, Massachusetts, USA
National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham; Massachusetts, USADivision of Preventive Medicine, Boston University School of Medicine, Boston, Massachusetts, USA
Address for reprints: Emelia J. Benjamin, MD, ScM, Framingham Heart Study, Boston University School of Medicine, 5 Thurber Street, Framingham, Massachusetts 01702
National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham; Massachusetts, USADivision of Cardiology, Boston University School of Medicine, Boston, Massachusetts, USADivision of Preventive Medicine, Boston University School of Medicine, Boston, Massachusetts, USA
Little information is available on the prevalence and determinants of valvular regurgitation in the general population. This study sought to assess the prevalence and clinical determinants of mitral (MR), tricuspid (TR), and aortic (AR) regurgitation in a population-based cohort. Color Doppler echocardiography was performed in 1,696 men and 1,893 women (aged 54 ± 10 years) attending a routine examination at the Framingham Study. After excluding technically poor echocardiograms, MR, TR, and AR were qualitatively graded from trace to severe. Multiple logistic regression analysis was used to examine the association of clinical variables with MR and TR (more than or equal to mild severity) and AR (more than or equal to trace severity). MR and TR of more than or equal to mild severity was seen in 19.0% and 14.8% of men and 19.1% and 18.4% of women, respectively, and AR of more than or equal to trace severity in 13.0% of men and 8.5% of women. The clinical determinants of MR were age (odds ratio [OR] 1.3/9.9 years, 95% confidence interval [CI] 1.2 to 1.5), hypertension (OR 1.6; 95% CI 1.2 to 2.0), and body mass index (OR 0.8/4.3 kg/m2; 95% CI 0.7 to 0.9). The determinants of TR were age (OR 1.5/9.9 years; 95% CI 1.3 to 1.7), body mass index (OR 0.7/4.3 kg/m2; 95% CI 0.6 to 0.8), and female gender (OR 1.2; 95% CI 1.0 to 1.6). The determinants of AR were age (OR 2.3/9.9 years; 95% CI 2.0 to 2.7) and male gender (OR 1.6; 95% CI 1.2 to 2.1). A substantial proportion of healthy men and women had detectable valvular regurgitation by color Doppler echocardiography. These data provide population-based estimates for comparison with patients taking anorectic drugs.
In the wake of controversy surrounding anorectic drugs and valvular regurgitation
there has been a sudden surge of interest in the prevalence and predictors of valvular regurgitation. Little information, however, is available on the prevalence and determinants of regurgitant valvular lesions in the general population. Color Doppler echocardiography, a sensitive technique for detecting valvular regurgitation, provides a semiquantitative method for estimating the severity of regurgitation.
There are no published reports of the prevalence rates of mitral, tricuspid, or aortic regurgitation in a large unselected sample of middle-aged men and women. The purpose of this study was twofold: (1) to use color Doppler echocardiography to establish the prevalence and distribution of mitral (MR), tricuspid (TR), and aortic regurgitation (AR) in a population-based cohort; and (2) to study the clinical determinants of these regurgitant valvular lesions.
Methods
Study sample
The Framingham Heart Study is a prospective epidemiologic study established in 1948 to evaluate potential risk factors for coronary heart disease. The original study cohort included 5,209 men and women, aged 28 to 62 years. In 1971, 5,124 additional subjects were entered into the Framingham Offspring Study. Study design and selection criteria have been published.
Subjects for the present investigation were Framingham Offspring Study subjects who had color Doppler echocardiographic examinations performed between 1991 and 1995 during their routine fifth examination cycle at the Framingham Heart Study clinic. Subjects were excluded if they met any of the following criteria: (1) technically poor echocardiogram (i.e., color Doppler of insufficient quality to assess accurately the severity of regurgitation); (2) mitral stenosis; (3) more than mild aortic stenosis, or (4) prosthetic or bioprosthetic heart valve.
The clinical variables included in this investigation were age, sex, hypertension, body mass index, smoking, total cholesterol level, diabetes mellitus, and history of myocardial infarction or congestive heart failure. The association between TR and percent predicted forced expiratory volume in 1 second was also examined. The diagnoses of myocardial infarction and congestive heart failure were confirmed by a committee of 3 physicians who evaluated records from the Framingham Heart Study clinic examinations, interim hospitalizations, and visits to personal physicians in accordance with published criteria.
Diabetes was defined as a fasting blood glucose level ≥140 mg/dl (>7.7 mmol/L) or the use of insulin or an oral hypoglycemic agent. Body height and weight measurements, medical history, physical examination, blood pressure measurements, and pulmonary function tests were performed routinely at the same examination.
