Current Vascular Pharmacology - Volume 13, Issue 1, 2015

Although a decline in the all-cause and cardiac mortality rates following myocardial infarction (MI) during the past 3 decades has been reported, MI is a major cause of death and disability worldwide. From a pathological point of view MI consists in a particular myocardial cell death due to prolonged ischemia. After the onset of myocardial ischemia, cell death is not immediate, but takes a finite period of time to develop. Once complete myocytes’ necrosis has occurred, a process leading to a healed infarction takes place. In fact, MI is a dynamic process that begins with the transition from reversible to irreversible ischemic injury and culminates in the replacement of dead myocardium by a fibrous scar. The pathobiological mechanisms underlying this process are very complex, involving an inflammatory response by several pathways, and pose a major challenge to ability to improve our knowledge. An improved understanding of the pathobiology of cardiac repair after MI and further studies of its underlying mechanisms provide avenues for the development of future strategies directed toward the identification of novel therapies. The chronologic dating of MI is of great importance both to clinical and forensic investigation, that is, the ability to create a theoretical timeline upon which either clinicians or forensic pathologists may increase their ability to estimate the time of MI. Aging of MI has very important practical implications in clinical practice since, based on the chronological dating of MI, attractive alternatives to solve therapeutic strategies in the various phases of MI are developing.

The innate immune system is well recognized as the first line defense of foreign pathogens; however, it can also recognize endogenous signals released from injured tissues and induce sterile inflammation. Toll-like receptors (TLRs) and Nod-like receptors (NLRs) have been identified as its receptors, and they have been shown to play a key role in the disease processes of sterile inflammation, including myocardial infarction (MI). In particular, NLRs are the key components of the caspase-1 activating platform known as the “inflammasome,” which produces the potent proinflammatory cytokine interleukin-1β. The current article reviews the role of the innate immune system, especially TLRs and inflammasomes, in the pathophysiology of MI.

Oxidative stress in heart failure or during ischemia/reperfusion occurs as a result of the excessive generation or accumulation of free radicals or their oxidation products. Free radicals formed during oxidative stress can initiate lipid peroxidation, oxidize proteins to inactive states and cause DNA strand breaks. Oxidative stress is a condition in which oxidant metabolites exert toxic effects because of their increased production or an altered cellular mechanism of protection. In the early phase of acute heart ischemia cytokines have the feature to be functional pleiotropy and redundancy, moreover, several cytokines exert similar and overlapping actions on the same cell type and one cytokine shows a wide range of biological effects on various cell types. Activation of cytokine cascades in the infarcted myocardium was established in numerous studies. In experimental models of myocardial infarction, induction and release of the pro-inflammatory cytokines like TNF-&alpha (Tumor Necrosis Factor &alpha), IL-1&beta (Interleukin- 1&beta) and IL-6 (Interleukin-6) and chemokines are steadily described. The current review examines the role of oxidative stress and pro-inflammatory cytokines response following acute myocardial infarction and explores the inflammatory mechanisms of cardiac injury.

Angiogenesis is central to cardiac repair following myocardial infarction (MI). Cardiac angiotensin converting enzyme (ACE)2 significantly increased postMI, which is coincident with activated angiogenesis. The function of ACE2 is to generate angiotensin (Ang)1-7, an active peptide with cellular actions mediated by Mas receptors. The current study is to determine whether Ang(1-7) is involved in cardiac angiogenesis and facilitates cardiac repair. In the first portion of the study, the temporal expressions of cardiac ACE2 and Mas receptors were detected in rats with MI. In the second portion, MI rats were treated with or without a Mas receptor antagonist, A779 (1mg/kg/day given by minipump) for 7 days. Vascular density and expression of angiogenic mediators in the infarcted myocardium and cardiac function were examined. Compared to controls, ACE2 and Mas receptor levels were significantly increased in the infarcted myocardium for 4 weeks of the observation period. Newly formed vessels were evident in the infarcted myocardium at day 7. Mas receptor blockade significantly reduced vascular density in the infarcted myocardium and impaired ventricular function. In addition, A779 treatment significantly suppressed the cardiac expressions of vascular endothelial growth factor (VEGF)-D and matrix metalloproteinase (MMP)-9 but not expression of other angiogenic mediators, including monocyte Chemoattractant protein (MCP-1), VEGF-C, transforming growth factor (TGF)-&beta1 and integrin &beta3. These observations indicate that Ang(1-7) promotes angiogenesis via stimulating the expression of cardiac VEGF-D and MMP-9, thus facilitating cardiac repair and ventricular function.

