Michael Südkamp

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.

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.

Effect of β-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 Ca2+-ATPase (SERCA) activity and the effects of the β-receptor antagonists metoprolol, carvedilol, and its metabolite BM-910228. Methods and Results—Isometric force of contraction was determined in isolated human myocardium. H2O2 1 mmol/L and Fe3+-nitrilotriacetic acid (Fe3+-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 Ca2+ 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 Ca2+ in atrial myocardial preparations. Metoprolol had no significant effect. The stimulation frequency (0.5 to 3.0 Hz)–dependent increase ...

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

Clinical studies have shown different effects of β‐blockers on the β‐adrenergic system, tolerability and outcome in patients with heart failure. The study examines β‐adrenoceptor‐G‐protein coupling and intrinsic activity of bucindolol, carvedilol and metoprolol in human ventricular myocardium. Radioligand binding studies ([125I]‐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. Bucindolol and carvedilol bound non‐selectively to β1‐ and β2‐adrenoceptors and exerted guanine nucleotide modulatable binding. Metoprolol was 35‐fold β1‐selective and lacked guanine nucleotide modulatable binding. All β‐blockers antagonized isoprenaline‐induced enhancement of contractility. 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. 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. Differences in intrinsic activity may contribute to differences in β‐adrenoceptor regulation and possibly to differences in tolerability and outcomes of patients with heart failure.

Single-channel properties support a potential contribution of hyperpolarization-activated cyclic nucleotide-gated channels and If to cardiac arrhythmias.

Background—The pacemaker current If is present in atrial and ventricular myocytes. However, it remains controversial whether If overexpression in diseased states might play a role for arrhythmogenesis, because first If activation in whole-cell recordings hardly overlapped the diastolic voltage of working myocardium. Methods and Results—To obtain further insight into IHCN and If properties, we provide for the first time detailed single-channel analysis of heterologously expressed hyperpolarization-activated cyclic nucleotide-gated (HCN) isoforms and native human If. HCN subtypes differed significantly in single-channel amplitude, conductance, and activation kinetics. Interestingly, threshold potentials of HCN isoforms were more positive than would have been expected from whole-cell measurements. Single-channel properties of cells cotransfected with HCN2 and HCN4 were distinct from cells expressing HCN2 or HCN4 alone, demonstrating that different HCN isoforms can influence current properties of a single HCN channel complex, thus providing direct functional evidence for HCN heteromerization. Pooled data of homomeric and heteromeric HCN channels and of native If extrapolated from maximum likelihood fits indicated a multistate gating scheme comprising 5 closed- and 4 open-channel states. Single-channel characteristics of If in human atrial myocytes closely resembled those of HCN4 or HCN2+HCN4, supporting the hypothesis that native If channels in atrial myocardium are heteromeric complexes composed of HCN4 and/or HCN2. Most interestingly, half-maximal activation of single-channel atrial If (−68.3±4.9 mV; k=−9.9±1.5; n=8) was well within the diastolic voltage range of human atrial myocardium. Conclusions—These observations support a potential contribution of HCN/If to the arrhythmogenesis of working myocardium under pathological conditions.

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.

Characterization of β1-selectivity, adrenoceptor-Gs-protein interaction and inverse agonism of nebivolol in human myocardium

Intrinsic activity and β1‐selectivity are important features of β‐blockers in the treatment of patients with coronary syndromes and heart failure. In human myocardium, intrinsic activity and β1‐selectivity of the novel β‐adrenoceptor antagonist nebivolol have not yet been determined. The study examines intrinsic activity, β‐adrenoceptor‐G‐protein coupling and β1‐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 ([125I]‐lodocyanopindolol) were performed on membrane preparations of human failing and nonfailing myocardium and on COS‐7 cells transfected with human β1‐ and β2‐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 β1‐selectivity for nebivolol and 16 – 20 fold β1‐selectivity for bisoprolol in human myocardium. In COS‐7‐cells, β1‐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 β1‐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.

Ablation of Ca(v)2.3 / E-type voltage-gated calcium channel results in cardiac arrhythmia and altered autonomic control within the murine cardiovascular system.

