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1.
Am J Transplant ; 15(1): 44-54, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25534445

ABSTRACT

Ensuring equitable and fair organ allocation is a central charge of the United Network for Organ Sharing (UNOS) as the Organ Procurement and Transplantation Network (OPTN) through its contract with the Department of Health and Human Services (DHHS). The OPTN/UNOS Board initiated a reassessment of the current allocation system. This paper describes the efforts of the OPTN/UNOS Heart Subcommittee, acting on behalf of the OPTN/UNOS Thoracic Organ Transplantation Committee, to modify the current allocation system. The Subcommittee assessed the limitations of the current three-tiered system, outcomes of patients with status exceptions, emerging ventricular assist device (VAD) population, options for improved geographic sharing and status of potentially disenfranchised groups. They analyzed waiting list and posttransplant mortality rates of a contemporary cohort of patient groups at risk, in collaboration with the Scientific Registry of Transplant Recipients to develop a proposed multi-tiered allocation scheme. This proposal provides a framework for simulation modeling to project whether candidates would have better waitlist survival in the revised allocation system, and whether posttransplant survival would remain stable. The tiers are subject to change, based on further analysis by the Heart Subcommittee and will lead to the development of a more effective and equitable heart allocation system.


Subject(s)
Health Care Rationing , Heart Diseases/surgery , Heart Transplantation , Resource Allocation , Tissue and Organ Procurement , Adult , Directed Tissue Donation , Humans , United States , Waiting Lists
2.
Arch Surg ; 136(11): 1263-6, 2001 Nov.
Article in English | MEDLINE | ID: mdl-11695970

ABSTRACT

The initial discovery of cardiac preconditioning has evolved into an exciting series of practical surgical applications. An enormous amount of evidence demonstrating both the safety and efficacy of ischemic preconditioning is available from animal studies. The challenging premise of intentionally subjecting patients and their organs to transient ischemia has acted as a formidable psychological and ethical impediment to the widespread clinical application of organ preconditioning. A more palatable alternative to ischemic preconditioning now involves approved medications designed to manipulate the cellular machinery mediating ischemic preconditioning. Pharmacologically induced preconditioning seems to confer equal organ protection. The relatively brief (but surgically relevant) window of protection provided by strategies such as ischemic preconditioning or adenosine agonists and potassium-adenosine triphosphate channel openers may, in the future, be extended. We have developed and reported the feasibility of liposomal delivery of heat shock protein to cardiac myocytes with subsequent protection against sepsis-induced dysfunction. Targeted strategies will ultimately broaden the therapeutic potential of organ preconditioning.


Subject(s)
Ischemic Preconditioning , Animals , Humans , Ischemic Preconditioning, Myocardial , Organ Transplantation , Plastic Surgery Procedures , Vascular Surgical Procedures
3.
Ann Thorac Surg ; 72(4): 1282-8; discussion 1288-9, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11603449

ABSTRACT

BACKGROUND: The purpose of this study was to determine whether coronary artery bypass grafting without cardiopulmonary bypass (off-pump CABG) decreases risk-adjusted operative death and major complications after coronary artery bypass grafting in selected patients. METHODS: Using The Society of Thoracic Surgeons (STS) National Adult Cardiac Surgery Database, procedural outcomes were compared for conventional and off-pump CABG procedures from January 1, 1998, through December 31, 1999. Mortality and major complications were examined, both as unadjusted rates and after adjusting for known base line patient risk factors. RESULTS: A total of 126 experienced centers performed 118,140 total CABG procedures. The number of off-pump CABG cases was 11,717 cases (9.9% of total cases). The use of an off-pump procedure was associated with a decrease in risk-adjusted operative mortality from 2.9% with conventional CABG to 2.3% in the off-pump group (p < 0.001). The use of an off-pump procedure decreased the risk-adjusted major complication rate from 14.15% with conventional CABG to 10.62% in the off-pump group (p < 0.0001). Patients receiving off-pump procedures were less likely to die (adjusted odds ratio 0.81, 95% CI 0.70 to 0.91) and less likely to have major complications (adjusted odds ratio 0.77, 95% CI 0.72 to 0.82). CONCLUSIONS: Off-pump CABG is associated with decreased mortality and morbidity after coronary artery bypass grafting. Off-pump CABG may prove superior to conventional CABG in appropriately selected patients.


