Siegfried Hagl

Guidelines for Reporting Mortality and Morbidity After Cardiac Valve Interventions

uidelines for Reporting Mortality and Morbidity fter Cardiac Valve Interventions ary W. Akins, MD, D. Craig Miller, MD, Marko I. Turina, MD, icholas T. Kouchoukos, MD, Eugene H. Blackstone, MD, ary L. Grunkemeier, PhD, Johanna J. M. Takkenberg, MD, PhD, irone E. David, MD, Eric G. Butchart, MD, David H. Adams, MD, avid M. Shahian, MD, Siegfried Hagl, MD, John E. Mayer, MD, and ruce W. Lytle, MD The American Association for Thoracic Surgery, Beverly, Massachusetts; The Society of Thoracic Surgeons, Chicago, Illinois; and The European Association for Cardio-Thoracic Surgery, Windsor, Berks, United Kingdom

Interleukin-1 beta promotes matrix metalloproteinase expression and cell proliferation in calcific aortic valve stenosis

Calcific aortic valve stenosis (AS), the main heart valve disease in the elderly, is characterized by extensive remodeling of the extracellular matrix. Matrix metalloproteinases (MMPs) are upregulated in calcific AS and might modulate matrix remodeling. The regulatory mechanisms are unclear. As recent studies have suggested that calcific AS might result from an inflammatory process involving leukocyte invasion and activation, the present study aimed to elucidate the role of the pro-inflammatory cytokine interleukin (IL)-1 beta on MMP expression and cell proliferation in human aortic valves. Immunohistochemistry for leukocytes, IL-1 beta and MMP-1 was performed on aortic valves with (n=6) and without (n=6) calcification obtained at valve replacement or autopsy. Stenotic valves showed marked leukocyte infiltration and associated expression of IL-1 beta and MMP-1. In control valves only scattered leukocytes, low staining for MMP-1 and no staining for IL-1 beta were present. Double-label immunostaining localized IL-1 beta expression mainly to leukocytes and MMP-1 expression to myofibroblasts. Stimulation of cultured human aortic valve myofibroblasts with IL-1 beta lead to a time-dependently increased expression of MMP-1 and MMP-2 by Western blotting and zymography, whereas MMP-9 remained unchanged. Cell proliferation was increased by IL-1 beta as determined by bromodesoxyuridine incorporation. Thus, IL-1 beta may regulate remodeling of the extracellular matrix in calcific AS.

The effect of hemodilution on regional myocardial function in the presence of coronary stenosis

