Gene therapy for ischemic heart disease

INTRODUCTION: Coronary artery disease (CAD) is still the leading cause of death in industrialized nations. Even though revascularization strategies such as percutaneous coronary intervention (PCI) and coronary artery bypass graft surgery (CABG) as well as drug therapy have significantly reduced mortality, about 30% of patients will develop chronic heart failure over time. Ischemic heart disease and heart failure are characterized by an adverse remodeling of the heart, featuring cardiomyocyte hypertrophy, increased fibrosis and capillary rarification. AREAS COVERED: Beside an assessment of current vector systems, this review focuses on potential target genes affecting angiogenesis/arteriogenesis and contractility. The potential of micro RNA (miRNA) modulation for the de-repression of survival and pro-angiogenic genes is discussed. Since gene therapy of the target region is preferable to avoid systemic contamination, application routes are discussed. Expert opinion: miRNAs are a promising new development for successful gene therapy, especially for acute myocardial infarction since their miRNA antagonists are easy to apply and appear to be selectively absorbed by the ischemic myocardial tissue. Rapid uptake and prolonged presence of known antimirs and antagomirs support this notion. For ischemic heart disease the most promising gene therapeutic approach seems to be the regional intravenous application of suitable AAV vectors and vascular growth factors, providing the full scope of angiogenesis, vessel maturation and collateral growth optionally combined with genes enhancing contractility.     

Inhibitors of Erythropoiesis

Abstract

Background: It has been questioned whether bone marrow-derived mesenchymal stromal cells (MSCs) from patients with ischemic heart disease are suitable for use in regenerative stem cell therapy. We compared MSCs from patients with chronic coronary artery disease (CAD) and MSCs from young healthy donors with respect to phenotype, proliferation and endothelial differentiation capacity. Methods: MSCs from 16 young healthy donors and 15 elderly CAD patients were isolated, expanded by ex-vivo cultivation for two cell passages and characterized by flow cytometry, real time PCR and angiogenesis assay. Results: MSCs from healthy donors and CAD patients expressed the same surface markers and had similar proliferation capacity. In both groups VEGF-stimulation significantly increased the expression of the endothelial genes thrombospondin 1, Tie-2 and von Willebrand Factor and induced the capacity to form ring structures on extracellular matrix. Discussion: MSCs from young healthy donors and CAD patients proliferate equally well, express the same surface markers and increase in endothelial gene expression and ring structure formation capacity in the angiogenesis assay upon VEGF-stimulation. MSCs from CAD patients do not seem to be inferior to MSCs from young healthy donors thus indicating that autologous MSCs may be suitable for cell therapy in CAD patients.     

The association of ghrelin polymorphisms with coronary artery disease and ischemic chronic heart failure in an elderly Chinese population

ObjectiveTo investigate the association of coronary artery disease (CAD) and ischemic heart failure (IHF) with polymorphisms of the ghrelin gene in elderly Chinese patients.Design and methodsFifty-six patients with ischemic heart failure, sixty patients with coronary artery disease without heart failure, and one hundred healthy control subjects participated in the study. The polymorphisms were evaluated by polymerase chain reaction, sequencing, and fragment length polymorphism analysis.ResultsOnly one single nucleotide polymorphism (SNP), Leu72Met (408C/A), was observed across all samples. Gene frequencies of CC and allele frequencies of C were significantly greater in the CAD with IHF group than those in the CAD without IHF group (p = 0.025, p = 0.011). There was no significant association between the Leu72Met SNP with coronary artery disease risk factors.ConclusionOur results suggest that a C allele at position 408 of the ghrelin gene is associated with genetic susceptibility to ischemic heart failure in Chinese elders.     

Extracorporeal cardiac shock wave therapy for angina pectoris

Prognosis of severe ischemic heart disease with no indication of percutaneous coronary intervention or coronary artery bypass grafting remains poor. Extracorporeal shock wave (SW) therapy was introduced for medical therapy more than 20 years ago to break up kidney stones. We have demonstrated that extracorporeal cardiac SW therapy at a low level (about 10% of the energy density that used for urinary lithotripsy), effectively induces coronary angiogenesis and improves myocardial ischemia in a porcine model of chronic myocardial ischemia in vivo. Also, our extracorporeal cardiac SW therapy improved symptoms and myocardial ischemia in patients with severe coronary artery disease. Importantly, no procedural complications or adverse effects were noted. These results indicate that our extracorporeal cardiac SW therapy is an effective and non-invasive treatment for ischemic heart disease.     

