Drug and Cell-Based Therapies to Reduce Pathological Remodeling and Cardiac Dysfunction After Acute Myocardial Infarction

摘要

Remarkable advances have been made in the treatment of cardiovascular diseases (CVD), however, CVD still accounts for the most deaths in industrialized nations. Ischemic heart disease (IHD) can lead to acute coronary syndrome (ACS) (myocardial infarction [MI]). The standard of care is reperfusion therapy followed by pharmacological intervention to attenuate clinical symptoms related to the MI. While survival from MI has dramatically increased with the implementation of reperfusion therapy, these individuals will inevitably suffer progressive pathological remodeling leaving them predispose to develop heart failure (HF). HF is a clinical syndrome defined as the impairment of the heart to maintain organ perfusion at rest and/or during times of exertion (i.e. exercise intolerance). Clinically, this is accompanied by dyspnea, pulmonary or splanchnic congestion and peripheral edema. Physiologically, there is neurohormal activation through the classical beta--adrenergic and PKA--dependent signaling cascade to maintain cardiac output (CO) and mean arterial pressure (MAP). Overtime, the heart becomes desensitized or increases negative feedback loops which alter beta--adrenergic increases in contractility. Presently the only solution for HF is cardiac transplantation. All other interventions either attenuate the symptoms, slow the progression of disease or offer a bridge to transplant. Novel strategies to improve cardiac pump function and inhibit pathological remodeling are necessary to reduce the number of patients who suffer from HF. The overarching theme of this dissertation is to investigate novel therapeutic strategies to combat episodic/ acute decompensation (ADHF) or alter the pathological remodeling observed after ischemia--reperfusion (I/R). We performed studies which looked at two separate and distinct novel treatment strategies.;First, we investigated the therapeutic potential of a novel positive inotrope, ruboxistaurin (RBX), which inhibits protein kinase C, a negative regulator of contractility in models and patients with HF. We wanted to establish structural and functional abnormalities that are consistent with patient who present with HF with reduced ejection fraction (HFrEF) secondary to MI; then compared RBX to a more well established positive inotrope, dobutamine (DOB), and looked at functional, cellular and molecular changes within the myocardium. This allowed us to comprehend whether or not RBX was more efficacious when compared to a standard of care treatment strategy for those who present with ADHF. We demonstrate that after MI there is progressive pathological remodeling observed through ventricular dilation, reduced contractility and less contractile reserve when administered DOB as compared to pre--MI. When we administered RBX there were distinct advantages to utilizing this pharmacological agent in comparison to DOB. RBX too increased contractility as observed through hemodynamic parameters but also reduced LV capacitance, through an observed shift in the EDPVR. Furthermore, RBX altered PKCalpha activity, yet had no effect on phospholamban (PLN) phosphorylation, a major downstream target of classical PKA--dependent signaling. These data confirmed that RBX is a PKA--independent strategy to increase contractility in a large animal model of early stage HF. While safe and seemingly efficacious, if we could create novel therapeutics which would inhibit or reverse pathological remodeling which leads to HF we could revolutionize the way patients are treated when they present with an MI. This is the strategy we used in our second treatment, utilizing a novel stem cell population from the cortical bone to alter pathological remodeling post MI in a preclinical large animal model.;Our hypothesis consists of the idea that if we can alter the initial reperfusion injury, that it will change the trajectory of structural and functional abnormalities observed post MI. We performed an MI in a large animal model, which we previously describe develops a HFrEF phenotype. Immediately following MI, we deliver cortical bone stem cells (CBSCs) or vehicle, in a blinded, randomized fashion, through transendocardial injection using the NOGA MYOSTAR RTM catheter. We then followed the animals for 3 days, looking at alterations to initial injury and cell retention, and at 3 months, giving the model time to develop characteristics of HF. Our results clearly demonstrate no change in initial injury with CBSC treatment and that the cells are retained for at least 72hrs. At 3 months' post MI, there was preserved EF, and increased cardiac systolic reserve with a DOB stress response. A reduction in scar size and compensatory hypertrophic response, at the cellular level, was observed with CBSC treatment too. While the mechanism of action needs to be studied further, we believe that the CBSCs modulate the inflammatory response which occurs upon reperfusion therapy.;Collectively, the data presented in this dissertation provide comprehensive evidence that (1) PKCalpha activity is increased with disease burden, and thus is one mechanism for reduced contractility after MI; and that inhibition of PKCalpha, with RBX, increases contractility, reduces LV capacitance without alteration of classical beta--adrenergic and PKA--dependent signaling. (2) That cell--based therapy, immediately post MI, preserves cardiac structure and functional reserve after acute MI, potentially through immune--modulation, altering pathological remodeling and inducing proliferation of endogenous myocytes. Elucidating and investigating novel targets and therapeutic strategies, such as these, in a large animal model, is important for translating these treatments to patients who suffer from IHD, leading to pathological remodeling and cardiac dysfunction associated with acute MI, which subsequently manifest itself as HFrEF.