Studies of the nucleoside transporter inhibitor, draflazine, in the human myocardium.

1. The aim of the present study was to determine the effect of the nucleoside transporter inhibitor, draflazine, on the force of contraction in human myocardium and the affinity of the compound for the nucleoside transporter. Nucleoside transport inhibitors, like draflazine, are of potential importance for cardiopreservation of donor hearts for heart transplantation. 2. Functional experiments were performed in isolated electrically driven (1 Hz, 1.8 mmol l-1 Ca2+) human atrial trabeculae and ventricular papillary muscle strips. The affinity of draflazine for the myocardial nucleoside transporter was studied in isolated membranes from human ventricular myocardium and human erythrocytes in radioligand binding experiments using [3H]-nitrobenzylthioinosine ([3H]-NBTI). Dipyridamole was studied for comparison. 3. In membranes from human myocardium and erythrocytes, [3H]-NTBI labelled 1.18 pmol mg-1 protein and 23.0 pmol mg-1 protein, respectively, nucleoside transporter molecules with a KD value of 0.8 nmol l-1. Draflazine concentration-dependently inhibited binding of [3H]-NBTI to myocardial and erythrocyte membranes with a K(i)-value of 4.5 nmol l-1. The potency as judged from the K(i) values was ten times greater than that of dipyridamole in both myocardial and erythrocyte membranes. 4. Draflazine, at concentrations up to 100 mumol l-1, did not produce negative inotropic effects in atrial and ventricular myocardium. (-)-N6-phenylisopropyladenosine (R-PIA) and carbachol did not reduce force of contraction in ventricular myocardium, but exerted concentration-dependent direct negative inotropic effects in atrial myocardium. 5. The data provide evidence that draflazine specifically binds to the nucleoside transporter of the human heart and erythrocytes with high affinity. The compound does not produce negative inotropic effects at concentrations as high as 100 micromol 1-1.6. Draflazine could be a useful agent for cardio preservation because it does not produce cardio depressant effects. Thus, it may be possible to perfuse explanted hearts directly with this agent without the hazard of cardiodepression.

Alterations of cell-mediated immunity following cardiac operations: clinical implications and open questions.

Cardiac surgery with cardiopulmonary bypass (CPB) is known to induce an immune response whose nature has been increasingly elucidated during the recent decade. Clinically, patients usually show two to three of the four symptoms, which define the so-called systemic inflammatory response syndrome (SIRS). In addition, all parameters of the innate, nonspecific immune system, e.g., polymorphonuclear cells, elastase, and complement, are activated. This also applies to the proinflammatory mediators interleukin (IL)-1beta, -6, and -8, and tumor necrosis factor (TNF)-alpha. Within the adaptive, specific immune system, a decrease of T lymphocytes and T helper (TH) cells is observed, whereas suppressor/ cytotoxic T cells and B cells appear to be nearly unaffected. Cytokine measurements provide more detailed information: IL-2 and IL-12, which are important for the activation of the type-1 TH-cell (TH1)-mediated immune response, are depressed following cardiac operation. In contrast, IL-10 and transforming growth factor-beta essential to TH2-mediated humoral or anti-inflammatory immune response, are upregulated. In vivo tests, e.g., delayed type hypersensitivity skin reaction and tetanus antibody production, confirm the polarization of the adaptive immune response towards the TH2 pathway. However, all these alterations usually do not result in clinical adverse events. Therefore, more information is needed about the immune response of patients at high preoperative risk or with serious perioperative complications to find out whether clinically relevant events are correlated to alterations of immune response. For this purpose, more readily available, standardized methods for immunologic monitoring appear highly desirable.

Registration of thoracic electrical bioimpedance for early diagnosis of rejection after heart transplantation.

