Gene delivery approaches to heart failure treatment

Heart failure remains a leading cause of worldwide morbidity and mortality. Despite recent advances in treatment and our increasing knowledge of pathophysiology and the molecular derangements involved in the failing heart, our ability to affect the underlying cardiac disease processes is limited. In recent years, there has been considerable interest in myocardial gene transfer as both an investigational and potential therapeutic modality. Ultimately, the goal of any such strategy is to reprogramme failing cardiac myocytes and correct the aberrant molecular events causing heart failure. So far, viral vectors have been utilised with success more frequently than any other method of gene delivery in animal models. Studies in animal models and in failing human cardiomyocytes in culture targeting specific molecular pathways, including the β-adrenergic receptor cascade and the myocyte intracellular calcium handling system, have shown encouraging results and offer hope that gene manipulation may provide novel adjunctive therapeutic modalities for human heart failure.     

Gene therapy for heart failure

Despite our continued advances in the management of coronary artery disease, there have been no significant reductions in the morbidity or mortality related to end-stage heart failure. The syndrome of heart failure represents a common endpoint for several disease processes, however, at the molecular level there are certain biochemical similarities common to all failing myocardium. Targeting these derangements with gene therapy represents a promising option in the treatment of heart failure. In this review, we will discuss the common biochemical changes that occur in the failing heart, novel therapeutic targets, including the beta-adrenergic receptor system and intracellular calcium regulation, and the vectors and transfer methodology responsible for delivering these transgenes to the myocardium.     

基因治疗与心力衰竭

目的:探讨基因治疗方案的有效性和安全性。资料来源:应用计算机检索PUBMED1980-01/2006-10和EMCC 1994-10/2006-10与心力衰竭的基因治疗相关文章,检索词“Gen Therapy,Heart Failure”,并限定文章语言种类为“English”;同时计算机检索CMCC 1994-01/2006-10的相关文章,限定文章语言种类为中文,检索词“基因治疗、心力衰竭”。资料选择:对资料进行初审,选取试验包括上述治疗组和对照组的文献,然后筛除明显不随机临床试验的研究,对剩余的文献开始查找全文,进一步判断是否为RCT。纳入标准为:①试验包含平行对照组,即一般药物治疗。②治疗组为转基因治疗。资料提炼:共收集到49篇相关的随机和未随机试验,31个试验符合纳入标准。其余的排除。资料综合:31个试验包括478例动物模型,分别对应用不同靶点的转基因或基因敲除等方案进行治疗者予以评价。31篇文章中有10篇未达到预期的治疗目标,主要是在目的基因的选择及转染载体的选择方面出现了偏差。结论:虽动物试验取得了一定的成果,但尚无人体基因治疗的文献报道,随着基因技术的进步,基因治疗有望成为治疗心力衰竭的新途径。     

Gene therapy to restore electrophysiological function in heart failure

Introduction: Heart failure (HF) is a major public health epidemic and a leading cause of morbidity and mortality in the industrialized world. Existing treatments for patients with HF are often associated with pro-arrhythmic activity and risk of sudden cardiac death. Therefore, development of novel, effective and safe therapeutic options for HF patients is a critical area of unmet need.

Areas covered: In this article, we review recent advances in the emerging field of cardiac gene therapy for the treatment of tachy- and bradyarrhythmias in HF. We provide an overview of gene-based approaches that modulate myocardial conduction, repolarization, calcium cycling and adrenergic signaling to restore heart rate and rhythm.

Expert opinion: We highlight major advantages of gene therapy for arrhythmias, including the ability to selectively target specific cell populations and to limit the therapeutic effect to the region that requires modification. We illustrate how advances in our fundamental understanding of the molecular origins of arrhythmogenic disorders are allowing investigators to use targeted gene-based approaches to successfully correct abnormal excitability in the atria, ventricles and conduction system. Translation of various gene therapy approaches to humans may revolutionize our ability to combat lethal arrhythmias in HF patients.     

