Intra- and interobserver reproducibility of Doppler-assessed indexes of left ventricular diastolic function in a population-based study (the Framingham Heart Study).

The reproducibility of a variety of Doppler indexes of diastolic function in an epidemiologic setting and in atrial fibrillation have not been reported. This study examined the reproducibility of left ventricular inflow in subjects in sinus rhythm (n = 80) and atrial fibrillation (n = 12), randomly selected from the original cohort of the Framingham Heart Study. The following Doppler indexes were assessed for all subjects: peak and integral of early (E) diastolic inflow velocity, acceleration slope and time, deceleration slope and time, and pressure half-time. For subjects in sinus rhythm, the following parameters also were measured: the peak and integral of late (A) diastolic inflow velocity, ratios of peak velocities and integrals E/A, and atrial filling fraction. Intraobserver and interobserver variability were evaluated by statistical methods including Student's t test of the systematic differences (bias), percent bias, correlation coefficients, measurement precision, and percent precision. In subjects in sinus rhythm, although the interobserver bias was statistically significant for most of the parameters, it was < 10% for all but 1 parameter (acceleration time). For the peak and integral measures, the intra- and interobserver correlations were > or = 0.89, with intra- and interobserver percent precision measures within 2.2 to 13.0% of the corresponding mean values. The acceleration, deceleration and pressure half-time measures had somewhat lower correlations (interobserver correlations ranging from 0.59 to 0.96), with percent precision measures further from the corresponding means (interobserver percent precision ranging from 10.1 to 19.5%).(ABSTRACT TRUNCATED AT 250 WORDS)

Determinants of Doppler indexes of left ventricular diastolic function in normal subjects (the Framingham Heart Study).

Normative Doppler values and determinants of left ventricular (LV) diastolic function in healthy subjects have not been fully elucidated. Subjects from the Framingham Heart Study were examined to describe reference values and determinants of echocardiographic Doppler indexes of diastolic function. One hundred twenty-seven randomly selected, rigorously defined, normal subjects, approximately evenly distributed by sex and age from the third through the eighth decades were studied by Doppler echocardiography. Normative values for 7 frequently used Doppler indexes of LV diastolic function are presented. Doppler indexes of LV diastolic function change dramatically with age; the peak velocity of early filling divided by late filling (peak velocity E/A) ranges from a mean of 2.08 +/- 0.55 for subjects in their third decade to 0.84 +/- 0.29 for those in their eighth decade. A peak velocity E/A ratio less than 1 is abnormal in subjects aged less than 40 years, but occurs in most subjects aged greater than or equal to 70 years. The high correlations between age and Doppler indexes of LV diastolic function are not greatly attenuated after adjustment for other clinical parameters associated with diastolic function; the multivariate partial correlation coefficient between age and peak velocity E/A is -0.80 (p less than 0.0001). Heart rate, PR interval, LV systolic function, sex and systolic blood pressure are minor determinants of Doppler indexes of diastolic function. Body mass index, left atrial diameter, and LV wall thickness, internal dimension and mass have little or no association with Doppler indexes in healthy subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Impact of heart rate and PR interval on Doppler indexes of left ventricular diastolic filling in an elderly cohort (the Framingham Heart Study).

The relations of heart rate and PR interval to Doppler-derived diastolic indexes were examined in 260 men (mean age 75 years) and 462 women (mean age 76 years) from the Framingham Heart Study. Subjects receiving any antihypertensive or cardiac medications were excluded from eligibility; those with mitral stenosis or prosthesis, pacemaker, atrial fibrillation, arrhythmia, left bundle branch block, congestive heart failure, previous myocardial infarction, and technically inadequate Doppler study were also excluded. Peak velocity of early (E) and late (A) diastolic left ventricular (LV) filling, ratio of peak velocities E/A, ratio of time velocity integrals E/A, and atrial filling fraction were studied by multivariable analyses adjusting for age, sex, blood pressure, heart rate and PR interval. Heart rate was a major determinant of all 5 Doppler indexes of diastolic filling; heart rate was inversely associated with peak velocity E, E/A, and time velocity integral E/A, and was directly associated with peak velocity A and atrial filling fraction. PR interval was inversely associated with time velocity integral E/A (p < 0.01) and directly associated with atrial filling fraction. The results were largely unaltered after further adjustment for LV wall thickness, LV end-diastolic diameter and left atrial diameter (in addition to age, sex and blood pressure). Heart rate and PR interval are independent contributors to Doppler-assessed LV diastolic filling in the elderly. The atrial contribution to LV filling depends on its timing in the cardiac cycle and on heart rate. Failure to account for heart rate and PR interval may lead to inappropriate assessment of Doppler diastolic filling.

Prevalence and clinical determinants of mitral, tricuspid, and aortic regurgitation (the Framingham Heart Study)

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.

Echocardiographic assessment of left ventricular structure and diastolic filling in elderly subjects with borderline isolated systolic hypertension (the Framingham Heart Study).