In this study, registration of thoracic electrical bioimpedance was used for early detection of acute rejection after heart transplantation. Thirty-five heart transplant recipients were monitored by registration of thoracic electrical bioimpedance signals during the immediate postoperative period and during the outpatient follow-up. At the same time, endomyocardial biopsy specimens were taken. In addition to cardiac stroke volume index and ejection fraction, the acceleration index (seconds -2) was calculated. This acceleration index describes the acceleration of blood volume and represents a function parameter of the myocardial inotropy. Seventeen acute rejection episodes were diagnosed during the follow-up period. The average acceleration index value during the 17 rejection episodes was 92.5 +/- 11.7 sec-2 and thus significantly lower when compared with the nonrejection levels (p < 0.05). The acceleration index values decreased during acute rejections by an average of 36.4 +/- 19.3 sec-2 (28%). The sensitivity of this diagnostic parameter in the examined patients was 71%, and the specificity was 100%. Thus registration of thoracic electrical bioimpedance and calculation of the acceleration index represents a quick and noninvasive monitoring technique and can ideally be used in the outpatient clinic as a supplement to invasive endomyocardial biopsies.

One-incision approach for insertion of implantable cardioverter defibrillators.

The placement of a transvenous implantable cardioverter defibrillator (ICD) system through a single infraclavicular skin incision has been a surgical goal for years. The development of a new investigational model of ICD with substantially reduced dimensions (volume, 83 cm3; mass, 132 g) has made the one-incision approach a clinical reality. Between March and September 1993, 4 female and 19 male patients (mean age, 60 +/- 9.6 years; range, 46 to 73 years) underwent implantation of this device for the treatment of ventricular fibrillation (n = 14) or ventricular tachycardia (n = 9). One transvenous lead was placed in the right ventricular apex and another in the left subclavian vein. A subpectoral pocket was formed in the infraclavicular area from the same incision to house the ICD generator and, if necessary, the subcutaneous patch. The mean operation time (81.5 +/- 32.7 minutes; range, 54 to 195 minutes) was significantly shorter than that noted for a previous series made up of patients undergoing traditional transvenous ICD implantations. In 20 patients (87%), endovenous defibrillation without a subcutaneous patch successfully caused externally induced ventricular fibrillation to revert with a mean minimum energy output of 21.9 +/- 3.5 J (range, 12 to 24 J). Endovenous defibrillation was more successful when biphasic (n = 16/17 [94%]) shocks rather than monophasic shocks (n = 4/6 [67%]) were used. No mortality, morbidity, or surgical complications were observed. These results indicate that the one-incision approach and the small size of the ICD generator can substantially facilitate ICD implantation and result in a reduction in the surgical trauma, the operation time, and the amount of material implanted.

New morphologic aspects of explanted Hancock Extracorporeal pericardial bioprostheses.

Between 1981 and 1987 a total of 479 Hancock Extracorporeal bovine pericardial bioprostheses were implanted in 458 patients. During the time period from 1990 to 1993, 21 valves, 15 in the aortic and six in the mitral position, had to be removed 72 to 109 months after implantation. The mean age of these patients at the time of implantation was 49.7 +/- 10.5 years. All 21 removed as well as one unimplanted bioprosthesis were morphologically investigated. Visual examination, radiography, histology and ultrastructural observations were performed using scanning and transmission electron microscopy. In addition, clinical data were correlated to morphological findings. All valves failed due to cusp tears originating at the stent posts. Calcification was minimal in five valves, moderate in 10, and severe in five valves. Only one valve showed no mineralization at all. The late morphologic changes were associated with thickening of valve leaflets, tissue delamination, calcification, degeneration of collageneous network, and extensive insudation of plasma proteins and lipids. The present findings suggest that denatured collagen molecules may be capable of inducing immune response.

Alterations of cell-mediated immune response following cardiac surgery.

