Natriuretic peptide receptor-3 gene (NPR3): nonsynonymous polymorphism results in significant reduction in protein expression because of accelerated degradation.

BACKGROUND- The primary role of natriuretic peptide receptor-3 (NPR3) or NPR-C is in the clearance of natriuretic peptides that play an important role in modulating intravascular volume and vascular tone. Genetic variation in NPR3 has been associated with variation in blood pressure and obesity. Despite the importance of NPR3, sequence variation in the gene has not been addressed using DNA from different ethnic populations.

Dual functional BAFF receptor aptamers inhibit ligand-induced proliferation and deliver siRNAs to NHL cells.

The B-cell-activating factor (BAFF)-receptor (BAFF-R) is restrictedly expressed on B-cells and is often overexpressed in B-cell malignancies, such as non-Hodgkin's lymphoma. On binding to its ligand BAFF, proliferation and cell survival are increased, enabling cancer cells to proliferate faster than normal B-cells. Nucleic acid aptamers can bind to target ligands with high specificity and affinity and may offer therapeutic advantages over antibody-based approaches.

In-vivo evaluation of an in situ polymer precipitation delivery system for a novel natriuretic peptide.

This study reports on the release of a novel natriuretic peptide, CD-NP, from an in situ polymer precipitation delivery system. Following extensive screening of in-vitro release profiles, an in-vivo evaluation of the efficacy of the delivery system was carried out in Wistar rats. Gel injection was performed subcutaneously on the back of the rats.

Clinical course and predictive value of congestion during hospitalization in patients admitted for worsening signs and symptoms of heart failure with reduced ejection fraction: findings from the EVEREST trial.

Aims: Signs and symptoms of congestion are the most common cause for hospitalization for heart failure (HHF). The clinical course and prognostic value of congestion during HHF has not been systemically characterized.

Methods And Results: A post hoc analysis was performed of the placebo group (n = 2061) of the EVEREST trial, which enrolled patients within 48 h of admission (median ~24 h) for worsening HF with an EF ≤ 40% and two or more signs or symptoms of fluid overload [dyspnoea, oedema, or jugular venous distension (JVD)] for a median follow-up of 9.

Protein kinase C controls vesicular transport and secretion of apolipoprotein E from primary human macrophages.

Macrophage-specific apolipoprotein E (apoE) secretion plays an important protective role in atherosclerosis. However, the precise signaling mechanisms regulating apoE secretion from primary human monocyte-derived macrophages (HMDMs) remain unclear. Here we investigate the role of protein kinase C (PKC) in regulating basal and stimulated apoE secretion from HMDMs.

CD-NP: a novel engineered dual guanylyl cyclase activator with anti-fibrotic actions in the heart.

Natriuretic peptides (NPs) are cardioprotective through the activation of guanylyl cyclase (GC) receptors A and B. CD-NP, also known as cenderitide, is a novel engineered NP that was designed to uniquely serve as a first-in-class dual GC receptor agonist. Recognizing the aldosterone suppressing actions of GC-A activation and the potent inhibitory actions on collagen synthesis and fibroblast proliferation through GC-B activation, the current study was designed to establish the anti-fibrotic actions of CD-NP, administered subcutaneously, in an experimental rat model of early cardiac fibrosis induced by unilateral nephrectomy (UNX).

Recent developments in the genetics of LDL deficiency.

Purpose Of Review: Inherited diseases of lipoprotein metabolism may give rise to marked hypocholesterolemia with low or absent levels of LDL, depending on the gene involved and mode of inheritance of the condition, together with the severity of the mutation or mutations present. In this review, we discuss the recent developments in the genetics of LDL deficiency.

Recent Findings: Carriers of a single loss-of-function variant in ANGPTL3 have reduced LDL-cholesterol and triglyceride concentrations, whereas homozygotes have markedly reduced LDL-cholesterol, triglyceride and HDL-cholesterol concentrations, a recessive form of hypocholesterolemia designated as familial combined hypolipidemia.

Anti-PCSK9 therapies for the treatment of hypercholesterolemia.

