Cardiac Tissue Injury Research Articles

Left Ventricular Assist Device (LVAD) Implantation Transiently Increases Plasma TGF-β1 in Heart Failure Patients: Potential Impact of Lvad on Platelet Activation

Although survival and quality of life have improved in patients with advanced heart failure (HF) after implantation of left ventricular assist devices (LVADs), they still pose risks of hemocompatibility-related complications, including thrombosis and bleeding. Development of biomarkers predictive of these LVAD-associated complications could guide decision making for both clinicians and patients. Recently, we showed higher plasma TGF-β1 levels within one-week after implantation with a miniaturized mechanical-bearing axial-flow pump HeartMate II (HM-II), and reasoned that platelet activation by the rotor may have caused the release of TGF-β1 in plasma in HF patients (Mancini et al. Transl. Res. 2018; 192:15-29). Recent clinical trials with the newest LVAD, the Heartmate 3 (HM-3), which uses a fully magnetically-levitated pump, showed superior clinical outcomes, including significantly reduced incidences of pump thrombosis and stroke (Mehra et al. N Engl J Med. 2019; 380:1618-1627). In this study, we evaluated release of TGF-β1 in plasma following implantation of HM-II and HM-3 LVADs compared to either coronary artery bypass graft (CABG) surgery or extracorporeal membrane oxygenation (ECMO) therapy. We measured serial total TGF-β1 levels in 38 Stage-D HF patients (11 received HM-II and 27 received HM-3). As a control, we collected blood samples from 10 patients undergoing CABG surgery, and 10 patients receiving ECMO therapy following acute onset cardio-pulmonary failure. Blood samples were collected before and 4-8 hours after procedures, and thereafter daily for up to one week. Plasma was prepared by centrifuging blood at 12,000 rpm for 5 min at 4°C within 10 min of blood drawing, which reduces in vitro release of TGF-β1 from platelets and thus allows accurate measurement of plasma TGF-β1. Total TGF-β1 levels were measured after acidification and neutralization of samples using DUO-ELISA kit (R&D Systems). Baseline total plasma TGF-β1 levels were higher in HF patients before LVAD implantation than in healthy controls [4.7 ± 1.9 ng/mL in HF patients (n= 38); 3.3 ± 0.8 ng/mL in healthy controls (n= 6); p=0.006)]. Total TGF-β1 levels surged transiently to 14.6 ± 6.1 ng/mL within 4-8 hours after LVAD implantation [(p<0.0001 compared to patients 4-12 hours after CABG surgery (3.6 ± 1.4 ng/mL) or ECMO therapy (4.9 ± 1.3 ng/mL)]. Interestingly, however, we found that the transient surge of TGF-β1 in HM-3 recipients was significantly lower than in HM-II recipients (Figure-1; p=0.04). TGF-β1 levels then gradually decreased and reached near basal levels 2-3 days after LVAD implantation, but remained significantly elevated in plasma of HM-II recipients until day 5 (p=0.049). TGF-β1 levels remained unchanged in both CABG and ECMO patients at all time points (Figure 1). We conclude that LVAD implantation causes a transient surge in total plasma TGF-β1 within a few hours after the procedure, presumably due to platelet activation by LVAD, not the surgery itself, as CABG or circulating blood through ECMO did not cause the surge. The observation that a reduced initial surge and lower levels of TGF-β1 in HM-3 vs. HM-II recipients needs further investigation to determine whether these differences are due to LVAD-specific factors (different rotors causing variable shear effects) or to confounding differences in implantation procedures, such as, by-pass time, cardiac tissue injury, number of platelet transfusions, blood suction with catheters etc. or other unknown factors. Our data suggest that serial TGF-β1 measurements after LVAD implantation may serve as a surrogate biomarker for platelet activation in association with hemocompatibility-related adverse events (Uriel et al. Circ. 2017; 135:2003-2012). Disclosures No relevant conflicts of interest to declare.

Cardiac Effects of Hyperoxia During Resuscitation From Hemorrhagic Shock in Swine.