Gene therapy targeted at calcium handling as an approach to the treatment of heart failure

Chronic congestive heart failure primarily of ischemic origin remains a leading cause of morbidity and mortality in the United States and other leading countries. The current main stream of therapy is, however, palliative and uses a complex regimen of drugs, the actions of which are not understood completely. On the other hand, unfavorable remodeling after cardiac injuries of multiple causes has been thought to lead to cardiac contractile dysfunction in heart failure, and a body of scientific evidence points to a central role of intrinsic defects in intracellular calcium handling in cardiomyocytes that arise from the distorted functions of several key regulatory molecules on plasma membrane or sarcoplasmic reticulum (SR), a muscle-specific intracellular membrane complex that stores calcium at high concentration. Accordingly, the initial appetite to use gene transfer strategies to modulate calcium regulatory proteins was to validate molecular targets for the development of new pharmaceuticals; however, remarkable therapeutic efficacies found in an initial series of studies using various heart failure animal models immediately promoted us to seek ways to directly apply gene transfer to cure clinical heart failure. The first part of this article reviews our up-to-date knowledge of various functional components to regulate calcium handling in cardiomyocytes, including beta-adrenergic receptor, L-type calcium channel, ryanodine receptor (RyR) and its associated proteins, sarco-endoplasmic reticulum calcium ATPase (SERCA), and phospholamban (PLN), and their abnormalities in failing hearts. A series of new somatic gene transfer attempts targeting calcium handling in cardiomyocytes are discussed thereafter.     

Gene therapy targets in heart failure: the path to translation

Heart failure (HF) is the common end point of cardiac diseases. Despite the optimization of therapeutic strategies and the consequent overall reduction in HF-related mortality, the key underlying intracellular signal transduction abnormalities have not been addressed directly. In this regard, the gaps in modern HF therapy include derangement of β-adrenergic receptor (β-AR) signaling, Ca(2+) disbalances, cardiac myocyte death, diastolic dysfunction, and monogenetic cardiomyopathies. In this review we discuss the potential of gene therapy to fill these gaps and rectify abnormalities in intracellular signaling. We also examine current vector technology and currently available vector-delivery strategies, and we delineate promising gene therapy structures. Finally, we analyze potential limitations related to the transfer of successful preclinical gene therapy approaches to HF treatment in the clinic, as well as impending strategies aimed at overcoming these limitations.     

New approaches to detect and manage edema and renal insufficiency in heart failure

Earlier detection of edema and renal insufficiency, before overt decompensation, is fundamental to further advances in altering the natural history of heart failure. Progress is being made in the earlier detection of these complications through the use of new devices that monitor for hemodynamic compromise and through monitoring of select cardiac and renal biomarkers. In addition, diuretic-sparing approaches to heart failure management, novel drug classes, new devices, and nonpharmacologic therapies are emerging to reduce reliance on diuretic therapy and manage edema with less renal compromise.     

Pharmacologic treatment of heart failure

An increased understanding of the pathophysiologic changes underlying CHF, advanced monitoring technology, and a wider array of drug therapy have improved the prognosis of patients with this disorder. These advances allow for greater individualization of therapy, improve patient compliance, and lower the incidence of undesirable side effects. Of course, with the increase in complexity of treatment choices comes the need for more knowledgeable practitioners who can select the most appropriate therapeutic approach. All practitioners also must make every effort to educate the patients about their disease, treatments, and necessary lifestyle changes so that optimal benefits can be realized.     

Beta-blocker treatment in heart failure

Heart failure treatment has markedly changed during the last few decades, with demonstration of benefit of afterload reduction by vasodilator therapy and introduction of the concept of the deleterious consequences of the neuro-hormonal compensatory stimulation. Blockade of beta-adrenergic receptors, initially contra-indicated in heart failure, provide a marked reduction of mortality and morbidity in combination with diuretics and angiotensin-converting enzyme inhibitors, as demonstrated in many clinical trials. We performed a review of all clinical trials that compare beta-blockers vs. placebo in chronic heart failure. Beta-blockers with different pharmacological profiles have been tested, mainly metoprolol, bisoprolol, bucindolol and carvedilol. With progressive dose increment, tolerance of such treatment was generally good, left ventricular function improved, hospitalisations for heart failure were less frequent and mortality was reduced. The meta-analysis of the 16 randomised trials, with at least one death in each treatment group, provides a 24% relative risk reduction for such hospitalisations (95% CI=19%-29%) and 22% reduction for mortality (95% CI=16%-28%). Heterogeneity of beta-blocker effect for mortality was found and related to the non-significant benefit obtained in the BEST trial with bucindolol. When such a trial is excluded, the effect model analysis shows that relative risk reduction (beta-blocker induced benefit) is constant whatever the severity of the disease. The mechanism of beta-blocker induced benefit remains unclear, but is at least partly related to left ventricular function improvement and prevention of severe ventricular arrhythmias. In conclusion, beta-blocker treatment has become an established therapy for heart failure, in combination with diuretics and ACE inhibitors. Complementary informations will be needed to clarify the mechanism of benefit and to define the best therapeutic strategy according to the individual characteristics of patients with heart failure.     

