Rationale,design and organisation of an efficacy and safety study of oxypurinol added to standard therapy in patients with NYHA class III – IV congestive heart failure

Oxypurinol, the active metabolite of allopurinol and a potent xanthine oxidase inhibitor (XOI), is under evaluation as a novel agent for the treatment of congestive heart failure (HF). Several lines of evidence provide the rationale for the hypothesis that XOIs will improve clinical outcomes in patients with HF. First, XOIs have unique positive inotropic effects, improving myocardial contraction and performance while simultaneously improving myocardial energy metabolism. Second, XOIs ameliorate endothelial dysfunction in humans with HF. Finally, XO activity is upregulated in the heart and vasculature of subjects with HF, which may in turn contribute to oxidative stress and/or increased uric acid levels. Together these findings form the rationale for the Controlled Efficacy and Safety Study of Oxypurinol Added to Standard Therapy in Patients with New York Heart Association (NYHA) class III – IV Congestive Heart Failure (OPT-CHF) trial (Food and Drug Adminstration IND 65,125), a Phase II – III prospective, randomised, double-blind, placebo-controlled trial, which will include patients with stable symptomatic HF in NYHA class III – IV congestive HF who are deemed clinically stable on a standard and appropriately maximised heart failure therapy regimen. The efficacy end point for OPT-CHF is a composite that incorporates measures of patient outcome and well-being.     

Enalapril. An update of its pharmacological properties and therapeutic use in congestive heart failure

Enalapril provides significant haemodynamic, symptomatic and clinical improvement when added to maintenance therapy with digitalis and diuretics in patients with congestive heart failure [NYHA (New York Heart Association) classes II to IV]. These effects are not attenuated during long term therapy. More significantly, a clinical study demonstrated that enalapril reduces mortality when added to established therapy in patients with severe congestive heart failure (NYHA class IV) refractory to digitalis, diuretics and other vasodilators. Thus, ACE inhibitors such as enalapril offer a significant advance in the treatment of congestive heart failure. Because these drugs improve symptoms in patients with classes II to IV failure, and reduce mortality in patients with severe heart failure, they should be considered as first choice adjuvant therapy when a vasodilator is needed in addition to conventional treatment with digitalis and diuretics.     

Ibopamine: long-term safety study in patients with congestive heart failure. The Italian Ibopamine Working Group

Ibopamine is a new orally active dopamine analogue with positive inotropic and vasodilating activity. The tolerability of the drug administered at the dose of 100 mg thrice daily for 12 months was studied in 302 patients with congestive heart failure, New York Heart Association (NYHA) class II and III. Of the 302 patients, 198 completed the study (65%); 59 patients (19%) were withdrawn for clinical events; 27 of them died (9%); 35 patients (12%) did not complete the study for non-compliance and 10 (3%) for protocol violations. Clinical events were generally related to the cardiovascular system and 85% of deaths were from cardiovascular causes. None of the deaths was considered related to treatment by the investigators. Clinically significant laboratory abnormalities were observed during the study in four patients only. This trial suggests that ibopamine is well tolerated in patients with congestive heart failure, NYHA class II and III, at the dose of 100 mg thrice daily for up to one year.     

Steady-state pharmacokinetics of carvedilol and its enantiomers in patients with congestive heart failure

Carvedilol is a relatively new drug with beta- and alpha 1-receptor blocking activity and antioxidant effects recently approved for the treatment of congestive heart failure (CHF). An ascending, multiple-dose study was completed in 20 male patients with stable New York Heart Association (NYHA) Class III or IV CHF. The pharmacokinetics of carvedilol, S(-)-carvedilol, R(+)-carvedilol, and the active metabolites of carvedilol was assessed at steady state after twice-daily oral administration of carvedilol for 7 days at 6.25, 12.5, 25, and 50 mg doses. Carvedilol exhibited stereoselective pharmacokinetics in CHF patients with dose-proportional increases in steady-state plasma concentrations of carvedilol and its enantiomers. Mean AUC and Cmax values for carvedilol were up to twofold higher in patients with Class IV CHF as compared to those with Class III CHF. Steady-state plasma concentrations of the active metabolites also increased in a dose-proportional manner and were typically 10% or less of that observed for carvedilol. In general, carvedilol was adequately tolerated by adult male CHF patients at the dose levels (6.25-50 mg) evaluated in this study as adverse events were consistent with those frequently observed in patients with CHF.     

