Impact of initiating carvedilol before angiotensin-converting enzyme inhibitor therapy on cardiac function in newly diagnosed heart failure

OBJECTIVES: The purpose of this research was to evaluate the therapeutic value of initiating a beta-blocker before an angiotensin-converting enzyme inhibitor (ACEI) in the treatment of heart failure. BACKGROUND: Although ACEI and carvedilol produce benefits in heart failure, whether the order of initiation of therapy determines the impact on left ventricular (LV) function and New York Heart Association functional class (NYHA FC) has not been determined. METHODS: A single-center, prospective, randomized, open-label study was performed. We evaluated whether initiation of therapy with carvedilol either before (n = 38) or after (n = 40) perindopril therapy in newly diagnosed patients in NYHA FC II to III heart failure with idiopathic dilated cardiomyopathy, with the addition of the alternative agent after six months, determined subsequent changes in NYHA FC and LV function (echocardiography and radionuclide ventriculography). Study drugs were titrated to maximum tolerable doses. RESULTS: There were no differences in baseline characteristics between the study groups. After 12 months 11 patients died (6 in the group where the ACEI was initiated). At 12 months the group receiving carvedilol as initial therapy achieved a higher tolerable dose of carvedilol (43 +/- 17 mg vs. 33 +/- 18 mg, p = 0.03); a lower dose of furosemide (p < 0.05); and better improvements in symptoms (NYHA FC, p < 0.002), LV ejection fraction (radionuclide: 15 +/- 16% vs. 6 +/- 13%, p < 0.05; echocardiographic, p < 0.01), and plasma N-terminal pro-brain natriuretic peptide concentrations (p < 0.02). CONCLUSIONS: As opposed to the conventional sequence of drug use in the treatment of heart failure, initiation of therapy with carvedilol before an ACEI results in higher tolerable doses of carvedilol and better improvements in FC and LV function.     

Carvedilol increases two-year survivalin dialysis patients with dilated cardiomyopathy: a prospective,placebo-controlled trial

OBJECTIVES: We sought to evaluate the effects of carvedilol on mortality and morbidity in dialysis patients with dilated cardiomyopathy. BACKGROUND: Several lines of evidence support the concept that therapy with beta-blocking agents reduces morbidity and mortality in patients with congestive heart failure (HF), but the demonstration of such a survival benefit in dialysis patients with dilated cardiomyopathy is still lacking. METHODS: A total of 114 dialysis patients with dilated cardiomyopathy were randomized to receive either carvedilol or placebo in addition to standard therapy. A first analysis was performed at one year and was followed by an additional follow-up period of 12 months. RESULTS: Two-year echocardiographic data revealed a significant attenuation of pathologic remodeling, with smaller cavity diameters and higher ejection fractions in the active treatment group than in the placebo group. At two years, 51.7% of the patients died in the carvedilol group, compared with 73.2% in the placebo group (p < 0.01). Furthermore, there were significantly fewer cardiovascular deaths (29.3%) and hospital admissions (34.5%) among patients receiving carvedilol than among those receiving a placebo (67.9% and 58.9%, respectively; p < 0.00001). The exploratory analyses revealed that fatal myocardial infarctions, fatal strokes, and hospital admissions for worsening HF were lower in the carvedilol group than in the placebo group. A reduction in sudden deaths and pump-failure deaths was also observed, though it did not reach statistical significance. CONCLUSIONS: Carvedilol reduced morbidity and mortality in dialysis patients with dilated cardiomyopathy. These data suggest the use of carvedilol in all dialysis patients with chronic HF.     

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.     

A controlled study of the effects of carvedilol on clinical events, left ventricular function and proinflammatory cytokines levels in patients with dilated cardiomyopathy

