Transplantation of skeletal myoblast in ischemic heart disease 2

CHAPTER I INTRODUCTION SECTION I ISCHEMIC HEART DISEASE 1.1.1 Introduction to Ischemic Heart Disease Ischemic heart disease (IHD) is receiving a continuously growing interest because of the increased prevalence and incidence. In USA, based on Heart Disease and Stroke Statistics Updates 2006, American Heart Association, the prevalence for IHD in 2003 was around 13,200,000. The incidence of IHD is around an estimated 1,200,000/year, with approximately 700,000 new and 500,000 recurrent cases. It is estimated that an additional 175,000 cases of silent first heart attack occur each year. In Singapore, IHD ranks the 3rd most prevalent cause of hospitalization (3.7% in total hospitalizations) according to statistics from Ministry of Health, Singapore. The magnitude of the problem is expected to be even further amplified in the forthcoming years because of the aging population and paradoxically, the improved postinfarction survival rates resulting from recent pharmacological and interventional treatment. IHD is mainly caused by atherosclerosis, a process in which fatty deposits (atheroma) accumulate in the cells lining the wall of the coronary arteries. When more than 50% of the luminal diameter decreases (75% decrease of luminal area), it results in ischemia. Complete occlusion of the blood vessel results in a myocardial infarction (MI), characterized by compromised coronary blood flow, massive cardiomyocyte death and impaired left ventricle contractile function. Based on the 44 year follow-up of the National Heart, Lung, and Blood Institute’s Framingham Heart Study, IHD -1- remains the leading cause of congestive heart failure (CHF).When patients with IHD also have an IHD-leading CHF, it is described as ischemic cardiomyopathy. The pathophysiology that follows an IHD and eventually leads to ischemic cardiomyopathy is very profound. Initially, there is a massive death of cardiomyocytes because of acute, severe ischemia. In the acute setting, loss of cardiomyocytes reduces overall ventricular pump function. This reduces blood pressure and cardiac output, which activates sympathetic nervous system as well as the rennin-angiotensin-aldosterone system. In the short term, these factors attempt to restore cardiac output and blood pressure. However, if sustained, neurohormonal activation and increased mechanical stresses conspire in a maladaptive process. Within the healing infarct area, ischemia resistant fibroblasts are recruited and eventually replace the dead cardiomyocytes, leading to areas of fibrosis. Unfortunately, this process does not improve any heart contract function. In an attempt to compensate for the decrease of the heart function, a process so called cardiac remodeling occurs. Importantly, in the post infarct heart, the remodeling process affects not only regions of infarction but also previous normally perfused myocardium. The situation can be even worse in ischemic cardiomyopathy because non-infarcted regions can be supplied by stenosed coronary arteries so that active myocardial ischemia can influence the remodeling process. In this process, compensatory mechanism in response to a loss of functioning contractile units includes cardiomyocyte hypertrophy and elongation, extracellular matrix exchanges, and subcellular remodeling etc. However, none of them regenerates contractile tissue and further compensates for the heart performance. -2- 1.1.2 Current Status on IHD Treatment Therapeutic interventions for IHD include behavioral and dietary modifications, pharmacological therapies (including anti-platelet agents, nitrates, β-blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and calcium channel blockers etc), and invasive revascularization procedures such as coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI). Although significant advances have reduced the mortality of IHD, the number of cardiac interventions continues to grow. In 2003, a total of 1.4 million inpatient cardiac revascularizations, 664,000 PCI procedures and 467,000 CABG procedures were performed in USA alone (Heart Disease and Stroke Statistics Updates 2006, American Heart Association). PCI is the most common treatment option for single vessel disease as well as simple multi-vessel disease. However, high rate of restenosis is still a major disadvantage and limits the application in selected cases. Most recently, the development of drug-eluting stents seems to solve the problem of recurrent restenosis. CABG is mostly recommended for patients with complex and life