Alpha-adrenoceptors and alpha-adrenoceptor-mediated positive inotropic effects in failing human myocardium

Experiments were designed to characterize cardiac alpha-adrenoceptors and the alpha-adrenoceptor-mediated positive inotropic effects in human myocardial tissue from patients with moderate New York Heart Association (NYHA) class II-III and severe (NYHA class IV) heart failure. The number of cardiac alpha-adrenoceptors was low but similar in moderate and severe heart failure (NYHA class II-III: 6.7 +/- 0.8 fmol/mg protein 3H-prazosin bound, n = 12; NYHA class IV: 7.4 +/- 0.9 fmol/mg protein 3H-prazosin bound, n = 9; NS). Correspondingly, the alpha-adrenoceptor-mediated positive inotropic effect (phenylephrine in the presence of propranolol) did not significantly differ in both groups. In the same hearts, the number of beta-adrenoceptors was measured. The number of beta-adrenoceptors was significantly reduced in severe heart failure (NYHA class II-III: 22.0 +/- 1.5 fmol/mg protein 3H-CGP 12177 bound, n = 12; NYHA class IV: 11.9 +/- 0.8 fmol/mg protein 3H-CGP 12177 bound, n = 9; p less than 0.05). The positive inotropic effect of isoprenaline was significantly reduced in NYHA class IV. The positive inotropic effect of Ca2+ was similar in both groups. In conclusion, cardiac beta-adrenoceptors and the beta-adrenoceptor-mediated positive inotropic effects were reduced in severely failing myocardium. Cardiac alpha-adrenoceptors and the positive inotropic effect resulting from their stimulation is unchanged. Therefore, down regulation in response to increased sympathetic stimulation or a compensatory increase of alpha-adrenoceptors does obviously not occur in the human heart.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of the phosphodiesterase inhibitor UK 61260 on human myocardial inotropy and diastolic relaxation.

The phosphodiesterase inhibitor UK 61260 exhibits positive inotropic activity in animal studies and is under clinical investigation for treatment of congestive heart failure (CHF). We examined the lusitropic and inotropic responses to UK 61260 in electrically driven (1 Hz, 37 degrees C) human auricular trabeculae (AUT, aortocoronary bypass operation, nonfailing hearts, n = 13) and in papillary muscle strips (PAP) from moderately (New York Heart Association, NYHA II-III, mitral valve replacement, n = 6) and terminally (NYHA IV, heart transplantation, n = 7) failing human hearts. For comparison, we studied the effects of UK 61260 after prestimulation with forskolin (FOR 0.03 microM) and isoprenaline (ISO 0.03 microM), as well as the effects of milrinone (MIL 1-1,000 microM), ISO (0.01-10 microM), ouabain (OUA, 0.1 microM), and Ca2+ (1.8-15 mM) in failing human myocardium alone. UK 61260 increased force of contraction (FOC), peak rate of tension increase (+T) and decay (-T) significantly (p less than 0.01) in AUT but not in PAP of NYHA II-III and NYHA IV. Only after prestimulation (FOR and ISO), was UK 61260 effective in stimulating FOC in NYHA II-III and NYHA IV. UK 61260 increased (p less than 0.01) +T and -T, resulting in a shortening of twitch time. As judged from the EC50 values, UK 61260 increased FOC more potently than MIL. The effectiveness of OUA and Ca2+ in increasing developed tension in human failing myocardium was significantly higher as compared with UK 61260. We conclude that during stimulation of the cardiac beta-adrenoceptor-adenylate-cyclase system, UK 61260 increases myocardial systolic and diastolic function in failing human myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)     

