Minimally invasive partial inferior sternotomy for congenital heart defects in children.

AIM: Minimally invasive approaches for repair of congenital heart defects have gained in popularity. Aim of the study was to evaluate the safety and efficiency of the partial inferior sternotomy approach to repair various congenital heart defects. METHODS: Since 1998, 100 children (55 males; mean age: 3.8 ± 3.7; mean weight: 15.1 ± 8.7 kg) were operated on via a limited median vertical skin incision and partial inferior sternotomy. Preoperative diagnoses were: ASD II (N.=46), sinus venosus defect with partial anomalous pulmonary venous connection (N.=12), partial AV-canal (N.=4), VSD (N.=35), tetralogy of Fallot (N.=2), and double chambered right ventricle (N.=1). Cannulation was always performed via the chest incision. RESULTS: There were no deaths. Mean cross-clamp time was 49.9 ± 30.6 minutes, and mean operation time 192 ± 46 minutes. Mean postoperative mechanical ventilation time, Intensive Care Unit stay and hospital stay were 9.7 ± 10.4 hours, 1.8 ± 0.7 days, and 12 ± 3.0 days, respectively. Complications included pneumothorax requiring drainage in 2 patients, atrioventricular block necessitating a permanent pacemaker in 1 patient. The incisions healed properly. All patients are in excellent condition after a mean follow-up of 32 ± 25 months. On echocardiography no residual defect was evident in 98 patients, and a mild mitral insufficiency in two patients operated on partial atrioventricular canal. CONCLUSION: The partial inferior sternotomy approach to congenital heart operations is less invasive than and cosmetically superior to full sternotomy with reduced postoperative pain and discomfort for the patients. This approach ensures a safe procedure with excellent exposure without additional incisions. It is our standard approach in infants/children with septal defects.

Clinical relevance of eNOS T-786C polymorphism for hospital mortality and morbidity in cardiac surgical patients.

AIM: The endothelial nitric oxide (eNOS) gene T-786C polymorphism may influence as a genetic risk factor cardiovascular diseases and shows association with cardiovascular mortality. We hypothesized that this polymorphism may lead to increase mortality and morbidity after cardiac surgery with cardiopulmonary bypass (CPB). METHODS: In 500 patients who underwent cardiac surgery with CPB we investigated the eNOS T-786C polymorphism by DNA-sequencing. The patients were grouped according to their genotype in three groups (TT, TC, and CC). RESULTS: The overall genotype distribution of T-786C polymorphism was TT=41.6%, TC=51.2%, and CC=7.2% respectively. The groups did not differ in age and gender. No significance was shown in preoperative risk factors, excluding peripheral disease (P=0.03). No difference was shown in Euroscore, APACHE II, and SAPS II. The usage of norepinephrine (P=0.03) and nitroglycerine (P=0.01) was significant higher in TC allele carrier. The mortality was quite uniform across elective and urgent subgroup. However, we found a significant difference concerning mortality and emergency cardiac procedures in homozygous C-allele carrier (P=0.014). CONCLUSION: The present study demonstrates that this polymorphism contributes to a higher prevalence of postoperative mortality after emergency cardiac surgery. Thus, the eNOS T-786C polymorphism could serve as a possibility to differentiate high risk subgroups in heterogeneous population of individuals with cardiac diseases who need cardiac surgery with CPB.

Histological changes in neonatal kidneys after cardiopulmonary bypass and deep hypothermic circulatory arrest.

