Natural innate cytokine response to immunomodulators and adjuvants in human precision-cut lung slices.

Prediction of lung innate immune responses is critical for developing new drugs. Well-established immune modulators like lipopolysaccharides (LPS) can elicit a wide range of immunological effects. They are involved in acute lung diseases such as infections or chronic airway diseases such as COPD. LPS has a strong adjuvant activity, but its pyrogenicity has precluded therapeutic use. The bacterial lipopeptide MALP-2 and its synthetic derivative BPPcysMPEG are better tolerated. We have compared the effects of LPS and BPPcysMPEG on the innate immune response in human precision-cut lung slices. Cytokine responses were quantified by ELISA, Luminex, and Meso Scale Discovery technology. The initial response to LPS and BPPcysMPEG was marked by coordinated and significant release of the mediators IL-1ß, MIP-1ß, and IL-10 in viable PCLS. Stimulation of lung tissue with BPPcysMPEG, however, induced a differential response. While LPS upregulated IFN-γ, BPPcysMPEG did not. This traces back to their signaling pathways via TLR4 and TLR2/6. The calculated exposure doses selected for LPS covered ranges occurring in clinical studies with human beings. Correlation of obtained data with data from human BAL fluid after segmental provocation with endotoxin showed highly comparable effects, resulting in a coefficient of correlation >0.9. Furthermore, we were interested in modulating the response to LPS. Using dexamethasone as an immunosuppressive drug for anti-inflammatory therapy, we found a significant reduction of GM-CSF, IL-1ß, and IFN-γ. The PCLS-model offers the unique opportunity to test the efficacy and toxicity of biological agents intended for use by inhalation in a complex setting in humans.

[100 years Heidehaus--from sanatorium for tuberculosis to a modern chest hospital]. / 100 Jahre Heidehaus--vom Tuberkuloseheim zum modernen Lungenzentrum.

When the sanatorium "Heidehaus" was founded on June 1, 1907 in the northern countryside of Hannover with Dr. Otto Ziegler as head about 120 beds for patients with tuberculosis were available. By 1914 about 200 patients were being treated by 4 physicians and 10 nurses. An operating theatre and a modern radiology unit were added in 1927. Shortly after the 2nd World War 400 patients with tuberculosis were hospitalised simultaneously. With the introduction of antituberculous triple drug treatment the number of patients dropped significantly. During this period many traditional facilities, used to care for patients with tuberculosis lost their financial basis and closed. However in the 1960s Prof. Schindler, the head of Heidehaus, widened the spectrum of the hospital into a modern chest hospital, focused on lung and airway diseases. In particular in the 1980s and 1990s this trend continued and 2 independent departments, i. e., pneumology and thoracic surgery were founded. In 2005 due to restructuring by the community of Hannover the "Heidehaus" moved completely and merged with another traditional hospital to become the new "Oststadt-Heidehaus". In its new surroundings both departments for pulmonary medicine and thoracic surgery offer a broad spectrum of modern thoracic medicine in cooperation with other disciplines.

[Laser-induced thermotherapy of lung metastases and primary lung tumors]. / Laserinduzierte Thermotherapie von Lungenmetastasen und primären Lungentumoren.

We present laser-induced thermotherapy (LITT) of primary and secondary lung tumors analysing indications and technical concepts. Thirty patients with lung metastases of different primary tumors (n=24) as well as localized lung tumors (n=6) were prospectively treated in 41 sessions using laser-induced thermotherapy (LITT). An MR-compatible puncture system was used with direct puncture technique. The puncture was performed via CT guidance in care vision technique. Eight patients were thermoablated using MR tomographical monitoring, 22 patients using CT monitoring. Local therapy effects, tumor control rate, side effects, complications, and survival were evaluated. In 74% of cases (28/38 lesions) of 24 patients with lung metastases and in all cases of the 6 patients with lung carcinoma a complete local ablation could be achieved. The complication rate (pneumothorax) was 9,8%. One patient with bronchial carcinoma had to be thoracotomized and resected. 93% of the patients are still alive. Percutaneous LITT of lung tumors permits a complete ablation of lung metastases and lung carcinomas with a low complication rate. Indications for the procedure were defined for patients with no more than 5 metastases up to 3 cm in size.

