Cpxm2 as a novel candidate for cardiac hypertrophy and failure in hypertension.

Treatment of hypertension-mediated cardiac damage with left ventricular (LV) hypertrophy (LVH) and heart failure remains challenging. To identify novel targets, we performed comparative transcriptome analysis between genetic models derived from stroke-prone spontaneously hypertensive rats (SHRSP). Here, we identified carboxypeptidase X 2 (Cpxm2) as a genetic locus affecting LV mass. Analysis of isolated rat cardiomyocytes and cardiofibroblasts indicated Cpxm2 expression and intrinsic upregulation in genetic hypertension. Immunostaining indicated that CPXM2 associates with the t-tubule network of cardiomyocytes. The functional role of Cpxm2 was further investigated in Cpxm2-deficient (KO) and wild-type (WT) mice exposed to deoxycorticosterone acetate (DOCA). WT and KO animals developed severe and similar systolic hypertension in response to DOCA. WT mice developed severe LV damage, including increases in LV masses and diameters, impairment of LV systolic and diastolic function and reduced ejection fraction. These changes were significantly ameliorated or even normalized (i.e., ejection fraction) in KO-DOCA animals. LV transcriptome analysis showed a molecular cardiac hypertrophy/remodeling signature in WT but not KO mice with significant upregulation of 1234 transcripts, including Cpxm2, in response to DOCA. Analysis of endomyocardial biopsies from patients with cardiac hypertrophy indicated significant upregulation of CPXM2 expression. These data support further translational investigation of CPXM2.

Statin intolerance - a question of definition.

INTRODUCTION: Statin therapy is the backbone of pharmacologic therapy for low-density lipoproteins cholesterol lowering and plays a pivotal role in cardiovascular disease prevention. Statin intolerance is understood as the inability to continue using a statin to reduce individual cardiovascular risk sufficiently, due to the development of symptoms or laboratory abnormalities attributable to the initiation or dose escalation of a statin. Muscle symptoms are the most common side effects observed. Areas covered: The main aim of this article is to present a review on published definitions of statin intolerance. In addition, a brief review on clinical aspects and risk factors of statin intolerance is provided and features for a common definition for statin intolerance are suggested. Expert opinion: A definition of statin intolerance by major drug regulatory agencies is not available. In clinical studies, different definitions are chosen and results are not comparable; different medical associations do not agree on one common definition. There is an unmet need to establish a common definition of statin intolerance to ensure an appropriate clinical use of this important drug class. Further work is required to develop a consensus definition on statin intolerance that could have significant positive impact on both research and clinical management.

Drug-drug interactions and safety of linezolid, tedizolid, and other oxazolidinones.

INTRODUCTION: Oxazolidinones are synthetic antimicrobials with strong bacteriostatic activity against Gram-positive organisms. Recently, tedizolid phosphate was approved for clinical use becoming the second agent of this class after linezolid available in clinical practice. AREAS COVERED: Oxazolidinone pharmacology including structure-activity relationships, mode of action, pharmacokinetics, drug-drug interactions, and adverse drug reactions is reviewed. Furthermore, bacterial resistance, approved indications, use in paediatric populations, and tuberculosis treatment with oxazolidinones are discussed, and differences in indications and pharmacotoxicological properties between the two approved agents are elucidated. A MEDLINE PubMed search for articles published in English from January 1960 to June 2015 was completed using the terms: oxazolidinone, oxazolidinone-induced toxicity, oxazolidinone pharmacokinetics, serotonin syndrome, oxazolidinone drug-drug interactions, antituberculotic treatment. EXPERT OPINION: Linezolid illustrates an important antimicrobial in several Gram-positive infections especially when methicillin-resistant Staphylococcus aureus strains are involved. Myelosuppression and neuropathy are toxicities of high relevance particularly in case of prolonged treatment periods. The significance of linezolid in the treatment of extensively drug-resistant tuberculosis has to be further investigated. Tedizolid phosphate represents a welcome addition in our anti-infective arsenal, and future research will clarify its role in indications other than the already approved acute bacterial skin infections.

Fetal-adult cardiac transcriptome analysis in rats with contrasting left ventricular mass reveals new candidates for cardiac hypertrophy.