Subject(s)
Cardiopulmonary Bypass , Coronary Artery Bypass , Coronary Disease/surgery , Postoperative Complications/mortality , Aged , Coronary Disease/mortality , Female , Follow-Up Studies , Hospital Mortality , Humans , Male , Middle Aged , Risk , Survival Rate
4.
Ann Surg ; 234(4): 464-72; discussion 472-4, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11573040

ABSTRACT

OBJECTIVE: To review the Department of Veteran Affairs (VA) and the Society of Thoracic Surgeons (STS) national databases over the past 10 years to evaluate their relative similarities and differences, to appraise their use as quality improvement tools, and to assess their potential to facilitate improvements in quality of cardiac surgical care. SUMMARY BACKGROUND DATA: The VA developed a mandatory risk-adjusted database in 1987 to monitor outcomes of cardiac surgery at all VA medical centers. In 1989 the STS developed a voluntary risk-adjusted database to help members assess quality and outcomes in their individual programs and to facilitate improvements in quality of care. METHODS: A short data form on every veteran operated on at each VA medical center is completed and transmitted electronically for analysis of unadjusted and risk-adjusted death and complications, as well as length of stay. Masked, confidential semiannual reports are then distributed to each program's clinical team and the associated administrator. These reports are also reviewed by a national quality oversight committee. Thus, VA data are used both locally for quality improvement and at the national level with quality surveillance. The STS dataset (217 core fields and 255 extended fields) is transmitted for each patient semiannually to the Duke Clinical Research Institute (DCRI) for warehousing, analysis, and distribution. Site-specific reports are produced with regional and national aggregate comparisons for unadjusted and adjusted surgical deaths and complications, as well as length of stay for coronary artery bypass grafting (CABG), valvular procedures, and valvular/CABG procedures. Both databases use the logistic regression modeling approach. Data for key processes of care are also captured in both databases. Research projects are frequently carried out using each database. RESULTS: More than 74,000 and 1.6 million cardiac surgical patients have been entered into the VA and STS databases, respectively. Risk factors that predict surgical death for CABG are very similar in the two databases, as are the odds ratios for most of the risk factors. One major difference is that the VA is 99% male, the STS 71% male. Both databases have shown a significant reduction in the risk-adjusted surgical death rate during the past decade despite the fact that patients have presented with an increased risk factor profile. The ratio of observed to expected deaths decreased from 1.05 to 0.9 for the VA and from 1.5 to 0.9 for the STS. CONCLUSION: It appears that the routine feedback of risk-adjusted data on local performance provided by these programs heightens awareness and leads to self-examination and self-assessment, which in turn improves quality and outcomes. This general quality improvement template should be considered for application in other settings beyond cardiac surgery.


Subject(s)
Cardiac Surgical Procedures/mortality , Cardiac Surgical Procedures/standards , Heart Diseases/mortality , Heart Diseases/surgery , Quality Assurance, Health Care , Thoracic Surgery/standards , Databases, Factual , Female , Heart Diseases/diagnosis , Hospitals, Veterans , Humans , Male , Odds Ratio , Registries , Risk Assessment , Sensitivity and Specificity , Societies, Medical , Survival Analysis , Thoracic Surgery/trends , Treatment Outcome , United States
5.
Ann Thorac Surg ; 72(1): 114-9, 2001 Jul.
Article in English | MEDLINE | ID: mdl-11465163

ABSTRACT

BACKGROUND: The impact of off-pump median sternotomy coronary artery bypass grafting procedures on risk-adjusted mortality and morbidity was evaluated versus on-pump procedures. METHODS: Using the Department of Veterans Affairs Continuous Improvement in Cardiac Surgery Program records from October 1997 through March 1999, nine centers were designated as having experience (with at least 8% coronary artery bypass grafting procedures performed off-pump). Using all other 34 Veterans Affairs cardiac surgery programs, baseline logistic regression models were built to predict risk of 30-day operative mortality and morbidity. These models were then used to predict outcomes for patients at the nine study centers. A final model evaluated the impact of the off-pump approach within these nine centers adjusting for preoperative risk. RESULTS: Patients treated off-pump (n = 680) versus on-pump (n = 1,733) had lower complication rates (8.8% versus 14.0%) and lower mortality (2.7% versus 4.0%). Risk-adjusted morbidity and mortality were also improved for these patients (0.52 and 0.56 multivariable odds ratios for off-pump versus on-pump, respectively, p < 0.05). CONCLUSIONS: An off-pump approach for coronary artery bypass grafting procedures is associated with lower risk-adjusted morbidity and mortality.


