Lung function abnormalities are ubiquitous in heart failure (HF). It is unclear, however, if abnormal lung diffusion capacity is associated with cardiac remodeling and antedates HF. We hypothesized ...that lower lung diffusion capacity for carbon monoxide (DLCO) is associated with worse left ventricular (LV) systolic and diastolic function cross-sectionally, and with higher risk of HF prospectively.
We evaluated 2423 Framingham Study participants (mean age 66 years, 55% women) free of HF who underwent routine echocardiography and pulmonary function tests. We used multivariable regression models to relate DLCO, forced vital capacity (FVC), and forced expiratory volume in 1 second (FEV1) to left ventricular ejection fraction (LVEF), left atrial (LA) emptying fraction (LAEF), E/e', E/A, LV mass, and LA diameter (LAD). Multivariable-adjusted Cox proportional hazards regression was used to relate DLCO, FEV1, and FVC to incident HF.
In multivariable-adjusted cross-sectional analyses, DLCO, FEV1, and FVC (dependent variables) were associated positively with LVEF (βDLCO = 0.208, βFEV1 = 0.021, and βFVC = 0.025 per 5% increment in LVEF; p<0.005 for all), and LAEF (βDLCO = 0.707, βFEV1 = 0.058 and βFVC = 0.058 per 5% increment in LAEF; p<0.002 for all). DLCO and FVC were inversely related to E/A (βDLCO = -0.289, βFVC = -0.047 per SD increment in E/A; p<0.001 for all). Additionally, DLCO, FEV1 and FVC were inversely related to HF risk (108 events, median follow-up 9.7 years; multivariable-adjusted hazard ratios per SD increment 0.90, 95% CI 0.86-0.95; 0.42, 95% CI 0.28-0.65, and 0.51, 95% CI 0.36-0.73, respectively). These results remained robust in analyses restricted to non-smokers.
Our large community-based observations are consistent with the concept that lower lung diffusion capacity and expiratory flow rates are associated with cardiac remodeling and may antedate HF. Additional studies are needed to confirm our findings and to evaluate the prognostic utility of pulmonary function testing for predicting HF.
Central pressure augmentation is associated with greater backward wave amplitude and shorter transit time and is higher in women for reasons only partially elucidated. Augmentation also is affected ...by left ventricular function and shapes of the forward and backward waves. The goal of this study was to examine the relative contributions of forward and backward wave morphology to central pressure augmentation in men and women. From noninvasive measurements of central pressure and flow in 7437 participants (4036 women) aged from 19 to 90 years (mean age, 51 years), we calculated several variables: augmentation index, backward wave arrival time, reflection factor, forward wave amplitude, forward wave peak width, and slope of the backward wave upstroke. Linear regression models for augmentation index, adjusted for height and heart rate, demonstrated nonlinear relations with age (age: B=4.6±0.1%; P<0.001; age2: B=−4.2±0.1%; P<0.001) and higher augmentation in women (B=4.5±0.4%; P<0.001; model R2=0.35). Addition of reflection factor and backward wave arrival time improved model fit (R2=0.62) and reduced the age coefficients: age (B=2.3±0.1%; P<0.001) and age2 (B=−2.2±0.1%; P<0.001). Addition of width of forward wave peak, slope of backward wave upstroke, and forward wave amplitude further improved model fit (R2=0.75) and attenuated the sex coefficient (B=1.9±0.2%; P<0.001). Thus, shape and amplitude of the forward wave may be important correlates of augmentation index, and part of the sex difference in augmentation index may be explained by forward and backward wave morphology.
Exercise blood pressure (BP) is an important marker of left ventricular hypertrophy, incident hypertension, and future cardiovascular events. Although impaired vascular function is hypothesized to ...influence the BP response during exercise, limited data exist on the association of vascular function with exercise BP in the community.
Framingham Offspring cohort participants (n=2115, 53% women, mean age 59 years) underwent a submaximal exercise test (first 2 stages of the Bruce protocol), applanation tonometry, and brachial artery flow-mediated dilation testing. We related exercise systolic and diastolic BP at second stage of the Bruce protocol to standard cardiovascular risk factors and to vascular function measures. In multivariable linear regression models, exercise systolic BP was positively related to age, standing BP, standing heart rate, smoking, body mass index, and the total cholesterol-to-high-density cholesterol ratio (P≤0.01 for all). Similar associations were observed for exercise diastolic BP. Carotid-femoral pulse wave velocity (P=0.02), central pulse pressure (P<0.0001), mean arterial pressure (P=0.04), and baseline brachial flow (P=0.002) were positively associated with exercise systolic BP, whereas flow-mediated dilation was negatively associated (P<0.001). For exercise diastolic BP, forward pressure wave amplitude was negatively related (P<0.0001), whereas mean arterial pressure was positively related (P<0.0001).
Increased arterial stiffness and impaired endothelial function are significant correlates of a higher exercise systolic BP response. Our findings suggest that impaired vascular function may contribute to exaggerated BP responses during daily living, resulting in repetitive increments in load on the heart and vessels and increased cardiovascular disease risk.