BACKGROUND: Renal failure after open-heart surgery is a serious complication resulting in increased mortality and morbidity. The aim of the study was to find out whether different strategies for open-heart surgery would result in renal histological differences in a neonatal animal model. METHODS: The renal tissue of newborn piglets was examined after mild hypothermic cardiopulmonary bypass (CPB group; n = 10), deep hypothermic circulatory arrest (DHCA group; n = 8), instrumentation without extracorporeal circulation (sham; n = 3), and the data were compared with those of normal porcine neonatal kidneys (control; n = 6). The severity of tissue damage was graded using a 4-point scoring system (0: normal morphology, 3: severe damage). Apoptotic cells and granulocytes were counted. RESULTS: The histological score was higher in all groups compared with controls ( P < 0.05) and higher in the CPB group compared with the DHCA group ( P < 0.05). More apoptotic cells and granulocytes were found in the CPB group compared with controls and the DHCA group ( P < 0.05). CONCLUSIONS: Although changes in the kidney tissue of newborn piglets are detectable after any cardiac procedure, changes are more profound after cardiopulmonary bypass with mild hypothermia.

Influence of angiotensin-I-converting-enzyme insertion/deletion gene polymorphism on perioperative hemodynamics after coronary bypass graft surgery.

AIM: The angiotensin I-converting enzyme insertion/ deletion polymorphism (ACE-I/D), including three genotypes (II, ID, DD), with a known impact on midterm mortality and morbidity in patients after coronary artery bypass graft surgery (CABG), was studied. Since this polymorphism has been linked with increased vascular response to phenylephrine during cardiopulmonary bypass (CPB), we investigated its possible effect on perioperative hemodynamics in patients undergoing CABG. METHODS: Genotyping for the ACE-I/D was performed by polymerase chain reaction (PRC) amplification in 110 patients who underwent elective CABG with CPB. Patients were assigned to two groups according to their genotype (group II [II genotype] and group ID/DD [ID and DD genotypes]). Systemic hemodynamics were measured directly before and at 4 h, 9 h, and 19 h after CPB. RESULTS: Genotype distribution of ACE-I/D was 18%, 57%, and 25% in genotypes II, ID, and DD, respectively. The two groups were similar in age (group II: 66+/-6 years, group ID/DD: 66+/-8 years), body-mass-index (BMI) (group II: 28+/-2, group ID/DD: 29+/-5 kg/m2), male: female ratio (group II: 16: 4, group ID/DD: 63: 27) and Euroscore (group II: 3.1+/-1.9, group ID/DD: 3.5+/-2.1). There were no differences in mortality rate or perioperative systemic hemodynamics. The pulmonary vascular resistance before cardiopulmonary bypass was higher in the ID/DD genotypes than in the II genotypes (227+/-121 vs 297+/-169 dyn.s(-1).m2.cm(-5)). Four hours after CPB no difference remained; at 9 h after cardiopulmonary bypass there was a slight difference in pulmonary vascular resistance between the two groups (247+/-134 vs 290+/-117 dyn.s(-1).m2.cm(-5)) and a significant difference in pulmonary arterial pressure (19+/-6 vs 23+/-8); at 19 h after CPB the differences were no longer detectable. CONCLUSION: ACE-I/D had no influence on perioperative systemic hemodynamics. However, transitory differences in pulmonary hemodynamic were observed after CPB. These differences may have been due to changes in serum ACE activity during CPB.

Influence of eNOS gene polymorphisms (894G/T; - 786C/T) on postoperative hemodynamics after cardiac surgery.

