Cardiac microstructural alterations measured by echocardiography identify sex-specific risk for heart failure.

OBJECTIVE: Established preclinical imaging assessments of heart failure (HF) risk are based on macrostructural cardiac remodelling. Given that microstructural alterations may also influence HF risk, particularly in women, we examined associations between microstructural alterations and incident HF. METHODS: We studied N=2511 adult participants (mean age 65.7±8.8 years, 56% women) of the Framingham Offspring Study who were free of cardiovascular disease at baseline. We employed texture analysis of echocardiography to quantify microstructural alteration, based on the high spectrum signal intensity coefficient (HS-SIC). We examined its relations to incident HF in sex-pooled and sex-specific Cox models accounting for traditional HF risk factors and macrostructural alterations. RESULTS: We observed 94 new HF events over 7.4±1.7 years. Individuals with higher HS-SIC had increased risk for incident HF (HR 1.67 per 1-SD in HS-SIC, 95% CI 1.31 to 2.13; p<0.0001). Adjusting for age and antihypertensive medication use, this association was significant in women (p=0.02) but not men (p=0.78). Adjusting for traditional risk factors (including body mass index, total/high-density lipoprotein cholesterol, blood pressure traits, diabetes and smoking) attenuated the association in women (HR 1.30, p=0.07), with mediation of HF risk by the HS-SIC seen for a majority of these risk factors. However, the HS-SIC association with HF in women remained significant after adjusting for relative wall thickness (representing macrostructure alteration) in addition to these risk factors (HR 1.47, p=0.02). CONCLUSIONS: Cardiac microstructural alterations are associated with elevated risk for HF, particularly in women. Microstructural alteration may identify sex-specific pathways by which individuals progress from risk factors to clinical HF.

High-throughput digitization of analog human echocardiography data.

Echocardiographic imaging has been acquired in historical longitudinal cohorts of cardiovascular disease. Many cohorts were established prior to digital recording of echocardiography, and thus have preserved their archival imaging on Video Home System (VHS) tapes. These tapes require large physical storage space, are affected by physical degradation, and cannot be analyzed using modern digital techniques. We have designed and implemented a standardized methodology for digitizing analog data in historical longitudinal cohorts. The methodology creates a pipeline through critical steps of initial review, digitization, anonymization, quality control, and storage. The methodology has been implemented in the Framingham Offspring Study, a community-based epidemiological cohort study with echocardiography performed during serial examinations between 1987 and 1998. We present this method as an accessible pipeline for preserving and repurposing historical imaging data acquired from large cohort studies. The described technique:•Outlines a generalizable pipeline for digitization of analog recordings of echocardiography stored on VHS tapes•Addresses research concerns including quality control, anonymization, and storage•Expresses the authors' individual experience regarding observed image quality, training needs, and potential limitations to help readers understand the costs and benefits of this method.

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.

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.

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.

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.

AIMS: 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. METHODS AND RESULTS: We used speckle-tracking echocardiography to assess LV strain and synchrony in the Framingham Offspring Study (n = 2816; mean age 67 years, 54% women). In multivariable regression analyses, male gender (vs. female, P < 0.001), higher heart rate (P < 0.0001), and presence of cardiovascular disease (P < 0.001) were associated with worse global peak strains across all planes analysed (longitudinal, transverse, circumferential, and radial). Higher diastolic blood pressure and diabetes were associated with worse longitudinal strain (P < 0.01), and greater body mass index was associated with worse radial strain (P = 0.0004). Overall, however, clinical correlates accounted for only 4-19% of the variation in measures of LV mechanical function. Select measures of LV strain were heritable: longitudinal strain (h(2) = 16%, P = 0.002), transverse strain (h(2) = 15%, P = 0.006), and circumferential strain (h(2) = 30%, P < 0.0001). Furthermore, in a subset of 1437 participants with parental data available, parental heart failure was associated with worse circumferential strain in the offspring free of heart failure (P = 0.01). CONCLUSIONS: Our investigation in a large community-based sample identified heritablity and clinical correlates of LV mechanical function, and highlighted an association of parental heart failure with worse global circumferential strain in offspring.

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.

Arterial stiffness in mild-to-moderate CKD.

Whether arterial stiffness correlates with mild-to-moderate CKD and albuminuria in the community is unclear. We studied the association between arterial stiffness and mild-to-moderate CKD and albuminuria in the Framingham Heart Study. CKD was present in 6.7% (181 of 2682) of participants and microalbuminuria was present in 8.2% (479 of 5818). The measures of arterial stiffness were the carotid femoral pulse wave velocity, forward pressure wave amplitude, central pulse pressure, augmentation pressure, augmentation index, and mean arterial pressure. In cross-sectional analyses, arterial stiffness did not associate with CKD (defined by estimated GFR <60 ml/min/1.73 m(2)) in either age- and gender-adjusted or multivariable-adjusted linear regression models. Carotid femoral pulse wave velocity associated with both urinary albumin-to-creatinine ratio and microalbuminuria (P < 0.0001 after multivariable adjustment). In longitudinal analyses, we used logistic regression models to examine the associations between baseline arterial stiffness measures (exposure variables) and incident CKD or microalbuminuria (n = 1675 for CKD analyses and n = 1252 for microalbuminuria analyses). Baseline arterial measures did not associate with incident CKD or incident microalbuminuria. In summary, arterial stiffness correlates with albuminuria but not with mild-to-moderate CKD.