Therapeutic Potential of c-Myc Inhibition in the Treatment of Hypertrophic Cardiomyopathy

Abstract

Investigating the pathophysiological importance of the molecular and mechanical development of cardiomyopathy is critical to find new and broader means of protection against this disease that is increasing in prevalence and impact. The current available treatment options for cardiomyopathy mainly focus on treating symptoms and strive to make the patient more comfortable while preventing progression of disease and sudden death. The proto-oncogene c-Myc (Myc) has been shown to be increased in many different types of heart disease, including hypertrophic cardiomyopathy, before any signs of the disease are present. As the mechanisms of action and multiple pathways of dependent actions of Myc are being dissected by many research groups, inhibition of Myc is becoming an attractive paradigm for prevention and treatment of cardiomyopathy and heart failure. Elucidating the role Myc plays in the development, propagation and perpetuation of cardiomyopathy and heart failure will one day translate into potential therapeutics for cardiomyopathy.

Introduction

Cardiomyopathy is a general term for a large group of complex and heterogeneous conditions characterized by disease of the heart muscle. While classification of this group of conditions is challenging, and no single system is entirely comprehensive, based on gross changes, three major types of cardiomyopathies (i.e. dilated, restrictive and hypertrophic) have been widely reported and studied.

First, in spite of having many different causes, dilated cardiomyopathy (DCM) follows a disease process where cardiomyocytes become injured which decreases the heart's contractility [Dec and Fuster, 1994]. To compensate, the ventricular chambers enlarge without increasing ventricle wall size which increases the preload of the ventricles. This in turn increases the contractile force of the heart. When dilation occurs beyond a certain point, the contractions begin to weaken due to the increases in sarcomere length and less actin—myosin overlap and cross-bridge formation. The heart continues to enlarge and the patient eventually develops the signs and symptoms of congestive heart failure (CHF), angina, thromboembolic events and arrhythmias [Dec and Fuster, 1994]. The incident rate is 0.4 per 1000 people and the prognosis of DCM is fairly bleak with a 70% 5-year mortality rate [Goldberger et al. 2008].

Restrictive cardiomyopathy (RCM) also follows a similar disease course. An increase in either infiltrates or abnormal depositions cause a decrease in myocardial compliance. This decrease in compliance causes a significant increase in end diastolic pressure which results in increased systemic and pulmonary pressures [Kushwaha et al. 1997]. Patients with these conditions are at higher risk of thromboembolitic events and the treatment options for RCM are insufficient. In general, only anticoagulation therapy, conservative diuretic use, heart rate control and ultimately transplant are currently offered for treatment of RCM. Medications used to reduce cardiomyocyte workload such as angiotensinconverting enzyme (ACE) inhibitors are avoided in RCM due to the risk that they could cause an unsafe drop in blood pressure. Discouragingly, RCM has a 5-year mortality rate of 30% [reviewed by Zangwill and Hamilton, 2009].

Finally, hypertrophic cardiomyopathy (HCM) is characterized by hypertrophy of the left ventricle and is commonly associated with either a sporadic or familial autosomal dominant mutation in sarcomeric genes [Braunwald et al. 2002]. These mutations cause myocardial fiber disarray and hypertrophy [St John Sutton et al. 1980] which can lead to diastolic dysfunction, mitral regurgitation, ischemic disease and, most importantly, outflow obstruction. Patients can present with sudden death due to either cardiovascular collapse secondary to outflow obstruction or fatal arrhythmias. Other symptoms include diastolic heart failure and angina [Braunwald et al. 2002]. The treatment of HCM consists of beta blockers, calcium channel blockers, implantable cardiac defibrillator and avoidance of extreme exertion or dehydration. HCM is rather common, affecting up to 1 in 500 people; however, the prognosis of HCM is better than related cardiomyopathies with an annual mortality rate of 0.5-3.6% with the risk of sudden death of 1-2% [Agarwal et al. 2004].

