Depression in chronic heart failure: novel pathophysiological mechanisms and therapeutic approaches

Depression is four to five times as common in chronic heart failure (CHF) patients as in the general population, may confer a higher risk of developing CHF in susceptible populations, and is significantly related to higher hospital readmission rates and increased mortality in established CHF. This effect may be mediated via the pathophysiological mechanisms that are shared between CHF and depression, including increased hypothalamic-pituitary-adrenal function, sympathoadrenal hyperactivity, diminished heart-rate variability and excessive pro-inflammatory cytokine activation. Each of these pathways of linkage represents a potential therapeutic target to improve outcome in CHF. This paper reviews the recent investigational observations that clarify the direct effects of antidepressants on immune functions, as well as the indirect effects of anticytokine pharmacological agents on depressive symptoms in CHF. With recent evidence suggesting that selective serotonin re-uptake inhibitors improve survival after myocardial infarction in patients with depression, diagnosis and treatment of this comorbidity may beneficially affect the functional capacity and prognosis of CHF patients.     

Natriuretic peptides in therapy for decompensated heart failure

Congestive heart failure (CHF) is the most frequent cause of hospitalization for patients >65 years of age and continues to be a major public health burden among the ageing population. Unlike therapy for chronic CHF, there has been only modest progress in medical treatment for acutely decompensated CHF over the past several decades. Moreover, current treatment—consisting generally of diuretic, inotropic, and vasodilatory agents–is associated with many limitations in clinical practice. Natriuretic peptides provide a promising mechanism of action in the pathophysiologic background for CHF treatment based on their vasodilatory and diuretic properties and effective inhibition of the renin–angiotensin–aldosterone system, which is activated early in the course of CHF. Nesiritide (Natrecor® or Noratak®) is a recombinant natriuretic peptide that has the same 32 amino-acid sequence as human B-type natriuretic peptide. Nesiritide has been shown to improve dyspnea and hemodynamic parameters in patients with decompensated heart failure. Ularitide is a synthetic form of urodilatin, a natriuretic peptide hormone secreted by the kidney. Recent clinical studies suggest that ularitide may play a role in managing decompensated heart failure. This review provides an update on natriuretic peptides and their therapeutic potential in advanced CHF.     

Effect of exercise training on renal function and renal aquaporin‐2 expression in rats with chronic heart failure

1. Chronic heart failure (CHF) is often accompanied by renal dysfunction. Exercise training may relieve the symptomatic burden and improve the overall prognosis of CHF. In the present study, the effects of exercise training on renal function and renal aquaporin (AQP)‐2 expression in CHF rats were examined to determine whether exercise training could relieve renal dysfunction in CHF rats. 2. Male Sprague–Dawley rats were divided into three groups: sham, sedentary CHF (Sed‐CHF) and exercise training CHF (Ex‐CHF) groups. Cardiorenal function was assessed in each group by haemodynamic measurement and ultraviolet spectrophotometry. Pathological changes in cardiac and renal tissues were evaluated histologically and the collagen volume fraction (CVF) was calculated. The expressions of AQP‐2 and β‐tubulin were determined by western blotting and immunohistochemistry. 3. The Sed‐CHF rats were found to have increased left ventricular end‐diastolic pressure (LVEDP) and CVF in the heart compared with sham rats. Exercise training decreased LVEDP and CVF values in Ex‐CHF rats. The Sed‐CHF rats were found to have increased serum levels of creatinine (sCr), blood urea nitrogen (BUN) and arginine vasopressin (AVP), as well as increased CVF in the kidney, compared with sham rats. Exercise training decreased levels of sCr, BUN, AVP and CVF in Ex‐CHF rats. Moreover, exercise training decreased AQP‐2 and β‐tubulin protein expression in the kidney of CHF rats. 4. The results suggest that exercise training can significantly improve the renal dysfunction in CHF rats and that the underlying mechanism may be related to water reabsorption and preventing changes to the cytoskeleton.     

