COVID-19 Vaccine Hesitancy Among Healthcare Personnel Who Generally Accept Vaccines.

To identify psychological antecedents of COVID-19 vaccine hesitancy among healthcare personnel (HCP). We surveyed 4603 HCP to assess psychological antecedents of their vaccination decisions (the '5 Cs') for vaccines in general and for COVID-19 vaccines. Most HCP accept vaccines, but many expressed hesitancy about COVID-19 vaccines for the psychological antecedents of vaccination: confidence (vaccines are effective), complacency (vaccines are unnecessary), constraints (difficult to access), calculation (risks/benefits), collective responsibility (need for vaccination when others vaccinate). HCP who were hesitant only about COVID-19 vaccines differed from HCP who were consistently hesitant: those with lower confidence were more likely to be younger and women, higher constraints were more likely to have clinical positions, higher complacency were more likely to have recently cared for COVID-19 patients, and lesser collective responsibility were more likely to be non-white. These results can inform interventions to encourage uptake of COVID-19 vaccines in HCP.

Coronavirus Disease 2019 (COVID-19) Seropositivity and Asymptomatic Rates in Healthcare Workers Are Associated with Job Function and Masking.

BACKGROUND: Although the risk of exposure to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is higher for frontline healthcare workers, not all personnel have similar risks. Determining infection rate is difficult due to the limits on testing and the high rate of asymptomatic individuals. Detection of antibodies against SARS-CoV-2 may be useful for determining prior exposure to the virus and assessing mitigation strategies, such as isolation, masks, and other protective equipment. METHODS: An online assessment that included demographic, clinical, and exposure information and a blood sample was collected from 20 614 participants out of ~43 000 total employees at Beaumont Health, which includes 8 hospitals distributed across the Detroit metropolitan area in southeast Michigan. The presence of anti-SARS-CoV-2 IgG was determined using the EUROIMMUN assay. RESULTS: A total of 1818 (8.8%) participants were seropositive between April 13 and May 28, 2020. Among the seropositive individuals, 44% reported that they were asymptomatic during the month prior to blood collection. Healthcare roles such as phlebotomy, respiratory therapy, and nursing/nursing support exhibited significantly higher seropositivity. Among participants reporting direct exposure to a Coronavirus Disease 2019 (COVID-19) positive individual, those wearing an N95/PAPR mask had a significantly lower seropositivity rate (10.2%) compared to surgical/other masks (13.1%) or no mask (17.5%). CONCLUSIONS: Direct contact with COVID-19 patients increased the likelihood of seropositivity among employees but study participants who wore a mask during COVID-19 exposures were less likely to be seropositive. Additionally, a large proportion of seropositive employees self-reported as asymptomatic. (Funded by Beaumont Health and by major donors through the Beaumont Health Foundation). CLINICALTRIALS.GOV NUMBER: NCT04349202.

Dried blood spots are a valid alternative to venipuncture for COVID-19 antibody testing.

BACKGROUND: Serologic analysis is an important tool towards assessing the humoral response to COVID-19 infection and vaccination. Numerous serologic tests and platforms are currently available to support this line of testing. Two broad antibody testing categories are point-of-care lateral flow immunoassays and semi-quantitative immunoassays performed in clinical laboratories, which typically require blood collected from a finger-stick and a standard venipuncture blood draw, respectively. This study evaluated the use of dried blood spot (DBS) collections as a sample source for COVID-19 antibody testing using an automated clinical laboratory test system. METHODS: Two hundred and ninety-four participants in the BLAST COVID-19 seroprevalence study (NCT04349202) were recruited at the time of a scheduled blood draw to have an additional sample taken via finger stick as a DBS collection. Using the EUROIMMUN assay to assess SARS-CoV-2 anti-spike IgG status, DBS specimens were tested on 7, 14, 21, and 28 days post- collection and compared to the reference serum sample obtained from a blood draw for the BLAST COVID-19 study. RESULTS: SARS-CoV-2 anti-spike IgG status from DBS collections demonstrated high concordance with serum across all time points (7-28 days). However, the semi-quantitative value from DBS collections was lower on average than that from serum, resulting in increased uncertainty around the equivocal-to-positive analytical decision point. CONCLUSIONS: DBS collections can be substituted for venipuncture when assaying for COVID-19 IgG antibody, with samples being stable for at least 28 days at room temperature. Finger-stick sampling can therefore be advantageous for testing large populations for SARS-CoV-2 antibodies without the need for phlebotomists or immediate processing of samples. We have high confidence in serostaus determination from DBS collections, although the reduced semi-quantitative value may cause some low-level positives to fall into the equivocal or even negative range.

