SARS-CoV-2 as an inflammatory cardiovascular disease: current knowledge and future challenges.

SARS-CoV-2 is responsible for the 2020 global COVID-19 pandemic. In patients with COVID-19, multiple cardiovascular (CV) manifestations have been reported. SARS coronavirus 2 infection can lead to inflammatory CV disease first via takeover of the angiotensin-converting enzyme-2 enzyme as a cell receptor as well as the macrophage activation syndrome in severe illness. We review the CV manifestations of COVID-19 and therapeutics under investigation. We discuss the potential long-term CV sequelae after recovery from COVID-19 and the gaps in knowledge including the pathophysiological links between acute cardiac injury, myocardial inflammation and chronic cardiomyopathy. Future investigational efforts could result in significant diagnostic and therapeutic advances potentially impacting the broader field of chronic heart failure and cardiac recovery.

Lay abstract COVID-19 has led to a global pandemic, and many patients infected with this novel virus develop cardiovascular (CV) complications including heart attacks, strokes, heart failure and sudden cardiac death. We will review the pathophysiology behind how a viral infection can place a patient at risk and cause multiple CV diseases. Additionally, we will review our current knowledge regarding treatment for the novel corona virus and long-term risk for patients who recover from COVID-19. At last, we will discuss the future perspective regarding what we can learn about how a virus can cause CV disease and how we can better equip ourselves for future pandemics.

Acousto-Optic Cerebral Blood Flow Monitoring During Induction of Anesthesia in Humans.

BACKGROUND: Past transcranial Doppler (TCD) studies have documented the effects of the sequence of anesthesia induction followed by intubation on cerebral blood flow (CBF) velocity. The purpose of this study was to determine whether acousto-optic CBF monitoring would detect changes in CBF which are known to occur with propofol and subsequent endotracheal intubation. METHODS: Seventy-two patients scheduled for elective non-intracranial surgery were evaluated. A Cerox 3215F (Ornim Medical) acousto-optic CBF monitor was used. The acousto-optic transducers were applied bifrontally prior to induction. Baseline cerebral flow index (CFI) values were obtained for at least 2 min prior to induction, set to a unitless value of 100. Subsequent relative changes in CFI from baseline were determined at the lowest value over 3 min after propofol injection but before laryngoscopy; and the highest value over 5 min after the start of laryngoscopy. CFI data were evaluated using Friedman's test. RESULTS: The median dose of propofol [interquartile range] given was 200 mg [160-250]. CFI decreased to 84 % of baseline after propofol and increased to 147 % of baseline after endotracheal intubation (both p < 0.001); MAP decreased after intravenous induction of anesthesia from 103 ± 15 to 86 ± 15 mmHg (p < 0.001) and then returned following endotracheal intubation to 104 ± 20 mmHg. CONCLUSIONS: Our data are congruent with previous observations made with TCD under similar experimental conditions. Such observations support the notion that acousto-optic monitoring yields valid real-time measures of changes in CBF in humans. Further validation against other quantitative measures of CBF would be appropriate.

Intravenous GLP-1 (7-36) amide for prevention of hyperglycemia during cardiac surgery: a randomized, double-blind, placebo-controlled study.

OBJECTIVE: The authors sought to evaluate the efficacy of an intravenous glucagon-like peptide-1 (GLP-1) infusion, compared with placebo, to mitigate intraoperative hyperglycemia. DESIGN: Prospective, double-blinded, randomized, placebo-controlled. SETTING: University hospital. PARTICIPANTS: Diabetic (non-insulin dependent) and non-diabetic patients undergoing elective cardiac surgery with cardiopulmonary bypass. INTERVENTIONS: Patients were randomized in a 1:1 fashion to GLP-1 (7-36) amide infusion (1.5 pmol/kg/min) or placebo. Insulin was administered intraoperatively to both groups per a standardized protocol. MEASUREMENTS AND MAIN RESULTS: A total of 77 patients were included for analysis (GLP-1, n = 37; placebo, n = 40). Mean blood glucose during cardiopulmonary bypass was 127.5 mg/dL and 142.5 mg/dL (p = 0.002) in the GLP-1 and placebo groups, respectively. Mean blood glucose values during the entire intraoperative course were 12.2 mg/dL lower for subjects given GLP-1 (95% CI 2.3, 22, p = 0.015), independent of time. During the period of cardiopulmonary bypass, mean blood glucose values in subjects given GLP-1 were 14.1 mg/dL lower than those who received placebo (95% CI 3.5, 24.8, p = 0.009), independent of time. The incidence of hypoglycemia did not differ significantly between the 2 groups. CONCLUSIONS: Administration of intravenous GLP-1 (7-36) amide to patients undergoing cardiac surgery significantly reduced their plasma glucose levels intraoperatively and may represent a novel therapeutic strategy to prevent perioperative hyperglycemia.