BACKGROUND: Differences in vascular reactivity have been associated with variable NO release due to 894G/T and -786C/T polymorphisms of the eNOS gene. Carriers of the 894T and -786C alleles are known to have enhanced vascular responsiveness to vasoconstrictor stimulation due to decreased NO generation. Thus, we hypothesized that eNOS gene polymorphism could influence perioperative hemodynamics and catecholamine support in patients undergoing cardiac surgery with CPB. METHODS: In 105 patients undergoing elective CABG with CPB, systemic hemodynamics, cardiac index (CI), systemic and pulmonary vascular resistance indices (SVRI, PVRI) and catecholamine support were measured at baseline and 1 h, 4 h, 10 h and 24 h after CPB. Genotyping for the 894G/T and -786C/T eNOS gene polymorphisms was performed by polymerase chain reaction amplification. Patients were divided according to their genotype (894G/T: GG=group 1, GT and TT=group 2; -786C/T: TT=group 3, CT and CC=group 4). RESULTS: Genotype distribution for 894G/T polymorphism was 41% (GG), 52.4% (GT), 6.6% (TT) and for -786C/T polymorphism 37.1% (TT), 41.9% (CT) and 21% (CC). Pre- and intraoperative characteristics and systemic hemodynamics did not differ between groups. CI, SVRI and PVRI remained unaffected by genotype distribution. Statistical analysis of postoperative data revealed no difference between groups, especially for pharmacologic inotropic or vasopressor support. Also, coexistence of the 894T and -786C alleles had no impact on perioperative variables compared to homozygous 894G and -786T allele carriers. CONCLUSIONS: In contrast to current suggestions, the 894G/T and -786C/T genetic polymorphisms of the eNOS gene do not influence early perioperative hemodynamics after cardiac surgery with CPB.

Effects of preoperative statin therapy on cytokines after cardiac surgery.

INTRODUCTION: In addition to their lipid-lowering action, it has been demonstrated that statins can exert direct anti-inflammatory effects. We investigated the effect of preoperative statin therapy on systemic inflammatory markers and myocardial NF-kappaB inhibitor IkappaB-alpha after cardiac surgery. METHODS: Thirty-six patients undergoing elective coronary artery bypass grafting with cardiopulmonary bypass (CPB) with cardioplegia were divided into two groups (statin group, n = 18; control group, n = 18). Plasma concentrations of pro-inflammatory cytokines (tumor necrosis factor alpha [TNFalpha], interleukin [IL]-6, IL-8) and anti-inflammatory IL-10 were measured before and 1, 4, 10, and 24 hours (h) after CPB. Phosphorylated IkappaB-alpha/total IkappaB-alpha ratio was assessed before and after CPB in right atrial biopsies. RESULTS: Baseline and operative data did not differ between groups. Statin therapy was associated with lower preoperative low-density lipoprotein levels compared to control (73+/-6 vs. 92+/-6 mg/dL; P=0.03). Release of IL-6 was attenuated in the statin group at 4 h (2270+/-599 vs. 5120+/-656 pg/ml; P<0.01) and 10 h (1295+/-445 vs. 3116+/-487 pg/ml; P<0.05) compared to the control group. IL-10 increased after surgery in both groups (P<0.05), but was higher in the statin group at 1 h (66+/-15 vs. 26+/-16 pg/mL; P<0.01). Phosphorylated IkappaB-alpha/total IkappaB-alpha ratio before CPB did not differ between groups, but was elevated after CPB in both groups (P<0.05), indicating enhanced degradation of IkappaB-alpha. Statin therapy had no effect on TNFalpha and IL-8. CONCLUSIONS: Preoperative statin therapy attenuates the release of pro-inflammatory IL-6 and up-regulates anti-inflammatory IL-10 after cardiac surgery with cardioplegia, but fails to inhibit phosphorylation of myocardial IkappaB-alpha.

Ultrastructure of right ventricular myocardium subjected to acute pressure load.

BACKGROUND: Ultrastructural data on acute right ventricular pressure load in pigs are rare. MATERIALS AND METHODS: In control (n = 7) and banding groups (n = 6), right ventricular pressure (micromanometry) and function (sonomicrometry) were measured. Right ventricular pressure was increased 2.5-fold in the banding group by pulmonary artery constriction. Right ventricular biopsies were taken at baseline and after 6 h and processed for electron microscopy. Parameters of cellular injury were determined stereologically. Three perfusion -fixed hearts were investigated qualitatively in each group. RESULTS: Stereology revealed an increase in the sarcoplasmic volume fraction and the cellular edema index in the banding group ( p < 0.05). Mitochondrial surface-to-volume ratio and volume fraction did not show significant alterations. Subendocardial edema and small amounts of severely injured myocytes were observed in the perfusion-fixed hearts after banding. Ultrastructure was normal in controls. After an initial increase, the right ventricular work index declined progressively in the banding group but remained unchanged in controls. CONCLUSIONS: Ultrastructural alterations resulting from acute right ventricular pressure load were characterized by edema of subendocardial myocytes and single cell necrosis. Focal adrenergic overstimulation and mechanical stress are probably more relevant in the pathogenesis of these lesions than ischemia.

