Inherited cardiomyopathies—Novel therapies

    Inherited cardiomyopathies – novel therapies Dror B. Leviner, Edith Hochhauser, Michael Arad PII: DOI: Reference:

S0163-7258(15)00161-8 doi: 10.1016/j.pharmthera.2015.08.003 JPT 6807

To appear in:

Pharmacology and Therapeutics

Please cite this article as: Leviner, D.B., Hochhauser, E. & Arad, M., Inherited cardiomyopathies – novel therapies, Pharmacology and Therapeutics (2015), doi: 10.1016/j.pharmthera.2015.08.003

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Inherited cardiomyopathies – novel therapies

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Dror B. Leviner1,2 MD, Edith Hochhauser PhD2, Michael Arad3 MD

Department of Cardiothoracic Surgery, Rabin Medical Center, Petah Tikva, Israel

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Cardiac Research Laboratory, Felsenstein Medical Research Center, Petah Tikva and

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Sackler School of Medicine, Tel Aviv University

Leviev Heart Center, Sheba Medical Center, Tel Hashomer and Sackler School of

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Medicine, Tel Aviv University

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Michael Arad MD,

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Address and details of the corresponding author:

Leviev Heart Center, Sheba Medical Center, Tel Hashomer, Ramat-Gan 52621, Israel

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+972-3-5304560, fax +972-3-5304540 E-mail: [email protected]

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Abstract Cardiomyopathies arising due to a single gene defect represent various pathways that

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evoke adverse remodeling and cardiac dysfunction. While the gene therapy approach

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is slowly evolving and has not yet reached clinical "prime time" and gene correction

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approaches are applicable at the bench but not at the bedside, major advances are being made with molecular and drug therapies. This review summarizes the contemporary drugs introduced or being tested to help manage these unique disorders

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bearing a major impact on the quality of life and survival of the affected individuals.

The restoration of the RNA reading frame facilitates the expression of partly

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functional protein to salvage or alleviate the disease phenotype. Chaperones are used

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to prevent the degradation of abnormal but still functional proteins, while other molecules are given for pathogen silencing, to prevent aggregation or to enhance

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clearance of protein deposits. Absence of protein may be managed by viral gene delivery or protein therapy. Enzyme replacement therapy is already a clinical reality

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for a series of metabolic diseases. The progress in molecular biology, based on the knowledge of the gene defect, helps generate small molecules and pharmaceuticals targeting the key events occurring in the malfunctioning element of the sick organ. Cumulatively, these tools augment the existing armamentarium of phenotype oriented symptomatic and evidence-based therapies for patients with inherited cardiomyopathies.

Key words: 6 Hypertrophic cardiomyopathy, Dilated cardiomyopathy, Arrhythmogenic cardiomyopathy, Amyloidosis, Duchenne Muscular Dystrophy, Gene therapy

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Introduction

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2.

Hypertrophic cardiomyopathy (HCM)

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Novel therapeutic strategies in HCM

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Dilated cardiomyopathy (DCM)

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Novel therapeutic strategies in familial DCM

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Dystrophinopathy

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Arrhythmogenic cardiomyopathy (ACM)

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Novel therapeutic strategies in familial ACM

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Restrictive cardiomyopathy (RCM)

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Novel therapeutic strategies in familial RCM

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Transthyretin amyloidosis

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Metabolic and related cardiomyopathies

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Pompe disease

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Anderson Fabry disease

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Danon disease and disorders of autophagy

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Summary

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1.

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Table of Contents

Conflict of Interest Statement

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15.

References

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Figure legend

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Abbreviations ACM - arrhythmogenic cardiomyopathy

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AON - antisense oligo-nucleotide

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α-Gal A - α-galactosidase-A

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BMD - Becker Muscular Dystrophy cMyBPC - myosin- binding protein C

DMD - Duchenne muscular dystrophy ERT – enzyme replace therapy

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GAA - lysosomal acid α-glucosidase

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DCM – dilated cardiomyopathy

Gb3 - Globotriaosylceramide

HF - heart failure

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LV - left ventricle

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HCM - hypertrophic cardiomyopathy

LVOT - LV outflow tract

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LVEF – left ventricular ejection fraction PLN - phospholamban RCM - restrictive cardiomyopathy SAP - serum amyloid P component SCD - sudden cardiac death SR - sarcoplasmic reticulum TTR-FAP - familial amyloidotic polyneuropathy WPW – Wolff Parkinson White

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1.

Introduction Cardiomyopathies arising due to a single gene defect represent various

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pathways to evoke adverse remodeling and cardiac dysfunction. While the gene

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therapy approach is slowly evolving and has not yet reached clinical "prime time" and

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gene correction approaches are being developed at the bench but not at the bedside, progress is gradually being made with medical therapies. This review summarizes the contemporary drugs being tested and introduced into the clinical arena to help manage

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these diseases. We selected drugs soon to be used in the clinic, those being tested in

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clinical trials or having abundant experimental evidence in their favor and are about to start clinical experimentation in various cardiomyopathy groups (Table 1).

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We hereby grouped the cardiomyopathies according to the principal subtypes as

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defined by the most recent cardiomyopathy classification (Elliott, et al., 2008), while paying specific attention to unique subtypes characterized by Red Flags useful for

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disease diagnosis (Rapezzi, et al., 2013). There are numerous diverse diseases caused by metabolic defects, substrate accumulation and protein aggregates. Being unable to

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address every particular gene-variant, we describe the representative examples to demonstrate the status of current therapy and future directions (see Table 1).

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Hypertrophic cardiomyopathy (HCM)

Clinical overview HCM is the most common genetic cardiovascular disease with an estimated prevalence of 1 in 500. It is characterized by a thickened, but not dilated, left ventricle (LV) without a secondary cause for the hypertrophy (such as aortic stenosis). HCM is the most common cause of sudden cardiac death (SCD) in the young and in athletes. Adults may suffer from effort intolerance due to angina or heart failure while in the

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elderly atrial fibrillation and strokes are common complications. Yet, many individuals with the disease have a normal life expectancy and have little, if any,

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medical limitations (Maron, et al., 2009; Maron, et al., 2013).

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Genetics: HCM is the result of a mutation in one of 11 genes encoding components of

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the sarcomere or (sometimes) the Z-disc. Of the genetically diagnosed patients, 70% have a mutation in the β-myosin heavy chain and myosin-binding protein C

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(cMyBPC) (Richard, et al., 2003). Abnormalities in myofilament contraction and in the intracellular calcium management are considered to trigger the hypertrophic

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response leading to an abnormal ventricular remodeling. Although transmitted in an autosomal dominant fashion, there is significant phenotypic heterogeneity, implying

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that there is a role for modifier genetic and environmental factors. Known mutations

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can only be identified in ~50% of affected probands, a fact that complicates genetic counseling. Moreover, there is limited correlation between mutations and clinical

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outcome (Landstrom, et al., 2010). Thus, the major contribution for genetic testing today is in ruling out the carrier state in family members of affected individuals and

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identifying patients with an alternate condition mimicking HCM (such as Fabry's disease, familial amyloidosis) (Weidemann, et al., 2009). Diagnosis and clinical course: Diagnosis might be a consequence of a cardiac event, family screening, or an abnormal physical examination or ECG (Adabag, et al., 2006). Currently, diagnosis is made with echocardiography or cardiovascular magnetic resonance imaging which show an unexplained increase of LV wall thickness ≥ 15 mm (21-22mm on average) (Rickers, et al., 2005). Hypertrophy develops in different patterns, even in patients with the same mutation, and might be accompanied with obstruction of the LV outflow tract (LVOT). As previously noted, there is a variable clinical course ranging from asymptomatic patients to SCD at a young age,

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development of heart failure (HF) or atrial fibrillation with stroke. HF is usually the result of diastolic dysfunction, LVOT obstruction and atrial fibrillation (Melacini, et

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al., 2010). Only a small percentage develops systolic dysfunction, often commencing

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in severe heart failure where the only effective treatment is heart transplantation

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(Maron, et al., 2010). SCD is more common in patients under 35 years of age and can be the first presentation of HCM. While cases occurring during competitive sports get most publicity, sudden death most commonly occurs while the patient is sedentary or

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engaged in mild activity.