Nosocomial infections in patients following cardiac surgery are frequently associated with opportunistic microorganisms indicating a dysregulation of cell-mediated immune response. The objective of this prospective randomized trial, therefore, was to investigate the mechanisms of dysregulation and the counterregulatory effects of immunomodulation. Twenty patients underwent conventional postoperative therapy, another 20 patients received indomethacin, which inhibits synthesis of the down-regulating mediator prostaglandin E2, and a further 20 patients were given thymopentin in addition to indomethacin, thereby augmenting activation and differentiation of the T-lymphocytes. The immunologic parameters studied included T-lymphocytes and monocytes as well as interleucin (IL)-1 and IL-6 synthesis by monocytes, and IL-2 and IL-6 synthesis by T-lymphocytes. Following cardiac surgery a significant, persistent reduction of T-lymphocytes and IL-2 synthesis as well as significant monocytosis could be observed. Indomethacin treatment resulted in a normalization of the cellular imbalance at the end of the first postoperative week, but IL-2 synthesis remained significantly reduced during the entire observation period. Conversely, with combined indomethacin and thymopentin treatment restoration of cellular distribution as well as protection of IL-2 synthesis could be achieved. These results indicate a quantitative and functional impairment of the forward regulation of cell-mediated immunity. It was shown for the first time that combined indomethacin and thymopentin treatment could successfully counteract these immunomechanistic alterations.

An imbalance in T-helper cell subsets alters immune response after cardiac surgery.

Growing evidence indicates that cell-mediated immunity is altered after cardiac surgery with cardiopulmonary bypass (CPB). The objective of this prospective randomized study was to investigate (1) if an imbalance in T-helper cell (TH) subsets, i.e. TH1/TH2, may be responsible for these alterations and (2) if they can be counteracted. Twenty patients formed control group A. Twenty group B patients received indomethacin and thymopentin for immunomodulation. In vitro tests included measurements of TH, interleukin (IL)-2 as a cytokine primarily produced by TH1 cells, and IL-6 as a cytokine primarily produced by TH2. Delayed-type hypersensitivity (DTH) skin response and specific antibody (AB) production were used as in vivo tests for TH1- and TH2-induced immune response, respectively. Postoperatively, group A patients showed a persistent, significant reduction of TH, IL-2 synthesis and DTH skin response as compared to baseline values, while IL-6 synthesis remained unaltered and AB production increased (P < 0.05). In group B patients no change in TH, IL-2 and IL-6 synthesis, or DTH skin response was observed (P < 0.05 vs A). Postoperative AB production increased significantly in group B. These results indicate a significant suppression of TH1-induced cell-mediated immune response following CPB, while TH2-induced response remains normal. A normal TH2 response may be helpful for recovery following cardiac surgery by cleaning the body of the byproducts of CPB. A suppression of TH1 response may gain clinical significance whenever a postoperative infection requires this response, but can be effectively counteracted by immunomodulatory intervention with indomethacin and thymopentin.

CT and MR evaluation of pericardial constriction: a new diagnostic and therapeutic concept.

Eighty patients with pericardial constriction confirmed by catheter data were studied by CT (n = 79), MR imaging (n = 24), or both. To determine the validity of these imaging methods for subsequent treatment, 30 patients' studies were evaluated retrospectively (1980-1984) and 50 (1985-1991) prospectively. Twenty patients from the first group and 30 patients from the second group underwent pericardiectomy. By systematic analysis of CT scans and MR images it was possible to characterize the morphology of pericardial constriction (n = 80); to identify global (n = 27), right-sided (n = 46), left-sided (n = 2), annular (n = 2), effusive (n = 2), and epicardial (n = 1) forms of pericardial constriction; and to define parameters of myocardial atrophy and fibrosis (n = 17). Seventeen patients had myocardial atrophy, fibrosis, or both. Seven of them underwent pericardiectomy; all died of acute myocardial failure (100%). Four (9.3%) of 43 patients without myocardial atrophy or fibrosis died as a consequence of other complications. The method of thoracotomy and periepicardiectomy was continuously adjusted to the preoperative CT and MR findings. Thus, the clinical use of CT and MR imaging in patients with known or suspected pericardial constriction is based on (a) exclusion of patients with restrictive hemodynamics from diagnostic thoracotomy, (b) preoperative determination of the method of thoracotomy and extent of pericardiectomy, and (c) exclusion of patients with myocardial atrophy or fibrosis from pericardiectomy.