Volociximab in cancer

Importance of the field: Despite the advances in the cardiovascular field, cardiovascular diseases remain an important health problem with a high mortality rate. Novel therapeutic attempts that target myocardial ischemia and heart failure offer attractive adjuncts and/or alternatives to commonly employed regimens. The development of novel laboratory technologies over the last decade has led to substantial progress in bringing new therapies to the bedside.

Areas covered in this review: Current experimental and clinical trials in the use of erythropoietin (EPO) in cardiovascular diseases are reviewed.

What the reader will gain: This review will widen knowledge of the therapeutic potential of EPO's non-erythropoietic beneficial effects in a clinical cardiovascular setting.

Take home message: Results from preclinical trials regarding the non-erythropoietic effects of erythropoietin are really encouraging. Further clinical studies are warranted to define the beneficial role of EPO in the clinical setting of coronary artery disease, heart failure and peripheral artery disease.     

超声微泡造影剂在冠状动脉粥样硬化性心脏病治疗中的应用进展

冠状动脉粥样硬化性心脏病(CHD)是威胁人类健康和生命的疾病之一,药物、介入及外科治疗均不能根治.外源性给予某些促血管生成因子或治疗基因能促进缺血心肌血管再生和侧支循环建立,改善心肌缺血.超声微泡造影剂作为促血管生成因子或治疗基因的载体,联合超声辐照能更安全、高效、靶向地导入缺血心肌组织,为CHD的治疗开辟了一个新的应用前景.本文就近年来超声微泡造影剂在CHD治疗中的应用进展做一综述.     

Mesenchymal stem cells at the intersection of cell and gene therapy

Importance of the field : Mesenchymal stem cells have the ability to differentiate into osteoblasts, chondrocytes and adipocytes. Along with differentiation, MSCs can modulate inflammation, home to damaged tissues and secrete bioactive molecules. These properties can be enhanced through genetic-modification that would combine the best of both cell and gene therapy fields to treat monogenic and multigenic diseases.

Areas covered in this review: Findings demonstrating the immunomodulation, homing and paracrine activities of MSCs followed by a summary of the current research utilizing MSCs as a vector for gene therapy, focusing on skeletal disorders, but also cardiovascular disease, ischemic damage and cancer.

What the reader will gain: MSCs are a possible therapy for many diseases, especially those related to the musculoskeletal system, as a standalone treatment, or in combination with factors that enhance the abilities of these cells to migrate, survive or promote healing through anti-inflammatory and immunomodulatory effects, differentiation, angiogenesis or delivery of cytolytic or anabolic agents.

Take home message: Genetically-modified MSCs are a promising area of research that would be improved by focusing on the biology of MSCs that could lead to identification of the natural and engrafting MSC-niche and a consensus on how to isolate and expand MSCs for therapeutic purposes.     

Molecular aspects of ischemic heart disease: ischemia/reperfusion-induced genetic changes and potential applications of gene and RNA interference therapy

Molecular biologic techniques have a variety of applications in the study of ischemic heart disease, including roles in elucidating cardiac genetic changes resulting from ischemia as well as in developing therapeutic interventions to treat ischemic heart disease. This review describes recent studies documenting genetic changes associated with myocardial ischemia and infarction as well as those investigating the safety and effectiveness of gene therapy for stimulating angiogenesis, protecting the heart against reperfusion injury, and treating heart failure. Also discussed are future research directions, including the potential use of RNA interference and combined stem cell therapy and gene therapy for the treatment of cardiovascular disease.     

Cyclocreatine protects against ischemic injury and enhances cardiac recovery during early reperfusion

ABSTRACT

Introduction: A critical mechanism of how hypoxia/ischemia causes irreversible myocardial injury is through the exhaustion of adenosine triphosphate (ATP). Cyclocreatine (CCr) and its water-soluble salt Cyclocreatine-Phosphate (CCrP) are potent bioenergetic agents that preserve high levels of ATP during ischemia.

Areas covered: CCr and CCrP treatment prior to the onset of ischemia, preserved high levels of ATP in ischemic myocardium, reduced myocardial cell injury, exerted anti-inflammatory and anti-apoptotic activities, and restored contractile function during reperfusion in animal models of acute myocardial infarction (AMI), global cardiac arrest, cardiopulmonary bypass, and heart transplantation. Medline and Embase (1970 – Feb 2019), the WIPO databank (up to Feb 2019); no language restriction.