心力衰竭患者血清NT-proBNP、hs-CRP和ALD的联合检测意义研究

目的探讨心力衰竭（HF）患者血清N端B型脑钠肽（NT-proBNP）、超敏C反应蛋白（hs-CRP）和醛固酮（ALD）的联合检测意义。方法选择我院心力衰竭患者共50例,根据美国纽约心脏协会（NYHA）制定的心功能分级标准：Ⅲ级患者24例,Ⅳ级别患者26例。同时选择我院同期健康体检者50例,作为对照组。上述所选对象均取清晨空腹静卧位肘静脉血,测定血清NT-proBNP、hs-CRP和ALD水平。结果心功能Ⅲ患者和心功能Ⅳ级患者NT-proBNP、hs-CRP和ALD水平均显著高于对照组,差异有统计学意义（P〈0.01）;心功能Ⅳ级患者血清NT-proBNP、hs-CRP和ALD水平均显著高于心功能Ⅲ患者,差异有统计学意义（P〈0.01）。冠心病患者血清hs-CRP水平显著高于扩张型心肌病和高血压心脏病患者,差异有统计学意义（P〈0.01）,而扩张型心肌病和高血压心脏病患者之间血清hs-CRP水平差异无统计学意义（P〉0.05）;冠心病、扩张型心肌病和高血压心脏病患者之间,血清NT-proBNP和ALD水平差异无统计学意义（P〉0.05）。结论 NT-proBNP、ALD和hs-CRP联合检测有助于了解心力衰竭患者的病因及其严重程度,并为临床治疗提供帮助。     

Thiazolidinediones in patients with type 2 diabetes mellitus and heart failure.

PURPOSE: A review of the significant findings related to the use of the thiazolidinediones (TZDs) in the treatment of patients with type 2 diabetes mellitus and heart failure was conducted. SUMMARY: TZDs are antihyperglycemic medications that increase insulin sensitivity and improve the underlying defect of insulin resistance and type 2 diabetes mellitus, and they have the potential to slow or decrease the cardiovascular damage that results from these conditions. TZDs are also implicated in weight gain; however, this is accompanied by an improvement in insulin sensitivity and, therefore, its clinical significance is unclear. Edema has been well characterized in patients treated with TZDs. Edema is more common in patients treated with a TZD in combination with insulin and higher doses of TZDs. Because of the potential for fluid retention and worsening edema, clinical studies have excluded patients with New York Heart Association (NYHA) functional class III or IV heart failure. In patients at risk for heart failure or those who have NYHA functional class I or II symptoms, initiation of therapy should be at the lower dose for TZDs with close monitoring of weight gain, edema, and other signs of worsening heart failure. CONCLUSION: Current data suggest that TZDs may be used cautiously in patients with type 2 diabetes mellitus who are at risk for heart failure or who have NYHA functional class I or II heart failure. Patients with NYHA functional class III or IV heart failure should not receive TZDs.     

Metoprolol: a review of its use in chronic heart failure

Metoprolol, a relatively selective beta1-blocker, is devoid of intrinsic sympathomimetic activity and possesses weak membrane stabilising activity. The drug has an established role in the management of essential hypertension and angina pectoris, and more recently, in patients with chronic heart failure. The effects of metoprolol controlled-release/extended-release (CR/XL) in patients with stable, predominantly mild to moderate (NYHA functional class II to III) chronic heart failure have been evaluated in the large Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF) trial and the much smaller Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) pilot study. Treatment with metoprolol CR/XL was initiated at a low dosage of 12.5 to 25 mg once daily and gradually increased at 2-weekly intervals until the target dosage (200 mg once daily) or maximal tolerated dosage had been attained in patients receiving standard therapy for heart failure. At 12 months, metoprolol CR/XL was associated with a 34% reduction in relative risk of all-cause mortality in patients with chronic heart failure due to ischaemic or dilated cardiomyopathy in the MERIT-HF trial. The incidence of sudden death and death due to progressive heart failure were both significantly decreased with metoprolol CR/XL. Similarly, a trend towards decreased mortality in the metoprolol CR/XL group compared with placebo was observed in the RESOLVD trial. Data from small numbers of patients with severe (NYHA functional class IV) heart failure indicate that metoprolol CR/XL is effective in this subset of patients. However, no firm conclusions can yet be drawn. Improvement from baseline values in NYHA functional class, exercise capacity and some measures of quality of life with metoprolol CR/XL or immediate-release metoprolol were significantly greater than those with placebo. The drug is well tolerated when treatment is initiated in low dosages and gradually increased at intervals of 1 to 2 weeks. Conclusions: Metoprolol CR/XL effectively decreases mortality and improves clinical status in patients with stable mild to moderate (NYHA functional class II or III) chronic heart failure due to left ventricular systolic dysfunction, and the drug is effective in patients with ischaemic or dilated cardiomyopathy. Although limited data indicate that metoprolol CR/XL is effective in patients with severe (NYHA functional class IV) chronic heart failure, more data are needed to confirm these findings. Treatment with metoprolol CR/XL significantly reduced the incidence of sudden death and death due to progressive heart failure.     

