An investigation of CYP2D6 genotype and response to metoprolol CR/XL during dose titration in patients with heart failure: a MERIT-HF substudy.

To explore the pharmacogenetic effects of the cytochrome P450 (CYP)2D6 genotype in patients with systolic heart failure treated using controlled/extended-release (CR/XL) metoprolol, this study assessed the CYP2D6 locus for the nonfunctional *4 allele (1846G>A; rs3892097) in the Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF; n = 605). Participants were characterized as extensive, intermediate, or poor metabolizers (EMs, IMs, or PMs, respectively), based on the presence of the CYP2D6*4 allele (EM: *1*1, 60.4%; IM: *1*4, 35.8%; and PM: *4*4, 3.8%). Plasma metoprolol concentrations were 2.1-/4.6-fold greater in the IM/PM groups as compared with the EM group (P < 0.0001). Metoprolol induced significantly lower heart rates and diastolic blood pressures during early titration, indicating a CYP2D6*4 allele dose-response effect (P < 0.05). These effects were not observed at maximal dose, suggesting a saturable effect. Genotype did not adversely affect surrogate treatment efficacy. CYP2D6 genotype modulates metoprolol pharmacokinetics/pharmacodynamics during early titration; however, the MERIT-HF-defined titration schedule remains recommended for all patients, regardless of genotype.

Impact of the ß1-adrenoceptor Arg389Gly polymorphism on heart-rate responses to bisoprolol and carvedilol in heart-failure patients.

This pharmacogenetic substudy of the prospective, double-blind, randomized CIBIS-ELD trial determined the impact of the ß1-adrenoceptor Arg189Gly polymorphism on heart-rate responses to bisoprolol or carvedilol in elderly patients with heart failure (421 with sinus rhythm, 107 with atrial fibrillation). Patients were randomized 1:1 to bisoprolol or carvedilol with a fortnightly dose-doubling scheme and guideline target doses. Patients with sinus rhythm responded essentially identically to bisoprolol and carvedilol, independent of genotype. Atrial fibrillation patients homozygous for Arg389 had a much smaller response to carvedilol than carriers of at least one Gly389 allele (mean difference 12 bpm, P < 0.00001). Carvedilol up to 2 × 12.5 mg did not reduce heart rate in Arg389Arg homozygotes at all. Interestingly, the immediate response to carvedilol did not differ between genotypes. The Arg389Gly polymorphism has a major impact on the heart-rate response to carvedilol (but not bisoprolol) in patients with heart failure plus atrial fibrillation.

Effects of complete heart block on myocardial function, morphology, and energy metabolism in the rat.

AIMS: Severe sustained bradycardia may cause acute and possibly chronic congestive heart failure (CHF). The aim of this study was to investigate acute and chronic effects of complete heart block (CHB) on cardiac function, morphology, and creatine (Cr) metabolism. METHODS AND RESULTS: CHB was induced in male Sprague-Dawley rats (approximately 250 g, n = 11) by means of electrocautery applied to the region of AV node and were compared with controls (n = 15). The rats were investigated at 1, 3, and 12 weeks after CHB induction with transthoracic echocardiography. Invasive haemodynamic assessment of left and right ventricular pressures was performed at 12 weeks. After the sacrifice, the hearts were freeze-clamped for analysis of myocardial Cr, and high energy phosphometabolites. The efficacy of operative procedure was 54%. The peri-operative mortality rate was 20%. Heart rate (HR) decreased by approximately 50% (P < 0.01) while stroke volume (SV) increased 2.5 times (P < 0.01) in the CHB rats. Cardiac index remained unchanged. The rats with CHB grew normally and were in no apparent distress. Filling pressures in left and right ventricles were normal. The CHB rats developed marked cardiomegaly with biventricular dilatation and eccentric left ventricular hypertrophy (P < 0.01). There was no change in the myocardial content of Cr and high energy phosphometabolites. CONCLUSION: Rats with CHB are compensating for reduction in HR with increased SV without haemodynamic and biochemical characteristics of CHF. This model may be useful to study the effects of CHB and bradycardia on myocardial structure, function, electrophysiology, and metabolism as well as for studies of cell therapy for reparation of AV conductance.