Expert opinion: This review provides the basis for a number of clinical applications of CCrP and CCr to minimize ischemic injury and necrosis. One strategy is to administer CCrP to AMI patients in the pre-hospital phase, as well as during, or after Percutaneous Coronary Intervention (PCI) procedure to potentially achieve protection of the myocardium, reduce infarcted-size, and, thus, limit the progression to heart failure. Another clinical applications are in predictable myocardial ischemia where pretreatment with CCrP would likely improve outcome and quality of life of patients who will undergo cardiopulmonary bypass for coronary revascularization and end-stage heart failure patients scheduled for heart transplantation.     

Therapeutic angiogenesis for myocardial ischemia

Therapeutic angiogenesis offers promise as a novel treatment for ischemic heart disease, particularly for patients who are not candidates for current methods of revascularization. The goal of treatment is both relief of symptoms of coronary artery disease and improvement of cardiac function by increasing perfusion to the ischemic region. Protein-based therapy with cytokines including vascular endothelial growth factor and fibroblast growth factor demonstrated functionally significant angiogenesis in several animal models. However, clinical trials have yielded largely disappointing results. The attenuated angiogenic response seen in clinical trials of patients with coronary artery disease may be due to multiple factors including endothelial dysfunction, particularly in the context of advanced atherosclerotic disease and associated comorbid conditions, regimens of single agents, as well as inefficiencies of current delivery methods. Gene therapy has several advantages over protein therapy and recent advances in gene transfer techniques have improved the feasibility of this approach. The safety and tolerability of therapeutic angiogenesis by gene transfer has been demonstrated in phase I clinical trials. The utility of therapeutic angiogenesis by gene transfer as a treatment option for ischemic cardiovascular disease will be determined by adequately powered, randomized, placebo-controlled Phase II and III clinical trials. Cell-based therapies offer yet another approach to therapeutic angiogenesis. Although it is a promising therapeutic strategy, additional preclinical studies are warranted to determine the optimal cell type to be administered, as well as the optimal delivery method. It is likely the optimal treatment will involve multiple agents as angiogenesis is a complex process involving a large cascade of cytokines, as well as cells and extracellular matrix, and administration of a single factor may be insufficient. The promise of therapeutic angiogenesis as a novel treatment for no-option patients should be approached with cautious optimism as the field progresses.     

Bone marrow-derived mononuclear cell therapy for patients with ischemic heart disease and ischemic heart failure

Objective: This meta-analysis aimed to assess whether bone marrow-derived mononuclear cells (BMMNCs) therapy may improve cardiac functional parameters in patients with ischemic heart disease (IHD) or ischemic heart failure (IHF).

Methods: Relevant randomized controlled trials (RCTs) were searched from web databases. Weighted mean difference was calculated for changes in left ventricular ejection fraction (LVEF), left ventricular end-diastolic and end-systolic volumes by using a random effects model.

Results: 13 RCTs met inclusion criteria. Compared with controls, BMMNCs therapy improved LVEF by 3.83% (95% confidence interval (CI): 2.10 – 5.56%; p < 0.0001) in patients with ischemic heart conditions. Notably, in patients with IHF, a more severe clinical condition when compared with IHD, BMMNCs therapy appeared more effective in LVEF improvement. While LVEF increased by 5.67% (95% CI: 3.65 – 7.69%; p < 0.00001) in IHF patients, it only increased by 2.19% (95% CI: 0.37 – 4.00%; p = 0.02) in patients with IHD.

Conclusions: BMMNCs therapy is associated with moderate but significant improvement over regular therapy in LVEF in patients with IHD and IHF. This observation, therefore, supports further RCTs conducting safety and efficiency of BMMNCs therapy with longer-term follow-up.     