Effects of ACE Inhibitors or ↓-Blockers in Patients Treated with the Fixed-Dose Combination of Isosorbide Dinitrate/Hydralazine in the African-American Heart Failure Trial

BACKGROUND: In the A-HeFT (African-American Heart Failure Trial), treatment of African-American patients with New York Heart Association (NYHA) class III/IV heart failure (HF) with fixed-dose combination (FDC) of isosorbide dinitrate/hydralazine (I/H) reduced mortality and morbidity and improved patient reported functional status compared with standard therapy alone. OBJECTIVE: To examine the benefit of FDC I/H in subgroups based on baseline drug therapy and to investigate whether ACE inhibitors and/or angiotensin receptor antagonists (angiotensin receptor blockers) [ARBs] or beta-adrenoceptor antagonists (beta-blockers) provided additional benefit in FDC I/H-treated African-American patients with HF. STUDY DESIGN: The A-HeFT was a double-blind, placebo-controlled study enrolling 1050 patients stabilized on optimal HF therapies and with NYHA class III/IV HF with systolic dysfunction conducted during the years 2001-4 with up to 18 months follow-up. The primary endpoint was a composite of mortality, first HF hospitalization, and improvement of quality of life at 6 months. Secondary endpoints included mortality, hospitalizations, and change in quality of life. Prospective Kaplan-Meier survival analyses were used for differences between FDC I/H and placebo groups and retrospective analyses were conducted within FDC I/H-treated and placebo groups. RESULTS: Subgroup analysis for mortality, event-free survival (death or first HF hospitalization), and HF hospitalization showed that FDC I/H, compared with placebo, was effective with or without ACE inhibitors or beta-blockers or other standard medications with all-point estimates favoring the FDC I/H group. Within the placebo-treated group, beta-blockers or ACE inhibitors and/or ARBs were efficacious in improving survival (hazard ratio [HR] 0.33; p<0.0001 for [beta]-blocker use and HR 0.39; p=0.01 for ACE inhibitor and/or ARB use). However, within the FDC I/H-treated group, use of beta-blockers, but not ACE inhibitors and/or ARBs, provided additional significant benefit for survival (HR 0.44; p=0.029 and HR 0.60; p=0.34, respectively), event-free survival (HR 0.62; p=0.034 and HR 0.72; p=0.29, respectively) and the composite score of death, HF hospitalization and change in quality of life (p=0.016 and p=0.13, respectively). CONCLUSION: Based on the analysis of baseline medication use in the A-HeFT, FDC I/H was superior to placebo with or without beta-blockers or ACE inhibitor. However, beta-blockers but not ACE inhibitors and/or ARBs provided additional significant benefit in African-Americans with HF treated with FDC I/H. These analyses are hypotheses generating and their confirmation in clinical trials needs to be considered.     

