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OBJECTIVES: This study investigates the effects of a change of beta-adrenergic blocking agent treatment from metoprolol to carvedilol and vice versa in patients with heart failure (HF). BACKGROUND: Beta-blockers improve ventricular function and prolong survival in patients with HF. It has recently been suggested that carvedilol has more pronounced effects on left ventricular ejection fraction (LVEF) compared with metoprolol. It is uncertain whether a change from one beta-blocker to the other is safe and leads to any change of left ventricular function. METHODS: Forty-four patients with HF due to ischemic (n = 17) or idiopathic cardiomyopathy (n = 27) that had responded well to long-term treatment with either metoprolol (n = 20) or carvedilol (n = 24) were switched to an equivalent dose of the respective other beta-blocker. Before and six months after crossover of treatment, echocardiography, radionuclide ventriculography and dobutamine stress echocardiography were performed. RESULTS: Six months after crossover of beta-blocker treatment, LVEF had further improved with both carvedilol and metoprolol (carvedilol: 32 +/- 3% to 36 +/- 4%; metoprolol: 27 +/- 4% to 30 +/- 5%; both p < 0.05 vs. baseline), without interindividual differences. There were no changes in either New York Heart Association functional class or any other hemodynamic parameters at rest. Dobutamine stress echocardiography revealed a more pronounced increase of heart rate after dobutamine infusion in metoprolol- compared with carvedilol-treated patients. After dobutamine infusion, LVEF increased in the carvedilol- but not in the metoprolol-treated group. CONCLUSIONS: When switching treatment from one beta-blocker to the other, improvement of LVEF in patients with HF is maintained. Despite similar long-term effects on hemodynamics at rest, beta-adrenergic responsiveness is different in both treatments.

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The prerequisite of atherosclerosis, endothelial dysfunction, is characterised by impaired endothelium-dependent vasodilation caused by the reduced bioavailibility of nitric oxide (NO). In order to assess the role of acute ACE inhibition in this setting, coronary arterial endothelial function was quantified following acute intracoronary administration of the angiotensin-converting enzyme (ACE) inhibitor quinapril. Twenty-one patients with non-limiting coronary artery disease were studied before and after acute intracoronary administration of 10 mg quinapril. Nine patients received pre-treatment with the angiotensin AT(1)-receptor antagonist losartan (2 x 50 mg, p.o.). Coronary cross-sectional diameter was measured via quantitative angiography and microvascular reaction was investigated by intracoronary Doppler flow measurement during intracoronary infusion of 0.1 to 10 micromol/l acetylcholine. Quinapril acutely improved endothelial dysfunction on the macro- as well as the microvascular level. Losartan did not alter macrovascular function but facilitated microvascular endothelial function. Acute quinapril application led to no further improvement of endothelial dysfunction in patients pre-treated with losartan. Acute quinapril infusion improved endothelial function in patients with coronary heart disease. Treatment with the AT(1)-receptor antagonist losartan led to a slight improvement in microvascular endothelial function, but pre-treatment with losartan blunted the vascular effect of quinapril, suggesting that the combination of ACE inhibition and AT(1)-receptor antagonism may not exert a synergistic benefical impact on the coronary vasculature.

