A.S. Cruz-Solbes

A specifically designed nanoconstruct associates, internalizes, traffics in cardiovascular cells, and accumulates in failing myocardium: a new strategy for heart failure diagnostics and therapeutics.

Ongoing inflammation and endothelial dysfunction occurs within the local microenvironment of heart failure, creating an appropriate scenario for successful use and delivery of nanovectors. This study sought to investigate whether cardiovascular cells associate, internalize, and traffic a nanoplatform called mesoporous silicon vector (MSV), and determine its intravenous accumulation in cardiac tissue in a murine model of heart failure.

Pulmonary Hypertension Associated with Idiopathic Pulmonary Fibrosis: Current and Future Perspectives

Pulmonary hypertension (PH) is commonly present in patients with chronic lung diseases such as Chronic Obstructive Pulmonary Disease (COPD) or Idiopathic Pulmonary Fibrosis (IPF) where it is classified as Group III PH by the World Health Organization (WHO). PH has been identified to be present in as much as 40% of patients with COPD or IPF and it is considered as one of the principal predictors of mortality in patients with COPD or IPF. However, despite the prevalence and fatal consequences of PH in the setting of chronic lung diseases, there are limited therapies available for patients with Group III PH, with lung transplantation remaining as the most viable option. This highlights our need to enhance our understanding of the molecular mechanisms that lead to the development of Group III PH. In this review we have chosen to focus on the current understating of PH in IPF, we will revisit the main mediators that have been shown to play a role in the development of the disease. We will also discuss the experimental models available to study PH associated with lung fibrosis and address the role of the right ventricle in IPF. Finally we will summarize the current available treatment options for Group III PH outside of lung transplantation.

Epithelial to Mesenchymal Transition (EMT) and Endothelial to Mesenchymal Transition (EndMT): Role and Implications in Kidney Fibrosis

Tubulointerstitial injury is one of the hallmarks of renal disease. In particular, interstitial fibrosis has a prominent role in the development and progression of kidney injury. Collagen-producing fibroblasts are responsible for the ECM deposition. However, the origin of those activated fibroblasts is not clear. This chapter will discuss in detail the concept of epithelial to mesenchymal transition (EMT) and endothelial to mesenchymal transition (EndMT) in the context of fibrosis and kidney disease. In short, EMT and EndMT involve a change in cell shape, loss of polarity and increased motility associated with increased collagen production. Thus, providing a new source of fibroblasts. However, many controversies exist regarding the existence of EMT and EndMT in kidney disease, as well as its burden and role in disease development. The aim of this chapter is to provide an overview of the concepts and profibrotic pathways and to present the evidence that has been published in favor and against EMT and EndMT.

Rapamycin nanoparticles localize in diseased lung vasculature and prevent pulmonary arterial hypertension.

Vascular remodeling resulting from pulmonary arterial hypertension (PAH) leads to endothelial fenestrations. This feature can be exploited by nanoparticles (NP), allowing them to extravasate from circulation and accumulate in remodeled pulmonary vessels. Hyperactivation of the mTOR pathway in PAH drives pulmonary arterial smooth muscle cell proliferation. We hypothesized that rapamycin (RAP)-loaded NPs, an mTOR inhibitor, would accumulate in diseased lungs, selectively targeting vascular mTOR and preventing PAH progression. RAP poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-PCL) NPs were fabricated. NP accumulation and efficacy were examined in a rat monocrotaline model of PAH. Following intravenous (IV) administration, NP accumulation in diseased lungs was verified via LC/MS analysis and confocal imaging. Pulmonary arteriole thickness, right ventricular systolic pressures, and ventricular remodeling were determined to assess the therapeutic potential of RAP NPs. Monocrotaline-exposed rats showed increased NP accumulation within lungs compared to healthy controls, with NPs present to a high extent within pulmonary perivascular regions. RAP, in both free and NP form, attenuated PAH development, with histological analysis revealing minimal changes in pulmonary arteriole thickness and no ventricular remodeling. Importantly, NP-treated rats showed reduced systemic side effects compared to free RAP. This study demonstrates the potential for nanoparticles to significantly impact PAH through site-specific delivery of therapeutics.

Anemia after continuous-flow left ventricular assist device implantation: characteristics and implications

Background Anemia is common in patients with heart failure and is associated with adverse outcomes. Management of anemia in CF-LVAD patients is not well studied. Our purpose is to characterize and identify the etiology of anemia in CF-LVAD patients. Secondary objectives are to describe the effect of CF-LVAD on pre-existing anemia and assess its impact after CF-LVAD support. Methods Cross-sectional study from January to July 2015 of ambulatory patients supported with a CF-LVAD for at least 6-months that presented with hemoglobin <12 g/dL and no recent gastrointestinal bleeding. Patients were classified as iron-deficient and non-iron-deficient and compared. Additionally, a retrospective analysis of 116 consecutive patients who underwent CF-LVAD from 2008 to 2013 with reported hemoglobin at 6 months as outpatients were divided into anemic or non-anemic and compared. Results In our cross-sectional cohort, iron deficiency was the most common cause of anemia. Notably, 49% of the iron-deficient patients were already on iron supplementation. In our retrospective cohort, 59% of the patients were anemic after 6 months of support. Anemic patients were older, had lower albumin, higher brain natriuretic peptide (BNP), worse renal function and New York Heart Association (NYHA) class. Anemia had a HR of 3.16 (95%CI 1.38–7.26) to predict a composite of 1-year death and HF readmissions, as well as HF-readmissions alone. Conclusions The most common cause of anemia in our study was iron-deficiency; almost half of the patients were iron deficient despite treatment, suggesting that oral iron may not be sufficient to reverse anemia. Anemia regardless of etiology was associated with adverse outcomes.

Melding a High-Risk Patient for Continuous Flow Left Ventricular Assist Device into a Low-Risk Patient

The model for end-stage liver disease (MELD) has been used as a predictor of mortality after left ventricular assist device (LVAD) placement. However, improvement or worsening of MELD and how those changes affect outcomes is unknown. We performed a retrospective analysis of 244 patients implanted with a continuous flow (CF) LVAD. Patients were dichotomized at admission into low- or high-risk categories using a cutoff of MELD ≥ 19, and they were reclassified at day of implant forming four groups: Group LL (low to low, remained low risk), LH (low to high, worsened to high risk), HH (high to high, remained high risk), and HL (high to low, improved to low risk). Patients who improved to a low risk (group HL) had the same 1 year survival as those that remained low risk (group LL; 80% vs. 77%; p = 0.6). However, patients who were initially classified as low risk and worsened to a high risk (group LH) had a survival that was worse than those that were consistently high risk (group HH; 55% vs. 10%; p = 0.01). Model for end-stage liver disease reclassification after adjusting for commonly attributed risk factors remained an independent predictor for mortality, including patients classified as Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) 1 and 2. In conclusion, our MELD score reclassification is an independent and powerful predictor of mortality in patients undergoing LVAD implantation.

RAPAMYCIN POLYMER NANOTHERAPEUTICS FOR PULMONARY HYPERTENSION TREATMENT

Pulmonary hypertension (PH) ultimately leads to right side heart failure. Targeting dysregulated pathways, such as the PI3K/Akt/mTOR cascade, proves attractive but requires suitable drug carriers. Nanoparticles (NPs) increase drug circulation lifetimes and accumulation in areas of increased vascular