The influence of genotype on vascular endothelial growth factor and regulation of myocardial collateral blood flow in patients with acute and chronic coronary heart disease

Abstract

Objective: To test the hypothesis that mutations in the vascular endothelial growth factor (VEGF) gene are associated with plasma concentration of VEGF and subsequently the ability to influence coronary collateral arteries in patients with coronary heart disease (CHD). Methods: Blood samples from patients with chronic ischemic heart disease (n=53) and acute coronary syndrome (n=61) were analysed. Coronary collaterals were scored from diagnostic biplane coronary angiograms. Results: The plasma concentration of VEGF was increased in patients with acute compared to chronic CHD (p=0.01). The genotype frequencies differed significantly from Hardy-Weinberg equilibrium in three of 15 examined loci. Four new mutations in addition to the already described were identified. The VEGF haplotype did not seem to predict plasma VEGF concentration (p=0.5). There was an association between the genotype in locus VEGF-1154 and coronary collateral size (p=0.03) and a significant association between the VEGF plasma concentration and the collateral size (p=0.03). Conclusion: VEGF plasma concentration seems related to coronary collateral function in patients with CHD. The results did not support the hypothesis that polymorphisms in the untranslated region of the VEGF gene were associated with the concentration of circulating VEGF. Increased understanding of VEGF in the regulation of myocardial collateral flow may lead to new therapies in CHD.     

Additive value of adult bone-marrow-derived cell transplantation to conventional revascularization in chronic ischemic heart disease: a systemic review and meta-analysis

Objective: Whether adult bone marrow (BM)-derived cells (BMCs) transplantation benefits patients with chronic ischemic heart disease (IHD) remains controversial. This systemic and meta-analysis study aimed to assess the potential therapeutic effects of BMCs transplantation with revascularization in chronic IHD.

Research design and methods: Randomized controlled trials of BMCs in combination with coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) for chronic IHD were identified by searching Medline, Embase, the Cochrane Controlled Trials Register, the Cochrane Library, and the Web of Science. We conducted a random-effects meta-analysis across eligible studies measuring the same outcomes.

Results: Ten randomized controlled trials including 422 participants were reviewed. In the trials with six months of follow-up, BMCs transplantation improved left ventricular (LV) ejection fraction (LVEF) by 4.02% and reduced LV end-systolic and end-diastolic volumes. Subgroup analysis revealed a statistically significant difference in LVEF associated with primary intervention, route of cell delivery, cell type, and baseline LVEF, but not with cell dose or storage duration.

Conclusions: Selected-BMCs transplantation through myocardial injection after surgical revascularization may benefit patients with chronic IHD and severely impaired LV function. Due to the limitation of patient number, RCT with larger sample size and long follow-up are required for future research.     

基因转导技术治疗心力衰竭的研究进展

慢性心力衰竭（CHF）是构成全球人口发病率和病死率的主要原因,无论在经济方面还是社会方面都给人类带来了巨大的负担。目前,虽然常规治疗方法在降低心力衰竭病死率方面有着稳定和实质性的进展,但是新的药物以及常规心脏外科手术在延长5年生存率方面并没有取得满意的临床效果。基因治疗是在上世纪70年代随着重组DNA技术的发展而引入的。幸运的是,近年来随着基于载体的基因转导策略在动物模型以及初步临床试验中的应用,基因治疗可能会为CHF提供理想的替代治疗方案。20年来,研究者针对心力衰竭基因治疗的不同基因,不同信号转导通路和不同转导方式进行了大量研究。目前CHF基因治疗的主要目的是抑制心肌细胞凋亡,并通过最有效的心肌转染减少不良重塑和增加收缩力。在本文中,将总结多种心力衰竭模型中的基因转导技术,讨论这些转导策略在基于载体介导的心脏基因转导系统中的优势和不足,并着重论述基于外科方法的再循环转导技术。     

Gene therapy for peripheral arterial disease

Introduction: Gene therapy has emerged as a novel therapy to promote angiogenesis in patients with critical limb ischemia (CLI) caused by peripheral artery disease. Researchers working in this area have focused on pro-angiogenic factors, such as VEGF, fibroblast growth factor (FGF) and hepatocyte growth factor (HGF). Based on the elaborate studies and favorable results of basic research using naked plasmid DNA (pDNA) encoding these growth factors, some clinical Phase I and Phase II trials have been performed. The results of these studies demonstrate the safety of these approaches and their potential for symptomatic improvement in CLI patients. However, the Phase III clinical trials have so far been limited to HGF gene therapy. Because one pitfall of the Phase III trials has been the limited transgene expression achieved using naked pDNA alone, the development of more efficient gene transfer systems, such as ultrasound microbubbles and the needleless injector, as well as the addition of other genes will make these novel therapies more effective and ease the symptoms of CLI.