A review of heart failure treatment

Heart failure is a common and costly medical condition. Ischemic heart disease and hypertension account for most cases of heart failure in developed countries. Estimates of the one-year mortality rates for patients with New York Heart Association (NYHA) Class II, III, and IV are 10%, 20%, and 40%, respectively. Angiotensin-converting enzyme (ACE) inhibitors reduce mortality of heart failure patients by approximately 25% (odds ratio 0.77, 95% CI 0.67 0.88). Larger doses of ACE inhibitors are more effective in preventing hospitalization than are lower doses. Angiotensin II receptor blockers (ARBs) are an alternative for patients who cannot tolerate ACE inhibitors because of their side effects (e.g., cough). Evidence for benefits of using combination of ACE inhibitors and ARBs is encouraging, but requires further study. For patients who cannot tolerate either ACE inhibitors or ARBs, vasodilator therapy with hydralazine and nitrates will probably provide benefit. (Diuretic therapy, while a mainstay of heart failure treatment, is primarily used for symptom relief.) There is also evidence that spironolactone reduces mortality (relative risk reduction 30%, 95% CI 18 40%) for patients with NYHA class III and IV heart failure. When administering spironolactone to heart failure patients, monitoring for hyperkalemia is essential. After two centuries of use, randomized controlled trials have finally demonstrated that digoxin is effective in preventing hospitalizations (relative risk reduction 28%, 95% CI 21 34%). There is now overwhelming evidence that beta-blockers are safe for heart failure patients but that they reduce the risk of death for these patients by approximately 30%. In addition to these medical interventions, heart failure patients may also benefit from a number of non-pharmacological interventions.     

充血性心力衰竭患者心肌纤维化变化的研究

目的：研究充血性心力衰竭患者心肌纤维化的变化情况。方法选取2012年3月～2014年1月本院收治的60例充血性心力衰竭患者为观察组,并以同期的60名健康体检人员为对照组,比较两组的血清心肌纤维化指标,并比较观察组中不同心功能NYHA分级心力衰竭患者的心肌纤维化指标水平。结果观察组的血清心肌纤维化指标[血清Ⅲ型前胶原肽（PⅢP）、Ⅳ型胶原（CⅣ）及Ⅲ型前胶原（PCⅢ）,其他纤维化相关指标为基质金属蛋白酶-9（MMP-9）、透明质酸（HA）及层粘连蛋白（LN）]水平均明显高于对照组,且观察组中高NYHA分级患者的上述指标水平高于低NYHA分级患者（P＜0.05）。结论充血性心力衰竭患者心肌纤维化指标的变化较大,呈现较高的表达状态,且受心功能分级影响较大。     

Does the C-type natriuretic peptide have prognostic value in chagas disease and other dilated cardiomyopathies?

Atrial natriuretic peptides (ANP) and brain natriuretic peptides (BNP) are powerful neurohormonal indicators of left-ventricular function and prognosis in heart failure (HF). Chagas disease (CD) caused by the protozoan Trypanosoma cruzi remains a major cause of HF in Latin America. We assessed whether the plasma concentration of the third natriuretic peptide, C-type natriuretic peptide (CNP), also has diagnostic and prognostic properties in patients with CD or other dilated cardiomyopathies (DCM). Blood samples were obtained from 66 patients with CD, 50 patients with DCM from other causes, and 30 gender- and age-matched healthy subjects. Patients were subdivided according to the New York Heart Association (NYHA) class. The CNP concentration was determined by radioimmunoassay (Immundiagnostik, Bensheim, Germany). The main duration of follow-up was 31.4 months (range 13 to 54 months); 19 patients had died and 11 patients received a heart transplant. CNP concentrations were only significantly altered in patients with DCM or CD of the NYHA classes III and IV (P < 0.05). The Pearson correlation of echocardiographic data with CNP revealed an association only with the left-ventricular end systolic volume (P = 0.03) in patients with DCM. Furthermore, CNP did not predict mortality or the necessity for heart transplant. Our data are the first to demonstrate the raised levels of the third natriuretic peptide CNP in CD and other DCM. Whereas ANP and BNP have a high predictive value for mortality in both diseases, CNP is without any predictive potency.     

老年慢性心力衰竭患者血清肌钙蛋白T及尿酸检测的临床意义

目的探讨老年慢性心力衰竭（CHF）患者血清肌钙蛋白T（cTnT）及尿酸（UA）水平检测的意义。方法回顾性分析200例老年慢性心力衰竭患者临床资料,心功能Ⅰ级为对照组,Ⅱ、Ⅲ、Ⅳ级患者为观察组,每组50例。分析血UA、cTnT与慢性心力衰竭的发生是否存在相关性。按cTnT浓度分为正常组和增高组,比较其住院期间及随访2年发生的心脏事件（心力衰竭反复或加重、死亡）的发生情况。结果观察组cTnT与UA含量明显高于对照组。cTnT增高组患者心脏事件的发生率明显高于正常组（P〈0．05）。结论心衰越重,cTnT与UA增高越明显,血尿酸、肌钙蛋白T与充血性心力衰竭密切相关,是充血性心力衰竭发病的危险因素,二者联合可作为评价老年心力衰竭严重程度的指标。cTnT对判断老年慢性心力衰竭患者的预后有较好的预测价值。     