Hyperoxia (ventilation with FIO2 = 1.0) has vasoconstrictor properties, in particular in the coronary vascular bed, and, hence, may promote cardiac dysfunction. However, we previously showed that hyperoxia attenuated myocardial injury during resuscitation from hemorrhage in swine with coronary artery disease. Therefore, we tested the hypothesis whether hyperoxia would also mitigate myocardial injury and improve heart function in the absence of chronic cardiovascular comorbidity.After 3 h of hemorrhage (removal of 30% of the calculated blood volume and subsequent titration of mean arterial pressure to 40 mm Hg) 19 anesthetized, mechanically ventilated, and instrumented pigs received FIO2 = 0.3(control) or hyperoxia(FIO2 = 1.0) during the first 24 h. Before, at the end of and every 12 h after shock, hemodynamics, blood gases, metabolism, cytokines, and cardiac function (pulmonary artery thermodilution, left ventricular pressure-conductance catheterization) were recorded. At 48 h, cardiac tissue was harvested for western blotting, immunohistochemistry, and mitochondrial respiration.Except for higher left ventricular end-diastolic pressures at 24 h (hyperoxia 21 (17;24), control 17 (15;18) mm Hg; P = 0.046), hyperoxia affected neither left ventricular function cardiac injury (max. Troponin I at 12 h: hyperoxia:9 (6;23), control:17 (11;24) ng mL; P = 0.395), nor plasma cytokines (except for interleukin-1β: hyperoxia 10 (10;10) and 10 (10;10)/control 14 (10;22), 12 (10;15) pg mL, P = 0.023 and 0.021 at 12 and 24 h, respectively), oxidation and nitrosative stress, and mitochondrial respiration. However, hyperoxia decreased cardiac tissue three-nitrotyrosine formation (P < 0.001) and inducible nitric oxide synthase expression (P = 0.016). Ultimately, survival did not differ significantly either.In conclusion, in contrast to our previous study in swine with coronary artery disease, hyperoxia did not beneficially affect cardiac function or tissue injury in healthy swine, but was devoid of deleterious side effects.

Abstract 339: A Novel Strategy to Harness Stem Cell-Intrinsic Mechanobiological Properties for Advanced Tissue Repair: Implication in Cardiac Tissue Injury

Rationale: Stem cells are constantly exposed to biomechanical and biochemical signals when transplanted in a continuously beating cardiac environment for treatment. Here, we postulated that an in vitro miniaturized beating cardiac microenvironment can induce unique biomechanical stimuli to co-cultured MSCs that can influence therapeutic potential of the later. This project aimed (i) to pre-condition mesenchymal stem cells (MSCs) with continuous mechanobiological stimuli using a 3D cardiac tissue environment (ii) to intramyocardially inject pre-conditioned MSCs into mice heart with myocardial infarction (MI) for tissue repair. Methods: We fabricated an in vitro cardiac platform as shown in Fig 1 , using an electro-conductive hydrogel and human iPSC-derived cardiac cells. Adipose MSCs were then injected to the beating hydrogel platform. After 7 days, activated (MB+) and non-activated MSCs (MB-) were isolated for in vitro and in vivo analysis. Results: The force generated by the constant beating of cardiomyocytes induced profound effects in on MSC behavior in the MB+ group. Several mechano-transduction factors (YAP1, TAZ), actin polymerization genes involved in cardiac muscle contractions ( ACTA2 , CDC42, TNNT2 ) and angiogenic genes were upregulated in MB+. RNA-seq analysis further confirmed these findings. 3 week study in mice with MI demonstrated significant increase in capillary density and reduction in infarct sizes in MB+ (n=6) compared to MB- group. Furthermore, the MB+ group showed significantly higher cardiac performance in echocardiography. We can conclude MB-activated MSCs can have significant impact in future treatment strategies for patients with MI.

An Aptamer-based Biosensor for Troponin I Detection in Diagnosis of Myocardial Infarction

Acute myocardial infarction (MI) accounts for one third of deaths. Cardiac troponin I (TnI) is a reliable biomarker of cardiac muscle tissue injury and is employed in the early diagnosis of MI. In this study, a molecular method is introduced to early diagnosis of MI by rapid detection of TnI. The detection method was based on electrochemical aptasensing, being developed using different methods and evaluation steps. A gold electrode was used as a transducer to successful immobilize 76base aptamer to fabricate a TnI biosensor. The designed aptasensor could detect TnI in a range of 0.03 to 2.0 ng mL-1 without using any label, pre-concentration or amplification steps. The limit of detection was attained as 10 pg mL-1 without significant trouble of interfering species. The TnI biosensor demonestrated a stable, regenerative and reproducible function. 89 human samples were used to evaluate the performance of the TnI biosensor, and it represented 100% and 81%, diagnostic sensitivity and specificity, respectively. This aptasensor may be used as an applicable tool in the future of early medical diagnosis of MI.