SummaryHemodilution decreases blood viscosity and circulatory input impedance and thus reduces afterload. Its use in treatment of LV power failure has been advocated, but the safe limits of isovolemic hemodilution are not known. Compensation of the reduced O2-capacity of the blood was therefore studied with normal and impaired coronary reserve.In 20 dogs the LAD was stenosed to a degree just not affecting the supplied region and central and coronary hemodynamics were studied. Regional myocardial function was assessed by ultrasound transit time between transducers implanted in the LV wall. Lowering the hematocrit to 15% by isovolumic exchange of blood for Dextran 60 increased CVP (18%), PAP (47%), LAP (64%), LVedP (46%), CO (67%), and flow to the intact area (LCA: 211%). Flow in the stenosed LAD increased slightly. Enddiastolic length (EDL) of LAD dependent, muscle segments rose to 120% and their contraction amplitude ΔL was decreased by 46%. Whereas non-ischemic segments showed compensatory rise in ΔL (38%) at almost constant EDL (+9%). After release of the LAD stenosis EDL and ΔL returned to normal.During progressive anemia myocardial O2-demand is not adequately met if coronary reserve capacity is depleted. Reversion of hypokinesia after removal of the stenosis shows unimpaired myocardial function at a hematocrit as low as 15% provided the coronary circulation is intact.ZusammenfassungWährend Hämodilution nimmt die Blutviskosität ab, und die aortale Eingangsimpedanz sinkt. Die klinische Anwendung bei Linksherzversagen with vorgeschlagen, jedoch sind die zu steckenden Grenzen der isovolämischen Hämodilution weitgehend unbekannt. In dieser Arbeit wurde untersucht, inwieweit die reduzierte O2-Transportkapazität des Blutes unter normaler und eingeschränkter Koronarreserve die Funktion des linken Ventrikels beeinflußt.Im akuten Experiment an 20 Hunden wurde die LAD subkritisch stenosiert und sowohl die Pumpfunktion des linken Ventrikels als auch die Koronarversorgung untersucht. Die regionale Myokardfunktion wurde nach dem Ultraschall-Laufzeitprinzip bestimmt. Dazu wurden piezoelektrische Wandler in die Wand des linken Ventrikels implantiert. Eine schrittweise Senkung des Hämatokrit bis auf 15% erfolgte durch isovolumischen Blutaustausch mit Dextran 60. Als Folge konnte ein Anstieg des CVP (+18%), des PAP (+47%), des LAP (+64%), des LVedP (+46%) und des CO (+67%) verzeichnet werden. Der Blutflu\ in die normal versorgten Myokardbezirke stieg um das dreifache (QLCA: +211%), während in der LAD nur eine geringfügige Flußzunahme registriert wurde. Die enddiastolische Länge EDL in den minderversorgten Myokardbezirken erhöhte sich auf 120%; deren Kontraktionsamplitude ΔL fiel jedoch um 46% ab. Zugleich wurde in den nichtischämischen Myokardarealen ein kompensatorischer Anstieg der ΔL um +38% bei nur minimal vergrößerter EDL (+9%) deutlich. Nach Entfernung der Stenose kehrten die EDL und ΔL auf ihren Ausgangswert zurück.Bei zunehmender Anämie kann der Sauerstoffbedarf in Myokardbezirken mit erschöpfter Koronarreserve nicht mehr in ausreichendem Maße gedeckt werden. In diesen Bereichen entstehl eine ischämische Dysfunktion. Die Gesamtventrikelfunktion kann jedoch durch kompensatorische Hyperkinesie des Restventrikels erhalten bleiben. Selbst bei einem Hämatokrit von 15% ist die Hypokinesie nach Eröffnung der Stenose in den bisland ischämischen Arealen reversibel.

Does the completeness of revascularization affect early survival after coronary artery bypass grafting in elderly patients

OBJECTIVE Usefulness and risks of incomplete versus complete revascularization are still matters of ongoing discussions. Because an increasing number of elderly patients are undergoing coronary artery bypass grafting (CABG), the question arises whether a less extensive surgical approach is more prudent than complete revascularization. METHODS Of 6531 patients undergoing isolated CABG, 859 were 75 and older at the time of operation. Mean age of the 859 patients was 77+/-2.7 years (median: 76 years); 65% were men. Follow-up enquiry by questionnaire was performed at the 180th postoperative day with a completeness of 95.6%. Assessment of the impact of incomplete revascularization utilized both multivariable analysis and propensity score matching to account for selection factors. RESULTS Incomplete revascularization was performed in 133 patients (16%). The most common reasons for incomplete revascularization were small vessels (55%) and massive calcification (32%). Mortality until 180 days after CABG was higher (n=32; 24%) after incomplete than after complete revascularization (n=105; 15%; P=0.005). By logistic multivariable regression, incomplete revascularization was identified as an independent risk factor for death (Odds ratio, 1.8; P=0.015). By time-related analysis, incomplete revascularization predominantly affected the early period after CABG (P=0.001). Aortic cross clamping time was only slightly shorter for the group with incomplete (59+/-27 min (median: 55 min) vs. 63+/-26 min (median: 58 min); P=0.1). CONCLUSIONS Incomplete revascularization increases the early risk of death after CABG in patients aged 75 years and older. The potential compensating benefit of the shorter aortic cross clamping time does not outweigh the advantages of complete revascularization. Thus, in the era of high-volume interventional approaches and minimally invasive techniques, the advantages of complete revascularization need to be considered.

