Current Pharmaceutical Design - Volume 19, Issue 25, 2013

Coronary reperfusion using primary percutaneous coronary intervention (PCI) dramatically reduces morbidity and mortality among patients with acute myocardial infarction (AMI). Nevertheless, inadequate myocardial perfusion, known as the “no-reflow” phenomenon, is observed in approximately 15% of patients and is associated with poor outcomes. No-reflow is caused not only by mechanical occlusion of the microvasculature due to thromboembolism but also by myocardial injury. Transmural myocardial damage before PCI and the size of the associated area are major factors in the development of no-reflow. There is evidence indicating that inflammation, oxidative injury, morphological changes of endothelial cells, hyperglycemia, and absence of ischemic preconditioning also contribute to the development of no-reflow. Several strategies have been attempted to counteract these risk factors. To prevent microembolization related to PCI, thrombus aspiration appears promising, but distal protection devices have failed to demonstrate the expected results among patients with AMI. Most cardioprotective agents developed to modify the risk factors for no-reflow have been effective in animal experiments but have disappointed in clinical trials. Adjunctive treatments using statins, adenosine, atrial natriuretic peptide, nicorandil, or glycoprotein IIb/IIIa antagonists have been effective in reducing the infarct size or improving outcomes after AMI in clinical studies, although some have shown inconsistent results. It is probable that the relevance of each component associated with no-reflow is different for individual patients, and therefore the attempt to indiscriminately apply one treatment to all patients will not be as successful as expected. Individual susceptibility has to be evaluated when selecting an appropriate adjunctive treatment to prevent no-reflow in patients with AMI.

The pathophysiology of myocardial damage in the setting of ischemic cardiomyopathy is complicated by the fact that the process of restoring blood flow to the ischemic cardiomyocytes can itself induce injury to the myocardium. This phenomenon, termed reperfusion injury, reduces the benefits of vessel recanalization and contributes to the damage initiated by occlusion. The interest on techniques aiming at protecting the heart from ischemia-reperfusion (IR) injury has constantly grown over the last two decades. Three main actors of IR injury can be identified: 1) cardiomyocite-related damage, 2) vascular-related injury and 3) inflammatory-related injury. Ideally targeting the series of molecular events that take place during myocardial reperfusion, this area of research focuses on the different strategies that may help to render the heart more resistant to the ischemic insult. The aim of this article is to highlight the clinical relevance of IR injury, how IR-injury can be assessed clinically as well as to review the current strategies, both pharmacological and non pharmacological, that show promise for translation to clinical practice.

Ischemic heart disease (IHD) is the leading cause of death and disability worldwide. The major pathological consequences of IHD arise from the detrimental effects of acute ischemia-reperfusion injury (IRI) on the myocardium. Therefore, in order to improve clinical outcomes in patients with IHD, novel therapeutic strategies are required to protect the myocardium from acute IRI and preserve cardiac function (cardioprotection). In this regard, endogenous cardioprotective strategies such as ischemic preconditioning (IPC), ischemic postconditioning (IPost) and remote ischemic conditioning (RIC) may provide novel approaches for protecting the heart in clinical settings in which the patient experiences acute myocardial IRI. In this review article, we provide an overview of these endogenous cardioprotective strategies with respect to the pre-clinical experimental literature, exploring their major characteristics and underlying signaling mechanisms. The application of these therapeutic strategies in the clinical setting for potential patient benefit is reviewed in another article in this special issue.

The primary goal in patients with ST-elevation myocardial infarction (STEMI) is the restoration of myocardial tissue-level perfusion. In a variable proportion of patients with STEMI, however, microcirculatory impairment may persist after epicardial coronary artery recanalization. This phenomenon is known as “myocardial no-reflow”. Of note, no-reflow is associated with a worse prognosis both at short- and long-term follow-up. Depending on the population under study and the diagnostic technique used for its detection, the incidence of no-reflow ranges from 5 to 50%. No-reflow can be directly assessed in the cath-lab in several ways, including angiographic Thrombolysis in Myocardial Infarction (TIMI) flow grade assessment and more complex angiographic indexes, such as TIMI frame count, TIMI perfusion grade, myocardial blush grade, or by direct invasive assessment of coronary flow. After the cath-lab, both the evaluation of electrocardiographic ST-segment resolution and imaging techniques, as myocardial contrast echocardiography or cardiac magnetic resonance, are able to monitor no-reflow evolution, with imaging playing a crucial role in its quantification. In this article, we review indexes of no-reflow used both in the cath-lab and thereafter.

Distal embolization (DE) can be either spontaneous or iatrogenic, occurring during percutaneous coronary intervention (PCI). The nature, composition and biochemical properties of embolized material differ according to the setting in which DE occurs: acute coronary syndromes (ACS) or stable coronary artery disease (CAD). DE occurrence is related to increased cardiac biomarkers, negative left ventricular remodeling and associated with a poor prognosis. Prevention and treatment of DE represent some of the most debated topics in interventional cardiology. This review paper is focused on mechanisms of DE and on the strategies for its prevention and treatment in both ACS and stable CAD.