Methylphenidate clinically oral doses improved brain and heart glutathione redox status and evoked renal and cardiac tissue injury in rats

Methylphenidate (MPH) is a first-line stimulant drug to treat attention deficit hyperactivity disorder (ADHD). Overdiagnosis of ADHD and MPH abuse lead to serious concerns about the possible long-term adverse consequences of MPH in healthy children and adolescents. We aimed to evaluate MPH effects in adolescent male Wistar rats (postnatal day 40) using an oral dose scheme (2 daily MPH doses 5 mg/kg in a 5% sucrose solution, 5 h apart, for 7 days) that mimics the therapeutic doses given to human adolescents. Twenty-four hours after the last MPH administration, rats were sacrificed and brain areas [cerebellum, prefrontal cortex (PFC), hippocampus, and striatum], peripheral organs (liver, heart, and kidneys), and blood were collected for biochemical and histological analysis.MPH treatment did not alter rats’ body temperature or weight, neither food or water intake throughout the experiment. The ratio of reduced glutathione/oxidized glutathione (GSH/GSSG) significantly increased in the PFC and hippocampus of MPH-treated rats, meanwhile protein carbonylation remained unchanged in the brain. In the heart, the GSH/GSSG ratio and GSH levels were significantly increased, with decreased GSSG, while histology revealed significant damage, namely interstitial edema, vascular congestion, and presence of a fibrin-like material in the interstitial space. In the kidneys, MPH treatment resulted in extensive necrotic areas with cellular disorganization and cell infiltration, and immunohistochemistry analysis revealed a marked activation of nuclear factor-ĸB.This study showed that clinically relevant oral MPH doses improve the GSH redox status in the brain and heart, but evoke heart and kidney tissue damage to adolescent rats.

The Antioxidant Activity of Pistachios Reduces Cardiac Tissue Injury of Acute Ischemia/Reperfusion (I/R) in Diabetic Streptozotocin (STZ)-Induced Hyperglycaemic Rats.

Diabetes mellitus is an important risk factor for the development of heart pathology. Myocardial infarction is the cause of death occurring after prolonged ischemia of the coronary arteries. Restoration of blood flow is the first intervention against heart attack, although the process of restoring blood flow to the ischemic myocardium could cause additional injury. This phenomenon, termed myocardial ischemia-reperfusion (MI-R) injury, is characterized by the formation of oxygen radicals. Pistachios have significant glucose- and insulin-lowering effects and can improve the inflammatory contest by downregulating both the expression and the circulating levels of several metabolic risk markers. The monocyte/macrophage cell line J774 was used to assess the extent of protection by natural raw (NP) and roasted salted (RP) pistachios against lipopolysaccharide (LPS)-induced inflammation. Moreover, antioxidant activity of NP and RP was assessed in an in vivo model of paw edema in rats induced by carrageenan (CAR) injection in the paw. This study evaluates the antioxidant properties of pistachios on the inflammatory process associated with myocardial ischemia/reperfusion injury (I/R) in diabetic rats. Rats were pre-treated with either NP or RP pistachios (30 mg/kg) 18 h prior to the experimental procedure.Results: Here, we demonstrated that treatment with NP reduced myocardial tissue injury, neutrophil infiltration, adhesion molecules (ICAM-1, P-selectin) expression, proinflammatory cytokines (TNF-α, IL-1β) production, nitrotyrosine and PAR formation, NF-κB expression and apoptosis (Bax, Bcl-2) activation. This data clearly showes modulation of the inflammatory process, associated with MI-R injury, following administration of pistachios.

Characterization of Rubia cordifolia L. root extract and its evaluation of cardioprotective effect in Wistar rat model.

