Biomedical subjects
Publications and source records attributed to M C Deng.
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In situations of depressed myocardial function, the role of immunological mechanisms has been studied recently. In different pathophysiological situations, such as chronic heart failure, open heart surgery with extracorporal circulation, cardiac transplantation, myocardial infarction and angina pectoris, patterns have been described with elevation of proinflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-1, interleukin-6, and reversible myocardial dysfunction, which may represent a final common pathway. The available data suggest a modulation of important determinants of pump function, i.e., contractility, preload, afterload, and heart rate, by cytokines. Potential mechanisms include the beta-adrenoceptor- and nitric oxide pathway, as well as a direct impact on intracellular calcium homeostasis. Interventional strategies based on this understanding are beginning to emerge.
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Severe postoperative mitral regurgitation renders information on the underlying mechanism before reoperation very important, as a potential for mitral valve reconstruction may facilitate the decision whether to reoperate, especially in the very young. This study compares the efficacy of transthoracic echo-cardiography (TTE) and left-ventricular angiography with that of transesophageal echocardiography (TEE) for detection of the mechanism underlying mitral regurgitation and its quantitative assessment in children after repair of common atrioventricular septal defect. Five children aged 1.5 to 16 years were evaluated by TTE, TEE, and angiography for postoperative mitral regurgitation 1 to 21 months after initial repair. TEE showed septal detachment of the mitral leaflet in four patients and reopening of the mitral cleft in one patient as the cause of mitral regurgitation whereas TTE failed in four and angiography in all patients. TEE allows definite identification of morphologic characteristics of mitral regurgitation and reliable assessment of its severity. Thus redo surgery may be safety performed on the bases of TEE findings alone without confirmation by cardiac catheterization.
Impairment of splanchnic and peripheral tissue perfusion during cardiopulmonary bypass (CPB) may be responsible for endotoxin-mediated systemic inflammation and acute phase responses. We examined the effects of dopexamine on hemodynamic parameters, creatinine clearance, systemic and splanchnic oxygenation, gastric mucosal pH (pHi), and mixed and hepatic venous plasma levels of endotoxin, interleukin-6 (IL-6), serum amyloid A (SAA), and C-reactive protein (CRP) in 44 patients scheduled for coronary artery bypass grafting. Patients were randomized to receive continuous infusions of 0.5, 1.0, or 2 micrograms.kg-1.min-1 dopexamine (n = 10 per group) or placebo (n = 14) prior to surgery, intraoperatively, and postoperatively. Dopexamine infusion increased systemic oxygen delivery (P < or = 0.01). Hepatic venous oxygen saturation did not change, and pHi decreased during and after CPB in all patients (P < or = 0.01). Postoperative increases in IL-6 were smallest in patients who received 2.0 micrograms.kg-1.min-1 dopexamine (P < or = 0.02). SAA and CRP increases during the postoperative period were less pronounced with dopexamine throughout the study. Creatinine clearance was elevated in all dopexamine groups (P < or = 0.025). This elevation was higher with lower dopexamine doses (P < or = 0.025). We conclude that dopexamine improves creatinine clearance and reduces systemic inflammation without affecting splanchnic oxygenation.
