**1. Introduction: cardiomyopathies**

Cardiomyopathies (CMs) refer basically to diseases of the heart muscle, which can be acquired or inherited [1]. CMs can affect people of all ages. However, people in certain age groups are more likely to have certain types of CMs, as inherited forms predominate in younger individuals and acquired diseases increase with age [2–8].

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Most frequently, four main clinical forms are described, meaning hypertrophic, dilated, and restrictive types as well as arrhythmogenic CM. These diseases have many causes, signs, symptoms, and treatments. We exclude ischemic cardiopathies from this overview, and focus more precisely on disorders of the heart muscle of non-ischemic origin. This does, however, not exclude anomalies of the perfusion of the myocardium, because pathophysiology of these diseases is usually complex, interleaving different mechanisms.

Myocardial remodelling involves not only the cardiomyocytes, but also non-myocyte cells and the extracellular matrix. Fibrosis is an essential process in the repair of damaged tissues and wounds, but its accumulation in organs and tissues can lead to scarring, organ dysfunction, and, ultimately, failure. Development of interstitial and perivascular fibrosis of varying degrees is observed in most CMs. However, *in vivo* diagnosis of the extent and distribution of fibrosis remains difficult. New approaches such as ultrasound elastographic and cardiac NMR techniques might provide appropriate outcome measures to monitor more specifically

Gene Therapy for Cardiomyopathies http://dx.doi.org/10.5772/intechopen.80478

Immune mechanisms modulate interstitial fibrosis, cardiomyocyte cell death, and hypertrophy, all of which are central processes leading to maladaptive remodelling in response to a variety of stimuli. Acute inflammation, as observed in myocarditis, might be out of the scope of the present overview, and would need a dedicated review. However, in chronic heart failure (CHF) patients, a chronic inflammatory activation has long been recognized. Heart failure is associated with a wide array of mechanisms subsumed under the term "inflammation." This chronic inflammation harms the myocardium instead of healing it. Gene therapy might

Similarly to the structural modifications of the myocardium, functional alterations contribute to the definition of CM. From a perspective of pathophysiology, alterations of preload and afterload largely contribute to diastolic/systolic dysfunctions. Pressure–volume relationship

Moreover, a more detailed understanding of excitation–contraction coupling reveals new

Furthermore, and beyond the triggering causes of CM, as heart muscle becomes weaker over time, a common clinical condition described as heart failure develops. From a pathophysiological and therapeutic perspective, heart failure could be considered as a specific disease stage, independent of the acquired or inherited origin of CM. Gene therapy could also be

Many medicines are used to treat CM and CHF, but despite this, CM and CHF remain leading causes of morbidity and mortality even in developed countries. Correcting hemodynamic imbalances, such as fluid control (preload) or vascular resistance control (afterload), remains primordial, but cannot change the myocardial contractility *per se* (**Figure 1**). Fundamentally, determinants of cardiac output are the same as those of myocardial energy consumption. Therefore, tackling the problem of decreased contractility raises in parallel the problem of increased energy requirements. Several attempts to increase inotropism on a chronic basis led to overall negative results because energy consumption exceeded production. Gene therapy might offer new therapeutic options. The pressure–volume relationship demonstrates the contracting and relaxing portions of the cardiac cycle (**Figure 2**). The slope of the end-systolic

best defines myocardium alteration beyond the hemodynamic parameters.

myocardial fibrosis, and thus potential therapeutic effects [16].

find new therapeutic targets in this context.

targets for innovative therapeutic strategies.

**2. Therapeutic options: why gene therapy?**

considered at this stage.

Diagnosis of non-ischemic CM is a challenging process that influences patient morbidity and mortality. Multiple biomarkers and imaging tools contribute to the adequate ranking of the clinical presentation of these diseases. More recently, nuclear magnetic resonance (NMR) imaging appeared as a robust diagnostic tool that offers various techniques to assess the structure, function, perfusion, and scarring of myocardial tissue, thus providing better understanding of the underlying causes of CMs [9–12]. At a molecular level, genotyping identifies precisely the causal mutations in inherited forms of CMs. Moreover, a systems biology approach can investigate more fully the molecular profiles of different phenotypic stages of CM.