Cardiomyopathy can be genetically inherited and usually presents as a mutation in contractile proteins. Idiopathic cardiomyopathy results from other risk factors such as smoking and alcohol use and comorbidities such as hypertension, diabetes and being overweight [Vasan et al. 1995]. For many patients, cardiomyopathy ultimately ends in CHF which presents with symptoms of low cardiac output, congestion, edema, paroxysmal nocturnal dyspnea, fatigue, gastrointestinal discomfort and orthopnea [Jessup et al. 2009]. The main goals of current treatments and therapies are to minimize those symptoms and discomfort. This is achieved through the use of diuretics which reduce edema through modulating ion channels and decreasing water reabsorption in the kidneys, nitrates that relax vascular smooth muscle cells and decrease myocardial oxygen demand, beta blockers that increase adrenergic receptor coupling and decrease apoptosis, and ACE inhibitors or angiotensin II receptor blockers (ARBs) which both act to block the angiotensin II pathway and decrease hypertrophy and fibrosis [Hunt et al. 2009].

Currently, treatments focus on reducing symptoms of cardiomyopathy; however, multiple pathways and molecules are disrupted or dysfunctional and may provide additional targets for therapy. In addition to the known contractile gene mutations, pathways such as the cell cycle and apoptosis have been shown to be altered in the hypertrophic response and repair processes of cardiomyopathy, and genes important in development such as c-Myc (Myc) are re-expressed and upregulated [Starksen et al. 1986]. Myc has been found to be increased in both physiologically relevant hypertrophy such as during chronic exercise and pregnancy and also in pathological hypertrophy, prevalent in HCM when the heart enlarges to compensate for an increase in pressure overload caused by hypertension or aortic stenosis [Trenerry et al. 2007; Sole and Liew, 1988].

The proto-oncogene and transcription factor, Myc, has been shown to play a role in cardiomyogenesis, cell cycle re-entry, apoptosis, angiogenesis and oxidative stress response via mitochondrial activation [Nieminen et al. 2007]. Myc has been implicated to play an important role in initiation and maintenance of hypertrophy and cardiac contractility [Lee et al. 2009; Xiao et al. 2001]. In addition to cardiomyopathy, Myc has been implicated in several comorbidities associated with cardiomyopathy and heart failure, namely cancer and diabetes, making Myc an important candidate in new therapeutic targets of cardiomyopathy [Yusuf et al. 2008; Riu et al. 1996].

Treating the clinical symptoms and improving the quality of life in patients with HCM is important but it is equally important to study and characterize the molecular mechanisms of HCM because the development of new and more efficient therapeutic strategies aimed at targets implicated in pathogenic initiation and maintenance of myocardial growth and dysfunction are urgently required.

History of hypertrophic cardiomyopathy

Cardiomyopathy, a disease of the heart muscle, was first clinically diagnosed in 1958 [Maron et al. 2008], but the recognition of hypertrophy, the enlargement of cardiomyocytes by growth and not cell division, came from as early as the late 1600s when Theophile Bonet (1620–1689), John Baptiste Morgagni (1682–1771) and Giovanni Maria Lancisias (1654–1720) described many large hearts at postmortem after sudden deaths. Lancisi also was the first to describe hereditary patterns in cardiac disease [White and Boursy, 1971; Lancisi, 1728]. Ultimately, the credit of putting all of the puzzle pieces of HCM together goes to Donald Teare, a London pathologist who, in his 35-year career, collected many cases and published his findings in an article in British Heart Journal [Teare, 1958]. Along with contributions from Eugene Braunwald, HCM is described as a primary disorder of the myocardium that is characterized by unexplained hypertrophy in a nondilated ventricle [Maron et al. 2009]. Historically, the symptoms of cardiomyopathy were treated with digitalis and mercurial diuretics, but over the past 50 years advances in cardiology have included transplantation, cardiac catheterization, bypass surgery, electrophysiology and imaging, all of which contribute to the diagnosis and treatment of cardiomyopathy [Coats and Hollman, 2008]. Major advances preventing sudden death include the invention of the implantable cardiac defibrillator and dual-chamber pacing [Maron et al. 2000; Nishimura et al. 1996]. In addition, advances in genetics allowed mapping of the first gene locus for HCM to chromosome 14 [Jarcho et al. 1989] and identification of the multiple mutations in contractile genes. The advent of genetic screening allows for early identification and diagnosis of individuals at greatest risk for developing HCM and has focused on β-myosin heavy chain (MHY7), myosin-binding protein C (MYBPC3), cardiac troponin type 2 (TNNT2), cardiac troponin I type 3 (TNNI3) and tropomyosin I (TPM1) [Fokstuen et al. 2008; Erdmann et al. 2003; Mohiddin et al. 2003; Richard et al. 2003].