This study investigated the effects of the L-17 compound of the group of substituted 5R1, 6H2- 1,3,4-thiadiazine-2-amines on the immune response and the plasma level of circulating cytokines in acute myocardial infarction (MI) in rats. The study was based upon experimental work which demonstrated the role of local and systemic inflammatory reactions in MI. Acute MI in rats was induced by left coronary artery coagulation. Histological study of the myocardium sections has been carried out at the 1th and 7th days of the experimental myocardial infarction. Serum activity of creatine phosphokinase (CPK), aspartate aminotransferase (AST), isoenzymes 1 and 2 and lactate dehydroge nase (LDH1-2) were investigated at days 1thand 7th. ELISA analysis for plasma cytokine levels was performed using commercially available test kits following the manufacturer&aposs instructions. Biochemical analysis in animals with the administration of the L-17 compound after MI showed that the AST and CPK levels at days 5 and 7 of experiments did not differ significantly from the values of intact animals. In animals of the group with MI without the administration of the L-17 compound, the IL-1 level 8 times and the TNF level 7.8 times exceeded the normal indicators, while the use of L-17 compound in the therapy resulted in only 1.8 times increase of IL-1 level and 4.7 times increase of TNF level in comparison with the norm. Thus, the introduction of L-17 compound in case of experimental MI delays exudative/alternative phase of inflammation, accelerates granulocytic and decreased the inflammation and anti-inflammation interleukins level.

Doxorubicin (DOX) is widely used as an anti-cancer agent although it causes irreversible cardiomyopathy by increasing oxidative stress and deregulating nitric oxide production. Beraprost (BPS), a stable prostacyclin (PGI2) analog, is a potent vasodilator that has beneficial effects on myocardial ischemia. The objectives of the present study were to delineate the uncertain effects of prostcyclin therapy on DOX induced cardiomyopathy and to explore the mechanisms underlying PGI2 and DOX interaction. For this reason, we stimulated endogenous PGI2 production using bicistronic COX-1/PGIS gene transfer and BPS supplementation, and investigated the effects on DOX-induced cardiomyopathy. Caspase-dependent protein content, lactate dehydrogenase (LDH), DNA fragmentation, and TUNEL positive cells were elevated in DOX-treated cardiomyocytes. These indicators were further elevated by adenovirus-COX- 1/PGIS transfection or BPS supplementation. In addition, PGI2 overexpression further increased iNOS expression and superoxide accumulation in cardiomyocytes compared with DOX alone, which may be the reason for aggravated cytotoxicity. Moreover, BPS can induce cAMP response elements (CRE) binding to the iNOS promoter and phospho- cAMP response element binding protein (CREB) expression in a cyclic AMP-dependent manner. Our in vivo studies show that MnTBAP and aminoguanidine treatment of DOX and BPS co-administered in mice can attenuate caspase-3 and PARP-1 protein expression, and improve mouse survival, as observed in the iNOS gene-deleted mice. In conclusion, we demonstrated that BPS or adv-COX-1/PGIS increases PGI2 levels through iNOS expression and peroxynitrite production, via CREB protein phosphorylation; thereby aggravating DOX-mediated cardiotoxicity.