Effects of preservative-free heparin on plasma histamine concentration and on hemodynamics in patients undergoing aortocoronary bypass surgery.

Several reports, dealing with typical cardiovascular reactions immediately after injection of heparin during cardiac surgery, have been presented. A possible reason for these reactions is a short-lasting elevation of plasma histamine concentration following heparin injection. As most types of heparin contain antibacterial preservatives such as benzyl alcohol, which can cause adverse reactions, both substances, heparin itself and the preservative, can theoretically be responsible for this reaction. Therefore, this study was carried out in order to measure the effects of preservative-free heparin on plasma-histamine levels and on hemodynamic parameters. It became evident that preservative-free heparin also entails characteristical hemodynamic effects, such as a decrease in arterial mean pressure and peripheral vascular resistance as well as an increase in cardiac output. A significant increase in plasma-histamine concentration could be shown 20-120 seconds after injection of heparin. We conclude that benzyl alcohol is not the major reason for the hemodynamic effects and elevation of plasma-histamine concentration, following heparin injection, but we cannot exclude that benzyl alcohol does in fact play a minor role. The results of this study suggest that the cardiovascular reactions and the elevation of plasma histamine concentration following heparin injection are heparin-specific phenomena.

Homograft aortic root replacement for destructive valve endocarditis. The benefit of an in-house homograft bank.

This report concerns the surgical treatment of a 45-year old patient with active staphylococcus-endocarditis of the aortic valve which resulted in an aortic root abscess and consequently in a ventricular aortic discontinuity. A technique of homograft aortic root replacement after removal of all infected and necrotic areas is described. After a six month follow-up, the patient is asymptomatic (New York Heart Association functional class I) and shows no signs of recurrence of endocarditis. This case report makes the benefit of an in-house homograft-bank system obvious.

Endothelialization of cardiac valve bioprostheses.

The main disadvantage of implanted xenograft valves used in cardiac surgery is their poor clinical long-term result, due to early tissue degeneration. In order to improve the performance of such glutaraldehyde fixed bioprostheses, a biological coating with viable endothelial cells was suggested. Therefore, glutaraldehyde preserved bovine pericard patches, as well as commercially available xenograft valves, were lined using human venous endothelial cells or microvascular cells from the subcutaneous fat tissue. Before cells were transplanted into their new environment, grafts were treated with an amino acid solution in order to neutralize the cytotoxic effect of free aldehydes, and precoated with fibronectin-heparin and basic fibroblast growth factor (bFGF) or endothelial cell growth supplement (ECGS) in order to enhance cell proliferation. Coated specimens were kept in culture conditions for a further seven days. Proliferation of transplanted cells was verified by an increase of activation following 3H-thymidine incorporation, while the maintained metabolic cell activity was demonstrated via Prostacycline (PGI2) measurement. Morphology was evaluated by means of scanning electron microscopy (SEM). As evaluated by the beta-Counter, 7 ng/ml bFGF (288,727 +/- 39,668 counts on day 4) substantially enhanced cell proliferation after seeding, opposed to the stimulation with 30,000 ng/ml ECGS (91,924 +/- 1129 counts on day 4), (p < 0.001). The PGI2 release of transplanted cells was stimulated with 25 microM Na arachidonic acid by the factor 2.6 +/- 0.3 and inhibited with 5 mM acetylsalicylic acid by the factor 0.7 +/- 0.2 on day 4 when compared with the basic level.(ABSTRACT TRUNCATED AT 250 WORDS)

Procalcitonin levels after different types of conventional thoracic surgery.