Areas covered: This study reviews the previously published basic research and clinical trials that have studied VEGF, FGF and HGF gene therapies for the treatment of CLI. Adjunctive therapies, such as the addition of prostacyclin synthase genes and the development of more efficient gene transfer techniques for pDNA, are also reviewed.

Expert opinion: To date, clinical studies have demonstrated the safety of gene therapy in limb ischemia but the effectiveness of this treatment has not been determined. Larger clinical studies, as well as the development of more effective gene therapy, are needed to achieve and confirm beneficial effects.     

Cardiovascular magnetic resonance imaging in heart failure

Introduction: Heart failure is a complex clinical syndrome resulting from heart structural remodeling and impaired function in ejecting blood; its incidence is increasing markedly worldwide. The observed variations in the structure and function of the heart are attributable to differences in etiology of heart failure. Cardiac magnetic resonance imaging (CMR) can characterize myocardial tissue, assess myocardial viability, and help diagnose specific cardiomyopathies. The emergence of T1 mapping techniques further improves our knowledge and the clinical assessment of myocardial diffuse fibrosis. Physicians, therefore, must identify the variations using CMR to improve patient’s symptoms, survival, and quality of life.

Area covered: Current reports regarding CMR and the evidence for heart failure diagnosis and therapy as a potential marker of therapeutic response, including low- and high-risk patients, were reviewed. Literature search was performed using PubMed and Google Scholar for literature relevant to CMR, late gadolinium enhancement, T1 mapping, assessment of fibrosis and remodeling, coronary artery, myocardial infarction, heart failure, and its outcomes.

Expert commentary: The authors review current evidence and discuss the potential ability of CMR to guide, diagnose, plan risk strategies, and treat patients with heart failure.     

Impact of atrial fibrillation on levels of high-sensitivity troponin I in a 75-year-old population

Abstract

Purpose. Atrial fibrillation (AF) has been associated with elevated levels of cardiac troponins; however, it is not clear if this association is independent of underlying cardiovascular disease. The aim of this study was to investigate the impact of AF on cardiac troponin I levels in a 75-year-old cohort from the general population, using a recently introduced, highly sensitive assay. Methods. All 75-year-old citizens in Asker and Baerum counties were invited to participate in a prevalence study of AF. High-sensitive troponin I (hs-TnI) levels were measured (Abbott Diagnostics) in serum samples collected from 62 subjects with AF and a gender-matched control group of 126 subjects in sinus rhythm. Results. Hs-TnI was detectable in all subjects (median 7.3 ng/L [range 3.0–88.7]). Patients with AF had higher levels than subjects in sinus rhythm (8.3 ng/L [3.7–88.7] vs. 6.8 ng/L [3.0–77.5]; p = 0.011). Male gender (p = 0.002), hypertension (p = 0.001), coronary heart disease (p < 0.001), heart failure (p < 0.001), prior stroke or transient ischemic attack (p = 0.013) and serum creatinine (p < 0.001) were all associated with higher levels of hs-TnI in univariate analysis. Heart failure and coronary heart disease remained significantly associated with hs-TnI in multivariate analysis, whereas the relation between AF and hs-TnI was no longer statistically significant. Conclusion. All subjects had detectable levels of hs-TnI. AF patients had higher hs-TnI levels than subjects in sinus rhythm; however, this difference was not statistically significant after adjustment for heart failure and coronary heart disease.     

Gene delivery technologies for cardiac applications

Ischemic heart disease (IHD) and heart failure (HF) are major causes of morbidity and mortality in the Western society. Advances in understanding the molecular pathology of these diseases, the evolution of vector technology, as well as defining the targets for therapeutic interventions has placed these conditions within the reach of gene-based therapy. One of the cornerstones of limiting the effectiveness of gene therapy is the establishment of clinically relevant methods of genetic transfer. Recently there have been advances in direct and transvascular gene delivery methods with the use of new technologies. Current research efforts in IHD are focused primarily on the stimulation of angiogenesis, modify the coronary vascular environment and improve endothelial function with localized gene-eluting catheters and stents. In contrast to standard IHD treatments, gene therapy in HF primarily targets inhibition of apoptosis, reduction in adverse remodeling and increase in contractility through global cardiomyocyte transduction for maximal efficacy. This article will review a variety of gene-transfer strategies in models of coronary artery disease and HF and discuss the relative success of these strategies in improving the efficiency of vector-mediated cardiac gene delivery.