In vivo MR imaging of magnetically labeled human embryonic stem cells.

INTRODUCTION: Human embryonic stem cells (hES) have emerged as a potentially new therapeutic approach for treatment of heart and other diseases applying the concept of regenerative medicine. A method for in vivo visualization and tracking of transplanted hES would increase our understanding of in vivo hES behavior in both experimental and clinical settings. The aim of this study was to evaluate the feasibility of magnetic labeling and visualization of hES with magnetic resonance imaging (MRI). METHODS: hES were established and expanded according to standard procedures. After expansion, the cells were cultured under feeder free conditions and magnetically labeled by addition of dextran-coated Ferrum-oxide particles (Endorem) to the medium. Accumulation of small particles of iron-oxide (SPIO) in hES was assessed by Prussian blue staining and electron microscopy. For in vitro MRI, the labeled and unlabeled hES were examined in cell solution and after transplantation into explanted mouse heart ( approximately 100,000 cells) on a Bruker Avance DMX 500 vertical magnet at 11.75 T. A multi-slice, multi spin-echo T(2)-weighted images were obtained. For in vivo imaging, the experiments were performed on male Sprague-Dawley using Bruker Biospec 2.35 T magnet. The hES were directly injected ( approximately 500,000 cells) after surgical procedure (thoracotomy) into anterior left ventricular (LV) wall. Multi-slice T(2)-weighted gradient echo images were obtained using cardiac gating. RESULTS: hES appeared to be unaffected by magnetic labeling and maintained their ability to proliferate and differentiate. No additive agent for membrane permeabilisation was needed for facilitation of intracellular SPIO accumulation. Prussian blue and electron microscopy have revealed numerous iron particles in the cytoplasm of hES. On T(2)-weighted images, the labeled cells have shown well-defined hyopintense areas at the site of injection in anterior LV wall both in vitro and in vivo. CONCLUSIONS: It is feasible to magnetically label and visualize hES both in vitro and in vivo. MR visualization of magnetically labeled hES may be a valuable tool for in vivo tracking of hES.

Selective beta1-blockade attenuates post-infarct remodelling without improvement in myocardial energy metabolism and function in rats with heart failure.

OBJECTIVE: To investigate in vivo effects of long-term selective beta1-blockade on cardiac energy metabolism, remodelling, function and plasma cytokines in a rat model of post-infarct congestive heart failure (CHF). METHODS: Myocardial infarction (MI) was induced in male rats by ligation of the left coronary artery. Three different groups of rats were studied, MI rats treated with metoprolol (n=17), MI rats treated with saline (n=14) and sham-operated rats (n=12). The treatment with metoprolol 1 mg/kg/h was initiated in the third week post-infarct for a period of 6 weeks. All rats were investigated non-invasively with volume-selective 31P magnetic resonance spectroscopy and echocardiography for evaluation of left ventricular (LV) energy metabolism, morphology and function. Plasma concentration of IL-1beta and IL-6 and density of beta-adrenergic receptors were analyzed. RESULTS: Metoprolol attenuated the increase in LV dimensions and volumes. Treatment with metoprolol had no effect on PCr/ATP and LV function. Plasma level of IL-1beta was higher and IL-6 was lower in the metoprolol group. Density of beta-adrenergic receptors was similar in all three groups. CONCLUSION: Selective beta1-blockade in rats with chronic CHF attenuates post-infarct structural remodelling, without concomitant improvement in myocardial energy metabolism and function. Improvements in myocardial energy metabolism and function do not precede and are not a prerequisite for an anti-remodelling effect of beta1-blockade in the setting of chronic CHF.