BACKGROUND: Procalcitonin (PCT) is currently discussed as an indicator of postoperative complications following thoracic surgery. Serum levels of PCT are different after thoracoscopic and conventional surgical approaches. We conducted this study to test the hypothesis that different types of conventional thoracic surgery are associated with different postoperative serum levels of acute-phase proteins or pro-inflammatory mediators. METHODS: Serum levels of interleukin (IL)-6, C-reactive protein (CRP), lipoprotein-binding protein (LBP) and PCT were measured preoperatively (pre), immediately after surgery (0 h), 6 hours after surgery (6 h), and on the 1st (d1), 3rd (d3) and 5th (d5) postoperative days in 48 patients undergoing elective conventional pneumonectomy (n = 6), lobectomy (n = 20) or wedge resection (n = 22). RESULTS: In all study groups, IL-6 and PCT increased after surgery, peaking at 6 h and on d1, respectively. The time courses of IL-6, CRP, LBP and PCT release were not influenced by the type of surgical procedure. All parameters increased more markedly after lobectomy and wedge resection than after pneumonectomy. CONCLUSIONS: Surgical trauma and lung ischaemia/reperfusion injury could be the main factors determining the release of IL-6 and PCT after surgery. From an immunological point of view, pneumonectomy is less severe than wedge resection or lobectomy in terms of tissue injury. Different types of conventional thoracic surgery are associated with differences in postoperative PCT and IL-6 synthesis. For this reason, expected ranges of PCT and IL-6 levels should be established for the various surgical procedures before these parameters can be used as indicators of postoperative complications.

Immunoglobulin levels and lymphocyte subsets following cardiac operations: further evidence for a T-helper cell shifting.

BACKGROUND: Recent data indicate that cardiac surgery with cardiopulmonary bypass (CPB) results in an imbalance of T-helper cell subsets towards the anti-inflammatory pathway mediating humoral immune response. However, little is known about immunoglobulin levels as an important part of humoral immune response after CPB. Therefore, the objectives of this study were 1) to elucidate the effects of CPB on perioperative immunoglobulin levels, and 2) to find out if alterations in lymphocyte subsets are related to these findings. METHODS: Blood samples from 83 patients undergoing elective cardiac operation were taken preoperatively (d0), on the first (d1), third (d3), and fifth day (d5) after operation. Levels of immunoglobulin (Ig) E, IgM, and IgG, including the subclasses IgG 1 - 4, were measured. IgG2/IgE-ratio was used as indicator for TH1/TH2 shifting, and production of tetanus antibodies (AB) was investigated as an in vivo parameter of humoral immune reaction. The number and percentage of T- and B-lymphocyte subsets were assessed in a subgroup of 50 patients to answer the second question. RESULTS: Clinically, no mortality or major morbidity were observed. IgE levels did not change until d3 and increased significantly on d5. In contrast, both IgG and IgM levels decreased significantly on d1. While IgM returned to baseline (BL) on d5, IgG levels remained below BL until d5. IgG2/IgE-ratio decreased significantly on d1, reached its nadir on d3 and remained depressed until d5. The number of T-lymphocytes decreased on d1 as well as the number of B-cells. T-cells returned to BL on d5, B-cells on d3. However, while the percentage of T-cells decreased on d1, the percentage of B-cells increased. The percentage of T-cells returned to BL on d3, and B-cell percentage returned to BL on d5. Tetanus AB production did not change until d5 when it increased significantly. CONCLUSIONS: 1) Increase of IgE and tetanus AB production indicate that humoral immune response is not affected by CPB, but possibly even enhanced. The relative increase of B-cells is in line with this hypothesis. 2) Postoperative changes in immunoglobulin levels provide further evidence for a TH1/TH2-shifting. 3) The transient deficit in IgM-and IgG levels did not result in clinically adverse events. Thus, therapeutic intervention appears not to be required.

Complications in dual chamber pacing: a six-year experience.