Adjustable tricuspid valve annuloplasty assisted by intraoperative transesophageal color Doppler echocardiography

Intraoperative transesophageal echocardiography (TEE) can play a major role in active guidance of cardiac surgery. This study describes a new application of TEE for assisting tricuspid suture annuloplasty. Twenty-five patients (aged 52 +/- 11 years) who underwent mitral valve replacement and tricuspid valve annuloplasty were studied intraoperatively by TEE. After cardiopulmonary bypass, the suture annuloplasty was adjusted on the beating heart until palpable regurgitation was eliminated. Further adjustment of the suture was performed under echocardiographic guidance until color Doppler flow imaging showed the most adequate correction of tricuspid regurgitation (TR). A significant decrease in the semiquantitative grade of TR, of regurgitant jet area and of the ratio jet area/right atrial area was obtained when the suture was adjusted under echocardiographic guidance. The peak inflow velocity and the gradient across the tricuspid valve did not show significant changes throughout the procedures. The results showed that the tricuspid suture annuloplasty guided by TEE enables a substantial reduction in residual TR without creating valve stenosis.

Myocardium from Patients with Heart Failure Due To Mitral and Aortic Valve Disease

We determined stimulation rates of cardiac adenylate cyclase activity by isoproterenol and impromidine in particulate sarcolemmal membrane preparations from human papillary muscles resected during open heart replacement of mitral and aortic valves. In addition, specific receptor binding studies with [3H]dihydroalprenolol [( 3H]DHA) to cardiac beta-receptors and [3H]tiotidine [( 3H]TIOT) to cardiac H2-receptors were carried out in the same preparations. Compared with the response in patients with pure mitral valve stenosis, the response of cardiac adenylate cyclase activity to isoproterenol showed a marked decrease (-90%) in patients with combined mitral and aortic valve disease, corresponding to the severity of degree of insufficiency at both valves. Similar changes were observed in receptor binding studies with [3H]DHA, in which the reduction of beta-receptor density was of the same order of magnitude. In contrast, stimulation of the enzyme by impromidine and binding capacity of [3H]TIOT to cardiac H2-receptors were found to be unaltered in the same membrane preparations of all 16 patients. We conclude that treatment with H2-agonists may be a new therapeutic approach to congestive heart failure, especially in patients not responding to beta-adrenoceptor stimulation with beta-sympathomimetic drugs.

Expression and activity of matrix metalloproteinase-2 in calcific aortic stenosis.