Ten year survival after heart transplantation: palliative procedure or successful long term treatment?

OBJECTIVE: To investigate the long term outcome and prognostic factors after heart transplantation. SETTING: University hospital. SUBJECTS: 120 heart transplant patients (98 male, 22 female; underlying disease: dilated cardiomyopathy in 69, coronary artery disease in 42, miscellaneous in nine) who had undergone heart transplantation between October 1984 and October 1987. Immunosuppressive treatment was comparable in all patients and rejection episodes were treated in a uniform manner. METHODS: Functional status, quality of life, and potential predictors for long term survival were investigated. RESULTS: Actuarial survival rates were 65% at five years and 48% at 10 years; 58 patients survived > 10 years. The major causes of death were cardiac allograft vasculopathy (39%), acute rejection (18%), infection (11%), and malignancy (11%). Long term survivors had good exercise tolerance assessed by the New York Heart Association classification: 47 (81%) in grade I/II; 11 (19%) in grade III/IV. Echocardiography showed good left ventricular function in 48 patients. On angiography, severe allograft vasculopathy was present in only 16 patients (28%). Renal function was only slightly impaired, with mean (SD) serum creatinine of 148.5 (84.9) micromol/l. Multiple potential predictors of long term survival were analysed but none was found useful. CONCLUSIONS: Heart transplantation represents a valuable form of treatment. Survival for more than 10 years with a good exercise tolerance and acceptable side effects from immunosuppression can be achieved in about 50% of patients.

External stimuli in the form of vibratory massage after heart or lung transplantation.

Manual vibratory massage is part of the preventive physiotherapeutic activities performed in intensive care units. The vibratory massage can be performed manually or as electrovibratory massage. The manual massage is a fast rhythmical vibration performed by the arm and shoulder muscles of the masseur and transferred to the patient's thorax by the hand. The hand of the masseur has to achieve a tremor with a frequency of 8 to 11 tremors/s. The aim of the pilot study was to examine the influence of manual vibratory massage on the pulmonary function of postoperative patients who were receiving mechanical ventilation, with special interest being focused on pulmonary ventilation and perfusion and cerebral blood flow velocity. Manual vibratory massage was performed postoperatively in the intensive care unit on eight patients: three patients had undergone heart transplantation, three had undergone lung transplantation, and two had undergone coronary artery bypass grafting (mean age, 53.6+/-8 yr). With the aid of continuous monitoring, we examined the changes of the respiration parameters and the cerebral blood flow velocity (measured by transcranial Doppler sonography). The vibratory massage was performed with a frequency of 8 to 10 vibrations/s for 15 min, 7.5 min on each side of the thorax, starting from the lower costal arch and progressing to the upper thoracic aperture. For 10 min before, during, and 10 min after the massage, the parameters of peripheral oxygen saturation, central venous pressure, mean arterial pressure, heart rate, lung resistance and compliance, tidal volume, respiration rate, and cerebral blood flow velocity were recorded at 2-min intervals. Moreover, before and after vibratory massage, arterial blood gases were determined. In four of the eight patients, it was possible to determine pulmonary arterial pressure, pulmonary capillary wedge pressure, as well as pulmonary vascular resistance. During the vibratory massage, we could prove a significant increase of the mean tidal volume by 30% (P = 0.008). The percutaneous oxygen saturation significantly increased also, from 92 to 93.6% (P = 0.002). Central venous pressure significantly decreased by 11% (P = 0.04), and pulmonary vessel resistance was reduced by 18.3% (P = 0.001). The pulmonary resistance decreased from 10.5 to 9.2 H2O/l/s (P < 0.05) by the end of the observation period. Cerebral blood flow velocity showed no significant change. Vibratory massage seems to improve pulmonary mechanism and perfusion, thus, reducing ventilation perfusion mismatch and increasing oxygen saturation.

