[The use of Deep Inferior Epigastric Vessels to Revascularise Free Flaps for Reconstruction of Complex Oncosurgical Defects of the Thigh and the Abdomen]. / Epifaszial verlagerte tiefe inferiore epigastrische Gefäße als Anschlussgefäße für die mikrochirurgische Rekonstruktion komplexer onkochirurgischer Defekte des Abdomens und des Oberschenkels.

BACKGROUND: The resection of large soft-tissue sarcoma requires reconstruction with free flaps. The choice of recipient vessels is crucial for the success of surgery. PATIENTS: We report four cases with large soft-tissue sarcomas with complex anatomical relationships: two tumors of the thigh surrounding the femoral neurovascular structures and two tumors of the abdomen with infiltration of the thorax and the abdomen. All cases received multimodal interdisciplinary treatment. The anterolateral thigh (ALT) flap and the latissimus dorsi (LD) flap were employed twice for defect coverage in this series. In all cases the deep inferior epigastric (DIE) vessels were transposed to the subcutaneous compartment and used as recipient vessels. RESULTS: The mean duration of surgery was 694 ±â€…149 minutes. The mean weight of the tumor specimen was 3069 ±â€…1267 g. Three flaps healed primarily and one exhibited a minor necrosis, which was treated by excision and secondary suture. There were no cases of abdominal herniation due to the transposition of vessels. CONCLUSION: Transposition of DIE-vessels to the subcutaneus compartment is a good alternative for free flap revascularisation in this patient group. In this position, the vessels are easily accessed and used for microsurgery. This technical modification increases the reconstructive possibilities in large and previously irradiated surgical defects.

Effect of beta-blockers on free radical-induced cardiac contractile dysfunction.

BACKGROUND: We examined the effects of hydroxyl radicals (OH.) on human myocardial contractility and on sarcoplasmic reticulum Ca(2+)-ATPase (SERCA) activity and the effects of the beta-receptor antagonists metoprolol, carvedilol, and its metabolite BM-910228. METHODS AND RESULTS: Isometric force of contraction was determined in isolated human myocardium. H(2)O(2) 1 mmol/L and Fe(3+)-nitrilotriacetic acid (Fe(3+)-NTA) 0.1 mmol/L used for generation of OH. induced a decrease in basal force of contraction and an increase in diastolic tension in atrial and left ventricular myocardial preparations. After challenge with OH., the maximum positive inotropic response to Ca(2+) 1.8 to 15 mmol/L was decreased by 60% and by 39%, respectively. The effects of OH. could be blocked by catalase. Carvedilol and its metabolite BM-910228 attenuated the OH.-induced impairment of the inotropic response to Ca(2+) in atrial myocardial preparations. Metoprolol had no significant effect. The stimulation frequency (0.5 to 3.0 Hz)-dependent increase in force of contraction and decrease in diastolic tension were abolished after exposure of atrial trabeculae to OH. In parallel, SERCA activity was decreased by OH. concentration-dependently, as determined in myocardial membrane preparations. BM-910228 partially restored the force-frequency relationship and preserved SERCA activity. CONCLUSIONS: OH. radicals induce an impairment of contraction and relaxation and an attenuation of the force-frequency relationship in human myocardium accompanied by an inhibition of SERCA. Carvedilol and BM-910228 partly prevented OH.-induced contractile dysfunction. These observations could explain the improvement of ejection fraction in heart failure trials with carvedilol without a restoration of beta-adrenergic receptor density.

Effects of endotoxin on human myocardial contractility involvement of nitric oxide and peroxynitrite.

