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J W Horton

Publications and source records attributed to J W Horton.

At least 19 recordsLinked to original sources
PubMed2006

Detecting genetic predisposition for complicated clinical outcomes after burn injury.

Sepsis, septic shock and organ failure are common among patients with moderate to severe burns. The inability of demographic and clinical factors to identify patients at high risk for such complications suggests that genetic variation may influence clinical outcome. Moreover, the genetic predisposition to death from infection has been estimated to be greater than for cardiovascular disease or cancer . While it is widely accepted that genetic factors influence many complex disease processes, controversy has emerged regarding the most appropriate methods for detection and even the validity of many published allelic associations . This article will review the few studies of genetic predisposition that have been conducted in the setting of burn injury, then discuss some of the obstacles and potential approaches for the discovery of additional allelic associations.

Burns↗
PubMed2004

TLR4 and TNF-alpha polymorphisms are associated with an increased risk for severe sepsis following burn injury.

CONTEXT: Sepsis, organ failure, and shock remain common among patients with moderate to severe burn injuries. The inability of clinical factors to identify at-risk patients suggests that genetic variation may influence the risk for serious infection and the outcome from severe injury. OBJECTIVE: Resolution of genetic variants associated with severe sepsis following burn injury. PATIENTS: A total of 159 patients with burns > or =20% of their total body surface area or any smoke inhalation injury without significant non-burn related trauma (injury severity score (ISS)> or =16), traumatic or anoxic brain injury, or spinal cord injury and who survived more than 48 h post-admission. METHODS: Candidate single nucleotide polymorphisms (SNPs) within bacterial recognition (TLR4 +896, CD14 -159) and inflammatory response (TNF-alpha -308, IL-1beta -31, IL-6 -174) loci were evaluated for association with increased risk for severe sepsis (sepsis plus organ dysfunction or septic shock) and mortality. RESULTS: After adjustment for age, full-thickness burn size, ethnicity, and gender, carriage of the TLR4 +896 G-allele imparted at least a 1.8-fold increased risk of developing severe sepsis following a burn injury, relative to AA homozygotes (adjusted odds ratio (aOR) 6.4; 95% confidence interval (CI) 1.8 to 23.2). Carriage of the TNF-alpha -308 A-allele imparted a similarly increased risk, relative to GG homozygotes (aOR = 4.5; 95% CI 1.7 to 12.0). None of the SNPs examined were significantly associated with mortality. CONCLUSIONS: The TLR4 +896 and TNF-alpha -308 polymorphisms were significantly associated with an increased risk for severe sepsis following burn trauma.

Adult↗
PubMed2001

Metabolic disorder in myocardiac intracellular free calcium after thermal injury.

Cutaneous burn trauma causes functional inhibition of the heart, but the mechanism is unclear. Using a high dissociation constant (K(D)) calcium indicator TF-BAPTA and 19F MR spectroscopy, the relationship between the changes of cytosolic free calcium and cardiac function after burn trauma was examined. Sprague-Dawley rats received scald (43% TBSA) or sham burns. Twenty-four hours later, the hearts were excised and perfused by the Langendorff method with a modified phosphate-free Krebs-Henseleit bicarbonate buffer. Left ventricular developed pressure (LVDP) was recorded through a catheter attached to an intraventricular balloon. At the same time, 31P and 19F nuclear magnetic resonance (NMR) spectroscopy was perforined before and after TF-BAPTA loading. LVDP of the heart from burned rats was 40% less than in sham burn rats (65+/-6 vs 110+/-12 mmHg, P<0.01). Cytosolic free calcium increased about four-fold in those hearts from the burn group compared to the sham burn group (0.807+/-0.192 vs 3.891+/-0.929 microM). Loading TF-BAPTA in those hearts only caused about a 15-20% decrease in LVDP. PCr/Pi ratio also decreased significantly with this loading, but ATP signals were not affected. In conclusion, the inhibition of cardiac contractility caused by burn trauma correlated with the overload of cytosolic free calcium in the heart.