Subject(s)
Cardiopulmonary Bypass , Coronary Artery Bypass , Coronary Disease/surgery , Minimally Invasive Surgical Procedures , Angina Pectoris/mortality , Angina Pectoris/surgery , Coronary Disease/mortality , Heart Failure/mortality , Heart Failure/surgery , Hospital Mortality , Hospitals, Veterans , Humans , Postoperative Complications/mortality , Risk , Survival Analysis
7.
J Thorac Cardiovasc Surg ; 121(3): 448-53, 2001 Mar.
Article in English | MEDLINE | ID: mdl-11241079

ABSTRACT

OBJECTIVES: Mycobacterium tuberculosis continues to be a major cause of morbidity and mortality throughout the world. Complacency by the medical profession and by patients has caused a new strain of Mycobacterium tuberculosis to emerge that is highly resistant to current antibiotics. The possibility of a new worldwide epidemic of drug-resistant Mycobacterium tuberculosis is of concern. Optimal therapy for patients infected with multi-drug resistant tuberculosis often requires surgical intervention to eradicate the infection. We report on our experience with pulmonary resection for multi-drug resistant tuberculosis. METHODS: During a 17-year period, 172 patients underwent 180 pulmonary resections. All patients had multi-drug resistant tuberculosis and had a minimum of 3 months of medical therapy before surgery. Muscle flaps were frequently used to avoid residual space and bronchial stump problems. RESULTS: During the study period, 98 lobectomies and 82 pneumonectomies were performed. Eight patients underwent multiple procedures. Operative mortality was 3.3% (6/180). Three patients died of respiratory failure, 2 patients died of a cerebrovascular accident, and 1 patient had a myocardial infarction. Late mortality was 6.8% (11/166). Significant morbidity was 12% (20/166). One half (91) of the patients had positive sputum at the time of surgery. After the operation, the sputum remained positive in only 4 (2%) patients. Mean length of follow-up was 7.6 years (range 4-204 months). CONCLUSIONS: Surgery remains an important adjunct to medical therapy for the treatment of multi-drug resistant Mycobacterium tuberculosis. In the setting of localized disease, persistent sputum positivity, or patient intolerance of medical therapy, pulmonary resection should be undertaken. Pulmonary resection for multi-drug resistant tuberculosis can be performed with acceptable operative morbidity and mortality.


Subject(s)
Pneumonectomy , Tuberculosis, Multidrug-Resistant/surgery , Tuberculosis, Pulmonary/surgery , Adolescent , Child , Child, Preschool , Female , Humans , Infant , Male , Postoperative Complications , Retrospective Studies
9.
J Surg Res ; 90(2): 191-6, 2000 May 15.
Article in English | MEDLINE | ID: mdl-10792962

ABSTRACT

INTRODUCTION: Consistently, clinical series record supraventricular tachyarrhythmias in approximately 30% of patients following coronary artery bypass surgery (CABG). Ischemic preconditioning and adenosine preconditioning (Ado-PC) decrease postischemia/reperfusion (I/R) myocardial stunning, infarct size, and pharmacologically induced arrhythmias in all species including man. We hypothesized that adenosine preconditioning would decrease spontaneous pre- and postischemic atrial arrhythmias in human myocardium. The purposes of this study were to determine the effect of in vivo and in vitro Ado-PC on atrial arrhythmias. METHODS: Human atrial trabeculae were harvested from CABG patients, placed in organ baths, and paced (1 Hz). Developed force (DF) was recorded during simulated I/R (30/45 min). Prior to I/R, trabeculae were treated with Ado (125 microM) for 5 min (in vitro), or patients were treated with Ado (12 mg iv) 5 min (in vivo) prior to harvest of trabeculae. Contraction frequency >4 Hz (defined as atrial tachyarrhythmias) was recorded in all groups pre- and postischemia. RESULTS: Control trabeculae exhibited increased tachyarrhythmias pre- and postischemia. In vivo and in vitro Ado-PC suppressed both pre- and postischemic arrhythmias. CONCLUSIONS: Adenosine preconditioning suppresses the frequency of pre- and postischemic tachyarrhythmias against an ischemia/reperfusion insult in human myocardium. This antiarrhythmic effect occurs with both in vitro and in vivo administration of adenosine. Preconditioning with adenosine prior to elective ischemia/reperfusion is a promising strategy of reducing spontaneous atrial arrhythmias in patients undergoing myocardial revascularization.