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Dilated cardiomyopathy (DCM) is a major cause of heart failure in younger individuals. Its prognosis is poor with 40-50% of patients dying within 2 years after diagnosis. Although the etiology of DCM is poorly understood, there is increasing evidence that DCM may represent an autoimmune disease in a significant subset of patients. In order to identify candidate antigens in DCM, we applied a molecular strategy which combines recombinant expression cloning and autoimmunological screening procedures. A left ventricle from a male DCM patient was explanted at heart transplantation and a human DCM left ventricular cDNA-expression library was constructed. 2 x 10(6) clones were immunologically screened with serum collected from the same patient prior transplantation. Subsequent rounds of screening and purification allowed isolation of a positive clone which was sequenced and identified as Recombination Signal Binding Protein-jkappa (RBP-jkappa). RBP-jkappa is an already identified transcription factor, e.g., involved in Epstein-Barr-virus-induced immortalization processes. Radioactively labeled RBP-jkappa protein was synthesized via in vitro translation using the isolated RBP-jkappa cDNA. This RBP-jkappa protein was used for immunoprecipitation reactions to screen sera of healthy controls and patients suffering of DCM for the presence of RBP-jkappa autoantibodies. Analysis revealed that only 31% (n = 16) of healthy but 70.6% of DCM patients (n = 17) carry an autoantibody against RBP-jkappa. Patients suffering from ischemic cardiomyopathy showed a prevalence of 22% of RBP-jkappa autoantibodies. Western analysis with an monoclonal antibody raised against RBP-jkappa showed that RBP-jkappa was overexpressed to 488 +/- 140% in DCM hearts compared to non-failing controls (n = 8). Autologous immunological screening of a cDNA expression library is a powerful and novel technology to gain insights into the etiology of human idiopathic DCM. Human DCM displays an autoimmune response against RBP-jkappa and an overexpression of RBP-jkappa. Since RBP-jkappa is involved in cellular immortalization and exerts antiapoptotic effects, the increased RBP-jkappa autoantibody level during DCM may inhibit this growth-regulating feature of RBP-jkappa. In this setting, enhanced myocardial RBP-jkappa expression could represent a compensatory but ineffective response to counteract the increased rate of apoptosis in DCM. Furthermore, RBP-jkappa may be a useful diagnostic marker for DCM.

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This report describes a 61-year-old female with an anomalous drainage of the right superior vena cava into the left atrium. The patient presented progressively severe dyspnea and precordial pain on exertion, lightheadedness, easy fatiguability and a constant decline in her performance but normal cardiac and pulmonary findings. Following a suspicious lung perfusion scan, diagnosis was assessed by echocardiography and confirmed by cardiac catheterization and nuclear magnetic resonance imaging. This anomaly leading to a right to left shunt appears to be a rare congenital cardiac malformation, particularly if diagnosed in the adult. The calculated shunt volume at rest was approximately 15% of the total body circulation. Although the functional relevance appears questionable, exercise of the upper limbs caused a significant decrease in systemic O2-saturation.

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BACKGROUND: The AT1 receptor has been implicated in the pathogenesis of hypertension and atherosclerosis. Estrogen deficiency is also associated with cardiovascular diseases. Therefore, we examined the AT1 receptor gene expression in ovariectomized rats with and without estrogen replacement therapy and the influence of estrogen on AT1 receptor expression in cultured vascular smooth muscle cells. METHODS AND RESULTS: Rat aortic tissue was examined 5 weeks after ovariectomy. In one group, estrogen (1.7 mg estradiol) was administered during the 5-week period. Functional experiments assessed angiotensin II-induced contraction of aortic rings. AT1 receptor mRNA levels were measured by quantitative polymerase chain reaction and Northern blotting. AT1 receptor density was assessed by radioligand binding assays. These techniques were also applied in cultured vascular smooth muscle cells. The efficacy of angiotensin II on vasoconstriction was significantly increased in aortas from ovariectomized rats. As assessed by radioligand binding assays, AT1 receptor density was increased to 160% without changes in receptor affinity during estrogen deficiency. AT1 receptor mRNA levels were consistently increased to 187% in ovariectomized rats compared with sham-operated animals. Estrogen substitution therapy in ovariectomized rats reversed this AT1 receptor overexpression. To explore the underlying mechanisms, the direct influence of estradiol on AT1 receptor expression was investigated in VSMCs. Estradiol (1 micromol/L) led to a time-dependent downregulation of AT1 receptor mRNA, with a maximum of 33.3% at 12 hours. There was a correlative decrease in AT1 receptor density. CONCLUSIONS: This novel observation of estrogen-induced downregulation of AT1 receptor expression could explain the association of estrogen deficiency with hypertension and atherosclerosis, because activation of the AT1 receptor plays a key role in the regulation of blood pressure, fluid homeostasis, and vascular cell growth.

