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Introduction:Use of angiotensin converting enzyme inhibitors (ACEi) for the primary prevention of anthracycline cardiomyopathy (ACM) remains controversial. Prior clinical studies use isolated measures of cardiac function with short term follow up. Cardiac MRI (CMR) robustly characterizes myocardial tissue, and may quantify the effects of a primary prevention ACEi strategy.Purpose:We performed a pilot study to determine the feasibility of serial CMR to identify treatment effects of ACEi in a murine ACM model.Methods:Female BL6 mice (N=5/group) underwent 5 week induction with intraperitoneal doxorubicin injection 5mg/kg/wk (DOX), DOX + concurrent oral captopril for 5 weeks (EARLY), DOX + captopril for weeks 5-10 (LATE), or saline injection for 5 weeks (SHAM). CMR was performed on a Bruker 7T MRI using Intragate phase-gating at baseline (BL), 5, and 10 weeks. Image processing was performed using Circle-CVI42.Results:We observed equivalent 10-week survival in the DOX, EARLY and SHAM mice, all LATE mice died before 10 weeks (60% vs 0%, p<0.05). In surviving mice (N=3/group), no difference was observed in LVEF, end diastolic volume (EDV), myocardial mass (MM) or LV strain (2-factor ANOVA, p>0.2). However, there was a trend toward reduction of LVEF during induction in DOX and EARLY mice v. SHAM (-6% v. -12% v. 0.1% p=0.6), and EF improvement at 5 to 10 weeks in all mice (7%, v. 16% v. 1.4% p= 0.5). Similarly, EDV decreased during induction in the DOX and EARLY mice v. SHAM (-2.3 v.-8.6 v. 4.1 uL, p=0.3), with continued reduction at 5 to 10 weeks in DOX and increase in EARLY and SHAM mice (-1.6 v. 9.6 v. 2.2 uL, p= 0.3). MM decreased during induction in DOX and EARLY mice v. SHAM (-8 v. -18 v. -3 mg, p=0.04) with recovery at 5-10 weeks in EARLY mice similar to SHAM (-0.2 v. 16 v. 14 mg, p=0.02). We identified a trend toward improved LV radial, circumferential and longitudinal strain in EARLY mice during weeks 5-10. Changes in LV torsion were not significant (p=0.8).Conclusions:Serial CMR is a feasible method to assess murine ACM, however dose adjustments and increased sample sizes are necessary in further experiments. Delayed treatment with ACEi in mice was associated with increased mortality whereas early treatment appears to ameliorate the late adverse cardiac effects of ACM.

Introduction:Congenital heart disease (CHD) patients suffer higher incidence of neurocognitive impairment. Whether this is driven by abnormal placenta, hemodynamic perturbations from the CHD, cumulative injury, and/or patient intrinsic/genetic factors are difficult to address in human studies. Here we implemented in uteromulti-modal imaging for multi-factorial interrogation of fetal neurodevelopment in a mouse model of hypoplastic left heart syndrome (HLHS).Methods:HLHS mutant mouse embryos were generated by CRISPR targeting of Pcdha9 and Sap130. Intercrossing of double heterozygous parents yielded mouse embryos in the same litter with different genotypes. Fetal brain and placenta volumes were measured by volumetric analysis from fetal MRI (Fig.A); fetal ejection fraction (EF) was measured by echocardiography (Fig.BC); and placenta substrate delivery were evaluated by radioactive Tc99-sestamibi detected by SPECT (Fig.D).Results:Multi-modal imaging in uterowas conducted on a litter of 8 fetuses that included 3 wildtype (WT), 3 single (Sap130 or Pcdha9) heterozygous, and two double homozygous Sap130/Pcdha9 fetuses. Fetuses of the same genotypes segregated into different clusters in 3D plot of brain volume-placenta volume-substrate delivery (Fig.E). Overall fetal brain volume correlated with placenta volume (Fig. G) and substrate delivery (Fig. H), but not with fetal EF (Fig.I). In the double homozygous mutants, fetal brain and placental volumes and substrate delivery to placenta were markedly reduced.Conclusion:Our findings show that in the HLHS mouse model, fetal brain development is correlated with genotypes, placental volume, and placental substrate delivery, but independent of fetal cardiac output. These findings suggest that intrinsic genetic factors and placental function rather than fetal hemodynamics play crucial roles in neurodevelopment in the HLHS mouse model.

Background:Exercise-induced pulmonary hypertension (EIPH) portends early stage PH. However, there are no rodent models of EIPH, and its pathogenesis remains unclear. We hypothesizedthat ZSF-1 rats (which have metabolic syndrome and develop heart failure with preserved ejection fraction (HFpEF), treated with and without sugen (SU5416) to induce pulmonary vascular remodeling, would display EIPH with alterations in pulmonary artery vascular smooth muscle cell (PAVSM) soluble guanylate cyclase (sGC)-mediated signaling.Methods and Results:We utilized ZSF-1 lean (Ln), obese (Ob), and obese treated with SU5416 (OS) (N=5-8/group). RV and LV catheters were implanted to evaluate hemodynamics at rest (R) and during exercise (EX). During exercise, Ob rats showed significantly increased RV systolic pressure (R vs EX, Ln 28.8+/-1.0 vs 39.9+/-1.4; Ob 29.1+/-1.0 vs 53.2+/-2.9*#; OS; 38.0+/-1.1 vs 69.2+/-2.4*# mmHg; * p<0.05 vs same group at rest, # p<0.05 vs EX Ln), and increased LV end-diastolic pressure. Echocardiography post-exercise showed (? p<0.05 vs Ln) increased RV diastolic dimension in Ob (3.3+/-0.1mm?) and OS (4.0+/-0.1mm?) compared to Ln (2.7+/-0.1mm), and increased total pulmonary resistance index (Ob 2.6+/-0.1?; OS 3.9+/-0.3?; Ln 1.5+/-0.05), revealing RV dysfunction and exercise intolerance. Ln and Ob had similar RV function at rest, whereas OS rats showed significantly worse RV dysfunction, suggesting advanced HFpEF/PH. MRI showed no differences at rest between Ln and Ob in the cardiac contraction-dependent change of PA diameter (?PAd), whereas post-dobutamine challenge, Ob rats had significantly decreased ?PAd (Ln 1.0+/-0.08; Ob 0.66+/-0.06mm?). While Ln (R 18+/-2.5; EX 35+/-2.9pM/ml*) increased plasma cGMP levels after exercise, Ob (R 8.6+/-1.7#; EX 6.0+/-1.4# pM/ml) and OS (R 9.3+/-0.9; EX 11+/-2.5# pM/ml) had lower cGMP levels at rest that did not increase after exercise. Compared to cultured Ln PAVSM cells, Ob cells had lower relative sGC protein levels (Ln 1.0+/-0.06; Ob 0.5+/0.04?) and cGMP production (Ln 2.1?0.3; Ob, 0.8?0.2 ?M/mg protein?).Conclusions:This novel model shows exercise-induced PH and RV dysfunction, in which a deficit in PAVSM cell sGC activity occurs with lower cGMP levels and vascular responses to exercise.