Adenosine Triphosphate↗
PubMed2001

A primary burn wound does not slow the contraction rate of an adjacent excisional wound.

The response to major burn injury includes systemic release of mediators that may have an effect on wound healing. The authors evaluated the effect of a burn injury on the contraction of an excisional wound adjacent to the burn, and the effect of plasma derived from burn-injured animals on the contraction of the fibroblast-populated collagen matrix (FPCM). Nine rats (90-100 days old) under anesthesia received a standardized 40% total body surface area burn to the dorsum, and eight rats (controls) were sham burned. Immediately thereafter all animals had a square (2.25 cm2) of unburned dermis excised from the dorsum, superior to the burn wound. The excisional wound area was measured at 2 to 3-day intervals postoperatively. Plasma was collected from some animals on postburn day 15; the contraction-stimulating ability of burn vs. control plasma was measured in the FPCM. All animals remained free of sepsis. The excisional wound area in all animals decreased to 50% and then 25% of the initial area after approximately 4 and 8 days respectively. The rate of wound contraction (i.e., wound area reduction) did not differ between burn and control animals. Contraction stimulated by 5% plasma in the FPCM (expressed as a percentage of the original matrix area) was 70.2+/-6.4 (standard deviation) mm2 vs. 62.4 +/-3.9 mm2 for burn vs. control rats respectively (p>0.05). Burn injury in this model did not alter the contraction of an excisional wound at an unburned site. There was no significant difference in the contraction-stimulating ability (FPCM model) of plasma from the burned rats compared with plasma from unburned control rats. Burn injury appears to have an inconsequential effect on the contraction of an adjacent wound.

Animals↗
PubMed2001

Antioxidant vitamin therapy alters burn trauma-mediated cardiac NF-kappaB activation and cardiomyocyte cytokine secretion.

BACKGROUND: This study examined the effects of antioxidant vitamins A, C, and E on nuclear transcription factor-kappa B (NF-kappaB) nuclear translocation, on secretion of inflammatory cytokines by cardiac myocytes, and on cardiac function after major burn trauma. METHODS: Adult rats were divided into four experimental groups: group I, shams; group II, shams given oral antioxidant vitamins (vitamin C, 38 mg/kg; vitamin E, 27 U/kg; vitamin A, 41 U/kg 24 hours before and immediately after burn); group III, burns (third-degree scald burn over 40% total body surface area) given lactated Ringer's solution (4 mL/kg/% burn); and group IV, burns given lactated Ringer's solution plus vitamins as described above. Hearts were collected 4, 8, 12, and 24 hours after burn to assay for NF-kappaB nuclear translocation, and hearts collected 24 hours after burn were examined for cardiac contractile function or tumor necrosis factor-alpha secretion by cardiomyocytes. RESULTS: Compared with shams, left ventricular pressure was lower in burns given lactated Ringer's solution (group III) (88 +/- 3 vs. 64 +/- 5 mm Hg, p < 0.01) as was +dP/dt max (2,190 +/- 30 vs. 1,321 +/- 122 mm Hg/s) and -dP/dt max (1,775 +/- 71 vs. 999 +/- 96 mm Hg, p < 0.01). Burn injury in the absence of vitamin therapy (group III) produced cardiac NF-kappaB nuclear migration 4 hours after burn and cardiomyocyte secretion of tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 by 24 hours after burn. Antioxidant therapy in burns (group IV) improved cardiac function, producing left ventricular pressure and +/-dP/dt (82 +/- 2 mm Hg, 1,880 +/- 44 mm Hg, and 1,570 +/- 46 mm Hg/s) comparable to those measured in shams. Antioxidant vitamins in burns inhibited NF-kappaB nuclear migration at all times after burn and reduced burn-mediated cytokine secretion by cardiomyocytes. CONCLUSION: These data suggest that antioxidant vitamin therapy in burn trauma provides cardioprotection, at least in part, by inhibiting translocation of the transcription factor NF-kappaB and interrupting cardiac inflammatory cytokine secretion.