Does Aspirin Interfere with the Therapeutic Efficacy of Angiotensin-converting Enzyme Inhibitors in Hypertension or Congestive Heart Failure?

We conducted a MEDLINE search of published literature from 1966 to January 1998 regarding the impact of aspirin (ASA) on the therapeutic effect of angiotensin-converting enzyme (ACE) inhibitors in hypertension and congestive heart failure. Selected references from these articles and results of recent clinical trials were also included. By inhibiting cyclooxygenase, ASA may interfere with the prostaglandin-mediated hemodynamic effects of ACE inhibitors. Although other nonsteroidal antiinflammatory drugs may increase blood pressure in hypertensive patients taking an ACE inhibitor, low-dosage (≤ 100 mg/day) ASA does not. However, higher dosages of ASA may attenuate the benefits of ACE inhibitors in patients with hypertension and/or congestive heart failure (CHF). Low-dosage ASA appears to interact little with ACE inhibitors, whereas higher dosages may produce a more significant interaction. Patients with CHF may also be more susceptible to this interaction because of underlying disease.     

Aldosterone antagonists in congestive heart failure

The role of aldosterone in the pathophysiology of congestive heart failure (CHF) has long been recognized. The recent RALES (Randomized Aldactone Evaluation Study) trial demonstrated early reduction in morbidity and mortality using spironolactone, an aldosterone receptor antagonist, in combination with angiotensin converting enzyme (ACE) inhibitor and loop diuretic, in patients with heart failure. This effect of spironolactone highlighted the importance of understanding the contributions of the renin-angiotensin-aldosterone system (RAAS) in the progression of CHF, and increased interest in the use of aldosterone antagonists. While ACE inhibitors have had the largest impact on adverse events in CHF, numerous studies have shown that these drugs fail to completely suppress aldosterone. Blocking the effects of residual aldosterone has now been demonstrated to affect prognosis in these patients. This review will discuss the role of aldosterone in the pathophysiology of CHF, with an emphasis on both known and potential therapeutic benefits of aldosterone antagonism.     

Beta-adrenoceptor antagonists in elderly patients with chronic heart failure: therapeutic potential of third-generation agents

Chronic heart failure (CHF) is a common and disabling condition with an incidence and prevalence that increase sharply with age. The median age of presentation of new heart failure cases is > 75 years. Effective treatments, including beta-adrenoceptor antagonists, have been proven in randomised, controlled trials. The average age in these placebo-controlled mortality and morbidity studies of beta-adrenoceptor antagonists in heart failure has, however, been < 63 years, and all patients with an ejection fraction > or = 40% were excluded. This lack of a representative sample of elderly patients with heart failure has raised concerns about extrapolating the available evidence for beta-adrenoceptor antagonists to a more elderly heart failure population. Beta-adrenoceptor antagonists may have a less beneficial effect or even an adverse effect in elderly heart failure patients. There is evidence that beta-adrenoceptor antagonists are less frequently prescribed in elderly CHF patients, and that this lack of treatment is associated with impaired outcomes. Establishing which beta-adrenoceptor antagonists, if any, are effective in elderly CHF is therefore of extreme importance. The elderly have a reduced cardiovascular reserve and may be less tolerant of the introduction of a vasoconstricting beta-adrenoceptor antagonist. In addition, the higher proportion of elderly CHF patients with relatively preserved systolic function (for which no treatment has been proven to reduce mortality and morbidity) means that we cannot say with certainty that beta-adrenoceptor antagonists have been proven to be effective in a general elderly CHF population. Third-generation beta-adrenoceptor antagonists with vasodilating actions in addition to their beta-adrenoceptor antagonist effects may offer several theoretical advantages over earlier beta-adrenoceptor antagonists for elderly CHF patients. Three of this class (carvedilol, bucindolol and nebivolol) have been evaluated with respect to their efficacy in reducing mortality and morbidity in CHF, and only two of these (carvedilol and nebivolol) had a proven outcome benefit in a properly powered randomised, controlled trial. Only the Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure (which used the vasodilating third-generation beta-adrenoceptor antagonist nebivolol) has prospectively investigated the treatment of CHF in elderly patients, including those with preserved systolic function, and demonstrated a significant reduction in the risk of death or cardiovascular hospitalisation. In conclusion, prescribers are advised that nebivolol should be preferred in elderly patients with CHF, because of its proven efficacy in a representative group of elderly CHF patients.     