[Cerebral hemodynamics during implantation of cardioverter-defibrillator systems]. / Zerebrale Hämodynamik während der Implantation von Kardioverter-Defibrillator-Systemen.

OBJECTIVE: During ICD-implantation it is necessary to prove the function and to determine the optimal threshold by means of induced ventricular fibrillation (VF). Provoked cardiac arrests cause a circulator stop of the cerebral perfusion. Our aim was to examine the changes of cerebral blood flow velocity (CBFV(MCA)) after induced VF depending on the duration of fibrillation and prior values of CBFV(MCA). PATIENTS AND METHODS: Sixty induced episodes of VF in 9 patients (mean age +/- SD 53.5 +/- 8 years) were examined during ICD-implantation. Beside the standardized anaesthesiological monitoring, transcranial Doppler sonography was used to record the cerebral blood flow velocity in the middle cerebri artery CBFV(MCA). The duration of the fibrillation-period and the range and duration of the CBFV increase during the post defibrillation-period were correlated. Additionally, we examined whether systematic differences existed between the episodes of each patient (time-trend) by means of 5 following episodes of a patient. RESULTS: During all episodes of VF and hyperperfusion was present, that means a time interval showing increased values of CBFV(MCA), compared to the values present before VF. The duration of hyperperfusion depended significantly on the fibrillation time (r = 0.57; p < 0.001). The equation of regression is: hyperperfusion time = 11.1 + 1.22 x fibrillation time. The amount of hyperperfusion, that means the maximal CBFV after defibrillation, increase significantly with CBFV(MCA) before VF (correlation = 0.88; p < 0.001). The equations of regression is hyperperfusion height = 6.11 + 1.22 x CBFV(MCA) before VF. The duration of hyperperfusion is not influenced by the maximal CBFV(MCA) after defibrillation (r = 0.08; p = 0.52). In the examined patients no significant differences in the hyperperfusion time maximal CBFV(MCA) after defibrillation between the episodes were found. CONCLUSION: After induced VF you always have to expect a reactive cerebral hyperperfusion. The amount of increase of CBFV after defibrillation depends on the prior values of CBFV before fibrillation and shows a nearly proportional relation to these. The duration of hyperperfusion shows a linear dependency on VF-times. This may show that we had VF-times, in which the cerebral autoregulation and other cerebral physiological reactions compensate the drop of the CBFV(MCA) during VF in the postfibrillation time. In further studies will be examined if there are similar changes in the cerebral metabolism as in CBFV(MCA).

Long-term follow up of patients with implantable cardioverter-defibrillators and mild, moderate, or severe impairment of left ventricular function.

OBJECTIVE: To determine whether patients with life threatening ventricular tachyarrhythmias, impaired left ventricular function, and severe heart failure will benefit from implantable cardioverter-defibrillator (ICD) treatment. DESIGN: 410 patients were followed up after ICD implant. Left ventricular function was assessed by the New York Heart Association (NYHA) functional class of heart failure: 50 patients (12%) were in NYHA I-II, 151 (37%) in NYHA II, 117 (29%) in NYHA II-III, and 92 (22%) in NYHA III. Epicardial ICD implantation was performed in 209 patients (51%) and 201 patients (49%) received non-thoracotomy ICDs. RESULTS: Perioperatively, 12 patients (3%) died, more often after epicardial ICD implant (11/209 patients, 5%) than after transvenous implant (1/201 patients, < 1%) (P < 0.05). During a mean (SD) follow up of 28 (24) months (range < 1 to 114 months), 90 patients (23%) died: nine (2%) died from sudden arrhythmia; five (1%) also died suddenly but probably not from arrhythmic causes; 55 (14%) died from cardiac causes (congestive heart failure, myocardial reinfarction); 21 (5%) died from non-cardiac causes. The three year, five year, and seven year survival was 92-96% for arrhythmic mortality in NYHA class I, II and III, compared to a three year survival of 94% and a five year and seven year survival of 84% for patients in NYHA class II-III. 338 patients (82%) received ICD shocks (21 (SD 43) shocks per patient); patients in NYHA class II (83%), class II-III (84%), and class III (90%) received ICD discharges more often than those in class I-II (64%) (P < 0.05). The mean (SD) time interval between ICD implant and the first ICD shock was shorter in NYHA class II (16 (17) months), class II-III (19 (27) months), and class III (16 (19) months) than in class 0-I (22 (24) months) (P < 0.05). CONCLUSIONS: Patients with mild, moderate, and severe left ventricular dysfunction benefit from ICD treatment and these patients survive for a considerable time after the first shock. Survival is influenced by the degree of left ventricular dysfunction; aggressive treatment of heart failure is necessary as well as ICD therapy.

