Current Pharmaceutical Design - Volume 24, Issue 25, 2018

Background: Ischemic heart disease has long been considered to be exlusively caused by stenosis or occlusion. However, the coronary microcirculation too may play an important role in ischemic conditions. Also, the crucial role of microvessels in not only regulating blood flow on a local level but also mediating vascular permeability or inflammatory responses has been recognized. Objective: To review important physiological and pathophysiological mechanisms of coronary microcirculatory control with focus on heterogeneity of local perfusion, microvascular permeability and inflammation. Method: Selective research of the literature. Results: Heterogeneity is a characteristic of microvascular networks and affects structural and functional parameters such as vessel diameter, length, and connection pattern, flow velocity, wall shear stress, and oxygenation. Microvascular networks are optimized to meet the metabolic demand of all tissue compartments. This requires continuous vascular adaptation regulated by local hemodynamic and metabolic stimuli. Compromising this regulation results in functional arterio-venous shunting and tissue areas with either hyperperfusion or hypoxia in close proximity. In ischemia-reperfusion, increased microvascular permeability may aggravate tissue hypoxia by increasing extravascular pressure and seems to contribute to adverse myocardial remodeling. Transendothelial transport mechanisms and deterioration of the endothelial glycocalyx seem to be major contributors to tissue edema. Also in the context of ischemia-reperfusion, an inflammatory response mediated by venular endothelium expressing specific adhesion molecules contributes to tissue injury. However, anti-inflammatory therapies failed in clinical studies and a multi-targeted approach for cardiac protection is required. Conclusion: Disturbances of the coronary microcirculation are involved in different pathophysiological aspects of reperfusion injury.

Myocardial ischemia is the consequence of an unbalance between coronary flow that can be achieved and myocardial metabolic needs. Pathological state of both epicardial and intramyocardial vessels may be responsible for inducing ischemia. However, revascularization decision should be based on the severity of each epicardial lesion that is evaluated. There are different diagnostic tools that may help for the evaluation of each compartment which is based on the measurement of coronary hemodynamics. Pressure-derived indices are recommended by current guidelines for evaluation of epicardial stenosis significance. We assess the complex interaction between hemodynamic parameters in order to understand how different parameters are influenced in the settings of microvascular dysfunction.

Vasospastic angina is an important cause of chest pain due to coronary artery vasospasm that is related to poor quality of life and can lead to myocardial infarction, arrhythmias and death. Since its first description as “Prinzmetal or variant angina” which was believed to be a focal spam that occurred in non-obstructed epicardial coronary arteries, physician and researchers were gradually confronted with the clinical reality and came to the conclusion that the coronary artery vasospasm was considerably more polymorphic than initially described. Although mechanism leading to vasospastic angina is not completely understood, nowadays the medical community acknowledges that it exhibits a large variability in clinical practice ranging from focal to diffuse epicardial vasospasm. Main proposed mechanisms are impairment of parasympathetic activity, coronary vascular and microvascular dysfunction due to blunted response to nitric oxide endothelium-dependent coronary vasodilatation, increased release of vasoconstricts, and oxidative stress.

In various metabolic diseases, both the coronary circulation and cardiac metabolism are altered. Here we summarize the effects of a condition called hyperhomocysteinemia (HHcy) - which can develop due to genetic and/or environmental causes - on the function of coronary microvessels and heart. This metabolic disease is underappreciated, yet even mild or moderate elevation of plasma concentrations of homocystein (Hcy, plasma Hcy >16 μM), a sulfur-containing amino acid produced via methionine metabolism) leads to coronary and peripheral artery and even venous vessel diseases, eliciting vasomotor dysfunction and increased thrombosis, consequently increased morbidity and mortality. Yet the underlying mechanisms have not yet been revealed. Recent studies indicated that there are common pathomechanisms, which may affect several cellular functions. With methionin diet-induced HHcy two main pathomechanisms were revealed: the dysfunction of nitric oxide (NO) pathway resulting in reduced dilator responses of arteries and arterioles, and the simultaneously increased thromboxane A2 (TXA2) activity both in vessels and platelets. These changes are likely due to an increased production of reactive oxidative species (oxidative stress) due to increased NADPH oxidase assembly, which eventually lead to inflammatory processes (indicated by increases in TNFα, NFΚbeta, p22phox, p67phox, and rac-1, levels) and changes in various gene expressions and morphological remodeling of vessels. Increased superoxide production and reduced availability of NO alter the regulation of mitochondrial function in the myocardium. The interactions of these pathomechanisms may explain why HHcy increases the uptake of glucose and lactate and decreases the uptake of free fatty acid by the heart. The pathological consequences of HHcy could be worsening by the simultaneous presence of other risk factors, such as hyperlipidemia, diabetes mellitus and metabolic syndrome. All in all, HHcy and associated pathometabolism lead to severe changes and dysfunctions of coronary arterial vessels and cardiac function, which may not always be apparent in clinical settings but most likely contribute to the increased prevalence of cardiovascular diseases and mortality, which however can be reduced by appropriate prevention and treatments. We believe that HHcy is an underestimated - likely due to inappropriate clinical trials - but serious disease condition because it promotes the development of atherosclerosis in large arterial vessels, vasomotor dysfunction in microvessels, hypertension and thrombosis. In this review, we will summarize previous functional findings focusing on coronary vessels and cardiac function and the underlying cellular and molecular mechanisms enabling the development of novel treatments.