Die degenerativ- kalzifizierende Aortenstenose ist die häufigste Herzklappenerkrankung und Hauptursache eines Herzklappenersatzes im fortgeschrittenen Alter. Sie führt zu massiver Verkalkung sowie zu einem extensivem Umbau der extrazellulären Matrix; es wird vermutet, dass Matrix-Metalloproteinasen (MMPs) hierbei eine pathogenetische Rolle spielen. Wir untersuchten daher die Expression der Gelatinase MMP-2 und MMP-9 sowie ihres endogenen Inhibitors „Tissue Inhibitor of Metalloproteinase-2“ (TIMP-2) sowie die gelatinolytische Aktivität in 24 stenotischen und 8 normalen Aortenklappen. In der immunhistochemischen Färbung zeigten die stenotischen Klappen eine signifikant höhere Färbeintensität für MMP-2 und TIMP-2 im Vergleich zu den Kontrollklappen. Eine geringe Färbung von MMP-9 war ausschließlich bei stenotischen Klappen nachweisbar. In der in situ Zymographie wiesen normale Klappen eine minimale basale gelatinolytische Aktivität auf, die durch Zugabe des MMP-Aktivators p-Aminophenymercuroazetat (APMA) signifikant gesteigert werden konnte. In stenotischen Klappen war hingegen eine deutlich vermehrte Enzymaktivität nachweisbar, die durch Zugabe von APMA nicht mehr signifikant gesteigert werden konnte. MMP-2 und TIMP-2 zeigen somit eine differentielle Expression bei kalzifizierender Aortenstenose. MMP-2 liegt in normalen Klappen vorwiegend als inaktives Proenzym vor, in stenotischen Klappen hingegen in der aktivierten Form. Diese Ergebnisse sprechen für einen durch MMP-2 vermittelten Umbau der extrazellulären Matrix bei kalzifizierender Aortenstenose. Calcific aortic stenosis is the main heart valve disease in the elderly, leading to massive focal calcification and thickening of the valve cusps. Matrix metalloproteinases (MMPs) are thought to contribute to this process. Therefore, the study assessed the expression of the gelatinases MMP-2 and MMP-9 and the endogenous tissue inhibitor of metalloproteinase (TIMP)-2 as well as the gelatinolytic activity in normal and stenotic valves. Human tricuspid aortic valves with and without calcific aortic stenosis were studied by immunohistochemistry for MMP-2, MMP-9 and TIMP-2. The gelatinolytic activity in native valve sections was assessed by gelatin in situ zymography with or without addition of the MMP activator p-aminophenymercuric acetate (APMA). Staining intensities for MMP-2 and TIMP-2 were elevated in stenotic valves as compared to controls. Minor staining of MMP-9 was present exclusively in stenotic valves. The morphologic distribution of gelatinolytic activity was comparable to the staining pattern of MMP-2, and since MMP-9 immunostaining demonstrated only a low number of positive cells, the observed gelatinolytic activity is likely due to MMP-2. Gelatinolytic activity was low in normal valves but significantly increased by the MMP activator APMA. In contrast, stenotic valves showed a strong basal gelatinolytic activity that could not be significantly enhanced by APMA suggesting that MMP-2 is present as a latent pro-enzyme in normal valves and activated in stenotic valves. Thus, MMP-2 might be involved in the matrix remodeling during calcific aortic stenosis.

Kill kinetics ofBorrelia burgdorferi and bacterial findings in relation to the treatment of lyme borreliosis