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OBJECTIVES: This study tested the hypothesis that metoprolol restores the reduction of the inotropic effect of the cyclic adenosine monophosphate (cAMP)-phosphodiesterase inhibitor milrinone, which is cAMP dependent but beta-adrenoceptor independent. BACKGROUND: Treatment with beta-adrenergic blocking agents has been shown to lessen symptoms and improve submaximal exercise performance and left ventricular ejection fraction in patients with heart failure. Restoration of the number of down-regulated beta-adrenoceptors has been suggested to be one mechanism of beta-blocker effectiveness. However, the reversal of postreceptor events, namely, an increase in inhibitory G-protein alpha-subunit concentrations, could also play a role. METHODS: Fifteen patients with heart failure due to dilated cardiomyopathy (left ventricular ejection fraction 24.6 +/- 1.5% [mean +/- SD], New York Heart Association functional class II or III) were treated with metoprolol (maximal dose 50 mg three times daily) for 6 months. Before and after metoprolol treatment, inotropic responses to milrinone (5 to 10 micrograms/kg body weight per min) were measured echocardiographically. For comparison, responses to milrinone were determined under control conditions and after accelerated application of 150 mg of metoprolol to inactivate beta-adrenoceptors in subjects with normal left ventricular function. RESULTS: In subjects with normal left ventricular function, treatment with metoprolol did not alter the increase in fractional shortening or pressure/dimension ratio of circumferential fiber shortening after application of milrinone. In patients with heart failure, treatment with metoprolol significantly increased left ventricular ejection fraction, fractional shortening and submaximal exercise tolerance and reduced heart rate, plasma norepinephrine concentrations and functional class. After metoprolol treatment, milrinone increased fractional shortening but had no effect before beta-blocker treatment. CONCLUSIONS: Milrinone increases inotropic performance independently of beta-adrenoceptors in vivo. Metoprolol treatment restores the blunted inotropic response to milrinone in patients with heart failure, indicating that postreceptor events (e.g., increase in inhibitory G-protein) are favorably influenced. This mechanism could contribute to the beneficial effects observed in the study patients and represents an important mechanism of how beta-blocker treatment influences the performance of the failing heart.

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Supersensitive negative chronotropic and dromotropic effects have been described for adenosine after human heart transplantation. The present study investigated a potential antiadrenergic negative inotropic effect of adenosine in heart transplant recipients compared to normal subjects. Sinus cycle length, PR interval, blood pressure, and inotropic response in vivo were compared in seven orthotopic heart transplant recipients and seven healthy volunteers (controls). Fractional shortening, velocity of circumferential fiber shortening, and systolic pressure/dimension ratio were calculated using M-mode echocardiography. Baseline ventricular contractility was normal in both groups. Although adenosine induced a significant exaggeration of the negative chronotropic and dromotropic effect in the transplant group, the positive inotropic effect of 20 ng/kg x min isoproterenol (FS 53.2 +/- 8.8 vs 51.0 +/- 4.6%, P/D 5.8 +/- 1.9 vs 6.0 +/- 0.8 mm Hg/mm, Vcf 0.21 +/- 0.04 vs 0.20 +/- 0.02%/ms for heart recipients vs controls) was not reduced by the additional administration of 150 micrograms/kg adenosine (FS 52.2 +/- 8.6 vs 51.7 +/- 5.6%, P/D 5.5 +/- 1.5 vs 5.4 +/- 0.8 mm Hg/mm, Vcf 0.24 +/- 0.07 vs 0.21 +/- 0.02%/ms for transplant recipients vs controls). In contrast to a chronotropic and dromotropic supersensitivity, adenosine does not attenuate the catecholamine-induced increase in contractility in the human ventricle in vivo after heart transplantation.