Increased exercise ejection fraction and reversed remodeling after long-term treatment with metoprolol in congestive heart failure: a randomized, stratified, double-blind, placebo-controlled trial in mild to moderate heart failure due to ischemic or idiopathic dilated cardiomyopathy.

BACKGROUND: the effects of long-term administration of beta-blockers on left ventricular (LV) function during exercise in patients with ischemic heart disease (IHD) and idiopathic dilated cardiomyopathy (DCM) are controversial. PATIENTS AND METHODS: patients with stable congestive heart failure (CHF) (New York heart association [NYHA] class II and III) and ejection fraction (EF) < or =0.40 were randomized to metoprolol, 50 mg t.i.d. or placebo for 6 months. Patients were divided into two groups: ischemic heart disease (IHD) and idiopathic dilated cardiomyopathy (DCM). The mean EF was 0.29 in both groups and 92% were taking angiotensin-converting enzyme (ACE) inhibitors. In the IHD group, 84% had suffered a myocardial infarction (MI) and 64% had undergone revascularization at least 6 months before the study. LV volumes were measured by equilibrium radionuclide angiography. Mitral regurgitation was assessed by Doppler echocardiography. All values are changes for metoprolol subtracted by changes for placebo. RESULTS: metoprolol improved LV function markedly both at rest and during sub-maximal exercise in both groups. The mean increase in EF was 0.069 at rest (P<0.001) and 0.078 during submaximal exercise (P<0.001). LV end-diastolic volume decreased by 22 ml at rest (P=0.006) and by 15 ml during exercise (P=0.006). LV end-systolic volume decreased by 23 ml both at rest (P=0.001) and during exercise (P=0.004). Exercise time increased by 39 s (P=0.08). In the metoprolol group, mitral regurgitation decreased (P=0.0026) and only one patient developed atrial fibrillation vs. eight in the placebo group (P=0.01). CONCLUSION: metoprolol improves EF both at rest and during submaximal exercise and prevents LV dilatation in mild to moderate CHF due to IHD or DCM.

Different responses to dobutamine in the presence of carvedilol or metoprolol in patients with chronic heart failure.

OBJECTIVE: To determine whether patients with congestive heart failure on different beta adrenoreceptor blocking drugs have similar haemodynamic responses to dobutamine. DESIGN: Single centre, single blind, randomised, two period crossover study comparing carvedilol with metoprolol CR/XL. PATIENTS: Ten patients with stable chronic congestive heart failure (ejection fraction < 40%) on chronic treatment with metoprolol CR/XL. METHODS: Patients were treated with carvedilol or metoprolol CR/XL (target dose 50 mg twice daily and 200 mg once daily, respectively) for eight weeks. Stress echocardiography was undertaken at the end of each maintenance period, using dobutamine 5 and 15 microg/kg/min. RESULTS: No significant haemodynamic differences were seen at rest on the two treatments. There was a more pronounced increase in heart rate and cardiac output during dobutamine infusion when the patients were on metoprolol than when they were on carvedilol. Mean arterial pressure increased significantly when the patients were on carvedilol, and cardiac output increased during low dose dobutamine, without further change during high dose dobutamine. During the dobutamine infusion, there was no significant difference in ejection fraction between carvedilol and metoprolol treatment. CONCLUSIONS: Patients with congestive heart failure on a non-selective beta adrenoreceptor blocker or beta1 selective blocker responded differently to the inotropic drug dobutamine: the beta1 blockade caused by metoprolol could be counteracted by dobutamine, whereas with carvedilol a low dose of dobutamine increased cardiac output, and a higher dose of dobutamine caused a pressor effect. These findings may be clinically relevant when choosing an inotropic drug.

Growth hormone alone or combined with metoprolol preserves cardiac function after myocardial infarction in rats.