OBJECTIVES:Rubia cordifolia L. (RC) is a well-known and highly valuable medicinal plant in the Ayurvedic system. The present study involves evaluating antioxidant and cardioprotective property of RC root extract.MATERIALS AND METHODS:The characterization of RC root extract was carried out using standard phytochemical and biochemical analysis. The functional groups were analyzed by Fourier transform infrared (FTIR) spectroscopy and phytotherapeutic compounds were identified using high-resolution mass spectrometry (HR-MS). Cardioprotective activity of RC root extract was investigated against cyclophosphamide (CP; 100 mg/kg, i.p)-induced cardiotoxicity in male albino Wistar rats. RC (100, 200, and 400 mg/kg, p.o) or silymarin (100 mg/kg, p.o) was administered immediately after CP on the 1st day and the next consecutive 10 days. Biochemical and histopathological analysis was performed to observe the cardioprotective effects of RC root extract.RESULTS:Phytochemical analysis revealed the presence of secondary metabolites that include alkaloids, flavonoids, saponins, and anthraquinones in RC root extract. FTIR analysis revealed the presence of several functional groups. Based on HR-MS analysis, eight major phytotherapeutic compounds were identified in methanol root extract of RC. Biochemical analysis in CP-induced rat model administered with RC extract revealed significantly enhanced levels of antioxidant markers such as superoxide dismutase, catalase, and glutathione S-transferase. Histopathological study showed that the rat model treated with the root extract had reduced the cardiac injury.CONCLUSION:Our results have shown that the RC extract contains various antioxidant compounds with cardioprotective effect. Treatment with RC root extract could significantly protect CP-induced rats from cardiac tissue injury by restoring the antioxidant markers.

Chronic Electronic Cigarette Vapor Inhalation Induces Renal Injury and Functional Decline in Female Mice

Clinical studies indicate that combustible cigarette smoke increases renal and cardiac tissue injury progression and functional decline in the setting of chronic kidney disease (CKD). Novel nicotine delivery devices like electronic (e)‐cigarettes are used by over 10% of the population and produce vapor which may also induce renal injury. To establish whether e‐cigarette vapor inhalation induced renal injury in the form of fibrosis and decreased renal injury our current study utilized a nose‐only inhalation exposure system to induce 8 week‐old female mice to inhale e‐cigarette vapor containing 24mg/mL of nicotine suspended in a solution of 50% propylene glycol and 50% vegetable glycerin using the following parameters: 12 seconds of vapor exposure every 60 seconds for 60 minutes five days per week for 1‐, 3‐ and 6‐months. Following e‐cigarette exposure, assessment of renal fibrosis, glomerular filtration rate, and expression of the antifibrotic microRNA miR‐29b‐3p were evaluated. Mice exposed to e‐cigarette vapor suffered a 31% decline in renal tissue expression of miR‐29b‐3p vs air‐exposed controls (p&lt;0.05). Additionally, mRNA targets of miR‐29b‐3p that regulate fibrosis formation or are part of fibrosis were also significantly increased in the kidneys of e‐cigarette exposed mice versus air controls, i.e., Collagen 1A1 (increased 98%; p&lt;0.05); Collagen 3A1 (129% increase; p&lt;0.05); Collagen 4a1 (72% increase; p&lt;0.05); Integrin beta 1 (58% increase; p&lt;0.05); and Fibrillin 1 (100% increase; p&lt;0.05). Additionally, we observed a significant increase in renal fibrosis at the 3‐ and 6‐month time points as assessed by Trichrome staining in these animals. Lastly, following 3‐months of exposure to e‐cigarette vapor renal function was significantly reduced by 21% versus air exposed controls (p=0.017). These data are the first to indicate that e‐cigarettes induce renal fibrosis and functional decline. In addition, these data suggest a novel miR‐29b‐3p mediated mechanism linking e‐cigarette vapor exposure and renal injury and functional decline.Support or Funding InformationThis work was supported by the National Institutes of Health (1F32DK104615‐01 to CAD and HL‐105649 to JT. Additional support was from a Veterans Affairs BLR&amp;D Career Development Award (1IK2BX001313 to LCA), AHA Beginning Grant‐in‐aid (16BGIA27790079 to LCA), and O'Brien Center Daniel O'Connor Memorial Pilot Award to LCA. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

The Antioxidant Activity of Pistachios Reduces Cardiac Tissue Injury of Acute Ischemia/Reperfusion (I/R) In Diabetic Streptozotocin (STZ)‐Induced Hyperglycaemic Rats

