Drug-induced organ injury in coronavirus disease 2019 pharmacotherapy: Mechanisms and challenges in differential diagnosis and potential protective strategies.

The world is currently facing an unprecedented pandemic caused by a newly recognized and highly pathogenic coronavirus disease 2019 (COVID-19; induced by SARS-CoV-2 virus), which is a severe and ongoing threat to global public health. Since COVID-19 was officially declared a pandemic by the World Health Organization in March 2020, several drug regimens have rapidly undergone clinical trials for the management of COVID-19. However, one of the major issues is drug-induced organ injury, which is a prominent clinical challenge. Unfortunately, most drugs used against COVID-19 are associated with adverse effects in different organs, such as the kidney, heart, and liver. These side effects are dangerous and, in some cases, they can be lethal. More importantly, organ injury is also a clinical manifestation of COVID-19 infection. These adverse reactions are increasingly recognized as outcomes of COVID-19 infection. Therefore, the differential diagnosis of drug-induced adverse effects from COVID-19-induced organ injury is a clinical complication. This review highlights the importance of drug-induced organ injury, its known mechanisms, and the potential therapeutic strategies in COVID-19 pharmacotherapy. We review the potential strategies for the differential diagnosis of drug-induced organ injury. This information can facilitate the development of therapeutic strategies, not only against COVID-19 but also for future outbreaks of other emerging infectious diseases.

Cardiovascular toxicity of decabrominated diphenyl ethers (BDE-209) and decabromodiphenyl ethane (DBDPE) in rats.

Recent reports indicated that decabrominated diphenyl ether (BDE-209) and decabromodiphenyl ethane (DBDPE) exist extensively in the environment. The toxicity of BDE-209 has been reported in quite a few studies, whereas the data of DBDPE are relatively rare. However, databases regarding cardiovascular toxicities of both BDE-209 and DBDPE are lacking. In this study, we investigated the vascular/cardiac trauma induced by DBDPE after oral exposure and compared the results with those of BDE-209 using rat model. Male rats were orally administered with corn oil containing DBDPE or BDE-209 (5, 50, 500 mg/kg/day) for 28 days, then oxidative stress, morphological and ultrastructural changes of the heart and abdominal aorta, levels of creatine kinase (CK) and lactate dehydrogenase (LDH), inflammatory cytokines, endothelin-1 (ET-1), and intercellular adhesion molecule-1 (ICAM-1) in the serum were monitored. Results showed that BDE-209 and DBDPE caused heart and abdominal aorta morphological and ultrastructural damage, serum CK and LDH elevation, and antioxidant enzyme activity changes. BDE-209 and DBDPE-induced inflammation was characterized by the upregulation of key inflammatory mediators, including interleukin-1beta (IL-1ß), IL-6, IL-10, and tumor necrosis factor alpha (TNFα). Additionally, BDE-209 and DBDPE led to endothelial dysfunction, as evidenced by the ET-1 and ICAM-1 elevation. Our findings demonstrated that BDE-209 and DBDPE could induce oxidative stress, inflammation, and eventually lead to endothelial dysfunction and cardiovascular injury. Compared to DBDPE, these toxic responses were stronger in the hearts and abdominal aorta of Sprague-Dawley rats exposed to BDE-209. Our findings indicated a potential deleterious effect of BDE-209 and DBDPE on the cardiovascular system.

Advanced microscopy to elucidate cardiovascular injury and regeneration: 4D light-sheet imaging.

