Abstract 299: Cardiac Fibroblast-derived FGF21 is a Novel Therapeutic Target for Cardiac Pathological Remodeling

Background: Fibroblast Growth factor 21(FGF21) is an endocrine factor, secreted mainly by the liver, that exerts metabolic actions. It has been shown that FGF21 has an anti-hypertrophic action for cardiac hypertrophy. We previously reported that murine cardiac FGF21 expression was upregulated by pressure-overload. The objective of this study was to clarify the role of cardiac fibroblast-derived FGF21 in cardiac pathological remodeling. Methods and Results: We generated fibroblast-specific/tamoxifen-inducible FGF21 knockout mice crossing by FGF21flox mice and Col1a2-CreERT mice (FB-FGF21KO). FGF21flox control mice and KO mice were induced cardiac hypertrophy by transverse aortic constriction (TAC). After 3-weeks TAC surgery, we evaluated the cardiac function by echocardiography or conductance catheter. TAC-mediated cardiac hypertrophy or impairment of systolic function were exacerbated in FB-FGF21KO mice. Conductance catheter showed that Tau, diastolic relaxation marker, was exacerbated in FB-FGF21KO mice with TAC. FB-FGF21KO heart with TAC showed significant upregulation in profibrotic genes and down-regulation in Ca2+ ATPase in comparison with control TAC heart. Cardiac Sirt1, which plays a central role in energy metabolism or oxidative stress, increased by TAC was significantly attenuated in FB-FGF21KO heart. Conclusion: Deletion of FGF21 in cardiac fibroblasts exacerbates cardiac dysfunction in response to pressure overload suggesting that cardiac fibroblasts regulates pathological remodeling via FGF21 regulation.

Levels of agreement between cardiac magnetic resonance and conductance catheter measurements of right ventricular volumes after pulmonary artery banding

Background Pressure-volume analysis is the gold standard for quantifying pump function of the right ventricle (RV); however, volume measurements based on a conductive catheter may be imprecise. The reference method for volume assessment is cardiac magnetic resonance (CMR). Purpose To determine the levels of agreement between RV volume measurements obtained by cine CMR, phase-contrast CMR (PC CMR), and a conductance catheter in an animal model. Material and Methods CMR was performed in 20 sheep three months after pulmonary artery banding. Ejection fraction (EF), end-diastolic (EDV), end-systolic (ESV), and stroke volumes (SV) were obtained by cine CMR and conductance catheter. Results Statistically significant differences between cine CMR and conductance catheter derived volume measurements were found for EDV ( P < 0.001), ESV ( P < 0.05), and SV ( P < 0.05). Bland–Altman analysis showed very poor agreement between the two methods: EDV, bias 36.27 mL, agreement of limits 1.96–70.57 mL; ESV, bias 15.33 mL, agreement of limits –6.89–37.55 mL; and SV, bias 20.69 mL, agreement of limits 8.01–49.10 mL. Good agreement was found for SV between cine CMR and PC CMR (bias –7.0 mL, agreement of limits –24.01–9.98 mL), while SV derived from PC CMR measurements showed poor agreement with conductance catheter (bias 27.76 mL, agreement of limits –3.84–59.26 mL). Conclusion Poor agreement between the conductance catheter and CMR RV volume measurements was found. PC CMR and cine CMR measurements of SV agreed well.

Magnetic resonance hyperpolarization imaging detects early myocardial dysfunction in a porcine model of right ventricular heart failure