Mortality rates after heart transplantation: how to compare center-specific outcome data?

BACKGROUND: Studies of outcome in cardiac transplantation have focused primarily on identifying patient- and donor-related factors associated with patient mortality. Less consideration has been given to the impact of the transplant center. This study was undertaken to assess variability in heart transplantation outcome in Eurotransplant centers to provide a framework for auditing. METHODS AND RESULTS: In a 2-year period, 1,401 adult patients underwent heart transplantation in 45 centers. The 1-year patient survival rate was 76% (95% CI, 74%-78%) with a range of 0% to 100% at the center level. The risk-adjusted center effect on mortality was estimated by calculating a standardized difference between the observed number of deaths 1 year after transplantation and the expected number of deaths based on the case mix. By assessing within- and between-center variations with empirical Bayes (EB) methods, after adjustment for all registered prognostic factors, an improved estimate of the true center effect was obtained. Compared with the standard risk-adjusted center effect method, fewer outlying centers were identified with the EB method. CONCLUSION: EB methods, because they are known to incorporate more information from the data, enable a more precise and realistic portrayal of heart transplant centers' performances, compared with other risk-adjusted center effect methods. In the context of auditing procedures, EB methods should preferably be used for the identification of centers that deviate significantly from quality standards.

Effect of volatile anesthetics on the force-frequency relation in human ventricular myocardium: the role of the sarcoplasmic reticulum calcium-release channel.

BACKGROUND: In human ventricular myocardium, contractile force increases at higher stimulation frequencies (positive force-frequency relation). In failing hearts, the force-frequency relation (FFR) is negative. Data on the effect of volatile anesthetics on FFR are very limited. METHODS: The authors obtained left ventricular tissue from 18 explanted hearts from patients undergoing cardiac transplantation and tissue of 8 organ donors. The negative inotropic effect of halothane, isoflurane, and sevoflurane on isometric force of contraction of isolated muscle preparations at a stimulation frequency of 1 and 3 Hz and the effect of each anesthetic on the FFR were studied. Ryanodine and verapamil were studied for comparison. In addition, the effect of the anesthetics on Ca(2+)-dependent (3)H-ryanodine binding was investigated. RESULTS: In nonfailing myocardium, halothane was the strongest negative inotropic compound, and the positive FFR was not affected by either drug. In failing myocardium, halothane also showed the strongest negative inotropic effect, but the positive shape of FFR was restored by halothane and ryanodine. In contrast, isoflurane, sevoflurane, and verapamil did not change FFR. Only halothane shifted the Ca(2+)-dependent (3)H-ryanodine binding curve toward lower Ca(2+) concentrations. CONCLUSION: In nonfailing human myocardium, none of the anesthetics affect FFR, but halothane is the strongest negative inotropic compound. In failing myocardium, halothane, but not isoflurane or sevoflurane, restores the positive shape of FFR. Both the more pronounced negative inotropic effect of halothane and the restoration of the positive shape of FFR in failing myocardium in the presence of halothane can be explained by its interaction with the myocardial sarcoplasmic reticulum calcium-release channel.

The St. Jude "Silzone" valve: midterm results in treatment of active endocarditis.