Color Doppler echocardiography
Color Doppler examinations were performed with a commercially available system (Hewlett- Packard, Sonos 1000, Andover, Massachusetts) using a 2.5-MHz transducer. All images were recorded on videotape using a Panasonic VCR system (AG 7350, Matsushite Electrical Industrial Limited, Osaka, Japan). Conventional pulsed Doppler echocardiography was performed routinely in apical 4- and 5-chamber views by selective placement of the sample volume on the color Doppler echocardiographic regurgitation signals when present.
Color Doppler variations were represented by different groups of brightness and color intensity. Flow directed toward the transducer was conventionally coded in red and flow away from the transducer in blue. Valvular regurgitation was diagnosed using color-coded Doppler imaging proximal to the valve plane during its closure and extended into the chamber proximal to the valve. For color Doppler studies, gain settings were adjusted to eliminate background speckling and to maximize the extent of intracavitary velocity coding. MR was sought from the parasternal long-axis, apical 4- and 2-chamber, apical long-axis, and subcostal views. TR was sought from the parasternal right ventricular inflow, parasternal short-axis, apical 4-chamber, and subcostal views. AR was sought using the parasternal long-axis, parasternal short-axis, apical 5-chamber, and apical long-axis views.
MR was considered to be present if blue, green, or mosaic signals were seen originating from the mitral valve and spreading into the left atrium during systole. TR was considered to be present if blue, green, or mosaic signals were seen originating from the tricuspid valve and spreading into the right atrium during systole. AR was considered to be present if red, yellow, or mosaic signals (blue in the parasternal long axis) were seen originating from the aortic valve and spreading into the left ventricle during diastole. Valvular regurgitation was assessed qualitatively using semiquantitative guidelines and graded none, trace, mild, moderate, or severe (Table I)(Table IIa) (Table IIb).
All statistical analyses were valve specific. Prevalence rates of MR, TR, and AR were examined by grade of regurgitation in different age groups. Age- and sex-adjusted Spearman rank correlations were used to examine associations between clinical variables and each regurgitant lesion. The clinical variables included body mass index, hypertension, cholesterol, diabetes, smoking, history of myocardial infarction, or congestive heart failure.
were performed to assess the strength and independence of the clinical variables with MR and TR (≥mild severity) and AR (≥trace severity). This analysis was performed after excluding subjects with a history of myocardial infarction or congestive heart failure, because these disease states are known to be associated with valve regurgitation. Results are expressed as odds ratios (OR) and 95% confidence intervals (CI). ORs are expressed for 1 SD of the continuous variables. Statistically significant values were defined as a 2-tailed p <0.05. All analyses were done on a Sparcstation 2 (SUN Microsystems, Palo Alto, California) using the Statistical Analysis System (SAS, Cary, North Carolina).
Of 3,589 subjects (1,696 men and 1,893 women) who attended the baseline examination and underwent color Doppler echocardiographic examination, 21 were excluded for mitral stenosis or more than mild aortic stenosis and 9 for prosthetic heart valves. Subjects with technically poor color Doppler echocardiograms were also excluded (344 men and 334 women for MR, 354 men and 340 women for AR, and 668 men and 639 women for TR). A total of 2,881 subjects (1,336 men and 1,545 women) were eligible for assessing MR, 2,252 (1,012 men and 1,240 women) were eligible for assessing TR, and 2,865 (1,326 men and 1,539 women) were eligible for assessing AR. Subjects selected for analyses (age [mean ± SD], 54 ± 10 years) had a lower body mass index (mean ± SD: men, 27.6 ± 3.6 kg/m2; women, 26.0 ± 4.7 kg/m2) compared with subjects excluded from analysis for technically poor echocardiograms (men, 30.1 ± 4.7 kg/m2; women, 29.8 ± 6.9 kg/m2, p <0.0001).
Prevalence of valvular regurgitation
MR was detectable in 87.7% of men and 91.5% of women, whereas TR was detectable in 82.0% of men and 85.7% of women. AR was less prevalent and was observed in 13.0% of men and 8.5% of women (Table IIa and Table IIb). The prevalence of MR of more than or equal to mild severity was 19.0% in men and 19.1% in women and of TR, 14.8% in men and 18.4% in women. The prevalence of regurgitation of more than or equal to mild severity was much lower for all 3 valves in both sexes (range 0.4% to 2.0%). When examined across different age groups, the prevalence of MR and TR of more than or equal to mild severity, and AR of more than or equal to trace severity, increased with advancing age in both sexes (TABLE IIa, TABLE IIb).
A total of 944 men and 1,225 women had color Doppler echocardiograms technically adequate for all 3 valves. Regurgitation (MR or TR of more than or equal to mild severity or AR more than or equal to trace severity) involving a single valve was more common than regurgitation of ≥2 valves (Figure 1 ).