Age dependent efficacy of implantable cardioverter-defibrillator treatment: observations in 450 patients over an 11 year period.

OBJECTIVE: To determine whether implantable cardioverter-defibrillator (ICD) treatment is beneficial in elderly patients with life threatening ventricular tachyarrhythmias. DESIGN: Since January 1984, ICDs were implanted in 450 patients to evaluate surgical risk, complications and mean survival in relation to patient age; 81 patients (18%) were < or = 50 years at the time of ICD implant, 254 patients (56%) were between 51 and 64 years, and the remaining 115 (26%) were > or = 65 years. Epicardial lead systems were implanted in 209 patients (46%), while transvenous lead systems were implanted in 241 (54%). RESULTS: 13 patients (3%) died perioperatively, more often after epicardial (11 of 209 patients, 5%) than after transvenous ICD implantation (one of 241 patients, < 1%) (p < 0.05). During a mean (SD) follow up of 28 (24) months (range < 1 to 114 months), 90 patients (20%) died. Of these, nine (2%) died from sudden arrhythmic death; five (1%) died suddenly, probably as a result of non-arrhythmic causes; 55 (12%) died from other cardiac causes (congestive heart failure, myocardial infarction); and 21 (5%) died from non-cardiac causes. The three, five, and seven year survival for arrhythmic mortality was 95% in patients < or = 50 years compared with a three year survival of 93% and a five and seven year survival of 91% in patients of 51 to 64 years, and a three, five, and seven year survival of 99% in patients > or = 65 years. 362 patients (80%) received ICD discharges (21 (43) shocks per patient), with a similar incidence among all three patient groups (< or = 50 years, 80%; 51 to 64 years, 81%; > or = 65 years, 79%). The time interval between ICD implant and the first ICD treatment was shorter in patients > or = 65 years (8 (8) months) than in patients between 51 and 64 years (11 (14) months) or < or = 50 years (11 (11) months) (p < 0.05). Survival time following first appropriate shock was 30 (24) months in patients < or = 50 years, 30 (26) months in patients of 51 to 64 years, and 19 (20) months in patients > or = 65 years. CONCLUSIONS: Elderly patients benefit from ICD treatment, and survive for a considerable time after the first treatment. Therefore, elderly patients should be considered candidates for ICD implantation if life threatening ventricular tachy-arrhythmias are present.

Transvenous defibrillation leads: is there an ideal position of the defibrillation anode?

A potential benefit of two-lead transvenous defibrillation systems is the ability to independently position the defibrillation electrodes, changing the vector field and possibly decreasing the DFT. Using the new two-lead transvenous TVL lead system, we studied whether DFT is influenced by SVC lead position and whether there is an optimal position. TVL leads and Cadence pulse generators were implanted in 24 patients. No intraoperative or perioperative complications were observed. In each patient, the DFTs were determined for three SVC electrode positions, which were tested in random order: the brachiocephalic vein, the mid-RA, and the RA-SVC junction. The mean DFTs in the three positions were not statistically different, nor was any single lead position consistently associated with lower DFTs. However, an optimal electrode position was identified in 83% of patients, and the DFT from the best lead position for each patient was significantly lower than for any one of the electrode positions (P < 0.01). The mean safety margin for the best SVC lead position was approximately 27 J. These results demonstrate the advantage of a two-lead system, as well as the importance of testing multiple SVC lead positions when the patient's condition permits. Both of these factors can decrease the DFT and maximize the defibrillation safety margin. This will become increasingly important as pulse generator capacitors become smaller (as part of the effort to decrease generator size) and the energy output of the generators consequently decreases.