OBJECTIVES: This study examined the effects of endotoxin on cardiac contractility in human myocardium. BACKGROUND: In animal myocardium, endotoxin and cytokine treatment led to enhanced inducible nitric oxide synthase (iNOS) expression and contractile dysfunction. Effects in human myocardium are unknown. METHODS: Left ventricular myocardial preparations from failing (n = 18) and nonfailing (n = 5) human hearts were incubated for 6 and 12 h in tyrode solution or in tyrode plus lipopolysaccharides (LPS), with LPS plus N(G)-mono-methyl-L-arginine (L-NMMA), with LPS plus hemoglobin or with LPS plus the superoxide scavenger 4,5-dihydroxy-1,3-benzene disulfonic acid (Tiron). Force of contraction in response to isoprenaline (0.001 to 3 micromol/liter) was determined in electrically stimulated muscle preparations. The iNOS mRNA expression was examined by in situ hybridization and by polymerase chain reaction. The cyclic guanosine monophosphate (cGMP) levels were determined by radioimmunoassay. RESULTS: Isoprenaline concentration dependently increased force of contraction. Six and 12 hours of LPS treatment of failing myocardium decreased maximum inotropic response to isoprenaline by 54% (p = 0.009) and by 69% (p = 0.0023), respectively. In nonfailing myocardium, 12 h of LPS treatment decreased maximum inotropic effect of isoprenaline by 66% (p < 0.001). The LPS effects were attenuated by L-NMMA, hemoglobin and also Tiron. The iNOS mRNA was expressed in all LPS-treated preparations but also in most control myocardial preparations. In situ hybridization revealed iNOS expression within cardiac myocytes. There was no increase in myocardial cGMP content in response to endotoxin. CONCLUSIONS: Endotoxin exposure of human myocardium leads to a depression of cardiac contractility, which is mediated by enhanced iNOS activity and release of nitric oxide (NO). Consecutive reaction of NO with superoxide and formation of peroxynitrite may contribute to the decrease in force of contraction.

Sarcoplasmic reticulum Ca2+ATPase and phospholamban mRNA and protein levels in end-stage heart failure due to ischemic or dilated cardiomyopathy.

Abnormalities in intracellular Ca2+ handling play a crucial role in the pathogenesis of heart failure. The reduced capacity of failing human myocardium to restore low resting Ca2+ levels during diastole has been explained by the impairment of Ca2+ uptake into the sarcoplasmic reticulum (SR) via the SR Ca2+ATPase. It is unclear whether Ca2+ATPase function, protein levels, and mRNA steady-state levels correspond to one other, and whether the cause of heart failure, namely idiopathic dilated or ischemic cardiomyopathy, produces different changes. The present study examined SR Ca2+ATPase activity and both mRNA and protein levels of SR Ca2+ATPase, phospholamban, and Gi alpha 2 in left ventricular myocardium from eight nonfailing hearts, from eight hearts of patients with idiopathic dilated cardiomyopathy (DCM), and from six hearts from patients with ischemic cardiomyopathy (ICM). Compared to nonfailing myocardium, the activity of the SR Ca2+ATPase was significantly reduced in failing myocardium from patients with DCM (36%, P < 0.01) and from patients with ICM (37%, P < 0.001). Significantly lower levels of SR Ca2+ATPase mRNA levels (55% and -56%, P < 0.001 for DCM and ICM, respectively) and phospholamban mRNA (45%, P < 0.001 for DCM; 31%, P < 0.05 for ICM) were observed in failing than in nonfailing myocardium. In contrast, no significant changes were observed at the level of proteins, Gi alpha 2 mRNA and protein levels were both significantly increased in failing myocardium. There were no differences between idiopathic dilated and ischemic cardiomyopathy concerning the examined parameter. It is concluded that reduced SR Ca2+ATPase activity contributes to an altered intracellular Ca2+ handling by the SR in both dilated and ischemic cardiomyopathic hearts. However, changes in SR Ca2+ATPase and phospholamban steady-state protein levels do not contribute to these alterations. The dissociation between protein and mRNA levels provides evidence for a posttranscriptional or post-translational regulation of these proteins. The observed alterations are not dependent on the underlying cause of end-stage heart failure.

Different intrinsic activities of bucindolol, carvedilol and metoprolol in human failing myocardium.