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OBJECTIVE: To measure changes in haemodynamics and myocardial blood flow after acute intravenous (i.v.) and intracoronary (i.c.) injection of bisoprolol in patients with coronary heart disease. PATIENTS AND METHODS: A prospective, randomized controlled study of 14 patients (12 men, 2 women; mean age 65 [50-73] years) with angio-graphically proven coronary artery stenosis (reduced in lumen of at least 70%) in one or more major vessels. Seven patients received, before balloon angioplasty, either 0.01 mg/kg body weight directly into the coronaries (group 1, infusion through the guiding catheter) or 2.5 mg (group 2, via the sheath). Heart rate and blood pressure were measured before and after bisoprolol injection. Coronary blood flow was measured by the thermodilution method via two indwelling catheters in the coronary sinus. RESULTS: After bisoprolol there was a reduction in heart rate (group 1: from 83/min to 75/min; group 2: from 77/min to 72/min) and blood pressure (group 1: from 137/80 mm Hg to 125/70 mm Hg; group 2: from 135/86 mm Hg to 126/80 mm Hg). Coronary blood flow was lower after i.c. bisoprolol injection than before (group 1: 383 ml/min vs 352 ml/min, but higher after i.v. injection (group 2: 353 ml/min vs 384 ml/min). These differences were statistically not significant. CONCLUSION: While after-load was clearly reduced and myocardial blood flow remained unchanged, bisoprolol improved myocardial oxygen balance. No different effects could be detected after intracoronary vs intravenous application of bisoprolol.

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OBJECTIVES: The purpose of this study was to investigate the antiadrenergic effects of adenosine and carbachol on beta-adrenoceptor-stimulated human ventricular contractility in vivo. In addition, the antiadrenergic effects of adenosine and carbachol were compared in vitro. BACKGROUND: Adenosine is reported to exhibit an antiadrenergic negative inotropic response in the beta-adrenergic-stimulated ventricular myocardium in vitro. The effect of adenosine is similar to the antiadrenergic effect of m-cholinoceptor stimulation in vitro. METHODS: The inotropic response in vivo was assessed in seven healthy volunteers by M-mode echocardiography and simultaneous blood pressure monitoring. It was calculated as the increase in the rate-corrected velocity of circumferential fiber shortening and in the systolic pressure/dimension ratio. All volunteers received pretreatment with 450 mg of dipyridamole/day for 48 h. In addition, the effects of adenosine and carbachol in the presence of 0.03 mumol/liter of isoproterenol on cumulative concentration-response curves of isolated, electrically driven human ventricular muscle strips were compared in vitro (n = 13). RESULTS: The positive inotropic response to continuous infusion of 20 ng/kg per min of isoproterenol (increase of rate-corrected velocity of circumferential fiber shortening [10.2 +/- 2.1% x square root of beats/min per ms] and increase of systolic pressure/dimension ratio 1.09 +/- 0.3 mm Hg/mm) was significantly (p < 0.01) reduced by 3.6 micrograms/kg body weight of intravenous carbachol (4.2 +/- 1.2% x square root of beats/min per ms, 0.21 +/- 0.18 mm Hg/mm) but not by 50 micrograms/kg of intravenous adenosine (8.2 +/- 3.1% x square root of beats/min per ms, 1.35 +/- 0.42 mm Hg/mm), although adenosine induced a significant negative dromotropic effect. In vitro comparison of force of contraction with cumulative concentration-response curves in the presence of 0.03 mumol/liter of isoproterenol demonstrated an EC50 value (concentration producing half-maximal effect) for adenosine 466 times higher than that for carbachol (65.3 vs. 0.14 mumol/liter, p < 0.001). CONCLUSIONS: In contrast to carbachol, adenosine does not attenuate the catecholamine-induced increase in contractility in the human ventricle in vivo. These differences between the A1-adenosine receptor- and m-cholinoceptor-mediated effects could be due to fewer A1-adenosine receptors or a less efficient receptor-effector coupling, or both.