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Management: Symptomatic left ventricular outflow obstruction is usually managed by a combination of beta adrenergic blocker with disopyramide. Treating obstructive

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cardiomyopathy is often a challenge, in particular in the elderly with coexisting

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hypertension of conduction system disease. For patients with persistent symptoms despite optimal medical therapy, there is an indication for surgical myectomy (or

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alcohol septal reduction as an alternative) with the goal of relieving LVOT obstruction (Kwon, et al., 2008; Ommen, et al., 2005). Treatment of HF with diastolic

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dysfunction consists of beta blockers or verapamil with a cautious use of diuretics. Once the patient develops systolic failure, the treatment is similar to other forms of HF with reduced left ventricular ejection fraction, although none of the "evidence based" therapies has been validated in this population. Patients with hypokinetic HCM often develop severe symptoms and require heart transplantation rather early because of a coexistent diastolic dysfunction and the limited capacity of the fibrotichypertrophic ventricle to increase its volume by chamber dilatation. Identification of at-risk family members of a diagnosed patient via clinical or genetic screening is a key component of management. Defibrillators are implanted for primary or secondary prevention of sudden death. The indications for primary

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prevention are based on clinical criteria such as SCD in the family, massive LV hypertrophy, unexplained syncopal events and recurrent non sustained ventricular

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tachycardia on Holter monitoring (Gersh et al., 2011). An algorithm numerically

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assessing the 5-year risk of life-threatening arrhythmia has recently been introduced.

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In addition to the above clinical criteria it takes into account age, left atrial side and left ventricular outflow obstruction (Elliott, et al., 2014).

Novel therapeutic strategies in HCM

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Following are several examples of drugs/procedures aimed at alleviating HCM symptoms.

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- One mechanism that underlies arrhythmia leading to SCD in HCM is thought to be

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the increased sensitivity of the myofilaments to Ca2+. Blebbistatin is an inhibitor of actin-myosin interaction functioning independently of Ca2+ influx (Dou, et al., 2007).

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Use of blebbistatin in a murine model of troponin T mutation reduced arrhythmia susceptibility, establishing Ca2+ sensitization as a potential therapeutic target in HCM

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(Baudenbacher, et al., 2008). - Parvalbumin is a Ca2+ buffering molecule, which is not normally expressed in cardiac muscle, and also binds Mg2+. When Ca2+ concentration rises, Parvalbumin releases magnesium and bind calcium. Forced expression of parvalbumin in cardiac muscle was able to correct the slow relaxation (and thus improve diastolic dysfunction) in the rat and mouse models of HCM due to a mutation in α-tropomyosin (Coutu, et al., 2004). MYK-461, a novel allosteric modulator of the myosin molecule, attenuates abnormal excessive contraction and enhances relaxation. MYK-461 has recently entered into Phase I of a clinical program (MyoKardia, NCT02329184).

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- Enhanced Ca2+ uptake by the sarcoplasmic reticulum (SR) can also alter the progression of HCM phenotype. This was achieved by two means in a HCM mouse

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model caused by a tropomyosin mutation. The first was by an adenoviral delivery of

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SERCA2a (an SR protein) to 1-day-old transgenic mice. This single injection gene

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delivery resulted in a significantly increased expression of total cardiac SERCA2a protein up to a few weeks of age, and was sufficient to improve morphology and response to β-adrenergic stimulation up to 3–4 months of age (Pena, et al., 2010). The

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second method used was a knockout of the phospholamban (PLN) gene, a SERCA2a

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inhibitor. Thus, a knockout of PLN resulted in increased Ca2+ uptake by the SR (Gaffin, et al., 2011).

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- A recent work has shown the feasibility and effectiveness of gene-transfer of deleted

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genes by recombinant viral vectors of cMyBPC (Merkulov, et al., 2012), one of the most common causes of HCM. The increased levels of cMyBPC resulted in improved

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contractile function both in vitro and in vivo. - Another mechanism which may affect the altered Ca2+ homeostasis is the inhibition

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of the L-type Ca2+ channel by diltiazem (Semsarian, et al., 2002). The mutation in the α-cardiac myosin heavy chain in mice resulted in altered Ca2+ regulation on multiple levels. These changes appeared in advance of changes in the cardiac histology or morphology. Administration of diltiazem at an early stage resulted in the upregulation of SR proteins and attenuated the development of the HCM phenotype. A recently published study in humans suggests that diltiazem may alleviate left ventricular remodeling in asymptomatic sarcomere mutation carriers (Ho, et al., 2015). - Diversion of myocardial substrate utilization from free fatty acid oxidation to carbohydrates by perhexilin, which inhibits mitochondrial uptake of long-chain fatty

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acids, resulted in a more efficient ATP production and subsequent improvement in cardiac function (Abozguia, et al., 2010), (NCT00500552). Similarly, trimetazidine,

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can switch the heart metabolism from free fatty acid to carbohydrates utilization in

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parallel with its Ca2+ antagonism properties (clinical trial NCT01696370).

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- Ranolazine is another metabolic modulator having a similar effect to that of perhexilin and trimetazidine. In addition, ranolazine has recently been shown to shorten the action potential duration and reduce arrhythmias in human HCM

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cardiomyocytes by inhibiting the late sodium current INa (Coppini, et al., 2013).

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Ranolazine is currently approved for refractory angina in patients with coronary disease and has been advocated for HCM patients suffering from myocardial ischemia

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(in the absence of epicardial coronary artery disease). A multicentre, double-blind,

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placebo-controlled pilot study is currently underway to test the efficacy of ranolazine on exercise tolerance and diastolic function in symptomatic HCM patients (the

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RESTYLE-HCM, EUDRA-CT 2011-004507-20). Another selective inhibitor of INa, GS-6615, is being investigated as a means to improve exercise capacity in

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symptomatic HCM (Liberty trial, NCT02291237). - Aldosterone is elevated in humans with HCM. Spironolactone, an aldosterone inhibitor, has been found to reduce myocardial fibrosis, attenuate the extent of myocyte disarray and improve diastolic function in experimental models (Tsybouleva, et al., 2004). Eplerenone, another aldosterone antagonist, is similar in structure to spironolactone, but has far fewer adverse effects. Both compounds have an established role in post-myocardial infarction and in HF with reduced ejection fraction. Both are currently being tested in HCM. [Clinical trials, (NCT00879060) and (NCT01521546), respectively]

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- Losartan, an angiotensin II receptor blocker, has been found to ameliorate morphological changes in LV mass (as measured by MR imaging) in a small group of

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patients with HCM (Yamazaki, et al., 2007). Another angiotensin receptor blocker,

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candesartan, also had a favorable effect after one year of treatment, with a reduction

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in LV hypertrophy and an improvement of LV function (Penicka, et al., 2009). The greatest response was seen in patients with β-myosin heavy chain mutations. In disagreement with these, the recently published INHERIT trial (Axelsson, et al.,

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2015) examined 100 mg/day losartan in a large number of patients (n=133). The drug

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was well tolerated but did not affect the left ventricular mass after 12 months of therapy.