1. Clinical studies have shown different effects of beta-blockers on the beta-adrenergic system, tolerability and outcome in patients with heart failure. 2. The study examines beta-adrenoceptor-G-protein coupling and intrinsic activity of bucindolol, carvedilol and metoprolol in human ventricular myocardium. 3. Radioligand binding studies ([(125)I]-Iodocyanopindolol) were performed in membrane preparations of human failing and nonfailing myocardium. Functional experiments were carried out in isolated muscle preparations of human left ventricular myocardium from failing hearts. 4. Bucindolol and carvedilol bound non-selectively to beta(1)- and beta(2)-adrenoceptors and exerted guanine nucleotide modulatable binding. Metoprolol was 35-fold beta(1)-selective and lacked guanine nucleotide modulatable binding. 5. All beta-blockers antagonized isoprenaline-induced enhancement of contractility. 6. In preparations in which the coupling of the stimulatory G-protein to adenylate cyclase was facilitated by forskolin, bucindolol increased force of contraction in three and decreased it in five experiments. Carvedilol increased force in one and decreased it in six experiments. Metoprolol decreased force in all experiments by 89. 4+/-2.2% (P<0.01 metoprolol vs carvedilol and bucindolol). The negative inotropic effect of metoprolol was antagonized by bucindolol. 7. It is concluded that differences in intrinsic activity can be detected in human myocardium and have an impact on cardiac contractility. In human ventricular myocardium, bucindolol displays substantially higher intrinsic activity than metoprolol and carvedilol. Bucindolol can behave as partial agonist or partial inverse agonist depending on the examined tissue. 8. Differences in intrinsic activity may contribute to differences in beta-adrenoceptor regulation and possibly to differences in tolerability and outcomes of patients with heart failure.

Characterization of beta(1)-selectivity, adrenoceptor-G(s)-protein interaction and inverse agonism of nebivolol in human myocardium.

Intrinsic activity and beta(1)-selectivity are important features of beta-blockers in the treatment of patients with coronary syndromes and heart failure. In human myocardium, intrinsic activity and beta(1)-selectivity of the novel beta-adrenoceptor antagonist nebivolol have not yet been determined. The study examines intrinsic activity, beta-adrenoceptor-G-protein coupling and beta(1)-selectivity of nebivolol and bisoprolol in human ventricular myocardium. Furthermore, intrinsic activity of both compounds is compared to the one of bucindolol, carvedilol and metoprolol in human atrial myocardium. Radioligand binding studies ([(125)I]-lodocyanopindolol) were performed on membrane preparations of human failing and nonfailing myocardium and on COS-7 cells transfected with human beta(1)- and beta(2)-adrenoceptors, respectively. Functional experiments were carried out on isolated muscle preparations of human left ventricular and right atrial myocardium from failing and nonfailing hearts. Radioligand binding studies reveal 3 - 4 fold beta(1)-selectivity for nebivolol and 16 - 20 fold beta(1)-selectivity for bisoprolol in human myocardium. In COS-7-cells, beta(1)-selectivity is 3 fold for nebivolol and 15 fold for bisoprolol. Neither the binding of nebivolol nor of bisoprolol is affected by the presence of guanylylimidodiphosphate (Gpp(NH)p). Nebivolol and bisoprolol exert similar inverse agonist activity in human ventricular as well as atrial myocardium. In atrial myocardium, inverse agonism of both compounds is higher compared to bucindolol, equal to carvedilol and lower compared to metoprolol. Favourable haemodynamic effects of nebivolol in humans are not due to beta(1)-selectivity or partial agonist activity of this agent. Other mechanisms, i.e. the production of nitric oxide, may thus be responsible for its unique haemodynamic profile.

Mitral valve remodeling using autologous pericardium: an experimental study.