Cardiac dysfunction subsequent to chronic ozone exposure in rats.

A number of advancements have been made toward identifying the risk factors associated with cardiovascular disease (CVD) and have resulted in a decline in mortality. However, many patients with cardiac disease show no established previous risk. Thus, it appears that other unknown factors contribute to the pathophysiology of CVD. Out of 350,000 sudden cardiac deaths each year in the United States, 60,000 deaths have been linked to air pollution, suggesting a detrimental role of environmental pollutants in the development of CVD. This study tested the hypothesis that chronic ozone (O(3)) exposure diminishes myocardial function in healthy population. Male Sprague-Dawley rats were exposed 8 h/day for 28 and 56 days to filtered air or 0.8 ppm O(3). In vivo cardiac function was assessed by measuring LVDP, +dP/dt, -dP/dt, and LVEDP 24 h after termination of the O(3) exposure. Compared to rats exposed to filtered air, LVDP, +dP/dt, and -dP/dt were significantly decreased, and LVEDP was significantly increased in O(3) exposed animals. This attenuation of cardiac function was associated with increased myocardial TNF-alpha levels and lipid peroxidation as well as decreased myocardial activities of superoxidase dismutase and interleukin-10 levels. These novel findings suggest myocardial dysfunction subsequent to chronic O(3) exposure in normal adult rats may be associated with a decrease in antioxidant reserve and with an increased production of inflammatory mediators.

Differential expression of caveolin-1 and caveolin-3: potential marker for cardiac toxicity subsequent to chronic ozone inhalation.

Earlier studies from our laboratory have shown myocardial dysfunction subsequent to chronic O(3) exposure in rats may be associated with a decrease in antioxidant reserve and increased activity of inflammatory mediators. The present study tested the hypothesis that O(3)-induced cardiac dysfunction in healthy adult rats may be due to changes in caveolin-1 and caveolin-3 levels. Sprague-Dawley rats were exposed 8 h/day for 28 and 56 days to filtered air or 0.8 ppm O(3). In order to assess the chronic effects to O(3), in vivo cardiac function was assessed by measuring LVDP, 24 h after termination of O(3) exposure. Compared to rats exposed to filtered air, LVDP values significantly decreased in all O(3)-exposed animals. This attenuation of cardiac function was associated with increased myocardial TNF-α levels and decreased myocardial activities of superoxidase dismutase. Progressive increases in the expression of myocardial TNF-α in 28 days and 56 days O(3)-exposed animals were followed by decreases in cardiac caveolin-1 levels. On the other hand, differential changes in the expression of caveolin-3 in hearts from 28 and 56 days O(3)-exposed animals were independent of intra-cardiac TNF-α levels. These novel findings suggest the interesting possibility that a balance between caveolin-1 and caveolin-3 may be involved in O(3)-mediated cardiac toxicity.

COVID-19 Vaccination Concerns and Reasons for Acceptance Among US Health Care Personnel.

OBJECTIVES: Because health care personnel (HCP) are potentially at increased risk of contracting COVID-19, high vaccination rates in this population are essential. The objective of this study was to assess vaccination status, barriers to vaccination, reasons for vaccine acceptance, and concerns about COVID-19 vaccination among HCP. METHODS: We conducted an anonymous online survey at a large US health care system from April 9 through May 4, 2021, to assess COVID-19 vaccination status and endorsement of reasons for acceptance and concerns related to vaccination (based on selections from a provided list). RESULTS: A total of 4603 HCP (12.2% response rate) completed the survey, 3947 (85.7%) had received at least 1 dose of a COVID-19 vaccine at the time of the survey, and 550 (11.9%) reported no plans to receive the vaccine. Unvaccinated HCP were 30 times more likely than vaccinated HCP to endorse religious or personal beliefs as a vaccine concern (odds ratio = 30.95; 95% CI, 21.06-45.48) and 15 times more likely to believe that personal vaccination is not needed if enough others are vaccinated (odds ratio = 14.99; 95% CI, 10.84-20.72). The more reasons endorsed for vaccination (ß = 0.60; P < .001), the higher the likelihood of having received the vaccine. However, the number of concerns about COVID-19 vaccine was not related to vaccination status (ß = 1.01; P = .64). CONCLUSIONS: Our findings suggest that reasons for vaccination acceptance and concerns about vaccination need to be considered to better understand behavioral choices related to COVID-19 vaccination among HCP, because these beliefs may affect vaccination advocacy, responses to vaccine mandates, and promotion of COVID-19 vaccine boosters.

