- Open Access
Molecular pathogenesis of myocardial remodeling and new potential therapeutic targets in chronic heart failure
© Distefano and Sciacca; licensee BioMed Central Ltd. 2012
- Received: 25 June 2012
- Accepted: 26 August 2012
- Published: 12 September 2012
It is well known that the natural history of chronic heart failure (CHF),regardless of age and aetiology,is characterized by progressive cardiac dysfunction refractory to conventional cardiokinetic, diuretic and peripheral vasodilator therapy. Several previous studies, both in animals and humans, showed that the key pathogenetic element of CHF negative clinical evolution is constituted by myocardial remodeling. This is a complex pathologic process of ultrastructural rearrangement of the heart induced by various neuro-humoral factors released by cardiac fibrocells in response to biomechanical stress connected to chronic haemodynamic overload. Typical features of myocardial remodeling are represented by cardiomyocytes hypertrophy and apoptosis, extracellular matrix alterations, mesenchymal fibrotic and phlogistic processes and by cardiac gene expression modifications with fetal genetic program reactivation. In the last years, increasing knowledge of subtle molecular and cellular mechanisms involved in myocardial remodeling has led to the discovery of some new potential therapeutic targets capable of inducing its regression. In this paper our attention is focused on the possible use of antiapoptotic and antifibrotic agents, and on the fascinating perspectives offered by the development of myocardial gene therapy and, in particular, by myocardial regenerative therapy.
- Chronic heart failure
- Myocardial remodeling
- Molecular therapeutic targets
- Myocardial gene and regenerative therapy
Treatment of heart failure has been long based on three main drugs to augment contractile force and lighten the heart’s workload, i.e. cardiokinetics to correct ventricular contractile deficit, diuretics to eliminate hydric-saline retention and vasodilators to reduce increased systemic resistances caused by peripheral vasoconstriction. Hydric-saline retention and vasoconstriction result from the release of adrenergic amines, angiotensin and aldosterone in circulation due to the reflex activation of adrenergic and renin-angiotensin systems triggered off by the drop of intraaortic pressure determined by systolic output reduction [1, 2]. However, this neuro-hormonal response aimed at maintaining peripheral circulatory pressure tone and ensuring vital organs perfusion further jeopardizes myocardial kinesis because it determines volume and pressure overload. Moreover, it explains the utility of diuretic and vasodilatative therapy to restore normal circulation.
Furthermore, the same neuro-hormonal response can also be expressed to a greater degree inside the cardiac muscle and includes, together with catecholamines, angiotensin and aldosterone, other molecules such as endothelin, various proinflammatory cytokines (TNF-α, interleukin-β, interleukin-6) and some myocytic and vascular growth factors. These substances are released by cardiomyocytes after their mechano- receptors stimulation by biomechanical stress linked to chronic pressure and volume hemodynamic overload [6, 7].
One of the salient points in myocardial remodeling is altered cardiac gene expression, i.e. reactivation of fetal cardiac genetic program that can manifest with re-expression of genes that are hyperactive during the fetal period, including the gene of β-myosin (protein at low ATPasic activity poorly efficient in contractile function), some proapoptotic genes, and the gene of α subunit of Na,K dependent ATPase (an enzymatic variant having poor membrane stabilizing capacity). It may also involve inhibition of genes that are hyperactive in the adult heart, such as the genes of the sarcotubular ATPase (enzyme determining calcium reuptake from contractile filaments and hence essential for diastolic function), of β-adrenergic receptors (crucial for systolic activity), and of lipid β-oxidation (the main source of energy for the myocardium whose inhibition turns cardiac energetic metabolism into glycolysis that is poorly efficient for the heart) . In recent studies on cardiac gene expression in various experimental models of cardiovascular diseases associated with heart failure, Kuwahara and Nakao  identified a series of “transcriptional pathways” involved in cardiac remodeling and connected to the reactivation of fetal cardiac genes implicated in the genesis of myocardial hypertrophy and severe cardiac rhythm disorders.
Therefore, remodeling related processes determine marked changes in myocardium phenotype that make it functionally more precarious. These changes include anomalies involving important molecules regulating systolic and diastolic function (as alfa- myosin and sarcotubular ATPase), cytoskeletal proteins and extracellular matrix composition. In the cytoskeleton, enhanced protein filament expression and increased microtubular network density can lead to sarcomere disorganization, while in extracellular matrix, fibroblastic hyperplasia and augmented collagen synthesis with production of rigid type 1 collagen fibrils can reduce ventricular compliance .
The recent advances achieved in the knowledge of molecular pathogenetic mechanisms of CHF have paved the way for new therapeutic approaches aimed at reversing myocardial remodeling and combating apoptotic and fibrotic processes responsible, respectively, for cardiomyocytes loss and myocardial wall rigidity, and thus jeopardizing global heart function.