SummaryFor a better understanding of the persistence ofBorrelia burgdorferi sensu lato (s.l.) after antibiotic therapy the kinetics of killingB. burgdorferi s.l. under amoxicillin, doxycycline, cefotaxime, ceftriaxone, azithromycin and penicillin G were determined. The killing effect was investigated in MKP medium and human serum during a 72 h exposure to antibiotics. Twenty clinical isolates were used, including ten strains ofBorrelia afzelii and ten strains ofBorrelia garinii. The results show that the kinetics of killing borreliae differ from antibiotic to antibiotic. The killing rate of a given antibiotic is less dependent on the concentration of the antibiotic than on the reaction time. Furthermore, the data show that the strains ofB. afzelii andB. garinii have a different reaction to antibiotics used in the treatment of Lyme borreliosis and that different reactions to given antibiotics also exist within one species. TheB. garinii strains appear to be more sensitive to antibiotics used in therapy. Furthermore, the persistence ofB. burgdorferi s.l. and clinical recurrences in patients despite seemingly adequate antibiotic treatment is described. The patients had clinical disease with or without diagnostic antibody titers toB. burgdorferi.ZusammenfassungDie bakterizide Aktivität von Amoxicillin, Doxycyclin, Cefotaxim, Ceftriaxon, Azithromycin und Penicillin G gegenBorrelia burgdorferi s.l. Stämme wurde in MKP-Medium und Humanserum während der 72 Stunden Einwirkungszeit untersucht. Die Antiborrelienwirkung der Antibiotika wurde an 20 Patientenisolaten, zehnBorrelia afzelii und zehnBorrelia garinii Stämmen, getestet. Der Abtötungseffekt der einzelnen Antibiotika auf getestete Stämme ist sehr unterschiedlich. Die Unterschiede hinsichtlich der Keimreduktion bestehen zwischen den Stämmen derB. afzelii undB. garinii species als auch zwischen den Stämmen innerhalb einer Spezies. Der Anteil der abgetöteten Borrelien ist weniger abhängig von der Konzentration des Antibiotikums als von der Einwirkungszeit. DieB. garinii Stämme sind offensichtlich empfindlicher gegen die in der Therapie eingesetzten Antibiotika. Die Persistenz vonB. burgdorferi s.l. und Rezidive der Erkrankung nach der Antibiotikatherapie werden diskutiert.For a better understanding of the persistence ofBorrelia burgdorferi sensu lato (s.l.) after antibiotic therapy the kinetics of killingB. burgdorferi s.l. under amoxicillin, doxycycline, cefotaxime, ceftriaxone, azithromycin and penicillin G were determined. The killing effect was investigated in MKP medium and human serum during a 72 h exposure to antibiotics. Twenty clinical isolates were used, including ten strains ofBorrelia afzelii and ten strains ofBorrelia garinii. The results show that the kinetics of killing borreliae differ from antibiotic to antibiotic. The killing rate of a given antibiotic is less dependent on the concentration of the antibiotic than on the reaction time. Furthermore, the data show that the strains ofB. afzelii andB. garinii have a different reaction to antibiotics used in the treatment of Lyme borreliosis and that different reactions to given antibiotics also exist within one species. TheB. garinii strains appear to be more sensitive to antibiotics used in therapy. Furthermore, the persistence ofB. burgdorferi s.l. and clinical recurrences in patients despite seemingly adequate antibiotic treatment is described. The patients had clinical disease with or without diagnostic antibody titers toB. burgdorferi. Die bakterizide Aktivität von Amoxicillin, Doxycyclin, Cefotaxim, Ceftriaxon, Azithromycin und Penicillin G gegenBorrelia burgdorferi s.l. Stämme wurde in MKP-Medium und Humanserum während der 72 Stunden Einwirkungszeit untersucht. Die Antiborrelienwirkung der Antibiotika wurde an 20 Patientenisolaten, zehnBorrelia afzelii und zehnBorrelia garinii Stämmen, getestet. Der Abtötungseffekt der einzelnen Antibiotika auf getestete Stämme ist sehr unterschiedlich. Die Unterschiede hinsichtlich der Keimreduktion bestehen zwischen den Stämmen derB. afzelii undB. garinii species als auch zwischen den Stämmen innerhalb einer Spezies. Der Anteil der abgetöteten Borrelien ist weniger abhängig von der Konzentration des Antibiotikums als von der Einwirkungszeit. DieB. garinii Stämme sind offensichtlich empfindlicher gegen die in der Therapie eingesetzten Antibiotika. Die Persistenz vonB. burgdorferi s.l. und Rezidive der Erkrankung nach der Antibiotikatherapie werden diskutiert.

Endothelin-A and -B antagonists protect myocardial and endothelial function after ischemia/reperfusion in a rat heart transplantation model

OBJECTIVE Previous studies suggested that endothelin-1 (ET-1) may play a pathophysiological role in myocardial ischemia/reperfusion injury. This study was designed to investigate the effects of the selective ET-A receptor antagonist BQ123 and the selective ET-B receptor antagonist BQ788 on myocardial and endothelial function after reversible deep hypothermic ischemia in a heterotopic rat heart transplantation model. METHODS Isogenic intraabdominal heterotopic transplantation was performed in Lewis rats. After 1 h of cold ischemic preservation reperfusion was started either after application of placebo (control), BQ123 (3 mumol/kg/min). BQ788 (3 mumol/kg/min), ET-1 (8 pmol/kg/min) or simultaneous infusion of BQ123 or BQ788 and ET-1, respectively (n = 12 each). An implanted balloon was used to obtain pressure-volume relations of the transplanted heart. Myocardial blood flow (MBF) was assessed by the hydrogen-clearance method. Measurements were taken after 1 and 24 h of reperfusion. Endothelium-dependent vasodilation to acetylcholine (ACH) and endothelium-independent vasodilation to sodium nitroprusside were also determined. RESULTS Both BQ123 and BQ788 significantly improved myocardial and endothelial functional recovery during early reperfusion, whereas ET-1 significantly impaired myocardial and endothelial function. Simultaneous infusion of ET-1 diminished the effects of BQ123 and BQ788. Although myocardial function and baseline MBF were similar in all groups after 24 h of reperfusion, endothelium dependent vasodilation to ACH was still significantly higher in the BQ123 and BQ788 groups and lower in the ET-1 groups (p < 0.05). CONCLUSIONS These results suggest that endogenous ET release is involved in the pathogenesis of reperfusion injury after heart transplantation. ET-A and ET-B receptor antagonists may be useful to reduce ischemia/reperfusion injury.