Influence of endothelin 1 receptor inhibition on functional, structural and molecular changes in the rat heart after irradiation.

Radiation-induced heart disease is a severe side effect of thoracic radiotherapy. Studies suggest that mast cells play a protective role in radiation-induced heart disease and that the endothelin (ET) system mediates protective effects of mast cells in other disorders. This study examined whether mast cells modulate the cardiac ET system and examined the effects of ET receptor inhibition in a rat model of radiation-induced heart disease. Mast cell-deficient (Ws/Ws), mast cell-competent (+/+) and Sprague-Dawley rats received 18 Gy irradiation to the heart. Left ventricular mRNA of ET1 and its receptors (ETA and ETB) was measured in Ws/Ws and +/+ rats at 1 week and 3 months. Sprague-Dawley rats were treated with the ETA/ETB antagonist bosentan, and at 6 months cardiac changes were assessed using the Langendorff perfused rat heart preparation, immunohistochemistry and real-time PCR. Ws/Ws and +/+ rat hearts did not differ in baseline mRNA. In contrast, +/+ rats hearts exhibited up-regulation of ET1 after irradiation, whereas Ws/Ws rats hearts did not, suggesting the possibility of interactions between mast cells and the cardiac ET system. Bosentan induced reductions in left ventricular systolic pressure, developed pressure and +dP/dtmax but did not affect fibrosis. Because of the known opposing effects of ETA and ETB, studies with selective antagonists may clarify the role of each receptor.

Influence of mast cells on structural and functional manifestations of radiation-induced heart disease.

Radiation-induced heart disease (RIHD), characterized by accelerated atherosclerosis and adverse tissue remodeling, is a serious sequelae after radiotherapy of thoracic and chest wall tumors. Adverse cardiac remodeling in RIHD and other cardiac disorders is frequently accompanied by mast cell hyperplasia, suggesting that mast cells may affect the development of cardiac fibrosis. This study used a mast cell-deficient rat model to define the role of mast cells in RIHD. Mast cell-deficient rats (Ws/Ws) and mast cell-competent littermate controls (+/+) were exposed to 18 Gy localized single-dose irradiation of the heart. Six months after irradiation, cardiac function was examined by echocardiography and Langendorff-perfused isolated heart preparation, whereas structural changes were assessed using quantitative histology and immunohistochemical analysis. Mast cell-deficient rats exhibited more severe postradiation changes than mast cell-competent littermates. Hence, mast cell-deficient rats exhibited a greater upward/leftward shift in the left ventricular (LV) diastolic pressure-volume relationship (P = 0.001), a greater reduction in in vivo LV diastolic area (from 0.50 +/- 0.024 cm in age-matched controls to 0.24 +/- 0.032 cm after irradiation; P = 0.006), and a greater increase in LV posterior wall thickness (from 0.13 +/- 0.003 cm in age-matched controls to 0.15 +/- 0.003 cm after irradiation; P = 0.04). Structural analysis revealed more pronounced postradiation accumulation of interstitial collagen III but less myocardial degeneration in hearts from mast cell-deficient rats. These data show that the absence of mast cells accelerates the development of functional changes in the irradiated heart, particularly diastolic dysfunction, and suggest that, in contrast to what has been the prevailing assumption, the role of mast cells in RIHD is predominantly protective.

Cardiovascular Responsiveness to Vasopressin and α1-Adrenergic Receptor Agonists After Burn Injury.