Subject(s)
Adenosine/administration & dosage , Anti-Arrhythmia Agents/administration & dosage , Coronary Artery Bypass , Ischemic Preconditioning, Myocardial , Myocardial Ischemia/drug therapy , Tachycardia, Supraventricular/drug therapy , Electrocardiography , Humans , In Vitro Techniques , Myocardial Contraction , Myocardial Ischemia/surgery , Myocardial Reperfusion Injury/drug therapy , Myocardial Reperfusion Injury/surgery , Tachycardia, Supraventricular/diagnosis
11.
J Surg Res ; 89(1): 7-12, 2000 Mar.
Article in English | MEDLINE | ID: mdl-10720446

ABSTRACT

Myocardial stress can result in myocellular phenotypic changes including enhanced activity of antioxidant enzyme systems. Accordingly, endogenous tissue antioxidant enzyme activity has been associated with resistance to cardiac ischemia and reperfusion injury. The present study was designed to determine if environmental perturbations could alter myocardial antioxidant enzyme (catalase) activity and function after ischemia. Isolated perfused rat hearts (Langendorff apparatus, 37 degrees C) were subjected to 20 min global ischemia (37 degrees C) and 40 min reperfusion. Rats studied immediately following shipment had increased myocardial catalase activity (1330 +/- 3.5 U/g, P < 0.05 vs quarantined control) and increased resistance to ischemia and reperfusion injury (end reperfusion developed pressure, DP 55 +/- 4.0 mm Hg, P < 0.05 vs quarantined control). However, control rats that were quarantined for 4 weeks exhibited a progressive decrease in catalase activity (760 +/- 10 U/g) for 3 weeks of quarantine. There was a concurrent decrease in resistance to myocardial ischemia and reperfusion injury (DP 40 +/- 3.6 mm Hg). Similarly, quarantined rats subjected to construction-related noise levels in excess of 90 dB (A scale) had increased myocardial catalase activity (1140 +/- 3.3 U/g, P < 0.05) and functional tolerance to ischemia and reperfusion (DP 66 +/- 3.3 mm Hg, P < 0.05). Finally, rats experiencing 90-dB noise levels for 2 days exhibited increased myocardial catalase activity (1125 +/- 30 U/g, P < 0.05) and myocardial ischemia and reperfusion injury tolerance (DP 62 +/- 1.7 mm Hg, P < 0.05). We conclude that variations in environmental conditions can relate to changes in antioxidant defense mechanisms and tolerance to myocardial ischemia and reperfusion injury in the rat.


Subject(s)
Adaptation, Physiological , Myocardial Ischemia/physiopathology , Myocardial Reperfusion Injury/physiopathology , Noise , Transportation , Animals , Catalase/metabolism , Diastole , Male , Myocardium/enzymology , Pressure , Quarantine , Rats , Rats, Sprague-Dawley , Reference Values , Time Factors , Ventricular Function, Left
12.
J Surg Res ; 85(1): 77-82, 1999 Jul.
Article in English | MEDLINE | ID: mdl-10383841

ABSTRACT

BACKGROUND: Recent evidence has implicated the KATP channel as an important mediator of ischemic preconditioning (IPC). Indeed, patients taking oral sulfonylurea hypoglycemic agents (i.e., KATP channel inhibitors) for treatment of diabetes mellitus are resistant to the otherwise profoundly protective effects of IPC. Unfortunately, many cardiopulmonary bypass patients, who may benefit from IPC, are chronically exposed to these agents. Calcium preconditioning (CPC) is a potent form of similar myocardial protection which may or may not utilize the KATP channel in its mechanism of protection. The purpose of this study was to determine whether CPC may bypass the KATP channel in its mechanism of action. If so, CPC may offer an alternative to IPC in patients chronically exposed to these agents. METHODS: Isolated rat hearts (n = 6-8/group) were perfused (Langendorff) and received KATP channel inhibition (glibenclamide) or saline vehicle 10 min prior to either a CPC or IPC preconditioning stimulus or neither (ischemia and reperfusion, I/R). Hearts were subjected to global warm I/R (20 min/40 min). Postischemic myocardial functional recovery was determined by measuring developed pressure (DP), coronary flow (CF), and compliance (end diastolic pressure, EDP) with a MacLab pressure digitizer. RESULTS: Both CPC and IPC stimuli protected myocardium against postischemic dysfunction (P < 0.05 vs I/R; ANOVA with Bonferroni/Dunn): DP increased from 52 +/- 4 (I/R) to 79 +/- 2 and 83 +/- 4 mmHg; CF increased from 11 +/- 0.7 to 17 +/- 2 and 16 +/- 1 ml/min; and EDP decreased (compliance improved) from 50 +/- 7 to 27 +/- 5 and 31 +/- 7 mmHg. However, KATP channel inhibition abolished protection in hearts preconditioned with IPC (P < 0.05 vs IPC alone), but not in those preconditioned with CPC (P > 0.05 vs CPC alone). CONCLUSIONS: (1) Both IPC and CPC provide similar myocardial protection; (2) IPC and CPC operate via different mechanisms; i.e., IPC utilizes the KATP channel whereas CPC does not; and (3) CPC may offer a means of bypassing the deleterious effects of KATP channel inhibition in diabetic patients chronically exposed to oral sulfonylurea hypoglycemic agents.