Animals↗
PubMed2001

Development of an acute burn model in adult mice for studies of cardiac function and cardiomyocyte cellular function.

The increasing availability of mice with gene supplementation (transgenic), site-specific inactivation mutations (gene "knock-outs"), or site-specific genetic modification mutations (gene "knock-ins") has spurred interest in the development of murine trauma models. In this study, C57 BL/6 mice (28 g) were given a cutaneous burn over 40% total body surface area by applying brass probes (1 x 2 x 0.003 cm) heated to 100 degrees C in boiling water to the animals side and back for 5 s. Shams received anesthesia alone and not burn. Mice were killed 24 h post-burn to determine presence of partial-thickness or full-thickness burn injury, cardiac contractile function (Langendorff perfusion, n = 7 or 8 mice/group) or to examine cardiac myocyte cytokine secretion in isolated cardiomyocytes (collagenase perfusion, n = 4 or 5 mice/group). All mice were killed 24 h post-burn for subsequent cardiac or cardiomyocyte studies. Our studies confirm that this murine model of burn trauma produced mixed partial- or full-thickness burn injury, whereas there was no necrosis or inflammation in sham burn mice. Baseline hematocrits were similar in all mice (44+/-1) but decreased after burn trauma (37+/-1), likely because of the volume of fluid resuscitation and hemodilution. Burn trauma impaired cardiac contraction and relaxation as indicated by the lower left ventricular pressure (LVP) measured in burn (56+/-4) compared to that measured in shams (84+/-1 mmHg, P < 0.001), a lower rate of LVP rise (+dP/dt max, 1393+/-10 vs. 2000+/-41 mmHg/s, P < 0.002), and reduced LVP fall (-dP/dt max, 1023 - 40 vs. 1550+/-50, P < 0.001). These differences occurred despite similar coronary perfusion pressures and heart rates in both sham and burn mice. Ventricular function curves were shifted downward in the burn mice in the direction of contractile failure; in addition, hearts from burn mice had reduced LVP and +dP/dt responses to increases in coronary flow rate, increases in perfusate Ca2+, and to isoproterenol challenge (P < 0.05). Burn trauma promoted cardiac myocyte secretion of tumor necrosis factor (TNFalpha) (175+/-6 pg/mL) compared to that measured in shams (72+/-9 pg/mL, P < 0.05); burn trauma also increased cardiac myocyte secretion of interleukin 1beta (IL-1beta) (sham: 2+/-0.5; burn: 22+/-1 pg/mL, P < 0.05) and IL-6 (sham: 70+/-6; burn: 148+/-16 pg/mL, P < 0.05). Anti-TNFalpha strategies prevented burn-mediated cardiac contractile deficits. Burn trauma altered Ca2+ homeostasis in murine cardiomyocytes (Fura-2 AM loading). [Ca2+]i in myocytes from burns (185+/-4 nM) was higher than values measured in myocytes from shams (86+/-nM, P < 0.05). These data confirm that the murine burn model provides a reasonable approach to study the molecular and cell biology of inflammation in organ dysfunction after burn trauma.

Animals↗
PubMed2001

Overexpression of cardiac I-kappaBalpha prevents endotoxin-induced myocardial dysfunction.

Nuclear factor-kappa B (NF-kappaB) is an inducible transcription factor that regulates expression of many genes, such as tumor necrosis factor-alpha (TNF-alpha), which may contribute to myocardial dysfunction. We investigated whether cardiac NF-kappaB activation is involved in the development of myocardial dysfunction after lipopolysaccharide (LPS) challenge. Mice were intraperitoneally injected with LPS, and the hearts were harvested and assayed for NF-kappaB translocation. After LPS challenge, NF-kappaB activation was detected within 30 min and remained for 8 h. In transgenic mice constitutively overexpressing a nondegradable form of I-kappaBalpha (I-kappaBalphaDeltaN) in cardiomyocytes, myocardial NF-kappaB translocation was prevented after LPS challenge. Myocytes isolated from these transgenics secreted significantly less TNF-alpha than did wild-type cardiomyocytes after LPS stimulation. When whole hearts were excised, perfused in a Langendorff preparation, and challenged with endotoxin, I-kappaBalphaDeltaN transgenic hearts displayed normal cardiac function, whereas profound contractile dysfunction was observed in wild-type hearts. These data indicate that myocardial NF-kappaB translocates within minutes after LPS administration. Inhibition of myocyte NF-kappaB activation by overexpression of myocyte I-kappaBalpha is sufficient to block cardiac TNF-alpha production and prevent cardiac dysfunction after LPS challenge.