The effects of burn injury on cardiovascular responsiveness to vasoactive agents are not well understood. The aims of this study were to determine whether burn injury alters cardiovascular reactivity to vasoactive drugs in vivo and intrinsic function of isolated mesenteric resistance arteries. Anesthetized Sprague-Dawley rats were subjected to sham procedure or 30% TBSA dorsal scald burn, followed by crystalloid resuscitation (Parkland Formula). At 24, 72, 96, and 168 hours post burn, rats were reanesthetized, and the mean arterial blood pressure (MAP) responses to various doses of the α1-adrenergic receptor agonist phenylephrine and arginine vasopressin were tested. Mesenteric arteries were harvested from uninjured animals and at 24 and 168 hours post burn. The responsiveness of arteries to phenylephrine and arginine vasopressin was tested by pressure myography. Dose response curves were generated and EC50 concentrations, Hill slopes, and maximal effects were compared. The potency of phenylephrine to increase MAP was reduced 2-fold 24 hours post burn (P < .05 vs sham) and gradually normalized at later time points. The reactivity of isolated arteries to phenylephrine was not significantly altered after burns. The potency of arginine vasopressin to increase MAP and to constrict isolated arteries was increased 2- to 3-fold at 24 hours post burn (P < .05) and normalized at later time points. Our findings suggest that burn injury differentially regulates vasopressor and blood pressure effects of α-adrenergic and vasopressin receptor agonists. Intrinsic vasopressin receptor reactivity of resistance arteries is sensitized early after burns. These findings will help to optimize resuscitation strategies and vasopressor use in difficult to resuscitate burn patients.

Cardiovascular effects of hyperhomocysteinemia in conscious unrestrained rats.

BACKGROUND: Experiments were designed to determine whether hyperhomocysteinemia (Hhe) affects cardiovascular function when monitored in conscious unrestrained animals. METHODS: Adult, male Sprague-Dawley rats were fed a homocystine-supplemented diet for 6 months. Blood pressure (BP), heart rate, and pulse pressure were monitored continuously, 24 h a day, using biotelemetry techniques. RESULTS: The resulting intermediate level of Hhe was not associated with significant changes in heart rate, diastolic BP, systolic BP, or the circadian variation in heart rate. In spite of the lack of significant changes in systolic and diastolic BP, there was a slight but statistically significant increase in pulse pressure after 4 months of treatment that returned toward control levels after 6 months. CONCLUSIONS: Current results indicate that Hhe alone does not have significant effects on BP. Furthermore, they suggest that the previously reported Hhe-induced adverse cardiac remodeling and diastolic dysfunction in this animal model are not the result of pressure overload.

Effect of long-term hyperhomocysteinemia on myocardial structure and function in hypertensive rats.

BACKGROUND: Postulated mechanisms of hyperhomocysteinemia (Hhe) overlap with proposed mechanisms of adverse cardiac remodeling such as altered collagen metabolism and oxidant stress. Hence we examined the hypothesis that Hhe would promote myocardial fibrosis and systolic dysfunction. METHODS: Three-month-old spontaneously hypertensive rats (SHRs) were divided into three groups: (1) control, given amino-acid defined diet for 20 weeks; (2) Hhe group, given Hhe-inducing diet for 20 weeks; and (3) combined diet group, which were given Hhe-inducing diet for 10 weeks (which leads to myocardial fibrosis and diastolic dysfunction as shown in our prior studies) and subsequently returned to amino acid-defined diet for 10 more weeks. At the end of the treatment period, plasma homocysteine (Hcy) levels and blood pressure were measured, and hearts were isolated for histomorphometric and biochemical assessment of cardiac remodeling and myocardial oxidative stress, and for in vitro cardiac function studies. RESULTS: The Hhe animals demonstrated a significant increase in the ratio of collagenous to noncollagenous protein due to reactive interstitial fibrosis, and increased myocardial oxidant stress, compared to the control group. Systolic function was significantly depressed in the Hhe animals compared to the control group. These changes were partially prevented by return to control diet at 10 weeks. CONCLUSIONS: Our results demonstrate that clinically relevant levels of Hhe accelerate progression of hypertensive heart disease to systolic dysfunction and that increased myocardial oxidant stress may play a role in this process. Considering the high prevalence of hypertension and Hhe in the general population, our findings may have great clinical significance.

Proteasome Inhibition After Burn Injury.