BACKGROUND: Carvedilol is known to decrease the severity of ventricular dysfunction, to increase the left ventricular ejection fraction (LVEF), and, consequently, to reduce morbidity and mortality in patients with dilated cardiomyopathy. There is accumulating evidence that inflammatory cytokines have an important role in the pathogenesis of heart failure. OBJECTIVE: To establish whether the addition of carvedilol has an additive beneficial effect on cytokines in patients with dilated cardiomyopathy who are already receiving treatment with angiotensin-converting enzyme (ACE) inhibitors, digoxin and diuretics. METHODS AND RESULTS: In this single-centre, prospective, randomized study, 60 patients with dilated cardiomyopathy with an LVEF less than 40% and already receiving digoxin, ACE inhibitors and diuretics for six months as the standard therapy were randomly assigned to receive either carvedilol (n=30) or placebo (n=30). Patients received an initial dosage of 3.125 mg carvedilol or placebo twice daily for two weeks, which was then increased at two-week intervals (if tolerated), first to 6.25 mg, then to 12.5 mg, and, finally, to a target dosage of 25 mg twice daily. Clinical examinations, radionuclide studies, and determinations of plasma levels of tumour necrosis factor-alpha (TNF-a), interleukin (IL)-2 and IL-6 were performed at baseline and repeated four months after random assignment. Primary end points were New York Heart Association functional class, LV function and plasma cytokines levels. Eight patients died (seven in the placebo group, P=0.05). Patients treated with carvedilol had a significant improvement in functional class compared with the baseline values (P=0.001), with a decrease in the levels of cytokines (IL-6 [P=0.001] and TNF-a [P=0.001]). LVEF increased from 22.14+/-7.85% to 27.85+/-11.80% (P=0.002), but diastolic function did not change in the carvedilol group. CONCLUSIONS: In patients with dilated cardiomyopathy, the addition of carvedilol to treatment with digoxin, ACE inhibitors and diuretics is associated with a significant improvement in symptoms and in LV function, and suppression of inflammatory cytokines.     

Effects of carvedilol on left ventricular remodeling and systolic function in elderly patients with heart failure

BACKGROUND: Recent studies have shown that carvedilol therapy in patients with heart failure improves clinical outcome and survival, however, the effects of such treatment on left cardiac morphology and function in elderly patients with severe heart failure has not been widely studied. AIM: The purpose of this study was to establish the effect of carvedilol at short- and long-term on left ventricular size and performance with mono- and two-dimensional echocardiography, in subjects with dilated cardiomyopathy, NYHA III functional class, low LV ejection fraction (EF < 35%) and mean age of > 70 years. METHODS: We studied 48 patients, previously randomized to treatment with either carvedilol or placebo, and we performed echocardiographic evaluation at the start, and after 3 and 12 months. Left ventricular diameters, LV mass and fractional shortening were calculated by Deveraux formula; left ventricular volumes and ejection fraction were measured by area-length formula; pulmonary pressure was calculated by tricuspid reflow. RESULTS: After 3 months, only LV end-diastolic diameter was lower in the carvedilol group compared to the placebo group. Nevertheless, after 12 months, patients on carvedilol treatment showed a LV geometric and functional improvement compared to placebo. We found significant differences in: diastolic (P < 0.01) and systolic diameters (P < 0.001); on LV mass (P < 0.002); on LV systolic volume (P < 0.03); and on LV ejection fraction (P<0.01). Pulmonary pressure was also reduced in beta-blocker subjects (P < 0.001). CONCLUSIONS: Carvedilol therapy for 12 months reduced LV diameters and volumes. Thus, improving cardiac remodeling and LV systolic function in elderly patients with severe heart failure. Several months of therapy are required for these favorable effects to occur, as these changes do not occur in the short term.     

Combined therapy with carvedilol and amiodarone is more effective in improving cardiac symptoms, function, and sympathetic nerve activity in patients with dilated cardiomyopathy: comparison with carvedilol therapy alone.