Subject(s)
Adenosine Triphosphate/physiology , Calcium/pharmacology , Conditioning, Psychological , Ischemic Preconditioning, Myocardial , Potassium Channels/metabolism , Animals , Conditioning, Psychological/physiology , Heart/physiopathology , In Vitro Techniques , Ischemia/physiopathology , Male , Pressure , Rats , Rats, Sprague-Dawley
13.
J Mol Cell Cardiol ; 31(12): 2191-7, 1999 Dec.
Article in English | MEDLINE | ID: mdl-10640446

ABSTRACT

Although Ca(2+) channel blockers are commonly used to control both blood pressure and angina in patients with coronary artery disease, clinical trials have associated the use of L-type Ca(2+) channel blockers with increased cardiovascular mortality. Recent evidence has implicated Ca(2+) entry through the L-type Ca(2+) channel during transient ischemia as a proximal stimulus for ischemic preconditioning (IPC) in experimental animals. We therefore hypothesized that clinical L-type Ca(2+) channel blockade prevents IPC in human myocardium. Human atrial trabeculae were suspended in organ baths, field simulated at 1 Hz, and force development was recorded. Following 90 min equilibration, trabeculae from control patients and patients taking L-type Ca(2+) channel blockers were subjected to simulated ischemia/reperfusion (I/R: 45/120 min) with or without 5 min of simulated ischemia (IPC stimulus) prior to I/R. IPC increased post-ischemic developed force in control patients from 14.6+/-2.6 to 43.1+/-3.5% baseline developed force (%BDF P<0.05 I/R vs IPC). Whereas IPC failed to increase post-ischemic developed force in myocardium from patients taking L-type Ca(2+) channel blockers (15. 1+/-1.9 vs 16.6+/-1.7 %BDF, P>0.05 L-type I/R v L-type IPC). We conclude that: (1) atrial muscle can be preconditioned by transient ischemia; (2) atrial muscle from patients taking L-type Ca(2+) channel blockers cannot be preconditioned by transient ischemia; and (3) the increased cardiovascular mortality historically associated with the use of Ca(2) channel blockers in patients with coronary artery disease may be, in part, due to the pharmacological inhibition of ischemic preconditioning.


Subject(s)
Calcium Channel Blockers/pharmacology , Calcium Channels/physiology , Coronary Disease/physiopathology , Ischemic Preconditioning, Myocardial , Aged , Calcium Channel Blockers/therapeutic use , Clinical Trials as Topic , Coronary Disease/drug therapy , Female , Humans , Male , Middle Aged
14.
Circulation ; 98(19 Suppl): II214-8; discussion II218-9, 1998 Nov 10.
Article in English | MEDLINE | ID: mdl-9852905