The objective of this study was to assess the effects of proteasome inhibition on the development of burn-induced hypermetabolism. Rats underwent 30-40% total BSA scald burn or sham injury. The proteasome inhibitor bortezomib (0.1 mg/kg) or vehicle (n = 10) was administered i.p. 3× weekly starting at 2 hours (early bortezomib, n = 20) or 48 hours (late-bortezomib, n = 13) postburn. Body weights were determined weekly. Resting energy expenditures (REE) were measured at days 0 (baseline), 7, 14, 21, and 42 postburn. At day 42, blood and pectoral muscle were harvested. Routine blood chemistry parameters were analyzed. Proteasome content, proteasome peptidase activities, and ubiquitin-protein conjugates were measured in muscle extracts. As compared with sham-vehicle-treated animals, specific proteasome activities were increased after burn and vehicle treatment. Bortezomib treatment inhibited proteasome activities and increased ubiquitin-protein conjugates after sham and burn injury. Bortezomib treatment did not affect REE after sham procedure. REE significantly increased by 47% within 7 days and remained elevated until day 42 after burn and vehicle treatment. After early-bortezomib treatment, burn-induced increases in REE were delayed and significantly reduced by 42% at day 42, as compared with vehicle treatment. With late-bortezomib treatment, burn-induced increases in REE were also delayed but not attenuated at day 42. Mortality was 20% with vehicle, 65% (median survival time: 1.875 days) with early-bortezomib and 25% with late-bortezomib treatment after burns (P < .05 early-bortezomib vs vehicle and late-bortezomib). Proteasome inhibition delays development of burn-induced hypermetabolism. Although proteasome inhibition early after burn injury reduces the hypermetabolic response, it significantly increases early burn-associated mortality.

Effects of Mesalamine Treatment on Gut Barrier Integrity After Burn Injury.

Gut barrier disruption is often implicated in pathogenesis associated with burn and other traumatic injuries. In this study, the authors examined whether therapeutic intervention with mesalamine (5-aminosalicylic acid [5-ASA]), a common anti-inflammatory treatment for patients with inflammatory bowel disease, reduces intestinal inflammation and maintains normal barrier integrity after burn injury. Male C57BL/6 mice were administered an approximately 20% TBSA dorsal scald burn and resuscitated with either 1 ml normal saline or 100 mg/kg of 5-ASA dissolved in saline. The authors examined intestinal transit and permeability along with the levels of small intestine epithelial cell proinflammatory cytokines and tight junction protein expression 1 day after burn injury in the presence or absence of 5-ASA. A significant decrease in intestinal transit was observed 1 day after burn injury, which accompanied a significant increase in gut permeability. The authors found a substantial increase in the levels of interleukin (IL)-6 (by ~1.5-fold) and IL-18 (by ~2.5-fold) in the small intestine epithelial cells 1 day after injury. Furthermore, burn injury decreases the expression of the tight junction proteins claudin-4, claudin-8, and occludin. Treatment with 5-ASA after burn injury prevented the burn-induced increase in permeability, partially restored normal intestinal transit, normalized the levels of the proinflammatory cytokines IL-6 and IL-18, and restored tight junction protein expression of claudin-4 and occludin compared with that of sham levels. Together these findings suggest that 5-ASA can potentially be used as treatment to decrease intestinal inflammation and normalize intestinal function after burn injury.

Deoxycholyltaurine-induced vasodilation of rodent aorta is nitric oxide- and muscarinic M(3) receptor-dependent.

Emerging evidence indicates that some secondary bile acids interact functionally with muscarinic cholinergic receptors. Using thoracic aortic rings prepared from rats and mice, we examined the mechanism of deoxycholyltaurine-induced vasorelaxation. Increasing concentrations of both acetylcholine (1 nM to 0.1 mM) and deoxycholyltaurine (0.1 microM to 1 mM) stimulated relaxation of phenylephrine-constricted rings prepared from rat thoracic aortae. These effects were reduced by endothelial denudation and by treatment with an inhibitor of nitric oxide formation and with a synthetic acetylcholine:bile acid hybrid that acts as a muscarinic receptor antagonist. Likewise, both acetylcholine (1 nM to 0.1 mM) and deoxycholyltaurine (0.1 microM to 0.1 mM) stimulated relaxation of phenylephrine-constricted rings prepared from mouse thoracic aortae. These effects were reduced by endothelial denudation, addition of an inhibitor of nitric oxide formation, and by muscarinic M(3) receptor knockout. We conclude that the systemic vasodilatory actions of deoxycholyltaurine are mediated in part by a nitric oxide-, muscarinic M(3) receptor-dependent mechanism. In advanced liver disease, interaction of serum bile acids with endothelial muscarinic receptors may explain nitric oxide overproduction in the systemic circulation and resulting peripheral arterial vasodilation.