threatening IHD. The in-hospital mortality rate for CABG is 1-3% at many institutes. Despite the risk of vein graft failure, it remains the only form of therapy that has been shown to improve the life expectancy of patients with severe IHD. However, though various effective treatments are available, IHD remains a leading cause of death worldwide. IHD caused one of every five deaths in the United States in 2003. For those NYHA class patients, the mortality is still unacceptably high at 60%/year (The Journal of the American Medical Association). In Singapore, IHD stands the -3- 2nd contributing cause of death (18.1% in total deaths). The prevalence and the mortality of the disease are calling for new approaches in the treatment of IHD. 1.1.3 No-option Patients: a Target Population for Cell Therapy PCI and CABG are effective at relieving symptoms and improving outcomes in patients with IHD. However, some patients with symptomatic IHD are no longer candidates for PCI or CABG, or have exhausted or failed these modalities. A significant number of patients (5-21%) with ischemic heart disease are not optimal candidates for revascularization (PCI/CABG, McNeer et al.1974; Jones et al. 1983; Atwood et al. 1990; Feyter PJ 1992; Mukerjee et al. 1999), and many have residual angina despite maximal medical therapy. A recent study of 500 patients at Cleveland Clinic showed that about 12% patients (59 cases) were considered ineligible for revascularization (Mukherjee et al. 2001). The different estimates of the magnitude of the problem may be attributed to wide regional and institutional variability in treatment patterns of coronary disease including more or less aggressive revascularization practices. The conditions resulting in no-option status include recurrent in-stent restenosis, prohibitive expected failure, chronic total occlusion, poor targets for CABG/PCI, saphenous graft total occlusion, degenerated saphenous vein grafts, no conduits aorta, and comorbidities etc (McNeer et al.1974; Jones et al. 1983; Atwood et al. 1990; Feyter PJ 1992; Mukerjee et al. 1999; Mukherjee et al. 2001). However, no-option patients are a heterogeneous group there are two different clinical patterns in this population. The first group includes patients with a substantial -4- amount of viable myocardium, in whom angina is the predominant symptom (Rizzello et al. 2004; Di Carli et al. 1998). On the other hand, the second group includes patients with limited or no myocardial viability, in whom heart failure symptoms predominate. This group has a poorer response to increased myocardial perfusion (Rizzello V et al. 2005). The current management strategies for these patients are limited. The treatment of these patients is also a moving target since advances in interventional and surgical techniques have helped improve their quality of life. In addition, the development of various procedures such as endovascular cardiopulmonary bypass (Reichenspurner et al. 1998), rotational atherectomy for calcified undilatable lesions (Madina et al. 2003), and distal protection for vein graft interventions (Lev et al. 2004) has made possible the treatment of many patients previous deemed to be no-option. Thus before the definition of patients with nooption, consideration of advanced intervention is warranted. If all these options are exhausted, then patients are deemed truly without any options and alternative treatment strategies are needed. 1.1.4 Patients with End-stage Ischemic Cardiomyopathy: Another Target Population for Cell Therapy In the setting of ischemic cardiomyopathy, profound cardiac remodeling occurs, which affects not only regions of infarcted myocardium, but also normally perfused myocardium. The impact is really broad, affecting molecular, biochemical, metabolic, cellular, extracellular matrix and ventricular structural characteristics. This process is driven by increased mechanical stresses, in the form of increased preload and -5- afterload, as well as abnormally elevated levels of cytokines and neurohormones. Different from mechanism of normal heart failure, ischemic cardiomyopathy has large quantity of cardiomyocyte loss and severely impaired heart function. It is not surprising that treatment of these patients with medical management alone is dismal, especially those with advanced cardiac dysfunction (ejection fraction [EF] [...]