Myocardial infarction is a major cause of death and disability worldwide. Myocardial infarction may represent a major catastrophic event leading to severe hemodynamic failure or sudden death or it may occur repeatedly in patients with established heart disease. In this context, the role of imaging techniques may become useful for the understanding of the determinants in a preclinical setting before acute coronary events, and for an accurate and correct diagnosis of myocardial infarction. Three-dimensional noninvasive imaging techniques, such as Cardiac CT (CCT) and Cardiac MR imaging (CMR) were widely developed in the last two decades. These imaging techniques may provide new insights into understanding, assessment and follow-up of myocardial infarction. CCT is mainly oriented to morphological assessment including applications such as the detection of coronary artery stenoses even in acute settings, the evaluation of coronary atherosclerotic burden, and the follow-up of patients with known coronary artery disease who underwent myocardial revascularization. On the other hand, CMR is the reference standard for the functional assessment of the heart with evaluation of volumes, mass, and contractility of the ventricles. CMR myocardial viability imaging with delayed contrast enhancement has become broadly accepted for the detection and characterization of the extent of acute and chronic myocardial infarction.

Cardiac muscle necrosis is associated with inflammatory cascade that clears the infarct from dead cells and matrix debris, and then replaces the damaged tissue with scar, through three overlapping phases: the inflammatory phase, the proliferative phase and the maturation phase. Western blotting, laser confocal microscopy, Raman microscopy are valuable tools for studying the inflammatory response following myocardial infarction both humoral and cellular phase, allowing the identification and semiquantitative analysis of proteins produced during the inflammatory cascade activation and the topographical distribution and expression of proteins and cells involved in myocardial inflammation. Confocal laser scanning microscopy (CLSM) is a relatively new technique for microscopic imaging, that allows greater resolution, optical sectioning of the sample and three-dimensional reconstruction of the same sample. Western blotting used to detect the presence of a specific protein with antibody-antigen interaction in the midst of a complex protein mixture extracted from cells, produced semi-quantitative data quite easy to interpret. Confocal Raman microscopy combines the three-dimensional optical resolution of confocal microscopy and the sensitivity to molecular vibrations, which characterizes Raman spectroscopy. The combined use of western blotting and confocal microscope allows detecting the presence of proteins in the sample and trying to observe the exact location within the tissue, or the topographical distribution of the same. Once demonstrated the presence of proteins (cytokines, chemokines, etc.) is important to know the topographical distribution, obtaining in this way additional information regarding the extension of the inflammatory process in function of the time stayed from the time of myocardial infarction. These methods may be useful to study and define the expression of a wide range of inflammatory mediators at several different timepoints providing a more detailed analysis of the time course of the infarct.

Abdominal aortic aneurysm (AAA) is an age-related disease resulting in aortic wall weakening and dilatation which may progress to the fatal point of abrupt aortic wall rupture. Chronic inflammation is a driving force in the pathogenesis of AAA and extracellular matrix (ECM) proteases are considered central to aortic wall degradation. Considerable effort is dedicated to identifying the proteases responsible as well as the mechanism by which these proteases contribute to disease progression. As such, they are considered important molecular targets for pharmacological intervention. Along with smoking, male gender and family history, aging is a major risk factor for AAA. Examination of age-related changes of the immune system reveals an interwoven relationship between the processes of aging and chronic inflammation, collectively predisposing to AAA development. The present review explores current evidence as to the role of specific ECM proteases in AAA pathogenesis. The contribution of the aging process to disease pathogenesis is also explored to provide the relevant context and highlight key molecular pathways that should be considered while attempting to develop effective treatment approaches.

Hypertension (HTN) and chronic kidney disease (CKD) often coexist sharing common pathophysiological factors that both in combination and separately induce fibrotic changes in the heart provoking atrial fibrillation (AF). AF, per se, is associated with a 4- to 5-fold increased risk of stroke and a 2-fold increased risk of all-cause death. The co-existence of AF with HTN and renal dysfunction considerably increases morbidity and mortality. Management of AF in hypertensive patients with CKD is complex and multidisciplinary, since these patients have both a prothrombotic state and a coagulopathy with an increased tendency for bleeding. Novel oral anticoagulants such as dabigatran, rivaroxaban and apixaban offer better efficacy and safety especially in patients without optimal treatment with vitamin K antagonists.

