心力衰竭的药物治疗进展

近十年,心力衰竭药物治疗取得了突飞猛进的发展,神经内分泌拮抗剂和新型变性肌力药物的陆续出现,已经结束的和正在进行的,临床试验表明有一部分药物能更好的改善部分心力衰竭患者的临床症状和预后。现就心力衰竭的药物治疗进展作一综述。     

心力衰竭的药物治疗新进展

心力衰竭是各种器质性心脏病的终末期表现,致残率高、病死率高。近几年来随着基础研究以及临床研究的迅猛发展,在心力衰竭的药物治疗方面出现了许多新的亮点,如：β受体阻滞剂新的临床证据、他汀类药物、内皮素受体拮抗剂、重组B型利钠肽、血管加压素受体拮抗剂、钙增敏剂、istaroxime等,为心血管内科医生及患者带来了新的希望。     

老年慢性心力衰竭药物治疗

老年慢性心力衰竭是当今西方国家患者住院的首要原因,患病率及住院费用随年龄增长而增加,且老年患者由于自身生理功能的改变及合并症较多等,因而在药物治疗上有其特殊性.为此,现对老年慢性心力衰竭的常用药物治疗作一综述.     

New Insights into Diabetes Cell Therapy

Since insulin discovery, islet transplantation was the first protocol to show the possibility to cure patients with type 1 diabetes using low-risk procedures. The scarcity of pancreas donors triggered a burst of studies focused on the production of new β cells in vitro. These were rapidly dominated by pluripotent stem cells (PSCs) demonstrating diabetes-reversal potential in diabetic mice. Subsequent enthusiasm fostered a clinical trial with immunoisolated embryonic-derived pancreatic progenitors. Yet safety is the Achilles’ heel of PSCs, and a whole branch of β cell engineering medicine focuses on transdifferentiation of adult pancreatic cells. New data showed the possibility to chemically stimulate acinar or α cells to undergo β cell neogenesis and provide opportunities to intervene in situ without the need for a transplant, at least after weighing benefits against systemic adverse effects. The current studies suggested the pancreas as a reservoir of facultative progenitors (e.g., in the duct lining) could be exploited ex vivo for expansion and β cell differentiation in timely fashion and without the hurdles of PSC use. Diabetes cell therapy is thus a growing field not only with great potential but also with many pitfalls to overcome for becoming fully envisioned as a competitor to the current treatment standards.     

Prognostic Significance of Longitudinal Clinical Congestion Pattern in Chronic Heart Failure: Insights From TIME-CHF Trial

BackgroundThe relationship between longitudinal clinical congestion pattern and heart failure outcome is uncertain. This study was designed to assess the prevalence of congestion over time and to investigate its impact on outcome in chronic heart failure.MethodsA total of 588 patients with chronic heart failure older than 60 years of age with New York Heart Association (NYHA) functional class ≥ II from the TIME-CHF study were included. The endpoints for this study were survival and hospitalization-free heart failure survival. Orthopnea, NYHA ≥ III, paroxysmal nocturnal dyspnea, hepatomegaly, peripheral pitting edema, jugular venous distension, and rales were repeatedly investigated and related to outcomes. These congestion-related signs and symptoms were used to design a 7-item Clinical Congestion Index.ResultsSixty-one percent of patients had a Clinical Congestion Index ≥ 3 at baseline, which decreased to 18% at month 18. During the median [interquartile range] follow-up of 27.2 [14.3-39.8] months, 17%, 27%, and 47% of patients with baseline Clinical Congestion Index of 0, 1-2, and ≥ 3 at inclusion, respectively, died (P < .001). Clinical Congestion Index was identified as an independent predictor of mortality at all visits (P < .05) except month 6 and reduced hospitalization-free heart failure survival (P < .05). Successful decongestion was related to better outcome as compared to persistent congestion or partial decongestion (log-rank P < 0.001).ConclusionsThe extent of congestion as assessed by means of clinical signs and symptoms decreased over time with intensified treatment, but it remained present or relapsed in a substantial number of patients with heart failure and was associated with poor outcome. This highlights the importance of appropriate decongestion in chronic heart failure.     