... applied in patients with acute MI (Strauer et al., 20 02; Assmus et al., 20 02; Britten et al 20 03; Schachinger et al 20 04; Fernandez-Aviles et al 20 04; Kuethe et al 20 04; Wollert et al 20 04), myocardial ischemia without revascularization (Hamano et al 20 01; Tse et al 20 03; Fuchs et al 20 03; Perin et al 20 03; Perin et al 20 04), and ischemic cardiomyopathy (Stamm et al 20 03; Stamm et al 20 04; Assmus et al 20 04)... remodeling of the remote, non-infarcted heart (Mangi et al., 20 03; Shake et al., 20 02) Moreover, cultured MSCs secreted angiogenic cytokines, which improved collateral blood flow recovery in a murine hind limb ischemic model (Kinnaird et al., 20 04) As MSC clones have been reported of a low immunogenicity, they might be applied in allogeneic transplantation in future clinical studies (Pittenger et al., 20 04)... electromechanical mapping (Smits et al, 20 02) This approach allows delivering cells parallel to the ventricular wall and deep into the injured myocardium However, positioning of the injection catheter in a specific coronary vein is technically more challenging as it has restrictions associated with the tortuosity of coronary veins and lack of site-specific targeting (Siminiak et al 20 04) 1 .2. 2.3 Transvascular... technique is mainly applied in the treatment of recently injured myocardium due to highly expressed chemoattractants and cell adhesion molecules (Barbash et al., 20 03; Kawamoto et al., 20 01) 1 .2. 2.3.1 Intravenous Infusion Intravenous infusion of stem cells seems a promising approach for practical and economical reasons, since it is the least invasive way of delivering cells Intravenously infused stem... application in a recent study in postAMI patients (Wollert et al., 20 01) Additionally, since the technique relys on physiologic homing signals, it would be most applicable after AMI and less useful for treating chronic myocardial ischemia 1 .2. 2.3 .2 Intracoronary Artery Infusion Intracoronary injection allows homogeneous homing of cells into areas bordering the infarction zone It is the most popular mode of. .. et al 20 01 Rat Jain et al 20 01 Rat Gulbins et al 20 02 Dib et al 20 02 Ghostine et al 20 02 30 days Rat Ligation Autologous SkMs Zhong et al 20 03 Dog Ligation Autologous SkMs IM 8 weeks Tambara et al 20 03 Rat Ligation Neonatal SkMs IM 4 weeks Haider et al 20 04 32 Al Attar et al 20 03 IM IM Pig Ligation Xeno- SkMs IM 7months Suzuki et al 20 04 Mouse Normal Allogeneic SkMs IM 72hours 1year Grafted myoblasts... treating chronic ischemia (Wang et al., 20 05; Boyle et al., 20 05) Further, safety concerns should be always attended because of concern about tumorigenesis (Boyle et al., 20 05) 1 .2. 2 .2 Direct Intramyocardial Injection Intramyocardial injection, injected through the epicardium, endocardium, or coronary vein, has been performed in chronic myocardial ischemia (Herreros et al., 20 03; Dib et al., 20 05; Siminiak... 20 04) However, the homing process of 26 injected stem cells solitarily to the targeted organ needs to be investigated in detail The risk of side effects from homing to non-cardiac organs limits the clinical applicability of this approach (Barbash et al., 20 03; Nagaya et al., 20 04) Indeed, significant myocardial homing of unselected BMCs was observed only after intracoronary delivery but not after intravenous... to optimize the benefits of this procedure 1 .2. 2 .2. 1 Transepicardial injection 23 Transepicardial delivery of stem cells is the most commonly used technique in cardiac stem cell therapy Cells are injected into infarct border zones or areas of infarcted/scarred myocardium under direct visualization (Herreros et al., 20 03; Dib et al., 20 05; Siminiak et al., 20 04; Pagani et al., 20 03), which performs as... catheters By 27 intracoronary approach, unselected BMCs, HSCs, and MSCs have been delivered to patients with AMI and ischemic cardiomyopathy (Fernández-Avilés et al., 20 04; Siminiak et al., 20 03; Strauer et al., 20 01; Strauer et al., 20 02; Assmus et al., 20 02; Britten et al., 20 03; Schachinger et al., 20 04; Kuethe et al., 20 04; Wollert et al., 20 04; Chen et al 20 04; Vanderheyden et al 20 04) However, . - CHAPTER I INTRODUCTION SECTION I ISCHEMIC HEART DISEASE 1.1.1 Introduction to Ischemic Heart Disease Ischemic heart disease (IHD) is receiving a continuously growing interest because of the increased. orthotopic heart transplantation (Müller et al., 20 02; Quanini, et al., 20 02) , or myocardial infarction (D. Orlic, et al., 20 01; Beltrami et al, 20 01), and even surmising the existence of resident. prevalence and incidence. In USA, based on Heart Disease and Stroke Statistics Updates 20 06, American Heart Association, the prevalence for IHD in 20 03 was around 13 ,20 0,000. The incidence of IHD is