Validation study of Doppler-derived transmitral valve gradients compared to near simultaneously obtained directly measured catheter gradients immediately after mitral valve repair surgery.

OBJECTIVE: To evaluate the accuracy of Doppler-derived transmitral valve gradients immediately after mitral valve repair by comparing them with near simultaneously obtained direct catheter gradients. DESIGN: A prospective study. SETTING: A tertiary care medical center. PARTICIPANTS: Twenty elective adult surgical patients presenting for mitral valve repair surgery. METHODS: Mitral valve surgery proceeded in standard fashion except for the use of a smaller than usual left ventricular vent catheter (Medtronic DLP 10 French left heart vent catheter). After completion of the mitral valve repair and subsequent cardiac de-airing, the patient was weaned from cardiopulmonary bypass. Immediately after separation, the study period began. Near simultaneous transmitral Doppler gradients were obtained with directly measured catheter gradients via the vent catheter. RESULTS: While the mean peak gradient difference of 1.1 mmHg was small (p-value 0.18, 95% CI: -0.54 to 2.73 mmHg), the correlation between Doppler and catheter gradient measurements (Pearson correlation coefficient r = 0.54, p = 0.055) only approached statistical significance due to the large variance associated with the small sample size. In all patients with a peak gradient greater than 10 mmHg (4 of the 20 patients), overestimation of catheter gradients by Doppler occurred, with two showing a 62% to 73% discrepancy. In these two cases, there was also evidence for elevated left ventricular end-diastolic pressure (LVEDP) along with high transmitral blood flow velocities. CONCLUSION: Doppler-derived transmitral gradients provide a simple, safe, and reliable measure of the true physiologic transmitral valve gradient. At the same time, it is important to recognize that significant Doppler over-estimation of catheter gradients may occur in patients with elevated Doppler transmitral velocities. The causes of these overestimations are unknown. They may be related to technical recording errors. They may also be related to an inherent weakness in Doppler technology--its inability to account for any distal recovery of pressure, which in a select group of patients could be significant.

Implementation of an intraoperative glycemic control protocol for cardiac surgery in a high-acuity academic medical center: an observational study.

STUDY OBJECTIVE: To examine the effect on morbidity and mortality of an established intraoperative insulin protocol in cardiac surgical patients. DESIGN: Retrospective observational study. SETTING: Single-center, 782 bed, metropolitan academic hospital. PATIENTS: 1,616 adult patients undergoing cardiac surgical procedures with cardiopulmonary bypass (CPB). INTERVENTIONS: An intraoperative, intravenous (IV) insulin protocol designed to maintain blood glucose values less than 150 mg/dL was implemented. MEASUREMENTS: Blood glucose was evaluated on entry to the operating room, every 30 minutes during CPB, and at least once after discontinuation of CPB. Blood glucose values were followed postoperatively, as dictated by institutional policy. MAIN RESULTS: Intraoperative predictors of 30-day mortality using multivariate logistic regression included hyperglycemia on initiation of CPB (OR 1.0, P = 0.05). The strongest predictor of 30-day mortality was the development of postoperative renal failure requiring hemodialysis (OR 3.26, P = 0.001). CONCLUSIONS: Implementation of an intraoperative IV insulin protocol, while associated with improved glycemic control, was not associated with improved outcomes. While improved glycemic control on initiating CPB was associated with decreased 30-day mortality, the effect was small. Implementation of our insulin protocol was highly associated with decreased renal failure postoperatively. Further prospective studies are warranted to better establish causality.

Human Alzheimer and inflammation biomarkers after anesthesia and surgery.