The advent of 4-dimensional (4D) light-sheet fluorescence microscopy (LSFM) has provided an entry point for rapid image acquisition to uncover real-time cardiovascular structure and function with high axial resolution and minimal photo-bleaching/-toxicity. We hereby review the fundamental principles of our LSFM system to investigate cardiovascular morphogenesis and regeneration after injury. LSFM enables us to reveal the micro-circulation of blood cells in the zebrafish embryo and assess cardiac ventricular remodeling in response to chemotherapy-induced injury using an automated segmentation approach. Next, we review two distinct mechanisms underlying zebrafish vascular regeneration following tail amputation. We elucidate the role of endothelial Notch signaling to restore vascular regeneration after exposure to the redox active ultrafine particles (UFP) in air pollutants. By manipulating the blood viscosity and subsequently, endothelial wall shear stress, we demonstrate the mechanism whereby hemodynamic shear forces impart both mechanical and metabolic effects to modulate vascular regeneration. Overall, the implementation of 4D LSFM allows for the elucidation of mechanisms governing cardiovascular injury and regeneration with high spatiotemporal resolution.

Possible Muscle Repair in the Human Cardiovascular System.

The regenerative potential of tissues and organs could promote survival, extended lifespan and healthy life in multicellular organisms. Niches of adult stemness are widely distributed and lead to the anatomical and functional regeneration of the damaged organ. Conversely, muscular regeneration in mammals, and humans in particular, is very limited and not a single piece of muscle can fully regrow after a severe injury. Therefore, muscle repair after myocardial infarction is still a chimera. Recently, it has been recognized that epigenetics could play a role in tissue regrowth since it guarantees the maintenance of cellular identity in differentiated cells and, therefore, the stability of organs and tissues. The removal of these locks can shift a specific cell identity back to the stem-like one. Given the gradual loss of tissue renewal potential in the course of evolution, in the last few years many different attempts to retrieve such potential by means of cell therapy approaches have been performed in experimental models. Here we review pathways and mechanisms involved in the in vivo repair of cardiovascular muscle tissues in humans. Moreover, we address the ongoing research on mammalian cardiac muscle repair based on adult stem cell transplantation and pro-regenerative factor delivery. This latter issue, involving genetic manipulations of adult cells, paves the way for developing possible therapeutic strategies in the field of cardiovascular muscle repair.

Cooperative Role of Mineralocorticoid Receptor and Caveolin-1 in Regulating the Vascular Response to Low Nitric Oxide-High Angiotensin II-Induced Cardiovascular Injury.

Aldosterone interacts with mineralocorticoid receptor (MR) to stimulate sodium reabsorption in renal tubules and may also affect the vasculature. Caveolin-1 (cav-1), an anchoring protein in plasmalemmal caveolae, binds steroid receptors and also endothelial nitric oxide synthase, thus limiting its translocation and activation. To test for potential MR/cav-1 interaction in the vasculature, we investigated if MR blockade in cav-1-replete or -deficient states would alter vascular function in a mouse model of low nitric oxide (NO)-high angiotensin II (AngII)-induced cardiovascular injury. Wild-type (WT) and cav-1 knockout mice (cav-1(-/-)) consuming a high salt diet (4% NaCl) received Nω-nitro-l-arginine methyl ester (L-NAME) (0.1-0.2 mg/ml in drinking water at days 1-11) plus AngII (0.7-2.8 mg/kg per day via an osmotic minipump at days 8-11) ± MR antagonist eplerenone (EPL) 100 mg/kg per day in food. In both genotypes, blood pressure increased with L-NAME + AngII. EPL minimally changed blood pressure, although its dose was sufficient to block MR and reverse cardiac expression of the injury markers cluster of differentiation 68 and plasminogen activator inhibitor-1 in L-NAME+AngII treated mice. In aortic rings, phenylephrine and KCl contraction was enhanced with EPL in L-NAME+AngII treated WT mice, but not cav-1(-/-) mice. AngII-induced contraction was not different, and angiotensin type 1 receptor expression was reduced in L-NAME + AngII treated WT and cav-1(-/-) mice. In WT mice, acetylcholine-induced relaxation was enhanced with L-NAME + AngII treatment and reversed with EPL. Acetylcholine relaxation in cav-1(-/-) mice was greater than in WT mice, not modified by L-NAME + AngII or EPL, and blocked by ex vivo L-NAME, 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ), or endothelium removal, suggesting the role of NO-cGMP. Cardiac endothelial NO synthase was increased in cav-1(-/-) versus WT mice, further increased with L-NAME + AngII, and not affected by EPL. Vascular relaxation to the NO donor sodium nitroprusside was increased with L-NAME + AngII in WT mice but not in cav-1(-/-) mice. Plasma aldosterone levels increased and cardiac MR expression decreased in L-NAME + AngII treated WT and cav-1(-/-) mice and did not change with EPL. Thus, during L-NAME + AngII induced hypertension, MR blockade increases contraction and alters vascular relaxation via NO-cGMP, and these changes are absent in cav-1 deficiency states. The data suggest a cooperative role of MR and cav-1 in regulating vascular contraction and NO-cGMP-mediated relaxation during low NO-high AngII-dependent cardiovascular injury.