The aim of this study was to assess in vivo the efficacy of a new technique for remodeling the mitral valve. In 6 dogs during cardiopulmonary bypass and cardioplegic cardiac arrest, both mitral valve leaflets were totally separated from the mitral ring and resected subtotally, leaving intact their narrow margins with insertion sites of the chordae tendineae of the first and second order. To mimic pathologic conditions, the chordae tendineae were then altered by placing two shortening sutures for every chordal stem. Based on standardized geometric calculations and using autologous pericardium treated with 0.62% glutaraldehyde solution, the new leaflets were then remodeled intraoperatively and sutured in place, merging them with the subvalvular apparatus and the native mitral ring. After restoration of stable circulatory conditions, valve function was evaluated under rest and defined loading conditions using a 5.0-MHz ultrasound transducer, applied epicardially. We found that intraoperative remodeling of the mitral valve leaflets using autologous pericardium with preservation of the subvalvular apparatus is possible and reproducible, and can be performed even when the subvalvular apparatus is altered morphologically. Functionally, the remodeled valve proved to be satisfactory under conditions of rest and stress. The benefits conferred by autologous tissue, the reproducibility of the surgical technique, the good functionality of the remodeled valve, and the preservation of the subvalvular apparatus could make this technique a useful surgical alternative for extensive mitral valve reconstruction procedures in pediatric and adult patients.

Effects of angiotensin II and angiotensin-converting enzyme inhibitors on human myocardium.

Human myocardial angiotensin II receptors and the angiotensin AT1 and AT2 receptor subtypes were characterised using the partial angiotensin II receptor agonist [125I][Sar1,IIe8]angiotensin II and the selective antagonists losartan (2-n-butyl-4-chloro-5-hydroxymethyl-1-[2'((1H-tetrazol-5-yl)biphen yl-4-yl)- methyl]imidazole) and PD 123177 (1-[(4-amino-3-methylphenyl)methyl]-5-(diphenyl-acetyl)- 4,5,6,7-tetrahydro-1H-imidazol[4,5-c]pyridine-6-carboxylic acid). The density of angiotensin II receptors was higher in atrial than in ventricular myocardium. Angiotensin AT2 receptors were predominant in atria and ventricles (80-85% of total angiotensin II receptors). Only in isolated, electrically driven atrial trabeculae but not in ventricular preparations, angiotensin II did produce a concentration-dependent positive inotropic effect, which was antagonized exclusively by the angiotensin AT1 receptor antagonist losartan and which amounted to about 20% of the positive inotropic effect of milrinone and isoprenaline. The application of the angiotensin-converting enzyme inhibitors captopril, enalaprilat and ramiprilat had no inotropic effect in either tissue. It is concluded that angiotensin AT1 receptors exclusively mediate direct positive inotropic effects in atrial myocardium. Since angiotensin-converting enzyme inhibitors do not produce any inotropic effect, tonic regulation of basal force of contraction by angiotensin II does not occur.

Risk stratification in heart surgery: comparison of six score systems.

OBJECTIVE: Risk scores have become an important tool in patient assessment, as age, severity of heart disease, and comorbidity in patients undergoing heart surgery have considerably increased. Various risk scores have been developed to predict mortality after heart surgery. However, there are significant differences between scores with regard to score design and the initial patient population on which score development was based. It was the purpose of our study to compare six commonly used risk scores with regard to their validity in our patient population. METHODS: Between September 1, 1998 and February 28, 1999, all adult patients undergoing heart surgery with cardiopulmonary bypass in our institution were preoperatively scored using the initial Parsonnet, Cleveland Clinic, French, Euro, Pons, and Ontario Province Risk (OPR) scores. Postoperatively, we registered 30-day mortality, use of mechanical assist devices, renal failure requiring hemodialysis or hemofiltration, stroke, myocardial infarction, and duration of ventilation and intensive care stay. Score validity was assessed by calculating the area under the ROC curve. Odds ratios were calculated to investigate the predictive relevance of risk factors. RESULTS: Follow-up was able to be completed in 504 prospectively scored patients. Receiver operating characteristics (ROC) curve analysis for mortality showed the best predictive value for the Euro score. Predictive values for morbidity were considerably lower than predictive values for mortality in all of the investigated score systems. For most risk factors, odds ratios for mortality were substantially different from ratios for morbidity. CONCLUSIONS: Among the investigated scores, the Euro score yielded the highest predictive value in our patient population. For most risk factors, predictive values for morbidity were substantially different from predictive values for mortality. Therefore, development of specific morbidity risk scores may improve prediction of outcome and hospital cost. Due to the heterogeneity of morbidity events, future score systems may have to generate separate predictions for mortality and major morbidity events.