BACKGROUND AND OBJECTIVE: Beta-adrenoreceptor blocking agents are important for the treatment of myocardial infarction (MI). Accumulating evidence also indicates that growth hormone (GH) improves cardiac function after MI in rats. We aimed to investigate the cardiovascular effects of combined treatment in an animal model of MI. METHODS: MI was induced in rats by ligation of the left coronary artery. Three days after MI, animals were randomly assigned to one of four groups: controls (C) (n=19); GH (n=19) receiving s.c. 2 mg/kg per day rhGH; metoprolol (M) group (n=19) receiving 24 mg/kg per day and combined group (GHM) (n=20) treated with both GH (2 mg/kg per day s.c.) and M (24 mg/kg per day) for 9 days. Transthoracic echocardiography was performed before and after treatment. RESULTS: Serum levels of insulin-like growth factor I were significantly elevated in the GH-group but not in the GHM group compared to controls. Left ventricular volumes, cardiac index, systolic blood pressure, were similar in all groups. Percent changes in ejection fraction compared to baseline were; GH (6.1+/-5.0%) and GHM (6.1+/-4.2%) vs. C (-12.5+/-3.0%), P<0.01, M (-7.3+/-4.2%). The occurrence of aneurysms was not significantly different between the various treatment regimes. CONCLUSION: Treatment with growth hormone alone or in combination with metoprolol preserved left ventricular function after MI.

Metoprolol controlled release/extended release in patients with severe heart failure: analysis of the experience in the MERIT-HF study.

OBJECTIVES: This study analyzed the effect of the beta(1)-selective beta-blocker metoprolol succinate controlled release/extended release (CR/XL) once daily on mortality, hospitalizations and tolerability in patients with severe heart failure. BACKGROUND: There continues to be resistance to the incorporation of beta-blockers into clinical care, largely due to concerns about their benefit in patients with more severe heart failure. METHOD: SA subgroup of patients from Metoprolol CR/XL Randomized Intervention Trial in chronic Heart Failure (MERIT-HF) in New York Heart Association (NYHA) functional class III/IV with left ventricular ejection fraction < 0.25 were identified (n = 795). The analysis was by intention-to-treat. RESULTS: The mean ejection fraction at baseline was 0.19, and the yearly placebo mortality during follow-up was 19.1%. Treatment with metoprolol CR/XL compared to placebo resulted in significant reductions in all predefined mortality end points including: total mortality, 45 versus 72 deaths (risk reduction 39%; 95% confidence interval 11% to 58%; p = 0.0086); sudden death, 22 vs. 39 deaths (45% [7% to 67%]; p = 0.024); and death due to worsening heart failure, 13 vs. 28 deaths (55% [13% to 77%]; p = 0.015). Metoprolol CR/XL also reduced the number of hospitalizations for worsening heart failure by 45% compared with placebo (p < 0.0001). The NYHA functional class improved in the metoprolol CR/XL group compared with placebo (p = 0.0031). Metoprolol CR/XL was well tolerated, with 31% fewer patients withdrawn from study medicine (all causes) compared with placebo (p = 0.027). CONCLUSIONS: This subgroup analysis of the MERIT-HF study shows that patients with severe heart failure receive a similar mortality benefit and a similar reduction in hospitalizations for worsening heart failure with metoprolol CR/XL treatment as those patients included in the total study.

Challenges of subgroup analyses in multinational clinical trials: experiences from the MERIT-HF trial.

