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Chronic wounds are becoming an increasingly common clinical problem due to an aging population and an increased incidence of diabetes, atherosclerosis, and venous insufficiency, which are the conditions that impair and delay the healing process. Patients with diabetes constitute a group of subjects in whom the healing process is particularly prolonged regardless of its initial etiology. Circulatory dysfunction, both at the microvascular and macrovascular levels, is a leading factor in delaying or precluding wound healing in diabetes. The prolonged period of wound healing increases the risk of complications such as the development of infection, including sepsis and even amputation. Currently, many substances applied topically or systemically are supposed to accelerate the process of wound regeneration and finally wound closure. The role of clinical trials and preclinical studies, including research based on animal models, is to create safe medicinal products and ensure the fastest possible healing. To achieve this goal and minimize the wide-ranging burdens associated with conducting clinical trials, a correct animal model is needed to replicate the wound conditions in patients with diabetes as closely as possible. The aim of the paper is to summarize the most important molecular pathways which are impaired in the hyperglycemic state in the context of designing an animal model of diabetic chronic wounds. The authors focus on research optimization, including economic aspects and model reproducibility, as well as the ethical dimension of minimizing the suffering of research subjects according to the 3 Rs principle (Replacement, Reduction, Refinement).

A large body of evidence indicates that vasopressin (AVP) and steroid hormones are frequently secreted together and closely cooperate in the regulation of blood pressure, metabolism, water–electrolyte balance, and behavior, thereby securing survival and the comfort of life. Vasopressin cooperates with hormones of the hypothalamo–pituitary–adrenal axis (HPA) at several levels through regulation of the release of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and multiple steroid hormones, as well as through interactions with steroids in the target organs. These interactions are facilitated by positive and negative feedback between specific components of the HPA. Altogether, AVP and the HPA cooperate closely as a coordinated functional AVP-HPA system. It has been shown that cooperation between AVP and steroid hormones may be affected by cellular stress combined with hypoxia, and by metabolic, cardiovascular, and respiratory disorders; neurogenic stress; and inflammation. Growing evidence indicates that central and peripheral interactions between AVP and steroid hormones are reprogrammed in cardiovascular and metabolic diseases and that these rearrangements exert either beneficial or harmful effects. The present review highlights specific mechanisms of the interactions between AVP and steroids at cellular and systemic levels and analyses the consequences of the inappropriate cooperation of various components of the AVP-HPA system for the pathogenesis of cardiovascular and metabolic diseases.

Doxorubicin (DOX) is an important drug used in the treatment of many malignancies. Unfortunately DOX causes various side effects, with cardiotoxicity being the most characteristic. Risk factors for DOX induced cardiotoxicity (DIC) include cumulative dose of DOX, preexisting cardiovascular diseases, dyslipidemia, diabetes, smoking, along with the use of other cardiotoxic agents. Development of DIC is associated with many pathological phenomena – increased oxidative stress, as well as upregulation of ferroptosis, apoptosis, necrosis, and autophagy. In DIC expression of many microRNAs is also deregulated. In order to avoid cardiotoxicity and still use DOX effectively DOX derivatives such as epirubicin were synthesized. Nowadays a new liposomal form of DOX (L-DOX) appeared as an alternative to conventional treatment with greatly reduced cardiotoxicity. L-DOX can be divided into two groups of substances – pegylated (PLD) with increased solubility and stability, and non-pegylated (NLPD). Many metaanalyses, clinical along with preclinical studies have shown L-DOX treatment is associated with a smaller decrease of left ventricular ejection fraction (LVEF) and other heart functions, but efficacy of this treatment is comparable to the use of convenctional DOX.

Myocardial infarction is one of the major causes of mortality worldwide and is a main cause of heart failure. This disease appears as a final point of atherosclerotic plaque progression, destabilization, and rupture. As a consequence of cardiomyocytes death during the infarction, the heart undergoes unfavorable cardiac remodeling, which results in its failure. Therefore, therapies aimed to limit the processes of atherosclerotic plaque progression, cardiac damage during the infarction, and subsequent remodeling are urgently warranted. A hopeful therapeutic option for the future medicine is targeting and regulating non-coding RNA (ncRNA), like microRNA, circular RNA (circRNA), or long non-coding RNA (lncRNA). In this review, the approaches targeted at ncRNAs participating in the aforementioned pathophysiological processes involved in myocardial infarction and their outcomes in preclinical studies have been concisely presented.