Dyslipidemia is widely accepted as one of the major risk factors in cardiovascular disease mainly due to its contribution in the pathogenesis of atherosclerosis in medium-sized and large arteries. However, it has become increasingly accepted that high-cholesterol levels can also adversely affect the microvasculature prior to the development of overt atherosclerosis. Moreover, hypercholesterolemia has shown, in preclinical animal models, to exert detrimental effects beyond the vascular tree leading to larger infarcts and adverse cardiac remodeling post-myocardial infarction. At a functional level, hypercholesterolemia has shown to impair endotheliumdependent vasodilation because on defects on nitric oxide bioavailability. The pathogenic mechanisms underlying microvascular dysfunction involve an enhanced arginase activity, enhanced production of free radicals and the activation, recruitment and accumulation of leukocytes, primarily neutrophils, via their diffusion through postcapillary venules. In turn, recruited inflammatory cells and certain inflammatory mediators enhance platelet adhesion, overall inducing a proinflammatory and prothrombotic phenotype. Within the present review, we aim to discuss the existing evidence regarding the presence of dyslipidemia - particularly high low density lipoprotein-cholesterol levels - and the occurrence of microvascular dysfunction, the mechanism by which high cholesterol levels induce functional alterations in the microvascular bed and, finally comment on the impact of dislipidemia-induced microvascular dysfunction at the myocardial level.

Timely delivered coronary revascularization with no residual anatomical stenosis does not always lead to prompt restoration of anterograde coronary flow and complete myocardial reperfusion. This condition is known as coronary no-reflow and is associated with major clinical adverse events and poor prognosis. The pathophysiology of no-reflow phenomenon is still poorly understood. Proposed mechanisms include distal microembolization of thrombus and plaque debris, ischemic injury, endothelial dysfunction and individual susceptibility to microvascular dysfunction/obstruction. Older age, diabetes, hypercholesterolemia, prolonged ischemic time, hemodynamic instability, high thrombus burden, complex angiographic lesions and multivessel disease are frequently reported to be associated with the no-reflow phenomenon. There is no general consensus on the correct prevention and management of no-reflow. Non-pharmacological measures such as distal embolic protection devices and manual thrombus aspiration did not result in improved flow or reduction of infarct size. Current preventive measures include reduction of time from symptoms onset to reperfusion therapy, and intracoronary administration of vasodilators such as adenosine, verapamil or nitroprusside.

The no-reflow phenomenon refers to the post-percutaneous coronary intervention condition in which, despite re-establishing epicardial coronary vessel patency, the flow to the previously ischemic myocardium is markedly reduced. When it does occur, it attenuates the beneficial effect of reperfusion therapy and substantial regions of the myocardium fail to receive adequate perfusion. The pathophysiology of this phenomenon is not completely understood. The possible mechanisms could be related to alterations in the microvascular circulation. Various mechanisms such as activation of inflammatory pathways, vascular damage and hemorrhage, leukocyte infiltration, and cellular edema may be responsible. As the no-reflow phenomenon is associated with adverse clinical consequences, it is of great importance to identify exact responsible mechanisms and apply effective preventive and therapeutic strategies. In this review, we describe an updated overview of the pathophysiological mechanisms and the current preventive tools for no-reflow as well as therapeutic interventions in order to improve coronary blood flow and consequently the prognosis for these patients.

Myocardial contrast echocardiography has been used in clinical arena and for scientific research extensively in the last fifteen years. This non-invasive, bed-side and radiation free imaging technique offers several important possibilities: better delineation of the endocardial border, more reliable assessment of the left ventricular wall motion abnormalities, both in rest and during stress, and myocardial perfusion evaluation. Here we provide an overview on different applications of the myocardial contrast echocardiography in the ischemic heart disease with the special focus on perfusion studies and evaluation of coronary microcirculation.