BACKGROUND: International placebo-controlled survival trials (Metoprolol Controlled-Release Randomised Intervention Trial in Heart Failure [MERIT-HF], Cardiac Insufficiency Bisoprolol Study [CIBIS-II], and Carvedilol Prospective Randomized Cumulative Survival trial [COPERNICUS]) evaluating the effects of b-blockade in patients with heart failure have all demonstrated highly significant positive effects on total mortality as well as total mortality plus all-cause hospitalization. Also, the analysis of the US Carvedilol Program indicated an effect on these end points. Although none of these trials are large enough to provide definitive results in any particular subgroup, it is natural for physicians to examine the consistency of results across various subgroups or risk groups. Our purpose was to examine both predefined and post hoc subgroups in the MERIT-HF trial to provide guidance as to whether any subgroup is at increased risk, despite an overall strongly positive effect, and to discuss the difficulties and limitations in conducting such subgroup analyses. METHODS: The study was conducted at 313 clinical sites in 16 randomization regions across 14 countries, with a total of 3991 patients. Total mortality (first primary end point) and total mortality plus all-cause hospitalization (second primary end point) were analyzed on a time to first event. The first secondary end point was total mortality plus hospitalization for heart failure. RESULTS: Overall, MERIT-HF demonstrated a hazard ratio of 0.66 for total mortality and 0.81 for mortality plus all-cause hospitalization. The hazard ratio of the first secondary end point of mortality plus hospitalization for heart failure was 0.69. The results were remarkably consistent for both primary outcomes and the first secondary outcome across all predefined subgroups as well as for nearly all post hoc subgroups. The results of the post hoc US subgroup showed a mortality hazard ratio of 1.05. However, the US results regarding both the second primary combined outcome of total mortality plus all-cause hospitalization and of the first secondary combined outcome of total mortality plus heart failure hospitalization were in concordance with the overall results of MERIT-HF. Tests of country by treatment interaction (14 countries) revealed a nonsignificant P value of.22 for total mortality. The mortality hazard ratio for US patients in New York Heart Association (NYHA) class III/IV was 0.80, and it was 2.24 for patients in NYHA class II, which is not consistent with causality by biologic gradient. We have not been able to identify any confounding factor in baseline characteristics, baseline treatment, or treatment during follow-up that could account for any treatment by country interaction. Thus we attribute the US subgroup mortality hazard ratio to be due to chance. CONCLUSIONS: Just as we must be extremely cautious in overinterpreting positive effects in subgroups, even those that are predefined, we must also be cautious in focusing on subgroups with an apparent neutral or negative trend. We should examine subgroups to obtain a general sense of consistency, which is clearly the case in MERIT-HF. We should expect some variation of the treatment effect around the overall estimate as we examine a large number of subgroups because of small sample size in subgroups and chance. Thus the best estimate of the treatment effect on total mortality for any subgroup is the estimate of the hazard ratio for the overall trial.

Selective beta(1)-blockade improves cardiac bioenergetics and function and decreases neuroendocrine activation in rats during early postinfarct remodeling.

In spite of the solid evidence that beta-blockade reduces mortality and morbidity in congestive heart failure (CHF) this therapy continues to be underused in clinical praxis. The reason for this may lie in scarcity of knowledge about the mechanisms of beta-blockade action. The major aim of this study was to investigate in vivo whether selective beta(1)-blockade may improve cardiac energy metabolism in rats with myocardial infarction in early postinfarct remodeling phase. Myocardial infarction (MI) was induced in male Sprague-Dawley rats by ligation of the left coronary artery. Two different groups of rats were studied, rats with MI treated with metoprolol (5 mg/kg/h; n = 9) and rats with MI saline treated (n = 9). The treatment with metoprolol was given by subcutaneously implanted minipumps and was initiated at 3 days postinfarct and during the period of 4 weeks. All rats were investigated with noninvasive methods (31)P magnetic resonance spectroscopy (MRS) and transthoracic echocardiography 3 days after induction of MI and 4 weeks later. Phosphocreatine/ATP ratio was normalized after the treatment with metoprolol while it was 50% lower in the saline group (p < 0.001). In the metoprolol group stroke volume and ejection fraction increased while deceleration time of mitral early filling was longer (all p < 0.05). Left ventricular weight as well as volumes and dimensions were similar between the groups. Plasma levels of noradrenaline (p = 0.058), adrenaline (p < 0.01) and brain natriuretic peptide (p = 0.09) were lower in the metoprolol group. Selective beta(1)-blockade with high dose of metoprolol initiated in the early postinfarct phase improves myocardial energy metabolism and function and prevents overactivation of sympathetic system. The beneficial effect on myocardial bioenergetics may be an important mode of action of beta-blockers which contributes to the clinical benefits of the therapy in CHF.