AbstractVoltage–gated calcium channels are key components in cardiac electrophysiology. We demonstrate that Cav2.3 is expressed in mouse and human heart and that mice lacking the Cav2.3 voltage–gated calcium channel exhibit severe alterations in cardiac function. Amplified cDNA fragments from murine heart and single cardiomyocytes reveal the expression of three different Cav2.3 splice variants. The ablation of Cav2.3 was found to be accompanied by a compensatory upregulation of the Cav3.1 T–type calcium channel, while other voltage–gated calcium channels remained unaffected. Telemetric ECG recordings from Cav2.3 deficient mice displayed subsidiary escape rhythm, altered atrial activation patterns, atrioventricular conduction disturbances and alteration in QRS–morphology. Furthermore, time domain analysis of heart rate variability (HRV) in Cav2.3(–|–) mice exhibited a significant increase in heart rate as well as in the coefficient of variance (CV) compared to control mice. Administration of atropin/propranolol revealed that increased heart rate was due to enhanced sympathetic tonus and that partial decrease of CV in Cav2.3(–|–) mice after autonomic block was in accordance with a complete abolishment of 2nd degree atrioventricular block. However, escape rhythms, atrial activation disturbances and QRS–dysmorphology remained unaffected, indicating that these are intrinsic cardiac features in Cav2.3(–|–) mice. We conclude that the expression of Cav2.3 is essential for normal impulse generation and conduction in murine heart.

Ablation of Cav2.3 / E–type voltage–gatedcalcium channel results in cardiac arrhythmiaand altered autonomic control within themurine cardiovascular system

AbstractVoltage–gated calcium channels are key components in cardiac electrophysiology. We demonstrate that Cav2.3 is expressed in mouse and human heart and that mice lacking the Cav2.3 voltage–gated calcium channel exhibit severe alterations in cardiac function. Amplified cDNA fragments from murine heart and single cardiomyocytes reveal the expression of three different Cav2.3 splice variants. The ablation of Cav2.3 was found to be accompanied by a compensatory upregulation of the Cav3.1 T–type calcium channel, while other voltage–gated calcium channels remained unaffected. Telemetric ECG recordings from Cav2.3 deficient mice displayed subsidiary escape rhythm, altered atrial activation patterns, atrioventricular conduction disturbances and alteration in QRS–morphology. Furthermore, time domain analysis of heart rate variability (HRV) in Cav2.3(–|–) mice exhibited a significant increase in heart rate as well as in the coefficient of variance (CV) compared to control mice. Administration of atropin/propranolol revealed that increased heart rate was due to enhanced sympathetic tonus and that partial decrease of CV in Cav2.3(–|–) mice after autonomic block was in accordance with a complete abolishment of 2nd degree atrioventricular block. However, escape rhythms, atrial activation disturbances and QRS–dysmorphology remained unaffected, indicating that these are intrinsic cardiac features in Cav2.3(–|–) mice. We conclude that the expression of Cav2.3 is essential for normal impulse generation and conduction in murine heart.

Effects of sildenafil (viagra) on human myocardial contractility, in vitro arrhythmias, and tension of internal mammaria arteries and saphenous veins.

Sildenafil (Viagra) has been proved effective in the therapy for erectile dysfunction. Cardiovascular adverse effects are a matter of continuous debate. The aim of the study was to investigate effects of sildenafil on isolated human cardiovascular tissue directly. Isometric force of contraction was determined in isolated, electrically stimulated (1 Hz, 37°C) human right atrial and left ventricular muscle strips. Vascular tension was determined in rings of human internal mammaria arteries and saphenous veins. Sildenafil (0.0001–10 &mgr;M) neither in human atrium (n = 12) nor in failing (n = 8) or nonfailing (n = 5) ventricle exerted a significant inotropic response. Furthermore, no effect on isoprenaline-elicited arrhythmias was observed. Neither addition of isoprenaline (0.1 &mgr;M) nor addition of the nitric oxide donor S-nitroso-N-acetylpenicillamine (SNAP) (100 &mgr;M) affected myocardial contractility in the presence of sildenafil (10 &mgr;M). In precontracted arteries and veins, addition of sildenafil (0.1–10 &mgr;M) led to pronounced vasorelaxation (maximal 35.5 ± 2.2% and 45.6 ± 6.3%, respectively, in the presence of 10 &mgr;M sildenafil). In the presence of SNAP (0.03 &mgr;M), this effect was markedly increased in arteries (72.4 ± 10.1%, n = 4, P < 0.02) as well as in veins (73.5 ± 6.3%, n = 6, P < 0.02). Sildenafil exerts potent vasodilatory actions but has no direct influence on human myocardial contractility or proarrhythmic effects in vitro.