Inhibition of atrial fibrillation by pulmonary vein isolation and auricular resection--experimental study in a sheep model.

OBJECTIVE: The MAZE procedure has proven effective for surgically treating atrial fibrillation, but its acceptance has been limited due to the complex dissection pattern. A new simplified operative technique, that comprises two important components of the MAZE procedure, has been evaluated in an established animal model of induced sustained atrial fibrillation. METHODS: In eight sheep, median sternotomy was performed for cardiopulmonary bypass via femoral and bicaval cannuiation. Bipolar atrial and ventricular electrodes (16) were applied for computerized EKG-sampling. Atrial fibrillation was induced during continuous theophylline infusion (0.5 mg/kg/min) by repetitive (10x) biatrial stimulation. Atrial response was monitored and mapped. The operative procedure was accomplished in induced ventricular fibrillation: Right and left atrial appendices were resected and a circumferential transmural incision around all pulmonary veins was performed and closed. After defibrillation, the atria were stimulated again using the above protocol and EKGs were sampled. RESULTS: Sustained atrial fibrillation was inducible in all animals (80 stimulation episodes, median duration 31 s, 6 incessant episodes) prior to dissection. Post resection of the atrial appendices and pulmonary vein isolation, atrial fibrillation was not inducible in any of the eight animals (80 stimulation episodes). A significant interatrial (104 +/- 13 ms) and atrioventricular (208 +/- 19 ms) conduction delay was observed post dissection. CONCLUSION: We conclude that the described procedure is effective for the inhibition of sustained atrial fibrillation in morphologically unaltered atria. The operative approach involves less dissection than the MAZE procedure, which could facilitate its use in concomitant mitral procedures. The clinical significance of the observed AV-Delay has to be evaluated.

Contractile responses to histamine, serotonin, and angiotensin II are impaired by 17 beta-estradiol in human internal mammary arteries in vitro.

There is accumulating evidence that estrogen replacement therapy protects against the development of coronary atherosclerosis and myocardial infarction in postmenopausal women. The mechanism of this protective effect is uncertain. The purpose of the present study was to determine whether 17 beta-estradiol acutely modifies vascular smooth muscle contractile responses to various agonists in human arteries in vitro. Human mammary artery rings were obtained during aortocoronary bypass operations. Rings were suspended in organ baths for isometric tension measurements. Concentration response curves induced by serotonin (0.01-30 mumol/l), histamine (0.01-300 mumol/l), and angiotensin II (0.1-100 nmol/l) were generated after pre-incubation for 30 min with either 17 beta-estradiol (3 mumol/l) or solvent (0.2% ethanol). The presence of 17 beta-estradiol significantly reduced the maximal contractile effects induced by histamine, serotonin, and angiotensin II, but not by 80 mmol/l potassium chloride. It is concluded that short-term incubation with 17 beta-estradiol reduces the maximal contractile responses to serotonin, histamine, and angiotensin II. These modulating effects of estrogen on vascular tone may contribute to the proposed beneficial role of estrogen replacement therapy on the incidence of myocardial infarction in postmenopausal women.

First experience with a new nonthoracotomy defibrillation lead system.