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- N-acetylcysteine, a precursor of glutathione, the largest intracellular thiol pool

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against oxidative stress, reversed cardiac hypertrophy and fibrosis in transgenic rabbits with a HCM phenotype (Lombardi, et al., 2009). A clinical trial to test its

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effect on HCM patients is now being conducted and is at the recruiting stage

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(NCT01537926).

Dilated cardiomyopathy (DCM)

Clinical overview DCM is a myocardial disease characterized by LV (or biventricular) enlargement and decreased systolic function. The majority of cases in the Western hemisphere are caused by coronary artery disease. The prevalence of non-ischemic DCM is 1:2000-3000 and it constitutes a major cause of HF and heart transplantation. DCM may arise via multiple, sometimes interacting etiologies including hypertension, inflammation, endocrine-metabolic, toxic and even infiltrative lesions. In about 25-

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35% of cases it is a familial disease having more than 40 causative genes identified to date (Burkett, et al., 2005).

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Genetics: in contrast to HCM, the genes identified in DCM encode for a number of

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cellular components, such as the nuclear envelope, gene transcription, calcium

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handling, the sarcomere, cytoskeleton and sarcolemmal proteins (Dellefave, et al., 2010). These gene mutations evoke diverse mechanisms of cell damage triggering molecular responses which become maladaptive leading to decreased function and

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adverse remodeling. Eventually, various causes of DCM converge to a final common

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pathway which comprises decreased calcium stores and myofilament calcium sensitivity, reduced ejection fraction and ventricular dilatation. Yet, there are

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important differences in the propensity for ventricular arrhythmia, the presence of

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conduction system disease, skeletal myopathy, unique morphologic features such as left ventricular non-compaction and, rarely, extracardiac manifestations (deafness,

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etc.). Inheritance is mostly autosomal dominant, although x-linked, autosomal recessive and mitochondrial forms have been reported.

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Diagnosis and clinical course: Medical evaluation starts with a detailed clinical history that is aimed at ruling out risk factors and other causes of DCM (such as coronary disease, chemotherapy exposure or excess alcohol consumption). Physical examination will reveal signs of HF (left-sided or biventricular) but may be rather unremarkable at an early stage of the disease. The ECG may show LBBB, left axis deviation or a nonspecific cardiomyopathy pattern (low limb lead but high precordial lead voltage and poor R wave progression in the chest leads). Echocardiography will show a globally hypokinetic LV with variable degrees of ventricular enlargement and atrio-ventricular valve regurgitation. The right ventricle works against a lower afterload and often develops the disease on a later stage but may deteriorate

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concomitantly with the LV. Coronary angiography or radionuclide perfusion imaging is important to rule out ischemic heart disease as a cause for DCM in clinically

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relevant scenarios. Cardiac MRI may help distinguish between ischemic and non-

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ischemic DCM and provide clues to a specific diagnosis such as arrhythmogenic

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cardiomyopathy, myocarditis, sarcoidosis, left ventricular non-compaction, amyloid and hemochromatosis. Endomyocardial biopsy is sometimes necessary when myocardial inflammatory or infiltrative process are suspected or have to be ruled out.

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Meticulous family history and screening of first degree family members by ECG and

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echo-Doppler are important to identify a familial disease. Familial DCM is typically defined when there is at least one first degree family member affected by the same

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disease or died suddenly before age 35 years (Mestroni, et al., 1999).

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Management: Genetically determined DCM is treated according to contemporary HF guidelines (Yancy, et al., 2013). No etiology-specific treatment exists today except

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several rare metabolic conditions (such as carnitine deficiency, fatty acid acyl-Co A dehydrogenase deficiency) which respond to a specific therapy. Patients are treated

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with angiotensin converting enzyme (ACE) inhibitors, -blockers and diuretics similar to that used with other causes of systolic HF. Mineralocorticoid antagonism is indicated in patients with symptomatic HF. LCZ696, comprising an angiotensin receptor blocker with a neutral endopeptidase inhibitor (McMurray, et al., 2014), is about to be approved for clinical use in HF with reduced systolic function instead of ACE inhibitors/ARBs. Cardiac resynchronization therapy is warranted in patients with a prolonged QRS and left ventricular dyssynchrony (Chung, et al., 2008). Family management starts with screening of first order relatives of affected individuals in order to find members at risk. Screening should include history, physical examination, ECG and echocardiography since asymptomatic DCM is

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common. Age-dependent and incomplete penetrance is a common feature in familial DCM, so most patients will present in the forth-to-seventh decade of life. Some

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require an additional stress such as hypertension or pregnancy to express the disease.

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Genetic testing may be accomplished by gene sequencing of panels of multiple DCM-

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related candidate genes (40 and up to 130) (Sturm, et al., 2013). Founder mutations are uncommon but shall be considered as a cause of DCM in certain populations (Dhandapany, et al., 2009; van der Zwaag, et al., 2012).

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The optimal time of initiating "evidence based" cardioprotective therapy in

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DCM gene carriers is not well established. Carvedilol may have some efficacy in preventing left ventricular dilatation in asymptomatic individuals with 'early' familial

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DCM (Yeoh, et al., 2011). In case of a severe disease represented by Duchenne

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Muscular Dystrophy (DMD), perindopril delayed the onset and progression of LV dysfunction (Duboc, et al., 2005) and reduced mortality as shown by a 10-year

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follow-up study.

The yield of gene testing in DCM is quite low: only ~ 30% have their disease-

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causing mutation identified. Several genes and certain phenotypes warrant particular attention: 

Mutations in a nuclear envelope protein lamin A/C (LMNA) are associated with conduction system disease and early life-threatening ventricular arrhythmia occurring when the ventricular function is relatively preserved. LMNA accounts to 5-7% of all DCM and to 30% of DCM with conduction system disease (van Rijsingen, et al., 2012).

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Dystrophin (DYS) gene on X chromosome is responsible for DMD and Becker Muscular Dystrophy (BMD), but is also the cause of 5-8% of DCM evaluated in cardiology clinic. While these patients are characterized by severe

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ventricular dilatation and mild myopathy and/or CK elevation, ventricular arrhythmias are uncommon (Diegoli, et al., 2011). Sarcomere protein gene mutations cumulatively account for 5-10% of dilated

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

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cardiomyopathy and are typically characterized by early disease onset. The

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giant protein titin constitutes a molecular ruler responsible for structural integrity and diastolic tension. While known to be a DCM gene, the TTN gene was considered to be a rare cause of disease. The introduction of

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contemporary sequencing techniques led to identification of truncating TTN

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mutations in 25% of familial and 18% of sporadic DCM cases (Herman, et al., 2012). This genocopy is typically characterized by a late onset presentation

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and variable expression which is affected by hemodynamic load as well as

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other environmental and genetic modifiers.

Novel therapeutic strategies in familial DCM

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The role of humoral immunity in DCM is well established not only in inflammatory cardiomyopathy but also in genetically determined disease (Caforio, et al., 2007). It has been shown that anti--adrenergic receptor autoantibodies have a pathogenic role in the development of DCM in mice (Jahns, et al., 2004) and humans (Iwata, et al., 2001). This led to trials of immunomodulation as a treatment strategy. Immunoadsorption which removes circulating auto-antibodies was used to treat DCM in 45 patients (Staudt, et al., 2004). A significant result was only achieved in those patients in whom antibodies proved to be cardio-depressing in mice. This treatment option is currently being tested in a randomized trial of 200 patients (NCT00558584).

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As previously noted in DCM patients, the presence of anti-1-receptor autoantibodies has been shown to predict increased depressed left ventricular function, a

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raised prevalence of serious ventricular arrhythmias, SCD and cardiovascular

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mortality (Iwata, et al., 2001). In the rat model of autoimmune cardiomyopathy, COR-

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1 cyclopeptide has been shown to bind to, and therefore decrease, the anti--receptor autoantibody effect (Jahns, et al., 2010). Recently, a phase I trial of COR-1 was proved safe and effective in humans with no unwanted side effects on the immune

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system (Munch, et al., 2012).