Animals↗
PubMed2001

Hypertonic saline-dextran suppresses burn-related cytokine secretion by cardiomyocytes.

Whereas hypertonic saline-dextran (HSD, 7.5% NaCl in 6% D70) improves cardiac contractile function after burn trauma, the mechanisms of HSD-related cardioprotection remain unclear. We recently showed that cardiomyocytes secrete tumor necrosis factor-alpha (TNF-alpha), a response that was enhanced by burn trauma. This study addressed the question: does HSD modulate cardiac contraction/relaxation by altering cardiomyocyte TNF-alpha secretion? Wistar-Furth rats (325 g) were given a burn injury over 40% of the total body surface area and were then randomized to receive a bolus of either isotonic saline or HSD (4 ml/kg, n = 14 rats/group). Sham burn rats were given either isotonic saline or HSD (n = 14 rats/group) to provide appropriate controls for the two burn groups. Hearts were isolated 24 h postburn for either Langendorff perfusion (n = 8 hearts/group) or to prepare cardiomyocytes (n = 6 hearts/group). Myocytes were stimulated with lipopolysaccharide (LPS) (0, 10, 25, or 50 microg for 18 h) to measure cytokine secretion. Burn trauma increased myocyte TNF-alpha and interleukin-1 beta and -6 secretion, exacerbated cytokine response to LPS stimulus, and impaired cardiac contraction. HSD treatment of burns decreased cardiomyocyte cytokine secretion, decreased responsiveness to LPS challenge with regard to cytokine secretion, and improved ventricular function. These data suggest that HSD mediates cardioprotection after burn trauma, in part, by downregulating cardiomyocyte secretion of inflammatory cytokines.

Animals↗
PubMed2001

Changes in cardiac contractile function and myocardial.

Cutaneous burn trauma causes cardiac contraction and relaxation defects, but the mechanism is unclear. Previous studies suggest that burn-related changes in myocyte handling of calcium may play an important role in postburn cardiac dysfunction. With the use of a high dissociation constant (K(d)) calcium indicator 1,2-bis(2-amino-5,6-difluorophenoxy)-ethane-N,N,N',N'-tetraacetic acid (TF-BAPTA) and (19)F NMR spectroscopy, this study examined the correlation between the changes in cytosolic free calcium concentration ([Ca(2+)](i)) and cardiac function after burn trauma. Sprague-Dawley rats were given scald burn (over 40% of the total body surface area) or sham burn. Twenty-four hours later, the hearts were excised and perfused by the Langendorff method with a modified phosphate-free Krebs-Henseleit bicarbonate buffer. Left ventricular (LV) developed pressure (LVDP), calculated from peak systolic LV pressure and LV end-diastolic pressure, was assessed through a catheter attached to an intraventricular balloon. At the same time, (31)P and (19)F NMR spectroscopy was performed before and after TF-BAPTA loading. LVDP measured in hearts from burned rats was <40% than that measured in hearts from sham burn rats (65 +/- 6 vs. 110 +/- 12 mmHg, P < 0.01); [Ca(2+)](i) was increased fourfold in hearts from the burned group compared with that measured in the sham burn group (0.807 +/- 0.192 vs. 3.891 +/- 0.929 microM). Loading TF-BAPTA in hearts transiently decreased LVDP by 15%. Phosphocreatine-to-P(i) ratio decreased, but ATP and intracellular pH remained unchanged by either TF-BAPTA loading or burn trauma. In conclusion, burn trauma impaired cardiac contractility, and this functional defect was paralleled by a significant rise in [Ca(2+)](i) in the heart.