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BACKGROUND: In severe human heart failure, an increase in frequency of stimulation is accompanied by a reduced force of contraction in vivo and in vitro. The present study was aimed to investigate whether inotropic stimulation influences the inverse force-frequency relationship in failing human myocardium. METHODS AND RESULTS: The effects of the cAMP-independent positive inotropic agents ouabain (0.01 mumol/L) and BDF 9148 (0.1 mumol/L) as well as the beta-adrenoceptor agonist isoprenaline (0.01 mumol/L and 0.1 mumol/L) on the force-frequency relationship in electrically driven papillary muscle strips from nonfailing (brain death, n = 5) and terminally failing (NYHA class IV, heart transplants, dilated cardiomyopathy, n = 22) human myocardium were studied. For comparison, we examined the effect of elevation of the extracellular Ca2+ concentration (3.2 mmol/L and 6.2 mmol/L). In nonfailing myocardium, force of contraction, peak rate of tension rise, and peak rate of tension decay increased, whereas time to peak tension and time to half relaxation decreased following an increase of stimulation frequency. In NYHA class IV, force of contraction gradually declined followed by changes of other parameters of isometric contraction. Moderate stimulation of contractility by isoprenaline (0.01 mumol/L) partly reversed the negative force-frequency relationship in NYHA class IV and preserved the positive force-frequency relationship in nonfailing myocardium. The addition of ouabain and BDF 9148 together restored completely the force-frequency relationship in NYHA class IV. In contrast, high concentrations of isoprenaline (0.1 mumol/L) and an elevation of the extracellular Ca2+ concentration enhanced the decline in force of contraction in the presence of higher stimulation frequencies. CONCLUSIONS: It is concluded that functionally important changes occur in the intracellular Ca2+ handling, leading to the negative force-frequency relationship in terminally failing human myocardium. Interestingly, the negative force-frequency relationship can be restored by agents producing positive inotropic effects by elevation of the intracellular Na+ concentration. These findings suggest that hitherto unknown changes in the intracellular ionic homeostasis occur in the failing human heart. Even though increasing [Ca2+]i in failing heart cells may be detrimental, increasing [Na+bdi may be beneficial through a mechanism independent of an increase in [Ca2+]i.

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The relevance of an indirect negative inotropic effect of pharmacological or vagally mediated M-cholinoceptor stimulation in the human ventricle in vivo is unknown. The inotropic response induced by isoproterenol (isoprenaline, 20 ng.kg-1 x min-1), measured by m-mode echocardiography as the increase of fractional shortening in seven healthy subjects, was reduced from 17.1 +/- 4.3 to 9.1 +/- 3.9% (P < 0.01) by M-cholinoceptor stimulation using intravenous injection of 3.6 micrograms/kg carbachol. However, the inotropic response of increasing doses of isoprenaline (5-20 ng.kg-1 x min-1) did not differ in 13 healthy subjects without and after M-cholinoceptor blockade (atropine, 0.015 mg/kg i.v.); the increase of fractional shortening amounted to 17.4 +/- 4.0 vs. 19.5 +/- 4.8% (NS) in response to 20 ng.kg-1 x min-1 isoprenaline. It is concluded that pharmacological M-cholinoceptor stimulation of the human ventricle significantly reduces the inotropic response of beta-adrenoceptor stimulation. This may offer a new therapeutic approach to attenuate an increased cardiac sympathetic tone. However, M-cholinoceptor blockade, i.e., interruption of parasympathetic influences, does not augment the inotropic response to beta-adrenoceptor stimulation. Therefore, in healthy resting humans a physiological role of the parasympathetic nervous system in mediating an indirect negative inotropic effect on ventricular contractility seems to be absent.