Figure 1Histogram showing prevalence of valvular regurgitation by number of regurgitant valves. One indicates any single regurgitant valve; Two, any 2 regurgitant valves; Three, combined aortic, mitral, and tricuspid regurgitation. Regurgitation was defined as ≥mild severity for mitral and tricuspid regurgitation and ≥trace severity for aortic regurgitation.
Age was related positively to the severity of MR, TR, and AR (p <0.0001) (Table IIIa). (Table IIIb) (Table IIIc)The prevalence of AR was greater in men, whereas tricuspid regurgitation was more common in women. In models that adjusted for age and sex, the severity of MR and TR correlated with lower body mass index and history of congestive heart failure and myocardial infarction (TABLE IIIa, TABLE IIIb). Mitral regurgitation was also related to presence of systemic hypertension. Figure 2 shows the predicted prevalence of MR, TR, and AR in the population in relation to body mass index.
TABLE IIIaClinical Characteristics and Severity of Mitral Regurgitation
Figure 2Graphic representation of the mean predicted prevalence of mitral, tricuspid, and aortic regurgitation for the population subdivided into deciles, on the basis of their body mass index (kg/m2).
Multiple logistic regression analyses were performed after excluding subjects with a history of myocardial infarction or congestive heart failure (Table IV). The clinical determinants of MR (more than or equal to mild severity) were age, lower body mass index, and systemic hypertension; the determinants of TR (more than or equal to mild severity) were age, lower body mass index, and female sex; and the determinants of AR (more than or equal to trace severity) were age and male sex.
TABLE IVResults of Multivariable Regression Analyses
The results of our study show that valvular regurgitation detectable by color Doppler echocardiography was highly prevalent in the general population. MR and TR were most common, followed by AR. Obesity was associated with a lower prevalence of TR and MR. These data provide population-based estimates for comparison with patients taking anorectic drugs.
Prevalence of valvular regurgitation
Previous studies using conventional pulsed Doppler methodology have varied widely in their estimates of the prevalence of valvular regurgitation. In normal subjects, prevalence rates of TR have been 24% to 96%, MR 10% to 80%, and AR 0% to 33%.
Color Doppler flow imaging, which superimposes color-coded flow patterns on the real-time 2-dimensional image, is a more comprehensive and sensitive, yet less tedious, method than conventional pulsed-wave Doppler echocardiography.
Consequently, color Doppler echocardiography has become the procedure of choice to detect and measure valvular regurgitation. The reported prevalence has varied widely, from 15% to 100% for TR, 38% to 58% for MR, and 0% to 18% for AR.
Prevalence rates in the Framingham Heart Study sample differed markedly according to threshold definitions (i.e., trace vs mild severity). The high prevalence of trace regurgitation suggests that this may be an artifact of valve closure
Age was observed to exert a profound influence on the prevalence of valve regurgitation in the population. Our findings that the prevalence of MR, TR, and AR increased with age are consistent with earlier Doppler studies.
Although left-sided valves (aortic and mitral) are exposed to high pressures and are likely to undergo degenerative changes earlier than right-sided valves, the prevalence rates of MR and TR were comparable at all ages.
Systemic hypertension was associated with MR but not with AR. Increased afterload may play an important role in the genesis of minor degrees of MR. Earlier reports have suggested that hypertension predisposes to aortic root enlargement and, consequently, to AR.
Our observation of a lack of association between hypertension and AR is supported by a recent study demonstrating the lack of an association between blood pressure and dilation of the aortic root at the site of commissural attachment and AR.
have shown a strong association between AR and age, which in turn may explain the lack of association between hypertension and AR after adjusting for age in the multivariable model.
Obesity and regurgitation
The severity and prevalence of MR and TR decreased as a function of increasing body mass index. This may be because ultrasonic penetration becomes poorer in obese persons, and ultrasound may be too attenuated to permit adequate detection of Doppler signals from distally located areas. To minimize this bias, we purposefully excluded subjects with technically poor Doppler echocardiograms. The inverse relation between body mass index and MR and TR persisted despite exclusion of technically limited studies. Because obesity is associated with changes in cardiac structure, hemodynamics, and altered ventricular inflow patterns,
Importance of obesity, race and age to the cardiac structural and functional effects of hypertension. The Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents.
it may be speculated that mechanisms other than technical factors are involved in the inverse association between body mass index and valvular regurgitation. Further studies are needed to examine this association.
Acknowledgements
We gratefully acknowledge the Hewlett-Packard Foundation for upgrading our Hewlett Packard Ultrasound system to a Sonos 1000.
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Importance of obesity, race and age to the cardiac structural and functional effects of hypertension. The Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents.
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