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N-3 polyunsaturated fatty acids (nPUFA) are fatty acids derived from fish oil which are important for the normal human metabolism. PUFA are under investigation

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in diverse clinical settings, from gastric cancer to arrhythmias. PUFA administration

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prevented cardiac remodeling in a rat aortic banding model (Duda, et al., 2009) and

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resulted in a small decrease in mortality in patients with HF from any cause (Tavazzi, et al., 2008). PUFA were recently tested in a randomized trial of DCM patients where they improved LV systolic and diastolic function, as well as functional capacity

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(Nodari, et al., 2011).

Gene therapy can target different stages in the course of the development of

DCM. One target that has been tested in humans is the defective SR calcium handling as a result of decreased SERCA2a levels (discussed in the chapter on HCM). In a study using an adeno-associated virus (AAV) serotype 1 vector to carry the SERCA2a gene to cardiac muscle, a 3-year follow-up of 39 patients showed a tendency towards improved survival and reduced cardiovascular events, especially in the high dose group. There was no increase in arrhythmias in the treatment group and a long term vector persistence was demonstrated on cardiac biopsies (Jaski, et al., 2009; Zsebo, et al., 2014). Of note, only patients without preformed, naturally occurring antibodies to

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AAV1 are eligible for this treatment. A larger study is now being conducted (NCT0164330), as well as a study in patients with LVAD (NCT00534703).

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Intracoronary stem cells transplantation was first used in the setting of

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ischemic heart disease (IHD) and acute MI. Evidence of microvascular dysfunction as

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well as dysfunction of bone marrow cells (BMCs) and endothelial progenitor cells in DCM was the trigger for the use of stem cells in DCM. After harvesting CD34+ cells (previously by aspiration but currently by peripheral harvesting after administration of

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G-CSF), the cells were introduced via intracoronary infusion to predefined

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myocardial areas with contractile dysfunction. This resulted in a 1-year improvement of both clinical and echocardiographic parameters (6-minute walk, LVEF, survival

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(Vrtovec, et al., 2011). The same group recently published a 5-year follow up

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showing consistent results with most of the benefits of therapy in the first year. This study also demonstrated a positive correlation between myocardial homing of the

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stem cells and the response to therapy (Vrtovec, et al., 2013). The mechanisms involved are still unknown but might include paracrine effects, such as attenuation of

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apoptosis of endogenous cardiomyocytes and endothelial cells, promotion of angiogenesis, activation of resident cardiac stem cells, or induction of an antiinflammatory effect (Ebelt, et al., 2007). As mentioned in the HCM treatment section, ranolazine, an inhibitor of the late sodium current INa, L is being tested in multiple clinical scenarios such as HCM, as an anti-arrhythmic and angina relief. Another recently initiated trial, aims to determine if ranolazine improves myocardial perfusion in patients with DCM (NCT02133911). Ixmyelocel-T is an autologous multicellular therapy expanded from bone marrow mononuclear cells. As a result of the manufacturing process, it comprises

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both lymphoid and myeloid cells with a large number of M2-like macrophages and mesenchymal stromal cells (Bartel, et al., 2012). Due to this multicellular

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composition, Ixmyelocel-T has demonstrated multiple activities relevant to tissue

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repair and regeneration (Ledford, et al., 2013). Ixmyelocel-T was recently tested in

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Phase IIA clinical trials in patients with ischemic and non-ischemic DCM. After harvesting bone marrow cells from the iliac crest patients underwent intramyocardial injection of Ixmyelocel-T, either surgically or with a percutaneous technique. In both

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studies there was no effect in the non-ischemic DCM group but a clinically significant

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effect in the ischemic group. The latter clinical improvement is in contrast to the lack of improvement in LVEF, LVEDD and other laboratory measures (NCT00765518,

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NCT01020968). This might be a result of the lack of a true placebo group (i.e., no

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bone marrow aspiration was done in the control group). Ixmyelocel-T is being further tested in ischemic DCM (NCT01670981).

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Pharmacological myofilament Ca2+ sensitization by agents such as levosimendan has been shown to be of clinical benefit in advanced HF with

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hemodynamic compromise (NCT01290146). A recent study has suggested that intermittent administration may improve functional status and prevent hospitalization. Newer drugs from the same category (Pimobendan, EMD 53998 and MCI-154) are being developed. Another class of drugs are the cardiac myosin activators, which act by accelerating the transition from weekly bound myosin to strongly bound myosin without altering the Ca2+ transient and without being affected by -blockers (Malik, et al., 2011). Omecamtiv mecarbil, the representative drug in this class, was compared to dobutamine in a canine model of HF. Its use resulted in an increase in stroke volume and cardiac output without affecting oxygen consumption (Shen, et al., 2010). In a phase II clinical trial in 45 patients with DCM (both ischemic and non-ischemic)

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treatment with IV Omecamtiv mecarbil resulted in a dose dependent increase in the duration of left ventricular systole. The drug was generally well tolerated unless high

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plasma concentrations were reached, when signs and symptoms of ischemia were

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noted (Cleland, et al., 2011). Omecamtiv mecarbil is currently being tested in a trial of

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acute HF (NCT01300013).

Qili qiangxin, a Chinese traditional medicine, enhances heart function in chronic HF, in part by regulating the balance of TNF- and IL-10 (Xiao, et al., 2009).

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Qili qiangxin was approved for use in CHF patients by the Chinese food and drug

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administration in 2004. In a randomized, double blind, placebo controlled trial of nearly 500 patients with DCM (with over 50% of them with non-ischemic DCM),

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addition of Qili qiangxin to standard medical therapy resulted in a significant decrease

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in NT-proBNP levels concomitant with improvement in the 6-minute walk test and EF (X. Li, et al., 2013). This drug is now being examined as a supplement to standard

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therapy in a large cohort of DCM patients (NCT01293903). Disease-specific treatment strategies are just beginning to evolve. Abnormal

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activation of mitogen-activated protein (MAP) kinase signaling pathway through p38α was detected in LMNA mutant mice prior to the onset of significant cardiac impairment. Pharmacological inhibition of p38α prevented LV dilation and deterioration of fractional shortening in mice with DCM caused by LMNA (Muchir, et al., 2012). Approaches to correct the gene defect are described in detail in the chapter on dystrophinopathies.

6. Dystrophinopathy

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DMD, an X-linked disease of skeletal and cardiac muscle caused by dystrophin gene defects is the prototype of dystrophynopathies. This lethal disease has

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a high incidence among newborn males (approximately 1:3500). The disease follows

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a course of progressive muscle weakness, which further involves the cardiac and

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respiratory muscles, resulting in early-age mortality for the vast majority of affected boys, and to a lesser extent, motion disability at the age of 12. To date, no curative treatment for DMD is present, though the molecular basis of the disease is highly

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elucidated. Over the years, the life expectancy of DMD has immensely increased,

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probably as a result of the effect of combined corticosteroids, antibiotics therapy, noninvasive ventilation and improved airway hygiene. DCM is a characteristic feature of

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DMD and currently constitutes a major cause of morbidity and mortality (Fayssoil, et

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al., 2010). Dystrophin gene mutations have been established as the sole cause of DMD, resulting in the complete or partial abrogation of the protein. The dystrophin

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gene located on the short arm of the X chromosome constitutes the largest gene in the human genome, covering 2.2 mega-bases and composed of 79 exons and 7 promoter

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regions. Dystrophin protein is localized in the sarcolemma of muscle fibers and postulated as an essential molecular shock absorber of the contractile apparatus, thus protecting the sarcolemma from mechanically-induced damage. Various types of mutations leading to DMD have been reported, such as deletions (most common), duplication of exons and point mutations (usually stop codons). Classical DMD patients are characterized by the complete lack of the dystrophin protein, because the mutation leads to a loss of a reading frame. By contrast, mutations resulting in less defective, albeit still partially functional dystrophin protein, lead to a milder phenotype, and are typically diagnosed as BMD, where cardiac manifestations often precede skeletal muscle weakness.

