Abstract P163: Rescue of Preexisting Severe Pulmonary Hypertension and Right Ventricular Failure by Intralipid

Pulmonary hypertension (PH) is characterized by pulmonary vascular remodeling leading to right ventricular (RV) hypertrophy and failure (RVF). Intralipid (ILP) is the first safe lipid emulsion for human use. Several constituents of ILP, like γ-linolenic acid and soy- phytoestrogens are protective for lungs and heart. Previously we showed that ILP prevents the development of PH. Here we test a more clinically relevant hypothesis if ILP can rescue pre-existing severe PH and RV dysfunction. To induce PH, male rats received single monocrotaline (MCT, 60mg/kg) injection. At day 21, when severe PH had been well-established (PH group, n=7), rats were given ILP (1mL of 20% ILP/day, i.p., n=7) from day 21-30. Other MCT rats were left untreated to develop RVF (RVF group, n=9) by day 30. Saline treated rats were control (CTRL, n=5). Serial echocardiography was done to monitor cardiopulmonary hemodynamics. Cardiac catheterisation was performed just before sacrifice to record RV pressure (RVP). CD31 staining for RV capillary density and smooth muscle actin staining for pulmonary arteriolar medial hypertrophy were performed. Rats developed severe PH and RV dysfunction 21 days after MCT in PH group [RVP=67±1 vs. 31±1mmHg in CTRL, RV-ejection fraction (RVEF)=39% vs. 65±1%; RV/(LV+IVS)=0.64±0.05 vs. 0.24±0.02; medial hypertrophy=2.8 fold vs. CTRL; all p&lt;0.05]. Interestingly, we found that even 10-day ILP therapy not only prevented the progression of PH to RVF but also rescued pre-existing PH and RV dysfunction [RVP=44±1 mmHg vs. 70±2 mmHg in RVF; RVEF=53±1 vs. 30±1%; RV/(LV+IVS)=0.39±0.02 vs. 0.66±0.08; medial hypertrophy=3 fold less vs. RVF; all p&lt;0.05]. ILP therapy resulted in 100% survival compared to only 25% survival in RVF. Next we investigated if ILP rescue was associated with stimulation of RV neoangiogenesis. We found that RV capillary density was decreased in PH (0.7±0.07 vs. 1±0.07 capillaries per myocyte in CTRL; p&lt;0.05) and worsened in RVF (0.52±0.07 capillaries per myocyte; p&lt;0.05 vs. CTRL). ILP therapy resulted in stimulation of neoangiogenesis (capillary density=0.98±0.01 capillaries per myocyte; p&lt;0.05 vs. PH and RVF). ILP therapy rescues severe pre-existing PH and retards the development of RV failure possibly via stimulation of RV neoangiogenesis.</jats:p

Abstract P130: Estrogen Receptor β Mediates the Rescue of Cardiac Function in Advanced Heart Failure by Promoting Neoangiogenesis and Reducing Fibrosis

Estrogen can act via the estrogen receptor alpha (ERa) or estrogen receptor beta (ERb) to exert its biological effects, and both of these receptors are present in the heart. We have previously shown that short-term estrogen (E2) treatment can rescue pressure overload-induced decompensated heart failure (HF) in mice, and that this rescue is achieved mainly through the ERb. Furthermore, E2 has been shown to regulate angiogenesis in different tissues. Because HF has been associated with decreased angiogenesis and increased fibrosis, here we investigated whether the E2-induced rescue of HF by the selective ERb agonist DPN can regulate cardiac fibrosis and neoangiogenesis. We used transaortic constriction to induce HF, and once the ejection fraction (EF) reached ∼30%, one group of animals was sacrificed (HF group), and the other three groups received either 17b-estradiol via a subcutaneous pellet implant (0.012mg/pellet, n=16), selective ERa agonist (PPT, 0.625mg/kg/day), or selective ERb agonist (DPN, 0.625mg/kg/day) for 10 days. Serial echocardiography was performed to monitor cardiac structure and function. As expected, E2 rescued HF by restoring EF from 33.17±1.12% to 53.05±1.29%. Mice treated with DPN had a significant EF improvement from 33.17±1.12% to 45.25±2.1% (n=7), while the EF of PPT-treated mice did not improve (31.09±2.3%, n=6). Similarly, only the fractional shortening of DPN-treated mice improved from 15.7±0.58% in HF to 21.95±1.65% with DPN treatment vs. 14.72±1.24% with PPT. Next, we examined whether promotion of cardiac neoangiogenesis and suppression of fibrosis by the selective ERb agonist are possible mechanisms in the rescue action of HF by DPN. DPN treatment was able to reverse the interstitial and perivascular fibrosis observed in HF, while PPT had no effect. The selective ERb agonist also stimulated neoangiogenesis, as the capillary density was increased from 0.46±0.04 microvessels/cardiomyocyte in HF to 0.67±0.07 with DPN treatment, whereas PPT treatment had no effect (0.43±0.03). Our data strongly suggests that upregulation of cardiac neoangiogenesis and reversal of fibrosis are pivotal mechanisms in rescuing advanced HF by the estrogen receptor beta agonist DPN.</jats:p