BackgroundLeft atrial (LA) size, a marker of atrial structural remodeling, is associated with increased risk for atrial fibrillation (AF) and cardiovascular disease (CVD). LA function may also relate to AF and CVD, irrespective of LA structure. We tested the hypothesis that LA function index (LAFI), an echocardiographic index of LA structure and function, may better characterize adverse LA remodeling and predict incident AF and CVD than existing measures.Methods and ResultsIn 1786 Framingham Offspring Study eighth examination participants (mean age, 66±9 years; 53% women), we related LA diameter and LAFI (derived from the LA emptying fraction, left ventricular outflow tract velocity time integral, and indexed maximal LA volume) to incidence of AF and CVD on follow‐up. Over a median follow‐up of 8.3 years (range, 7.5–9.1 years), 145 participants developed AF and 139 developed CVD. Mean LAFI was 34.5±12.7. In adjusted Cox regression models, lower LAFI was associated with higher risk of incident AF (hazard ratio=3.83, 95% confidence interval=2.23–6.59, lowest [Q1] compared with highest [Q4] LAFI quartile) and over 2‐fold higher risk of incident CVD (hazard ratio=2.20, 95% confidence interval=1.32–3.68, Q1 versus Q4). Addition of LAFI, indexed maximum LA volume, or LA diameter to prediction models for AF or CVD did not significantly improve model discrimination for either outcome.ConclusionsIn our prospective investigation of a moderate‐sized community‐based sample, LAFI, a composite measure of LA size and function, was associated with incident AF and CVD. Addition of LAFI to the risk prediction models for AF or CVD, however, did not significantly improve their performance.
Background Translation of preclinical findings could benefit from a simple, reproducible, high throughput human model to study myocardial signaling. Alpha-1A-adrenergic receptors (ARs) are expressed at very low levels in the human heart, and it is unknown if they function. Objectives To develop a high throughput human myocardial slice culture model, and to test the hypothesis that alpha-1A- ARs are functional in the human heart. Methods Cores of LV free wall 8 mm diameter were taken from 52 hearts (18 failing and 34 nonfailing). Slices 250 μm thick were cut with a Krumdieck apparatus and cultured using a rotating incubation unit. Results About 60 slices were cut from each LV core, and a typical study could use 96 slices. Myocyte morphology was maintained, and diffusion into the slice center was rapid. Slice viability was stable for at least 3 days in culture by ATP and MTT assays. The beta-AR agonist isoproterenol stimulated phospholamban phosphorylation, and the alpha-1A-AR agonist A61603 stimulated ERK phosphorylation, with nanomolar EC50 values in slices from both failing and nonfailing hearts. Strips cut from the slices were used to quantify activation of contraction by isoproterenol, A61603, and phenylephrine. The slices supported transduction by adenovirus. Conclusions We have developed a simple, high throughput LV myocardial slice culture model to study signaling in the human heart. This model can be useful for translational studies, and we show for the first time that the alpha-1A-AR is functional in signaling and contraction in the human heart.
Background: Left atrial (LA) remodeling is a predictor of cardiovascular disease (CVD). We performed measurement of the LA function index (LAFI), a composite measure of LA structure and function, in a community-based cohort and here report the distribution and cross-sectional correlates of LAFI. Methods: In 1,719 Framingham Offspring Study participants (54% women, mean age 66 ± 9 years), we derived LAFI from the LA emptying fraction, left ventricular (LV) outflow tract velocity time integral, and indexed maximal LA volume. We used multivariable linear regression to assess the clinical and echocardiographic correlates of LAFI adjusting for age, sex, anthropometric measurements, and CVD risk factors. Results: The average LAFI was 35.2 ± 12.1. Overall, LAFI declined with advancing age (β = −0.27, P < .001). LAFI was significantly higher (37.5 ± 11.6) in a subgroup of participants free of CVD and CVD risk factors compared with those with either of these conditions (34.5 ± 12.2). In multivariable models, LAFI was inversely related to antihypertensive use (β = −1.26, P = .038), prevalent atrial fibrillation (β = −4.46, P = .001), heart failure (β = −5.86, P = .008), and coronary artery disease (β = −2.01, P = .046). In models adjusting for echocardiographic variables, LAFI was directly related to LV ejection fraction (β = −14.84, P < .001) and inversely related to LV volume (β = −7.03, P < .001). Conclusions: LAFI was inversely associated with antihypertensive use and prevalent CVD and was related to established echocardiographic traits of LV remodeling. Our results offer normative ranges for LAFI in a white community-based sample and suggest that LAFI represents a marker of pathological atrial remodeling.
The alpha-1A-adrenergic receptor (AR) subtype is associated with cardioprotective signaling in the mouse and human heart. The rabbit is useful for cardiac disease modeling, but data on the alpha-1A in the rabbit heart are limited. Our objective was to test for expression and function of the alpha-1A in rabbit heart. By quantitative real-time reverse transcription PCR (qPCR) on mRNA from ventricular myocardium of adult male New Zealand White rabbits, the alpha-1B was 99% of total alpha-1-AR mRNA, with <1% alpha-1A and alpha-1D, whereas alpha-1A mRNA was over 50% of total in brain and liver. Saturation radioligand binding identified ~4 fmol total alpha-1-ARs per mg myocardial protein, with 17% alpha-1A by competition with the selective antagonist 5-methylurapidil. The alpha-1D was not detected by competition with BMY-7378, indicating that 83% of alpha-1-ARs were alpha-1B. In isolated left ventricle and right ventricle, the selective alpha-1A agonist A61603 stimulated a negative inotropic effect, versus a positive inotropic effect with the nonselective alpha-1-agonist phenylephrine and the beta-agonist isoproterenol. Blood pressure assay in conscious rabbits using an indwelling aortic telemeter showed that A61603 by bolus intravenous dosing increased mean arterial pressure by 20 mm Hg at 0.14 μg/kg, 10-fold lower than norepinephrine, and chronic A61603 infusion by iPRECIO programmable micro Infusion pump did not increase BP at 22 μg/kg/d. A myocardial slice model useful in human myocardium and an anthracycline cardiotoxicity model useful in mouse were both problematic in rabbit. We conclude that alpha-1A mRNA is very low in rabbit heart, but the receptor is present by binding and mediates a negative inotropic response. Expression and function of the alpha-1A in rabbit heart differ from mouse and human, but the vasopressor response is similar to mouse.
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