OBJECTIVES: To assess the expression of mixed and hepatic venous serum amyloid A (SAA) concentrations and its relationship to plasma concentrations of C-reactive protein, interleukin-6 (IL-6), and endotoxin during and after cardiopulmonary bypass (CPB). DESIGN: Prospective, consecutive sample with repeated measurements. SETTING: Surgical intensive care unit (ICU) in a university hospital. PATIENTS: Twenty patients who underwent elective coronary bypass grafting. INTERVENTIONS: A radial artery catheter, pulmonary artery catheter, and right hepatic vein catheter were inserted. Blood samples were collected to determine the different mediators, lactate concentrations, and oxygen saturations. MEASUREMENTS AND MAIN RESULTS: After induction of anesthesia, baseline values were obtained and the following parameters were determined 20 mins after onset of CPB, 20 mins after termination of CPB, at admission to the ICU, and 6, 8, 12, and 24 hrs later: hemodynamics, body core temperature, hepatic venous oxygen saturation, and mixed and hepatic venous lactate, endotoxin, interleukin (IL)-6, C-reactive protein (CRP), and SAA concentrations. Endotoxin and IL-6 plasma concentrations increased during CPB, peaked 6 hrs after admission to the ICU (endotoxin: 23.1 +/- 6.2 pg/mL; IL-6: 646 +/- 104 pg/mL), and decreased thereafter; SAA and CRP concentrations began to increase after 6 and 8 hrs, respectively, with the highest concentrations reached 24 hrs postoperatively (CRP: 14 +/- 3.6 mg/L; SAA: 668 +/- 114 micrograms/mL). Lactate concentrations began to increase 20 mins after CPB, and continued to increase until 12 hrs postoperatively. There were no significant differences between mixed and hepatic venous values of endotoxin, IL-6, CRP, SAA, and lactate (p < .05). Body core temperature, which was < 37.5 degrees C before surgery for all patients, increased 6 hrs after admission to the ICU and peaked 12 hrs postoperatively (38.3 +/- 1.1 degrees C). Hepatic venous oxygen saturation did not change. Correlations were obtained between IL-6 values and heart rate (r2 = .20; p < .005), and endotoxin concentrations and systemic vascular resistance (r2 = .18; p < .001). Body core temperature correlated significantly closer with SAA (r2 = .52; p < .0001) values than with IL-6 (r2 = .27; p < .0001) or CRP (r2 = .16; p < .001) values (p < .05). CONCLUSIONS: SAA is an additional and sensitive marker of the acute-phase response following CPB; the increase in SAA concentrations parallels the temporary increase in body core temperature and is preceded by endotoxemia and IL-6 secretion.
A novel, hemodynamically guided exercise protocol with two different left ventricular assist device settings in two long-term recipients is presented. This protocol allows for quantitation of the contribution of the native left ventricle to total cardiac output. It facilitates estimation of the risk associated with device dysfunction, as well as prediction of left ventricular recovery and the potential for weaning.
Medical data monitoring is an effective tool to insure high quality and efficient performance of health care providers. In the Department of Thoracic and Cardiovascular Surgery of the University of Muenster this is based on a comprehensive data management system. This system has been custom tailored to enable optimal monitoring of quality, performance and cost aspects based on access to all available data. Data acquisition is achieved online and allows for continuous data analysis. This data monitoring is the basis for objective quality control of medical performance as well as for the evaluation of the impact of politically induced economic restrictions on the quality of care.
Proinflammatory cytokines have been implicated in the pathophysiology of chronic heart failure. We determined mixed venous levels of interleukin-6 (IL6) in 18 heart transplant candidates before, 1, 4, and 24 h after initiation of dobutamine infusion (3 micrograms/kg/min) during hemodynamic evaluation. During the first 4 h of dobutamine, systemic vascular resistance decreased (1358 to 1024 dyn x s x cm-5, P = 0.01) while cardiac index (2.3 to 2.9 l/min/m2, P = 0.008) increased. Both returned to baseline after 24 h. IL6 was elevated at baseline compared to age-matched controls (1.5 (0/4.3) vs. 0 (0/0.5) P = 0.003). There was an increase in IL6 from 1.5 (0/4.3) to 3.6 (0.3/5.3) pg/ml after 24 h (P = 0.04). We found higher IL6 levels in the sicker half of patients as defined by pulmonary capillary wedge pressure > 24 mmHg (P = 0.005), mean pulmonary arterial pressure > or = 35 mmHg (P = 0.01), right atrial pressure > 13 mmHg (P = 0.02), and heart rate > or = 87/min (P = 0.02) as well as mean arterial pressure < 82 mmHg (P = 0.005). In conclusion, in this pilot study IL6 correlates with the severity of chronic heart failure during low dose dobutamine infusion.