Abnormalities in left ventricular (LV) structure and function have been shown in patients with diastolic hypertension and recently in subjects with isolated systolic hypertension. The purpose of this study was to determine whether abnormalities of cardiac structure or function are present in elderly subjects with borderline isolated systolic hypertension (defined as systolic blood pressure [BP] between 140 and 159 mm Hg, and diastolic BP < 90 mm Hg). Ninety-one subjects (mean age 77 years) from the original Framingham Heart Study with untreated borderline isolated systolic hypertension, who were free of cardiovascular disease, were compared with 139 normotensive (BP < 140/90 mm Hg) subjects (mean age 76 years). Measurements included M-mode values for LV structure, and 6 Doppler indexes of LV diastolic filling. Subjects with borderline isolated systolic hypertension and the control group differed in mean systolic (147 vs 125 mm Hg) and diastolic (76 vs 70 mm Hg) BP. Borderline systolic hypertension was the most frequent form of untreated hypertension in this elderly group. The sum of LV wall thicknesses (septum+posterior wall) was significantly higher in borderline hypertensive subjects than in normotensive ones (20.5 vs 19.7 mm; p = 0.002). No difference was detected in LV internal dimension or systolic function. After adjustment for age and other clinical variables, comparisons between the groups revealed significant differences in indexes of Doppler diastolic filling. Peak velocity of early filling, and the ratio of early to late peak velocities were lower in the hypertensive group (40 vs 44 cm/s [p = 0.03] and 0.69 vs 0.76 [p = 0.01], respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Reference values for Doppler indexes of left ventricular diastolic filling in the elderly.

Congestive heart failure increases in prevalence with age. A large number of elderly subjects with heart failure have either normal or slightly reduced left ventricular (LV) systolic function; their symptoms are due to diastolic LV dysfunction. Reference values for Doppler indexes of LV diastolic filling in a large sample of the very elderly (> 70) have not been reported previously. The objective of this study was to generate reference values for Doppler indexes of LV filling in a population of apparently healthy elderly men and women. A total of 1201 surviving original subjects of the Framingham Heart Study were evaluated by Doppler echocardiography. A subset of 114 rigorously selected healthy subjects (26 men and 88 women) aged 70 to 87 years (mean 76) constituted the study group. Measurements of seven commonly used Doppler indexes were obtained. Mean and 2.5, 5, 10, 25, 50, 75, 90, 95, and 97.5 percentile values for Doppler diastolic indexes were generated. Stepwise regression analyses were performed to determine the relation of diastolic LV filling to age group (70 to 74 years, 75 to 79 years, and 80 years and over), sex, and other clinical variables. Reference values for the various Doppler parameters were generated on the basis of this healthy elderly cohort. There was evidence for a slight progressive decline in indexes of LV inflow with age. In 87% of this elderly population the ratio of peak early to late velocities of LV diastolic inflow was less than 1.0.(ABSTRACT TRUNCATED AT 250 WORDS)

A pair of tandemly repeated genes code for gp24, a putative adhesion protein of Dictyostelium discoideum.

The glycoprotein gp24 has been implicated in cell-cell adhesion of Dictyostelium discoideum. We have used a cDNA clone that codes for gp24 to screen cloned genomic fragments. Two closely linked genes (GP24A and GP24B) were recognized that generate mRNAs of about 650 base pairs after excision of a small intron and addition of poly(A). They appear to have arisen by tandem duplication of about 800 base pairs, followed by divergence. These genes are expressed within a few hours of the initiation of development; their mRNAs accumulate to a peak at 12 hr and persist until culmination. Both genes have short guanine-rich sequences (G boxes) upstream that have been shown to be involved in transcriptional regulation of other genes expressed during development of Dictyostelium. Their mRNAs code for proteins that are 85% identical. GP24A and GP24B mRNAs code for proteins with a hydrophobic domain followed by a highly charged carboxyl-terminal domain.

Antisense RNA inhibition of expression of a pair of tandemly repeated genes results in a delay in cell-cell adhesion in Dictyostelium.

Two tandem genes code for a protein recognized by antibodies to gp24, a small surface protein implicated in cell-cell adhesion of Dictyostelium discoideum. However, these genes do not appear to code for gp24 itself. We have transformed cells with a cloned vector that directs the synthesis of antisense RNA from one of the pair of tandemly repeated genes during the first 4 hr of development. During this period, gp24 protein fails to accumulate and the cells do not become mutually adhesive. Antisense RNA encoded by this vector is unstable and rapidly disappears after synthesis stops. gp24 protein then accumulates and the cells acquire cell-cell adhesion and proceed through development.

Surface glycoprotein, gp24, involved in early adhesion of Dictyostelium discoideum.