The clinical efficacy and safety of a new nonthoracotomy defibrillation lead system (TVL lead system, Ventritex, inc., Sunnyvale, Calif.) was studied in patients with ventricular tachycardia or fibrillation. Implantation of the TVL lead system and a Cadence pulse generator (Ventritex, Inc.) was attempted in 27 patients. A subcutaneous patch lead was added if required to achieve adequate defibrillation energy. Patients were monitored for an average of 6 +/- 4 months (range 1 week to 14 months). Implantation was successful in 26 patients (96%). Twenty-three of those patients (88%) were implanted in a lead-alone configuration; the remaining three (12%) required a subcutaneous patch lead. The mean defibrillation threshold was 401 +/- 120 V (12 +/- 7 J) at implantation, 467 +/- 134 V (15 +/- 8 J) at predischarge testing, and 452 +/- 151 V (14 +/- 9 J) at 4-month follow-up. The mean defibrillation threshold at 4 months was not significantly different from that at implant. No deaths, sensing anomalies, infections, lead fractures, or lead dislodgments occurred. One patient required addition of a subcutaneous patch 4 months after device implantation because of an elevated defibrillation threshold. Eight patients (31%) experienced 545 spontaneous arrhythmic episodes, and all episodes were successfully terminated by the device. In conclusion, the TVL lead system combined with Cadence tiered-therapy defibrillator has a high success rate and low complication rate, and it can be recommended for treatment of patients with life-threatening ventricular tachyarrhythmias.

Graft coronary vasculopathy in cardiac transplantation--evaluation of risk factors by multivariate analysis.

The development of coronary vasculopathy is the main determinant of long-term survival in cardiac transplantation. The identification of risk factors, therefore, seems necessary in order to identify possible treatment strategies. Ninety-five out of 397 patients, undergoing orthotopic cardiac transplantation from 10/1985 to 10/1992 were evaluated retrospectively on the basis of perioperative and postoperative variables including age, sex, diagnosis, previous operations, renal function, cholesterol levels, dosage of immunosuppressive drugs (cyclosporin A, azathioprine, steroids), incidence of rejection, treatment with calcium channel blockers at 3, 6, 12, and 18 months postoperatively. Coronary vasculopathy was assessed by annual angiography at 1 and 2 years postoperatively. After univariate analysis, data were evaluated by stepwise multiple logistic regression analysis. Coronary vasculopathy was assessed in 15 patients at 1 (16%), and in 23 patients (24%) at 2, years. On multivariate analysis, previous operations and the incidence of rejections were identified as significant risk factors (P < 0.05), whereas the underlying diagnosis had borderline significance (P = 0.058) for the development of graft coronary vasculopathy. In contrast, all other variables were not significant in our subset of patients investigated. We therefore conclude that the development of coronary vasculopathy in cardiac transplant patients mainly depends on the rejection process itself, aside from patient-dependent factors. Therapeutic measures, such as the administration of calcium channel blockers and regulation of lipid disorders, may therefore only reduce the progress of native atherosclerotic disease in the posttransplant setting.

Arrhythmogenic mortality in heart-transplant candidates.

Sudden cardiac death represents a major problem in patients awaiting heart transplantation (HTx). A retrospective analysis of 1019 patients accepted for HTx revealed a high actuarial risk for sudden death accounting to 14% after 1 year and 20% after 2 years waiting time. Underlying disease and hemodynamic characteristics had no predictive value. The use of implantable cardioverter/defibrillator therapy is discussed.

Valve reconstruction or replacement for long-term biopsy-induced tricuspid regurgitation following heart transplantation.

Tricuspid regurgitation following heart transplantation can become a severe problem in a subset of patients, where medical therapy fails. Operative findings are described and results of subsequent results with surgical intervention including repair and replacement are analysed. Although follow-up is short, tricuspid replacement seems superior to reconstruction following heart transplantation. Best results are obtained, if replacement is performed, before right ventricular function deteriorates.

[Lung transplantation in obstructive diseases]. / Lungentransplantation bei obstruktiven Erkrankungen.

The transplantation of the lung is a therapeutical option in the treatment of patients with terminal lung emphysema. In the presence of limiting prognostic factors, like severe obstruction without massive air trapping and pulmonary hypertension, the results are superior to lung volume reduction. Guidelines for indications, perioperative course and functional development are discussed. Bilateral transplantation provides early rehabilitation due to excellent functional recovery of the lungs.