Ewa Osypiuk

Clinical Correlates and Heritability of Flow-Mediated Dilation in the Community: The Framingham Heart Study

Background—Studies in selected samples have linked impaired endothelial function with cardiovascular disease and its risk factors. The clinical correlates and heritability of endothelial function in the community have not been described. Methods and Results—We examined a measure of endothelial function, brachial artery flow-mediated dilation (FMD), expressed as both percent (FMD%) and actual dilation by ultrasound with the occlusion cuff below the elbow in 2883 Framingham Study participants (52.9% women; mean age, 61 years). A subset of 1096 participants performed a 6-minute walk test before FMD determination. Mean FMD% was 3.3±3.0% in women and 2.4±2.4% in men. In stepwise multivariable linear regression models, FMD% was inversely related to age, systolic blood pressure, body mass index (BMI), lipid-lowering medication, and smoking, whereas it was positively related to female gender, heart rate, and prior walk test. The estimated heritability of FMD% was 0.14. FMD actual dilation findings were similar, except that female sex and BMI were not significantly associated. Conclusions—Increasing age, systolic blood pressure, BMI, and smoking were associated with lower FMD% in our community-based sample, whereas prior exercise and increasing heart rate were associated with higher FMD%. The estimated heritability of FMD was modest. Future research will permit more complete characterization of the genetic and environmental determinants of endothelial function and its prognostic value in the community.

Brachial Artery Vasodilator Function and Systemic Inflammation in the Framingham Offspring Study

Background—In experimental studies, traditional risk factors and proinflammatory processes alter the regulatory functions of the vascular endothelium to promote atherosclerosis. These alterations include expression of leukocyte adhesion molecules and decreased bioavailability of endothelium-derived nitric oxide, an important regulator of vascular homeostasis and tone. The precise relations among risk factors, inflammation, and nitric oxide bioavailability remain uncertain. Methods and Results—To test the hypothesis that inflammation impairs endothelial function in humans, we measured brachial artery flow-mediated dilation, reactive hyperemia, and serum concentrations of C-reactive protein (CRP), interleukin-6 (IL-6), soluble intracellular adhesion molecule-1 (sICAM-1), and monocyte chemotactic protein-1 (MCP-1) in 2701 participants from the Framingham Study (mean age 61 years, 53% women). There were modest unadjusted inverse correlations between flow-mediated dilation and CRP, IL-6, and sICAM-1 (P<0.001 for all) that were rendered nonsignificant after accounting for traditional coronary risk factors. For reactive hyperemia, we observed inverse correlations with markers of inflammation in unadjusted models that were attenuated 57% to 74% after accounting for risk factors. However, partial correlations of CRP, IL-6, and sICAM-1 with reactive hyperemia remained significant. Conclusions—Our observations are consistent with the hypothesis that risk factors induce a state of inflammation that impairs vascular function. For flow-mediated dilation, we found no evidence that inflammation has additional effects beyond those attributable to traditional risk factors. The incremental contribution of CRP, IL-6, and sICAM-1 to reactive hyperemia above and beyond known risk factors suggests that systemic inflammation may contribute to impaired vasomotor function in forearm microvessels.

Reproducibility of speckle-tracking-based strain measures of left ventricular function in a community-based study.

BACKGROUND The reproducibility of echocardiographic measurements of myocardial strain, performed in a community-based setting, has not been reported previously. METHODS The reproducibility of left ventricular strain measurements was examined in two samples of 20 participants each from the Offspring Cohort of the Framingham Heart Study (mean age, 63 ± 9 years; 59% women). Two-dimensional speckle-tracking-based measurements of global peak left ventricular strain in systole were performed in the apical four-chamber, apical two-chamber, and midventricular parasternal short-axis views. RESULTS Interobserver intraclass correlation coefficients were ≥0.84 for all global strain measurements, with average coefficients of variation of ≤4% for global longitudinal and circumferential strain and <8% for global transverse and radial strain. For left ventricular strain measurements performed in each of the three views, intraobserver intraclass correlation coefficients were ≥0.91 among time points spanning a total 8-month period. The average coefficients of variation were <6% for global longitudinal and circumferential strain and <9% for global transverse and radial strain. Interobserver and intraobserver reproducibility findings were similar in analyses adjusting for frame rate. CONCLUSIONS Excellent reproducibility of global longitudinal and circumferential strain measurements and very good reproducibility of global transverse and radial strain measurements were observed. Taken together, these findings demonstrate the reproducibility of performing echocardiographic strain measurements in a large, epidemiologic community-based setting.