BACKGROUND: The prevalence of postoperative cognitive disturbance, coupled with growing in vitro, cell, and animal evidence suggesting anesthetic effects on neurodegeneration, calls for additional study of the interaction between surgical care and Alzheimer neuropathology. The authors studied human cerebrospinal fluid (CSF) biomarkers during surgery. METHODS: Eleven patients undergoing idiopathic nasal CSF leak correction were admitted to this Institutional Review Board-approved study. Lumbar subarachnoid catheters were placed before the procedure. Anesthesia was total intravenous propofol or remifentanil or inhalational sevoflurane, depending on provider choice. CSF samples were taken after catheter placement (base), at procedure end (0 h), and then at 6, 24, and 48 h. CSF was analyzed using xMAP Luminex immunoassay (Luminex, Austin, TX). RESULTS: Of the 11 patients (age range, 53 ± 6 yr), 8 were women; 4 received intravenous anesthesia, 6 sevoflurane, and 1 mixed. Procedures lasted 6.4 ± 2 h. Mean CSF amyloid-ß(1-42) remained unchanged, but total-tau and phosphorylated-tau181P increased progressively until at least 48 h. Total-tau, phosphorylated-tau, or amyloid-ß(1-42) concentrations were not different between anesthetic groups. CSF interleukin-10, S100Beta, and tumor necrosis factor α were increased similarly in both anesthetic groups at 24 h, but interleukin-6 was increased more in the inhalational group. CONCLUSION: These data indicate a robust neuroinflammatory response, including not only the usual markers (interleukin-6, tumor necrosis factor α, interleukin-10), but also S100Beta and tau, markers of injury. The total-tau/amyloid-ß(1-42) ratio increased in a pattern consistent with Alzheimer disease, largely because of an increase in total-tau rather than a decline in amyloid-ß(1-42). The differences in CSF interleukin-6 concentrations suggest that anesthetic management may make a difference in neuroinflammatory response.

Design, structure-activity relationships and in vivo characterization of 4-amino-3-benzimidazol-2-ylhydroquinolin-2-ones: a novel class of receptor tyrosine kinase inhibitors.

The inhibition of key receptor tyrosine kinases (RTKs) that are implicated in tumor vasculature formation and maintenance, as well as tumor progression and metastasis, has been a major focus in oncology research over the last several years. Many potent small molecule inhibitors of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) kinases have been evaluated. More recently, compounds that act through the complex inhibition of multiple kinase targets have been reported and may exhibit improved clinical efficacy. We report herein a series of potent, orally efficacious 4-amino-3-benzimidazol-2-ylhydroquinolin-2-one analogues as inhibitors of VEGF, PDGF, and fibroblast growth factor (FGF) receptor tyrosine kinases. Compounds in this class, such as 5 (TKI258), are reversible ATP-competitive inhibitors of VEGFR-2, FGFR-1, and PDGFRbeta with IC(50) values <0.1 microM. On the basis of its favorable in vitro and in vivo properties, compound 5 was selected for clinical evaluation and is currently in phase I clinical trials.

Mothers' social communicative adjustments to young children with mild developmental delays.

The social communication and compliance patterns of 63 mothers interacting with their young children who had mild developmental delays in social play and instructional tasks were examined in a longitudinal study. Results were consistent with the hypothesis that mothers appropriately adjust their social communications in accordance with children's developmental characteristics and task demands. The extent of scaffolding specificity that mothers used in the instructional task also indicated a high level of sensitivity to children's developmental characteristics. Analyses conducted over a 2-year period revealed that adjustments were commensurate with children's emerging social communication abilities, suggesting that mothers of children with developmental delays continue to display social communication patterns that are supportive of their child's development.

Developmentally delayed children's influence attempts with mothers predict interactions with peers over time.

We examined whether influence attempts of 4-6 year-old children with mild developmental delays occurring when interacting with their mothers predicted children's interactions with peers two years later. Hierarchical regressions controlling for relevant child characteristics and a measure of direct parental actions to influence their children's peer interactions revealed a consistent association between influence attempts with mothers and four important aspects of children's peer relationships: successful social bids to peers, initiations to peers, extent of involvement with peers, and overall level of peer interactions. Results were consistent with social communicative processes likely to emerge during children's influence attempts with mothers, which are relevant to peer relationships. The fact that influence attempts with mothers were associated with peer interactions over a time period when peers occupy a more dominant role in children's social relationships supports the role of indirect family influences as a potential intervention strategy to further the peer competence of children with delays.

