Platelet "-omics" in health and cardiovascular disease.

The importance of platelets for cardiovascular disease was established as early as the 19th century. Their therapeutic inhibition stands alongside the biggest achievements in medicine. Still, certain aspects of platelet pathophysiology remain unclear. This includes platelet resistance to antiplatelet therapy and the contribution of platelets to vascular remodelling and extends beyond cardiovascular disease to haematological disorders and cancer. To address these gaps in our knowledge, a better understanding of the underlying molecular processes is needed. This will be enabled by technologies that capture dysregulated molecular processes and can integrate them into a broader network of biological systems. The advent of -omics technologies, such as mass spectrometry proteomics, metabolomics and lipidomics; highly multiplexed affinity-based proteomics; microarray- or RNA-sequencing-(RNA-seq)-based transcriptomics, and most recently ribosome footprint-based translatomics, has enabled a more holistic understanding of platelet biology. Most of these methods have already been applied to platelets, and this review will summarise this information and discuss future developments in this area of research.

Preclinical development of a miR-132 inhibitor for heart failure treatment.

Despite proven efficacy of pharmacotherapies targeting primarily global neurohormonal dysregulation, heart failure (HF) is a growing pandemic with increasing burden. Treatments mechanistically focusing at the cardiomyocyte level are lacking. MicroRNAs (miRNA) are transcriptional regulators and essential drivers of disease progression. We previously demonstrated that miR-132 is both necessary and sufficient to drive the pathological cardiomyocytes growth, a hallmark of adverse cardiac remodelling. Therefore, miR-132 may serve as a target for HF therapy. Here we report further mechanistic insight of the mode of action and translational evidence for an optimized, synthetic locked nucleic acid antisense oligonucleotide inhibitor (antimiR-132). We reveal the compound's therapeutic efficacy in various models, including a clinically highly relevant pig model of HF. We demonstrate favourable pharmacokinetics, safety, tolerability, dose-dependent PK/PD relationships and high clinical potential for the antimiR-132 treatment scheme.

Preoperative high-dose atorvastatin for prevention of atrial fibrillation after cardiac surgery: a randomized controlled trial.

OBJECTIVE: The preventative effect of statins on postoperative atrial fibrillation has been hypothesized. However, all studies to date have examined patients who did not receive statins before their further allocation to treatment or no treatment. Because guidelines recommend the routine use of statins in patients with coronary artery disease, we set out to examine the effect of intensive statin pretreatment versus continuation of usual statin dose on atrial fibrillation after cardiac surgery. METHODS: Patients receiving routine statin treatment and undergoing coronary artery bypass surgery or aortic valve replacement with no history of atrial fibrillation or antiarrhythmic medication were randomized to receive atorvastatin 80 mg or atorvastatin 10 mg for 7 days before surgery in a single-blind fashion. The primary end point was the development of postoperative atrial fibrillation during hospital stay. RESULTS: A total of 104 consecutive patients were included. Postoperative atrial fibrillation occurred in 33 patients (32.4%). No significant differences were found in demographics, medical history, or intraoperative variables between treatment groups, with the exception of higher rate of ß-blocker use in the atorvastatin 10 mg group (75% vs 53%, P = .002) and previous myocardial infarction (62% vs 42%, P = .049). The incidence of postoperative atrial fibrillation was lower in the atorvastatin 80 mg group when compared with the atorvastatin 10 mg group, but this difference did not reach statistical significance (29% vs 36%, P = .43). CONCLUSIONS: High-dose atorvastatin for 7 days before cardiac surgery conferred a nonsignificant reduction in postoperative atrial fibrillation when compared with a low-dose regimen. A larger study would be necessary to confirm the beneficial effect of high-dose statins in this setting.

Protein kinase D selectively targets cardiac troponin I and regulates myofilament Ca2+ sensitivity in ventricular myocytes.

Protein kinase D (PKD) is a serine/threonine kinase with emerging myocardial functions; in skinned adult rat ventricular myocytes (ARVMs), recombinant PKD catalytic domain phosphorylates cardiac troponin I at Ser22/Ser23 and reduces myofilament Ca(2+) sensitivity. We used adenoviral gene transfer to determine the effects of full-length PKD on protein phosphorylation, sarcomere shortening and [Ca(2+)](i) transients in intact ARVMs. In myocytes transduced to express wild-type PKD, the heterologously expressed enzyme was activated by endothelin 1 (ET1) (5 nmol/L), as reflected by PKD phosphorylation at Ser744/Ser748 (PKC phosphorylation sites) and Ser916 (autophosphorylation site). The ET1-induced increase in cellular PKD activity was accompanied by increased cardiac troponin I phosphorylation at Ser22/Ser23; this measured approximately 60% of that induced by isoproterenol (10 nmol/L), which activates cAMP-dependent protein kinase (PKA) but not PKD. Phosphorylation of other PKA targets, such as phospholamban at Ser16, phospholemman at Ser68 and cardiac myosin-binding protein C at Ser282, was unaltered. Furthermore, heterologous PKD expression had no effect on isoproterenol-induced phosphorylation of these proteins, or on isoproterenol-induced increases in sarcomere shortening and relaxation rate and [Ca(2+)](i) transient amplitude. In contrast, heterologous PKD expression suppressed the positive inotropic effect of ET1 seen in control cells, without altering ET1-induced increases in relaxation rate and [Ca(2+)](i) transient amplitude. Complementary experiments in "skinned" myocytes confirmed reduced myofilament Ca(2+) sensitivity by ET1-induced activation of heterologously expressed PKD. We conclude that increased myocardial PKD activity induces cardiac troponin I phosphorylation at Ser22/Ser23 and reduces myofilament Ca(2+) sensitivity, suggesting that altered PKD activity in disease may impact on contractile function.