Diabetes mellitus represents one of the most important risk factors for the development of heart pathology. By itself it represents a source of vascular and heart dysfunction through formation of reactive oxygen species (ROS) and can compromise the recovery from cardiovascular diseases. Myocardial infarction is the leading cause of death occurring after prolonged ischemia of the coronary arteries. Restoring blood flow is the first intervention after a heart attack, although the process of restoring blood flow to the ischemic myocardium could induce additional injury. This phenomenon, termed myocardial ischemia‐reperfusion (MI‐R) injury, is characterized by the formation of oxygen radicals. Pistachios are excellent sources of antioxidants, such as lutein, β‐carotene, and γ‐tocopherol in addition to selenium, flavonoids, and proanthocyanidins. Pistachios have important glucose‐ and insulin‐lowering effects and can improve the inflammatory profile by downregulating both the expression and the circulating levels of several metabolic risk markers.The present study evaluates the antioxidant properties of pistachios treatment on the inflammatory process associated to myocardial ischemia/reperfusion injury (I/R) in diabetic rats.Left anterior descending (LAD) ligation has been used to induced MI‐R injury in diabetic rats. Occlusion of coronary artery was prolonged for 30 min followed by 2 h reperfusion. Rats were pre‐treated with either raw or roasted salted pistachios (30 mg/kg) 18h prior to the experimental procedure.Here we demonstrated that treatment with raw pistachios reduced myocardial tissue injury (I/R 3.5±0.3 vs raw pistachios 2.0±0.2 p ≤0.05), neutrophil infiltration (I/R 35.0±3.0 vs raw pistachios 22.0±2.0 p ≤0.05), adhesion molecules (ICAM‐1, (I/R 7.0±0.3 vs raw pistachios 3.0±0.2 p ≤0.05) P‐selectin (I/R 5.0±0.1 vs raw pistachios 2.0±0.1 p ≤0.05)) expression, pro‐inflammatory cytokines (TNF‐α, I/R 11.0±2.0 vs raw pistachios 4.0±0.2 p ≤0.05)IL‐1β (I/R 12.0±0.2 vs raw pistachios 6±0.2 p ≤0.05)) production, nitrotyrosine and PAR formation, NF‐kB expression (I/R 23361.6 ± 3656.0 vs raw pistachios 1911.95 ± 770.0 p ≤0.05)) and apoptosis (Bax, (I/R 29235.2 ± 3394.0 vs raw pistachios 2301.37 ± 869.1 p ≤0.05)) Bcl‐2) activation. The effect of raw pistachios was higher compared with roasted pistachios.This data have clearly showed a modulation of the inflammatory process, associated with MI‐R injury, following administration of pistachios.Support or Funding InformationThis work was funded by the American Pistachio Growers (CA, US).

The Impact of Circulating Mitochondrial DNA on Cardiomyocyte Apoptosis and Myocardial Injury After TLR4 Activation in Experimental Autoimmune Myocarditis

Background/Aims: Mitochondrial DNA (mtDNA), acting as a newly found ‘danger-associated molecular patterns’ (DAMPs), is released into circulation upon tissue injury and performs as a considerable activator of inflammation and immune response. However, the role of circulating mtDNA in experimental autoimmune myocarditis (EAM) as well as Toll like receptor4 (TLR4) mediated cardiac inflammation and injury remains unknown. Methods: A model of EAM was established in BALB/c mice by immunization with porcine cardiac myosin. Lipopolysaccharide (LPS) was used to stimulate TLR4 activation in EAM mice and H9C2 cells. Results: LPS stimulation significantly aggravated cardiac inflammation and tissue injury in EAM, as demonstrated by increased myocardium inflammatory cell infiltration, and up-regulated inflammatory cytokines and troponin I(TnI) level in serum. Circulating mtDNA level was increased in EAM and TLR4 activation led to a greater elevation, which may be related to Reactive oxygen species (ROS) stress involved mtDNA damage characterized by reduced mtDNA copy number in myocardium tissue. In addition, the expression of Toll like receptor9 (TLR9), a ligand of mtDNA, was significantly up-regulated in the myocardium of EAM and EAM LPS group; meanwhile, TLR9 inhibition by ODN 2088 caused an inhibited apoptosis in LPS treated H9C2 cells. Moreover, in EAM and EAM LPS group, simultaneously giving ODN 2088 treatment significantly ameliorated cardiac inflammation and tissue injury compared with untreated group. Conclusion: Increased circulating mtDNA combined with upregulated TLR9 expression may corporately play a role in EAM as well as TLR4 activation mediated cardiac inflammation and injury.

Cigarette smoking causes epigenetic changes associated with cardiorenal fibrosis.