BACKGROUND: The Silzone-coated St. Jude Medical valve (SJM "Silzone" valve), developed to reduce prosthetic valve endocarditis (PVE), was recalled by SJM due to a higher rate of paravalvular leaks. The aim of this study was to determine the efficacy of the SJM "Silzone" valve in avoiding PVE and to evaluate the frequency of paravalvular leaks, when the valve was used exclusively for active bacterial endocarditis. METHODS: From January 1998 to December 1999, the SJM "Silzone" valve was implanted in 40 consecutive patients with active endocarditis (20 aortic, 14 mitral, and 6 both valves). Late transesophageal echocardiography was performed in 87% of survivors, and transthoracic echocardiography in the remaining 13%. Follow-up was 100%. RESULTS: Hospital mortality was 17.5%. Early PVE occurred in 2 of 40 patients (5%). There were two late deaths without signs of recurrent PVE. A hemodynamic relevant paravalvular leak necessitating reoperation was seen in 2 patients within 6 months after operation. The rate of a minor paravalvular leak was 13% (4 of 31 patients). CONCLUSIONS: The SJM "Silzone" valve when implanted for active bacterial endocarditis does not give better results than other mechanical prostheses with regard to early recurrence of endocarditis. The rate of a hemodynamic relevant paravalvular leak requiring reoperation seems rather high during the early postoperative period, whereas the occurrence of minor paravalvular leaks is comparable with that of other mechanical prostheses. Routine observation, recommended for all patients with mechanical heart valves, is also sufficient for patients with the SJM "Silzone" valve.

Combined mitral valve and coronary artery surgery: ischemic versus non-ischemic mitral valve disease.

OBJECTIVES: Mitral valve combined with coronary artery surgery is associated with a higher hospital mortality than each operation in particular. Controversy exists regarding the predictive value of ischemic mitral valve disease (MVD) on outcome. METHODS: Between 1984 and 1997, 262 patients underwent mitral valve operations (replacement, n = 198; repair, n = 64) in combination with coronary revascularization. The etiology of MVD was secondary to ischemic heart disease (group I) in 82 (31%) patients, and non-ischemic (group II) in 180 (69%) patients (rheumatic, 139 patients (53%); degenerative, 41 patients (16%)). Both groups were similar in age, cardiac risk factors and pulmonary artery pressure. Patients of group I had significantly more severe coronary artery disease, more often an impaired left ventricle and myocardial infarction, and were in a worse functional condition. The mean number of bypass grafts was significantly higher in group I. The follow-up was 98% (230/234 patients). RESULTS: With 19.5%, the hospital mortality was significantly increased in group I compared with 6.7% in group II (P = 0.002; overall, 10.7%). Mitral valve repair or replacement had no influence on early outcome, although mitral valve repair was performed more often in group I (37 versus 19%). The survival (valve-related event-free survival) after discharge from hospital in the 1st, 5th and 10th year was 94 (94%), 70 (66%) and 53% (35%) in group I and 96 (95%), 79 (76%) and 54% (41%) in group II, respectively. The long-term functional capacity was equally good in both groups (New York Heart Association mean, 1.86 versus 1.72). CONCLUSIONS: Patients with ischemic MVD are in a worse cardiac condition with significantly higher hospital mortality than patients with non-ischemic MVD and coronary artery bypass grafting. Once discharged from hospital, both groups have comparable long-term outcomes, with the best results in patients with degenerative MVD.

Fulminant toxoplasmosis in a heart transplant recipient.

Toxoplasma gondii infections in heart transplant recipients emerge in most cases as newly acquired infections of the immunocompromised sero-negative patient from an exogenous source, usually the donor organ. We report on a 64-year-old heart transplant recipient who developed pneumonitis, myocarditis, and hyperacute encephalitis three weeks after transplantation. Histopathological examination of an endomyocardial biopsy revealed fulminant T. gondii infection. Although appropriate chemotherapy was administered immediately, the patient died the next day. Our case demonstrates that if a histological diagnosis is not rendered in time, fulminant toxoplasmosis may lead to a fatal outcome. In conclusion, a general screening of the donors and recipients for opportunistic infections, including toxoplasmosis, and an appropriate prophylaxis should always be considered.