BACKGROUND: Carvedilol therapy has been reported to be more effective than other beta-blockers in patients with chronic heart failure (CHF). Amiodarone is an anti-arrhythmic medicine that has also been reported to be effective in patients with CHF. But the usefulness of combined therapy with carvedilol and amiodarone has not been reported. METHODS: We compared 15 patients (M/F = 3/12, age = 57 +/- 8 y) with dilated cardiomyopathy (DCM) receiving carvedilol and amiodarone with 15 patients (M/F = 3/12, age = 61 +/- 9 y) receiving carvedilol alone. Patients were studied before and after 1 year of treatment (1Y). NYHA class and exercise capacity based on the specific-activity-scale (SAS), were assessed. Cardiac sympathetic nerve activity was estimated using total defect score (TDS), H/M ratio and washout rate (WR) of 123I-MIBG imaging. Cardiac function was evaluated using 99mTc-MIBI QGS. RESULTS: Combined therapy improved several parameters much more than carvedilol alone (p < 0.05) including delta-TDS (15.0 +/- 8.6 vs. 7.6 +/- 7.2) and delta-WR (15.9 +/- 11.0% vs. 7.3 +/- 10.0%) for 123I-MIBG imaging, delta-LVEF (26.1 +/- 11.4% vs. 15.5 +/- 13.8%), delta-end-systolic volume (100 +/- 63.8 ml vs. 58.9 +/- 47.3 ml), 1Y NYHA class (1.5 +/- 0.5 vs. 1.9 +/- 0.5), 1Y SAS (7.3 +/- 0.7 Mets vs. 6.2 +/- 1.0 Mets), and delta-SAS (3.4 +/- 0.8 Mets vs. 2.6 +/- 1.1 Mets). CONCLUSION: Combined therapy with carvedilol and amiodarone is more effective in improving cardiac symptoms, exercise capacity, cardiac function and cardiac sympathetic nerve activity in patients with DCM.     

Heart rate variability in heart failure

BACKGROUND: Heart rate variability (HRV) depicts the functional status of the autonomic nervous system and its effects on sinus node. Recently, HRV analysis has been introduced in patients with heart failure (CHF) to identify those who are at risk of cardiac death. AIM: To analyse HRV in patients with CHF with depressed left ventricular ejection fraction (EF) and to relate HRV parameters to EF, NYHA functional class and other clinical parameters. METHODS: The study group consisted of 105 patients with CHF (88 males, 17 females, mean age 54+/-12 years); 77 patients had ischaemic cardiomyopathy, and 28 - dilated cardiomyopathy. All patients were in NYHA class II-IV and had EF <40%. The mean value of echocardiographically assessed EF was 26.9+/-8.3%. The control group consisted of 30 gender- and age-matched healthy subjects. HRV analysis was performed in the time-domain from 24-hour Holter ECG. RESULTS: All HRV variables were significantly lower in patients with CHF than in controls. Patients with NYHA class II had higher values of SDNN and SDANN than those in class III or IV. Patients with sustained or non-sustained ventricular tachycardia (VT) detected during Holter monitoring had lower SDNN and SDANN values than those without VT. Patients with diabetes had significantly lower SDNN and rMSSD values than the patients without diabetes. Similar results were found when patients with or without hypertension were compared. HRV parameters were similar in patients either with ischaemic or dilated cardiomyopathy. Also the values of EF were similar (27.4+/-8.4 vs 25.0+/-8.3%, respectively, NS). In the whole group of patients with CHF the values of SDNN and SDANN significantly correlated with EF (SDNN p<0.001, r=0.42; SDANN p<0.001, r=0.51). This correlation was stronger in the subset of patients with ischaemic cardiomyopathy (SDNN p=0.002. r=0.54; SDANN p=0.002; r=0.53) than in those with dilated cardiomyopathy (SDNN p=0.012, r=0.23; SDANN p=0.008, r=0.42). A significant negative correlation was found between all HRV parameters and NYHA class (SDNN p<0.001, r = -0.33; SDANN p<0.001, r = -0.38; rMSSD p<0.001, r = -0.13). CONCLUSIONS: HRV is depressed in patients with CHF compared with healthy subjects. Among patients with CHF, HRV is further decreased in patients with more advanced NYHA class, lower EF and in those with diabetes, hypertension or VT on Holter monitoring.     