The advent of reperfusion therapy constituted a historical change for the management of myocardial infarction (MI) patients. However, shortly after, experimental models recognized an intrinsic damage, related to reperfusion itself, which was termed as ischemiareperfusion injury (IRI). Clinical studies attribute IRI a significant burden of morbidity and mortality observed in patients undergoing successful epicardial reperfusion. Several mechanisms have been identified and, as many strategies, have been investigated to address the phenomenon. In this review we will discuss the current evidence for IRI, pharmacological and non-pharmacological preventive strategies adopted both in experimental models and in clinical practice. Finally, we will try to provide a critical appraisal to the lack of consistent benefit observed in translational medicine.

As advancements in the field of nanoparticle imaging science are made, one of the first benefits will be in open and endoscopic conditions. There is considerable evidence indicating that the use of injected contrast agents can improve the detection of tumor margins and small metastases. New and innovative targeting and contrast agents including small molecules, antibodies and nanoparticles have to be developed for a broad range of tumor types such as breast, brain, pancreatic, and ovarian cancers. At present, a number of organic dye molecules have been approved for human use including (1) indocyanine green (ICG), a near-infrared fluorescent dye; (2) fluorescein, a green fluorescent dye; (3) photofrin, a mixture of fluorescent protoporphyrin oligomers approved for photodynamic therapy, and (4) 5-aminolevulinic acid (ALA), a small molecule that is preferentially taken up by tumor cells leading to biosynthesis and accumulation of protoporphyrin IX, a natural fluorophore with red fluorescence emission. On the other hand, nanoparticles have not received FDA approval for clinical imaging, as this technology needs a lot of development and lot of research is being carried out in this unexplored area. A major task is, therefore to develop biocompatible and nontoxic nanoparticle contrast agents with the potential for FDA approval and human use. Such agents need to show improved sensitivity and specificity for tumor imaging in comparison with small-molecule-dyes. In this regard, it is highly promising to develop smart or activatable nanoparticles with improved pharmacokinetic, tumor targeting and organ clearance properties, based on the use of natural, biodegradable polymers (dextran and heparin). Dextran-based particles are sensitive to pH, and can be rapidly broken down under acidic conditions. Under neutral or slightly basic conditions, on the other hand, the dextran nanoparticles are stable and are able to circulate systemically in blood for 14 to 15 hours. In contrast, self-assembled heparin nanoparticles have much shorter blood circulation half-lives (about 60-80 min). For intra-operative use, this short circulation time could be beneficial because the probes will be cleared from the body quickly, so that surgical operations and treatment can start without much delay or waiting. For near-term clinical applications, it is important that both the dextran and heparin particles are able to trap as FDA-approved dye (such as indocyanine green), leading to new class of imaging contrast agents with improved bio distribution and photo physical properties. This class of nanoparticle contrast agents could also be conjugated with tumor targeting ligands such as folate, Epidermal Growth Factor (EGF), or RGD (recognition sequence for integrins that contains Arg-Gly-Asp attachment site) for improved sensitivity and specificity in perfect cancer imaging technique agents. This review article actually highlights the new developments occurring in this area of imaging techniques in cancer research and the author himself is using the technique for developing newer fluorescent molecules for molecular imaging using nanotechnology.

Fuel sensors such as glucose, insulin or leptin, are known to be directly involved in the regulation of fertility at each level of the hypothalamic-pituitary-gonadal axis. The discovery of the peroxisome proliferator-activated receptor (PPAR) family of transcription factors has revealed the link between lipid/glucose availability and long-term metabolic adaptation. By binding to specific regions of DNA in heterodimers with the retinoid X receptors (RXRs), the members of the PPAR family (α, β/δ, γ) are able to regulate the gene expressions of several key regulators of energy homeostasis including several glucose regulators (glucose transporters, insulin receptor, substrate insulin receptor, etc), and also metabolic and endocrine pathways like lipogenesis, steroidogenesis, ovulation, oocyte maturation, maintenance of the corpus luteum, nitric oxide system, several proteases and plasminogen activator among others. All the three PPAR isoforms are expressed in different tissues of the female reproductive tract and regulate gametogenesis, ovulation, corpus luteum regression and the implantation process among others. The present review discusses the mechanisms involved in PPAR activation focusing on endogenous and synthetic ligands of PPAR not only in physiological but also in pathological conditions (such as polycystic ovary syndrome, pathologies of implantation process, chronic anovulation, etc).

Dysregulation of matrix metalloproteinase (MMP) activity can lead to a wide range of disease states such as atherosclerosis, inflammation or cancer. The ability to image MMP activity non-invasively in vivo, by radiolabelled synthetic inhibitors, would allow the characterization of atherosclerotic plaques, inflammatory lesions or tumors. Here we present an overview of radiolabelled MMP inhibitors (MMPIs) and MMP peptides for positron emission tomography (PET) and single photon emission computed tomography (SPECT) for the detection of proteolytic activity of MMPs. So far, most studies are at a preliminary stage; however, some hydroxamate-based tracers such as the peptidomimetics [111In]-DTPA-RP782, [99mTc]-(HYNIC-RP805)(tricine)(TPPTS), or Marimastat-ArB[18F]F3 and the picolyl- benzenesulfonamide [123I]I-HO-CGS 27023A identified specifically the enzymatic action of MMPs in animal models of various pathologies. The development of new compounds that may lead to novel tracers (e.g. modification of zinc-binding group, variation of substituents attached to the S1’, S2’ and S3’ pockets of the MMP inhibitors) and the use of antibodies and cell penetrating peptides are also discussed. In general, preclinical studies with atherosclerosis models proved to be more successful than those with oncological models.