Heart transplantation indicated only in the most severely ill patient: perspectives from the German heart transplant experience.

The COCPIT study, performed in a complete national cohort of adult patients consecutively listed for cardiac transplantation in Germany in 1997, found a beneficial effect only in the group that was at high risk of dying from heart failure without transplantation. If these results can be reproduced in other countries, the discussion on the respective roles of pharmacological and organ-saving surgical therapies for advanced heart failure, medical urgency and waiting time as heart transplantation allocation criteria, and the feasibility of a randomized clinical trial testing the survival benefit of transplantation must be reopened.

Cellular mechanisms of depressed atrial contractility in patients with chronic atrial fibrillation.

BACKGROUND: After cardioversion of atrial fibrillation (AF), the contractile function of the atria is temporarily impaired. Although this has significant clinical implications, the underlying cellular mechanisms are poorly understood. METHODS AND RESULTS: Forty-nine consecutive patients submitted for mitral valve surgery were investigated. Twenty-three were in persistent AF (>/=3 months); the others were in sinus rhythm. Before extracorporal circulation, the right atrial appendage was excised. ss-Adrenoceptors were quantified by radioligand binding, and G proteins were quantified by Western blot analysis. The isometric contractile response to Ca(2+), isoproterenol, Bay K8644, and the postrest potentiation of contractile force were investigated in thin atrial trabeculae, which were also examined histologically. The contractile force of the atrial preparations obtained from AF patients was 75% less than that in preparations from patients in sinus rhythm. Also, the positive inotropic effect of isoproterenol was impaired, and Bay K8644 failed to increase atrial contractile force. In contrast, the response to extracellular Ca(2+) was maintained, and the postrest potentiation was preserved. Beta-adrenoceptor density and G-protein expression were unchanged. Histological examination revealed 14% more myolysis in the atria of AF patients. CONCLUSIONS: After prolonged AF, atrial contractility was reduced by 75%. The impairment of beta-adrenergic modulation of contractile force cannot be explained by downregulation of ss-adrenoceptors or changes in G proteins. Dysfunction of the sarcoplasmic reticulum does not occur after prolonged AF. Failure of Bay K8644 to restore contractility suggests that the L-type Ca(2+) channel is responsible for the contractile dysfunction. The restoration of contractile force by high extracellular Ca(2+) shows that the contractile apparatus itself is nearly completely preserved after prolonged AF.

[Risk assessment of mitral valve surgery combined with myocardial revascularization]. / Valoración del riesgo de la cirugía mitral combinada con la revascularización miocárdica.

INTRODUCTION AND OBJECTIVES: Patients with combined mitral valve operation and coronary artery surgery represent a high risk group. The aim of this retrospective study was to evaluate which factors affect early and late postoperative results in this particular group of considered high risk patients. PATIENTS AND METHOD. Between 1984 and 1997, 264 patients (mean age: 63 +/- 7.3 years) underwent mitral valve surgery (199 patients; 75% mitral valve replacement, 25% mitral valve repair) in combination with coronary revascularization (mean 2.4 +/- 1.3 grafts). Follow-up comprised a mean of 69 +/- 42 months and was 98.3% complete. RESULTS: Early mortality was 10.6% (28/264). Ischemic mitral regurgitation operated on in emergent status, moderate to severe reduced left ventricular function and advanced age (> 60 years) were independently associated with early hospital mortality (p < 0.05). Ischemic etiology of mitral valve disease (emergency and elective operations), severity of mitral regurgitation and New York Heart Association (NYHA) functional class IV were related to early hospital mortality, only with univariate statistics. Actuarial survival was 86, 69 and 48% at 1, 5 and 10 years, respectively. The preoperative NYHA functional class was the only variable independently related to late survival. Eighty-five percent of the surviving patients were in NYHA functional class I and II. CONCLUSIONS: Mitral valve operation combined with coronary artery bypass grafting is associated with a high early hospital mortality. Independent risk factors of early mortality are emergency operation of ischemic mitral valve disease, reduced left ventricular function and advanced age. Long term survival is independently influenced only by preoperative NYHA functional class IV.