Clinical studies indicate that smoking combustible cigarettes promotes progression of renal and cardiac injury, leading to functional decline in the setting of chronic kidney disease (CKD). However, basic studies using in vivo small animal models that mimic clinical pathology of CKD are lacking. To address this issue, we evaluated renal and cardiac injury progression and functional changes induced by 4 wk of daily combustible cigarette smoke exposure in the 5/6th partial nephrectomy (PNx) CKD model. Molecular evaluations revealed that cigarette smoke significantly (P < 0.05) decreased renal and cardiac expression of the antifibrotic microRNA miR-29b-3 and increased expression of molecular fibrosis markers. In terms of cardiac and renal organ structure and function, exposure to cigarette smoke led to significantly increased systolic blood pressure, cardiac hypertrophy, cardiac and renal fibrosis, and decreased renal function. These data indicate that decreased expression of miR-29b-3p is a novel mechanism wherein cigarette smoke promotes accelerated cardiac and renal tissue injury in CKD. (155 words).

Pulmonary Microwave Ablation Near the Heart: Antenna Positioning Can Mitigate Cardiac Complications in a Porcine Model.

Purpose To determine how close to the heart pulmonary microwave ablation can be performed without causing cardiac tissue injury or significant arrhythmia. Materials and Methods The study was performed with approval from the institutional animal care and use committee. Computed tomographic fluoroscopically guided microwave ablation of the lung was performed in 12 swine. Antennas were randomized to either parallel (180° ± 20°) or perpendicular (90° ± 20°) orientation relative to the heart surface and to distances of 0-10 mm from the heart. Ablations were performed at 65 W for 5 minutes or until a significant arrhythmia (asystole, heart block, bradycardia, supraventricular or ventricular tachycardia) developed. Heart tissue was evaluated with vital staining and histologic examination. Data were analyzed with mixed effects logistic regression, receiver operating characteristic curves, and the Fisher exact test. Results Thirty-four pulmonary microwave ablations were performed with the antenna a median distance of 4 mm from the heart in both perpendicular (n = 17) and parallel (n = 17) orientation. Significant arrhythmias developed during six (18%) ablations. Cardiac tissue injury occurred with 17 ablations (50%). Risk of arrhythmia and tissue injury decreased with increasing antenna distance from the heart with both antenna orientations. No cardiac complication occurred with a distance of greater than or equal to 4.4 mm from the heart. The ablation zone extended to the pleural surface adjacent to the heart in 71% of parallel and 17% of perpendicular ablations performed 5-10 mm from the heart. Conclusion Microwave lung ablations performed more than or equal to 5 mm from the heart were associated with a low risk of cardiac complications. © RSNA, 2016.

Protective Effects of Silymarin against Cardiac Tissue Injury Caused By a High-dose Administration of Isotretinoin in Mice

Protective Effects of Silymarin against Cardiac Tissue Injury Caused By a High-dose Administration of Isotretinoin in Mice

Cardiac Tissue Injury and Remodeling Is Dependent Upon MR Regulation of Activation Pathways in Cardiac Tissue Macrophages.

Macrophage mineralocorticoid receptor (MR) signaling is an important mediator of cardiac tissue inflammation and fibrosis. The goal of the present study was to determine the cellular mechanisms of MR signaling in macrophages that promote cardiac tissue injury and remodeling. We sought to identify specific markers of MR signaling in isolated tissue macrophages (cardiac, aortic) vs splenic mononuclear cells from wild-type and myeloid MR-null mice given vehicle/salt or deoxycorticosterone (DOC)/salt for 8 weeks. Cardiac tissue fibrosis in response to 8 weeks of DOC/salt treatment was found in the hearts from wild-type but not myeloid MR-null mice. This was associated with an increased expression of the profibrotic markers TGF-β1 and matrix metalloproteinase-12 and type 1 inflammatory markers TNFα and chemokine (C-X-C motif) ligand-9 in cardiac macrophages. Differential expression of immunomodulatory M2-like markers (eg, arginase-1, macrophage scavenger receptor 1) was dependent on the tissue location of wild-type and MR-null macrophages. Finally, intact MR signaling is required for the phosphorylation of c-Jun NH2-terminal kinase in response to a proinflammatory stimulus in bone marrow monocytes/macrophages in culture. These data suggest that the activation of the c-Jun NH2-terminal kinase pathway in macrophages after a tissue injury and inflammatory stimuli in the DOC/salt model is MR dependent and regulates the transcription of downstream profibrotic factors, which may represent potential therapeutic targets in heart failure patients.