A systematic review and pooled analysis of CPR-associated cardiovascular and thoracic injuries.

OBJECTIVE: The incidence of thoracic injuries resulting from cardiopulmonary resuscitation (CPR) is not well characterized. We describe a case in which a CPR-associated atrial rupture was identified with ultrasound and successfully managed in the intensive care unit with a bedside thoracotomy and atrial repair. We then describe a systematic review with pooled data analysis of CPR-associated cardiovascular, pulmonary, pleural, and thoracic wall injuries. DATA SOURCES: PubMed, Scopus, EMBASE, and Web of Science were searched to identify relevant published studies. Unpublished studies were identified by searching the Australian and New Zealand Clinical Trials Registry, World Health Organization International Clinical Trials Registry Platform, Cochrane Library, ClinicalTrials.gov, Current Controlled Trials, and Google. STUDY SELECTION: Inclusion criteria for the pooled analysis were any clinical or autopsy study in which (a) patients underwent cardiopulmonary resuscitation, (b) chest compressions were administered either manually or with the assistance of active compression-decompression devices, and (c) autopsy or dedicated imaging assessments were conducted to identify complications. Exclusion criteria for the pooled analysis were pre-clinical studies, case reports and abstracts. DATA EXTRACTION: Nine-hundred twenty-eight potentially relevant references were identified. Twenty-seven references met inclusion criteria. DATA SYNTHESIS: A systematic review of the literature is provided with pooled data analysis. CONCLUSIONS: The incidence of reported CPR-associated cardiovascular and thoracic wall injuries varies widely. CPR with active compression-decompression devices has a higher reported incidence of cardiopulmonary injuries. Bedside ultrasound may be a useful adjunct to assess and risk-stratify patients to identify serious or life-threatening CPR-associated injuries.

Video laryngoscopy versus direct laryngoscopy for orotracheal intubation in the intensive care unit: a systematic review and meta-analysis.

PURPOSE: Single studies of video laryngoscopy (VL) use for airway management in intensive care unit (ICU) patients have produced controversial findings. The aim of this study was to critically review the literature to investigate whether VL reduces difficult orotracheal intubation (OTI) rate, first-attempt success, and complications related to intubation in ICU patients, compared to standard therapy, defined as direct laryngoscopy (DL). METHODS: We performed a systematic review and meta-analysis of randomized controlled trials, as well as prospective and retrospective observational studies, by searching PubMed, EMBASE, and bibliographies of articles retrieved. We screened for relevant studies that enrolled adults in whom the trachea was intubated in the ICU and compared VL to DL. We included studies reporting at least one clinical outcome of interest to perform a meta-analysis. We generated pooled odd ratios (OR) across studies. The primary outcome measure was difficult OTI. The secondary outcomes were first-attempt success, Cormack 3/4 grades, and complications related to intubation (severe hypoxemia, severe cardiovascular collapse, airway injury, esophageal intubation). RESULTS: Nine trials with a total of 2,133 participants (1,067 in DL and 1,066 in VL) were included in the current analysis. Compared to DL, VL reduced the risk of difficult OTI [OR 0.29 (95% confidence interval (CI) 0.20-0.44, p < 0.001)], Cormack 3/4 grades [OR 0.26 (95% CI 0.17-0.41, p < 0.001)], and esophageal intubation [0.14 (95% CI 0.02-0.81, p = 0.03)] and increased the first-attempt success [OR 2.07 (95% CI 1.35-3.16, p < 0.001)]. No statistically significant difference was found for severe hypoxemia, severe cardiovascular collapse or airway injury. CONCLUSIONS: These results suggest that VL could be useful in airway management of ICU patients.