Adenosine Triphosphate↗
PubMed2001

Role of p38 mitogen-activated protein kinase in cardiac myocyte secretion of the inflammatory cytokine TNF-alpha.

This study examined the hypothesis that burn trauma promotes cardiac myocyte secretion of inflammatory cytokines such as tumor necrosis factor (TNF)-alpha and produces cardiac contractile dysfunction via the p38 mitogen-activated protein kinase (MAPK) pathway. Sprague-Dawley rats were divided into four groups: 1) sham burn rats given anesthesia alone, 2) sham burn rats given the p38 MAPK inhibitor SB203580 (6 mg/kg po, 15 min; 6- and 22-h postburn), 3) rats given third-degree burns over 40% total body surface area and treated with vehicle (1 ml of saline) plus lactated Ringer solution for resuscitation (4 ml x kg(-1). percent burn(-1)), and 4) burn rats given injury and fluid resuscitation plus SB203580. Rats from each group were killed at several times postburn to examine p38 MAPK activity (by Western blot analysis or in vitro kinase assay); myocardial function and myocyte secretion of TNF-alpha were examined at 24-h postburn. These studies showed significant activation of p38 MAPK at 1-, 2-, and 4-h postburn compared with time-matched shams. Burn trauma impaired cardiac mechanical performance and promoted myocyte secretion of TNF-alpha. SB203580 inhibited p38 MAPK activity, reduced myocyte secretion of TNF-alpha, and prevented burn-mediated cardiac deficits. These data suggest p38 MAPK activation is one aspect of the signaling cascade that culminates in postburn secretion of TNF-alpha and contributes to postburn cardiac dysfunction.

Animals↗
PubMed2001

Time course of myocardial sodium accumulation after burn trauma: a (31)P- and (23)Na-NMR study.

In this study, (23)Na- and (31)P- nuclear magnetic resonance (NMR) spectra were examined in perfused rat hearts harvested 1, 2, 4, and 24 h after 40% total body surface area burn trauma and lactated Ringer resuscitation, 4 ml. kg(-1). %(-1) burn. (23)Na-NMR spectroscopy monitored myocardial intracellular Na+ using the paramagnetic shift reagent thulium 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methylenephosphonic acid). Left ventricular function, cardiac high-energy phosphates (ATP/PCr), and myocyte intracellular pH were studied by using (31)P NMR spectroscopy to examine the hypothesis that burn-mediated acidification of cardiomyocytes contributes to subsequent Na+ accumulation by this cell population. Intracellular Na+ accumulation was confirmed by sodium-binding benzofuran isophthalate loading and fluorescence spectroscopy in cardiomyocytes isolated 1, 2, 4, 8, 12, 18, and 24 h postburn. This myocyte Na+ accumulation as early as 2 h postburn occurred despite no changes in cardiac ATP/PCr and intracellular pH. Left ventricular function progressively decreased after burn trauma. Cardiomyocyte Na+ accumulation paralleled cardiac contractile dysfunction, suggesting that myocardial Na+ overload contributes, in part, to the progressive postburn decrease in ventricular performance.

Acidosis↗
PubMed2000

Nitric oxide modulation of TNF-alpha-induced cardiac contractile dysfunction is concentration dependent.