Pharmacological treatment of heart failure

This article provides an overview of heart failure (HF) and pharmacological treatment of systolic left ventricular dysfunction. The purpose of this article is to provide nurses the knowledge of current treatment recommendations and the Five Million Lives campaign sponsored by the National Institute of Healthcare Improvement. This initiative is a national campaign to protect 5 million patients from medical harm by promoting evidence-based standards of practice to improve the healthcare of Americans. HF has become part of this national initiative and the National Institute of Healthcare Improvement in conjunction with the American College of Cardiology/American Heart Association has implemented guidelines to improve the care of HF patients. Nurses would be expected to be familiar with these guidelines, as regulatory agencies will be using these guidelines as a benchmark to evaluate the quality of care provided to patients with this diagnosis.     

Targeting approaches to oral drug delivery

Heat shock proteins (Hsps), cyclophilins (Cyps) and FK binding proteins (FKBPs) form a family of intracellular chaperone molecules that facilitate protein folding and assembly. These stress proteins are selectively expressed in cells in response to a range of stimuli, including heat, lymphokine and microbial/viral infections. This review discusses the role of stress proteins in the HIV-1 viral life cycle, with regard to the development of specific Hsp-based therapeutic strategies against HIV-1 infection. Cumulative findings are cited implicating CypA, Hsp27, Hsp70 and FKBPs in host cell and viral activation, viral entry, assembly or formation of infectious virions. Biological response modifiers that show specific high-affinity interactions with Cyp, FKBPs and Hsps, including cyclosporins, FK-506 and cyclopentenone prostaglandins respectively, may block HIV-1 replication and infection, providing novel HIV-1 therapeutic strategies. Moreover, Hsp binding to viral complexes can enhance antiviral immunity, including natural killer (NK), antibody-dependent (ADCC), γδ T- cell and cytotoxic T-lymphocyte (CTL) activities against HIV-1 infected cells. The ability of Hsps to interact with HIV-1 viral proteins, combined with their inherent adjuvant and immunogenic properties indicates that Hsps may also serve as vehicles for antigen delivery and the design of AIDS vaccines.     

Novel approaches to ocular drug delivery

Recent advances in surgical techniques, therapeutic approaches and materials sciences have produced revolutionary new therapies for ocular diseases. The development of prodrug formulations and permeability enhancers, sustained-release drug delivery devices, novel injectable medications and new and improved vectors, both viral and non-viral, for delivery of genes to all segments of the eye has greatly increased the chances of success in treating eye diseases. This review will discuss the most recent advances in drug delivery systems for the treatment of ocular diseases.     

Modern approach to the treatment of decompensated heart failure

The initial approach to the treatment of acute decompensated heart failure is based on the clinical presentation and, in some, various additional examinations. The classical clinical–hemodynamic approach intends to evaluate the volume and perfusion status, based on clinical parameters. This approach appears overly simplistic and needs to be revised in order to incorporate modern diagnostic and therapeutic tools that have been developed in the last few years. We propose a new treatment algorithm that includes all available options of assessing perfusion and volume status, including biochemical and imaging techniques, and gives recommendations on intravenous agents early in the course of treatment. All efforts should be made to prevent worsening of hypotension and renal dysfunction during the hospital course, since both are strong prognostic markers. New therapeutic options, such as natriuretic peptides, calcium sensitizers and others in development, provide benefits beyond the usual drugs and can be used in scenarios where traditional agents would not be considered.     

Surgical treatment for chronic heart failure

Advances in the surgical treatment of chronic heart failure including ventricular re-modeling, artificial heart technology and bridge to recovery have revolutionized cardiac surgical management. This article summarizes the most popular surgical treatment of heart failure with experiences from various institutes. The author has stated that he does not have a significant financial interest or other relationship with any product manufacturer or provider of services discussed in this article.     

The pharmacologic treatment of heart failure

Congestive heart failure is common, affecting 4-5 million American's with more than 500,000 new cases each year. A number of therapies have been proposed for the treatment of CHF; some have been found useful and some not. Digoxin therapy long a mainstay of therapy has been found beneficial, but lower doses and caution with its use in women has been recently advised based on new information. Converting enzyme inhibitors and beta blockers both add benefit when used in combination. The addition of aldosterone antagonists to the digoxin, diuretic, ACE, and beta-blocker combination appears to offer benefit and the use of the new less toxic eplerone will become more frequently employed in selected patients. Sudden death is also an important contributor to mortality in CHF patients. Use of a amiodarone and ICD's have both been reported to offer benefit. Selecting the optimum cost effective therapy is a challenge to those treating heart failure patients. ICD's are recommended in class II, III CHF with EF < 30 and amiodarone may be the therapy of choice in selected class IV patients and in patients with EF > 30%.