Intraoperative amiodarone as prophylaxis against atrial fibrillation after coronary operations.

BACKGROUND: New onset of atrial fibrillation is a frequent complication after coronary artery bypass grafting and is a major cause of postoperative morbidity. Preoperative oral treatment with amiodarone hydrochloride has been shown to be efficacious as prophylaxis. The present study investigated whether intraoperative use of intravenous amiodarone has a preventive effect on the incidence of atrial fibrillation after coronary revascularization. METHODS: In a prospective study, 150 consecutive patients (mean age, 63 +/- 8 years; 132 men and 18 women) undergoing coronary artery bypass grafting were randomly assigned to one of three groups. Two groups received different doses of intravenous amiodarone (group I, 300-mg bolus and 20 mg x kg(-1) x day(-1) for 3 days; group II, 150-mg bolus and 10 mg x kg(-1) x day(-1) for 3 days) after aortic cross-clamping and one group, placebo (group III). Continuous electrocardiographic online monitoring was performed for 10 days. Arrhythmias were analyzed with respect to type, frequency, duration, and clinical relevance. RESULTS: New onset of atrial fibrillation occurred in 24% of patients in group I, 28% in group II, and 34% in group III (p = not significant). Atrial fibrillation with a rapid ventricular response (>120 beats per minute) was significantly more frequent in the control group (group I, 14%; group II, 24%; group III, 32%; p < 0.05, group I versus group III) and appeared significantly earlier (group I, day 4.3 +/- 2.5; group II, day 4.8 +/- 2.9; group III, day 2.6 +/- 1.3; p < 0.05, group III versus groups I and II). Temporary atrial pacing because of bradycardia (<60 beats per minute) was necessary significantly more often in group I (group I, 48%; group II, 40%; group III, 28%; p < 0.05, group I versus group III). Early mortality rate (group I, 4%; group II, 2%; group III, 4%), rate of perioperative complications (group I, 14%; group II, 20%; group III, 14%), and duration of hospital stay (group I, 14.0 days; group II, 14.4 days; group III, 14.7 days) were not different between groups. CONCLUSIONS: Intraoperative prophylactic use of amiodarone does not prevent new onset of atrial fibrillation in patients undergoing coronary artery bypass grafting and had no effect on outcome. Therefore, intraoperative prophylactic treatment with amiodarone at the tested doses does not appear to be justified.

Changes of beta-adrenergic signaling in compensated human cardiac hypertrophy depend on the underlying disease.

In human heart failure, desensitization of the beta-adrenergic signal transduction has been reported to be one of the main pathophysiological alterations. However, data on the beta-adrenergic system in human compensated cardiac hypertrophy are very limited. Therefore, we studied the myocardial beta-adrenergic signaling in patients suffering from hypertrophic obstructive cardiomyopathy (HOCM, n = 9) or from aortic valve stenosis (AoSt, n = 8). beta-Adrenoceptor density determined by [(125)I]iodocyanopindolol binding was reduced in HOCM and AoSt compared with nonhypertrophied, nonfailing myocardium (NF) of seven organ donors. In HOCM the protein expression of stimulatory G protein alpha-subunit (G(s)alpha) measured by immunoblotting was unchanged, whereas the inhibitory G protein alpha-subunit (Galpha(i-2)) was increased. In contrast, in AoSt, Galpha(i-2) protein was unchanged, but G(s)alpha protein was increased. Adenylyl cyclase stimulation by isoproterenol was reduced in HOCM but not in AoSt. Plasma catecholamine levels were normal in all patients. In conclusion, both forms of hypertrophy are associated with beta-adrenoceptor downregulation but with different changes at the G protein level that occur before symptomatic heart failure due to progressive dilatation of the left ventricle develops and are not due to elevated plasma catecholamine levels.