Introduction: Proprotein convertase subtilisin kexin type 9 (PCSK9), a serine protease that binds to the low density lipoprotein (LDL) receptor promoting its degradation, is an important regulator of LDL metabolism. PCSK9 'gain-of-function' mutations are rare and cause high plasma LDL-cholesterol and increase atherosclerotic cardiovascular disease, whereas more common 'loss-of-function' mutations cause low LDL-cholesterol and atheroprotection. PCSK9 is a novel, attractive and viable therapeutic target for the treatment of hypercholesterolemia, with human studies using a variety of anti-PCSK9 therapies underway.

Mipomersen and other therapies for the treatment of severe familial hypercholesterolemia.

Familial hypercholesterolemia (FH) is an autosomal dominant condition with a population prevalence of one in 300-500 (heterozygous) that is characterized by high levels of low-density lipoprotein (LDL) cholesterol, tendon xanthomata, and premature atherosclerosis and coronary heart disease (CHD). FH is caused mainly by mutations in the LDLR gene. However, mutations in other genes including APOB and PCSK9, can give rise to a similar phenotype.

Differential expression of the pro-natriuretic peptide convertases corin and furin in experimental heart failure and atrial fibrosis.

In heart failure (HF), the cardiac hormone natriuretic peptides (NPs) atrial (ANP), B-type (BNP), and C-type (CNP) play a key role to protect cardiac remodeling. The proprotein convertases corin and furin process their respective pro-NPs into active NPs. Here we define in a canine model of HF furin and corin gene and protein expression in normal and failing left atrium (LA) or ventricle (LV) testing the hypothesis that the NP proproteins convertases production is altered in experimental HF.

Current progress of RNA aptamer-based therapeutics.

Aptamers are single-stranded nucleic acids that specifically recognize and bind tightly to their cognate targets due to their stable three-dimensional structure. Nucleic acid aptamers have been developed for various applications, including diagnostics, molecular imaging, biomarker discovery, target validation, therapeutics, and drug delivery. Due to their high specificity and binding affinity, aptamers directly block or interrupt the functions of target proteins making them promising therapeutic agents for the treatment of human maladies.

Novel protein therapeutics for systolic heart failure: chronic subcutaneous B-type natriuretic peptide.

Objectives: The purpose of the present study was to translate our laboratory investigations to establish safety and efficacy of 8 weeks of chronic SC B-type natriuretic peptide (BNP) administration in human Stage C heart failure (HF).

Background: B-Type natriuretic peptide is a cardiac hormone with vasodilating, natriuretic, renin-angiotensin inhibiting, and lusitropic properties. We have previously demonstrated that chronic cardiac hormone replacement with subcutaneous (SC) administration of BNP in experimental HF resulted in improved cardiovascular function.

Human hypertension is characterized by a lack of activation of the antihypertensive cardiac hormones ANP and BNP.

Objectives: This study sought to investigate plasma levels of circulating cardiac natriuretic peptides, atrial natriuretic peptide (ANP) and B-type or brain natriuretic peptide (BNP), in the general community, focusing on their relative differences in worsening human hypertension.

Background: Although ANP and BNP are well-characterized regulators of blood pressure in humans, little is known at the population level about their relationship with hypertension. The authors hypothesized that hypertension is associated with a lack of activation of these hormones or their molecular precursors.

Opportunistic screening for familial hypercholesterolaemia via a community laboratory.

Background: Familial hypercholesterolaemia (FH) is an inherited disorder characterized by increased serum low-density lipoprotein (LDL)-cholesterol concentrations and premature atherosclerotic cardiovascular disease. The majority of people with FH are currently undiagnosed. We sought to determine the ability of a community laboratory to screen for individuals with potential FH.

Creating genetic resistance to HIV.

HIV/AIDS remains a chronic and incurable disease, in spite of the notable successes of combination antiretroviral therapy. Gene therapy offers the prospect of creating genetic resistance to HIV that supplants the need for antiviral drugs. In sight of this goal, a variety of anti-HIV genes have reached clinical testing, including gene-editing enzymes, protein-based inhibitors, and RNA-based therapeutics.