老年心力衰竭患者血清脑钠肽和同型半胱氨酸诊断价值的比较

目的：对血清脑钠肽（BNP）和同型半胱氨酸（HCY）水平的变化在老年心力衰竭患者中的诊断价值进行比较。方法70例NYHA分级II~IV级的老年心力衰竭患者作为心力衰竭组,25例心功能正常的老年人作为对照组。测定两组的血清BNP和HCY水平,分别比较两组间血清BNP和HCY的水平,并比较不同NYHA分级患者之间的血清BNP和HCY的水平。结果心力衰竭组与对照组相比,血清BNP和HCY水平都有显著的升高（P〈0.01）,不同的NYHA分级的患者组之间的比较发现,血清BNP水平在任意组之间差异都具有统计学意义（P〈0.01）,但是血清HCY水平只在NYHA II级组和IV级组之间差异具有统计学意义（P〈0.05）,而在II级组和III级组与III级组和IV级组之间差异无统计学意义（P〉0.05）。结论老年心力衰竭患者的血清BNP和HCY水平都较正常的水平显著升高,血清BNP水平随着NYHA分级的增加而逐步显著提高,而血清HCY水平只在II级和IV级之间有显著的升高。血清BNP水平可能成为预测老年心力衰竭进程的重要的监测标记物。     

Acute haemodynamic effects of ibopamine in patients with severe congestive heart failure.

Ten patients with congestive heart failure (CHF), in III and IV NYHA Class, were treated orally with a single dose of ibopamine ranging from 1.2-3.3 mg/kg, and were studied using the Swan-Ganz catheter and thermodilution technique. Cardiac index (CI) and stroke volume index (SVI) were increased, and mean pulmonary pressure (PAP), systemic vascular resistances (SVR) were lowered. Ibopamine increased CI (+33%) and SVI (+26%), and decreased PAP (-17%) and SVR (-24%). All changes were statistically significant. The maximum haemodynamic effect occurred 180 min after ibopamine administration. Blood pressure and heart rate were unaffected. Tolerability was good. This study shows that ibopamine when orally administered to human subjects improves cardiac performance and further investigations on its use as a therapeutic agent in the long term treatment of CHF are recommended.     

The effect of diltiazem hydrochloride upon sodium diuresis and renal function in chronic congestive heart failure

d-3-Acetoxy-cis-2,3-dihydro-5-]2-(dimethylamino)ethyl]-2-(p-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one hydrochloride (diltiazem HCl) was orally administered to 9 patients with chronic congestive heart failure (Class IIb to III, NYHA) to examine whether the drug induces sodium retention and aggravates congestive heart failure. Renal hemodynamics and urinary electrolytes excretion were measured for 3 h after the medication in 6 out of 9 patients. Four of the rest of patients had received chronic administration of the drug for about 2 weeks. There was a significant increase in urinary sodium excretion without noticeable change in renal hemodynamics after diltiazem administration, demonstrating the presence of its direct inhibitory action on renal tubules. The increase in urinary sodium excretion was more marked in patients with heart failure than in those without. This difference in the response to diltiazem may be due to the functional constriction of renal cortical vessels in heart failure. This constriction may be related to renin-angiotensin system which diltiazem was reported to antagonize. The chronic administration of the drug did not induce sodium retention and edema. There was no deterioration of symptoms due to congestive heart failure such as dyspnea and body weight increase. It may be concluded that diltiazem does not aggravate congestive heart failure through its diuretic action and probably its systemic vasodilating action.     