Current clinical treatments for hypertrophic cardiomyopathy

Current treatment of HCM and the sometimes resulting heart failure is mainly focused on resolving end symptoms in order to lessen the effects of the disease, preventing progression and reducing mortality risk. Because HCM can develop in many ways and all patients respond to treatment differently, there exist many different kinds of drugs to treat the symptoms of HCM; they include modulators of the renin-angiotensin system (RAS), modulators of β₁-adrenergic receptors, diuretics and inotropes. The RAS is an important modulator of blood pressure in the body but has several maladaptive effects in the setting of hypertension and cardiomyopathy. Angiotensin II (Ang II), a mediator of the RAS pathway, can cause the upregulation of genes that cause detriment to the heart; for instance, in a rat model of cardiac hypertrophy, the ACE gene was upregulated, representing an increase in Ang II, and was correlated to an increase in Myc, fos, junb and Egr1 [Hellman et al. 2010; Han et al. 2007]. Reactivation of the fetal program genes such as Myc, fos and jun are pathologic in the heart and can lead to hypertrophy and remodeling [Barry et al. 2008; Napoli et al. 2002]. In addition, Myc was increased in a mechanical stretch model in an Ang II-dependant fashion [Frank et al. 2008]. ACE inhibitors and ARBs are two important classes of drugs that block the RAS. ACE inhibitors block the conversion of Ang I to Ang II while ARBs block the ability of Ang II to interact with cell membrane receptors [Basile and Toth, 2009]. Both of these drugs reduce preload, reduce afterload and improve cardiac input [Katragadda and Arora, 2010]. Interestingly, they also have been shown to downregulate several genes such as Myc, perhaps through induced changes in the basic helix-loop-helix (HLH) leucine zipper domain required for protein dimerization or by dysregulation of Myc-interacting cell cycle regulators such as cyclin A or E2F [Napoli et al. 2002; Diez et al. 1997]. The major side effects of these drugs are hyperkalemia, hypotension and a significant cough [Kostis et al. 1996]. Several studies have documented the decreased mortality and morbidity of HCM in patients treated with ACE or ARB drugs [Pfeffer et al. 1992; SOLVD Investigators, 1992; CONSENSUS Trial Study Group, 1987].

Stimulation of β₁-adrenergic receptors in the heart can cause cellular abnormalities manifested by calcium cycling defects, dysregulating myocardial energetics and increasing the loss of cardiomyocytes through increases in necrosis and apoptosis [Sabbah, 2004]. Furthermore, unopposed stimulation of β₁-adrenergic receptor increased the risk of developing cardiomyopathy [Golf et al. 1985]. Long-term stimulation of beta receptors has been shown to have a harmful effect since downregulating the beta receptors limits the ability of the heart to respond to adrenergic stimulation [Javed and Deedwania, 2009; Brophy et al. 2001]. Activation of the adrenergic receptors has been shown to trigger the induction of the fetal gene program similar to Ang II [Sabbah, 2004]. Also, this stimulation is believed to upregulate several maladaptive genes such as Myc because the β₁-adrenergic receptor contains a binding site for Myc when bound to Max, a DNA binding partner and transcription factor [Wadhawan et al. 2003]. Interestingly, beta blockers are able to downregulate the fetal gene program including Myc [Lowes et al. 2002; Zimmer, 1997]. Treatment with beta blockers has been shown to prevent, reduce or improve many of the maladaptions caused by stimulation of β-adrenergic receptors and for these reasons have been used in treatment of HCM. Beta blockers have been shown to decrease mortality and facilitate positive cardiac remodeling [Foody et al. 2002]. They have been shown to improve left ventricular (LV) function and reverse LV dilation and hypertrophy [Sabbah, 2004]. Chronic therapy with beta blockers also decreases cardiomyocyte apoptosis and either prevents or decreases fibrosis which causes weakening of the heart muscle leading to heart failure [Sabbah et al. 2000]. In addition, beta blockers are an important drug for the treatment of arrhythmias and help decrease the risk of sudden death [Joglar et al. 2001; Rawles et al. 1990]. However, it is important to note that beta blockers will initially lower ejection fraction before showing an improvement. Therefore, it is important to not treat a patient with a beta blocker while the patient is in active heart failure. Other side effects of beta blockers increase the risk of hypoglycemia, nausea, dyspnea, heart block and hypotension [Hunt et al. 2009].

