Rationale: In heritable pulmonary arterial hypertension with germline mutation in the bone morphogenetic protein receptor type 2 (BMPR2) gene, right ventricle (RV) dysfunction is associated with RV lipotoxicity; however, the underlying mechanism for lipid accumulation is not known.Objectives: We hypothesized that lipid accumulation in cardiomyocytes with BMPR2 mutation occurs owing to alterations in lipid transport and impaired fatty acid oxidation (FAO), which is exacerbated by a high-lipid (Western) diet (WD).Methods: We used a transgenic mouse model of pulmonary arterial hypertension with mutant BMPR2 and generated a cardiomyocyte cell line with BMPR2 mutation. Electron microscopy and metabolomic analysis were performed on mouse RVs.Measurements and Main Results: By metabolomics analysis, we found an increase in long-chain fatty acids in BMPR2 mutant mouse RVs compared with controls, which correlated with cardiac index. BMPR2-mutant cardiomyocytes had increased lipid compared with controls. Direct measurement of FAO in the WD-fed BMPR2-mutant RV showed impaired palmitate-linked oxygen consumption, and metabolomics analysis showed reduced indices of FAO. Using both mutant BMPR2 mouse RVs and cardiomyocytes, we found an increase in the uptake of 14 C-palmitate and fatty acid transporter CD36 that was further exacerbated by WD.Conclusions: Taken together, our data suggest that impaired FAO and increased expression of the lipid transporter CD36 are key mechanisms underlying lipid deposition in the BMPR2-mutant RV, which are exacerbated in the presence of dietary lipids. These findings suggest important features leading to RV lipotoxicity in pulmonary arterial hypertension and may point to novel areas of therapeutic intervention.

Childhood survivors of cancer who are treated with anthacycline chemotherapy, such as doxorubicin (DOX), can develop late-onset cardiomyopathy years after chemotherapy. The mechanism(s) for progression of anthracycline cardiotoxicity to late cardiomyopathy is unknown. Because angiotensin II has been implicated in the progression of other cardiomyopathies, this investigation was undertaken to determine whether treatment with an angiotensinconverting enzyme (ACE) inhibitor, lisinopril, reduces the time-dependent effects of doxorubicin on cardiac gene expression and myocellular apoptosis. A single dose of saline (control) or doxorubicin (DOX treated; 2 mg/kg iv) was administered to rabbits. Control and DOX-treated groups were also subgrouped to receive lisinopril and designated as lisinopril or DOX + lisinopril, respectively (1 mg/kg/d oral), for 10 wk. Histopathology, as determined at the light and ultrastructural level, was consistent with a reduced number of cardiomyocytes relative to interstitial cells in the left ventricle (LV) of the DOX-treated group compared with control and DOX + lisinopril groups. Gene expression of the pro-atrial naturetic peptide (ANP), quantified by steady-state messenger ribonucleic acid (mRNA) levels with reverse transcriptase polymerase chain reaction (RT-PCR) and Southern blotting, increased approx 12-fold (n = 10; p < 0.05) in the LV of DOX-treated groups compared to control and DOX + lisinopril groups. Increased ANP mRNA expression following doxorubicin dosing was localized predominantly in ventricular myocytes by in situ hybridization. Deoxyribonucleic acid (DNA) fragmentation, determined by TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling), was increased in both DOX-treated and DOX + lisinopril groups compared to the control group. Lisinopril prevented both late-onset increased ventricular ANP expression and subsequent DOX-induced myocyte loss. The authors speculate that these protective effects of lisinopril are related to reduced ANP expression and myocyte loss, the latter possibly mediated by effects on myocellular apoptosis.

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SUMMARY A thermal diffusion flow probe which gave a continuous, dynamic, quantitative record of cortical blood flow (CBF) was used to assess CBF in experimental animals with controlled hypotension. Acute hypotension was produced by trimethaphan camsylate, halothane, and sodium nitroprusside. Halothane produced less reduction in CBF per drop in blood pressure than the other two agents.