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Much of the ongoing research is focused on gene therapy. The development of highly efficient and specific viral vectors for heart gene transfer, mainly AAV

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serotypes 5, 6, 8 and 9, enabled the insertion of synthetic gene fragments into the

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heart in order to either replace or repair the defective dystrophin gene. Genetically

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engineered minimized (mini- or micro-) dystrophin or utrophin (the dystrophin homolog) gene transduction has recently provided encouraging findings showing improved sarcolemmal integrity in cardiomyocytes in vivo and displaying reduced

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fibrosis and a normalized heart rate in dystrophin-null mdx mice. Significant

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improvement of calcium homeostasis was observed in mice to which an overexpression vector of SERCA2a was delivered, supporting the potential of gene-

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therapy as a game changer. Another encouraging strategy aims to exclude or skip an

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exon by taking advantage of antisense oligo-nucleotide (AON), which bind to specific splicing sites on pre-RNA (Kole, et al., 2012; Koo, et al., 2013). AON leads to the

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restoration of the reading frame (which was distorted by the mutation, usually causing exons-deletion) and to the production of smaller, though a sufficiently functional

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dystrophin protein. Deletions between exons 44-55, corresponding to the rod domain of the protein, account for nearly 75% of DMD patients and therefore most exon skipping therapies were directed to this region (45 PRO045). Importantly, since cardiomyocytes exhibit a poor AON uptake rate compared with skeletal muscle cells, the additional advantage of chemical modifications, including conjugating AON to nano-particles or to membrane penetrating peptides, provide great physiological benefits in mdx mice, thus paving the way for clinical trials. Stop codons causing protein truncation are another type of lethal mutation. There have been several attempts to 'read through' a stop codon by either gentamycin or drugs interacting with ribosomal subunits. Ataluren is the first drug in this class of

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oral medications, and has been recently approved as a potential therapy for ~ 13% of DMD patients who carry a nonsense mutation. Ataluren’s effect was demonstrated in

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a wide spectrum of diseases caused by nonsense mutations (Welch, et al., 2007) as

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well as in Phase IIa trials in DMD and cystic fibrosis patients (Finkel, et al., 2013). In

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a phase IIb study, 174 patients were randomized to different doses of ataluren or placebo. After a 48-week follow-up there was a reduction in the rate of decline in the 6-minute walk test in the treated patients (medium dose but not high dose). It is

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important to acknowledge that cardiac function was not targeted in any of these trials.

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A Phase III study is currently under way (NCT01826487) Since the defective protein is degraded through the misfolded protein response

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in the endoplasmic reticulum and through the proteasome, a research effort is made to

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prevent complete degradation by interfering with these pathways (Guerriero, et al., 2012). Proteasome inhibitors increased the expression of dystrophin and of associated

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membrane proteins in a murine model and in muscle biopsies of patients with DMD

7.

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and BMD (Gazzerro, et al., 2010).

Arrhythmogenic cardiomyopathy (ACM) Ventricular arrhythmias and fatty replacement of myocardium are the hallmarks

of ACM. This disease was previously called arrhythmogenic right ventricular cardiomyopathy but that term is inapt since up to 50% of cases develop biventricular involvement (Rizzo, et al., 2012). Rarely, the predominant feature of the disease is the involvement of the LV with ventricular arrhythmia (which is disproportionate to the degree of left ventricular dysfunction). The prevalence of ACM is about 1:5000 but due to variable disease expression many cases remain underdiagnosed and this estimate may be inaccurate (Peters, et al., 2004). The disease is an important cause of

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life threatening ventricular arrhythmia in young and middle-age adults and constitutes an important cause of sudden death in athletes. At a later stage, once the arrhythmia is

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controlled, HF becomes the main contributor to morbidity and mortality in this

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disease.

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Genetics: The principal genetic cause of ACM are mutations in the genes that encode for the desmosomal proteins which are responsible for adhesion on adjacent

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cardiomyocytes (Swope, et al., 2013). When sequencing DNA from a patient with the disease, definite mutations will be found in only ~50%, but many patients will have a

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single nucleotide change of unknown significance in one of the candidate genes. These variants may sometimes be found in healthy controls and have a modifying

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effect on the disease phenotype (Kapplinger, et al., 2011). Moreover, at least the

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major known disease genes (PKP2, JUP, DSG2, DSC2, DSP) must be sequenced

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because patients with more than one variant have a higher likelihood of disease (Quarta, et al., 2011).

Diagnosis and clinical course: The diagnosis of ACM is based on the combination of

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clinical, morphological, electrocardiographic and genetic findings, which are divided into major and minor diagnostic criteria as proposed in 2010 (Marcus, et al., 2010). Ventricular arrhythmias, usually of right ventricular origin, are the hallmark of the disease and are usually the presenting symptom. Ventricular dysfunction is common at a later stage but only a minority of patients develop overt HF (Rizzo, et al., 2012). Of note, SCD may occur even before major structural abnormalities occur. This fact emphasizes the importance of identifying family members of a proband (Tabib, et al., 2003). The ECG may show disease-specific epsilon waves or non-specific findings such as RBBB or T wave inversion in the right precordial leads. Visualization of right

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ventricular dilatation with regional dysfunction, often associated with wall thinning and aneurysm formation, is usually required for the diagnosis. Cardiac magnetic

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resonance is particularly useful to identify the right ventricular pathology and the

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extensive patchy delayed gadolinium enhancement which characterizes the left

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ventricular involvement. Cardiac biopsy and electrophysiological studies may be necessary.

Management: Currently, management is primarily focused on the early identification

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and control of ventricular arrhythmias. Competitive athletic activity and strenuous

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physical activity are forbidden since not only may they induce a life-threatening ventricular arrhythmia but may also enhance disease progression (Cruz, et al., 2015;

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James, et al., 2013; Saberniak, et al., 2014). -blockers or antiarrhythmic drugs such

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as sotalol or amiodarone are often used for arrhythmia control and prevention. Patients with aborted SCD and syncope have an indication for implantable

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cardioverter-defibrillator implantation. Another option for recurrent arrhythmia would be a catheter ablation of VT focus (Bai, et al., 2011; Tabib, et al., 2003). There is no

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established therapy for isolated right ventricular dysfunction. Once the LV ventricle starts to fail, patients are treated according to HF guidelines.

8.

Novel therapeutic strategies in familial ACM Based on the theory that reduction in wall stress can prevent progression of the

disease in genetically predisposed patients, a blind trial of preload reduction was held in plakoglobin-deficient mice (Fabritz, et al., 2011). Preload reduction with nitrates and diuretics prevented right ventricular enlargement, right ventricular conduction slowing and the induction of right ventricular arrhythmias. A clinical trial called PreVENT-ARVC, that is based on this approach is about to commence. The human

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trial will use a long-acting nitrate that does not induce nitrate tolerance (PETN) rather than isosorbid nitrates and a combination of a thiazide diuretic and a potassium-saving

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diuretic will be used instead of furosemide (Fabritz, et al., 2012).