Burn Injury Alters the Intestinal Microbiome and Increases Gut Permeability and Bacterial Translocation.

Sepsis remains one of the leading causes of death in burn patients who survive the initial insult of injury. Disruption of the intestinal epithelial barrier has been shown after burn injury; this can lead to the translocation of bacteria or their products (e.g., endotoxin) from the intestinal lumen to the circulation, thereby increasing the risk for sepsis in immunocompromised individuals. Since the maintenance of the epithelial barrier is largely dependent on the intestinal microbiota, we examined the diversity of the intestinal microbiome of severely burned patients and a controlled mouse model of burn injury. We show that burn injury induces a dramatic dysbiosis of the intestinal microbiome of both humans and mice and allows for similar overgrowths of Gram-negative aerobic bacteria. Furthermore, we show that the bacteria increasing in abundance have the potential to translocate to extra-intestinal sites. This study provides an insight into how the diversity of the intestinal microbiome changes after burn injury and some of the consequences these gut bacteria can have in the host.

Vasodilatory effects of cholinergic agonists are greatly diminished in aorta from M3R-/- mice.

Acetylcholine interacts with endothelial muscarinic receptors to enhance nitric oxide (NO) release and thereby cause vasodilation. The present study was designed to determine if this effect of acetylcholine is mediated by muscarinic M3 receptors. Thoracic aortae were isolated from wild-type (WT) and M3 receptor knock out (M3R-/-) male mice, and endothelium-intact (I) and -denuded (D) aortic rings were bathed in physiological buffer. Preparations were utilized to examine the contractile response to phenylephrine (1 x 10(-8) - 3 x 10(-4) M added cumulatively) and the vasodilatory actions of acetylcholine (10(-8) - 10(-4) M), carbachol (10(-9) - 10(-4) M), ATP (3 x 10(-5) M) and the NO donor SIN-1 (10(-4) M), each added in the presence of phenylephrine. Endothelium-dependent vasodilatory effects of acetylcholine and carbachol were obvious in aortae isolated from WT mice (56.3 +/- 9.8% and 49.1 +/- 4.1% reductions, respectively, in phenylephrine-induced contraction; p < 0.05), while acetylcholine and carbachol-associated relaxations observed in endothelium-intact M3R-/- preparations (17.9 +/- 2.6% and 13.5 +/- 4.2% reductions, respectively) did not differ significantly from time-control values. ATP-induced, endothelium-dependent vasodilation was similar in preparations from M3R-/- and WT mice, and SIN-1 elicited similar dilatory effects in intact and denuded WT and M3R-/- segments. Phenylephrine concentration-response curves were shifted leftwards by removal of the endothelium in both groups (EC50 values: WT-I/D--25.59 +/- 6.86/3.13 +/- 1.01 x 10(-7) M; M3R-/-I/D--13.92 +/- 4.21/1.52 +/- 0.46 x 10(-7) M; both p < 0.05); however, the phenylephrine response did not differ significantly when compared between the WT and M3R-/- groups. These results indicate that the attenuated vasodilatory effect of acetylcholine in endothelium-intact aortae from M3R-/- mice is due to the absence of muscarinic M3 receptors, and thus suggest that in mouse aorta, muscarinic M3 receptors play a major role in the endothelium-dependent acetylcholine-induced vasodilation.

Interaction of xenobiotics with myocardial signal transduction pathways.