Effects of continuous positive airway pressure on cardiac volumes in patients with ischemic and dilated cardiomyopathy

The effects of continuous positive airway pressure (CPAP) on left (LV) and right ventricular (RV) volumes in patients with congestive heart failure (CHF) have not been studied. We hypothesized that CPAP would cause greater reductions in cardiac volumes in CHF patients with idiopathic dilated cardiomyopathy (IDC) than in those with ischemic cardiomyopathy (IsC), because their ventricles are more compliant. The effects of a 30-min CPAP application at 10 cm H(2)O on RV and LV end-diastolic (EDV) and end-systolic volumes (ESV), determined by radionuclide angiography, were therefore tested in 22 patients with CHF due to IsC (n = 13) or IDC (n = 9). CPAP-induced reductions in LVEDV, LVESV, RVEDV, and RVESV were significantly greater (p < 0.05) in the IDC than in the IsC group. Whereas in the IsC group CPAP caused no significant changes in LV or RV volumes, in the IDC group it induced significant reductions in RVEDV (527 +/- 77 ml to 354 +/- 50 ml, p = 0.03) and RVESV (400 +/- 78 ml to 272 +/- 54 ml, p = 0.04) that were greater than any reductions in LVEDV and LVESV. We conclude that CPAP causes greater short-term reductions in RV and LV volumes in CHF patients with IDC than in those with IsC, and that among patients with IDC, CPAP causes greater reductions in RV than in LV volumes.     

Electrophysiological Effects of Carvedilol Administration in Patients with Dilated Cardiomyopathy

PURPOSE: Several studies suggest the clinical efficacy of carvedilol in reducing atrial and ventricular arrhythmias in patients with left ventricular dysfunction (LVD) due to congestive heart failure (CHF) or following myocardial infarction. However, the mechanisms supporting its antiarrhythmic efficacy have been derived from experimental studies. In this prospective, placebo-controlled trial we examined the electrophysiological effects of a high oral dose of carvedilol in patients with CHF and LVD due to non-ischemic dilated cardiomyopathy. METHODS: Thirty-one patients with stable CHF underwent electrophysiological study and were randomly assigned to treatment with carvedilol or placebo. After 2 months of treatment the study was repeated. RESULTS: Carvedilol prolonged almost all conduction times. In the same group atrial and ventricular effective refractory periods were significantly prolonged, while the parameters of repolarization remained virtually unchanged. The prolongation of refractoriness was most pronounced in the atrium. The change in ventricular refractoriness was correlated with ejection fraction (r = 0.94, p < 0.01) suggesting that patients with more preserved left ventricular function responded to treatment with greater prolongation. CONCLUSION: Even after a short period of administration carvedilol has marked and diffused electrophysiological effects that would be beneficial for patients with CHF and may contribute to the positive outcome of clinical trials.     

Delisting of infants and children from the heart transplantation waiting list after carvedilol treatment

OBJECTIVES: We performed a prospective, randomized, double-blind, placebo-controlled study of carvedilol effects in children with severe, chronic heart failure (HF), despite the use of conventional therapy. BACKGROUND: Little is known about the effects of carvedilol in youngsters with chronic HF and severe left ventricular (LV) dysfunction. METHODS: We conducted a double-blind, placebo-controlled study of 22 consecutive children with severe LV dysfunction. The children had chronic HF and left ventricular ejection fraction (LVEF) <30%. Patients were randomly assigned to receive either placebo (8 patients) or the beta-blocker carvedilol (14 patients) at 0.01 mg/kg/day titrated up to 0.2 mg/kg/day, followed-up for six months. RESULTS: During the follow-up and the up-titration period in the carvedilol group, four patients died and one underwent heart transplantation. In patients receiving carvedilol evaluated after six months, a significant increase occurred in LVEF, from 17.8% (95% confidence interval [CI], 14.1 to 21.4%) to 34.6% (95% CI, 25.2 to 44.0%); p = 0.001. Modified New York Heart Association (NYHA) functional class improved in nine patients taken off the transplant waiting list. All nine patients were alive at follow-up. In the placebo group, during the six-month follow-up, two patients died, and two underwent heart transplantation. Four patients persisted with HF symptoms (NYHA functional class IV). No significant change occurred in LVEF or fractional shortening. CONCLUSIONS: Carvedilol added to standard therapy may reduce HF progression and improve cardiac function, allowing some youngsters to be removed from the heart transplantation waiting list.     