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PLN is a regulator of the cardiac sarcoplasmic reticulum Ca2+ pump

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(SERCA2a), and is thus important for maintaining Ca2+ homeostasis. A mutation in the gene for PLN, R14del, was identified in 12% of Dutch patients with ACM and

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15% with DCM (van der Zwaag, et al., 2012), implying an overlap between these two seemingly separate clinical entities. This cohort of patients was more prone to

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arrhythmias with a generally poor prognosis (van Rijsingen, et al., 2014). On the microscopic level, a diminished plakoglobin signal at intercalated disks was

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associated with the ACM phenotype. An ongoing trial (NCT01857856) attempts to

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slow disease progression in presymptomatic patients with R14del using eplerenone, a mineralocorticoid with antifibrotic properties.

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The Wnt / β–catenin signaling pathway is modified by desmosomal proteins. Increased nuclear translocation of plakoglobin suppresses Wnt signaling of cardiac

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progenitor cells. Thus, plakoglobin inhibits myogenesis, while (instead) triggering adipogenesis. Pharmacological or genetic alterations which positively regulate the pathway or prevent plakoglobin nuclear translocation could be a good candidate for the treatment of ARVC.

Finally, PPAR¥s, an adipogenic transcription factor,

demonstrated an important role in the fibro-fatty change during ARVC progression, constituting a therapeutic target.

9.

Restrictive cardiomyopathy (RCM) This is apparently the least common of the inherited cardiomyopathies. It

usually presents as heart failure with severe diastolic dysfunction and normal or

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'preserved' systolic function (indicating LVEF on the lower side of the normal range such as 50%). Enlarged atria and atrial fibrillation are common features (Ammash, et

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al., 2000). The disease may evolve because of a pathological process causing

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cardiomyocyte stiffening, injuries (such as irradiation) which trigger extensive

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interstitial fibrosis or an infiltrative process within the interstitial layer. It is very important to differentiate between restriction and extra-myocardial causes such as constriction and compression as well as to distinguish between the acquired and

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inherited causes of restrictive cardiomyopathy.

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Genetics: The genetics of RCM have some overlap with HCM and indeed, some authors refer to RCM as HCM with a restrictive pattern (Kubo, et al., 2007).

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Regardless of the classification, there are a few sarcomere gene mutations that have

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been linked to RCM or to a mixed RCM/HCM phenotype. Mutations in Troponin I were the first to be identified in RCM families and are thought to cause the disease by

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impaired calcium dissociation from the myofilaments (Menon, et al., 2008). We have recently described a family with a lethal RCM by a de novo mutation in the giant

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filament titin (TTN), which is responsible for the diastolic tension of the sarcomere (Peled, et al., 2014). Other genetic variants are mediated by the intracellular accumulation of a defective protein (desmin), iron, various metabolites in several storage diseases (glycolipid in Fabry’s or mucopolysaccaride in MPS) or an extracellular protein polymer in hereditary amyloidosis.

Diagnosis and clinical course: The common clinical features are effort intolerance, atrial arrhythmias (due to enlarged atria), thromboembolic phenomena and frequent progression to HF with pulmonary and prominent systemic venous congestion. Systemic manifestations may accompany certain subtypes and lead to a specific

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diagnosis. Conduction disease is quite common. When occurring early in the course of the disease, certain conditions should be suspected, such as desminopathy or

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sarcoidosis. The prognosis for RCM is worse than that of HCM patients, death being

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the result of HF, SCD, or cerebrovascular accident (Ammash, et al., 2000; Kubo, et

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al., 2007).

Management: There is no specific treatment for RCM. Treatment focuses on treatment for arrhythmias, symptomatic treatment of HF and, in end stage cases, heart

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transplantation. Hemochromatosis may respond to iron chelation or phlebotomies,

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AL amyloidosis partly responds to hematological therapy and certain metabolic diseases have an enzyme therapy which may stop or slow the disease progression. As

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a rule, once the restrictive phenotype has evolved the prognosis is invariably poor.

10. Novel therapeutic strategies in familial RCM

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Fibrosis constitutes a central mechanism in the evolution of restrictive cardiomyopathy although it has prominent functional and arrhythmic impacts in other

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cardiomyopathy forms. While most evidence based therapies attenuate fibrosis secondary to their principle mechanism of action, so far no specific drug was developed to directly target fibrosis. Several attempts are being made in other forms with restrictive cardiomyopathy, such as diabetic and uremic myocardium and they might eventually be applicable for genetically determined RCM (Gonzalez-Quesada, et al., 2013; C. J. Li, et al., 2012; Lin, et al., 2015).

11. Familial amyloidosis Familial amyloidosis is caused by extracellular deposition of misfolded protein aggregates in various organs such as heart, kidney, gut and nervous tissue. The

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deposition of natural protein involved in the transport of retinol and thyroxine, transthyretine (TTR), causes a slowly progressive cardiomyopathy in the elderly

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called senile amyloidosis. Mutant TTR has a lower stability and gives rise to a

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prevalent form of familial amyloidosis, a maturity-onset disease which may manifest

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as familial amyloidotic polyneuropathy (TTR-FAP) or as cardiomyopathy. Abnormal protein production may be targeted through RNA interference (RNAi) or gene silencing molecule.

This is a novel therapeutic modality that utilizes cellular

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mechanisms of protein production inhibition. The ability to give the small interference

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RNA (siRNA) as a drug has been limited. Lately, however, there is the ability to target these molecules to the relevant organs. Delivery of a siRNA in a lipid

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nanoparticle to patients, as a treatment of TTR-FAP, has recently been tested in a

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phase I trial (Coelho, et al., 2013). This study assessed two different formulations of liver-targeted siRNA in a group of patients with early TTR-FAP and healthy

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volunteers. The result was a significant decline in hepatic TTR production after administration of a single dose with few adverse events. Tafamidis meglumine binds

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the two thyroxine binding sites of TTR thus preventing its dissociation into monomers. Two trials of tafamidis for the treatment of TTR-FAP showed modest, but promising results (Coelho, et al., 2012; Merlini, et al., 2013). The trials differed in the patients' mutations and the follow-up period. Both studies focused on neurological outcomes and quality of life measurements, but the more recently published one also measured cardiac function using several parameters. No deterioration in cardiac function was noted in a follow-up after 12 months, even in patients at high risk for cardiac complications (as assessed by NT-pro-BNP levels). A study of 400 patients to assess the cardiovascular benefit of Tafamidis is expected to end in 2018 (NCT01994889).

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Another strategy for stabilizing the TTR tetramer is by using diflunisal, a nonsteroidal anti-inflammatory (NSAID) drug. Naturally, treatment of patients with CHF

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with an NSAID causes concern, especially due to the risks of hypertension and

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deterioration of renal function. To assess safety and to gather primary efficacy data,

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an open label, single arm and short term trial in 13 patients was conducted (Castano, et al., 2012). A modest decline in renal function was the only adverse effect and in comparison to the TRACS cohort (Ruberg, et al., 2012) there was a trend toward a

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better outcome. A much larger, randomized, double blind study has recently been

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published (Berk, et al., 2013). The outcomes in this trial were focused on neurological parameters. The improvement in these parameters over the course of two years,

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accompanied by only a few serious adverse events holds promise for cardiac

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improvement as well. This study is currently being continued as an observational study with cardiac function being a secondary outcome (NCT01432587).