Intracoronary shunt insertion prevents myocardial stunning in a juvenile porcine MIDCAB model absent of coronary artery disease.

OBJECTIVE: The relevance of regional LV myocardial ischemia/reperfusion induced by temporary left anterior descending (LAD) coronary artery occlusion during minimally invasive direct coronary artery bypass (MIDCAB) grafting is controversial. The purpose of our study was (1) to determine the impact of conventional LAD occlusion during left internal thoracic artery (LITA)-LAD anastomosis on regional LV myocardial ischemia and function, and (2) to evaluate if intra-LAD shunt insertion during LITA-LAD anastomosis prevents potential regional LV ischemia and dysfunction in a pig model. METHODS: In 20 anesthetized, mechanically ventilated pigs we performed LITA-LAD anastomosis on the beating heart without cardiopulmonary bypass during either 15 min LAD occlusion (occlusion-group; n = 10) or 15 min intra-LAD shunt insertion to maintain blood supply to the myocardium beyond the anastomosis (shunt-group; n = 10). Besides standard hemodynamics we determined the global and regional LV wall motion score index (WMSI) using epimyocardial echocardiography. To quantitate structural myocardial alteration we determined the inducible heat-shock protein-70 (HSP-70) in LV anterior wall myocardial biopsies. Data were recorded at baseline, at 15 min of LAD occlusion or shunt insertion, respectively, and at 30 min of reperfusion. At the end of the experiments we determined myocardial adenine nucleotide (ATP, ADP, AMP) and glycogen content. RESULTS: In both groups WMSI was not significantly different at 15 min LAD occlusion or shunt insertion, respectively, as compared to baseline. However, at 30 min reperfusion both global and regional WMSI demonstrated significant LV dysfunction in the occlusion-group, whereas LV function in the shunt-group remained normal. This was associated with higher myocardial HSP-70 expression in the occlusion-group (P < 0.05). Myocardial adenine nucleotide and glycogen contents were significantly better preserved in the shunt-group. CONCLUSIONS: Our data show that in a porcine MIDCAB model 15 min LAD occlusion and 30 min reperfusion result in significant myocardial stunning. In contrast, maintenance of LAD perfusion using intracoronary shunt insertion minimizes ischemia/reperfusion injury and prevents regional LV dysfunction. Although our experiments were conducted in healthy pig hearts absent from coronary artery disease, similar results may--at least partially--be expected in humans, and thus, intracoronary shunts could be a useful tool for myocardial protection during 'off-pump revascularization'.

Current indication for endovascular treatment of thoracic aneurysms.

The morbidity and mortality for open treatment of thoracic aortic aneurysms have declined over the years, but it is still a major clinical problem. The reason for the mortality is in almost 50% of the cases cardiac failure. Endoluminal treatment of abdominal aortic aneurysm is widely distributed and with promising results, although not as free from complications as expected 10 years ago. This technique has also been adopted for the thoracic aortic aneurysm as the trauma is much less than in open surgery. In our own personal series no specific workup for coronary heart disease has been made and the mortality of stentgrafting of the thoracic aorta was 2.4%. A survey of the world literature, including elective and acute dissections and aneurysms revealed 642 patients treated with stentgraft with a mortality of 6.2%, although no cardiologic work up had been performed. These numbers compete well with those of open surgery, but a systematic prospective comparison would be needed in order to state the real mortality in both groups.

VDD-pacemaker in children--a long-term therapy?