Reduced myocardial sarcoplasmic reticulum Ca(2+)-ATPase protein expression in compensated primary and secondary human cardiac hypertrophy.

Pathological intracellular calcium handling has been proposed to underlie the alterations of contractile behavior in hypertrophied myocardium. However, the myocardial protein expression of intracellular calcium transport proteins in compensated human left ventricular hypertrophy has not yet been studied. We investigated septal myocardial specimens of patients suffering from hypertrophic obstructive cardiomyopathy (n=14) or from acquired aortic valve stenosis (n=11) undergoing myectomy or aortic valve replacement, respectively. For comparison, we studied non-hypertrophied myocardium of six non-failing hearts which could not be transplanted for technical reasons. The myocardial density of the calcium release channel of the sarcoplasmic reticulum (SR) was determined by(3)H-ryanodine binding. Myocardial contents of SR Ca(2+)-ATPase, phospholamban, calsequestrin and Na(+)/Ca(2+)-exchanger were analysed by Western blot analysis. The myocardial SR calcium release channel density was not significantly different in hypertrophied and non-failing human myocardium. In both hypertrophic obstructive cardiomyopathy and in aortic valve stenosis, SR Ca(2+)-ATPase expression was reduced by about 30% compared to non-failing myocardium (P<0.05), whereas the expression of phospholamban, calsequestrin, and the Na(+)/Ca(2+)-exchanger was unchanged. The decrease of SR Ca(2+)-ATPase expression was still observable when related to its regulatory protein phospholamban or to the myosin content of the homogenates (P<0.05). Furthermore, the SR Ca(2+)-ATPase expression was inversely correlated to the septum thickness assessed by echocardiography, but not to age, cardiac index or outflow tract gradient. In primary as well as in secondary hypertrophied human myocardium, the expression of SR Ca(2+)-ATPase is reduced and inversely related to the degree of the hypertrophy. The diminished SR Ca(2+)-ATPase expression might result in reduced Ca(2+)reuptake into the SR and might contribute to altered contractile behavior in hypertrophied human myocardium.

Altered force-frequency relation in hypertrophic obstructive cardiomyopathy.

The present study was designed to test the hypothesis that in hypertrophied myocardium of patients with hypertrophic obstructive cardiomyopathy (HOCM) a reduced contractile reserve provided by frequency dependent potentiation of force of contraction contributes to the myocardial dysfunction. Myectomy was performed in 8 HOCM patients with normal systolic left ventricular function at rest. Nonfailing myocardium from the hearts of three multiorgan donors was investigated for comparison. In thin myocardial strips we measured the inotropic effects of different stimulation frequencies (0.5-3.0 Hz) at different extracellular Ca2+ concentrations (1.8-16.2 mmol/l). At 1.8 mmol/l extracellular Ca2+ concentration, increasing stimulation rates had no positive inotropic effect in HOCM myocardium, whereas in nonfailing myocardium force of contraction increased up to 3 Hz. Increasing extracellular Ca2+ concentrations induced a positive force-frequency relation in HOCM with a maximum at 5.4 mmol/l Ca2+. A further increase to 16.2 mmol/l Ca2+ resulted in a negative force-frequency relation in these specimens. The time to peak tension and the time to relaxation decreased at increasing stimulation frequencies at all Ca2+ concentrations investigated. In conclusion, in hypertrophied myocardium of HOCM patients increasing stimulation frequencies failed to have a positive inotropic effect at physiological extracellular Ca2+ concentrations. The induction of a positive force-frequency relation by higher Ca2+ concentrations suggests that an abnormal cellular Ca2+ handling may play an important pathophysiological role.