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A combination of an antibiotic doxycycline with a bile acid TUDCA was shown to remove TTR amyloid deposits in mice (Cardoso, et al., 2010; Obici, et al.,

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2012) and is currently under a phase I trial in humans with Transthyretin Amyloid Cardiomyopathy (NCT01855360). A different target for treatment of amyloidosis is the serum amyloid P component (SAP). This plasma glycoprotein binds to amyloid fibrils and enhances fibrillogenesis. In knock-out mouse for SAP there was a reduction in amyloid deposits (Botto, et al., 1997), and a therapeutic compound CPHPC was thus designed to target SAP. CPHPC forms a complex with SAP that is quickly cleared by the liver. In the first attempt to treat amyloidosis patients of various etiologies there was a dramatic reduction of serum SAP and a sub-total reduction of tissue SAP (Gillmore, et al., 2010). Assessing clinical benefit was more difficult, especially as the patients treated were mostly in advanced stages of the

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disease. In a mouse model of amyloidosis, therapy with CPHAP was augmented by the use of anti-SAP antibodies which resulted in macrophage dependent clearance of

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tissue amyloid (Bodin, et al., 2010). The synergistic effect of CPHPC and an anti-SAP

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antibody is now being tested in a clinical trial (NCT01777243). This might emerge as

12. Metabolic and related cardiomyopathies

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the first effective therapy to reverse the tissue damage inflicted by AL amyloidosis.

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These rare diseases are designated Orphan Diseases and the drugs developed

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are defined as Orphan Drugs. While being unable to account for all possible metabolic defects eventually leading to cardiomyopathy, we chose several classical

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examples, in particular those which may be encountered in an adult cardiomyopathy

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Pompe disease

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clinic.

Glycogen storage disease type II, commonly referred as Pompe disease, is a

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rare autosomal recessive inherited disorder, caused by a deficiency of the lysosomal acid α-glucosidase (acid maltase, GAA) enzyme, resulting in a massive lysosomal glycogen accumulation in cardiac and skeletal muscles. In general, two forms of the disease are considered: the infantile form, characterized by massive cardiac hypertrophy and muscle weakness with a prominent mortality rate during the first year of life due to cardiac and/or respiratory failure; and the late-onset disease form, which is typified by a progressive course of muscle weakness in children. The involvement of respiratory muscles, ultimately leads to premature death. The difference between these two forms of the disease has been shown to originate from the wide variety of mutations on the GAA gene and the level of residual enzyme

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activity. Palliative treatments for Pompe disease include substrate reduction therapy and supportive care (van der Ploeg, et al., 2008).

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Enzyme replacement therapy (ERT) predominantly relies on the ability of

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cells to internalize synthetically recombinant lysosomal enzymes via the mannose-6-

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phosphate receptor pathway followed by their delivery to the lysosomes, where the replacement of the defective enzyme with the functional enzyme occurs. Clinical studies using a recombinant analog of -glucosidase, alglucosidase alfa have shown a

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significant increase in life-span in parallel with prominent decrease of cardiac

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hypertrophy, in both infantile and late-onset forms (Kishnani, et al., 2007). Furthermore, when administered before overt clinical symptoms become apparent, the

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beneficial effect is largely increased. Nevertheless, there are some drawbacks of this

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strategy: the high cost due to the need for life-long repeated infusions of the recombinant enzyme, poor targeting to muscles and enhanced immune response. All

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these led scientists to develop alternative therapeutic strategies for Pompe disease. The combination of ERT with recently introduced innovative strategies holds great

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promise in changing the natural history of the disease. While gene therapy using various viral vectors significantly elevated persistency (over 1 year) and transduction level after only a single systemic delivery, other methods combining ERT with immunomodulatory agents such as methotrexate, account for the immense reduction of immune response against the recombinant enzyme (Joly, et al., 2014). Strikingly, a work by van Til et al., has provided the first evidence for combining both beneficial features by harnessing the immune-tolerance and whole-body distribution capabilities of autologous hematopoietic stem cells (van Til, et al., 2010). Introducing the recombinant enzyme under the strong promotors of viral vectors into these cells, prior to transplantation enabled the major clearance of glycogen in the heart, diaphragm

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and liver and improved muscular strength and cardiac function and remodeling. Another strategy was developed based on the assumption that better delivery of the

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mutant enzyme to the lysosome (where it functions to breakdown glycogen) and

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increased stability of circulating protein would eventually lead to better glycogen

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clearance and improved phenotypic outcome. To address these issues, various pharmacological chaperones were used in conjunction with ERT in Pompe disease fibroblasts and GAA-KO mice, and the findings are extremely encouraging.

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Consequently, a Phase II clinical trial has been initiated for Pompe patients (Khanna,

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et al., 2012). Finally, pioneering experiments in GAA-KO mice have shown that the inhibition of glycogen synthase by either RNA interference techniques or by

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negatively regulating it via its signaling pathway both enhanced the beneficial effect

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of ERT, leading to an immense reduction in lysosomal glycogen storage. Hence, these techniques might be considered as a novel therapeutic option for Pompe patients

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(Clayton, et al., 2014).

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Anderson Fabry disease

Fabry's disease is another X-linked lysosomal storage disease where early

diagnosis is important because of the availability of an effective enzyme therapy. The disease is caused by a deficiency of the lysosomal enzyme β-galactosidase A, leading to the accumulation of globotriaosylceramide (Gb3) in various tissues. Principal manifestations include peripheral and autonomic neuropathy, nephropathy, premature stroke and white matter lesions and cardiomyopathy. Cardiomyopathy usually develops at a relatively advanced stage but constitutes a major cause of mortality. It typically manifests in middle aged males and elderly females as cardiac hypertrophy with diastolic dysfunction and involvement of the conduction tissue which eventually

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leads to conduction block and arrhythmia. While substrate manipulation and supporting care comprising HF medications, pacemaker/defibrillators, dialysis and

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pain control are part of the therapeutic arsenal, ERT revolutionized the natural history

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of this disease, in particular when initiated before the occurrence of irreversible organ

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damage. Novel approaches are developed to potentiate the effect of ERT. A recent study in a mouse model of Fabry disease suggests that abnormal androgen receptor activity is one of the mitigating factors in the development of the disease

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manifestations. In this study (Shen, et al., 2015), increased levels of IGF-1 and

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decreased levels of TGF-β1 were measured in the cardiac tissue of Fabry mice. Castration of asymptomatic mice prevented the development of cardiac and renal

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hypertrophy in the animals. Furthermore, castration of 12-month-old mice (who

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already had cardiac hypertrophy) resulted in a decrease of cardiac weight compared to WT mice. The availability of oral antiandrogens approved for treatment of other

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disorders renders this treatment strategy a viable option. PRX-102 is a novel enzyme produced by BY2 tobacco cell culture. It is a

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homo-dimer with a function equivalent to the current enzyme replacement available for clinical use, but showing a superior stability profile and pharmacokinetics (Kizhner, et al., 2015). PRX-102 is currently being tested in humans (NCT01981720). AT-1001 (Migalastat HCl) is a pharmacological chaperone which improves the folding, stability and lysosomal trafficking of mutant forms of α-galactosidase-A (α-Gal A). It was previously shown to reduce the levels of globotriaosylsphingosine when given as monotherapy in mice and humans (Young-Gqamana, et al., 2013). AT-1001 was recently given in co-formulation with α-Gal A, which resulted in higher tissue levels of the enzyme and lower levels of globotriaosylsphingosine when compared to enzyme replacement therapy alone (Xu, et al., 2015). This drug is

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currently under an extended period trial as monotherapy for certain genetic variants (NCT02194985).

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Efficacy of enzyme and substrate reduction therapy for Fabry disease with a

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novel antagonist of glucosylceramide synthase has been reported (Ashe, et al., 2015).

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A recent study discovered two new drugs that might be potential enhancers of pharmacological chaperones. The expectorant ambroxol, especially in combination with migalastat, raised α-Gal A levels in a cell free thermal denaturation test. . The

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PPAR-γ agonist rosiglitazone, was also tested in a similar modal, and showed

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promising results, especially in combination with migalastat (Lukas, et al., 2015).

