Early use of intrapartum intra-aortic balloon pump support for haemodynamic stabilization of peripartum and anthracycline-induced cardiomyopathy: a case report.

Background: Prior exposure to cardiotoxic cancer therapies has been associated with an increased risk of peripartum cardiomyopathy (PPCM). The management of PPCM in this population remains a clinical challenge. Few studies have explored the use of mechanical circulatory support in PPCM. We present a case of early implementation of intra-aortic balloon pump (IABP) therapy for acute stabilization and intrapartum support of PPCM. Case summary: A 36-year-old G4P2103 (4th pregnancy, two full-term, one premature birth, 0 abortions, and three living children) woman at 26 weeks and 5 days gestation with history of combined peripartum and anthracycline-induced cardiomyopathy [previously left ventricular ejection fraction (LVEF) 10-15% and recently 40-45%] presented with acute decompensated heart failure. Her clinical status deteriorated with a drop in LVEF to 15-20% with a significant increase in pulmonary pressures and worsening mitral regurgitation. A multidisciplinary decision with the cardio-obstetrics team was made to place a pulmonary artery catheter for invasive haemodynamic monitoring and IABP insertion prior to delivery. Intra-aortic balloon pump support had a profound immediate decrease in her systemic and pulmonary vascular resistance allowing for a successful repeat caesarean delivery. Her haemodynamics remained stable after IABP removal and pulmonary pressures improved. She was discharged one week following her delivery on guideline-directed medical therapy. Discussion: Our case highlights the use of prophylactic intrapartum IABP in combined anthracycline-induced and PPCM and begins to explore its safety and efficacy in this high-risk patient population.

Bioresorbable vascular scaffolds versus everolimus-eluting stents: a biomechanical analysis of the ABSORB III Imaging substudy.

AIMS: The Absorb bioresorbable vascular scaffold (BVS) has high rates of target lesion failure (TLF) at three years. Low wall shear stress (WSS) promotes several mechanisms related to device TLF. We investigated the impact of BVS compared to XIENCE V (XV) on coronary WSS after device deployment. METHODS AND RESULTS: In the prospective, randomised, controlled ABSORB III Imaging study (BVS [n=77] or XV [n=36]), computational fluid dynamics were performed on fused angiographic and intravascular ultrasound (IVUS) images of post-implanted vessels. Low WSS was defined as <1 Pa. There were no differences in demographics, clinical risks, angiographic reference vessel diameter or IVUS minimal lumen diameter between BVS and XV patients. A greater proportion of vessels treated with BVS compared to XV demonstrated low WSS across the whole device (BVS: 17/77 [22%] vs XV: 2/36 [6%], p<0.029). Compared to XV, BVS demonstrated lower median circumferential WSS (1.73 vs 2.21 Pa; p=0.036), outer curvature WSS (p=0.026), and inner curvature WSS (p=0.038). Similarly, BVS had lower proximal third WSS (p=0.024), middle third WSS (p=0.047) and distal third WSS (p=0.028) when compared to XV. In a univariable logistic regression analysis, patients who received BVS were 4.8 times more likely to demonstrate low WSS across the scaffold/stent when compared to XV patients. Importantly, in a multivariable linear regression model, hypertension (beta: 0.186, p=0.023), lower contrast frame count velocity (beta: -0.411, p<0.001), lower post-stent residual plaque burden (beta: -0.338, p<0.001), lower % underexpanded frames (beta: -0.170, p=0.033) and BVS deployment (beta: 0.251, p=0.002) remained independently associated with a greater percentage of stented coronary vessel areas exposed to low WSS. CONCLUSIONS: In this randomised controlled study, the Absorb BVS was 4.8 times more likely than the XV metallic stent to demonstrate low WSS. BVS implantation, lower blood velocity and lower residual post-stent plaque burden were independently associated with greater area of low WSS.

High Coronary Shear Stress in Patients With Coronary Artery Disease Predicts Myocardial Infarction.