Growth hormone improves bioenergetics and decreases catecholamines in postinfarct rat hearts.

The aims of this study were to examine, in vivo, the effects of GH treatment on myocardial energy metabolism, function, morphology, and neurohormonal status in rats during the early postinfarct remodeling phase. Myocardial infarction (MI) was induced in male Sprague Dawley rats. Three different groups were studied: MI rats treated with saline (n = 7), MI rats treated with GH (MI + GH; n = 11; 3 mg/kg x day), and sham-operated rats (sham; n = 8). All rats were investigated with 31P magnetic resonance spectroscopy and echocardiography at 3 days after MI and 3 weeks later. After 3 weeks treatment with GH, the phosphocreatine/ATP ratio increased significantly, compared with the control group (MI = 1.69 +/- 0.09 vs. MI + GH = 2.42 +/- 0.05, P < 0.001; sham = 2.34 +/- 0.08). Treatment with GH significantly attenuated an increase in left ventricular end systolic volume and end diastolic volume. A decrease in ejection fraction was prevented in GH-treated rats (P < 0.05 vs. MI). Myocardial and plasma noradrenaline levels were significantly lower in MI rats treated with GH. These effects were accompanied by normalization of plasma brain natriuretic peptide levels (sham = 124.1 +/- 8.4; MI = 203.9 +/- 34.7; MI + GH = 118.3 +/- 8.4 ng/ml; P < 0.05 vs. MI). In conclusion, GH improves myocardial energy reserve, preserves left ventricular function, and attenuates pathologic postinfarct remodeling in the absence of induction of left ventricular hypertrophy in postinfarct rats. The marked decrease in myocardial content of noradrenaline, after GH treatment, may protect myocardium from adverse effects of catecholamines during postinfarct remodeling.

Early changes in longitudinal performance predict future improvement in global left ventricular function during long term beta adrenergic blockade.

OBJECTIVE: Contraction of longitudinal and subendocardial myocardial muscle fibres is reflected in descent of the atrioventricular (AV) plane. The aim was therefore to determine whether beta blocker treatment with prolongation of diastole might result in improved function as reflected by AV plane movements in patients with chronic heart failure. DESIGN: Double blind, randomised, placebo controlled and open intervention study. SETTING: University hospital. PATIENTS: Patients with congestive heart failure: placebo controlled (n = 26) and an open protocol (n = 15). INTERVENTIONS: 12 months of metoprolol treatment. MAIN OUTCOME MEASURES: Short axis and long axis echocardiography, invasive haemodynamics, radionuclide angiography. RESULTS: Recovery of systolic and diastolic function during metoprolol treatment was reflected by early changes in mean (SD) AV plane amplitude, from 5.3 (2.0)% to 7.1 (3.2)% and 7.8 (3. 1)% (at 3 and 12 months, respectively; p < 0.05). In a multivariate analysis, only the change in AV plane amplitude by three months was independently associated with improvement in pulmonary capillary wedge pressure by six months (r = 0.80, p = 0.017). Change in AV plane amplitude by three months was also a better predictor of improvement in ejection fraction by 12 months (r = 0.78, p < 0.001) than changes in radionuclide ejection fraction by three months (r = 0.34, p = 0.049). CONCLUSIONS: Improvement in longitudinal contraction was closely associated with a decrease in left ventricular filling pressure during metoprolol treatment. This association was stronger than changes in short axis performance or radionuclide ejection fraction, emphasising the importance of AV plane motion for left ventricular filling and systolic performance in patients with heart failure.

Impairment of cardiac function and bioenergetics in adult transgenic mice overexpressing the bovine growth hormone gene.