Whereas previous studies suggest that tumor necrosis factor-alpha (TNF-alpha) induces cardiac contraction-relaxation deficits, the mechanisms remain unclear. Our recent studies have implicated cardiac-derived nitric oxide (NO). This study examined the detrimental and protective effects of NO donors S-nitroso-N-acetyl-penicillamine (SNAP) or (Z)-1- [N-(3-ammonio-propyl)-N-(n-propyl)amino]diazen-1-ium- 1,2diolate (PAPA/NO) on TNF-alpha-related changes in cardiac contractile function (Langendorff), cellular injury, and intracellular myocyte Ca(2+) concentration ([Ca(2+)](i)). Myocytes were incubated in the presence/absence of TNF-alpha (200-500 pg/ml x 10(5) cells) for 3 h; subsets of myocytes were incubated with one of several concentrations of SNAP or PAPA/NO (0.1, 0.3, 0.5, and 1.5 mM) for 15 min before TNF-alpha challenge. Supernatant creatine kinase (CK), cell viability (Trypan blue dye exclusion), and myocyte [Ca(2+)](i) (fura 2-acetoxymethyl ester) were measured. In parallel experiments, cardiac function (Langendorff) was examined after TNF-alpha challenge in the presence or absence of SNAP or PAPA/NO (0.1 and 1.5 mM). TNF-alpha in the absence of an NO donor impaired cardiac contraction and relaxation and produced cardiomyocyte injury. Pretreating perfused hearts or isolated cardiomyocytes with a low concentration of either SNAP or PAPA/NO decreased TNF-alpha-mediated cardiac injury and improved contractile dysfunction, whereas high concentrations of NO donor exacerbated TNF-alpha-mediated cardiac effects. These data provide one explanation for the conflicting reports of beneficial versus detrimental effects of NO in the face of inflammation and suggest that the effects of NO on organ function are concentration dependent; low concentrations of NO are cardioprotective, whereas high concentrations of NO are deleterious.

Animals↗
PubMed1999

Cardiovascular effect of 7.5% sodium chloride-dextran infusion after thermal injury.

HYPOTHESIS: Clinical study can help determine the safety and cardiovascular and systemic effects of an early infusion of 7.5% sodium chloride in 6% dextran-70 (hypertonic saline-dextran-70 [HSD]) given as an adjuvant to a standard resuscitation with lactated Ringer (RL) solution following severe thermal injury. DESIGN: Prospective clinical study. SETTING: Intensive care unit of tertiary referral burn care center. PATIENTS: Eighteen patients with thermal injury over more than 35% of the total body surface area (TBSA) (range, 36%-71%) were studied. INTERVENTIONS: Eight patients (mean +/- SEM, 48.2% +/- 2% TBSA) received a 4-mL/kg HSD infusion approximately 3.5 hours (range, 1.5-5.0 hours) after thermal injury in addition to routine RL resuscitation. Ten patients (46.0% +/- 6% TBSA) received RL resuscitation alone. MAIN OUTCOME MEASURES: Pulmonary artery catheters were employed to monitor cardiac function, while hemodynamic, metabolic, and biochemical measurements were taken for 24 hours. RESULTS: Serum troponin I levels, while detectable in all patients, were significantly lower after HSD compared with RL alone (mean +/- SEM, 0.45 +/- 0.32 vs 1.35 +/- 0.35 microg/L at 8 hours, 0.88 +/- 0.55 vs 2.21 +/- 0.35 microg/L at 12 hours). While cardiac output increased proportionately between 4 and 24 hours in both groups (from 5.79 +/- 0.8 to 9.45 +/- 1.1 L/min [mean +/- SEM] for HSD vs from 5.4 +/- 0.4 to 9.46 +/- 1.22 L/min for RL), filling pressure (central venous pressure and pulmonary capillary wedge pressure) remained low for 12 hours after HSD infusion (P = .048). Total fluid requirements at 8 hours (2.76 +/- 0.7 mL/kg per each 1% TBSA burned [mean +/- SEM] for HSD vs 2.67 +/- 0.24 mL/kg per each 1% TBSA burned for RL) and 24 hours (6.11 +/- 4.4 vs 6.76 +/- 0.75 mL/kg per each 1% TBSA burned) were similar. Blood pressure remained unchanged, and serum sodium levels did not exceed 150 +/- 2 mmol/L (mean +/- SD) in either group. CONCLUSIONS: The absence of deleterious hemodynamic or metabolic side effects following HSD infusion in patients with major thermal injury confirms the safety of this resuscitation strategy. Postburn cardiac dysfunction was demonstrated in all burn patients through the use of cardiospecific serum markers and pulmonary artery catheter monitoring. Early administration of HSD after a severe thermal injury may reduce burn-related cardiac dysfunction, but it had no effect on the volume of resuscitation or serum biochemistry values.