Other common drugs used to treat symptoms of cardiomyopathy also help to reduce congestion from heart failure or increase contractility and force of the heart. Diuretics are an important agent in reducing congestion and edema due to symptoms of heart failure secondary to cardiomyopathy and work by modulating ion channels in the nephrons which in turn decreases water reabsorption [Tarolli, 2003]. Digoxin, a well-studied positive inotrope, is believed to decrease morbidity while not affecting mortality and works by blocking the Na-K ATPase which is, in part, regulated by Myc [Baartscheer and van Borren, 2008; Orlov et al. 2003; Digitalis Investigation Group, 1997]. The rise of sodium levels in the myocyte increases calcium which increases the contractibility of the heart [Smith, 1988]. In addition, digoxin is also used to treat atrial fibrillation reducing the risk of sudden death [Gheorghiade et al. 2006].

Prevention is the goal, but treating the disease molecularly and mechanistically would provide the patient with the best outcome. Because HCM is a complex, multifactorial disease, the complete etiology is unknown but progress has been made in dissecting the genetic variants and dysfunctions found in the cell cycle, apoptosis and mitochondria.

Molecular dysregulation in hypertrophic cardiomyopathy

Many different pathological changes have been found to occur in HCM. In the 50-70% of the cases of HCM that are genetically inherited, mutations in genes important for cardiac contraction are present, those genes include β-myosin heavy chain (β-MHC), α-tropomyosin, cardiac troponin-T and myosin binding protein C [Niimura et al. 1998; Watkins et al. 1995b; Geisterfer-Lowrance et al. 1990]. Dysfunction of the contractile machinery of the cardiomyocyte leads to decreased cardiac function which leads to cardiomyopathy and heart failure. In cases where no mutations are found, other molecules and pathways have been implicated, such as an upregulation of proteins expressed in fetal cardiomyocytes, i.e. Myc and reactivation of cell cycle machinery both of which contribute to hypertrophy of the cardiomyocyte and an increase in apoptosis which contributes to the increase in fibrosis and weakening of the heart [Lee et al. 2009; Zhong et al. 2006; Starksen et al. 1986]. Interestingly, in patients with LV volume overload resulting from mitral or aortic regurgitation, Myc was increased by 88% even in the presence of no hypertrophy suggesting Myc elevation occurs early in heart disease development [Dzimiri et al. 2004].

Sarcomeric mutations contribute to both the impaired contraction leading to decreased ejection fraction and cardiac output and overall weakening of the heart muscle. For instance, mutations in cardiac myosin-binding protein C, accounting for 15% of all cases of familial HCM and later onset of disease, results in truncated peptides and missense mutations which are suggested to be unable to incorporate correctly into sarcomere A-bands or misregulate actin-activated cardiac myosin ATPase [Gilbert et al. 1996; Hartzell, 1985]. The truncation mutation has been suggested to result in an impairment of the structural integration of the contractile unit with the myocyte cytoskeleton [Niimura et al. 1998]. Additionally, the missense mutation may alter the phosphorylation of cardiac myosin-binding protein C and alter myofibril tension generation and contractile velocity leading to sarcomere dysfunction and HCM [Hofmann et al. 1991].