Aldosterone and prolactin responsiveness after prolonged treatment of congestive heart failure with captopril

After long-term captopril treatment, an inappropriate increase in aldosterone levels has been observed in hypertensive patients. It is not known, whether a similar change would occur in patients with severe congestive heart failure, and whether it is due to a decrease in endogenous dopaminergic inhibition of aldosterone secretion or to aldosterone stimulation by ACTH or an ACTH-related peptide. Therefore, the aldosterone and prolactin responses to metoclopramide have been studied in 10 patients with severe congestive heart failure (NYHA Class III or IV) after 6 months of captopril treatment, before and 11 h after pretreatment with dexamethasone. 7 placebo-treated patients served as double-blind controls. In captopril-treated patients, the supine aldosterone levels exceeded the normal range and were as high as in placebo-treated patients. The responsiveness of aldosterone and prolactin to metoclopramide was not influenced by captopril. Only in the placebo group were the aldosterone levels decreased by dexamethasone. Captopril increased plasma renin activity and serum potassium, and decreased supine epinephrine and norepinephrine and serum sodium. Thus, previous reports of inappropriately high aldosterone levels after long-term captopril treatment were confirmed in patients with severe congestive heart failure. It is concluded that increased aldosterone is due neither to a decrease in endogenous dopaminergic inhibition nor to dexamethasone-suppressible stimulation of aldosterone secretion.     

慢性心力衰竭患者55例N端脑钠肽前体水平临床意义分析

目的 探讨N端脑钠肽前体（NT-proBNP）水平在慢性心力衰竭患者体内变化的临床意义.方法 选择该院2012年1月至2013年6月收治的慢性心力衰竭患者55例,根据纽约心脏病学会（NYHA）心功能分级分为三组,NYHA Ⅱ级25例纳入Ⅱ组,NYHA Ⅲ级18例纳入Ⅲ组,NYHA Ⅳ级12例纳入Ⅳ组.另选择同期入住的非器质性心脏病患者30例作为对照组.结果 心力衰竭各组患者NT-proBNP、左心室舒张末期内径（LVEDD）、左心室射血分数（LVEF）与对照组比较,差异均有统计学意义（P〈0.05）;以上指标,各心力衰竭组间比较,差异也有统计学意义（P〈0.05）.Ⅲ、Ⅳ组患者NT-proBNP与LVEDD呈正相关[相关系数（r）=0.50、0.71],与LVEF呈负相关（r=-0.47、-0.66）,Ⅱ组患者NT-proBNP与LVEDD、LVEF无关.结论 慢性心力衰竭患者体内NT-proBNP水平变化与心功能呈一致性,可较为准确地反映心力衰竭进程.     

Pharmacology of SCH00013: a novel Ca2+ sensitizer

Cardiotonic agents that facilitate cardiac pump function by direct improvement of contractile dysfunction are indispensable for the treatment of hemodynamic disorders in acute myocardial failure and the aggravating phase of congestive heart failure. Cardiotonic agents currently available for the treatment of hemodynamic crisis in congestive heart failure are catecholamines, selective phosphodiesterase (PDE) III inhibitors and digitalis, all of which are Ca2+ mobilizers. Considering the number of serious adverse effects of these clinically available cardiotonic agents, development of agents that act via a novel mechanism of action may contribute to the progress of pharmacotherapy of congestive heart failure. Ca2+ sensitizers that act by increasing in myofilament Ca2+ sensitivity may be able to overcome the disadvantage of Ca2+ mobilizers. Ca2+ sensitizers do not increase activation energy, do not produce Ca2+ overload and may be effective even under pathophysiological states such as acidosis, myocardial stunning and heart failure. SCH00013 ((4,5-dihydro-6-[1-[2-hydroxy-2-(4-cyanophenyl)ethyl]-1,2,5,6-tetrahydropyrido-4-yl]pyridazin-3(2H)-one)) is a novel Ca2+ sensitizer that elicits a moderate positive inotropic effect without significant alteration of Ca2+ transients. SCH00013 does not have a positive chronotropic effect and has a weak PDE III inhibitory action and class III antiarrhythmic action. SCH00013 prolonged the survival in a animal heart failure model with genetic cardiomyopathy. The oral bioavailability of SCH00013 is high and equivalent to that via intravenous administration. The unique pharmacological profiles of SCH00013 imply that this agent may be potentially beneficial for pharmacotherapy of contractile dysfunction in congestive heart failure.