Nanomedicine for Ischemic Cardiomyopathy

Progress, Opportunities, and Challenges

Morteza Mahmoudi

• Publisher: Academic Press
• Year: 2020
• Print ISBN:
  9780128174340
• eBook ISBN:
  9780128174357
• Topic: Biological Sciences
• Subtopic: Biology
• Index: Biological Sciences

Nanomedicine for Ischemic Cardiomyopathy: Progress, Opportunities, and Challenges provides an overview on the recent advances in diagnostic and treatment of ischemic cardiomyopathy diseases including myocardial infarction. Shortcomings of the current methods and how nanomedicine can address those obstacles in the field are discussed including the limitations of newly developed cell therapy approaches to clinical translation and how nanomedicine may overcome crucial issues and facilitate the successful and efficient clinical translation of cell therapy. Biomolecular therapy is also explored as another powerful approach for regeneration of heart tissue including available methods and systematic delivery of biomolecules using nanocarriers to the injured part of myocardium through active targeting. Finally, coverage of major tissue engineering advances for myocardial regeneration, including use of epicardial nanostructured patches for regeneration of injured epicardium and the highly conductive patches for enhancing cross talks between the cardiomyocytes, is explored. This concise, yet rigorous coverage, of the field of cardiac nanotechnology outlines the innovative and necessary role of nanomedicine in regenerative medicine for cardiac repair allowing researchers, clinicians, and nanotechnologists to examine the strengths and limitations of current findings and predict future trends to advance the applications of nanotechnology in cardiovascular biomedical research. - Introduces concepts of the unique capacities of cardiac-nanotechnology - Points to potential and promising applications of engineering nanotechnologies on revolutionizing cell therapy and biomolecular therapy approaches for cardiac regeneration - Bridges the knowledge gap between cardiologists and cardiac regenerative nanomedicine experts

Chapter 1

Ischemic cardiomyopathy

Mehdi Mehrani^a; Seyed Hesameddin Abbasi^a; Ahmad Amin^b; Seyed Ebrahim Kassaian^a; Morteza Mahmoudi^{c a} Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
^b Rajaie Cardiovascular, Medical and Research Center, Iran University of Medical Science, Tehran, Iran
^c Precision Health Program, Michigan State University, East Lansing, MI, United States

Abstract

In this section, we will overview a summary of the mechanisms involved in the occurrence and progress of ischemic cardiomyopathy including pathophysiology of the heart failure and the associated roles of stunned and hibernating myocardium. We also briefly discuss how reperfusion process can cause injuries to the myocardium. Ultimately, we will summarize the stages in the development of heart failure and the conventional diagnostic approaches to identify each stage.

Keywords

Stunned myocardium; Hibernating myocardium; Reperfusion injury; Clinical implications of heart failure

Pathophysiology of heart failure

Ischemic cardiomyopathy is the result of pathophysiological conditions disturbing the balance between perfusion and contraction [1]. The main reason for this mismatch between perfusion and contraction is the irreversible loss of the myocardium after myocardial infarction, which leads to myocardial fibrosis and eventually a “remodeling” process [2]. As the initial phase after MI, remodeling results from fibrotic repair of the necrotic area with scar formation, and consequences include thinning and myocyte elongation of the infarcted area. At first, these changes are beneficial and associated with maintaining or even improving cardiac output. However, the remodeling process is driven predominantly by hypertrophic myocyte elongation in the noninfarcted zone.

This cellular rearrangement of the ventricular wall is associated with a significant rise in the LV volume, rendering it less elliptical and more spherical [3], with the magnitude of the remodeling being roughly related to the infarct size [4].

The myocardium consists of myocytes tethered together and supported by a connective tissue network composed largely of fibrillar collagen. The interstitium contains mainly of type I and type III collagen fibers, which are resistant to degradation by most proteases. Some enzymes, including metalloproteinases, have collagenolytic activity. In the wake of myocardial infarction, fibroblast stimulation augments collagen synthesis and begets fibrosis of both the infarcted and noninfarcted regions of the myocardium. In the healthy heart, metalloproteinases are present in their inactive form in the ventricle; however, myocardial injury triggers the activation of these proteases [5] and thus contributes to an increase in the chamber dimension and subsequent processes including myocyte slippage, which is thought to contribute to chamber remodeling [6]. For example, the marked overexpression of MMP-9 after myocardial infarction may be a mediator of collagen accumulation and remodeling [7, 8].