Role of nitric oxide in intrarenal hemodynamics in experimental diabetes mellitus in rats

The role of nitric oxide (NO) in the regulation of the intrarenal microcirculation in streptozotocin (STZ)-induced diabetes mellitus in rats is not clear. We examined renal cortical and papillary hemodynamics in STZ rats and determined the effects of systemic inhibition and stimulation of NO synthesis. Renal blood flow in cortical (QCC), and inner medullary ascending (QAV) and descending (QDV) vasa recta capillaries was measured by fluorescence videomicroscopy in STZ Munich-Wistar rats and nondiabetic control rats. Ten days after STZ injection (80 mg/kg ip), basal QCC and QDV were significantly greater in STZ rats (n = 16) compared with control rats (n = 15). Infusion of N(G)-monomethyl-L-arginine (L-NMMA, 15 mg/kg bolus, 500 microg. min(-1). kg(-1) iv) decreased Q(CC) (-41%), QAV (-38%), and QDV (-37%) in control rats (n = 6) and to a significantly greater magnitude than in STZ rats (n = 7), Q(CC) (-14%), QAV (-20%), and QDV (-25%). Coinfusion of L-arginine (L-Arg, 1 mg. kg(-1). min(-1) iv) with L-NMMA increased Q(CC) to a significantly greater extent (P < 0.01) in control rats compared with STZ rats. In subsequent studies, infusion of L-Arg alone increased QCC (+50%), QAV (+16%), and QDV (+11%) in control rats (n = 5) but had no effect in STZ rats (n = 5). These results show that the response of renal cortical and papillary capillary blood flow to both inhibition and stimulation of NO synthesis is attenuated in the early onset of STZ-diabetes mellitus rats compared with control rats.The role of nitric oxide (NO) in the regulation of the intrarenal microcirculation in streptozotocin (STZ)-induced diabetes mellitus in rats is not clear. We examined renal cortical and papillary hemodynamics in STZ rats and determined the effects of systemic inhibition and stimulation of NO synthesis. Renal blood flow in cortical (QCC), and inner medullary ascending (QAV) and descending (QDV) vasa recta capillaries was measured by fluorescence videomicroscopy in STZ Munich-Wistar rats and nondiabetic control rats. Ten days after STZ injection (80 mg/kg ip), basal QCC and QDV were significantly greater in STZ rats ( n = 16) compared with control rats ( n = 15). Infusion of N G-monomethyl-l-arginine (l-NMMA, 15 mg/kg bolus, 500 μg ⋅ min-1 ⋅ kg-1iv) decreased QCC (-41%), QAV (-38%), and QDV (-37%) in control rats ( n = 6) and to a significantly greater magnitude than in STZ rats ( n = 7), QCC (-14%), QAV (-20%), and QDV (-25%). Coinfusion ofl-arginine (l-Arg, 1 mg ⋅ kg-1 ⋅ min-1iv) with l-NMMA increased QCC to a significantly greater extent ( P < 0.01) in control rats compared with STZ rats. In subsequent studies, infusion ofl-Arg alone increased QCC (+50%), QAV (+16%), and QDV (+11%) in control rats ( n = 5) but had no effect in STZ rats ( n = 5). These results show that the response of renal cortical and papillary capillary blood flow to both inhibition and stimulation of NO synthesis is attenuated in the early onset of STZ-diabetes mellitus rats compared with control rats.