Age- and sex-based reference limits and clinical correlates of myocardial strain and synchrony: the Framingham Heart Study.

Background— There is rapidly growing interest in applying measures of myocardial strain and synchrony in clinical investigations and in practice; data are limited regarding their reference ranges in healthy individuals. Methods and Results— We performed speckle-tracking–based echocardiographic measures of left ventricular myocardial strain and synchrony in healthy adults (n=739, mean age 63 years, 64% women) without cardiovascular disease. Reference values were estimated using quantile regression. Age- and sex-based upper (97.5th quantile) limits were: −14.4% to −17.1% (women) and −14.4 to −15.2% (men) for longitudinal strain; −22.3% to −24.7% (women) and −17.9% to −23.7% (men) for circumferential strain; 121 to 165 ms (women) and 143 to 230 ms (men) for longitudinal segmental synchrony (SD of regional time-to-peak strains); and 200 to 222 ms (women) and 216 to 303 ms (men) for transverse segmental synchrony. In multivariable analyses, women had ≈1.7% greater longitudinal strain, ≈2.2% greater transverse strain, and ≈3.2% greater circumferential strain (P<0.0001 for all) compared with men. Older age and higher diastolic blood pressure, even within the normal range, were associated with worse transverse segmental synchrony (P<0.001). Overall, covariates contributed to ⩽12% of the variation in myocardial strain or synchrony in this healthy sample. Conclusions— We estimated age- and sex-specific reference limits for measures of left ventricular strain and synchrony in a healthy community-based sample, wherein clinical covariates contributed to only a modest proportion of the variation. These data may facilitate the interpretation of left ventricular strain-based measures obtained in future clinical research and practice.

Familial Clustering of Mitral Valve Prolapse in the Community

Background— Knowledge of mitral valve prolapse (MVP) inheritance is based on pedigree observation and M-mode echocardiography. The extent of familial clustering of MVP among unselected individuals in the community using current, more specific echocardiographic criteria is unknown. In addition, the importance of nondiagnostic MVP morphologies (NDMs; first described in large pedigrees) has not been investigated in the general population. We hypothesized that parental MVP and NDMs increase the risk of offspring MVP. Methods and Results— Study participants were 3679 Generation 3 individuals with available parental data in the Offspring or the New Offspring Spouse cohorts. MVP and NDMs were distinguished by leaflet displacement >2 versus ⩽2 mm beyond the mitral annulus, respectively. We compared MVP prevalence in Generation 3 participants with at least 1 parent with MVP (n=186) with that in individuals without parental MVP (n=3493). Among 3679 participants (53% women; mean age, 40±9 years), 49 (1%) had MVP. Parental MVP was associated with a higher prevalence of MVP in Generation 3 participants (10 of 186, 5.4%) compared with no parental MVP (39 of 3493, 1.1%; adjusted odds ratio, 4.51; 95% confidence interval, 2.13–9.54; P<0.0001). When parental NDMs were examined alone, the prevalence of Generation 3 MVP remained higher (12 of 484, 2.5%) compared with those without parental MVP or NDMs (27 of 3009, 0.9%; adjusted odds ratio, 2.52; 95% confidence interval, 1.25–5.10; P=0.01). Conclusions— Parental MVP and NDMs are associated with increased prevalence of offspring MVP, highlighting the genetic substrate of MVP and the potential clinical significance of NDMs in the community.