Cardiovascular abnormalities represent the major cause of death in patients with acromegaly. We evaluated cardiac structure, function, and energy status in adult transgenic mice overexpressing bovine GH (bGH) gene. Female transgenic mice expressing bGH gene (n = 11) 8 months old and aged matched controls (n = 11) were used. They were studied with two-dimensional guided M-mode and Doppler echocardiography. The animals (n = 6) for each group were examined with 31P magnetic resonance spectroscopy to determine the cardiac energy status. Transgenic mice had a significantly higher body weight (BW), 53.2+/-2.4 vs. 34.6+/-3.7 g (P < 0.0001) and hypertrophy of left ventricle (LV) compared with normal controls: LV mass/BW 5.6+/-1.6 vs. 2.7+/-0.2 mg/g, P < 0.01. Several indexes of systolic function were depressed in transgenic animals compared with controls mice such as shortening fraction 25+/-3.0% vs. 39.9+/-3.1%; ejection fraction, 57+/-9 vs. 77+/-5; mean velocity of circumferential shortening, 4.5+/-0.8 vs. 7.0+/-1.1 circ/sec, p < 0.01. Creatine phosphate-to-ATP ratio was significantly lower in bGH overexpressing mice (1.3+/-0.08 vs. 2.1+/-0.23 in controls, P < 0.05). Ultrastructural examination of the hearts from transgenic mice revealed substantial changes of mitochondria. This study provides new insight into possible mechanisms behind the deteriorating effects of long exposure to high level of GH on heart function.

MIC trial: metoprolol in patients with mild to moderate heart failure: effects on ventricular function and cardiopulmonary exercise testing.

UNLABELLED: Beta-blocker therapy results in a functional benefit in patients with heart failure (CHF) due to idiopathic dilated cardiomyopathy (DCM). This study assessed if similar effects were observed in patients with ischemic heart disease (CAD), NYHA II-III after 6 months of therapy with metoprolol. METHODS AND RESULTS: Fifty-two patients with CHF secondary to DCM (26 patients) and CAD (26 patients) and a left ventricular ejection fraction (EF)<40% were enrolled in the placebo-controlled study. The study medication was titrated over 6 weeks, the mean final dosage was 135 mg/day. Three patients died due to cardiogenic shock, two received placebo and one metoprolol. Eight patients did not complete the study due to non-compliance. Metoprolol significantly reduced heart rate at rest and after submaximal and maximal exercise. Vo(2)-max and Vo(2)-AT as well as the 6-min walk test improved significantly after metoprolol treatment. There was a significant increase in EF at rest (27.3-35. 2%), submaximal (28.5-37.7%) and maximal exercise (28.7-40.9%) in the metoprolol-treated patients. No differences were found between patients with CAD and DCM. We also observed reduced left ventricular volumes. CONCLUSION: The additional therapy with metoprolol improved cardiac function and the cardiopulmonary exercise capacity in patients with CHF.

In vivo metabolic imaging of cardiac bioenergetics in transgenic mice.

Recent advances in transgenic technology have made the mouse a particularly interesting small animal in cardiovascular research. Increasingly sophisticated experimental methods and tools are needed for detailed characterization of cardiovascular physiology and biochemistry in the mice. The objective of this study was to develop a method for noninvasive evaluation of cardiac energy metabolism in the mouse. Cardiac gated (31)P magnetic resonance spectroscopy using Image Selected in Vivo Spectroscopy (ISIS) method was applied in old mice overexpressing bovine growth hormone (bGH) (n = 5) and control mice (n = 5). The localized volumes of interest were 128 and 112 microL, respectively. Phosphocreatine-to-ATP ratio was 1.5 +/- 0.13 in the bGH mice and 2.1 +/- 0.04 in the control group (P < 0.01). The study demonstrates the feasibility of application of volume-selective (31)P MRS for evaluation of cardiac energy metabolism in the mouse under maintained physiological conditions.