Patients with unstable angina present clinical characteristics of atherosclerotic plaque vulnerability, contrary to chronic coronary syndrome patients. The process of athersclerotic plaque destabilization is also regulated by microRNA particles. In this study, the investigation on expression levels of microRNAs inhibiting the expression of proteins that protect from atherosclerotic plaque progression (miR-92a inhibiting KLF2, miR-10b inhibiting KLF4, miR-126 inhibiting MerTK, miR-98 inhibiting IL-10, miR-29b inhibiting TGFβ1) was undertaken. A number of 62 individuals were enrolled—unstable angina (UA, n = 14), chronic coronary syndrome (CCS, n = 38), and healthy volunteers (HV, n = 10). Plasma samples were taken, and microRNAs expression levels were assessed by qRT-PCR. As a result, the UA patients presented significantly increased miR-10b levels compared to CCS patients (0.097 vs. 0.058, p = 0.033). Moreover, in additional analysis when UA patients were grouped together with stable patients with significant plaque in left main or proximal left anterior descending (“UA and LM/proxLAD” group, n = 29 patients) and compared to CCS patients with atherosclerotic lesions in other regions of coronary circulation (“CCS other” group, n = 25 patients) the expression levels of both miR-10b (0.104 vs. 0.046; p = 0.0032) and miR-92a (92.64 vs. 54.74; p = 0.0129) were significantly elevated. In conclusion, the study revealed significantly increased expression levels of miR-10b and miR-92a, a regulator of endothelial protective KLF factors (KLF4 and KLF2, respectively) in patients with more vulnerable plaque phenotypes.

Background/Objectives: Anthracyclines remain a pivotal element of numerous tumor management regimens; however, their utilization is associated with a range of adverse effects, the most significant of which is cardiotoxicity. Research is constantly being conducted to identify substances that could be incorporated into ongoing cancer chemotherapy to mitigate anthracycline-induced cardiotoxicity. Recently, the apelinergic system has received a lot of attention in this field due to its involvement in cardiovascular regulation. Therefore, the aim of our study was to investigate the ability of the apelinergic system to inhibit the cardiotoxic effects of anthracycline—doxorubicin (DOX). Methods: In this study, 54 Sprague–Dawley rats were divided into seven groups and received intraperitoneal injections with DOX once a week for 4 consecutive weeks. The osmotic pumps provided a continuous release of NaCl (control groups), apelin-13 and elabela at two different doses, and the apelin receptor (APJ) antagonist ML221. Electrocardiography (ECG) and transthoracic echocardiography (TTE) with assessment of left ventricular (LV) systolic parameters were conducted on the first and last days of the experiment. Results: Lower doses of APJ agonists prevented the prolongation of QT and QTc intervals induced by DOX, while higher doses of these drugs exerted no such effect. The TTE examination confirmed DOX-induced LV systolic dysfunction. Moreover, the TTE examination revealed an improvement in the LV systolic parameters in the DOX-treated groups that were simultaneously administered APJ agonists. Conclusions: Our findings support the use of apelin and elabela as potential cardioprotective agents against anthracycline-induced cardiotoxicity.

Atherosclerotic plaque is the pathophysiological basis of important and life-threatening diseases such as myocardial infarction. Although key aspects of the process of atherosclerotic plaque development and progression such as local inflammation, LDL oxidation, macrophage activation, and necrotic core formation have already been discovered, many molecular mechanisms affecting this process are still to be revealed. This minireview aims to describe the current directions in research on atherogenesis and to summarize selected studies published in recent years—in particular, studies on novel cellular pathways, epigenetic regulations, the influence of hemodynamic parameters, as well as tissue and microorganism (microbiome) influence on atherosclerotic plaque development. Finally, some new and interesting ideas are proposed (immune cellular heterogeneity, non-coding RNAs, and immunometabolism) which will hopefully bring new discoveries in this area of investigation.