AIMS: Transvenous AV-synchronous pacing in children started with the invention of smaller sized VDD leads and miniaturization of pacemakers. Whether or not this is a favourable long-term therapy was retrospectively investigated by us based on data from our records. METHODS: From May 1977 to July 2001 we implanted pacemakers in 104 children younger than 15 years of age. In 55 patients transvenous leads were implanted. Twelve of these (21.8 %) received a VDD pacemaker for hemodynamic reasons. RESULTS: Ages ranged from 11 months to 14.5 years (mean 7.7 +/- 4.3 y). Sizes of the children ranged from 67 to 141 cm (mean 105.9 +/- 15.5 cm) and body weight ranged from 5.3 to 62.0 kg (mean 22.5 +/- 9.8 kg). The mean follow-up period was 47.5 +/- 15.1 months. In 86.3 % of the time during follow-up pacemakers of which we obtained data were working in the VDD mode. Five of the twelve VDD patients (41.7 %) had to be reoperated because of severe traction on the leads. In all five patients the VDD systems were explanted and the patients changed to dual chamber pacemakers. The period of time between implantation and VDD lead explantation ranged from 24 to 74 months (48.6 +/- 18.5). CONCLUSIONS: VDD pacemakers can be implanted safely even in children with a low complication rate perioperatively. 41.7 % of our VDD patients had to be reoperated within the surveillance time because of severe lead tension due to thoracic growth. In our experience VDD pacemakers in smaller children seem to be a temporary solution to bridge AV-synchrony from a young age to DDD pacing in young adulthood.

[Is measuring by portable heart rate monitors (sport watches) dependable in patients with an implanted pacemaker?]. / Messen tragbare Herzfrequenz-Messgeräte (Sportuhren) bei Schrittmacherpatienten zuverlässig?

BACKGROUND AND OBJECTIVE: Regular physical exercise is advantageous for physical fitness and endurance. The intensity of exercising can be controlled by portable heart rate monitors. The aim of the study was to investigate if wearable monitors work properly in pacemaker patients. PATIENTS AND METHODS: In 30 patients with an implanted single or dual chamber pacemaker made by five different manufacturers their heart rate was determined simultaneously by surface ECG and Holter ECG, and was compared with the heart rates derived from portable heart rate monitors (Polar A1) at rest, during 6 minutes in-house walk, and while exercising at 25, 50, and 75 watts in a bicycle exercise test. The tests were done with pacing set at uni- as well as bipolar stimulation mode. RESULTS: At rest in two of 30 patients (6,6 %) paced in unipolar mode the portable heart rate monitors counted double. Under exercise conditions the portable monitors counted double in six of 26 patients (23 %) while being stimulated in unipolar mode. In bipolar stimulation mode, the portable heart rate monitors were working properly in all patients under all conditions. CONCLUSIONS: Patients with an implanted bipolar pacing system can control their physical exercising safely and accurately by means of portable heart rate monitors. Pacemaker patients who are planning regular physical exercising should be provided with an implanted bipolar pacemaker system.

Beta-blockade as an alternative to cardioplegia.

As an alternative to cardioplegic arrest, "cardiac surgical conditions" (i.e. a flaccid heart which facilitates surgery) have been created by continuously perfusing the coronary arteries with normothermic blood and suppressing myocardial chronotropy and inotropy with the ultra-short acting beta-blocker esmolol. In contrast to cardioplegic arrest, minimal cardiac contraction is maintained. Using this technique, the myocardium is protected against ischemia by antegrade coronary blood flow and reduced metabolism. In addition, the presence of minimal cardiac contractions protects the myocardium against edema formation by maintaining myocardial fluid balance. This paper presents both the rationale for and the application of "beta-blocker-induced cardiac surgical conditions" as an alternative concept for myocardial protection during coronary artery surgery.

Absence of hemodynamic and ECG changes in a patient with traumatic left ventricular injury and puncture of the left anterior descending branch.

Patients with penetrating cardiac injury usually present with cardiac tamponade and shock upon hospital arrival. However, absence of hemodynamic depression does not exclude a potentially fatal injury of the heart. This article reports on a patient who developed neither hemodynamic depression nor ECG changes for several hours, despite two left ventricular lacerations with puncture of the LAD. Echocardiography is advocated as the diagnostic tool of choice, and it is emphasized that no penetrating objects should be removed from the wound before surgical access to the heart is established, as this may result in the sudden development of cardiac tamponade.