Early onset of hypertrophy and poor survival has been associated with gene mutations in β-MHC and cardiac troponin T [Anderson et al. 1995; Epstein et al. 1992]. β-MHC is predominantly expressed in the ventricles, is responsible for muscle contraction and cell motility, and is responsible for about 30% of cases of HCM where mutations are identified [Perrot et al. 2005]. Impaired contractility, reduced force generation and decreased velocity of actin filament sliding are features of cardiac myosin isolated from homozygous mice with β-MHC mutations and results in decreased mechanical activities of myosin leading to myocyte disarray and hypertrophy [Debold et al. 2007; Lowey, 2002; Tyska et al. 2000; Marian et al. 1999]. In a quantitative proteomics study, the Myc-associated zinc finger protein, MAZ, was shown to transactivate myosin heavy chain as well as other muscle gene promoters such as α-actin, myogenin and desmin in the cardiac myocytes [Himeda et al. 2008]. Overexpression of Myc in the adult myocardium was shown to upregulate β-cardiac myosin heavy chain [Xiao et al. 2001]. Another correlative link between β-cardiac myosin heavy chain and Myc is found in a d-myo-inositol 1,4,5-tris-phosphate induced model of hypertrophy, where Myc, c-fos, β-MHC and β-actin were upregulated upon induction of cardiac hypertrophy [Zhu et al. 2005]. Mutations in cardiac troponin T, the thin filament protein which binds to tropomyosin and helps the cardiomyocyte regulate force and velocity of contraction, leads to myocardial disarray, increased collagen synthesis and diastolic dysfunction [Oberst et al. 1998]. The R92AQ mutation in cardiac troponin T is linked to familial HCM, but the functional consequences are not fully understood. However, in a transgenic mouse expressing this mutation, sensitivity to calcium in force generation and tension was increased possibly due to altered troponin-tropomyosin interactions or by increased expression of Myc [Chandra et al. 2001; Sole and Liew, 1988].

In contrast to the β-MHC and cardiac troponin T, α-tropomyosin is expressed ubiquitously; however, missense mutations in α-tropomyosin give rise to disease restricted to cardiac muscle [Watkins et al. 1995a]. Mutations in α-tropomyosin account for only 3% of total cases of familial HCM [Watkins et al. 1995a]. This thin filament protein which makes up part of the sarcomere and contributes to flexibility of contraction causes reduced contractility and contributes to myofibril disarray [Wieczorek et al. 2008].

When sarcomeric mutations are not found, alterations in other pathways and molecules have been implicated in the pathogenesis of cardiomyopathy such as fetal gene re-expression, re-entry into the cell cycle, mitochondrial dysfunction and apoptosis. Of the fetal genes re-expressed during cardiomyopathy, Myc has been shown to play a role in many of the molecular alterations. Under metabolic and physical stresses, the reappearance of genes expressed during developmental stages, including cell cycle related proteins, has been demonstrated as a representative marker for cardiac remodeling in human patients and animal studies without actual proliferation of cardiomyocytes [Kai et al. 1998]. For instance, studies have shown reactivation of Myc, atrial natriuretic pep-tide (ANP), b-type natriuretic peptide (BNP), β-MHC and α-skeletal actin (α-SKA) in cardiomyocytes undergoing pathological changes related to HCM [Kai et al. 1998]. However, in response to chronic exercise, Myc was increased during physiologic hypertrophy, indicating a primary role for Myc in inducing hypertrophy, physiological or pathological [Trenerry et al. 2007]. Owing to other pathologic insults such as pressure overload, hypertension or aortic stenosis, hypertrophy induced by Myc is detrimental instead of compensatory. Myc can upregulate protein machinery components such as RNA polymerase III which induce the hypertrophic program [Goodfellow et al. 2006].