Combination Drug Therapy in Chronic Heart Failure: Is Treatment Part of the Problem in Heart Failure?

Despite advances in medical treatment, the annual mortality associated with severe heart failure remains over 40%, and even in mild heart failure the associated mortality is 40% over 4 years. Once it has been demonstrated that the morbidity and mortality to heart failure can be adequately addressed by combinations of drug therapy, then it is logical to attempt to strip out redundant components of these therapeutic regimes. In the meantime, however, combination therapy is required to counter many of the pathophysiological facets of the heart failure syndrome, including fluid retention, neuroendocrine activation, progressive ventricular dysfunction, and sudden cardiac death. Diuretics and ACE inhibitors are well-established drug treatments. Digoxin appears to lessen the rate of progression of heart failure without altering survival. New evidence suggests that beta-blockers may be useful additions to the heart failure therapeutic armamentarium, although whether all beta-blockers are equally effective remains to be established.     

Baroreflex Activation Therapy in Congestive Heart Failure: Novel Findings and Future Insights

Congestive heart failure is characterized by hemodynamic and non-hemodynamic abnormalities, the latter including an activation of the sympathetic influences to the heart and peripheral circulation coupled with an impairment of baroreceptor control of autonomic function. Evidence has been provided that both these alterations are hallmark features of the disease with a specific relevance for the disease progression as well as for the development of life-threatening cardiac arrhythmias. In addition, a number of studies have documented in heart failure the adverse prognostic role of the sympathetic and baroreflex alterations, which both are regarded as major independent determinants of cardiovascular morbidity and mortality. This represents the pathophysiological and clinical background for the use of carotid baroreceptor activation therapy in the treatment of congestive heart failure. Promising data collected in experimental animal models of heart failure have supported the recent performance of pilot small-scale clinical studies, aimed at providing initial information in this area. The results of these studies demonstrated the clinical safety and efficacy of the intervention which has been tested in large-scale clinical studies. The present paper will critically review the background and main results of the published studies designed at defining the clinical impact of baroreflex activation therapy in congestive heart failure patients. Emphasis will be given to the strengths and limitations of such studies, which represent the background for the ongoing clinical trials testing the long-term effects of the device in heart failure patients.     

Gene Therapy for Heart Failure: New Perspectives

Purpose of Review

The current knowledge of pathophysiological and molecular mechanisms responsible for the genesis and development of heart failure (HF) is absolutely vast. Nonetheless, the hiatus between experimental findings and therapeutic options remains too deep, while the available pharmacological treatments are mostly seasoned and display limited efficacy. The necessity to identify new, non-pharmacological strategies to target molecular alterations led investigators, already many years ago, to propose gene therapy for HF. Here, we will review some of the strategies proposed over the past years to target major pathogenic mechanisms/factors responsible for severe cardiac injury developing into HF and will provide arguments in favor of the necessity to keep alive research on this topic.

Recent Findings

After decades of preclinical research and phases of enthusiasm and disappointment, clinical trials were finally launched in recent years. The first one to reach phase II and testing gene delivery of sarcoendoplasmic reticulum calcium ATPase did not yield encouraging results; however, other trials are ongoing, more efficient viral vectors are being developed, and promising new potential targets have been identified. For instance, recent research is focused on gene repair, in vivo, to treat heritable forms of HF, while strong experimental evidence indicates that specific microRNAs can be delivered to post-ischemic hearts to induce regeneration, a result that was previously thought possible only by using stem cell therapy.

Summary

Gene therapy for HF is aging, but exciting perspectives are still very open.