BACKGROUND: Coronary lesions with low fractional flow reserve (FFR) that are treated medically are associated with higher revascularization rates. High wall shear stress (WSS) has been linked with increased plaque vulnerability. OBJECTIVES: This study investigated the prognostic value of WSS measured in the proximal segments of lesions (WSSprox) to predict myocardial infarction (MI) in patients with stable coronary artery disease (CAD) and hemodynamically significant lesions. The authors hypothesized that in patients with low FFR and stable CAD, higher WSSprox would predict MI. METHODS: Among 441 patients in the FAME II (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation II) trial with FFR ≤0.80 who were randomized to medical therapy alone, 34 (8%) had subsequent MI within 3 years. Patients with vessel-related MI and adequate angiograms for 3-dimensional reconstruction (n = 29) were propensity matched to a control group with no MI (n = 29) by using demographic and clinical variables. Coronary lesions were divided into proximal, middle, and distal, along with 5-mm upstream and downstream segments. WSS was calculated for each segment. RESULTS: Median age was 62 years, and 46 (79%) were male. In the marginal Cox model, whereas lower FFR showed a trend (hazard ratio: 0.084; p = 0.064), higher WSSprox (hazard ratio: 1.234; p = 0.002, C-index = 0.65) predicted MI. Adding WSSprox to FFR resulted in a significant increase in global chi-square for predicting MI (p = 0.045), a net reclassification improvement of 0.69 (p = 0.005), and an integrated discrimination index of 0.11 (p = 0.010). CONCLUSIONS: In patients with stable CAD and hemodynamically significant lesions, higher WSS in the proximal segments of atherosclerotic lesions is predictive of MI and has incremental prognostic value over FFR.

Implications of a peroxisome proliferator-activated receptor alpha (PPARα) ligand clofibrate in breast cancer.

Inflammatory and invasive breast cancers are aggressive and require better understanding for the development of new treatments and more accurate prognosis. Here, we detected high expression of PPARα in human primary inflammatory (SUM149PT) and highly invasive (SUM1315MO2) breast cancer cells, and tissue sections of human breast cancer. PPARα ligands are clinically used to treat dyslipidemia. Among lipid lowering drugs clofibrate, fenofibrate and WY14643, clofibrate showed high chemo-sensitivity towards breast cancer cells. Clofibrate treatment significantly induced PPARα DNA binding activity, and remarkably reduced cyclooxygenase-2/PGE2 and 5-lipoxygenase/LTB4 inflammatory pathways. Clofibrate treatment reduced the proliferation of breast cancer cells probably by inhibiting NF-κB and ERK1/2 activation, reducing cyclinD1, cyclinA, cyclinE, and inducing pro-apoptotic P21 levels. Surprisingly, the expression of lipogenic pathway genes including SREBP-1c (sterol regulatory element-binding protein-1c), HMG-CoA synthase, SPTLC1 (serine palmitoyltransferase long-chain), and Acyl-CoA oxidase (ACO) decreased with a concurrent increase in fatty acid oxidation genes such as CPT-1a (carnitine palmitoyltransferase 1a) and SREBP-2 (Sterol regulatory element-binding protein-2). Clofibrate treatment induced secretion of free fatty acids and effectively decreased the level of phosphorylated active form of fatty acid synthase (FASN), an enzyme catalyzing de novo synthesis of fatty acids. High level of coactivators steroid receptor coactivator-1 (SRC-1) and histone acetylase CBP-300 (CREB binding protein-300) were observed in the nuclear complexes of clofibrate treated breast cancer cells. These findings implicate that stimulating PPARα by safe, well-tolerated, and clinically approved clofibrate may provide a safer and more effective strategy to target the signaling, lipogenic, and inflammatory pathways in aggressive forms of breast cancer.

The Kaposi's sarcoma-associated herpesvirus (KSHV)-induced 5-lipoxygenase-leukotriene B4 cascade plays key roles in KSHV latency, monocyte recruitment, and lipogenesis.