Continuity and Change From Full-Inclusion Early Childhood Programs Through the Early Elementary Period.

A large and well-characterized group of children with mild developmental delays initially enrolled in full-inclusion preschool or kindergarten programs was followed for 3 years. Changes in the type of inclusive placements as children transitioned to first and second grades were monitored, and associations between placement type and child and family characteristics were examined. Results revealed a high level of continuity in that most children remained in partial or full inclusion settings over time. However, a substantial reduction in full-inclusion placements occurred between the 2nd and 3rd year when children were completing the transition to first and second grades. Placements in less inclusive settings were associated with children's levels of cognitive and language development but not their adaptive, social, or behavioral characteristics. A hypothesis was put forward that placement in full-inclusion programs during the early childhood years creates a momentum to continue maximum participation in inclusive settings over time.

Enhancing a classroom social competence and problem-solving curriculum by offering parent training to families of moderate- to high-risk elementary school children.

The Incredible Years parent and classroom interventions were evaluated for the first time in elementary schools. Culturally diverse, socioeconomically disadvantaged schools were randomly assigned to intervention or control (CON). In intervention schools, all children received a 2-year classroom intervention beginning in kindergarten. In addition, indicated children were randomly assigned to also receive parent training (PT + CR) or only the classroom intervention (CR). PT + CR mothers reported that, following intervention, children showed fewer externalizing problems and more emotion regulation than CR or CON children. Observations showed that child-mother bonding was stronger in the PT + CR condition than in the CON condition, and PT + CR mothers were significantly more supportive and less critical than CR or CON mothers. Teachers reported that PT + CR mothers were significantly more involved in school and that children in the PT + CR and the CR conditions had significantly fewer externalizing problems than in the CON condition.

The Friendships of Young Children with Developmental Delays: A Longitudinal Analysis.

This longitudinal study examined the social interactions of children with mild developmental (cognitive) delays with friends across the early childhood and early elementary years. Results revealed increases in many forms of social exchange with effect sizes in the moderate range, but no changes in sustained interactive play. Social interaction patterns, difficulties in identifying friends to participate in the study, and concerns evident in children's peer and friendship networks suggest the general absence of reciprocal friendships. These findings are consistent with the hypothesis that children's limited peer-related social competence constrains all aspects of their development of friendships. Despite these problems, the potential benefits of interventions designed to support relationships at this stage of friendship development for children with delays were noted.

Linkages between delayed children's social interactions with mothers and peers.

The social dimensions of family-peer linkages of 4- to 6-year-old children (N=63) with developmental delays (IQ range, 50-80) were examined in this study. Hierarchical regressions revealed consistent and meaningful patterns of association relating children's influence attempts directed toward their mothers and their interactions with peers. A similar association with peer interactions was found for children's ability to obtain compliance from their mothers. Evidence suggested the existence of a core behavioral pattern that children exhibit with different partners and in different contexts. The role of horizontal forms of parent-child interactions in promoting the peer relationships of children with delays was suggested, particularly in terms of an intervention approach for this group of children.

Promoting the peer-related social development of young children with mild developmental delays: effectiveness of a comprehensive intervention.

To address the unusual peer-related social competence difficulties characteristic of young children with mild developmental delays, we conducted a randomized clinical trial to evaluate the effectiveness of a comprehensive, developmentally oriented, highly individualized intervention extending over a 2-year period. Outcome measures emphasized generalization of peer interactions in unfamiliar playgroups. Results revealed modest effects of the intervention, with children who had lower cognitive levels benefiting most. Intervention effects were best conceptualized as preventative, minimizing the negative features and atypical patterns of children's social play with peers. Our discussion of future work was focused on alternative implementation models to enhance intervention intensity, inclusion of specific subgroups of children, and direct measurement of children engaging in social tasks.

Stability, change, and correlates of the peer relationships of young children with mild developmental delays.

The peer relationships of young children with mild developmental (cognitive) delays recruited at 4-6 years of age were examined in a longitudinal study across a 2-year period. Results revealed only modest increases in children's peer interactions, a high degree of intraindividual stability, and the existence of a poorly organized and conflict-prone pattern of peer interactions. Child cognitive and language levels as well as family stress and support were associated with children's peer interactions. A subgroup was identified of initially low interactors who were at especially high risk for future peer interaction problems. These findings further underscore the importance of designing and implementing early intervention programs in the area of peer relationships for children with mild developmental delays.