ABSTRACT

BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) is an autocrine contributor to myocardial dysfunction and cardiomyocyte death in ischemia-reperfusion (I/R) injury, sepsis, chronic heart failure, and cardiac allograft rejection. Cardiac resident macrophages, infiltrating leukocytes, and cardiomyocytes themselves produce TNF-alpha. Although adenosine reduces macrophage TNF-alpha production and protects myocardium against I/R, it remains unknown whether ischemic preconditioning, which is mediated by adenosine, decreases postischemic myocardial TNF-alpha production. METHODS AND RESULTS: Isolated rat hearts were crystalloid perfused with the Langendorff method and subjected to global, normothermic I/R (20/40 minutes), with or without prior transient ischemic preconditioning (5 minutes) or adenosine pretreatment. Postischemic cardiac TNF-alpha (ELISA) and function were determined (Langendorff). I/R increased cardiac TNF-alpha and impaired myocardial function. Ischemic preconditioning or adenosine decreased myocardial TNF-alpha and improved postischemic functional recovery. Sequestration of myocardial TNF-alpha (TNF binding protein) during the I/R experiments similarly improved postischemic myocardial function. CONCLUSIONS: This study constitutes the initial demonstration that in addition to its other beneficial effects, preconditioning decreases postischemic myocardial TNF-alpha, an autocrine contributor to postischemic myocardial dysfunction. Reduced myocardial TNF-alpha production may represent the distal effector mechanism of preconditioning.


Subject(s)
Ischemic Preconditioning, Myocardial , Myocardial Ischemia/metabolism , Myocardium/metabolism , Tumor Necrosis Factor-alpha/biosynthesis , Animals , Heart/physiopathology , In Vitro Techniques , Male , Myocardial Ischemia/physiopathology , Rats , Rats, Sprague-Dawley
15.
Am J Physiol ; 275(3): H805-13, 1998 09.
Article in English | MEDLINE | ID: mdl-9724283

ABSTRACT

Ischemic preconditioning (PC) attenuates cardiac acidosis during global ischemia. This adaptation to ischemia is detectable before other better known indexes of PC are manifested. Clarification of the endogenous mechanisms may provide insights into how protein kinase C (PKC) signaling might be linked to altered intracellular biochemistry. 31P NMR studies of isolated, buffer-perfused rat heart were performed to determine whether functionally cardioprotective PC by cyclic ischemia (CI) and alpha1-adrenergic stimuli [phenylephrine (PE)] attenuated acidosis during ischemia and, if so, whether this 1) involves a PKC-dependent pathway and is due to 2) decreased glycolytic proton production, 3) an increase in proton buffering, or 4) proton extrusion. At the end of 20 min of global ischemia, both CI-PC (pH = 6.86 +/- 0.14) and PE-PC (pH = 6.90 +/- 0.13) attenuated end-ischemic acidosis (control pH = 6.54 +/- 0.1). PKC blockade with chelerythrine (Chel) prevented the attenuation of ischemic acidosis by PC stimuli (end-ischemic pH: CI + Chel, 6.43 +/- 0.06; PE + Chel, 6.17 +/- 0.17). End-ischemic lactate accumulation was decreased in CI-PC hearts (7.54 +/- 0.5 vs. control, 14.61 +/- 2.1 micromol/g wet wt) but not in those preconditioned through the alpha1-adrenergic receptor (12.25 +/- 0.9 micromol/g wet wt). Physiologically relevant buffers were not increased in the preconditioned groups. Blockade of the Na+/H+ exchanger [NHE; with 5-(N-ethyl-N-isopropyl) amiloride (EIPA) or HOE-694] eliminated the attenuation of ischemic acidosis seen with PC stimuli (pH: CI + EIPA, 6.5 +/- 0.1; PE + EIPA, 6.46 +/- 0.2; PE + HOE-694, 6.26 +/- 0.15; not significantly different from control). We conclude that CI and alpha1-adrenergic PC stimuli attenuate ischemic acidosis, and this may involve the cardiac amiloride-sensitive NHE. The signaling pathways of both these two stimuli appear to involve PKC.


Subject(s)
Acidosis/prevention & control , Ischemic Preconditioning, Myocardial , Myocardial Ischemia/complications , Protein Kinase C/physiology , Sodium-Hydrogen Exchangers/physiology , Acidosis/etiology , Adenosine Triphosphate/metabolism , Adrenergic alpha-Agonists/pharmacology , Amiloride/analogs & derivatives , Amiloride/pharmacology , Animals , Guanidines/pharmacology , Hydrogen-Ion Concentration , Kinetics , Male , Phenylephrine/pharmacology , Phosphates/metabolism , Rats , Rats, Sprague-Dawley , Signal Transduction , Sodium-Hydrogen Exchangers/antagonists & inhibitors , Sulfones/pharmacology
16.
Surgery ; 124(2): 291-6; discussion 297, 1998 Aug.
Article in English | MEDLINE | ID: mdl-9706151