Intravenous and Intramuscular Formulations of Antiseizure Drugs in the Treatment of Epilepsy.

Intravenous and intramuscular antiseizure drugs (ASDs) are essential in the treatment of clinical seizure emergencies as well as in replacement therapy when oral administration is not possible. The parenteral formulations provide rapid delivery and complete (intravenous) or nearly complete (intramuscular) bioavailability. Controlled administration of the ASD is feasible with intravenous but not intramuscular formulations. This article reviews the literature and discusses the chemistry, pharmacology, pharmacokinetics, and clinical use of currently available intravenous and intramuscular ASD formulations as well as the development of new formulations and agents. Intravenous or intramuscular formulations of lorazepam, diazepam, midazolam, and clonazepam are typically used as the initial treatment agents in seizure emergencies. Recent studies also support the use of intramuscular midazolam as easier than the intravenous delivery of lorazepam in the pre-hospital setting. However, benzodiazepines may be associated with hypotension and respiratory depression. Although loading with intravenous phenytoin was an early approach to treatment, it is associated with cardiac arrhythmias, hypotension, and tissue injury at the injection site. This has made it less favored than fosphenytoin, a water-soluble, phosphorylated phenytoin molecule. Other drugs being used for acute seizure emergencies are intravenous formulations of valproic acid, levetiracetam, and lacosamide. However, the comparative effectiveness of these for status epilepticus (SE) has not been evaluated adequately. Consequently, guidelines for the medical management of SE continue to recommend lorazepam followed by fosphenytoin, or phenytoin if fosphenytoin is not available. Intravenous solutions for carbamazepine, lamotrigine, and topiramate have been developed but remain investigational. The current ASDs were not developed for use in emergency situations, but were adapted from ASDs approved for chronic oral use. New approaches for bringing drugs from experimental models to treatment of human SE are needed.

Case report: severe reversible cardiomyopathy associated with systemic inflammatory response syndrome in the setting of diabetic hyperosmolar hyperglycemic non-ketotic syndrome

BackgroundThis case study features a woman who presented with clinical and laboratory findings consistent with hyperosmolar hyperglycemic non-ketotic syndrome (HHNS), systemic inflammatory response syndrome (SIRS), and non-thyroidal illness syndrome (NTIS) who was noted to have a transient decrease in myocardial function. To our knowledge, this is the first case discussing the overlapping pathophysiological mechanisms could increase susceptibility to SIRS-induced cardiomyopathy. It is imperative that this clinical question be investigated further as such a relationship may have significant clinical implications for prevention and future treatments, particularly in patients similar to the one presented in this clinical case.Case presentationA 53-year old Caucasian female presented to the Emergency Department for cough, nausea, vomiting and “feeling sick for 3 weeks.” Labs were indicative of diabetic ketoacidosis. Initial electrocardiograms were suggestive of possible myocardial infarction and follow-up echocardiogram showed severely depressed left ventricular systolic function which resolved upon treatment of ketoacidosis.ConclusionWe suggest that her cardiomyopathy could have three synergistic sources: SIRS, HHNS and NTIS. Overlapping mechanisms suggest uncontrolled diabetes mellitus and NTIS could increase susceptibility to SIRS-induced cardiomyopathy as seen in this case. HHNS and SIRS cause cardiac tissue injury through mechanisms including impairment of fatty acid oxidation and formation of reactive oxygen species, as well as modifying the function of membrane calcium channels. As a result, it is conceivable that diabetes may amplify the deleterious effects of inflammatory stressors on cardiac myocytes. This novel case report offers a path for future research into prevention and treatment of SIRS-induced cardiomyopathy in, but not exclusive to, the setting of diabetes.