The function of Myc in activation of the cell cycle has been well established in various cells such as hematopoietic cells in which Myc prevents differentiation and induces tumorigenesis [Kaneko-Ishino et al. 1988; Lachman et al. 1986]. When Myc is constitutively overexpressed during developmental stages, it induces myocyte hyperplasia as transgenic animals have twice the number of cardiomyocytes compared with controls [Jackson et al. 1990]. However, when Myc is overex-pressed in adult cardiomyocytes it results in hypertrophy and heart failure, suggesting a different role for Myc in adult cardiomyocytes [Lee et al. 2009; Xiao et al. 2001]. A reactivation of cell cycle is evident in the cardiomyocytes the adult Myc overexpression system, while progress of cell cycle is limited to S-phase since no dividing cardiomyocytes have been observed. Myc may also directly link to myocardial disarray as Myc has been suggested to actively repress differentiation programs and cell adhesion [Claassen and Hann, 1999]. Cardiomyocytes become terminally differentiated and are connected to each other through intercalated discs which are composed of anchoring tight junctions and adherens junctions. Therefore, the prevention of differentiation and downregulation of adhesion molecules may contribute to the disorganization of cellular networks and eventual myocardial disarray [Gemayel et al. 2001].

Cardiomyocytes are physiologically active and contain a large number of mitochondria to provide ATP. In a healthy heart, mitochondria comprise one third of total cardiomyocyte mass; however, in heart disease, mitochondrial function is altered and harmful reactive oxygen species (ROS) or molecules responsible for an increase in apoptosis, such as cytochrome c, are released resulting in an increase in cardiac cell damage [Bernhard and Laufer, 2008]. Mitochondria have been implicated in oxidative stress, contributing to loss of cells and cell injury in various cardiac pathologies, including ischemia/reperfusion, cardiomyopathy and CHF [Gustafsson and Gottlieb, 2008]. ROS are a result of oxygen metabolism and play major roles in initiation and progression of chronic heart failure [Elahi and Matata, 2006; Landmesser and Harrison, 2001; Cai and Harrison, 2000; Yucel et al. 1998]. ROS generation is normal, playing an important role in oxidative phosphorylation and signaling pathways, but excess ROS are pathologic and trigger cell dysfunction, DNA damage and mutagenesis and lipid peroxidation leading to cell damage and even death [Giordano, 2005]. Myc has been shown to be decreased upon overexpression of superoxide dismutase 1 (SOD1), suggesting a causal link between Myc and oxidative stress [Huang et al. 2001]. Subsequently, Myc can induce the production of ROS and mitochondrial biogenesis induced by Myc may be associated with induction of mitochondrial ROS [Dang et al. 2005; Vafa et al. 2002]. In fact, ROS activate the specific signaling pathways to induce either hypertrophy or apoptosis in cardiomyocytes [Kwon et al. 2003]. Studies have shown that Myc was able to sensitize cells to apoptosis by inducing the release of cytochrome c from mitochondria [Pucci et al. 2000]. Thus, Myc is able to regulate cell proliferation as well as cell death and the induction of oxidative stress by Myc may be one of the central mechanisms in the ability of Myc to induce apoptosis in cardiomyopathy. In addition, studies have shown that the myocyte is able to initiate apoptosis in response to a wide range of stimuli including oxidative stress, hypoxia and work overload [Sabbah and Sharov, 1998]. Upon insult, apoptosis as well as necrosis can occur resulting in loss of myocytes as well as damage to surrounding tissue [Freude et al. 2000]. Transgenic mouse studies have directly linked cardiomyocyte apoptosis to heart failure, in which loss of the gp130 receptor, a cardiotrophin and interleukin-6 (IL-6) signal transducer, led to massive apoptosis, heart failure and eventually death [Hirota et al. 1999].

Potential and future therapies in hypertrophic cardiomyopathy

Myc has been shown to be an important target in the molecular and mechanical development of HCM as studies have shown an increase in Myc expression is evident in cardiomyocytes before any evidence of disease is present [Sole and Liew, 1988]. In addition, Myc expression in human HCM biopsies showed that the presence of Myc correlated with increased hypertrophy in the heart by 50% as compared with HCM biopsies not positive for Myc, and by almost 100% compared with control heart with no signs of HCM [Kai et al. 1998]. A study in a transgenic mouse model of cardiomyopathy has shown that genetic knockdown of Myc made the mice resistant to development of HCM, suggesting that targeting Myc may be able to prevent or treat the development of HCM [Zhong et al. 2006].