UNLABELLED: The aim of this study was to compare findings on coronary intravascular ultrasound and thallium-201 SPECT in patients following orthotopic heart transplantation. BACKGROUND: No data are available on whether pathological thallium scintigraphic findings in heart recipients are based on coronary vessel wall alterations identifiable by intravascular ultrasound. METHODS: 29 patients (mean age: 50.9 +/- 11.5 years; male n = 23) were investigated by means of intravascular ultrasound of selected coronary segments and thallium-201 myocardial SPECT. Patients were investigated 11.6 +/- 5.4 weeks post transplantation, a subgroup of 13 patients was re-investigated 70.2 +/- 18.4 weeks following transplantation. A total of 214 cross-sectional areas of the left coronary artery were examined using a 3.5 French intravascular ultrasound catheter to measure intimal index and the circumferential extension of a three-layer appearance of the vessel wall. Shortly after catheterisation, an ergometric stress-test was performed to examine all recipients by means of thallium-201 SPECT. In each patient, 20 segments of the left ventricle were evaluated using a score system of differentiate between persistent defects, redistribution, and reverse redistribution. A score was developed that measured the degree of inhomogeneity and severity of perfusion defects, respectively. Findings on scintigraphy were correlated to coronary intravascular ultrasound findings. RESULTS: At first investigation, mean intimal index of all evaluated coronary cross-sectional areas was 0.06 +/- 0.1. Sixty-four cross-sectional areas demonstrated a three-layer appearance of the vessel wall, mean circumferential extension was 72 +/- 122 degrees. Thallium scintigraphy demonstrated a total of 336 (40%) pathological left ventricular segments; 168 (20%) were regarded as permanent defects, 67 (8%) demonstrated redistribution and 101 (12%) showed reverse redistribution. The score of inhomogeneity was calculated as 5.8% +/- 2.6%. In the subgroup of patients at the follow-up study, the score was 6.4 +/- 2.8%. There was no correlation between intimal index and the score, nor could any correlation be confirmed between the score and the circumferential extension of a three-layer appearance of the vessel wall. At second investigation, no significant differences of intimal index (0.05 +/- 0.07) or circumferential extension of a three-layer appearance of the vessel wall (74 +/- 118 degrees) could be confirmed. The score was slightly, but significantly increased to 8.1 +/- 4.5% at the second investigation (P < 0.05). CONCLUSION: Early after orthotopic heart transplantation, pathologic thallium distribution patterns of the left ventricle could be observed. These pathological patterns did not correlate with the extent of diffuse coronary vessel wall alterations identifiable by intravascular ultrasound. After more than 1 year, the degree of scintigraphic abnormalities increased significantly, not accompanied by an increase of diffuse coronary vessel wall alterations.
The increasing discrepancy between the numbers of patients selected for cardiac transplantation and the available donor organs requires validation of markers of high risk at the time of initial evaluation that may help to determine which patients profit from aggressive therapy. We retrospectively examined the case records of 91 heart transplant candidates selected out of a total of 140 consecutive patients referred for evaluation. Of these 91 patients, 48 were transplanted during follow-up. Of the remaining 43 patients, 25 died after a mean survival time of 1.6 +/- 2.5 months. The causes of death were pump failure in 18 (72%) and sudden cardiac death in 7 (28%). Multivariate analysis identified 4 out of 26 parameters at initial evaluation that distinguished the 25 nonsurvivors from the 18 survivors. These were: mean arterial pressure (P = 0.03), pulmonary capillary wedge pressure (P = 0.002), mean pulmonary artery pressure (P = 0.001), and fractional shortening (P = 0.007). The mode of death could not be predicted. We conclude that there are prognostic markers at initial evaluation that allow more restrictive selection of patients for cardiac transplantation and mechanical bridging.
BACKGROUND: Although patients with reduced left ventricular ejection fraction undergoing cardiac operation experience a higher rate of perioperative complications, the contribution of proinflammatory cytokines released during extracorporeal circulation is not well defined. METHODS: We compared arterial and mixed venous levels of interleukin-6, tumor necrosis factor-alpha, soluble interleukin-2 receptor, and interleukin-2 at 10 points in time (24 hours before until 48 hours after extracorporeal circulation) in 21 patients with an ejection fraction of less than 0.45 (study group) to 15 patients with an ejection fraction of more than 0.55 (control group) undergoing elective coronary artery bypass grafting. The study and control group differed with regard to left ventricular ejection fraction (0.37 +/- 0.05 versus 0.66 +/- 0.11, p < 0.05) and reperfusion time (35 +/- 42 minutes versus 18 +/- 4 minutes, p = 0.07), but not age, sex, vessel involvement, number of grafts performed, cross-clamp time, extracorporeal circulation time, core temperature, and duration of ventilation. RESULTS: Six patients in the study group required mechanical support and 1 died. There were no complications in the control group. In the study group, there were higher preoperative interleukin-2 and tumor necrosis factor-alpha levels and a higher maximum cytokine response to extracorporeal circulation for interleukin-2, soluble interleukin-2 receptor, interleukin-6, and tumor necrosis factor-alpha (all p < 0.05). Interleukin-6 correlated with duration of extracorporeal circulation, dose of norepinephrine and epinephrine support, pulmonary capillary wedge pressure, mean pulmonary arterial pressure, right atrial pressure, heart rate, cardiac index, and inversely with systemic vascular resistance. Interleukin-6 was highest in patients with complications. Arterial and venous cytokine levels correlated closely. CONCLUSIONS: Preoperative left ventricular dysfunction is associated with a higher degree of proinflammatory cytokine release during elective coronary artery bypass grafting. This response is associated with impaired hemodynamics and a higher incidence of perioperative complications.