Pharmacological modulations of the renin-angiotensin-aldosterone system in human congestive heart failure: effects on peripheral vascular endothelial function

Elevated peripheral vascular tone has been proposed as one of the detrimental factors causing increased cardiac after load and reduced exercise capacity in patients with congestive heart failure (CHF). A number of studies have shown impaired endothelium-dependent vasodilation in limb resistance and conduit vessels in CHF, suggesting that this is one of the important etiologies of vascular dysfunction. Several clinical trials have shown that pharmacological inhibition of the renin-angiotensin-aldosterone system by angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, or aldosterone receptor antagonists, significantly improves prognosis in this disorder. However, the relationship between the clinical utility of this type of drug and its pharmacological effects on the peripheral vasculature has not been extensively assessed in patients with CHF. The present review summarizes recent reports including our own observations on the pharmacological effects and mechanisms of this type of drug on vascular endothelial function in the peripheral vasculature in human CHF.     

慢性阻塞性肺疾病合并慢性心力衰竭患者使用β阻滞剂的探讨

慢性阻塞性肺疾病（COPD）是呼吸系统常见病,是一组与年龄呈正相关的全身炎症性疾病;慢性心力衰竭（CHF）多系高血压、冠心病发展到一定程度后导致心功能损害为主的综合征。在临床上这两组疾病常常合并存在,且随着年龄的增加而增加。国内外的慢性心力衰竭指南均推荐使用心脏选择性β受体阻滞剂,但是临床医师遇到COPD合并CHF患者因担心β受体阻滞剂的不良反而拒绝或回避使用。近年来越来越多的证据表明,心脏选择性β受体阻滞剂在COPD合并CHF患者中没有明显的不良反应,且安全性得到证实,没有证据显示其降低肺通气功能如第1秒用力呼气量（FEVI）。但是在临床实际操作中有研究提示使用β受体阻滞剂亦可能导致病情恶化。笔者通过观察认为COPD合并CHF患者是否使用心脏选择性β受体阻滞剂时要采用“个体化”策略。     

Immunosuppressive Therapy for Heart Failure

Therapy with β-adrenoceptor antagonists, ACE inhibitors and most recently, Spironolactone was established for reducing all-cause mortality in patients with congestive heart failure (CHF), improving patient clinical status and inhibiting the disease progression. Unfortunately, despite optimal therapy for CHF in some patients, the disease progresses and, as yet, no conclusive mechanism has been identified for deterioration of cardiac function in patients with heart failure. Defining the cause of CHF in patients with dilated cardiomyopathy may have prognostic and therapeutic implications. Clinical and experimental evidence suggests that long-term inflammation may play a key part in the development of heart failure in patients with cardiomyopathy due to ischemic heart disease and those with cardiomyopathy due to non-ischemic cases. Because chronic immune myocardial injury, found in patients with CHF is myocardial restricted, endomyocardial biopsy with immunohistological markers of immune-mediated injury may offer us new guidelines to patient selection for immunomodulatory therapies. Few randomized placebo controlled studies addressing the effectiveness of suppression and modulation of the immune system in patients with heart failure gave unequivocal results. Moreover, none of the abovementioned randomized studies has shown decreased mortality in the immunosuppressively treated patients compared with conventionally treated patients. In the US Myocarditis Treatment Trial, for example, mortality was 20% overall at 1 year and 56% at 4.3 years of follow-up. In addition, spontaneous improvement of left ventricular systolic function has been reported in 30–40% of conventionally treated patients with CHF due to dilated cardiomyopathy. Given the high proportion of patients who improve spontaneously, selection of patients for immunosuppressive therapy should be preceded by treating heart failure with the individualized conventional therapy (ACE inhibitors, β-adrenoceptor antagonists, Spironolactone) for at least 6 months. Final decision to use immunomodulatory therapies should be based on comprehensive clinical measures of disease progression.     

