Background: Obesity is associated with incident heart failure (HF), particularly HF with preserved ejection fraction (HFpEF). Weight loss is difficult to achieve in patients with limited physical capacity and the benefits remain uncertain in established HF. Methods: Patients with EF > 50% and at least 1 objective criteria for HFpEF (BNP 200 pg/ml, elevated resting or exercise wedge pressure (15 or 25 mmHg) or pulmonary edema on CXR) and BMI 30 kg/m2 were enrolled in a 15-week weight management program that entailed weekly counseling, weight checks, and meal replacement (twice daily weeks 1-8, once daily weeks 9-12). Primary endpoints were change from baseline to 15-weeks for weight, Minnesota Living With HF (MLWHF) score and 6 minute walk (6MW). Paired t-test was used to test for differences from baseline to the 15 week clinical endpoint, and one-way ANOVA was used to evaluate if these differences persisted at 26 week follow up. Results: 65 patients signed consent, 41 completed the 15-week program and 37 had 26-week follow up. Mean age was 67±9 years, BMI 41±6 kg/m 2 , 65% were female, and 43% black. Mean weight decreased by 8.1±6.6 kg at the 15-week endpoint (p<0.001) and persisted at 26-week follow up (p<0.001). 74% of patients lost more than 5% of their baseline body weight at week 15. Blacks lost a mean of 6±6% body weight compared to 9±4% in Caucasians (p<0.05). At 15 weeks, mean 6MW distance increased from 221±111 m to 286±99 m (p<0.001) and then fell to 275±144 m at 26 weeks (p=0.043). MLWHF score improved from 60±24 to 38±27 (p<0.001) and 38±26 (p<0.001) at 15 and 26 weeks, respectively. BNP did not change (109 to 114 pg/ml). E/e’ decreased significantly from 13.9±6.8 to 11.9±5.6 at 26 weeks follow up (p<0.01). BNP levels decreased by 39±103 pg/ml in blacks vs. an increase of 17±53 mg/dl in Caucasians (p<0.05) at 15-week follow up. Conclusions: Clinically relevant weight loss is possible in patients with established HFpEF and when it occurs, this is associated with significant improvements in quality of life and exercise capacity. There may be racial differences in the biochemical response to weight management in this population.

Fetal alcohol syndrome is often associated with congenital heart defects. Our studies focus on the role of cardiac fibroblasts in the developing heart, and how they are affected by prenatal ethanol exposure. Fibroblasts are the most numerous cardiac cell type and play an essential role in development of the heart. They are responsible for synthesis of the extracellular matrix, which provides the scaffold for heart muscle. Our lab has previously shown that ethanol exposure in adult hearts promote fibroblast activation and transition into myofibroblasts. Based on this, we believe that in utero ethanol exposure causes alterations in fibroblast function that could contribute to dysregulation in collagen synthesis and impaired scaffolding of the neonatal heart. Therefore, we hypothesize that in utero ethanol activates neonatal cardiac fibroblasts, which leads to a profibrotic phenotype and cardiac dysfunction.To investigate these effects, we performed in utero EtOH administration in wildtype dams. Pregnant mice were intraperitoneally injected with 2.9 g EtOH/kg body weight to achieve a blood ethanol content of approximately 0.26 on gestation day 6.75. On neonatal day 5, pups were weighed prior to sacrifice. Body weight was decreased in the WT+EtOH pups, which is a hallmark of fetal alcohol syndrome. Hearts were homogenized, and Western Blot analysis was performed to determine protein expression. Collagen I decreased in ethanol exposed neonates, but collagen III expression was significantly increased, so the collagen I/III ratio was decreased. Collagen I gives hearts a more tensile and stiff phenotype, whereas collagen III gives a more compliant phenotype; therefore, a decrease in collagen I/III ratio would correlate with a dilated heart. Subsequently, this can significantly impair diastolic function. Overall, our data shows a correlation between prenatal ethanol exposure and a profibrotic phenotype in neonatal hearts.We were further interested in assessing whether these changes in collagen translated into changes in cardiac function. Left ventricular (LV) chamber dimension and function were assessed in sedated animals on neonatal day 5 using echocardiography. Eccentric index was calculated as a ratio of LV interior diameter and LV posterior wall thickness*2 at diastole and at systole. There was a significant increase in the eccentric index at both systole and diastole in ethanol exposed animals, indicative of LV dilation. This is in agreement with our previous collagen findings, which further supports the possibility of a dilated cardiac phenotype. In analyzing systolic function, LV end systolic volume increased, and both ejection fraction and fractional shortening decreased in the ethanol treated animals. Our functional measurements demonstrate that in utero ethanol exposure decreases collagen I/III protein ratio in neonatal hearts, which ultimately causes a decline in both diastolic and systolic function.Support or Funding InformationSaving Tiny Hearts SocietyThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The collagen crosslinking enzyme, lysyl oxidase (LOX), is elevated in human dilated cardiomyopathy and heart failure, but it is not known if LOX plays a causative role in disease. However, clinical evidence shows that diuretics with LOX inhibitory properties are more effective at slowing the progression of heart failure. Using the aortocaval fistula (ACF) rat model of volume overload, we assessed the efficacy of LOX inhibition to reverse cardiac fibrosis and dysfunction in rodents with established cardiac disease. Serial echocardiography was used to evaluate cardiac structural and functional changes. LOX inhibition (100 mg/kg/d BAPN; osmotic minipumps) was initiated 8 wks post‐surgery in ACF and SHAM‐operated rats. Treatment continued for 6 wks and hearts were collected for analysis. Left ventricular (LV) sections were stained with PSR for collagen volume fraction (CVF). Protein expression was assessed in LV homogenates by WB. Untreated ACF had significantly increased LV LOX expression (65% increase), concomitant with LV dilatation (43% increase), depressed fractional shortening (26% decrease), increased collagen cross‐linking (52% increase), and interstitial fibrosis (CVF; 135% increase) relative to SHAM (p<0.05). LOX inhibition reversed fibrosis (CVF; Treated ACF vs SHAM; p=NS) and partially restored cardiac function (20% increase vs Untreated ACF). However, there was no significant reversal of LV hypertrophy or dilatation. LV NADPH oxidase‐4 was increased in untreated ACF (52% increase vs SHAM), but was not different in treated ACF, indicating a possible role for oxidative stress in the observed beneficial effects of LOX inhibition. These data identify inhibition of LOX activity as a potential therapeutic approach for the regression of cardiac fibrosis and improvement of function in heart failure patients. Grant Funding Source: Supported by LSUSOM REF grant (jdg) and the American Heart Association GSA 11GRNT7700002 (jdg)

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