Damage control - trauma care in the first hour and beyond: a clinical review of relevant developments in the field of trauma care.

INTRODUCTION: Trauma provision in the UK is a topic of interest. Regional trauma networks and centres are evolving and research is blossoming, but what bearing does all this have on the care that is delivered to the individual patient? This article aims to provide an overview of key research concepts in the field of trauma care, to guide the clinician in decision making in the management of major trauma. METHODS: The Ovid MEDLINE(®), EMBASE™ and PubMed databases were used to search for relevant articles on haemorrhage control, damage control resuscitation and its exceptions, massive transfusion protocols, prevention and correction of coagulopathy, acidosis and hypothermia, and damage-control surgery. FINDINGS: A wealth of research is available and a broad range has been reviewed to summarise significant developments in trauma care. Research has been categorised into disciplines and it is hoped that by considering each, a tailored management plan for the individual trauma patient will evolve, potentially improving patient outcome.

Plexin structures are coming: opportunities for multilevel investigations of semaphorin guidance receptors, their cell signaling mechanisms, and functions.

Plexin transmembrane receptors and their semaphorin ligands, as well as their co-receptors (Neuropilin, Integrin, VEGFR2, ErbB2, and Met kinase) are emerging as key regulatory proteins in a wide variety of developmental, regenerative, but also pathological processes. The diverse arenas of plexin function are surveyed, including roles in the nervous, cardiovascular, bone and skeletal, and immune systems. Such different settings require considerable specificity among the plexin and semaphorin family members which in turn are accompanied by a variety of cell signaling networks. Underlying the latter are the mechanistic details of the interactions and catalytic events at the molecular level. Very recently, dramatic progress has been made in solving the structures of plexins and of their complexes with associated proteins. This molecular level information is now suggesting detailed mechanisms for the function of both the extracellular as well as the intracellular plexin regions. Specifically, several groups have solved structures for extracellular domains for plexin-A2, -B1, and -C1, many in complex with semaphorin ligands. On the intracellular side, the role of small Rho GTPases has been of particular interest. These directly associate with plexin and stimulate a GTPase activating (GAP) function in the plexin catalytic domain to downregulate Ras GTPases. Structures for the Rho GTPase binding domains have been presented for several plexins, some with Rnd1 bound. The entire intracellular domain structure of plexin-A1, -A3, and -B1 have also been solved alone and in complex with Rac1. However, key aspects of the interplay between GTPases and plexins remain far from clear. The structural information is helping the plexin field to focus on key questions at the protein structural, cellular, as well as organism level that collaboratoria of investigations are likely to answer.

Cardiovascular injury in systemic autoimmune diseases: an update.

It is well known in literature that systemic autoimmune diseases (SADs) are associated with enhanced atherosclerosis and impaired endothelial function early after the onset of the disease. Cardiovascular (CV) disease represents one of the leading causes of morbidity and mortality in SADs. There is considerable evidence suggesting a pathogenetic role of chronic inflammation and immune dysregulation for enhanced atherosclerosis in SADs, as demonstrated in several recent studies. Moreover, chronic inflammation, accelerated atherosclerosis and functional abnormalities of the endothelium suggest a subclinical CV involvement beginning rapidly soon after the onset of the disease and progressing with disease duration.

Suicide by head explosion: unusual blast wave injuries to the cardiovascular system.

