Sequential multidisciplinary minimally invasive therapeutic strategy for heart failure caused by four diseases: A case report.

BACKGROUND: The coexistence with patent ductus arteriosus (PDA), mitral valve prolapse (MVP), atrial fibrillation (AF) and hyperthyroidism is extremely rare and complex. The optimal therapeutic strategy is difficult to develop. CASE SUMMARY: A 27-year-old female with PDA, MVP, AF and hyperthyroidism presented with severe dyspnea. Given that a one-stage operation for PDA, MVP and AF is high risk, we preferred a sequential multidisciplinary minimally invasive therapeutic strategy. First, PDA transcatheter closure was performed. Hyperthyroidism and heart failure were simultaneously controlled via medical treatment. Video-assisted thoracoscopic mitral valve repair and left atrial appendage occlusion were performed when heart failure was controlled. Under this therapeutic strategy, the patient's sinus rhythm was restored and maintained. Two years after the treatment, the symptoms of heart failure were relieved, and the enlarged heart was reversed. CONCLUSION: Sequential multidisciplinary therapeutic strategies, which take advantage of both internal medicine and surgical approaches, might be reasonable for this type of disease.

Inhibition of farnesyl pyrophosphate synthase improves pressure overload induced chronic cardiac remodeling.

Farnesyl pyrophosphate synthase (FPPS) is a key enzyme in the mevalonate pathway. In our previous studies, we find that inhibition of FPPS attenuates angiotensin II-induced cardiac hypertrophy and fibrosis by suppressing RhoA while FPPS and Ras are up-regulated in pressure overload rats. In this study, we evaluate the effects and mechanisms of FPPS inhibition in pressure overload mice. Male FPPS-small interfering RNA (SiRNA) transgenic (Tg) mice and non-transgenic littermate control (NLC) were randomly divided into suprarenal abdominal aortic constriction (AAC) group and sham operation group. 12 weeks following AAC, mice were sacrificed by cervical dislocation. Histological and echocardiographic assessments showed that inhibition of FPPS improved chronic cardiac remodeling which was induced by AAC. The reductions of Ras farnesylation and GTP-Ras, as well as their downstream extracellular signal-related kinases 1/2 (ERK1/2) expression were observed in the heart of Tg-AAC mice compared with NLC-AAC mice, along with the reduction of fetal gene expression. We provide here important experimental evidence that inhibition of FPPS improves AAC induced chronic cardiac remodeling and fibrosis by the reduction of farnesylated Ras and the downregulation of Ras-ERK1/2 pathway.

Lentiviral-mediated silencing of farnesyl pyrophosphate synthase through RNA interference in mice.

Farnesyl pyrophosphate synthase (FPPS) plays a vital role in the mevalonate pathway and has been shown to be involved in hypertrophy and cardiovascular diseases. Lentivirus-mediated RNA interference (RNAi) to knock down a gene of interest has become a promising new tool for the establishment of transgenic animals. The interfering fragment, named pLVT202, was chosen from cardiomyocytes tested in vitro and was microinjected into the perivitelline space of zygotes from C57BL/6J mice via a lentivirus vehicle; 20 were identified as carrying copies of the transgene using the polymerase chain reaction (PCR). Real-time PCR and western blotting analysis showed that FPPS was downregulated in multiple tissues in the transgenic mice. The transgenic mouse model provides a novel means of studying the gene function of FPPS.

Inhibition of farnesyl pyrophosphate synthase attenuates angiotensin II-induced cardiac hypertrophy and fibrosis in vivo.

Farnesyl pyrophosphate synthase (FPPS), as a key branchpoint of the mevalonate pathway, catalyzes the synthesis of isoprenoid intermediates. The isoprenoid intermediates are needed for protein isoprenylation to participate in cardiac remodeling. We have previously demonstrated that both knockdown of FPPS with small interfering RNA and inhibition of FPPS by alendronate could prevent Ang II-induced hypertrophy in cultured cardiomyocytes. In this study, we evaluated the effects of FPPS inhibition in Ang II-mediated cardiac hypertrophy and fibrosis in vivo. Wild type mice were separately treated with saline, Ang II (2.88 mg/kg per day), FPPS inhibitor alendronate (0.1 mg/kg per day), or the combination of Ang II (2.88 mg/kg per day) and alendronate (0.1 mg/kg per day) for 4 weeks. The results showed that Ang II increased FPPS expression, and the increases of Ang II-induced synthesis of the isoprenoid intermediates, FPP and GGPP, were significantly inhibited by FPPS inhibitor. In the meantime, FPPS inhibition attenuated Ang II-mediated cardiac hypertrophy and fibrosis as indexed by the heart weight to body weight ratio, echocardiographic parameters, histological examinations and expression of ANP and BNP mRNA. Furthermore, it was also found that FPPS inhibitor attenuated Ang II-induced increases of RhoA activity and p-38 MAPK phosphorylation and TGF-ß1 mRNA expression. In conclusion, FPPS might play an important role in Ang II-induced cardiac hypertrophy and fibrosis in vivo, at least in part through RhoA, p-38 MAPK and TGF-ß1.

Cardiac-specific overexpression of farnesyl pyrophosphate synthase induces cardiac hypertrophy and dysfunction in mice.

AIMS: Farnesyl pyrophosphate synthase (FPPS) is a key enzyme in the mevalonate pathway. In our previous study, we found that inhibition of FPPS attenuates cardiac hypertrophy in spontaneously hypertensive rats (SHRs) and prevents angiotensin (Ang) II-induced hypertrophy in cardiomyocytes. Here, we further investigate the role of FPPS in cardiac hypertrophy and heart failure (HF) using a transgenic (Tg) model, and its mechanisms. METHODS AND RESULTS: Tg mice with cardiac-specific expression of FPPS were studied as an experimental model. The results showed that Tg mice with overexpression of FPPS exhibited cardiac hypertrophy, fibrosis, and HF, as well as increased synthesis of farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate in heart tissue. These pathological changes were associated with the activation of RhoA and other known kinases in the hypertrophic signalling pathway, such as extracellular signal-related kinases 1/2 and p38. Adenoviral infection of FPPS in cultured neonatal cardiomyocytes induced a hypertrophic response characterized by an increased cell size and an increased extent of sarcomeric organization, as well as an increased activation profile of small GTPases and downstream protein kinases concordant with those seen in vivo. Further investigation showed a marked increase of FPPS protein levels in hypertrophic ventricles of patients with valvular heart disease. CONCLUSION: Taken together, these results suggest that FPPS may function as a potent regulator in myocardial remodelling. The FPPS-regulated signalling pathway is relevant to the pathological changes in cardiac hypertrophy and HF.