Reactivation of fetal gene expression patterns has been implicated in common cardiac diseases in adult life including left ventricular (LV) hypertrophy (LVH) in arterial hypertension. Thus, increased wall stress and neurohumoral activation are discussed to induce the return to expression of fetal genes after birth in LVH. We therefore aimed to identify novel potential candidates for LVH by analyzing fetal-adult cardiac gene expression in a genetic rat model of hypertension, i.e. the stroke-prone spontaneously hypertensive rat (SHRSP). To this end we performed genome-wide transcriptome analysis in SHRSP to identify differences in expression patterns between day 20 of fetal development (E20) and adult animals in week 14 in comparison to a normotensive rat strain with contrasting low LV mass, i.e. Fischer (F344). 15232 probes were detected as expressed in LV tissue obtained from rats at E20 and week 14 (p < 0.05) and subsequently screened for differential expression. We identified 24 genes with SHRSP specific up-regulation and 21 genes with down-regulation as compared to F344. Further bioinformatic analysis presented Efcab6 as a new candidate for LVH that showed only in the hypertensive SHRSP rat differential expression during development (logFC = 2.41, p < 0.001) and was significantly higher expressed in adult SHRSP rats compared with adult F344 (+ 76%) and adult normotensive Wistar-Kyoto rats (+ 82%). Thus, it represents an interesting new target for further functional analyses and the elucidation of mechanisms leading to LVH. Here we report a new approach to identify candidate genes for cardiac hypertrophy by combining the analysis of gene expression differences between strains with a contrasting cardiac phenotype with a comparison of fetal-adult cardiac expression patterns.

Safety issues and drug-drug interactions with commonly used quinolones.

INTRODUCTION: Quinolones are widely used antimicrobials with good efficacy and favourable safety. Recently, forms of quinolone toxicity such as peripheral neuropathy, retinal detachment or QTc-prolongation have attracted attention. AREAS COVERED: Data on different aspects of direct quinolone toxicity are reviewed and consider risk factors and predisposing structural properties. Indirect forms of quinolone toxicity such as Clostridium difficile infections or adverse reactions associated with drug-drug interactions are also discussed. Finally, the role of transporters in the pharmacokinetics of these antimicrobials and their utilisation in critically ill patients are illustrated. A MEDLINE PubMed search for articles published in English from January 1960 to June 2014 was completed using the terms: quinolone, quinolone-induced toxicity, quinolone pharmacokinetics, quinolone and critically ill, drug-drug interactions. EXPERT OPINION: Quinolones exhibit an important component of the antibiotic arsenal. Although several adverse events have been associated with their use, taking into consideration risk factors, contraindications and potential drug-drug interactions can drastically reduce the respective risks.

Mapping and confirmation of a major left ventricular mass QTL on rat chromosome 1 by contrasting SHRSP and F344 rats.

An abnormal increase in left ventricular (LV) mass, i.e., LV hypertrophy (LVH), represents an important target organ damage in arterial hypertension and has been associated with poor clinical outcome. Genetic factors are contributing to variation in LV mass in addition to blood pressure and other factors such as dietary salt intake. We set out to map quantitative trait loci (QTL) for LV mass by comparing the spontaneously hypertensive stroke-prone (SHRSP) rat with LVH and normotensive Fischer rats (F344) with contrasting low LV mass. To this end we performed a genome-wide QTL mapping analysis in 232 F2 animals derived from SHRSP and F344 exposed to high-salt (4% in chow) intake for 8 wk. We mapped one major QTL for LV mass on rat chromosome 1 (RNO1) that demonstrated strong linkage (peak logarithm of odds score 8.4) to relative LV weight (RLVW) and accounted for ∼19% of the variance of this phenotype in F2 rats. We therefore generated a consomic SHRSP-1(F344) strain in which RNO1 from F344 was introgressed into the SHRSP background. Consomic and SHRSP animals showed similar blood pressures during conventional intra-arterial measurements, while RLVW was already significantly lower (-17.7%, P<0.05) in SHRSP-1(F344) in response to a normal-salt diet; a similar significant reduction of LV mass was also observed in consomic rats after high-salt intake (P<0.05 vs. SHRSP). Thus, a major QTL on RNO1 was confirmed with significant impact on LV mass in the hypertensive background of SHRSP.