Functional tests used in the catheterization laboratory have emerged as a very important adjunctive tool to coronary angiography that can identify patients with myocardial blood flow impairment. Fractional Flow Reserve (FFR) measurement is highly recommended for detection of ischemia-related coronary lesion(s) when objective evidence of vessel-related ischemia is not available. Recently, the much simpler instantaneous wave free ratio (iFR) was proposed as an alternative to FFR without the requirement for administration of vasodilators. More user-friendly techniques like iFR might further contribute to value-based care in coronary interventions.

The idea of coronary microcirculation playing a role in the pathophysiology of heart failure dates from decades ago, with authors hypothesizing that structural and functional alterations in the coronary microcirculation could potentially contribute to heart failure. It is known that in a wide range of primary cardiomyopathies, from dilated to hypertrophic, there are pathological alterations in myocardial vasculature structure and function, playing a role in the clinical course of the disease. Needless to say, many patients with normal epicardial coronary arteries can suffer from coronary microvascular dysfunction, that could lead to a wide variety of clinical problems – from impaired functional capacity to stable and unstable angina, Takotsubo syndrome, myocardial infarction with normal coronary arteries and can also end up with either acute or chronic heart failure. Furthermore, nowadays, it has been recognized that pathophysiology of the heart failure with preserved ejection fraction (HFpEF) is mainly due to the myocardial microcirculatory impairment. In heart failure with reduced ejection fraction (HFrEF) neurohumoral mechanisms affecting the peripheral vasculature have been identified as important factors in the development and progression of heart failure, leading to unfavourable remodelling, and thus some of them being important treatment targets. Among many new clinical scenarios where both myocardial and peripheral microcirculation play an important role, raising field of implantable continuous flow assist devices opens many questions and implies better understanding of their effects of microcirculation, as they usually lead to the improvement of end organ dysfunction caused by previous heart failure, which is probably through the positive effects of peripheral microcirculation.

Background: The Heart Failure with Preserved Ejection Fraction (HFpEF) is defined as the preserved left ventricular ejection fraction (LVEF) with the signs of heart failure, elevated natriuretic peptides, and either the evidence of the structural heart disease or diastolic dysfunction. The importance of this form of heart failure was increased after studies where the mortality rates and readmission to the hospital were founded similar as in patients with HF and reduced EF (HFrEF). Coronary microvascular ischemia, cardiomyocyte injury and stiffness could be important factors in the pathophysiology of HFpEF. Methods: The goal of this work is to analyse the relationship of HFpEF and coronary microcirculation in previous studies. Results: The useful diagnostic marker of coronary microcirculation in HFpEF may be the parameters measured by transthoracic echocardiography (TTE), the coronary flow reserve (CFR), as well as fractional flow reserve (FFR) and quantitative myocardial contrast echocardiography (MCE). Cardiac magnetic resonance (CMR) imaging represents the diagnostic gold standard in HFpEF. Coronary microvascular dysfunction in the absence of obstructive coronary artery disease (CAD) is poorly understood and may be more prevalent amongst women than men. Troponin level may be important in risk stratification of HEpEF patients. Conclusion: There are no precise answers with respect to the pathophysiological mechanism, nor are there any precise practical clinical assessment of and diagnostic method for coronary microvascular dysfunction and diastolic dysfunction. In accordance with that, there is no well-established treatment for HFpEF.

Advances in early reperfusion therapies focused on the revascularization of the ischemic tissues, in the last decades, lead to reduced mortality in acute myocardial infarction (MI) patients. However, a large proportion of patients show inadequate myocardial perfusion because of dysfunction of the microcirculation. The high prevalence of microvascular dysfunction after reperfusion therapies and the negative prognostic of this procedure justify the search for therapeutic strategies that aim to restore the microvascular network. It is well known that the size of the initial infarct, the duration of ischemia and the efficiency of reperfusion determine myocardial tissue damage and cardiomyocyte loss after myocardial infarction. Therefore any advancement on the mechanisms that induce the repair process of microvascular dysfunction after reperfused MI is of great interest. Here, we will review the different proteins and cells known to participate in angiogenesis induction post-MI and we will also discuss the potential pharmacological and cellular processes that promote the recovery of microvasculature by angiogenesis stimulation after MI.