Use of antagonists of neuro-humoral factors
This strategy represents the first approach to antiremodeling treatment and used antagonists of the various humoral factors(see above) released by cardiomyocytes and involved in myocardial remodeling : i.e. ACE-inhibitors and sartanics for angiotensin; spironolactone and natriuretic peptides for aldosterone; β- blockers for adrenergic amines; direct antagonists (bosentan) for endothelin; monoclonal antibodies and soluble fusion receptors for cytokines [12, 24]. The most commonly used β-blocker is cardvedilol that reduces oxygen requirements by slowing heart rhythm and by decreasing afterload through peripheral vasodilatation. It also possesses an antioxidant action and recovers intrinsic cardiac inotropism by increasing the number of adrenergic receptors and determining overexpression of α-myosin, a protein at high ATPasic activity, in cardiomyocytes [25, 26]. Anticytokines were used mainly against TNF-α which usually presents very high serum concentrations in patients with CHF. Nonetheless, it must be underlined that to date clinical experiences using all these drugs, alone or in combination, are rather fragmentary and the results do not always agree with the benefits found in animal studies. Moreover, it must be kept in mind that there are still no controlled prospective studies confirming long-term efficacy. The results obtained using endothelin antagonists are particularly disappointing , and those using anti-TNFα (both monoclonal antibodies and soluble receptors) are surprisingly modest even if this cytokine represents the most important biochemical marker of inflammatory processes in CHF [28–30]. On the other hand, pentoxfylline, an agent able to downregulate TNF synthesis and induce a wide immunomodulating action and vasodilatation, appears to be a potentially efficient anticytokine . The scarce effectiveness of direct TNF antagonists is probably linked to the multiple biochemical mechanisms causing inflammation in heart failure and to the frequent combination of inflammatory and oxidative events. Hence, in the future better clinical results may be achieved using substances targeting multiple proinflammatory signals. In effect, preclinical trials in rats reported that some substances such as histone deacetylase inhibitors could represent an innovative and very promising class of therapeutic agents thanks to their broad anti-inflammatory spectrum associated to antiapoptotic and antifibrotic properties .
Use of antiapoptotic and antifibrotic agents
The increasing knowledge of the biochemical signals activated during myocardial remodeling have recently focused scientists’ attention on agents that can directly reverse the damaging apoptotic and fibrotic processes that impair heart function [33, 34].
As regards antifibrotic treatment, preclinical studies (in murine models) have frequently shown that fibrosis can be curbed by various substances, such as inhibitors of TGF-β, a growth hormone that stimulates myofibroblasts collagen synthesis  and torasemide. The latter is a loop diuretic capable of inhibiting procollagen type 1 carboxy- terminal proteinase and lysyl oxidase enzymes that play an important role in promoting rigid and insoluble type I collagen fibrils production and deposition [45, 46]. Other useful substances are represented by the inhibitors of some specific micro ribonuleic acids whose overexpression is strictly associated with myocardial fibrosis .
Alongside these measures targeting apoptotic and fibrotic processes, the most noteworthy perspectives in the treatment of CHF are those connected to the development of myocardial gene therapy and myocardial regeneration therapy.
Myocardial gene therapy
In the field of cardiovascular research the potential of gene therapy has been mostly explored in several models of inherited monogenic cardiac diseases. Recent insights concerning the molecular mechanisms and the identification of numerous genes and relative coded proteins involved in the pathogenesis of various acquired heart diseases have extended its application to heart failure.
Myocardial gene therapy consists of an intramyocardial transfer of specific genes for some molecular targets involved in myocardial remodeling through viral (mainly adenovirus) or non viral vectors (plasmids or oligonucleotids). Extensive preclinical studies have shown that this therapeutic approach is able to modulate calcium homeostasis in cardiac myocytes, manipulate adrenergic receptors related biochemical signals and increase cardiomyocytes resistance to apoptosis. The results of these studies foresee the potential of a “molecular ventricular assistance” in the failing heart .
Over the last few years, recent advances in myocardial gene therapy include improved vectors provided with greater trophism for myocardial cells and more efficient delivery methods, and have paved the way for translating experimental observations into therapeutic strategies in humans [49, 50]. The first clinical trial targeting sarcoplasmic endoplasmin reticulum calcium ATPase (SERCA2a) was initiated after a satisfactory phase 1 study. This enzyme plays a crucial role in regulating calcium cycling (and hence modulating cardiac contractility) and is downregulated in CHF . The SERCA2a gene was transferred via a recombinant adeno-associated virus vector in 39 patients with advanced CHF utilizing percutaneous intracoronary infusion as delivery method . Recently, the results of this trial have conclusively shown positive biological outcome of the patients and have clearly demonstrated that SRCA2a is an important therapeutic target in CHF . At present, clinical experimentation includes two other on-going trials targeting SERCA2a in the United Kingdom and in France and some targeting adenylyl-cyclase (AC6 isoform), an enzyme activated by beta-adrenergic receptors stimulation that plays an important role in cardiac inotropism and is downregulated in the failing heart .
Whether also the results of these studies confirm the clinical efficacy and safety of the treatment and other molecular targets (specially antiapoptotic signals) susceptible to gene manipulation will be successfully explored  in the near future, myocardial gene therapy will certainly represent a viable and important tool to improve cardiac performance in patients with CHF.
Myocardial regenerative therapy
If all these extremely important experimental observations are confirmed by further studies, and if they can be reproduced in humans, in all likelihood intramyocardial delivery of a cocktail of natural and synthetic trophic substances capable of interacting positively in cardiac remodeling and myocardial regeneration can become the treatment of choice in CHF in the near future. Moreover, it may be the only therapy that can overcome the need for heart transplant that today represents the last chance for the survival of patients with this very severe disease. Finally, the combination of myocardial gene and regenerative therapy may achieve even better results.
The authors would like to thank Mr N. Bonanno for his technical collaboration.
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