Perioperative hemodynamic measurements with an implantable monitoring system (Chronicle) in a patient with severe heart failure undergoing non-cardiac surgery.

A 53-year-old male patient with severe chronic heart failure due to ischemic cardiomyopathy (LVEF 25%) awaiting heart transplantation was admitted for resection of a bladder tumor. The patient underwent implantation of a Chronicle implantable hemodynamic monitor (IHM) two years before. Thus, perioperative monitoring of heart rate, right ventricular systolic, diastolic and pulse pressure, dP/dt and estimated pulmonary artery diastolic pressure through a lead implanted in the right ventricle was performed. In the postoperative period the patient developed low-output syndrome requiring catecholamine treatment. The patient was weaned from mechanical ventilation uneventfully the same day. However, he developed symptomatic and hemodynamic worsening of heart failure shortly after reduction of inotropes and required prolonged medical treatment with catecholamines. Patients with cardiac disease are known to be at increased risk for cardiovascular complications after noncardiac surgery. Therefore, it has been suggested that such patients could potentially benefit from perioperative invasive hemodynamic monitoring. For the first time, we report a case of perioperative continuous hemodynamic monitoring with a long term-implanted device in a potential heart transplant patient.

Effects of the novel T-type calcium channel antagonist mibefradil on human myocardial contractility in comparison with nifedipine and verapamil.

Mibefradil (Ro 40-5967) is a novel nondihydropyridine calcium antagonist. The aim of our study was to compare the negative inotropic effects of the well-known 1,4-dihydropyridine nifedipine and the phenylalkylamine verapamil with those of mibefradil. Isometric force of contraction in response to these substances was determined in isolated, electrically driven left ventricular papillary muscle strips from failing human hearts (1 Hz, 37 degrees C). The hearts were obtained during cardiac transplantation (n = 9) and mitral valve-replacement operations (n = 9). The calcium antagonists studied significantly (p < 0.05) depressed basal force of contraction in a concentration-dependent manner. The effect started at concentrations > 0.001 microM for nifedipine and > 0.01 microM for verapamil, but only at concentrations > 10 microM for mibefradil. Only in the presence of nifedipine and verapamil was a significant rightward shift of the inotropic concentration--response curves to calcium and a depression of the maximal effects of calcium observed. With respect of the relation between the therapeutic active plasma concentration in vivo and the negative intropic potency in vitro, it became evident that the difference between therapeutically beneficial concentrations and potentially hazardous cardiodepressant activity increases from nifedipine to mibefradil. We conclude that this new generation of calcium antagonists, almost lacking cardiodepressant effects, could lead to a greater therapeutic index and greater safety in the treatment of cardiovascular diseases.

The ultrarapid and the transient outward K(+) current in human atrial fibrillation. Their possible role in postoperative atrial fibrillation.

Atrial fibrillation (AF) causes distinct changes in atrial conduction, characterized as electrical remodeling. Experimental data on the possible significance of alterations of specific K(+)outward currents in this process are still limited in human AF. The ultra-rapid delayed rectifier current (I(Kur)) has not been studied in AF with respect to its sensitivity to 4-Aminopyridine (4-AP). To clarify the role of (1) the 4-AP sensitive I(Kur)current, compared to recordings without using 4-AP (I(Kur*)), and (2) the transient outward current (I(to)) in changes of atrial repolarization associated with AF, whole cell voltage-clamp recordings were obtained from atrial myocytes of patients undergoing elective cardiac surgery, with and without a history of atrial fibrillation (AF/non-AF). Further, a possible relation between experimental data and postoperative AF was studied. In AF patients, I(Kur*)was reduced by 40% [5.00+/-0.32 pA/pF (non-AF) and 2.91+/-0. 45 pA/pF (AF) at +50 mV, P<0.0001, n=22/11], I(Kur)by 55% [3.81+/-0. 30 pA/pF (non-AF) and 1.71+/-0.20 pA/pF (AF) at +50 mV, P<0.0001, n=22/11]. The mean amplitude of I(Kur)was significantly smaller than I(Kur*). Consistently, I(to)was reduced by 44% [11.57+/-0.77 pA/pF (non-AF) and 6.51+/-1.31 pA/pF (AF), P<0.01, n=25/11]. In 48% of non-AF patients, postoperative AF was detected. The corresponding voltage-clamp recordings showed a trend to reduced I(Kur*)and I(Kur)currents, although it did not reach statistical significance. The consistent reduction of all three K(+)currents investigated due to the presence of AF indicates an important association of abnormalities in cellular repolarization with the onset and the self-sustaining nature of human AF.