电生理标测冠状静脉窦分支最延迟电激动处植入左室导线行心脏再同步化治疗

目的探讨电生理标测冠状静脉窦(CS)分支最延迟电激动处植入左室导线行心脏再同步治疗(CRT)。方法 10例中重度心力衰竭患者,均满足NYHA心功能Ⅲ～Ⅳ级,左室射血分数(LVEF)<0.35且QRS波时限≥120 ms。CRT术中在可植入左室导线的CS分支内进行电生理标测,将标测的最延迟心室电激动处作为左室导线的植入部位,观察该方法的可行性及临床疗效。结果 10例中,扩张型心肌病7例,缺血性心脏病3例;7例为窦性心律,3例为心房颤动;9例ECG表现为左束支传导阻滞,1例为室内传导阻滞。对10例的28个可作为左室导线植入部位的CS分支进行了电生理标测,10例均成功将左室导线植入在标测的最延迟电激动处,该处局部电位较体表ECG的QRS波起始延迟116±28 ms。术后即刻QRS波时限为121±17 ms,比术前153±30 ms明显缩短,P<0.01。8例CRT术后随访时间超过3个月,均有CRT应答(8/8,100%),其中3例超应答(3/8,37.5%),另外1例缺血性心肌病患者CRT术后2个月死于急性前壁心肌梗死;8例CRT应答患者NYHA心功能分级、6 min步行距离、LVEF值、左室收缩末容积、二尖瓣返流速度均较术前明显改善(1.6±0.5级vs 3.3±0.5级;405±92 m vs 307±82m;0.42±0.06 vs 0.30±0.04;121±38 ml vs 153±44 ml;3.9±1.2 m/s vs 4.5±1.5 m/s,P均<0.01)。结论电生理标测指引CS分支最延迟电激动处植入左室导线的CRT方法可行且短期疗效明显。     

Predictability of mitral regurgitation detected by Doppler echocardiography in patients referred for cardiac transplantation

Mitral regurgitation (MR) is common in patients with congestive heart failure (CHF), but the frequency in relation to the origin of ventricular dilatation has not been established. In 50 patients referred for cardiac transplantation, MR was assessed by Doppler echocardiography and the findings were compared with clinical information. Dilatation of the left ventricle, left atrium and mitral anulus was analyzed in 25 patients with respect to cause of CHF. All 50 patients had MR of at least moderate severity, regardless of cause (idiopathic dilated cardiomyopathy in 36, coronary artery disease in 14), length of symptoms (20 +/- 19 months, less than 6 months in 13 patients) or presence of murmurs (absent in 13 patients). Comparison of patients with nonischemic cardiomyopathy to those with ischemic heart disease revealed larger left ventricular volumes (215 +/- 81 vs 131 +/- 60 ml in systole, p less than 0.05) and left atrial volumes (124 +/- 70 vs 70 +/- 35 ml, p less than 0.05). Mitral anular dilatation was present only in patients with idiopathic cardiomyopathy (diameters 3.6 +/- 0.4 vs 3.1 +/- 0.2 cm, p less than 0.05). The frequency of significant MR in these patients with CHF suggests that it may have a major role in decompensation and in the therapeutic response.     

Usefulness of biventricular pacing to improve cardiac symptoms, exercise capacity and sympathetic nerve activity in patients with moderate to severe chronic heart failure.

BACKGROUND: Although cardiac resynchronization using biventricular pacing (BVP) results in significant clinical improvement in patients with chronic heart failure (CHF), there is no evidence of improvement in sympathetic nerve activity (SNA). METHODS AND RESULTS: Eighteen patients with CHF (dilated cardiomyopathy/ischemic cardiomyopathy =14/4) and left ventricular (LV) ejection fraction <40%, QRS duration >160 ms and dyssynchronous LV wall motion were classified into 2 groups based on the findings of (99m)Tc-methoxyisobutyl isonitrile (MIBI) quantitative gated single-photon emission computed tomography (SPECT) (QGS). Resynchronization was considered to be present when the difference between the QGS frame number for end-systole for the LV septal and lateral walls (dyssynchrony index) disappeared. Group A achieved resynchronization after BVP, but not Group B. In group A, New York Heart Association functional class (p=0.0002), specific activity scale (p=0.0001), total defect score (p<0.05), and the heart/mediastinum ratio of delayed (123)I-metaiodobenzylguanidine imaging (p<0.05) were significantly improved after resynchronization. However, there was no significant change in group B. CONCLUSIONS: Cardiac resynchronization after BVP can improve cardiac symptoms, exercise capacity, and SNA in patients with moderate to severe CHF.     