     

Impact of Systemic Venous Congestion in Heart Failure

Systemic venous congestion is one of the hallmarks of the syndrome of heart failure that results from activation of different deleterious neurohormonal pathways. Apart from contributing to patients’ symptoms and hospital admissions, growing evidence suggests that congestion itself drives further heart failure progression. In addition, systemic venous congestion exerts detrimental effects on other organs (such as kidneys and liver) due to ineffective organ perfusion. Endothelial cell activation, altered ventricular geometry, and functional mitral insufficiency are among the proposed mechanisms. Diuretics and vasodilators remain the mainstay of treatment options, mostly because of poor understanding of the underlying cardiorenal mechanisms involved. Recently, ultrafiltration has emerged as an invasive treatment option in the setting of diuretic resistance. Congestion ideally should be prevented, often initially through water and salt restriction. Early detection, possibly with the help of novel implantable sensor technology, may allow for early detection and intervention long before overt congestion is established.     

心力衰竭的基因治疗

心力衰竭是多种心脏疾病的终末阶段,一般常规治疗预后不佳。近年来不断涌现的基因治疗方法,补充缺失的正常功能蛋白质、抑制体内某些基因的过度表达等,可以从根本上达到治疗心力衰竭的目的,为心力衰竭治疗提供了新的契机。现就心力衰竭基因治疗的作用靶点以及心脏基因转运技术的研究进展等进行综述。     

干细胞治疗缺血性心力衰竭研究进展

干细胞移植已经被用于治疗如急性心肌梗死、心力衰竭等心脏疾病,其可以提高心功能、促进新生血管的形成和对心脏生理间接影响。被研究的干细胞包括胚胎干细胞、胎儿心肌细胞、骨骼肌肌原细胞、骨髓干细胞、外周血CD34 细胞、内皮祖细胞、心肌祖细胞和成纤维细胞。虽然干细胞治疗心力衰竭是一项革命性进展,但还有许多问题期待解决,比如说何种人群适合做干细胞治疗、移植细胞种类、移植方式、移植细胞数目和疗效的评估等都还没有明确。现从干细胞类型,移植后的效果及移植的方法等方面做一综述。     

Congestion Is the Driving Force Behind Heart Failure

Increased filling pressures, or congestion, cause symptoms of heart failure and lead to hospitalizations. A higher rate of hospitalizations determines higher mortality. The most reliable way to decrease admissions is to monitor for signs of congestion, by history and exam, intracardiac pressures or biomarkers, and to modify treatment based on these data. The role of congestion is best understood by comparison of heart failure with preserved and reduced ejection fraction. The morbidity and mortality in both conditions is almost identical. Decreased cardiac output and ventricular remodeling play a major role in patients with decreased ejection fraction but not in those with preserved ejection fraction. The key factor that is present in both conditions and determines their similarity is congestion. Decongestion, or fluid removal, is the most effective treatment for heart failure regardless of ejection fraction. Being the driving force of heart failure, congestion should be the focus of clinical and hemodynamic monitoring and therapy.     

Digoxin Therapy in Chronic Heart Failure

Digitalis has been used for more than 250 years, but its role in the treatment of chronic heart failure has been intensively investigated only during the past two decades. Digoxin increases cardiac output both at rest and during exercise, alone or in combination with ACE inhibitors, and these hemodynamic effects are sustained during chronic therapy. A daily dose of digoxin that achieves a serum concentration of approximately 1.2 ng/ml is associated with a significant improvement in central hemodynamics, particularly in patients with impaired cardiac function despite pretreatment with diuretics and ACE inhibitors. Acute administration of digoxin in patients with chronic heart failure has an immediate sympathoinhibitory effect, and chronic therapy is associated with a sustained decrease in serum norepinephrine concentration. Discontinuation of digoxin in patients with chronic heart failure resulted in hemodynamic deterioration, which was reversed when the drug was readministered. Randomized withdrawal of digoxin in patients receiving only diuretics (PROVED study), or its withdrawal in patients receiving diuretics and ACE inhibitors (RADIANCE study), was associated with worsening of the clinical evidence of heart failure and a decrease in left ventricular systolic function in both studies. In the only large-scale, placebo-controlled mortality study reported thus for (DIG Trial), 7788 patients received standard drug treatment for chronic heart failure in addition to either digoxin or placebo. Digoxin had no impact on survival over the 37 months of follow-up, but the incidence of hospitalizations due to worsening heart failure was significantly reduced in patients receiving the drug compared with those receiving placebo.