Neutral endopeptidase inhibition and the natriuretic peptide system: an evolving strategy in cardiovascular therapeutics.

Hypertension and heart failure (HF) are common diseases that, despite advances in medical therapy, continue to be associated with high morbidity and mortality. Therefore, innovative therapeutic strategies are needed. Inhibition of the neutral endopeptidase (NEPinh) had been investigated as a potential novel therapeutic approach because of its ability to increase the plasma concentrations of the natriuretic peptides (NPs).

TRV120027, a novel β-arrestin biased ligand at the angiotensin II type I receptor, unloads the heart and maintains renal function when added to furosemide in experimental heart failure.

Background: TRV120027 is a novel β-arrestin biased ligand of the angiotensin II type 1 receptor; it antagonizes canonical G-protein-mediated coupling while, in contrast to classical angiotensin II type 1 receptor antagonists, it engages β-arrestin-mediated signaling. Consequently, TRV120027 inhibits angiotensin II-mediated vasoconstriction while, via β-arrestin coupling, it increases cardiomyocyte contractility. We hypothesized that TRV120027 would elicit beneficial cardiorenal actions when added to furosemide in experimental heart failure.

Genetic analysis of familial hypercholesterolaemia in Western Australia.

Objective: To determine the spectrum of mutations associated with familial hypercholesterolaemia (FH) and their detection rate in the FH Western Australia (FHWA) Program.

Methods: Mutation testing of the LDLR gene, plus select regions in APOB and PCSK9, was performed in the first 343 patients considered to be phenotypic index cases of FH and classified on the basis of the Dutch Lipid Clinic Network Criteria (DLCNC) score as "possible", "probable", or "definite" FH.

Results: Overall, 86 different pathogenic (or likely pathogenic) mutations were identified in 129 patients, including four compound heterozygotes manifesting a more severe clinical phenotype.

Dalcetrapib , a cholesteryl ester transfer protein modulator.

Introduction: Cholesteryl ester transfer protein (CETP) plays an important role in reverse cholesterol transport by transferring cholesteryl esters from high-density lipoprotein (HDL) to the apolipoprotein B-containing lipoproteins. Inhibition of CETP is a target to increase HDL-cholesterol and potentially reduce atherosclerosis. Dalcetrapib is an orally administered CETP inhibitor developed for the treatment of primary hypercholesterolaemia and mixed hyperlipidaemia.

Cardiac micro-computed tomography imaging of the aging coronary vasculature.

Background: Alterations at the level of the coronary circulation with aging may play an important role in the evolution of age-associated changes in left ventricular (LV) fibrosis and function. However these age-associated changes in the coronary vasculature remain poorly defined primarily due to the lack of high resolution imaging technologies. The current study was designed to utilize cardiac micro-computed tomography (micro-CT) technology as a novel imaging strategy, to define the 3-dimensional coronary circulation in the young and aged heart and its relationship to LV fibrosis and function.

Efficacy of oral tolvaptan in acute heart failure patients with hypotension and renal impairment.

Aims: Although congestion is the main reason for admission in patients with worsening acute heart failure syndromes, patients presenting with low SBP and renal impairment often do not respond adequately to and may not tolerate traditional diuretic therapy. We sought to determine the short-term hemodynamic effects of tolvaptan in this high-risk population.

Methods: In a subset analysis of the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan trial, 759 patients (18% of total) had elevated blood urea nitrogen (BUN) (> 20  mg/dl) and low SBP (<105  mmHg) at admission.

Soluble guanylate cyclase: a potential therapeutic target for heart failure.

The number of annual hospitalizations for heart failure (HF) and the mortality rates among patients hospitalized for HF remains unacceptably high. The search continues for safe and effective agents that improve outcomes when added to standard therapy. The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway serves an important physiologic role in both vascular and non-vascular tissues, including regulation of myocardial and renal function, and is disrupted in the setting of HF, leading to decreased protection against myocardial injury, ventricular remodeling, and the cardio-renal syndrome.