In recent decades, drug-protein interactions have been widely studied and several methods of analysis of these phenomena have been developed and improved. These can be classified into separation, physical, chromatographic and electrophoretic methods. This review depicts the assumptions and mechanisms of methods from each group, details their strengths and weaknesses, and presents examples of their usage from the literature. Equilibrium dialysis, ultrafiltration, Hummel-Dreyer method or high performance affinity chromatography are given as representative examples, but this issue is far more expanded. Nowadays, increasing attention is paid to the computational methods and molecular modeling which are convenient tools to estimate protein binding affinity based on the physicochemical properties of compounds. To gain a broader overview, the study also examines the protein binding ability and pharmacotherapy of drugs against a range of substrates such as plasma, skin, tissue and human milk.

Background: Cerebral ischemia is a common cause of disability and death. Ischemic brain injury results from complex pathological processes, including oxidative stress, inflammation, and apoptosis. Thioredoxin( Trx) is an important multifunctional protein, which regulates cellular redox status. Increasing studies have demonstrated that Trx provides a neuroprotective role against cerebral ischemia-induced injury. Methods: A systematic search of PMC and the PubMed Database was conducted to summarize the protective effects of Trx against cerebral ischemia. Results: This article reviews the understanding of potential effects and mechanisms of Trx against cerebral ischemia, including the anti-oxidant, anti-apoptotic and anti-inflammatory effects, as well as the activation of prosurvival pathway. We also summarize that some natural compounds induce the expression of Trx, which is involved in their anti-ischemic effects. Conclusion: In conclusion, Trx has a potential neuroprotection in cerebral ischemia and may be very promising for clinical therapy of ischemic stroke in the future.

Amelogenins are enamel matrix proteins that play crucial roles in enamel formation. Previous studies have indicated that amelogenin and amelogenin C-terminal peptides have cell-signaling functions. Recently, adipocyte-derived mesenchymal stem cells (ADSCs) have received attention as a potential source of stem cells for use in regeneration therapy. In this study, we examined the effects of human full-length amelogenin (rh174) and amelogenin C-terminal peptide (amgCP) on the proliferation of ADSCs. ADSCs were cultured in the presence of amgCP or rh174. Cell proliferation was analyzed using BrdU immunoassay and MTS assay. Cell migration was evaluated by ELISA. The MAPK-ERK pathway was examined by phospho-p44/42 MAPK (Thr202/Tyr204) sandwich ELISA and western blotting. A specific MAPK inhibitor, U0126, was used to block ERK activity. ADSC proliferation and migration were significantly (P < 0.05) increased in the presence of rh174 or amgCP compared to non-treated control cells. The increased proliferation of ADSCs induced by rh174 or amgCP was significantly (P < 0.05) inhibited in the presence of 2 μg/ml U0126. The pERK/tERK ratio was significantly (P < 0.05) increased upon treatment with rh174 or amgCP compared to non-treated ADSCs, while this increase was significantly (P < 0.05) suppressed by the addition of U0126. Similar results were found by western blot analysis. In conclusion, amgCP and rh174 increase ADSC proliferation via the MAPK-ERK signaling pathway, and ADSCs may be useful for tissue regeneration in the orofacial region.

Background: The role of urinary cystatin C to early predict acute kidney injury (AKI) in children and neonates remains uncertain. The present study aimed to assess and compare the level of urinary cystatin C in neonates with and those without AKI. Methods: This cross-sectional study was performed on 55 available neonates who were involved by AKI and admitted to the neonatal department at Ali-Asghar hospital in Tehran in 2016. 97 neonates with jaundice and normal serum creatinine level were randomly selected as the control group. In both groups and on admission, the urine levels of cystatin C and creatinine were measured. Results: The average urinary level of cystatin C was 162.87 ± 56.50 mmol/mole creatinine in the group with AKI and 68.06 ± 57.16 mmol/mole creatinine in the control group that was significantly higher in former group (p < 0.001). The measurement of cystatin C level in urine could predict kidney injury with a sensitivity of 98.2%, a specificity of 39.2%, a positive predictive value of 47.8%, a negative predictive value of 97.4%, and an accuracy of 60.5%. Assessment of the area under the receiver operating characteristic (ROC) analysis showed that measuring urinary cystatin C level could effectively discriminate kidney injury from normal kidney condition in neonates (AUC = 0.868, 95CI: 0.811 – 0.925, P < 0.001). The best cutoff value of urinary cystatin C level to predict kidney injury was shown to be 41.5 mmol/mole creatinine yielding a sensitivity of 98.2% and a specificity of 46.4%. Conclusion: Measurement of cystatin C in urine is an early sensitive method to diagnose neonatal kidney injury.