There is an association between progressive heart failure and neurohumoral activation, which may initially be regarded as compensatory but may further the progression of structural abnormalities. For example, the concentration of plasma brain natriuretic peptide (BNP), which has some capacity to protect the failing heart against pathologic remodeling [9], is increased in progressive HF and is positively correlated with prognosis [10]. Another example is angiotensin-converting enzyme (ACE). In several clinical trials, its elevated inhibitors demonstrated improved survival after HF and can slow, and in some cases, even reverse certain parameters of cardiac remodeling [10, 11]. Research has shown that impaired LV function in patients with coronary heart disease is not always irreversible. It is noteworthy that transient postischemic dysfunction is termed “stunned” myocardium, while chronic but potentially reversible ischemic dysfunction due to a stenosed coronary artery is called “hibernating” myocardium.

Pathophysiology of stunned or hibernating myocardium

LV dysfunction is a significant consequence of CAD and can arise from either myocardial ischemia or myocardial infarction [12]. The term “stunned myocardium” was initially used to describe a condition demonstrated in the laboratory in which a total coronary artery occlusion lasting only between 5 and 15 min (a period not associated to cell death) created an abnormality in the regional LV wall motion that lingered for hours or days after reperfusion [13–15]. Consequently, the chief characteristics of the stunned myocardium scenario are short-term, total, or near-total decrease in coronary blood flow; reestablishment of the coronary blood flow; and resultant LV dysfunction of limited duration. In the clinical setting, there is a likelihood of the superimposition of stunned myocardium on ischemia or infarction following the reestablishment of blood flow [16].

The term “hibernating myocardium” denotes a condition in which myocardial and LV functions are persistently impaired at rest, secondary to a chronically diminished coronary blood flow that can be partially or fully restored to the normal state either through augmenting blood flow or by decreasing oxygen demand [17, 18].

Failure to provide timely treatment for hibernating myocardium may lead to progressive cellular damage, recurrent myocardial ischemia, myocardial infarction, heart failure, and ultimately death [19]. In patients undergoing revascularization, the presence of hibernating myocardium foretells an improvement in the chances of survival [20].

A meta-analysis of 24 viability studies on 3088 patients suffering from CAD and LV dysfunction with a mean left ventricular ejection fraction (LVEF) of 32% reported a rate of 42% for the prevalence of hibernating myocardium viability [21].

Reperfusion injury

Myocardial injury in the context of acute myocardial infarction is a consequence of ischemic and reperfusion injury. Reperfusion therapies such as fibrinolysis therapy and primary percutaneous coronary intervention swiftly restore blood flow to the ischemic myocardium and curb infarct size. Unexpectedly, nonetheless, the reestablishment of blood flow can beget additional cardiac damage and complications, referred to as reperfusion injury [22–24].

Reperfusion injury is typified by vascular, myocardial, or electrophysiological dysfunction brought about by the return of blood flow to ischemic tissue. When the blood flow to cardiac myocytes is disrupted by the occlusion of a coronary artery, a series of events results in cellular injury and death.

In the context of acute myocardial infarction, it has been posited that reperfusion injury is responsible for up to 50% of the final myocardial damage [25]. One of the main side effects of reperfusion injury is generation of reactive oxygen species (ROS), which are produced by several processes/pathways involving the myocardium and/or infiltrating inflammatory cells [26–28]. ROS deteriorate vital functions of ...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Contributors
• Chapter 1: Ischemic cardiomyopathy
• Chapter 2: Nanotechnology and nanomedicine
• Chapter 3: Atherosclerosis and thrombosis heart failure
• Chapter 4: Device-based treatment of heart failure
• Chapter 5: Stem cells and heart tissue regeneration
• Chapter 6: Exosomes as natural nanocarriers for therapeutic and diagnostic use in cardiovascular diseases
• Chapter 7: Use of nanoparticulate systems to salvage the myocardium
• Chapter 8: Nanoparticulate systems for monitoring of therapeutic cells
• Chapter 9: Cell-nanoparticle interactions
• Chapter 10: Nanoparticulate systems for delivery of biomolecules and cells to the injured myocardium
• Chapter 11: Nanoparticulate systems for sustained delivery of paracrine factors
• Chapter 12: Nano-bioink solutions for cardiac tissue bioprinting
• Chapter 13: Clinical cardiovascular medicine and lessons learned from cancer nanotechnology
• Index