A 57-year-old employee in a military scientific institute was found acephalous in a supine position in an anteroom to the bunker. On the walls was abundant spattering of blood and tissue, concentrated above shoulder height. A mobile ignition device stood on the control desk. The complete destruction of the head down to the cervical spine suggested that the explosive charge (RDX) detonated in his mouth. The hands were virtually uninjured. The pressure effect in vessels caused numerous tears to the wall of the carotid arteries and the left vertebral artery, a tear-off of the left carotid artery of the aortic arch, and a 2.5-cm long crack of the thoracic aorta with 540-ml blood in the pericardial sac and a shredded window-like disruption of the left aortic valve cusp. The autopsy also showed an infraction of the sternum from the inside, and a contusion of the superior lobes of both lungs. The trace pattern on the right arm suggested suicide. A bone fragment of the mandible penetrated the right biceps muscle as a secondary projectile.

Hypothermia as a cytoprotective strategy in ischemic tissue injury.

Hypothermia is a well established cytoprotectant, with remarkable and consistent effects demonstrated across multiple laboratories. At the clinical level, it has recently been shown to improve neurological outcome following cardiac arrest and neonatal hypoxia-ischemia. It is increasingly being embraced by the medical community, and could be considered an effective neuroprotectant. Conditions such as brain injury, hepatic encephalopathy and cardiopulmonary bypass seem to benefit from this intervention. It's role in direct myocardial protection is also being explored. A review of the literature has demonstrated that in order to appreciate the maximum benefits of hypothermia, cooling needs to begin soon after the insult, and maintained for relatively long period periods of time. In the case of ischemic stroke, cooling should ideally be applied in conjunction with the re-establishment of cerebral perfusion. Translating this to the clinical arena can be challenging, given the technical challenges of rapidly and stably cooling patients. This review will discuss the application of hypothermia especially as it pertains to its effects neurological outcome, cooling methods, and important parameters in optimizing hypothermic protection.

Cardiovascular issues in boxing and contact sports.

Despite the inherent risks associated with exercise in general and boxing in particular, the sport has had a limited number of catastrophic cardiovascular events. Screening should be based on risks involved and become more extensive with the advancement of the athlete. Anatomic and electrophysiologic risks need to be assessed and may preclude participation with resultant life style and economic complications. There should be adequate preparation for the rare potential cardiovascular complication at all events, with the ability to rapidly assess and treat arrhythmias.

Aliskiren enhances the protective effects of valsartan against cardiovascular and renal injury in endothelial nitric oxide synthase-deficient mice.

The protective effect of aliskiren, a direct renin inhibitor, against hypertensive cardiovascular and renal injury remains to be defined. This study was undertaken to examine the protective effects of the combination of aliskiren and valsartan, an angiotensin receptor blocker, against cardiovascular and renal injury. Endothelial NO synthase-deficient mice, subjected to cuff injury of femoral artery, were divided into 5 groups and were treated with the following: (1) vehicle; (2) aliskiren (25 mg/kg per day); (3) valsartan (8 mg/kg per day); (4) combined aliskiren (12.5 mg/kg per day) and valsartan (4 mg/kg per day); and (5) hydralazine (10 mg/kg per day) for 4 weeks. Aliskiren and valsartan alone markedly and similarly suppressed cardiac hypertrophy, inflammation and fibrosis, and coronary remodeling; prevented cuff injury-induced arterial intimal thickening; and reduced urinary albumin excretion, glomerular inflammation, and glomerulosclerosis in endothelial NO synthase-deficient mice. These beneficial effects of aliskiren and valsartan were associated with the significant attenuation of oxidative stress in these tissues. Hence, aliskiren and valsartan markedly exert the protective effects against cardiovascular and renal injury through the reduction of oxidative stress. Furthermore, compared with monotherapy with aliskiren or valsartan, the combination of a half dose of these drugs more greatly improved the above-mentioned cardiovascular and renal injuries of endothelial NO synthase-deficient mice, which were associated with greater attenuation of tissue oxidative stress by the combination therapy. Thus, the combination of aliskiren and valsartan exerts the synergistic organ-protective effects through synergistic attenuation of oxidative stress. The combination of aliskiren and valsartan seems to be a promising therapeutic strategy for hypertensive organ injury caused by endothelial NO synthase dysfunction.

