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.

Heart failure and statins--why do we need a clinical trial?

The effect of statins to reduce mortality and morbidity in primary and secondary prevention as well as in acute coronary syndrome is well established. Recent data show that pleiotropic effects might also have direct effects on the myocardial cell. However, in chronic heart failure the outcome is inversely related to LDL-plasma concentrations and other pleiotropic effects might impair mitochondrial function. Since there are no safety data on the use of statins in chronic heart failure, a controlled randomized and placebo-controlled trial is urgently needed.

A multicentre, randomized, double-blind, placebo-controlled, 1-year study of bupropion SR for smoking cessation.

BACKGROUND: Bupropion sustained release (bupropion SR) has been shown to increase smoking cessation success rates in the US studies. OBJECTIVE: To determine whether bupropion SR, in combination with counselling, is effective for smoking cessation in a multi-country study. METHODS: This randomized, double-blind, placebo-controlled trial enrolled 707 smokers. A total of 527 received bupropion SR 300 mg daily for 7 weeks and 180 received placebo. A total of 11 clinic visits and 10 telephone contacts were scheduled, during the course of 1 year. Seven-week and 12-month abstinence rates were the study outcomes. RESULTS: Both continuous and weekly point prevalence smoking abstinence rates were significantly higher in the bupropion SR group compared with placebo. The continuous abstinence rate from weeks 4 to 7 was 46% in the bupropion SR group compared with 23% in the placebo group [odds ratio (OR) = 2.82; 95% confidence interval (CI) 1.89-4.28; P < 0.001). At month 12, the continuous abstinence rates were 21% for the bupropion SR group and 11% for the placebo group (OR = 2.19; 95% CI 1.29-3.86, P = 0.002). For most nicotine-withdrawal symptoms small changes were measured. Adverse events were higher for the bupropion SR group compared with placebo (insomnia 24% vs. 15%; dry mouth 13% vs. 5%). CONCLUSION: Bupropion SR in combination with counselling increased the abstinence rate compared with placebo, and was well tolerated.

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.

Effect of smoking reduction and cessation on cardiovascular risk factors.

This open study examined the effect of smoking reduction and smoking cessation on established cardiovascular risk factors. Fifty-eight healthy adult smokers (smoking >or=15 cigarettes/day for at least 3 years) were provided with nicotine nasal spray (to be used ad libitum) and asked to stop smoking. The primary goal during the first 8 weeks, however, was to reduce their daily smoking by at least 50%. Subjects were then followed for another 8 weeks; at this point, 33 participants had successfully stopped smoking. Cardiovascular risk factors including fibrinogen, hemoglobin, hematocrit, triglycerides, and cholesterol were measured at baseline and at 9 and 17 weeks. After 8 weeks of smoking reduction, the mean number of cigarettes smoked per day had decreased from 21.5 +/- 0.6 (baseline) to 10.8 +/- 0.6 (p < 0.001). This was accompanied by significant improvements in fibrinogen (from 2.9 +/- 0.1 g/l at baseline to 2.6 +/- 0.1 g/l, p = 0.011), white blood cells (from 7.0 +/- 0.4 to 6.2 +/- 0.3 x 10(9)/l, p = 0.005) and the high-density/low-density lipoprotein (HDL/LDL) ratio (0.33 +/- 0.03 to 0.37 +/- 0.03, p < 0.005). Following 8 weeks of abstinence from smoking, the mean white blood cell count was further reduced (to 6.1 +/- 0.3 x 10(9)/l, p = 0.026 vs. baseline) and there were also significant improvements in HDL (from 1.16 +/- 0.06 mmol/l at baseline to 1.32 +/- 0.06, p < 0.001) and LDL (from 3.78 +/- 0.16 mmol/l at baseline to 3.52 +/- 0.17, p = 0.015). In conclusion, 8 weeks of smoking reduction resulted in clinically significant improvements in established cardiovascular risk factors. These improvements were even greater after an additional period of abstinence from smoking.

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.

Searches for new interstellar molecules, including a tentative detection of aziridine and a possible detection of propenal.

Rotational spectroscopy at millimeter wavelengths is a powerful means of investigating the chemistry of dense interstellar clouds. These regions can exhibit an interesting complement of gas phase molecules, including relatively complex organics. Here we report the tentative first astronomical detection of aziridine (ethylenimine), the possible detection of propenal (acrolein), and upper limits on the abundances of cyclopropenone, furan, hydroxyethanal (glycolaldehyde), thiohydroxylamine (NH2SH), and ethenol (vinyl alcohol) in various interstellar clouds.

Are patients truthful about their smoking habits? A validation of self-report about smoking cessation with biochemical markers of smoking activity amongst patients with ischaemic heart disease.