Adult↗
PubMed1999

Thermal injury alters myocardial sarcoplasmic reticulum calcium channel function.

BACKGROUND: We have previously shown that a major cutaneous thermal injury produces profound cardiac contractile dysfunction despite adequate resuscitation. While the molecular basis of this dysfunction is unknown, recent work has suggested that alterations in calcium flux between the myocyte sarcoplasmic reticulum (SR) to the cytoplasm may play a role. MATERIALS AND METHODS: To determine if thermal injury-induced contractile dysfunction is related to intracellular calcium transport across the SR membrane, we accessed myocardial microsomal preparations from scalded (43% TBSA) guinea pigs for the ability of the cardiac calcium efflux channel to bind radiolabeled ryanodine. Intracellular calcium flux was assessed by fluorescence spectrophotometry. RESULTS: Thermal injury resulted in severe cardiac contractile deficit characterized by loss of LVP and +/-dP/dt despite resuscitation. Analysis of isolated myocyte cultures showed a twofold increase in cytoplasmic [Ca2+]l by 24 h postburn. Competitive binding and Scatchard analysis demonstrated a single, high-affinity binding site present in both sham and burn animal hearts. Myocardial membrane vesicles revealed a significantly enhanced number of calcium efflux channels in the open configuration at both 8 and 24 h following thermal injury compared to time-matched shams (1.07 +/- 0.01 and 0.95 +/- 0.06 vs 0.85 +/- 0.01 pmol bound/mg protein, P < 0.05). The data indicate that altered function of the myocardial transmembrane SR calcium efflux channel following thermal injury was associated with elevated [Ca2+]l and contractile dysfunction. CONCLUSIONS: We conclude that postburn cardiac dysfunction may partly be a result of elevated cytoplasmic calcium concentrations and diminished regulation of SR calcium efflux channel activity.

Animals↗
PubMed1999

Calcium antagonists improve cardiac mechanical performance after thermal trauma.

Burn trauma initiates a pathophysiologic cascade, which includes cardiac dysfunction and intramyocyte calcium accumulation. This study examined the hypothesis that therapeutic interventions which limit intracellular cardiac Ca(2+) accumulation after burn trauma will improve cardiac function. Guinea pigs were anesthetized (methoxyflurane), burned over 43% of total body surface area, and fluid resuscitated (FR) for 24 h. Burn guinea pigs were randomly divided into three groups: Group 1, FR alone, Group 2, FR plus dantrolene (10 mg/kg body wt, IV, 30 min, 8 and 22 h postburn), a drug which inhibits the Ca(2+) release channel (ryanodine receptor) of the cardiac sarcoplasmic reticulum, and Group 3, FR plus diltiazem (0.20-0.22 mg/kg given IV as a slow infusion over 6 h postburn), a drug which specifically blocks Ca(2+) slow channels; sham burn guinea pigs were given vehicle (Group 4), dantrolene (Group 5), or diltiazem (Group 6) as described above (respective controls). Cardiac dysfunction was impaired in fluid-treated burns (Group 1) compared to sham burns (Group 4) as indicated by reduced developed left ventricular pressure (LVP) (86 +/- 2 vs 52 +/- 3 mm Hg, P < 0.05), rate of LVP rise, (+dP/dt max, 1379 +/- 64 vs 909 +/- 44 mm Hg/s, P < 0.05), and LVP fall (-dP/dt max, 1184 +/- 31 vs 881 +/- 40 mm Hg/s, P < 0.05), and time to peak pressure (110 +/- 2 vs 102 +/- 2 ms, P < 0.05). In addition, [Ca(2+)](i) rose in cardiomyocytes harvested from fluid-treated burns (Group 1, 307 +/- 29 nM) compared to vehicle-treated controls (Group 4, 152 +/- 6 nM, P < 0.05). Neither calcium antagonist altered ventricular function or [Ca(2+)](i) in sham burns (Groups 5 and 6). In contrast, antagonists given after burn injury reduced cardiomyocyte [Ca(2+)](i) (Group 2, dantrolene-treated burns: 196 +/- 8 nM, and Group 3, diltiazem treated burns: 216 +/- 8 nM) and improved cardiac performance compared to that measured in burns given FR alone. Our data suggest that calcium antagonists given after burn trauma restored intracellular Ca(2+) homeostasis, decreased cardiac cell injury, and improved cardiac contractile function.