Treating children with early-onset conduct problems: intervention outcomes for parent, child, and teacher training.

Families of 159, 4- to 8-year-old children with oppositional defiant disorder (ODD) were randomly assigned to parent training (PT); parent plus teacher training (PT + TT); child training (CT); child plus teacher training (CT + TT); parent, child, plus teacher training (PT + CT + TT); or a waiting list control. Reports and independent observations were collected at home and school. Following the 6-month intervention, all treatments resulted in significantly fewer conduct problems with mothers, teachers, and peers compared to controls. Children's negative behavior with fathers was lower in the 3 PT conditions than in control. Children showed more prosocial skills with peers in the CT conditions than in control. All PT conditions resulted in less negative and more positive parenting for mothers and less negative parenting for fathers than in control. Mothers and teachers were also less negative than controls when children received CT. Adding TT to PT or CT improved treatment outcome in terms of teacher behavior management in the classroom and in reports of behavior problems.

Subtypes of nonsocial play: comparisons between young children with and without developmental delays.

Subtypes of nonsocial play were examined for matched groups of young typically developing children and children with mild developmental (cognitive) delays. Based on intercorrelation patterns, interindividual stability, and associations with peer interaction measures, findings indicated that the nonsocial play of children with delays can be characterized as multidimensional in a manner similar to that of typically developing children. However, analyses suggest different interpretations of the psychological meaning of nonsocial play subtypes for both groups of children than indicated by previous work. Context factors did not influence nonsocial play subtypes. Evidence was found indicating considerable heterogeneity within subtypes, suggesting the need for longitudinal studies focusing on children's peer-related social competence, which may reveal subgroups within subtypes that both refine the constructs and provide direction for clinical interventions.

Family factors associated with the peer social competence of young children with mild delays.

A model addressing family influences on the peer-related social competence of young children with mild developmental (cognitive) delays was developed and tested. Constructs representing child peer competence, types of parent action (arranging play for their child and socialization strategies varying in degree of control or power), parent attitudes (beliefs as to the degree their child's peer interactions could be influenced by external actions), parent stress, social support, and child risk were examined. Path analytic techniques were used to evaluate the model. Results supported the importance of family influences on the peer-related social competence of young children with mild developmental delays. With the exception of parent attitude, all theoretical constructs were retained in the analysis and significant paths followed predicted relationships.

Selective glycogen synthase kinase 3 inhibitors potentiate insulin activation of glucose transport and utilization in vitro and in vivo.

Insulin resistance plays a central role in the development of type 2 diabetes, but the precise defects in insulin action remain to be elucidated. Glycogen synthase kinase 3 (GSK-3) can negatively regulate several aspects of insulin signaling, and elevated levels of GSK-3 have been reported in skeletal muscle from diabetic rodents and humans. A limited amount of information is available regarding the utility of highly selective inhibitors of GSK-3 for the modification of insulin action under conditions of insulin resistance. In the present investigation, we describe novel substituted aminopyrimidine derivatives that inhibit human GSK-3 potently (K(i) < 10 nmol/l) with at least 500-fold selectivity against 20 other protein kinases. These low molecular weight compounds activated glycogen synthase at approximately 100 nmol/l in cultured CHO cells transfected with the insulin receptor and in primary hepatocytes isolated from Sprague-Dawley rats, and at 500 nmol/l in isolated type 1 skeletal muscle of both lean Zucker and ZDF rats. It is interesting that these GSK-3 inhibitors enhanced insulin-stimulated glucose transport in type 1 skeletal muscle from the insulin-resistant ZDF rats but not from insulin-sensitive lean Zucker rats. Single oral or subcutaneous doses of the inhibitors (30-48 mg/kg) rapidly lowered blood glucose levels and improved glucose disposal after oral or intravenous glucose challenges in ZDF rats and db/db mice, without causing hypoglycemia or markedly elevating insulin. Collectively, our results suggest that these selective GSK-3 inhibitors may be useful as acute-acting therapeutics for the treatment of the insulin resistance of type 2 diabetes.