The heart, brain and kidneys are key targets of pulsatile damage in older people and in patients with longstanding hypertension. These central organs are exposed to central systolic and pulse ...pressures, which may differ from the corresponding peripheral pressures measured in the brachial artery. Studies employing the generalized transfer function as a means to estimate central pressure have demonstrated a large difference between central and peripheral systolic and pulse pressure that diminishes with age but remains substantial even in octogenarians. As a result of this persistent difference, some have advocated that central pressure may represent a more robust indicator of risk for target organ damage and major cardiovascular disease events. From the perspective of risk prediction, it is important to acknowledge that a new technique must add incremental predictive value to what is already commonly measured. Thus, in order to justify the added complexity and expense implicit in the measurement, central pressure must be shown to add significantly to a risk factor model that includes standard cardiovascular disease risk factors. A limited number of studies have shown marginally better correlations between central pressure pulsatility and continuous measures of target organ damage in the heart. A similarly limited number of prospective studies in unique cohorts have suggested that central pressure may provide marginally better risk stratification, although no reclassification analysis has been published. Thus, currently available evidence does not provide sufficient justification for widespread adoption and routine use of central pressure measurements in clinical practice.
It is well established that coronary artery disease progresses along with myocardial disease. However, data on the association between coronary artery calcium (CAC) and echocardiographic variables ...are lacking.
Among 2,650 Framingham Study participants (mean age 51 yrs, 48% women; 40% with CAC>0), we related CT-based CAC score to left ventricular (LV) mass index (LVMi), LV ejection fraction (LVEF), E/e', global longitudinal strain (GLS), left atrial emptying fraction (LAEF), and aortic root diameter (AoR), using multivariable-adjusted generalized linear models. CAC score (independent variable) was used as log-transformed continuous ln(CAC+1) and as a categorical (0, 1-100, and ≥101) variable. Adjusting for standard risk factors, higher CAC score was associated with higher LVMi and AoR (βLVMI per 1-SD increase 0.012, βAoR 0.008; P<0.05, for both). Participants with 1≤CAC≤100 and those with CAC≥101 had higher AoR (βAoR 0.013 and 0.020, respectively, P = 0.01) than those with CAC = 0. CAC score was not significantly associated with LVEF, E/e', GLS or LAEF. Age modified the association of CAC score with AoR; higher CAC scores were associated with larger AoR more strongly in older (>58 years; βAoR0.0042;P<0.007) than in younger (≤58 years) participants (βAoR0.0027;P<0.03).
We observed that subclinical atherosclerosis was associated with ventricular and aortic remodeling. The prognostic significance of these associations warrants evaluation in additional mechanistic studies.
Previous reports from the Framingham Heart Study have identified cross-sectional associations of arterial stiffness, as reflected by carotid-femoral pulse wave velocity (CFPWV) and systolic blood ...pressure with vascular brain injury. The purpose of this study is to examine free water (FW), fractional anisotropy (FA), and white matter hyperintensities (WMH) in relation to arterial stiffness among subjects of the Framingham Offspring and Third-Generation cohorts.
In 2422 participants aged 51.3±11.6 years, FA, FW, and WMH were related to CFPWV using voxel-based linear and generalized linear regressions, adjusting for relevant covariables. Mean FW, mean FA, and WMH burden (log transformed) were computed within white matter (WM) region and related to systolic blood pressure and CFPWV using multiple mediation analyses.
CFPWV was found to be associated with higher FW, lower FA, and higher WMH incidence in WM areas covering, respectively, 356.1, 211.8, and 10.9 mL of the WM mask. Mediation analyses revealed that the effect of systolic blood pressure on FW was mediated by CFPWV (direct and indirect effects: a=0.040;
<0.001, and a'=0.020;
>0.05). Moreover, the effect of CFPWV on FA was mediated by FW (direct and indirect effects: b=-0.092;
<0.001, and b'=0.012;
>0.05), whose effect on WMH was, in turn, mediated by FA (direct and indirect effects: c=0.246;
<0.001, and c'=0.116;
>0.05).
From these data, we propose a biomechanical hypothesis designed for future research experiments to explain how hemodynamic alteration may lead to WM injury by impacting cerebral water content and more subtly WM integrity, to finally lead to WMH development.
Impaired vascular function contributes to the development of clinical cardiovascular disease. The relation between vasodilator function assessed noninvasively in the brachial and digital arteries ...remains incompletely defined. In the Framingham Offspring, Third Generation and Omni Cohorts, we measured flow-mediated dilation (FMD; n = 7031; age 48 ± 13 years; age range, 19 to 88 years; 54% women) and peripheral arterial tonometry (PAT) ratio (n = 4352; 55 ± 16 years; age range, 19 to 90 years; 51% women). Abnormal vascular function for each measure was defined by the sex-specific fifth percentile in a reference group free of conventional cardiovascular risk factors. The prevalence of abnormal FMD but not abnormal PAT ratio was higher with advancing age. In multivariable models, higher body mass index was associated with a higher prevalence of both abnormal FMD and PAT ratio. Additional correlates of abnormal FMD included increasing age and higher systolic blood pressure. In contrast, correlates of abnormal PAT ratio included lower systolic blood pressure, increasing total/high-density lipoprotein cholesterol ratio, diabetes, smoking, and lipid-lowering medication. Whereas women had higher FMD and PAT ratios compared with men, using sex-specific reference values, women had a higher prevalence of abnormal brachial and digital vascular function. In participants who had concurrent testing (n = 1843), PAT ratio was not significantly associated with FMD in multivariable models. In this large, community-based cohort, brachial and digital measures of vascular function had differing relations with cardiovascular risk factors and were nearly uncorrelated with each other. These results suggest that FMD and PAT provide distinct information regarding vascular function in conduit versus smaller digital vessels.
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