Animals↗
PubMed1999

Major burn trauma in rats promotes cardiac and gastrointestinal apoptosis.

The hypothesis that cardiac functional abnormalities that occur after major burn trauma are paralleled by an increased incidence of apoptosis in cardiac myocytes was examined. Adult Sprague-Dawley rats were given a full thickness scald burn comprising 43+/-1% of the total body surface area or were manipulated identically but not exposed to burn injury (sham burn); burned rats were fluid resuscitated with lactated Ringer's solution. Tissues from burn and sham burn animals were then examined by the TUNEL (TdT-mediated dUTP nick end labeling) assay and light microscopy to determine the presence of apoptosis 24 and 48 h after burn trauma. In parallel, the mechanical function of the heart was assayed in separate groups of rats. Tissues harvested from the hearts of sham-treated animals showed essentially no apoptosis, whereas a small number of apoptotic cells were noted in the intestinal villi and liver of sham-treated animals. Twenty-four hours after burn trauma, there was a marked increase in apoptotic cells in the left ventricle (+916%), and the number of apoptotic cells remained increased by eightfold 48 h postburn. Apoptosis was noted predominately in the subendocardial tissue of the left ventricle. The appearance of apoptotic cells was paralleled by a decrease in cardiac mechanical function with significant decreases in left ventricular pressure and +/-dP/dt(max). Burn injury also increased apoptosis in the small intestine significantly, whereas apoptosis in the liver did not increase with burn trauma. These data suggest that the apoptosis of the cardiac myocytes that occurs after burn trauma may contribute, in part, to postburn cardiac mechanical dysfunction.

Animals↗
PubMed1999

Cardiac responses to burn injury in young and adult guinea pigs.

The present study examined functional and biochemical differences in young compared to adult hearts, and determined if developmental differences altered the ability of the young heart to respond to burn injury. Compared to the adult heart, hearts from young sham burns had diminished responsiveness to isoproterenol, extracellular calcium, and increases in either ventricular filling or coronary flow rate. In contrast, there were no age-related differences in maximal calcium uptake (360+/-11 vs. 367+/-14 nmol/mg) or calcium uptake velocity (59+/-2 vs. 60+/-4 nmol/mg/min) in sarcoplasmic reticulum (SR) vesicles isolated from adult and compared to young control hearts. Burn injury (43% TBSA for adults, 35% TBSA for young) impaired myocardial function in all hearts, regardless of age. Age-related differences in adult and young hearts persisted after burn trauma with significantly lower left ventricular developed pressure (49+/-2 vs. 63 +/-3 mmHg, P < 0.01), +dP/dt max (860+/-89 vs. 1151+/-62 mmHg/sec, P < 0.01), and -dP/dt max (790+/-39 vs. 901+/-50 mmHg/sec, P < 0.02) in young vs. adult burn hearts. Burn injury reduced cardiac SR maximal calcium uptake in adults (sham, 360+/-11; burn, 298+/-12 nmol/mg, P < 0.05), but not in young hearts (sham, 367+/-14; burn, 380+/-12 nmol/mg); however, burn trauma increased the SR calcium velocity/capacity ratio in both young and adult burn groups. Our data confirm age-related differences in ventricular performance in young and adult guinea pigs; these differences persisted after burn trauma. The burn-mediated changes in SR Ca2+ transport suggest that disturbances in intracellular calcium handling may contribute, in part, to post-burn cardiac contractile deficits regardless of age.

Aging↗