Kaposi's sarcoma-associated herpesvirus (KSHV) is etiologically associated with Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). KS lesions are characterized by endothelial cells with multiple copies of the latent KSHV episomal genome, lytic replication in a low percentage of infiltrating monocytes, and inflammatory cytokines plus growth factors. We demonstrated that KSHV utilizes inflammatory cyclooxygenase 2/prostaglandin E2 to establish and maintain latency (Sharma-Walia, N., A. G. Paul, V. Bottero, S. Sadagopan, M. V. Veettil, N. Kerur, and B. Chandran, PLoS Pathog 6:e1000777, 2010 [doi:10.1371/journal.ppat.1000777]). Here, we evaluated the role of 5-lipoxygenase (5LO) and its chemotactic metabolite leukotriene B4 (LTB4) in KSHV biology. Abundant staining of 5LO was detected in human KS tissue sections. We observed elevated levels of 5LO and high levels of secretion of LTB4 during primary KSHV infection of endothelial cells and in PEL B cells (BCBL-1 and BC-3 cells). Blocking the 5LO/LTB4 cascade inhibited viral latent ORF73, immunomodulatory K5, viral macrophage inflammatory protein 1 (MIP-1), and viral MIP-2 gene expression, without much effect on lytic switch ORF50, immediate early lytic K8, and viral interferon-regulatory factor 2 gene expression. 5LO inhibition significantly downregulated latent viral Cyclin and latency-associated nuclear antigen 2 levels in PEL cells. 5LO/LTB4 inhibition downregulated TH2-related cytokine secretion, elevated TH1-related cytokine secretion, and reduced human monocyte recruitment, adhesion, and transendothelial migration. 5LO/LTB4 inhibition reduced fatty acid synthase (FASN) promoter activity and its expression. Since FASN, a key enzyme required in lipogenesis, is important in KSHV latency, these findings collectively suggest that 5LO/LTB4 play important roles in KSHV biology and that effective inhibition of the 5LO/LTB4 pathway could potentially be used in treatment to control KS/PEL.

NFAT and CREB regulate Kaposi's sarcoma-associated herpesvirus-induced cyclooxygenase 2 (COX-2).

COX-2 has been implicated in Kaposi's sarcoma-associated herpesvirus (KSHV) latency and pathogenesis (A. George Paul, N. Sharma-Walia, N. Kerur, C. White, and B. Chandran, Cancer Res. 70:3697-3708, 2010; P. P. Naranatt, H. H. Krishnan, S. R. Svojanovsky, C. Bloomer, S. Mathur, and B. Chandran, Cancer Res. 64:72-84, 2004; N. Sharma-Walia, A. G. Paul, V. Bottero, S. Sadagopan, M. V. Veettil, N. Kerur, and B. Chandran, PLoS Pathog. 6:e1000777, 2010; N. Sharma-Walia, H. Raghu, S. Sadagopan, R. Sivakumar, M. V. Veettil, P. P. Naranatt, M. M. Smith, and B. Chandran, J. Virol. 80:6534-6552, 2006). However, the precise regulatory mechanisms involved in COX-2 induction during KSHV infection have never been explored. Here, we identified cis-acting elements involved in the transcriptional regulation of COX-2 upon KSHV de novo infection. Promoter analysis using human COX-2 promoter deletion and mutation reporter constructs revealed that nuclear factor of activated T cells (NFAT) and the cyclic AMP (cAMP) response element (CRE) modulate KSHV-mediated transcriptional regulation of COX-2. Along with multiple KSHV-induced signaling pathways, infection-induced prostaglandin E(2) (PGE(2)) also augmented COX-2 transcription. Infection of endothelial cells markedly induced COX-2 expression via a cyclosporine A-sensitive, calcineurin/NFAT-dependent pathway. KSHV infection increased intracellular cAMP levels and activated protein kinase A (PKA), which phosphorylated the CRE-binding protein (CREB) at serine 133, which probably led to interaction with CRE in the COX-2 promoter, thereby enhancing COX-2 transcription. PKA selective inhibitor H-89 pretreatment strongly inhibited CREB serine 133, indicating the involvement of a cAMP-PKA-CREB-CRE loop in COX-2 transcriptional regulation. In contrast to phosphatidylinositol 3-kinase and protein kinase C, inhibition of FAK and Src effectively reduced KSHV infection-induced COX-2 transcription and protein levels. Collectively, our study indicates that mediation of COX-2 transcription upon KSHV infection is a paradigm of a complex regulatory milieu involving the interplay of multiple signal cascades and transcription factors. Intervention at each step of COX-2/PGE(2) induction can be used as a potential therapeutic target to treat KSHV-associated neoplasm and control inflammatory sequels of KSHV infection.