Effects of carvedilol on plasma levels of interleukin-6 and tumor necrosis factor-alpha in nine patients with dilated cardiomyopathy

OBJECTIVES: Whether beta-blocker therapy changes the circulating levels of cytokines as congestive heart failure improves remains uncertain. METHODS: Nine patients with idiopathic dilated cardiomyopathy, who had previously received conventional treatment and were classified as New York Heart Association (NYHA) functional class II, received carvedilol by stepwise dose increase up to 20 mg daily, and the plasma interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) levels were measured. RESULTS: IL-6 was significantly reduced from 0.80 +/- 0.49 pg/ml before therapy to 0.21 +/- 0.08 pg/ml after carvedilol was increased to 20 mg daily (p < 0.05). Moreover, IL-6 level had already decreased significantly compared to the baseline when the dose of carvedilol had reached 10 mg daily (0.28 +/- 0.12 pg/ml, p < 0.05). TNF-alpha levels did not change significantly. CONCLUSIONS: These results demonstrate that IL-6 concentration is significantly decreased by beta-blocker therapy. The efficacy for heart failure may be related to the change of IL-6 concentration.     

卡维地洛治疗充血性心力衰竭的临床研究

目的观察卡维地洛对充血性心力衰竭(CHF)左心功能的影响。方法患冠心病、原发性高血压、扩张型心肌病的CHF患者共174例随机分为治疗组和对照组各87例,治疗组在强心、利尿、血管紧张素转换酶抑制剂(A-CEI)治疗的基础上,每天给卡维地洛6.25~50mg口服治疗,疗程24周。作治疗前、后NYHA分级、心功能的对照。结果治疗后NYHA分级、心功能均得到改善。结论卡维地洛治疗CHF 24周后,能抑制CHF的恶化,改善心功能,改善生活质量。     

Efficacy and safety of long-term application of spironolactone in patients with moderate and severe chronic heart failure receiving optimal therapy

Aim of the investigation was the study of influence of spironolactone (25 - 75 mg/day) on clinico-functional status, parameters of left ventricular (LV) remodeling, as well as safety of its long term application in patients with chronic heart failure (CHF) receiving optimal therapy. Forty nine patients were included in the study - 44 men (89,8%) and 5 women (10,2%) in the age from 28 to 75 years with II-IV NYHA functional class (FC) CHF, LV ejection fraction (EF) 35%, plasma levels of creatinine 150 mmol/L and potassium 5 mmol/L. Main causes of development of CHF were dilated cardiomyopathy, ischemic heart disease (large focal postinfarction cardiosclerosis) and decompensated hypertensive heart [25/20/4 (51%/40,8%/8,2%), respectively]. As a result of randomization procedure 2 groups of observation were formed: group 1 - 19 patients receiving spironolactone in a 24 hour dose 25 - 75 mg, group 2 - control group - 30 patients without therapy with spironolactone. Inhibitors of angiotensin converting enzyme (ACE) took 100%, b-adrenoblockers - 63,2% of patients. Control examination was conducted before randomization, in 6 and 12 months of follow up. During period of observation no changes of FC were noted in control group. In the group of treatment with spironolactone after 6 months in 6 patients FC lowered ( =0,028). By the end of follow up the given effect lost its significance, but 5 (38,5%) patients by termination of the study had FC II of CHF, what was accompanied with moderate increase of distance walked during 6-minute walk test from 354 to 378 m. In patients in the group of spironolactone treatment already after 6 months of treatment there occurred decrease of LV volumes, what by the end of period of observation for LV end diastolic volume (EDV) amounted - 76 ( - 118; - 7), and for LV end systolic volume (ESV) - 53 ml ( - 96; - 7) ml ( =0,008) at absolute increment of LVEF by 3 (0; 12)% ( =0,05). In control group in 12 months decrease of LVEDV was less pronounced and LV ESV did not change. Finally after 12 months of observation the groups became to differ by change of LVEF ( =0,035) and LVESV ( =0,02). Changes of LV volumes were followed by lowering of median concentration of atrial natriuretic peptide (ANP) in plasma by - 51,9 ( - 87; - 43,9) mg/ml. At the same time in control group gradual rise of concentration of the given peptide was observed from initial 107,3 to 168,5 mg/ml at the moment of study termination. Changes of BP level, creatinine concentration in patients in the study were not fixed in any of treatment groups. Development of moderate hyperkaliemia amounted 21.0%, gynecomastia or pain in the region of mammary glands were fixed in 26,3% of patients in 12 months of treatment. Addition of spironolactone in a dose of 75 mg/day to optimal therapy, including ACE inhibitor and b-adrenoblocker is accompanied with improvement of clinical state and FC of patients with moderate and severe CHF. Long term therapy with spironolactone blocks processes of desadaptive LV remodeling and improves LV contractile function, what is reflected in lowering of ANP concentration in plasma of patients with CHF. Application of spironolactone in combination with ACE inhibitor and b-adrenoblocker bisoprolol does not lead to lowering of BP level and worsening of renal function, but is accompanied with development of hyperkaliemia in patients with CHF. Gynecomastia appears to be main reason limiting long term use of spironolactone in patients with CHF in a dose of 75 mg/day.     