[Risk stratification in heart surgery: do risk scores facilitate the determination of indications?]. / Risikostratifizierung in der Herzchirurgie--Entscheidungshilfe bei der Indikationsstellung.

Various risk scores have been developed for the assessment of operative risk in cardiac surgery. Although risk stratification has been acknowledged as a useful tool to analyze trends in therapy and changes in patient populations, its relevance in assessing the indication for surgery has been questioned. It was the goal of this prospective study to compare 6 common risk scores with regard to the predictive value for mortality in individual patients. Between September 1998 and February 1999 all adult patients undergoing heart surgery were prospectively scored according to the following scores: initial Parsonnet, Cleveland Clinic, French, Euro, Pons, and the Ontario Province Risk score. Early lethality was assessed within 30 days postoperatively. Follow-up was completed in 504 patients. With the exception of the Ontario Province Risk score, lethality in the high risk group was overestimated by all scores, whereas lethality in low to moderate risk groups was underestimated by several scores. Mean scores of surviving and deceased patients showed a broad overlap with high standard deviations. Preoperative risk scores are effective tools for stratification of patient populations and the analysis of surgical outcome. With the aid of risk scores, operative risk can be sufficiently predicted for patient populations or subpopulations. The Euro score best predicted the outcome of our patients. However, when the indication for surgery is to be determined in an individual patient, risk scores should be only considered as an orientation in the decision process.

Hyperpolarization-activated inward current in ventricular myocytes from normal and failing human hearts.

BACKGROUND: The hyperpolarization-activated inward current (I[f]) was found to be overexpressed in hypertrophied rat ventricular myocytes, indicating that I(f) might favor arrhythmias in hypertrophied or failing ventricular myocardium. In the present study, we evaluated whether I(f) is expressed in human ventricular myocardium, if it may be increased in human heart failure, and if its autonomic modulation may be altered. METHODS AND RESULTS: The whole-cell patch-clamp technique was used to record I(f) in isolated ventricular myocytes from 34 failing (dilated [DCM] or ischemic [ICM] cardiomyopathy) and 13 donor hearts (NF). I(f) was observed in all myocytes showing typical current properties, ie, time and voltage dependence, block by [Cs+]o, permeability for K+ and Na+, and current increase with raising [K+]o. There was a trend toward larger current densities in myopathic (at -130 mV in [K+]o 25 mmol/L; DCM: -1.37 +/- 0.12 pA/pF, n = 50; ICM: -1.39 +/- 0.24 pA/pF, n = 30) than in nonfailing cells (-1.18 +/- 0.21 pA/pF, n = 24), although this difference did not reach statistical significance (P=.23). Boltzmann distributions yielded an activation threshold of -80 mV and half-maximal activation at -110.96 +/- 0.06 mV in myopathic and normal myocytes. Isoproterenol (10(-5) mol/L) shifted the current activation by 10 mV (31 myopathic, 5 NF). Carbachol and adenosine had no direct effect on I(f) (6 and 12 myopathic, 3 and 3 NF, respectively) but reversibly antagonized beta-adrenergic stimulation (5 and 7 myopathic, 2 and 2 NF, respectively). Autonomic modulation was similar in failing and nonfailing cells. CONCLUSIONS: In end-stage heart failure, no significant change of I(f) could be found, although there was a trend toward increased I(f). Together with an elevated plasma norepinephrine concentration and a previously reported reduction in I(K1) in human heart failure, I(f) might favor diastolic depolarization in individual myopathic cells.