慢性心力衰竭1040例病因与治疗方法分析

目的了解我院10年来慢性心力衰竭(心衰)住院患者病因、药物治疗与转归的情况,为今后心衰病人的预防和治疗策略提供资料。方法对我院1993年至2003年的住院病历进行回顾性分析和比较。结果心衰病种主要是冠心病、风湿性心瓣膜病、高血压病;10年来住院期间治疗心衰的药物使用仍以利尿剂、硝酸酯类和洋地黄类为主;洋地黄使用率有下降,β-受体阻滞剂、血管紧张素转换酶抑制剂和醛固酮桔抗剂使用逐步上升。住院期间明显改善率逐渐递增,病死率明显递增,但明显高于同期心血管病病死率,心衰死亡占心血管病总病死率没有明显改变。结论10年来,慢性心力衰竭住院病人的主要病因从风心病演变为冠心病;住院心衰病人的用药仍以传统药物为主,β-受体阻滞剂和血管紧张素转换酶抑制剂明显增加;心衰患者占心血管病住院患者的比例没有下降,虽然心衰病死率下降,但其在心血管病中的死亡比率没有改变。     

Effect of amiodarone on dispersion of ventricular repolarization in a canine congestive heart failure model

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帕罗西汀治疗慢性心力衰竭合并抑郁症患者的疗效观察

目的：探讨帕罗西汀对慢性心力衰竭合并抑郁症患者的临床治疗疗效。方法将2010年1月至2012年6月52例伴抑郁症的慢性心力衰竭患者随机分为对照组和治疗组各26例,所有患者均给予常规抗心力衰竭治疗,治疗组在此基础上加用帕罗西汀抗抑郁治疗,疗程12周。分别于治疗前后测量和记录患者的左心室射血分数（LVEF）、生活质量（QOL）以及汉密尔顿抑郁量表-17（HAMD-17）评分,并计算抗抑郁治疗有效率。结果治疗组治疗后LVEF较对照组有明显提高,差异有统计学意义（P＜0.05）,QOL评分以及HAMD量表评分均有明显下降,差异均有统计学意义（P＜0.05）。治疗组抗抑郁治疗总有效率达69.2%（18/26）,对照组为38.5%（10/26）,两组比较,差异有统计学意义（P＜0.05）。结论帕罗西汀可以改善慢性心力衰竭合并抑郁症患者的抑郁症状,改善心功能,提高患者的QOL,值得临床推广。     

Overview of emerging pharmacotherapy in chronic heart failure

Chronic heart failure (CHF) is of constantly growing importance regarding incidence, prevalence and social and economic burden. The classical mere hemodynamic perception of CHF pathophysiology has been expanded towards a much more complex and inclusive approach combining neuroendocrine, inflammatory, metabolic and immunological factors. With this advance, new parameters and targets have been shifted into the focus of current investigations, and new therapeutic approaches have been tested. Several recent studies have failed, however, despite intriguing pathophysiological concepts and promising pilot data. In other studies, significant benefits have been observed in certain subgroups only, suggesting a tailored approach for individual risk and co-morbidity situations. The contemporary concept of CHF treatment is designed to shield the heart from adverse (over)compensatory mechanisms particularly of neuroendocrine activation. This shield needs to be expanded on systemic effects including both immunologic and metabolic aspects within CHF pathophysiology. New and future concepts in CHF therapy may not yield a homogenous treatment option applicable for every patient, but may require a new range of diagnostic strategies to design a tailored therapy, adapted to the patient's pathophysiological fingerprint. This review will focus on recent developments and potential future candidates of pharmacological CHF therapy.     