Unbreak My Heart: Targeting Mitochondrial Autophagy in Diabetic Cardiomyopathy

Diabetes is strongly associated with increased incidence of heart disease and mortality due to development of diabetic cardiomyopathy. Even in the absence of cardiovascular disease, cardiomyopathy frequently arises in diabetic patients. Current treatment options for cardiomyopathy in diabetic patients are the same as for nondiabetic patients and do not address the causes underlying the loss of contractility. Although there are numerous distinctions between Type 1 and Type 2 diabetes, recent evidence suggests that the two disease states converge on mitochondria as an epicenter for cardiomyocyte damage. Accumulation of dysfunctional mitochondria contributes to cardiac tissue injury in both acute and chronic conditions. Removal of damaged mitochondria by macroautophagy, termed "mitophagy," is critical for maintaining cardiomyocyte health and contractility both under normal conditions and during stress. However, very little is known about the involvement of mitophagy in the pathogenesis of diabetic cardiomyopathy. A growing interest in this topic has given rise to a wave of publications that aim at deciphering the status of autophagy and mitophagy in Type 1 and Type 2 diabetes. This review summarizes these recent studies with the goal of drawing conclusions about the activation or suppression of autophagy and mitophagy in the diabetic heart. A better understanding of how autophagy and mitophagy are affected in the diabetic myocardium is still needed, as well as whether they can be targeted therapeutically.

Complement system modulation as a target for treatment of arrhythmogenic cardiomyopathy.

Inflammation may contribute to disease progression in arrhythmogenic cardiomyopathy (ACM). However, its role in this process is unresolved. Our goal was to delineate the pathogenic role of the complement system in a new animal model of ACM and in human disease. Using cardiac histology, echocardiography, and electrocardiography, we have demonstrated that the desmin-null mouse (Des-/-) recapitulates most of the pathognomonic features of human ACM. Massive complement activation was observed in the Des-/- myocardium in areas of necrotic cells debris and inflammatory infiltrate. Analysis of C5aR-/-Des-/- double-null animals and a pharmaceutical approach using a C5a inhibitor were used to delineate the pathogenic role of the complement system in the disease progression. Our findings indicate that inhibiting C5aR (CD88) signaling improves cardiac function, histopathology, arrhythmias, and survival after endurance. Containment of the inflammatory reaction at the initiation of cardiac tissue injury (2-3 weeks of age), with consequently reduced myocardial remodeling and the absence of a direct long-lasting detrimental effect of C5a-C5aR signaling on cardiomyocytes, could explain the beneficial action of C5aR ablation in Des-/- cardiomyopathy. We extend the relevance of these findings to human pathophysiology by showing for the first time significant complement activation in the cardiac tissues of patients with ACM, thus suggesting that complement modulation could be a new therapeutic target for ACM.

Role of innate and adaptive immune mechanisms in cardiac injury and repair.

Despite the advances that have been made in developing new therapeutics, cardiovascular disease remains the leading cause of worldwide mortality. Therefore, understanding the mechanisms underlying cardiovascular tissue injury and repair is of prime importance. Following cardiac tissue injury, the immune system has an important and complex role in driving both the acute inflammatory response and the regenerative response. This Review summarizes the role of the immune system in cardiovascular disease - focusing on the idea that the immune system evolved to promote tissue homeostasis following injury and/or infection, and that the inherent cost of this evolutionary development is unwanted inflammatory damage.

Neural injury after use of vasopressin and adrenaline during porcine cardiopulmonary resuscitation

Background. Our aim was to investigate cerebral and cardiac tissue injury subsequent to use of vasopressin and adrenaline in combination compared with vasopressin alone during cardiopulmonary resuscitation (CPR).Methods. In a randomized, prospective, laboratory animal study 28 anesthetized piglets were subject to a 12-min untreated cardiac arrest and subsequent CPR. After 1 min of CPR, 10 of the piglets received 0.4 U/kg of arg8-vasopressin (V group), and 10 piglets received 0.4 U/kg of arg8-vasopressin, 1 min later followed by 20 µg/kg body weight of adrenaline, and another 1 min later continuous administration (10 µg/kg/min) of adrenaline (VA group). After 8 min of CPR, the piglets were defibrillated and monitored for another 3 h. Then they were killed and the brain immediately removed pending histological analysis.Results. During CPR, the VA group had higher mean blood pressure and cerebral cortical blood flow (CCBF) but similar coronary perfusion pressure. After restoration of spontaneous circulation there was no difference in the pressure variables, but CCBF tended to be (36% ± 16%) higher in the V group. Neuronal injury and signs of a disrupted blood–brain barrier (BBB) were greater, 20% ± 4% and 21% ± 4%, respectively, in the VA group. In a background study of repeated single doses of adrenaline every third minute after 5 min arrest but otherwise the same protocol, histological measurements showed even worse neural injury and disruption of the BBB.Conclusion. Combined use of vasopressin and adrenaline caused greater signs of cerebral and cardiac injury than use of vasopressin alone during experimental cardiopulmonary resuscitation.