Distinct Aspects of Left Ventricular Mechanical Function Are Differentially Associated With Cardiovascular Outcomes and All‐Cause Mortality in the Community

Background There are few data relating novel measures of left ventricular (LV) mechanical function to cardiovascular disease (CVD) outcomes in the community. Whether distinct components of LV mechanical function provide information regarding risk for different CVD outcomes is unclear. Methods and Results We used speckle tracking echocardiography to quantify distinct components of LV mechanical function (measured as LV strain in multiple planes) in 2831 Framingham Offspring Study participants (mean age, 66 years; 57% women, 97% with LV fractional shortening >0.29). Participants were followed for 6.0±1.2 years for onset of 69 coronary heart disease (CHD), 71 heart failure (HF), and 199 mortality events. Adjusting for CVD risk factors, longitudinal LV strain appeared associated with incident CHD (hazards ratio [HR] per SD increment, 1.29; 95% confidence interval [CI], 1.00–1.67; P=0.05), whereas circumferential and radial strain were not (P>0.37 for both); however, the association of longitudinal strain with CHD was nonsignificant after Bonferroni correction. By contrast, circumferential strain was a significant predictor of incident HF (HR per SD increment, 1.79; 95% CI, 1.35–2.37; P<0.0001). Decrements in circumferential, radial, and longitudinal strain measures were related to all‐cause mortality (P<0.008 for all). Results remained similar in multivariable models adjusting additionally for the conventional echocardiographic measures of LV mass and fractional shortening. Conclusions In our large, community‐based sample, distinct components of LV mechanical function were associated with specific CVD outcomes. Additional studies are needed to replicate these findings and investigate the prognostic and therapeutic utility of these novel measures of LV mechanical function.

Left ventricular mechanical function: clinical correlates, heritability, and association with parental heart failure.

Non‐invasive measures of cardiac mechanical function may have the potential to serve as markers of risk for heart failure; however, limited data exist regarding clinical correlates and heritability of these measures in the community.

Evolution of Mitral Valve Prolapse Insights From the Framingham Heart Study

Background— Longitudinal studies of mitral valve prolapse (MVP) progression among unselected individuals in the community, including those with nondiagnostic MVP morphologies (NDMs), are lacking. Methods and Results— We measured longitudinal changes in annular diameter, leaflet displacement, thickness, anterior/posterior leaflet projections onto the annulus, coaptation height, and mitral regurgitation jet height in 261 Framingham Offspring participants at examination 5 who had available follow-up imaging 3 to 16 years later. Study participants included MVP (n=63); NDMs, minimal systolic displacement (n=50) and the abnormal anterior coaptation phenotype (n=10, with coaptation height >40% of the annulus similar to posterior MVP); plus 138 healthy referents without MVP or NDMs. At follow-up, individuals with MVP (52% women, 57±11 years) had greater increases of leaflet displacement, thickness, and jet height than referents (all P <0.05). Eleven participants with MVP (17%) had moderate or more severe mitral regurgitation (jet height ≥5 mm) and 5 others (8%) underwent mitral valve repair. Of the individuals with NDM, 8 (80%) participants with abnormal anterior coaptation progressed to posterior MVP; 17 (34%) subjects with minimal systolic displacement were reclassified as either posterior MVP (12) or abnormal anterior coaptation (5). In comparison with the 33 participants with minimal systolic displacement who did not progress, the 17 who progressed had greater leaflet displacement, thickness, coaptation height, and mitral regurgitation jet height (all P <0.05). Conclusions— NDM may evolve into MVP, highlighting the clinical significance of mild MVP expression. MVP progresses to significant mitral regurgitation over a period of 3 to 16 years in one-fourth of individuals in the community. Changes in mitral leaflet morphology are associated with both NDM and MVP progression. # CLINICAL PERSPECTIVES {#article-title-33}Background— Longitudinal studies of mitral valve prolapse (MVP) progression among unselected individuals in the community, including those with nondiagnostic MVP morphologies (NDMs), are lacking. Methods and Results— We measured longitudinal changes in annular diameter, leaflet displacement, thickness, anterior/posterior leaflet projections onto the annulus, coaptation height, and mitral regurgitation jet height in 261 Framingham Offspring participants at examination 5 who had available follow-up imaging 3 to 16 years later. Study participants included MVP (n=63); NDMs, minimal systolic displacement (n=50) and the abnormal anterior coaptation phenotype (n=10, with coaptation height >40% of the annulus similar to posterior MVP); plus 138 healthy referents without MVP or NDMs. At follow-up, individuals with MVP (52% women, 57±11 years) had greater increases of leaflet displacement, thickness, and jet height than referents (all P<0.05). Eleven participants with MVP (17%) had moderate or more severe mitral regurgitation (jet height ≥5 mm) and 5 others (8%) underwent mitral valve repair. Of the individuals with NDM, 8 (80%) participants with abnormal anterior coaptation progressed to posterior MVP; 17 (34%) subjects with minimal systolic displacement were reclassified as either posterior MVP (12) or abnormal anterior coaptation (5). In comparison with the 33 participants with minimal systolic displacement who did not progress, the 17 who progressed had greater leaflet displacement, thickness, coaptation height, and mitral regurgitation jet height (all P<0.05). Conclusions— NDM may evolve into MVP, highlighting the clinical significance of mild MVP expression. MVP progresses to significant mitral regurgitation over a period of 3 to 16 years in one-fourth of individuals in the community. Changes in mitral leaflet morphology are associated with both NDM and MVP progression.