氯沙坦对充血性心衰患者心功能及循环NO／ET的影响

目的探讨氯沙坦治疗充血性心衰(CHF)的临床疗效及对循环NO和内皮素(ET)水平的影响。方法60例CHF患者在常规治疗基础上随机加用氯沙坦(25～50mg     

Evaluating Health-related quality-of-life outcomes in patients with congestive heart failure. A review of recent randomised controlled trials.

Congestive heart failure (CHF) is a chronic disorder characterised by fatigue, shortness of breath and congestion. Treatment is designed to relieve symptoms, halt or delay progression of the disease, prolong life and, ultimately, improve quality of life. The purpose of this paper is to identify recent trends in the assessment of health-related quality-of-life (HR-QOL) outcomes in randomised, controlled trials evaluating treatment effectiveness in patients with CHF. 41 studies using HR-QOL as an explicit outcome and published in English between 1990 and September 1998 were reviewed. Trends in the measurement of HR-QOL and evidence of treatment effectiveness are presented followed by a discussion of the implications for future research. Results suggest that pharmacological and nonpharmacological treatment regimens can have a positive impact on HR-QOL. However, treatment-related improvement in exercise capacity in patients with CHF was not consistently associated with improvement in all domains of HR-QOL. The primary HR-QOL domain affected by treatment appears to be the performance of daily activities, which may or may not be accompanied by enhanced well-being. This suggests that functional status should be considered a primary HR-QOL end-point in clinical intervention trials. Preference-based or utility assessment, ethnic group differences in treatment effectiveness, caregiver burden and cost effectiveness are understudied outcomes in CHF research.     

beta-Blockers in congestive heart failure

Recent advances in the understanding of the basic mechanisms underlying congestive heart failure (CHF) have focused on the role of neurohormonal activation. Chronic adrenergic overstimulation is directly toxic to myocardial cells, impairs function, causes peripheral vasoconstriction and may induce programmed cell death via apoptosis. beta-Adrenergic blockade can interrupt this pathological process. Accumulating evidence now points to a clear role for beta-blocking agents in the management of heart failure, reducing both the morbidity and mortality associated with CHF. This report will review the recent clinical trials supporting the use of beta-blockers in CHF, briefly highlight some practical considerations in the use of these drugs in patients with CHF and discuss several areas of controversy in which further study is needed.     

卡维地洛对慢性心衰合并肾功能不全患者肾功能的影响

目的:评价卡维地洛对慢性心衰(CHF)合并慢性肾功能不全(CRF)患者肾功能的影响。方法:入选27例CHF合并CRF患者,在充分抗心力衰竭治疗的基础上,加用卡维地洛,观察不同阶段左室射血分数(LVEF)和肾功能的变化。结果:卡维地洛治疗后,LVEF在治疗3个月后开始升高,12个月后显著高于基线水平(p<0.01)。治疗后1个月,血肌酐(Scr)升高(p<0.05),3个月时回落到基线水平以下(p<0.05),12个月时仍低于基线水平(p<0.05);治疗后1个月,内生肌酐清除率(Ccr)先轻度下降(p<0.05),3个月时回升高于基线水平(p<0.01),12个月时仍显著高于基线水平(p<0.01)。卡维地洛对尿微量白蛋白和24h尿蛋白定量影响不大(p>0.05)。结论:第三代β-受体阻滞剂卡维地洛,可改善慢性心衰合并慢性肾功能不全患者的心功能,早期引起肾功能的轻度降低,随后肾功能显著改善。     

Beta-blockers for congestive heart failure: what is the current consensus?