ABSTRACT

BACKGROUND: Oxidant stress caused by ischemia or endotoxemia induces myocardial dysfunction and cardiomyocyte death; however, mechanisms responsible remain unknown. We hypothesized that hydrogen peroxide (H2O2) induces myocardial dysfunction and cardiomyocyte death via P38 mitogen-activated protein kinase (MAPK)-mediated myocardial tumor necrosis factor (TNF) production. METHODS: Langendorff perfused rat hearts (6/group) were subjected to oxidant stress (H2O2 infusion; 300 mmol/L x 80 minutes), with and without prior infusion of a specific P38 kinase MAPK inhibitor (P38i = 1 mmol/L/min x 5 minutes) or TNF neutralization (20 mg TNF binding protein (BP)/min x 80 minutes). Developed pressure (DP), coronary flow, and end-diastolic pressure were continuously recorded. Myocardial creatine kinase (CK) loss was measured in the coronary effluent, and tissue TNF was measured in myocardial homogenates. RESULTS: Eighty minutes of H2O2 infusion induced a 6.5-fold increase in myocardial TNF production, which was associated with a 70% decrease in DP and increase in CK loss. P38 MAPK inhibition or TNF-BP decreased myocardial TNF production, cardiomyocyte death, and myocardial dysfunction. CONCLUSIONS: These results demonstrate that H2O2 alone induces myocardial TNF production. P38 MPAK is an oxidant-sensitive enzyme that mediates oxidant-induced myocardial TNF production, cardiac dysfunction, and cardiomyocyte death.


Subject(s)
Calcium-Calmodulin-Dependent Protein Kinases/metabolism , Heart Diseases/metabolism , Hydrogen Peroxide/pharmacology , Mitogen-Activated Protein Kinases , Oxidants/pharmacology , Tumor Necrosis Factor-alpha/metabolism , Animals , Creatine Kinase/metabolism , Enzyme Activation/drug effects , Heart Diseases/chemically induced , Male , Myocardium/chemistry , Myocardium/enzymology , Oxidative Stress/physiology , Rats , Rats, Sprague-Dawley , Ventricular Function, Left , p38 Mitogen-Activated Protein Kinases
17.
J Am Coll Cardiol ; 32(2): 458-67, 1998 Aug.
Article in English | MEDLINE | ID: mdl-9708476

ABSTRACT

OBJECTIVES: This study sought to characterize functional impairment after simulated ischemia-reperfusion (I/R) or Ca2+ bolus in senescent human myocardium and to determine if age-related alterations in myocardial concentrations of SERCA2a, phospholamban, or calsequestrin participate in senescent myocardial dysfunction. BACKGROUND: Candidates for elective cardiac interventions are aging, and an association between age and impairment of relaxation has been reported in experimental animals. Function of the sarcoplasmic reticulum resulting in diastolic dysfunction could be dysregulated at the level of cytosolic Ca2+ uptake by SERCA2a, its inhibitory subunit (phospholamban), or at the level of Ca2+ binding by calsequestrin. METHODS: Human atrial trabeculae from 17 patients (45-75 years old) were suspended in organ baths, field simulated at 1 Hz, and force development was recorded during I/R (45/120 min). Trabeculae from an additional 12 patients (53-73 years old) were exposed to Ca2+ bolus (2-3 mmol/L bath concentration). Maximum +/- dF/dt and the time constant of force decay (tau) were measured before and after I/R or Ca2+ bolus and related to age. SERCA2a, phospholamban, and calsequestrin from 12 patients (39-77 years old) were assessed by immunoblot. RESULTS: Functional results indicated that maximum +/-dF/dt and tau were prolonged in senescent (>60 years) human myocardium after I/R (p < 0.05). Calcium bolus increased the maximum +/-dF/dt and decreased tau in younger, but not older patients (p < 0.05). SERCA2a and the ratio of SERCA2a to either phospholamban or calsequestrin were decreased in senescent human myocardium (p < 0.05). CONCLUSIONS: Senescent human myocardium exhibits decreased myocardial SERCA2a content with age, which may, in part, explain impaired myocardial function after either I/R or Ca2+ exposure.