Hypertension (HTN) is a major risk factor for atherosclerosis. Flow-mediated vasodilation (FMD) is an ultrasonic method used to evaluate endothelial function, which is associated with HTN and related complications. We summarized clinical trials focusing on the effects of non-antihypertensive drugs on endothelial function, as evaluated by FMD, in patients with HTN. Hypercholesterolemic patients with HTN who used the cholesterol- lowering drugs HMG-CoA reductase inhibitors (statins) had improved FMD with a reduction in cholesterol levels and no significant change in blood pressure (BP). Non-diabetic patients with HTN who used the insulinsensitizing drug pioglitazone had improved FMD with a reduction in insulin resistance. Obese patients with HTN who used the anti-obesity drug orlistat had improved FMD with a reduction in BP and weight, and the improvement in FMD was correlated with weight reduction. Patients with HTN who used the selective cyclocxygenase-2 inhibitor celecoxib had improved FMD with no significant change in BP. Hypercholesterolemic patients with HTN who used aspirin added to a statin had improved FMD with a reduction in BP. Patients with HTN who used the advanced glycation endproduct crosslink breaker alagebrium had improved FMD with no significant change in BP. Postmenopausal women with HTN who used estrogen-replacement therapy had improved FMD. The possibility of improvement in FMD levels has, therefore, been suggested with several non-antihypertensive drugs. In addition to the direct effects of antihypertensive drugs on endothelial function, use of these non-antihypertensive drugs may give important insights into HTN management.

Levosimendan is a calcium-sensitizing agent that improves cardiac function, hemodynamic performance, and survival in critically ill adult patient. Few data exist on its off-label use in paediatric patients. We therefore performed a systematic review updated in September 2013 of all the published articles describing the use of levosimendan in paediatric patients. We identified 24 studies published in the period 2004-2013 that included a total of 623 patients, the largest one being a case series of 293 patients. Most of the patients underwent cardiac surgery, other settings consisting of chronic heart failure, primary congenital heart diseases and sepsis and cancer-associated cardiac dysfunction. Most studies reported improvement in ventricular function, central venous oxygen saturation, serum lactate levels or cardiac index. The 5 randomized studies published so far have all been performed in cardiac surgery and suggest a beneficial effect on hemodynamic data with no effect on intensive care unit stay, hospital stay or survival. Side effects (e.g. hypotension) were reported. This inodilator merits to be investigated with further randomized trials focusing on clinically relevant outcomes.

Background: The most common complications of chronic kidney disease (CKD) are hypertension and cardiovascular (CV) disorders. Renalase is produced and released by the kidney and also cardiomyocytes. Renalase deficiency was claimed to be responsible for hypertension and CV complication in CKD. There are contradictory data about serum renalase because of low activity and high levels revealed in hypertensive patients with CKD. We assessed serum renalase concentration in objects with CKD after one-side and both-side nephrectomy (on haemodialysis [HD]), or hemodiafiltration (HDF), in urine and ultrafiltrate in hemodialysis objects. We also evaluated the influence of hemodialysis sessions on renalase concentrations. Methods: The concentration of renalase in plasma, ultrafiltrate and urine of 100 hemodialysis patients was assessed by commercially accessible test. We evaluated renalase in 17 HDF objects and 24 healthy controls. Western Blot test was also used to assess renalase concentration. Results: Ultrafiltrate in hemodialysis objects contained renalase and there was no impact of dialysers&apos type (high-flux and low-flux). Renalase concentration of urine in control group was higher than in hemodialysis objects (n=60). The anuric group had higher renalase concentration comparing to those with remaining diuresis (p<0.001). Univariate analysis revealed the correlation between renalase concentration in plasma and in urine (r=-0.28, p<0.05) and ultrafiltrate renalase in hemodialysis group and between renalase in urine in the control group (r=0.61, p<0.01). There was a correlation between urinary renalase and residual diuresis, hemodialysis sessions non-significantly lowered renalase, the type of heparin had no effect on serum renalase levels. HDF patients had significantly lower renalase than HD patients. In Western blot analysis we found that patients after bilateral nephrectomy had the highest renalase, followed by unilateral nephrectomy. Conclusion: Kidneys eliminate renalase and it is possible that the increased renalase has the impact on cardiovascular diseases in chronic kidney disease.