Despite the availability of angiotensin converting enzyme (ACE) inhibitors for patients with congestive heart failure (CHF), mortality and morbidity remains unacceptably high. CHF is thought to progress as a result of activation of endogenous neurohormonal systems which are activated by the initial myocardial injury. The 2 neurohormonal systems which seem to be important in CHF are the sympathetic nervous system (SNS), and the renin-angiotensin-aldosterone system (RAAS). While stimulation of the SNS has important circulatory support functions in the short term, long term activation appears to have deleterious effects on cardiac function and outcomes. The purpose of this article is to review the literature on the use of beta-blockers in patients with CHF. The published randomised clinical trials of beta-blockers in patients with CHF have shown very promising effects on mortality and morbidity. Several systematic overviews of these trials also suggest beneficial effects on mortality, hospitalisation for CHFE need for transplant, and ejection fraction. The effect of beta-blockers on exercise tolerance. New York Heart Association Function Class (NYHA-FC) and quality of life remain equivocal. The recent presentation of the results from several large-scale trials which were terminated early because of significant survival benefit, has removed any concern over the robustness of the mortality data. Available evidence suggests that a wide variety of patients with CHF, including the elderly, should be considered for beta-blocker therapy. Caution is warranted in the initiation and titration of therapy, as symptoms of CHF may transiently worsen. Whether all beta-blockers are equally efficacious remains unknown.     

COPD合并心力衰竭患者B型钠尿肽水平的变化

目的:探讨慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD)合并充血性心力衰竭(congestive heart failure,CHF)患者B型钠尿肽(B-type natriuretic peptide,BNP)水平的变化及临床意义.方法:选取慢性阻塞性肺疾病急性加重期(acute exacerbation chronic obstructive pulmonary disease,AECOPD)患者(59例)作为A组,COPD合并CHF患者(63例)作为B组;另选取健康体检正常者(30例)作为C组.采用免疫荧光快速测试法测定受试者血浆BNP水平并分析.结果:血浆BNP水平B组显著高于A组和C组(P＜0.01);而A组显著高于C组(P＜0.01).B组患者治疗后血浆BNP水平明显下降(P＜0.01),治疗后血浆BNP水平B组略高于A组但无显著性差异(P＞0.05).结论:COPD合并CHF时BNP水平明显升高,提示BNP测定对鉴别COPD合并CHF有一定意义,同时可作为COPD合并CHF患者治疗效果的评价指标.     

Racial Differences in Responses to Drug Treatment

Chronic heart failure (CHF) is a common disease with high associated morbidity and mortality, and the outcome appears to be worse in black compared with white patients. There is currently no clear consensus for basing the pharmacological treatment of CHF on racial differences. Most studies that have investigated the potential effects of racial differences on pharmacological responses in heart failure have been based on African Americans and white participants. Using these data, this review will discuss the current understanding of the effects of racial differences in response to pharmacotherapy in heart failure, possible mechanisms for these observed differences, and how this may impact on patient management. Diuretics have favorable symptomatic benefits in both black and white patients with heart failure with evidence of fluid retention. ACE inhibitors seem to be less effective in the treatment of black patients with heart failure compared with white patients. This may be due to low pre-existing activity of the renin-angiotensin system in blacks. The role of angiotensin receptor blockers (ARBs) in the management of all patients with heart failure is incompletely defined and there are no clear trial data to show any difference in effect between black and white patients with heart failure. There is good evidence for the use of Spironolactone in all patients with heart failure, but no evidence for a different effect in black patients. Similarly, there is no conclusive data to suggest a difference in effect of digoxin in different racial groups. The evidence available would suggest that certain β-adrenoceptor antagonists (certainly Carvedilol but not bucindolol) are effective in both black and white patients with CHF. The combination of hydralazine and nitrates would appear to be particularly effective in black patients with CHF though the African American Heart Failure Trial (A-HeFT) trial should provide clearer evidence for the potentially greater beneficial effects of these two drugs in the black population. It is important to accept that racial categorization acts as only a surrogate marker for genetic or other factors responsible for individual responses to drug therapy and that any identified differences will not apply to all members of each stratified group. Nonetheless, in managing a complex, common and often fatal condition such as heart failure, recognizing potential individual differences in drug responses should enable the responsible clinician to provide a tailored and evidence-based approach to patient treatment.