We report on a 56-year-old patient who underwent coronary artery bypass grafting, tricuspid valve replacement, and pacemaker implantation within 49 months after heart transplantation. This case readily demonstrates that multiple cardiac procedures can be safely performed after heart transplantation and may thus serve as an alternative to retransplantation.
1. Diadenosine hexaphosphate (AP6A) exerts vasoconstrictive effects. The purpose of this study was to investigate whether AP6A has any effect on cardiac function. 2. The effects of AP6A (0.1-100 microM) on cardiac contractility and frequency were studied in guinea-pig and human isolated cardiac preparations. Furthermore, the effects of AP6A on the amplitude of the L-type calcium current, on the adenosine 3':5'-cyclic monophosphate (cyclic AMP) content and on the phosphorylation of regulatory phosphoproteins, i.e. phospholamban and troponin inhibitor, were investigated in guinea-pig isolated ventricular myocytes. 3. In isolated spontaneously beating right atria of the guinea-pig AP6A exerted a negative chronotropic effect and reduced the rate of contraction maximally by 35% (IC20 = 35 microM). 4. In isolated electrically driven left atria of the guinea-pig AP6A exerted a negative inotropic effect and reduced force of contraction maximally by 23% (IC20 = 70 microM). 5. In isolated electrically driven papillary muscles of the guinea-pig AP6A alone was ineffective, but attenuated isoprenaline-stimulated force of contraction maximally by 23% (IC20 = 60 microM). Furthermore, AP6A attenuated the relaxant effect of isoprenaline. 6. In human isolated electrically driven ventricular preparations AP6A alone was ineffective, but attenuated isoprenaline-stimulated force of contraction by maximally 42% (IC20 = 18 microM). Moreover, AP6A attenuated the relaxant effect of isoprenaline. 7. All these effects of AP6A were abolished by the selective A1-adenosine receptor antagonist 1,3-dipropyl-cyclopentyl-xanthine (DPCPX, 0.3 microM), whereas the M-cholinoceptor antagonist atropine (10 microM) and the P2-purinoceptor antagonist suramin (300 microM) failed to abolish the effects of AP6A. 8. AP6A 100 microM had no effect on the amplitude of the L-type calcium current, but attenuated isoprenaline-stimulated L-type calcium current. The maximum of the current-voltage relationship (I-V curve) was shifted to the left by isoprenaline and additional application of AP6A shifted the I-V curve back to the right to the control value. The phosphorylation state of phospholamban and the troponin inhibitor was unchanged by AP6A alone, but was markedly attenuated by AP6A in the presence of isoprenaline. Cyclic AMP levels remained unchanged by AP6A, even after stimulation with isoprenaline. 9. In summary, AP6A exerts negative chronotropic and inotropic effects in guinea-pig and human cardiac preparations. These effects are mediated via A1-adenosine receptors as all effects were sensitive to the selective A1-adenosine receptor antagonist DPCPX. Furthermore, the effects of AP6A on cyclic AMP levels, protein phosphorylation and the L-type calcium current are in accordance with stimulation of A1-adenosine receptors.