Protective effects of carvedilol against anthracycline-induced cardiomyopathy.

OBJECTIVES: The aim of this study was to determine the protective effect of carvedilol in anthracycline (ANT)-induced cardiomyopathy (CMP). BACKGROUND: Despite its broad effectiveness, ANT therapy is associated with ANT-induced CMP. Recent animal studies and experimental observations showed that carvedilol prevented development of CMP due to chemotherapeutics. However, there is no placebo-controlled clinical trial concerning prophylactic carvedilol use in preventing ANT-induced CMP. METHODS: Patients in whom ANT therapy was planned were randomized to administration of carvedilol or placebo. We enrolled 25 patients in carvedilol and control groups. In the carvedilol group, 12.5 mg once-daily oral carvedilol was given during 6 months. The patients were evaluated with echocardiography before and after chemotherapy. Left ventricular ejection fraction (EF) and systolic and diastolic diameters were calculated. RESULTS: At the end of 6 months of follow-up, 1 patient in the carvedilol group and 4 in the control group had died. Control EF was below 50% in 1 patient in the carvedilol group and in 5 in the control group. The mean EF of the carvedilol group was similar at baseline and control echocardiography (70.5 vs. 69.7, respectively; p = 0.3), but in the control group the mean EF at control echocardiography was significantly lower (68.9 vs. 52.3; p < 0.001). Both systolic and diastolic diameters were significantly increased compared with basal measures in the control group. In Doppler study, whereas E velocities in the carvedilol group decreased, E velocities and E/A ratios were significantly reduced in the control group. CONCLUSIONS: Prophylactic use of carvedilol in patients receiving ANT may protect both systolic and diastolic functions of the left ventricle.     

慢性心衰患者炎症细胞因子表达及其与心功能的关系

目的观察慢性心力衰竭（CHF）患者外周血炎症细胞因子白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）、纤维蛋白原（FG）、超敏C-反应蛋白（hs—CRP）水平变化及其与心功能状况的关系。方法选择60例CHF患者为病例组,包括冠心病30例、高血压性心脏病14例、心肌病16例（扩张型心肌病10例、肥厚型心肌病6例）。另外选择40例年龄、性别与病例组相匹配的健康受试者作为对照组。所有受试者均测定外周血IL-1β、IL-6、TNF—α、FG、hs—CRP水平和血脂（TC、TG、LDL—C、HDL—C）,同时询问吸烟史、高血压病史及糖尿病史。CHF患者评估NYHA心功能分级。结果CHF患者外周血炎症细胞因子IL-1β、IL-6、TNF—α、FG、hs—CRP水平显著高于对照组（P〈0．01）;不同病因心衰患者间IL-1β、IL-6、TNF—α、FG、hs—CRP水平差异无统计学意义（P〉0．05）;不同NYHA心功能分级组间IL-18、IL-6、TNF—α、FG、hs—CRP水平差异存在统计学意义（P〈0．05或P〈0．01）。结论CHF患者外周血炎症细胞因子IL-1β、IL-6、TNF—α、FG、hs—CRP水平显著高于对照组,不同NYHA心功能分级组间IL-1β、IL-6、TNF—α、FG、hs—CRP水平差异存在统计学意义。它们之间可能有相互作用,共同参与CHF的发病机制。     