AIMS: To validate self-report about smoking cessation with biochemical markers of smoking activity amongst patients with ischaemic heart disease. PATIENTS AND METHODS: Outpatients at the Division of Cardiology, 75 years of age or younger, who had been Hospitalized at Sahlgrenska University Hospital in Göteborg due to an ischaemic event and who consecutively participated in a nurse-monitored routine care programme for secondary prevention, from 6 February 1997 to 5 February 1998. Data concerning smoking habits were collected through interviews. Two chemical markers, cotinine in plasma and carbon monoxide (CO) in expired air, validated self-reports concerning smoking cessation. RESULTS: 260 former smokers were validated. In the vast majority of the study population, the anamnestic information concurred with the chemical marker. However, 17 patients had chemical markers that contradicted their self-report with raised CO (n = 6) and/or raised cotinine levels (n = 13) without alternative nicotine delivery. CONCLUSION: Most patients with coronary artery disease relating information concerning cessation of smoking are truthful. A few patients, however, seem to conceal their smoking. Testing by chemical markers may be questionable for ordinary care but should, however, be included in studies concerning the association between smoking and health.

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.

A novel polymorphism in the gene coding for the beta(1)-adrenergic receptor associated with survival in patients with heart failure.

AIMS: The adrenergic nervous system is of major importance in congestive heart failure. No genetic polymorphism has previously been identified in the beta(1)-adrenergic receptor gene. The aim of this study was to find possible mutations in this gene and to relate such findings to morbidity and prognosis in heart failure. METHODS AND RESULTS: Genomic DNA was extracted from blood leukocytes from patients with congestive heart failure (n=184) and from age-matched controls (n=77). The part of the beta(1)-adrenergic receptor gene corresponding to nucleotide 1-255 was amplified by polymerase chain reaction and analysed by automated sequencing. The patients were investigated by echocardiography and followed regarding symptoms and survival for 5 years. A missense mutation was identified at nucleotide position 145 in the beta(1)-adrenergic receptor gene, which predicted an amino acid substitution at position 49 (Ser49Gly). The allele frequency of the Gly49 variant was 0.13 in controls and 0.18 in patients (P=0.19). At the time of the 5-years follow-up, 62% of the patients with the wild type gene and 39% of the patients with the Ser49Gly variant had died or had experienced hospitalization (P=0.005). Patients without the mutation had significantly poorer survival compared to those with the mutation, risk ratio 2.34 (95% CI 1.30-4.20), P=0.003. In a mulivariate analysis, the risk ratio was 2.03 (95% CI 0.99-4.16) P=0.05. CONCLUSION: A novel missense mution in the beta(1)-adrenergic receptor gene was associated with a decreased mortality risk in patients with congestive heart failure. These data suggest that the beta(1)-receptor Ser49Gly variant might be associated with altered receptor function, resulting in myocardial protection in patients with heart failure.

Supervised physical activity in Sweden: in theory and practice.

The aim of this study was to assess to which extent community-run projects including physical activity could be identified, described and analysed in terms of objectives, organisation, evaluation and financing, as a resource in prevention and treatment of common lifestyle-related medical problems. The Swedish database Spriline was used as a main source of information. Identification of ongoing Swedish activities was followed by a mail questionnaire. In total, 151 projects were eventually identified. A semistructured questionnaire containing about 30 questions was mailed to the individual listed as responsible for the project, with a reminder 2 months later. Only 52 projects were viable; a follow-up of nonresponders showed that no relevant activity program had ever existed or that the person responsible had left. Walking, aerobics and water activities were the dominating types of activity. Most projects addressed both sexes, but eight weight reduction programs were designed for women only. Evaluation ranged from 'measuring attendance' to 'scientific evaluation'. Physical activity programs may not be as systematically organised as the Swedish database suggests and cannot generally be relied upon as support in patient care, unless critically evaluated in advance.

Autoantibodies against the angiotensin receptor (AT1) in patients with hypertension.

Sera from patients with malignant essential hypertension (n = 14), malignant secondary hypertension mainly attributable to renovascular diseases (n = 12) and renovascular diseases without malignant hypertension (n = 11) and from normotensive healthy blood donors (n = 35) were studied for the presence of autoantibodies against G-protein-coupled cardiovascular receptors. Autoantibodies against the angiotensin II receptor (AT1) were detected in 14, 33, 18 and 14% of patients with malignant essential hypertension, malignant secondary hypertension, renovascular diseases and control patients, respectively. Sensitivity of the enzyme immunoassay was assessed as 5 microg/ml IgG. Patients did not show antibodies against bradykinin (B2) or angiotensin II subtype 2 (AT2) receptors. Autoantibodies affinity-purified from positive patients localized AT receptors in Chinese hamster ovary transfected cells, and displayed a positive chronotropic effect on cultured neonatal rat cardiomyocytes. These results demonstrate the existence of autoantibodies against a functional extracellular domain of human AT1 receptors in patients with malignant hypertension, and suggest that these autoantibodies might be involved in the pathogenesis of malignant hypertension.