A membrane glycoprotein of 24,000 Da (gp24) was purified from developed cells of Dictyostelium discoideum and shown to neutralize a crude antiserum (R695) that blocks EDTA-sensitive cell-cell adhesion during the early developmental stages of this organism. Purified gp24 was used to raise rabbit polyclonal antibodies and mouse monoclonal antibodies. Rabbit antiserum R851 was shown to be highly specific to gp24 by both Western analysis and immunoprecipitation. IgG of R851 is able to block adhesion of dissociated cells swirled in suspension. Adhesion of wild-type cells is blocked by R851 antibodies during the first 8 hr of development but not thereafter when other adhesion mechanisms come into play. The glycoprotein gp80 plays an essential role in the second adhesion system that appears during the aggregation stage of D. discoideum. By adding both anti-gp24 and anti-gp80 antibodies, adhesion of aggregation stage cells could be blocked. Late in development a third adhesion mechanism appears that is not blocked by either antibodies to gp24 or gp80 or both antibodies together. Western analysis and immunoprecipitation with monoclonal antibody mLJ11, specific for gp24, indicated that gp24 is absent in cells growing exponentially on bacteria but is rapidly synthesized and accumulated following the initiation of development. Synthesis of gp24 is maximal during the first 4 hr of development and then continues at a reduced rate throughout the remainder of development. The coordinate appearance of gp24 and EDTA-sensitive cell-cell adhesion as well as the ability of this glycoprotein to neutralize the adhesion blocking activity of R695 and R851 antibodies indicates that it plays a role in early cell-cell adhesion.

Mitral annular calcification and the risk of stroke in an elderly cohort.

BACKGROUND: Previous clinical studies have suggested that there is an association between mitral annular calcification and the risk of stroke, but it is unclear whether this association is independent of the traditional risk factors for stroke. We examined the relation between mitral annular calcification and the incidence of stroke in a population-based study. METHODS: Subjects in the Framingham Study receiving a routine examination underwent M-mode echocardiography to determine the presence and severity (thickness in millimeters) of mitral annular calcification. The incidence of stroke during eight years of follow-up was analyzed with a proportional-hazards model adjusting for the calcification, age, sex, systolic blood pressure, diabetes mellitus, cigarette smoking, atrial fibrillation, and coronary heart disease or congestive heart failure. RESULTS: Among 1159 subjects whose echocardiograms could be assessed for mitral annular calcification and who had no history or current evidence of stroke at the index examination (51 percent of all subjects), the prevalence of mitral annular calcification was 10.3 percent in the men and 15.8 percent in the women. Multivariate analysis demonstrated that the presence of mitral annular calcification was associated with a relative risk of stroke of 2.10 (95 percent confidence interval, 1.24 to 3.57; P = 0.006). There was a continuous relation between the incidence of stroke and the severity of mitral annular calcification; each millimeter of thickening as shown on the echocardiogram represented a relative risk of stroke of 1.24 (95 percent confidence interval, 1.12 to 1.37; P less than 0.001). Furthermore, even when subjects with coronary heart disease or congestive heart failure were excluded from the analysis, subjects with mitral annular calcification still had twice the risk of stroke. CONCLUSIONS: In an elderly, longitudinally followed population-based cohort, mitral annular calcification was associated with a doubled risk of stroke, independently of traditional risk factors for stroke. Whether such calcification contributes causally to the risk of stroke or is merely a marker of increased risk because of its association with other precursors of stroke remains unknown.

Prevalence and clinical outcome of mitral-valve prolapse.

BACKGROUND: Mitral-valve prolapse has been described as a common disease with frequent complications. To determine the prevalence of mitral-valve prolapse in the general population, as diagnosed with the use of current two-dimensional echocardiographic criteria, we examined the echocardiograms of 1845 women and 1646 men (mean [+/-SD] age, 54.7+/-10.0 years) who participated in the fifth examination of the offspring cohort of the Framingham Heart Study. METHODS: Classic mitral-valve prolapse was defined as superior displacement of the mitral leaflets of more than 2 mm during systole and as a maximal leaflet thickness of at least 5 mm during diastasis, and nonclassic prolapse was defined as displacement of more than 2 mm, with a maximal thickness of less than 5 mm. RESULTS: A total of 84 subjects (2.4 percent) had mitral-valve prolapse: 47 (1.3 percent) had classic prolapse, and 37 (1.1 percent) had nonclassic prolapse. Their age and sex distributions were similar to those of the subjects without prolapse. None of the subjects with prolapse had a history of heart failure, one (1.2 percent) had atrial fibrillation, one (1.2 percent) had cerebrovascular disease, and three (3.6 percent) had syncope, as compared with unadjusted prevalences of these findings in the subjects without prolapse of 0.7, 1.7, 1.5, and 3.0 percent, respectively. The frequencies of chest pain, dyspnea, and electrocardiographic abnormalities were similar among subjects with prolapse and those without prolapse. The subjects with prolapse were leaner (P<0.001) and had a greater degree of mitral regurgitation than those without prolapse, but on average the regurgitation was classified as trace or mild. CONCLUSIONS: In a community based sample of the population, the prevalence of mitral-valve prolapse was lower than previously reported. The prevalence of adverse sequelae commonly associated with mitral-valve prolapse in studies of patients referred for that diagnosis was also low.