Interestingly, current treatments including ACE inhibitors and ARBs have the ability to downregulate Myc even though their mechanism of action is unclear [Diez et al. 1997]. Angiotensin II, the effector peptide of the RASs, is involved with cardiac and vascular growth and causes induction of Myc [Lijnen and Petrov, 1999]. In a rat model of hypertrophy, administration of captopril, an ACE inhibitor, reduced expression of Myc in the cardiomyocytes and cardiac fibroblasts of the left ventricle. It was also shown that captopril disrupted posttranscriptional translation of Myc, suggesting downregulation of Myc may be important in preventing hypertrophy [Chen et al. 1998; Su et al. 1998]. Quinapril, another ACE inhibitor, has been shown to inhibit Myc expression in spontaneously hypertensive rats, implicating hypertension in exacerbating cardiomyopathy and heart failure [Diez et al. 1997].

Compounds targeting Myc exist and have been tested in several clinical trials for other heart diseases but no trials are in place for inhibiting Myc in HCM and CHF. For example, in patients with coronary artery disease or coronary stent restenosis, an antisense drug, RESTEN-MP, to block Myc protein production was evaluated in a Phase I trial (NCT00244647, ClinicalTrials.gov, 2 October 2009). To follow up this clinical trial, RESTEN-MP was used in a Phase II trial to reduce in-stent restenosis following balloon angioplasty. Inhibiting Myc prevented lumen renarrowing, suggesting a hypertrophic role for Myc in vivo (NCT00248066, ClinicalTrials.gov, 17 May 2010). Another ongoing clinical trial is addressing a similar question to the restenosis trial and is using a drug eluting stent to deliver a Myc silencing molecule to investigate if inhibiting Myc can repair a lesion in the coronary arteries (NCT00777842, ClinicalTrials.gov, 17 May 2010). Myc antisense oligomers to inhibit protein production also were shown to reduce neointimal formation after carotid or coronary arterial injury and inhibited myointimal hyperplasia after balloon injury [Kipshidze et al. 2001; Bennett et al. 1997; Shi et al. 1994]. This approach for inhibiting Myc could be applied to HCM and, indeed, one study demonstrates that blocking Myc with a specific antisense oligonucleotide has been shown to delay and attenuate cold-induced cardiac hypertrophy in a rat model [Bello Roufai et al. 2007].

Control of Myc protein production rapidly affects cell behavior, and blocking or suppressing the downstream functions of Myc may be the key to controlling cellular damage and dysfunction. Downregulating and blocking expression of Myc with antioxidants and antisense oligonucleotides have been moderately successful in cancer models and cardiac disease models [Mezzetti et al. 1993]. For example, γ-tocopherol, an anti-oxidant and cell cycle inhibitor, has been used for treatment of CHF and α-tocopherol was used to manage diabetic cardiomyopathy [Celik et al. 2010]. They were both shown to downregulate Myc but, as antioxidants, their ability to manage heart failure was variable perhaps due to genetic polymorphisms [Gysin et al. 2002; Napoli et al. 2002]. Because Myc can bind to many promoters and has many actions in different cell types, a cardiomyocyte cell-specific knockdown or modulator of Myc would be an exciting treatment option in cardiomyopathy.

Conclusion

In conclusion, HCM can manifest in multiple ways and the pathogenesis of disease varies from inherited genetic mutations to environmental risk factors to developmental defects. The goals for treating HCM are symptom relief, preventing progression, and reducing mortality risk. Multiple types of medications exist for treating HCM but none of them are perfect and many have unwanted side effects. Current treatments are mainly focused on the end symptoms of HCM and attention needs to be focused on prevention of disease and treatment of molecular and mechanical causes. Myc has been shown to play a role in multiple aspects of disease development and progression and is an interesting target to inhibit for prevention of disease.