A monoclonal antibody directed against an autoimmune epitope on the human beta1-adrenergic receptor recognized in idiopathic dilated cardiomyopathy.

A monoclonal antibody (MAb M16) was obtained by immunizing Balb/C mice with free peptide H26R, corresponding to the second extracellular loop of the human beta1-adrenergic receptor (beta1AR), against which functional autoantibodies have been detected in patients with idiopathic dilated cardiomyopathy. The MAb was found to be of IgG2b type and directed against a conformational epitope, encompassing the sequence recognized by the human autoantibodies. BIAcore measurements yielded an equilibrium constant of 6.5 X 10(7) M1 with an association rate constant (kon) of 6.5 X 10(4) M(-1) sec(-1) and a dissociation rate constant (koff) of 1.0 X 10(-3) sec(-1). It immunoprecipitated only poorly the solubilized beta1AR of Sf9 cell membranes. Functionally, the MAb was capable of not only reducing the number of the maximal binding sites to the beta1-adrenergic receptor of transfected Sf9 cell membranes, but also of displaying a positive chronotropic effect on cultured neonatal rat cardiomyocytes. These properties, which the MAb shares with the human autoantibodies, makes it an interesting tool for passive transfer studies in mice.

Myocardial hypertrophy in transgenic mice overexpressing the bovine growth hormone (bGH) gene.

OBJECTIVES: The main purpose of the present study was to characterize cardiac muscle hypertrophy using both qualitative and quantitative microscopy in mice overexpressing the bovine growth hormone. RESULTS: Measurements of 30 fibres from each group revealed that fibre diameter in transgenic hearts was significantly larger than in control hearts. There was a significant decrease in interfibrillar space in transgenic hearts as compared with control hearts. The enlarged transgenic hearts displayed unchanged organelles such as normal myofibrils and mitochondria in a normal pattern, suggesting balanced growth. Myelin structures were occasionally observed between normal myofibrils. Moreover, myocardial beta-adrenergic receptors and muscarinic receptors in the hearts of transgenic mice overproducing GH were studied to see whether they are involved in the hypertrophic process. It was shown that the density of muscarinic receptors had decreased and the super-high affinity of muscarinic receptors was lost, without any significant changes in either the density or the affinity of beta-adrenergic receptors, as compared with controls. CONCLUSIONS: These results demonstrate that a GH excess was able to induce significant myocardial hypertrophy and that there was a downregulation of muscarinic receptors.

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.

Patients with uncomplicated coronary artery disease have reduced heart rate variability mainly affecting vagal tone.

AIM: To investigate whether uncomplicated chronic coronary artery disease causes changes in heart rate variability and if so, whether the heart rate variability pattern is different from that described in patients with acute myocardial infarction. METHODS: Heart rate variability was studied in 65 patients with angina who had no previous myocardial infarcts, no other diseases, and were on no drug that could influence the sinus node. Results were compared with 33 age matched healthy subjects. The diagnosis of coronary artery disease in angina patients was established by coronary angiography in 58, by thallium scintigraphy in six, and by exercise test only in one. Patients and controls were Holter monitored 24 hours outside hospital, and heart rate variability was calculated in the frequency domain as global power (GP: 0.01-1.00 Hz), low frequency peak (LF: 0. 04-0.15 Hz), high frequency peak (HF: 0.15-0.40 Hz), LF/HF in ms(2), and in the time domain as SDNN (SD of normal RR intervals), SDANN (SD of all five minute mean normal RR intervals), SD (mean of all five minute SDs of mean RR intervals), rMSSD (root mean square of differences of successive normal RR intervals) (all in ms), and pNN50 (proportion of adjacent normal RR intervals differing more than 50 ms from the preceding RR interval) as per cent. RESULTS: The mean age in patients and controls was 60.4 (range 32-81) and 59.1 (32-77) years, respectively (NS), the male/female ratio, 57/65 and 24/33 (NS), and the mean time of Holter monitoring, 23.0 (18-24) and 22.8 (18-24) hours (NS). Mortality in angina patients was 0% (0/65) at one year, 0% (0/56) at two years, and 3% (1/33) at three years. Compared with healthy subjects angina patients showed a reduction in GP (p = 0.007), HF (p = 0.02), LF (p = 0.02), SD (p = 0.02), rMSSD (p = 0.01), and pNN50 (p = 0.01). No significant difference was found in RR, LF/HF, SDNN, or SDANN. CONCLUSIONS: Uncomplicated coronary artery disease without previous acute myocardial infarction was associated with reduced high and low frequency heart rate variability, including vagal tone. SDANN and SDNN, expressing ultra low and very low frequencies which are known to reflect prognosis after acute myocardial infarction, were less affected. This is in agreement with the good prognosis in uncomplicated angina in this study.

Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in congestive heart failure (MERIT-HF). MERIT-HF Study Group.

CONTEXT: Results from recent studies on the effects of beta1-blockade in patients with heart failure demonstrated a 34% reduction in total mortality. However, the effect of beta1-blockade on the frequency of hospitalizations, symptoms, and quality of life in patients with heart failure has not been fully explored. OBJECTIVE: To examine the effects of the beta1-blocker controlled-release/extended-release metoprolol succinate (metoprolol CR/XL) on mortality, hospitalization, symptoms, and quality of life in patients with heart failure. DESIGN: Randomized, double-blind controlled trial, preceded by a 2-week single-blind placebo run-in period, conducted from February 14, 1997, to October 31, 1998, with a mean follow-up of 1 year. SETTING: Three hundred thirteen sites in 14 countries. PARTICIPANTS: Patients (n = 3991) with chronic heart failure, New York Heart Association (NYHA) functional class II to IV, and ejection fraction of 0.40 or less who were stabilized with optimum standard therapy. INTERVENTIONS: Patients were randomized to metoprolol CR/XL, 25 mg once per day (NYHA class II), or 12.5 mg once per day (NYHA class III or IV), titrated for 6 to 8 weeks up to a target dosage of 200 mg once per day (n = 1990); or matching placebo (n = 2001). MAIN OUTCOME MEASURES: Total mortality or any hospitalization (time to first event), number of hospitalizations for worsening heart failure, and change in NYHA class, by intervention group; quality of life was assessed in a substudy of 741 patients. RESULTS: The incidence of all predefined end points was lower in the metoprolol CR/XL group than in the placebo group, including total mortality or all-cause hospitalizations (the prespecified second primary end point; 641 vs 767 events; risk reduction, 19%; 95% confidence interval [CI], 10%-27%; P<.001); total mortality or hospitalizations due to worsening heart failure (311 vs 439 events; risk reduction, 31%; 95% CI, 20%-40%; P<.001), number of hospitalizations due to worsening heart failure (317 vs 451; P<.001); and number of days in hospital due to worsening heart failure (3401 vs 5303 days; P<.001). NYHA functional class, assessed by physicians, and McMaster Overall Treatment Evaluation score, assessed by patients, both improved in the metoprolol CR/XL group compared with the placebo group (P = .003 and P = .009, respectively). CONCLUSIONS: In this study of patients with symptomatic heartfailure, metoprolol CR/XL improved survival, reduced the need for hospitalizations due to worsening heart failure, improved NYHA functional class, and had beneficial effects on patient well-being.

Cardioprotection with beta-adrenoceptor blockers. Does lipophilicity matter?

Beta-blockers have several beneficial cardiovascular effects in patients with hypertension, angina pectoris, myocardial infarction, and congestive heart failure. In patients with myocardial infarction and congestive heart failure some beta-blockers have been found to reduce mortality and morbidity. The beta-blockers with a proven effect on prognosis include timolol, metoprolol, propranolol, bisoprolol, and carvedilol. One important question is whether all cardiovascular effects obtained by beta-blockers can be considered to be class effects. The beta-blockers with favorable effects on prognosis include two with more selective beta1-receptor blockade (metoprolol and bisoprolol) and three non-selective (timolol, propranolol and carvedilol). One non-selective beta-blocker, which also has a more pronounced class III effect, sotalol, has been studied in a large postinfarction study without a significant effect on mortality. However, sotalol reduced the incidence of reinfarction similarly to the other beta-blockers with proven effect on mortality after myocardial infarction. Sotalol had no influence at all on sudden cardiac death, while all the other beta-blockers referred to above have a very marked effect on sudden cardiac death, in fact more marked than on overall mortality. The beta-blockers with proven effect on mortality and on sudden death have one property in common and that is some degreee of lipophilicity. Sotalol and atenolol are hydrophilic. From animal experimental data it has been suggested that beta-bockers with some degree of lipophilicity penetrate into the brain and have an indirect effect on vagal activity, which is of importance for prevention of ventricular fibrillation and sudden cardiac death. It can be summarized that some beta-blockers have been found to reduce mortality and sudden cardiac death in patients after myocardial infarction and in congestive heart failure, while others have not. It seems that the major properties of the beta-blockers with proven effects on mortality and sudden cardiac death are beta1-receptor blockade and some degree of lipophilicity. Until we know more about the mechanisms behind prevention of death and especially sudden cardiac death by beta-blockers, only drugs with proven effects on prognosis should be used.