Relations Between Aortic Stiffness and Left Ventricular Mechanical Function in the Community

Background Aortic stiffness impairs optimal ventricular–vascular coupling and left ventricular systolic function, particularly in the long axis. Left ventricular global longitudinal strain (GLS) has recently emerged as a sensitive measure of early cardiac dysfunction. In this study, we investigated the relation between aortic stiffness and GLS in a large community‐based sample. Methods and Results In 2495 participants (age 39–90 years, 57% women) of the Framingham Offspring and Omni cohorts, free of cardiovascular disease, we performed tonometry to measure arterial hemodynamics and echocardiography to assess cardiac function. Aortic stiffness was evaluated as carotid–femoral pulse wave velocity and as characteristic impedance, and GLS was calculated using speckle tracking–based measurements. In multivariable analyses adjusting for age, sex, height, systolic blood pressure, augmentation index, left ventricular structure, and additional cardiovascular risk factors, increased carotid–femoral pulse wave velocity (B±SE: 0.122±0.030% strain per SD, P<0.0001) and characteristic impedance (0.090±0.029, P=0.002) were both associated with worse GLS. We observed effect modification by sex on the relation between characteristic impedance and GLS (P=0.004); in sex‐stratified multivariable analyses, the relation between greater characteristic impedance and worse GLS persisted in women (0.145±0.039, P=0.0003) but not in men (P=0.73). Conclusions Multiple measures of increased aortic stiffness were cross‐sectionally associated with worse GLS after adjusting for hemodynamic variables. Parallel reductions in left ventricular long axis shortening and proximal aortic longitudinal strain in individuals with a stiffened proximal aorta, from direct mechanical ventricular‐vascular coupling, offers an alternative explanation for the observed relations.

Heritability of Mitral Regurgitation: Observations From the Framingham Heart Study and Swedish Population

Background— Familial aggregation has been described for primary mitral regurgitation (MR) caused by mitral valve prolapse. We hypothesized that heritability of MR exists across different MR subtypes including nonprimary MR. Methods and Results— Study participants were FHS (Framingham Heart Study) Generation 3 (Gen 3) and Gen 2 cohort participants and all adult Swedish siblings born after 1932 identified in 1997 and followed through 2010. MR was defined as ≥ mild regurgitation on color Doppler in FHS and from International Classification of Diseases codes in Sweden. We estimated the association of sibling MR with MR in Gen 2/Gen 3/Swedish siblings. We also estimated heritability of MR in 539 FHS pedigrees (7580 individuals). Among 5132 FHS Gen 2/Gen 3 participants with sibling information, 1062 had MR. Of siblings with sibling MR, 28% (500/1797) had MR compared with 17% (562/3335) without sibling MR (multivariable-adjusted odds ratio, 1.20; 95% confidence interval [CI], 1.01–1.43; P=0.04). When we combined parental and sibling data in FHS pedigrees, heritability of MR was estimated at 0.15 (95% CI, 0.07–0.23), 0.12 (95% CI, 0.04–0.20) excluding mitral valve prolapse, and 0.44 (95% CI, 0.15–0.73) for ≥ moderate MR only (all P<0.05). In Sweden, sibling MR was associated with a hazard ratio of 3.57 (95% CI, 2.21–5.76; P<0.001) for development of MR. Conclusions— Familial clustering of MR exists in the community, supporting a genetic susceptibility common to primary and nonprimary MR. Further studies are needed to elucidate the common regulatory pathways that may lead to MR irrespective of its cause.