Aims Early detection of heart failure is important for timely treatment. During the development of heart failure, adaptive intracellular metabolic processes that evolve prior to macro-anatomic remodelling, could provide an early signal of impending failure. We hypothesized that metabolic imaging with hyperpolarized magnetic resonance would detect the early development of heart failure before conventional echocardiography could reveal cardiac dysfunction. Methods and results Five 8.5 kg piglets were subjected to pulmonary banding and subsequently examined by [1-13C]pyruvate hyperpolarization, conventional magnetic resonance imaging, echocardiography, and blood testing, every 4 weeks for 16 weeks. They were compared with a weight matched, healthy control group. Conductance catheter examination at the end of the study showed impaired right ventricular systolic function along with compromised left ventricular diastolic function. After 16 weeks, we saw a significant decrease in the conversion ratio of pyruvate/bicarbonate in the left ventricle from 0.13 (0.04) in controls to 0.07 (0.02) in animals with pulmonary banding, along with a significant increase in the lactate/bicarbonate ratio to 3.47 (1.57) compared with 1.34 (0.81) in controls. N-terminal pro-hormone of brain natriuretic peptide was increased by more than 300%, while cardiac index was reduced to 2.8 (0.95) L/min/m2 compared with 3.9 (0.95) in controls. Echocardiography revealed no changes. Conclusion Hyperpolarization detected a shift towards anaerobic metabolism in early stages of right ventricular dysfunction, as evident by an increased lactate/bicarbonate ratio. Dysfunction was confirmed with conductance catheter assessment, but could not be detected by echocardiography. Hyperpolarization has a promising future in clinical assessment of heart failure in both acquired and congenital heart disease.

The influence of acute unloading on left ventricular strain and strain rate by speckle tracking echocardiography in a porcine model

Noninvasive measurements of myocardial strain and strain rate by speckle tracking echocardiography correlate to cardiac contractile state but also to load, which may weaken their value as indices of inotropy. In a porcine model, we investigated the influence of acute dynamic preload reductions on left ventricular strain and strain rate and their relation to the pressure-conductance catheter-derived preload recruitable stroke work (PRSW) and peak positive first derivative of left ventricular pressure (LV-dP/d tmax). Speckle tracking strain and strain rate in the longitudinal, circumferential, and radial directions were measured during acute dynamic reductions of end-diastolic volume during three different myocardial inotropic states. Both strain and strain rate were sensitive to unloading of the left ventricle ( P < 0.001), but the load dependency for strain rate was modest compared with strain. Changes in longitudinal and circumferential strain correlated more strongly to changes in end-diastolic volume ( r = −0.86 and r = −0.72) than did radial strain ( r = 0.35). Longitudinal, circumferential, and radial strain significantly correlated with LV-dP/d tmax ( r = −0.53, r = −0.46, and r = 0.86), whereas only radial strain correlated with PRSW ( r = 0.55). Strain rate in the longitudinal, circumferential and radial direction significantly correlated with both PRSW ( r = −0.64, r = −0.58, and r = 0.74) and LV-dP/d tmax ( r = −0.95, r = −0.70, and r = 0.85). In conclusion, the speckle tracking echocardiography-derived strain rate is more robust to dynamic ventricular unloading than strain. Longitudinal and circumferential strain could not predict load-independent contractility. Strain rates, and especially in the radial direction, are good predictors of preload-independent inotropic markers derived from conductance catheter.

Abstract 17908: Milrinone Lacks Acute Inotropic And Lusitropic Effects Under Constant Afterload Conditions

Introduction: Phosphodiesterase III inhibitors are known to improve cardiac output in patients with heart failure. Whether this is due to a reduction in afterload, a positive inotropic effect, or an interaction of these factors is uncertain. We compared the inotropic and lusitropic effects of milrinone to those of commonly used catecholamines in a working Langendorff model under constant loading conditions. Methods: Sprague Dawley rats (n=35, 350-400 grams) were anesthetized and heparinized for cardiac explantation. The aorta and left atrium were immediately cannulated by a single experimenter. Left atrial pressure (10 mmHg) and aortic pressure (90 mmHg) were fixed. A conductance catheter (Millar) was inserted into the left ventricle. Following baseline measurements, infusions of milrinone, dopamine, dobutamine, epinephrine, or norephinephrine, alone and in commonly-used combinations, were initiated into the left atrium for 10 minute periods. Changes in cardiac output, contractility (dP/dTmax), diastolic performance (-dP/dT and Tau) relative to baseline were compared between groups by linear regression analysis. Results: Cardiac output increased in linear fashion for each of the catecholamines: Dobutamine>>Dopamine>Norepinephrine>Epinephrine (P<0.001 for each). Dobutamine, Norepinephrine, and Dopamine (P<0.05) significantly increased diastolic function, including negative dP/dT (C) and Tau (D), none of which were changed by Milrinone infusion. Conclusions: When afterload is fixed using a Starling resistor, milrinone at commonly used doses does not acutely change systolic or diastolic performance or cardiac output. It is possible that clinical improvements are due to milrinone’s vasodilatory properties.