The proportion of patients with left ventricular dysfunction (LVD) undergoing open heart surgery is increasing. In this patient group, the perioperative risk is elevated because of the preexisting pathophysiology. Detailed evaluation, interdisciplinary differential therapeutic considerations on the basis of the comparative benefit rationale as well as hemodynamic, antiischemic and antiarrhythmic optimization is mandatory. To plan the operation in patients with coronary artery disease, the issue of reversibility of LVD has to be resolved by sophisticated viability testing. The ultimate decision on revascularization versus aneurysmectomy and scar excision has to be met by the operating surgeon. If the patient's hemodynamics is severely compromised, the perioperative risk may be too high and cardiac transplantation, possibly with mechanical bridging, should be considered. If, in addition, intractable malignant tachyarrhythmias are encountered, antitachycardia operation and defibrillator implantation may be performed. During extracorporeal circulation which is associated with a systemic inflammatory response syndrome the compensatory potential is reduced in patients with LVD, and therefore, the risk of complications such as low-output syndrome, respiratory and renal failure is elevated. Advances in the understanding of pathophysiological mechanisms, an individualized preoperative tailored medical and mechanical therapy for preparation of the operation, anesthesiologic management, cardioprotection and postoperative intensive care have contributed to improvement of outcome in this patient group. Specifically patients with documented evidence of myocardial viability such as angina have profited from surgical revascularization as compared to medical therapy in large scale prospective trials. Perioperative mortality has been lowered to 2-20%. In the absence of angina and presence of overt heart failure and arrhythmias, however, the postoperative 3- and 5-year prognosis of 60% and 35%, respectively, continues to be reduced. Improvement of ejection fraction, angina class, functional capacity and quality of life has been documented in all studies. In conclusion, cardiac operations in patients with left ventricular dysfunction can nowadays be performed with a reasonable risk-benefit ratio, if a careful individualized preoperative evaluation and optimal pre-, intra-and postoperative management is performed.
Immunoregulatory cytokines have been implicated in the pathophysiology of graft dysfunction after heart transplantation (HTx). In 15 consecutive patients undergoing HTx we prospectively determined levels of interleukin-6 (IL-6), tumor-necrosis-factor-alpha (TNF-alpha), interleukin-2 (IL-2), and soluble-interleukin-2-receptor (sIL-2-R) at eight points in time during biopsy and right heart catheterization and within 12 hr of echocardiography during the first three months after HTx. Blood was taken from the pulmonary arterial line. IL-6-levels correlated positively with hemodynamic and echocardiographic parameters of pump dysfunction--namely, pulmonary capillary wedge pressure, pulmonary arterial pressure, right atrial pressure, heart rate--and negatively with isovolumic relaxation time and stroke volume independent of the degree of cellular rejection as classified by the ISHLT criteria. A similar pattern was found for TNF-alpha- and sIL-2-R, while IL-2 correlated negatively with left and right heart filling pressures and positively with fractional shortening. In the three patients who died of sepsis or multiorgan failure within the study period IL-6-, TNF-alpha, and sIL-2-R-levels were elevated and IL-2-levels were suppressed compared with the 12 patients with a stable clinical course. IL-6 and sIL-2-R correlated positively while IL-6 and IL-2 correlated negatively. In this pilot study, a cytokine pattern with elevated levels of IL-6, TNF-alpha, and sIL-2-R as well as suppressed levels of IL-2 in the early period after HTx corresponds to impaired hemodynamics independent of cellular rejection and may indicate an unfavorable prognosis. These cytokines may therefore be useful for monitoring and warrant further study.
BACKGROUND: In end-stage failing human hearts and in rat hearts after prolonged in vivo beta-adrenergic treatment, several proteins involved in the cAMP-dependent signal transduction are altered on the protein, mRNA, or transcriptional level, eg, beta-adrenoceptors, G-proteins, or proteins of Ca2+ homeostasis. In many tissues, cAMP-dependent transcriptional regulation occurs through the cAMP response element binding protein (CREB) and related transcription factors binding as dimers to cAMP response elements (CREs) in the promoter regions of regulated genes. METHODS AND RESULTS: To investigate a possible role of CREB in the human heart, nuclear protein of explanted failing and nonfailing human hearts was used to test for CRE specific binding properties in gel mobility shift assays. CRE specific binding was found in competition studies, and CREB and its phosphorylated form were immunologically identified in supershift experiments. The alternatively spliced CREB isoforms CREB327 and CREB341 were found to be expressed on the mRNA level by the reverse transcriptase-polymerase chain reaction. CONCLUSIONS: We conclude that in the failing and nonfailing human heart, CREB is expressed on the protein and mRNA levels and that CREB is phosphorylated and able to bind to CREs, indicating a functional role of CREB in the human heart.
The variety and complexity of therapeutic options available for the increasing number of patients with advanced chronic heart failure has lead to the institution of specialized heart failure/heart transplant programs. The central task consists of carefully evaluating and selecting potential transplant recipients, based on the comparative benefit rationale, i.e. the expected gain in life expectancy and quality of life by cardiac transplantation compared with all other treatment options. Further tasks include a comprehensive chronic heart failure management, high risk conventional cardiac surgery, mechanical and antiarrhythmic bridging and dedicated posttransplant care. This concept is described on the basis of the 5-year experience of the Interdisciplinary Heart Failure and Transplant Program Münster.