In a six-year period (1980-1985), 345 dual chamber pacing systems were implanted in our hospital. Intraoperative complications were rare (n = 5/345 = 1.4%). 25 patients (7%) have died, 11 (3%) were lost to follow-up. A total of 39 patients (13%) showed minor problems, which could be overcome by reprogramming. Another 48 complications (15%) required reoperation. Nearly 70% of those reoperations (n = 31/48) were caused by a malfunction of the atrial lead. This high complication rate of 9% related to all implanted atrial leads could be reduced in the last three years to 2%. We could maintain a dual chamber stimulation mode (DDD, DDI, DVI, VDD) in 396 patients (99%). We conclude that improvements in lead design, pulse generator's programmability, and surgical experience have reduced complication rates to acceptable low values. Meanwhile, dual chamber pacing can be considered as safe as single chamber pacemaker therapy.

Reliability of atrial screw-in leads.

The aim of this study was to investigate long-term performance of a carbon coated atrial screw-in lead. During implantation of 247 leads of this type we measured an average stimulation threshold of 0.74 (range: 0.2-1.6 V) at 1 ms pulse width. Mean lead impedance came to 446 ohms (range: 263-1000 ohms) resulting in an arithmetical energy consumption of 1.51 microJ (range: 0.1-7.21 microJ). Average P wave amplitude was 3.9 mV (range: 1.3-11 mV). After a mean follow-up of 16.4 months (range: 3-60 months) we found excellent threshold results in 76% of the patients permitting a safety programming at half of nominal value. An additional 14% nominal settings could be retained. With regard to chronic lead impedance of 488 ohms (range: 315-1327 ohms) we calculated an average chronic energy consumption of 10.83 microJ (range: 1.62-22.78 microJ) during safety programming. This made up 34.6% of the corresponding energy consumption during nominal programming. Eighty percent of the patients showed chronic P waves above 2 mV; nearly half of them (n = 94 = 38%) showed a proper sensing function even when programmed to minimal sensitivity settings or above 4 mV. In 19 leads (8%) we observed unsatisfying threshold results requiring high output programmings. All threshold increases occurred within the first year, 84% (n = 16/19) within the first 3 postoperative months. An additional five leads (2%) were found to have a loss of capture, and one (0.5%) a loss of sensing.(ABSTRACT TRUNCATED AT 250 WORDS)

Haemodynamic and oxymetric investigations on patients under rate-responsive dual-chamber stimulation during exercise.

Rate-response dual-chamber pacing combines the advantages of atrio-ventricular synchrony and rate adaptation in patients suffering from binodal disease. However, it is not known if patients really benefit from the additional rate response under exercise conditions. Therefore, 15 patients suffering from binodal disease received rate-responsive dual-chamber pacemakers. 1, 3, and 6 months postoperatively haemodynamic parameters and oxygen consumption were measured during treadmill ergometry under conventional (DDD) and rate-modulated AV-universal stimulation (DDDR). Using the NCCOM3-R7 (Osypka) technique, rate (f), cardiac index (CI), stroke volume index (SVI), and the end-diastolic volume index (EDVI) were determined non-invasively. Oxygen consumption (VO2) was measured with the Biotec Oxysuper. Based on preoperative status (NYHA) and ventricular contractility, which was determined by means of echocardiography, the patients were divided into two groups: Group I (n = 8) with normal ventricular contractility demonstrated a moderate increase of intrinsic heart rate during exercise. Group II (n = 7) with impaired ventricular contractility showed only a slight or no increase in intrinsic heart rate. When comparing DDD and DDDR pacing a significant increase of CI and VO2 was found for the rate-modulated pacing mode in group II. The reverse was found for patients of group I. The difference between the two groups was statistically significant. According to these results, only patients with nearly no increase in intrinsic sinus heart rate and impaired ventricular function can be expected to benefit from the additional rate-adaptation of a dual-chamber pacemaker.