From a pathophysiological and diagnostic perspective, it might be useful to consider a stratification of CMs slightly different from the clinical classification. Considering the various genes that can trigger the development and evolution of a CM, we propose to group inherited diseases as cytoskeletal CMs or cytoskeletalopathies, sarcomeric CMs or sarcomyopathies, and finally ion channel CMs or channelopathies.

Different structural alterations of the myocardium contribute in varying degrees to the different forms of the diseases, but common features may represent as many therapeutic targets.

The focus of more extensive cellular degeneration is one of the histological hallmarks of CM [13,14]. Necrosis is not the only mechanism leading to cell death. Apoptosis, or programmed cell death, is a highly regulated and active process that contributes to the maintenance of adult cardiac tissue [15]. Myocyte cell death is implicated in the architectural rearrangement occurring in the surviving myocardium. This remodelling leads to heterogeneity in the myocardial structure, created by the altered behaviour of non-myocyte cells, particularly cardiac fibroblasts, which are responsible for myocardial collagen metabolism and fibrous tissue accumulation. It may largely explain the appearance of diastolic and/or systolic myocardial failure [15]. Adverse left ventricular remodelling leads to alteration in the structure (dimension, mass, shape) of the heart that might at the beginning of the process be considered as compensatory for the disease process, but at the end will severely impair cardiac function. Remodelling is also a prominent feature of electrophysiological properties of the myocardium, translated as clinical presentation such as atrial fibrillation, flutter, complete heart block, ventricular ectopic pacing, and tachycardia.

Considering the remodelling process as a deleterious end effect, one can raise the question of potential reverse remodelling. Could that be an option for remission or cure of CM? It has been shown that prolonged mechanical unloading of failing hearts can preserve myocardial contractility but impairs relaxation. Could gene therapy provide new therapeutic options for those patients?

Myocardial remodelling involves not only the cardiomyocytes, but also non-myocyte cells and the extracellular matrix. Fibrosis is an essential process in the repair of damaged tissues and wounds, but its accumulation in organs and tissues can lead to scarring, organ dysfunction, and, ultimately, failure. Development of interstitial and perivascular fibrosis of varying degrees is observed in most CMs. However, *in vivo* diagnosis of the extent and distribution of fibrosis remains difficult. New approaches such as ultrasound elastographic and cardiac NMR techniques might provide appropriate outcome measures to monitor more specifically myocardial fibrosis, and thus potential therapeutic effects [16].

Immune mechanisms modulate interstitial fibrosis, cardiomyocyte cell death, and hypertrophy, all of which are central processes leading to maladaptive remodelling in response to a variety of stimuli. Acute inflammation, as observed in myocarditis, might be out of the scope of the present overview, and would need a dedicated review. However, in chronic heart failure (CHF) patients, a chronic inflammatory activation has long been recognized. Heart failure is associated with a wide array of mechanisms subsumed under the term "inflammation." This chronic inflammation harms the myocardium instead of healing it. Gene therapy might find new therapeutic targets in this context.

Similarly to the structural modifications of the myocardium, functional alterations contribute to the definition of CM. From a perspective of pathophysiology, alterations of preload and afterload largely contribute to diastolic/systolic dysfunctions. Pressure–volume relationship best defines myocardium alteration beyond the hemodynamic parameters.

Moreover, a more detailed understanding of excitation–contraction coupling reveals new targets for innovative therapeutic strategies.

Furthermore, and beyond the triggering causes of CM, as heart muscle becomes weaker over time, a common clinical condition described as heart failure develops. From a pathophysiological and therapeutic perspective, heart failure could be considered as a specific disease stage, independent of the acquired or inherited origin of CM. Gene therapy could also be considered at this stage.