Although the understanding of how toxicants alter cardiac ion-channel function has matured rapidly over the past 20-30 yr, little is known about how xenobiotics may alter the signaling pathways of cardiac myocyte growth and death. Signaling molecules and pathways responsible for the growth of cardiac myocytes include the mitogen-activated protein kinases (MAPKs), janus kinase-signal transducer and activator of transcription (JAK-STATs), nuclear receptor signaling, calcineurin, and the mobilization of free calcium. Signaling molecules and pathways responsible for programmed cardiac myocyte death include the death receptors, mitochondrial proteins, p53 tumor suppressor protein, ceramide signaling, and caspases. Overlap or "crosstalk" between the various growth and death pathways in the myocardium is evident, and these pathways likely exist in a delicate balance where, for example, slight reductions in growth signaling may favor pathways leading to cardiac myocyte apoptosis. Several classical cardiotoxicants are now known to alter signaling pathways in cardiac myocytes; however, the significance of these effects is not entirely clear. Furthermore, xenobiotics that alter the interstitium or extracellular matrix, or both, may significantly alter signaling pathways in cardiac myocytes. The goal of this review is to summarize current findings regarding the interaction of xenobiotics with myocardial signal transduction pathways in the hope of stimulating new insights and highlighting important areas for future research.

Linoleic acid metabolites act to increase contractility in isolated rat heart.

Previous in vivo studies in dogs suggest that the 9,10-monoepoxide of linoleic acid (9,10-cis-epoxyoctadecenoic acid [9,10-EOA]) has toxic cardiovascular effects that result in death at higher doses. More recent work with rabbit renal proximal tubule cells suggests that the 12,13-metabolites of linoleic acid are more toxic than the 9,10-isomers. Thus, in the current study, we tested the hypothesis that 12,13-EOA and 12,13-dihydroxyoctadecadienoic acid (12,13-DHOA) have direct adverse effects on the heart. Langendorff-perfused rat hearts were exposed to 30 microM linoleic acid, 30 microM 12,13-EOA, or 30 microM 12,13-DHOA for 60 min followed by a 30-min recovery period. As indicated by peak left intraventricular pressure and/or +dP/dt(max), all three of the agents elicited moderate increases in contractile function that peaked within 10 20 min. The effects of linoleic acid and 12,13-EOA returned to control values during the remainder of the 60-min exposure, whereas the positive inotropic response to 12,13-DHOA was maintained until washout. Sustained arrhythmias and negative inotropic actions were not observed with any of the three compounds. Subsequently, the monoepoxides were infused into conscious rats (35 mg/kg/h) while blood pressure, heart rate, and EKG were monitored for 24 h using biotelemetry techniques. The only effect observed was a slight decline in blood pressure. Thus, current data suggest that linoleic acid and its oxidative metabolites do not have direct cardiotoxic effects during acute exposure.

Activities of nonlysosomal proteolytic systems in skeletal and cardiac muscle during burn-induced hypermetabolism.

The aim of this study was to assess the activity of nonlysosomal proteolytic systems in skeletal and cardiac muscle during burn-induced hypermetabolism (BHM) in rats. Rats underwent 30% TBSA scald burn or sham injury and were observed for up to 42 days. Body weights and resting energy expenditures were determined weekly. Skeletal (soleus/pectoral) muscle and hearts were harvested on days 0 (=control), 7, 14, 21, and 42 after burn. Calpain, caspase-1, caspase-3/7, caspase-6, caspase-8, caspase-9, and proteasome peptidase activities were measured in tissue extracts. Hypermetabolism developed within 3 weeks after burns, as documented by increased resting energy expenditures and decreased body weights on postburn days 21 to 42 (P < 0.05 vs control). Calpain activities did not show significant alterations. Pan caspase activities increased by time and were significantly increased in skeletal and cardiac muscle extracts during hypermetabolism. Although increases in caspase-1, caspase-8, and caspase-9 activities were predominantly responsible for elevated pan caspase activities in skeletal muscle, increases in caspase-6 activities dominated in the heart. Proteasome peptidase activities in skeletal muscle extracts were not significantly altered. Proteasome peptidase activities in heart extracts increased time dependently and were significantly increased during BHM. Activation of caspase cascades during BHM constitutes a uniform response in skeletal and cardiac muscle and may contribute to enhanced metabolic protein turnover. Activation of myocardial proteasome activities may reflect persistent cardiac stress. Further exploration of caspase cascades and the proteasome as therapeutic targets to influence long-term consequences of BHM appears justified.