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There is no established treatment specifically aimed at protecting or restoring cardiac energy metabolism, which is greatly impaired by ischaemia. Even after reperfusion, myocardial content of ATP remains low for more than 72 h. Long-term post-ischaemic dysfunction and irreversibility of ischaemic damage have been associated with low ATP content. Evidence that the pentose sugar ribose stimulates ATP synthesis and improves cardiac function led us to test the possibility that ribose increases tolerance to myocardial ischaemia in patients with coronary artery disease (CAD). 20 men with documented severe CAD underwent two symptom-limited treadmill exercise tests on 2 consecutive days; we postulated that the ischaemia induced might bring about changes in ATP metabolism lasting for several days. Patients whose baseline tests showed reproducibility were randomly allocated 3 days of treatment with placebo or ribose 60 g daily in four doses by mouth. Exercise testing was repeated after treatment on day 5. At that time mean (95% confidence interval) treadmill walking time until 1 mm ST-segment depression was significantly greater in the ribose than in the placebo group (276 [220-331] vs 223 [188-259] s; p = 0.002). The groups did not differ significantly in time to moderate angina. In the ribose-treated group the changes from baseline to day 5 in both time to ST depression and time to moderate angina were significant (p less than 0.005), but these changes were not significant in the placebo group. In patients with CAD, administration of ribose by mouth for 3 days improved the heart's tolerance to ischaemia. The presumed effects on cardiac energy metabolism offer new possibilities for adjunctive medical treatment of myocardial ischaemia.

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We investigated whether optimized ischaemia monitoring during and after PTCA using continuous recording of standardized 12-lead ECG provides additional information regarding the presence and localization of ischaemia. We studied 50 patients undergoing PTCA who received a total of 173 balloon inflations. Chest leads showed not only significantly more frequent ischaemic changes compared with routine limb lead monitoring (116/173 (67%) vs 88/173 (51%)), but in addition, a significantly earlier appearance of changes; 15.4 +/- 6.2 s after the start of balloon inflation compared with 17.5 +/- 6.8 s in the limb leads. Anginal pain, however, first occurred at 35 +/- 14 s after vessel occlusion in 74/173 (43%) of inflations. The changes in ECG monitoring correlated well with the coronary wedge pressure; at coronary wedge pressures below 20 mmHg, 97% of inflations caused ischaemic ECG changes; at pressures greater than 40 mmHg, changes were noted in only 42% of inflations. PostPTCA, 6/36 (16.7%) patients undergoing continuous 12-lead monitoring showed ischaemic ST-segment changes (asymptomatic in five cases), which helped in decision-making regarding interventional measures. In summary, we have found standardized 12-lead monitoring both during and after PTCA to be more precise and reliable in ischaemia detection and useful for clinical decision making.

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In 22 patients we studied the effects of 0.2 mg nifedipine given intracoronary during the course of routine PTCA. In 9 patients the effect of the nifedipine-free solvent was additionally tested. Injections were made through the guiding catheters or balloon catheters as pre- and poststenotic injections. We monitored frequency and character of pain, ECG changes (continuous recording of full 12-lead ECG) and pressure recordings from the left ventricle and pre- and poststenotic coronary artery. Short-lasting "stinging" pain sensations were described by 41% of the patients after nifedipine and 33% after solvent injection (n.s.). Patients described the pain as different from their usual angina pectoris. Pain was more frequent after poststenotic injections (through the balloon catheter) than after pre-stenotic injections (59% vs. 19%, p less than 0.01). ECG changes were peaking T waves, ST elevation and ST depression. They were recorded after pre-stenotic injections in 21 of 22 cases for nifedipine and 6 of 9 for solvent and after poststenotic injections in 22 of 22 cases for nifedipine and 8 of 9 cases for solvent. After nifedipine 0.2 mg i.c. the pressures decreased by 3.5% pre-stenotic and 9.7% post-stenotic. LVEDP increased by 10.7%. Our results show that pain sensations and electrocardiographic changes occur with similar character and frequency after i.c. injections of nifedipine or nifedipine-free solvent. Thus these effects do not seem to be caused by nifedipine. Hemodynamic effects were small and there was no disproportionate decrease of poststenotic pressure.

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