Dealing with complications in laparoscopy.

With increasing adoption of laparoscopic surgery in gynaecology, there has been a corresponding rise in the types and rates of complications reported. This article sets out to classify complications associated with laparoscopy according to the phases of the surgery; assess the incidence, the mechanisms, the presentations; and recommend methods for preventing and dealing with complications in laparoscopic surgery. Its aim is to promote a culture of risk management based on the development of strategies to improve patient safety and outcome.

Cardiovascular problems in noncardiac surgery.

PURPOSE OF REVIEW: Perioperative cardiac complications remain a major area of concern as our surgical population increases in volume, age and frequency of comorbidity. A variety of strategies can be used to optimize patients and potentially reduce the incidence of these serious complications. RECENT FINDINGS: Recent literature suggests a trend towards less invasive testing for detection and quantification of coronary artery disease and greater interest in pharmacologic 'cardioprotection' using beta-blockers, statins and other agents targeting heart rate control and other mechanisms (e.g. reducing inflammatory responses). The recent Perioperative Ischemic Evaluation study has substantially altered this approach at least towards widespread application to lower/intermediate risk cohorts. Considerable attention has been focused on ensuring optimal standardized perioperative management of patients with a recent percutaneous coronary intervention, particularly those with an intracoronary stent. Widespread surveillance of postoperative troponin release and increasing recognition of the prognostic potential of elevated preoperative brain natriuretic peptides point towards changing strategies for long-term risk stratification. SUMMARY: The complexity of a particular patient's physiologic responses to a wide variety of surgical procedures, which are undergoing constant technological refinement generally associated with lesser degrees of invasivity and stress make calculation of patients' perioperative risk very challenging. At the present time, adequate information is available for the clinician to screen patients with high-risk preoperative predictors, delay elective surgery for patients with recent intracoronary stents and continue chronic beta-blockade in appropriate patients. New large-scale database and subanalyses of major trials (e.g. Perioperative Ischemic Evaluation and Coronary Artery Revascularization Prophylaxis) should provide additional information to minimize perioperative cardiac risk.

Blast overpressure in rats: recreating a battlefield injury in the laboratory.

Blast injury to the brain is the predominant cause of neurotrauma in current military conflicts, and its etiology is largely undefined. Using a compression-driven shock tube to simulate blast effects, we assessed the physiological, neuropathological, and neurobehavioral consequences of airblast exposure, and also evaluated the effect of a Kevlar protective vest on acute mortality in rats and on the occurrence of traumatic brain injury (TBI) in those that survived. This approach provides survivable blast conditions under which TBI can be studied. Striking neuropathological changes were caused by both 126- and 147-kPa airblast exposures. The Kevlar vest, which encased the thorax and part of the abdomen, greatly reduced airblast mortality, and also ameliorated the widespread fiber degeneration that was prominent in brains of rats not protected by a vest during exposure to a 126-kPa airblast. This finding points to a significant contribution of the systemic effects of airblast to its brain injury pathophysiology. Airblast of this intensity also disrupted neurologic and neurobehavioral performance (e.g., beam walking and spatial navigation acquisition in the Morris water maze). When immediately followed by hemorrhagic hypotension, with MAP maintained at 30 mm Hg, airblast disrupted cardiocompensatory resilience, as reflected by reduced peak shed blood volume, time to peak shed blood volume, and time to death. These findings demonstrate that shock tube-generated airblast can cause TBI in rats, in part through systemic mediation, and that the resulting brain injury significantly impacts acute cardiovascular homeostatic mechanisms as well as neurobehavioral function.