Comparative long term effects of nebivolol and carvedilol in hypertensive heart failure patients

Background

Beta-blockers improve left ventricular (LV) systolic function and prognosis in patients with chronic heart failure (CHF), but their different pleiotropic properties may influence their cardiovascular effects. This open-label study compared the effects of long-term treatment with nebivolol versus carvedilol on LV ejection fraction (LVEF), in hypertensive CHF patients. Secondary end points were to assess the effect of the 2 beta-blockers on exercise capacity and clinical outcome.

Methods and Results

A total of 160 hypertensive CHF patients, with LVEF <40% and in New York Heart Association (NYHA) functional class I, II, or III, were randomly assigned to receive nebivolol or carvedilol for 24 months. At baseline and at the end of treatment, all patients underwent clinical evaluation, echocardiography, and 6-minute walking test. The target doses were 10 mg/d for nebivolol and 50 mg/d for carvedilol. Compared with baseline values, LVEF increased by a similar extent in the carvedilol (C) and nebivolol (N) groups (C from 36.1% (SD 1.5%) to 40.9% (SD 1.9%), P < .001; N from 34.1% (SD 1.8%) to 38.5% (SF 2.2%), P < .001). Heart rate and NYHA functional class decreased significantly in both groups, and the 6-minute walking distance increased (C from 420 m (SD 104 m) to 490 m (SD 115 m), P < .001; N from 421 m (SD 118 m) to 487 m (SD 138 m), P < .001). During 24 months, 21 carvedilol recipients (26%) and 18 nebivolol recipients (22%) had cardiac events, including 3 and 4 deaths, respectively.

Conclusion

In the long term, nebivolol and carvedilol appear to be similarly effective in the treatment of hypertensive patients with CHF.     

Long-term effects of carvedilol in idiopathic dilated cardiomyopathy with persistent left ventricular dysfunction despite chronic metoprolol

OBJECTIVES

The purpose of this study was to analyze whether long-term treatment with the nonselective beta-adrenergic blocking agent carvedilol may have beneficial effects in patients with dilated cardiomyopathy (DCM), who are poor responders in terms of left ventricular (LV) function and exercise tolerance to chronic treatment with the selective beta-blocker metoprolol.

BACKGROUND

Although metoprolol has been proven to be beneficial in the majority of patients with heart failure, a subset of the remaining patients shows long-term survival without satisfactory clinical improvement.

METHODS

Thirty consecutive DCM patients with persistent LV dysfunction (ejection fraction ≤40%) and reduced exercise tolerance (peak oxygen consumption <25 ml/kg/min) despite chronic (>1 year) tailored treatment with metoprolol and angiotensin-converting enzyme inhibitors were enrolled in a 12-month, open-label, parallel trial and were randomized either to continue on metoprolol (n = 16, mean dosage 142 ± 44 mg/day) or to cross over to maximum tolerated dosage of carvedilol (n = 14, mean dosage 74 ± 23 mg/day).

RESULTS

At 12 months, patients on carvedilol, compared with those continuing on metoprolol, showed a decrease in LV dimensions (end-diastolic volume −8 ± 7 vs. +7 ± 6 ml/m², p = 0.053; end-systolic volume −7 ± 5 vs. +6 ± 4 ml/m², p = 0.047), an improvement in LV ejection fraction (+7 ± 3% vs. −1 ± 2%, p = 0.045), a reduction in ventricular ectopic beats (−12 ± 9 vs. +62 ± 50 n/h, p = 0.05) and couplets (−0.5 ± 0.4 vs. +1.5 ± 0.6 n/h, p = 0.048), no significant benefit on symptoms and quality of life and a negative effect on peak oxygen consumption (−0.6 ± 0.6 vs. +1.3 ± 0.5 ml/kg/min, p = 0.03).

CONCLUSIONS

In DCM patients who were poor responders to chronic metoprolol, carvedilol treatment was associated with favorable effects on LV systolic function and remodeling as well as on ventricular arrhythmias, whereas it had a negative effect on peak oxygen consumption.