The recent introduction of an entirely subcutaneous implantable cardioverter-defibril-lator (S-ICD) represents an important progress in the defibrillation technology towards a less invasive approach. This is a single-center observational study of S-ICD implantations in Poland. The S-ICD was implanted in 11 patients with standard indications for an ICD. Patients in whom the device was implanted were evaluated for adverse events and device function at hospital discharge. All hospitalization costs were calculated and summed up for all patients. Costs were divided into following categories: medical materials, pharmaceuticals, operating theatre staff, cardiology depart-ment staff, laboratory tests, non-laboratory tests and additional non-medical costs. The mean age of patients was 51.6 ± 16.4 years, 9 were men and 2 were women. Four pa-tients had atrial fibrillation as the basal rhythm, 1 patient had atrial flutter and 6 patients had sinus rhythm. All patients had at least one condition that precluded the use of a traditional ICD system or the S-ICD was preferred due to other conditions, i.e. a history complicated transvenous ICD therapy (18%), anticipated higher risk of infection (27%), lack or difficult vascular access (18%), young age and anticipated high cumulated risk of lifetime device therapy (36%). The mean duration of the im-plantation procedure was 2 h. One patient developed a postoperative pocket hematoma. Mean total time of hospitalization was 28 (6-92) days. Average cost of hospitalization per patient was 21,014.29 EUR (minimal = 19,332.71 EUR and maximal = 24,824.14 EUR). S-ICD implantation appears to provide a viable alternative to transvenous ICD, espe-cially for patients without pacing requirements.

Atherosclerotic plaque vulnerability is a vital clinical problem as vulnerable plaques tend to rupture, which results in atherosclerosis complications—myocardial infarctions and subsequent cardiovascular deaths. Therefore, methods aiming to stabilize such plaques are in great demand. In this brief review, the idea of atherosclerotic plaque stabilization and five main approaches—towards the regulation of metabolism, macrophages and cellular death, inflammation, reactive oxygen species, and extracellular matrix remodeling have been presented. Moreover, apart from classical approaches (targeted at the general mechanisms of plaque destabilization), there are also alternative approaches targeted either at certain plaques which have just become vulnerable or targeted at the minimization of the consequences of atherosclerotic plaque erosion or rupture. These alternative approaches have also been briefly mentioned in this review.

Current guidelines recommend potent platelet inhibition with prasugrel or ticagrelor for 12 months after an acute coronary syndrome managed with percutaneous coronary intervention (PCI). However, the greatest anti-ischaemic benefit of potent antiplatelet drugs over the less potent clopidogrel occurs early, while most excess bleeding events arise during chronic treatment. Hence, a stage-adapted treatment with potent platelet inhibition in the acute phase and de-escalation to clopidogrel in the maintenance phase could be an alternative approach. We aimed to investigate the safety and efficacy of early de-escalation of antiplatelet treatment from prasugrel to clopidogrel guided by platelet function testing (PFT). In this investigator-initiated, randomised, open-label, assessor-blinded, multicentre trial (TROPICAL-ACS) done at 33 sites in Europe, patients were enrolled if they had biomarker-positive acute coronary syndrome with successful PCI and a planned duration of dual antiplatelet treatment of 12 months. Enrolled patients were randomly assigned (1:1) using an internet-based randomisation procedure with a computer-generated block randomisation with stratification across study sites to either standard treatment with prasugrel for 12 months (control group) or a step-down regimen (1 week prasugrel followed by 1 week clopidogrel and PFT-guided maintenance therapy with clopidogrel or prasugrel from day 14 after hospital discharge; guided de-escalation group). The assessors were masked to the treatment allocation. The primary endpoint was net clinical benefit (cardiovascular death, myocardial infarction, stroke or bleeding grade 2 or higher according to Bleeding Academic Research Consortium [BARC]) criteria) 1 year after randomisation (non-inferiority hypothesis; margin of 30%). Analysis was intention to treat. This study is registered with ClinicalTrials.gov, number NCT01959451, and EudraCT, 2013-001636-22. Between Dec 2, 2013, and May 20, 2016, 2610 patients were assigned to study groups; 1304 to the guided de-escalation group and 1306 to the control group. The primary endpoint occurred in 95 patients (7%) in the guided de-escalation group and in 118 patients (9%) in the control group (pnon-inferiority=0·0004; hazard ratio [HR] 0·81 [95% CI 0·62–1·06], psuperiority=0·12). Despite early de-escalation, there was no increase in the combined risk of cardiovascular death, myocardial infarction, or stroke in the de-escalation group (32 patients [3%]) versus in the control group (42 patients [3%]; pnon-inferiority=0·0115). There were 64 BARC 2 or higher bleeding events (5%) in the de-escalation group versus 79 events (6%) in the control group (HR 0·82 [95% CI 0·59–1·13]; p=0·23). Guided de-escalation of antiplatelet treatment was non-inferior to standard treatment with prasugrel at 1 year after PCI in terms of net clinical benefit. Our trial shows that early de-escalation of antiplatelet treatment can be considered as an alternative approach in patients with acute coronary syndrome managed with PCI. Klinikum der Universität München, Roche Diagnostics, Eli Lilly, and Daiichi Sankyo.