Subject(s)
Aging/metabolism , Calcium-Transporting ATPases/analysis , Myocardium/chemistry , Sarcoplasmic Reticulum/enzymology , Adult , Aged , Analysis of Variance , Blotting, Western , Calcium/administration & dosage , Calcium/metabolism , Calcium/pharmacology , Calcium-Binding Proteins/analysis , Calsequestrin/analysis , Cohort Studies , Cytosol/metabolism , Diastole/physiology , Dose-Response Relationship, Drug , Female , Heart Atria , Humans , Linear Models , Male , Middle Aged , Myocardial Contraction/physiology , Myocardial Ischemia/metabolism , Myocardial Reperfusion , Myocardium/enzymology , Myocardium/metabolism
18.
Ann Thorac Surg ; 65(2): 439-43, 1998 Feb.
Article in English | MEDLINE | ID: mdl-9485242

ABSTRACT

BACKGROUND: The heart is a tumor necrosis factor-alpha (TNF-alpha)-producing organ. Recent basic experimental and clinical evidence suggests that TNF-alpha is an important mediator of myocardial injury during acute myocardial infarction, chronic heart failure, cardiac allograft rejection, and cardiopulmonary bypass operations. Although it is known that the myocardium itself is capable of producing TNF-alpha in response to endotoxin, it is unknown whether there is an increase in myocardial tissue TNF-alpha levels after ischemia-reperfusion injury. We hypothesized that ischemia-reperfusion induces the production of TNF-alpha by the heart. METHODS: To avoid blood-borne TNF-alpha as a potentially confounding variable, we examined myocardial TNF-alpha production in a crystalloid-perfused model of cardiac ischemia-reperfusion injury. Isolated rat hearts were perfused with crystalloid solution and subjected to ischemia-reperfusion. Postischemic myocardial TNF-alpha was measured using an enzyme-linked immunosorbent assay and correlated with developed pressure, coronary flow, end-diastolic pressure, and creatine kinase loss (assay of activity in coronary effluent). RESULTS: Ischemia-reperfusion induced a marked increase in myocardial TNF-alpha that was associated with decreased myocardial contractility and coronary flow and with increased end-diastolic pressure and postischemic creatine kinase loss. CONCLUSIONS: The heart produces TNF-alpha in response to ischemia-reperfusion. Ischemia-induced TNF-alpha production may contribute to postischemic myocardial stunning, necrosis, or both. Strategies designed to limit ischemia-induced myocardial TNF-alpha production may have therapeutic utility in the settings of planned myocardial ischemic events.


Subject(s)
Myocardial Reperfusion Injury/metabolism , Myocardium/metabolism , Tumor Necrosis Factor-alpha/biosynthesis , Animals , Coronary Circulation , Creatine Kinase/metabolism , Crystalloid Solutions , Enzyme-Linked Immunosorbent Assay , In Vitro Techniques , Isotonic Solutions , Male , Myocardial Contraction , Myocardial Reperfusion Injury/etiology , Myocardial Reperfusion Injury/physiopathology , Plasma Substitutes , Rats , Rats, Sprague-Dawley
19.
Ann Surg ; 226(5): 587-98, 1997 Nov.
Article in English | MEDLINE | ID: mdl-9389392

ABSTRACT

OBJECTIVE: The mechanisms of cellular priming resulting in both adaptive and maladaptive responses to subsequent injury and strategies for manipulating this priming to constructive therapeutic advantage are explored. BACKGROUND DATA: A cell is prepared or educated by an initial insult (priming stimulus). Investigations in both laboratory animals and humans indicate that cells, organs, and perhaps even whole patients respond differently to a proximal second insult ("second hit") by virtue of this prior environmental history. The opportunity to achieve the primed state appears to be conserved across almost all cell types. The initial stimulus transmits a message to the cellular machinery that influences the cell's response to a subsequent challenge. This response may result in an exaggerated inflammatory response in the case of the neutrophil (an often maladaptive process) or an improved tolerance to injury by the myocyte (adaptive response). Our global hypothesis is that cellular priming is a conserved, receptor-dependent process that invokes common intracellular targets across multiple cell types. We further postulate that these targets create a language based on the transient phosphorylation and dephosphorylation of intracellular enzymes that is therapeutically accessible. CONCLUSIONS: Priming is a conserved, receptor-dependent process transduced by means of intracellular targets across multiple cell types. The potential therapeutic strategies outlined involve the receptor-mediated manipulation of cellular events. These events are transmitted through an intracellular language that instructs the cell regarding its behavior in response to subsequent stimulation. Understanding these intracellular events represents a realistic goal of priming and preconditioning biology and will likely lead to clinical control of the primed state.


Subject(s)
Cell Physiological Phenomena , Adaptation, Physiological , Humans , Macrophages/immunology , Neutrophils/immunology , Reperfusion Injury
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