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Danon disease

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Danon disease is caused by LAMP2 defects leading to the inability to complete the autophagic process. The lysosomes fail to fuse with autophagosomes

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and the cell is left with undegraded contents such as protein aggregates, malfunctional organelles and old glycogen. For this reason the disease was originally named Pompe

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with normal acid maltase. Danon disease is a natural example of a primary failure of autophagy. It is now appreciated that secondary impairment of autophagy also contributes to the pathophysiology of other lysosomal storage diseases by the accumulation of toxic protein aggregates and defective mitochondria (Choi, et al., 2013). Danon's is an X linked disease and therefore males are more severely affected. Typically, a teenage boy has rapidly progressive hypertrophy which may reach extreme dimensions and be associated with Wolff–Parkinson–White (WPW) syndrome and arrhythmia (Arad, et al., 2005). Over several years, the heart progresses to the hypokinetic stage and develops severe HF leading to death unless heart transplantation takes place. Mental issues ranging from mild learning deficits to overt

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retardation and skeletal involvement ranging from asymptomatic CK elevation to overt myopathy are present

concomitantly or precede the diagnosis of

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cardiomyopathy. Male patients also have transaminase elevation without clinically

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significant liver disease (Arad, et al., 2005). Women present in adulthood as

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hypertrophic or dilated cardiomyopathy, sometimes in association with WPW syndrome or AV block. Teenage and young-adult presentation is also possible due to skewed X inactivation. Electrophysiological abnormalities follow, but may precede

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the development of cardiomyopathy. Enzyme abnormalities are uncommon in

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females. Because the stress of pregnancy and labor may lead to HF, some cases are wrongly diagnosed as peripartum cardiomyopathy and correct diagnosis is reached

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only after the development of a typical disease in a male offspring (D'Souza R, et al.,

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2014). Much needs to be learned about the fascinating process of autophagy wherein the cell recycles its defective components, removes its waste and adjusts to ongoing

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stresses. Modification of the processes triggering autophagy may help modify the course of this lethal disease while a targeted protein therapy would facilitate the

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restoration of the lysosomal function in Danon's disease. Impaired autophagy has a secondary role in other cardiomyopathies such as classical lysosomal storage diseases, protein aggregate diseases (such as desminopathy which causes dilated or restrictive cardiomyopathy with AV block), hypertrophic cardiomyopathy by MyBPC3 mutations and dilated cardiomyopathy by titin splice-variants (Choi, et al., 2013; Lieberman, et al., 2012; Schlossarek, et al., 2014). Interestingly, activating autophagy (Bhuiyan, et al., 2013) helps prevent the progression of desmin-like cardiomyopathy while inhibiting autophagy actually potentiates the effect of enzyme therapy in experimental Pompe disease. These findings are very important because autophagy

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appears to be a modifiable process amenable to drug therapy (Kroemer, 2015;

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Vakifahmetoglu-Norberg, et al., 2015).

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Mitochondrial DNA mutations and defects of oxidative phosphorylation manifest as a multisystem disease. As opposed to defects of oxidative phosphorylation caused by nuclear DNA mutations, which quite uniformly present in infancy, the presentation of

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mitochondrial DNA defects is more variable and age-dependent, related to tissue distribution of defective mitochondria, mutation load and mitochondrial aging

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(Holmgren, et al., 2003; Scaglia, et al., 2004). Organ dysfunction is caused by energy deficiency, oxygen radical damage and proapoptotic signaling by the damaged

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mitochondria. Oxygen radical scavengers have a variable efficacy. Novel

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mitochondrial protective agents such as bendavia (Brown, et al., 2014; Eirin, et al.,

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2014) may be useful in future to modify the disease course until a definitive therapy to correct the underlying defect is available.

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Friedreich's ataxia is an autosomal recessive neurodegenerative disease caused by frataxine mutations. Frataxin is located within the mitochondria and its defects are considered to cause abnormal iron ion accumulation and oxygen radical damage. Cardiac presentation is variable but usually manifests as hypertrophic cardiomyopathy eventually progressing to HF with conduction abnormalities. Oxygen radical scavengers (idebenon) have a variable effect on neurological function while the iron chelator diferipron seems to attenuate cardiac hypertrophy. Approaches to promote frataxine expression by small molecules or histone deacetylase inhibitors are also being promoted but have not yet reached the clinical experimentation stage (Gottesfeld, 2007).

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13. Summary

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The spectrum of potential approaches to treat inherited disorders, in particular

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genetically-determined cardiomyopathies, is rapidly evolving due to an access to

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molecular targets which were not available in the past (Table 1, Figure 1). While gene editing strategies to eliminate the mutation are effective at the bench but have not yet been accomplished at the bedside, techniques to restore the RNA reading frame or to

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silence pathogen expression have already arrived at the clinical arena. Chaperones are

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used to prevent degradation of abnormal but still functional proteins while other molecules are being introduced to prevent aggregation or enhance the clearance of

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protein deposits. Absence of protein may be managed by viral gene delivery or

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protein therapy. Enzyme replacement therapy is already a reality for a series of metabolic diseases. The progress in molecular biology, triggered by knowledge of the

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gene defect and analysis of the secondary responses ameliorates the understanding of the molecular pathways involved in disease pathophysiology. This helps generate

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small molecules and pharmaceuticals targeting the key events occurring in the malfunctioning element of the sick organ. Finally, improved symptomatic medical care and phenotype-based evidence-based medicine developed to treat common disorders, is being applied to inherited cardiomyopathies, offering a greater choice of available options for every one of these rare conditions (Figure 1). Introducing a novel therapy for a rare disease is typically hampered by the difficulty of enrolling an adequate number of patients for a clinical trial to demonstrate an unequivocal benefit of the new medicine. Ethical issues such as administration of placebo to critically ill subjects, as well as delaying drug registration until obtaining an unequivocal proof of efficacy, have to be dealt with sense but with

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determination. Drugs used for rare genetic diseases are often designated Orphan Drugs necessitating huge resource allocation for a small subgroup of patients and for

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protracted/lifelong periods of care. It is the role of the regulatory authorities to define

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the population which is expected to benefit most from any given intervention and the

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reasonable threshold for cost-efficacy. Some patients are always discouraged by such restrictions but their hope has to be mobilized to motivate participation in clinical

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14. Conflict of Interest Statement

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trials facilitating the optimization of care and new drug development.

References

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15.

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The authors declare that there are no conflicts of interest.

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Figure legend Figure 1: Potential approaches to target inherited cardiomyopathies.

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Mutation-based approaches try to fix the mutation or ameliorate the defect on the

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level of protein translation. Alternatively an attempt may be made to prevent a

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complete loss of a defective, but still functioning protein. Proteins where structural integrity is essential for function (such as enzymes) may need to be replaced. A phenotype-based approach tries to identify specific key molecular mechanisms which

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may be targeted by small molecules or overexpression of gene products. The entire

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cardiac tissue may be modified by means of cell therapy and extracellular matrix modification. Finally, gradual progress is continuously made in defining evidence-

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based therapies for different types of cardiac diseases.

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Table 1: Mechanisms and treatment strategies of main subtypes of inherited cardiomyopathies Type Genetics Principal Current Novel interventions and future mechanisms treatment targets

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Symptomatic, ICD implantation, stroke prevention, myectomy/septal reduction for persistent symptoms.

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Increased Ca2+ sensitivity, energy deficit

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Mostly autosomal dominant: Mutations in genes encoding components of the sarcomere or Zdisc. Significant phenotypic heterogeneity.

Mostly autosomal dominant: results from defects in multiple cellular components with a final common pathway of deranged cardiomyocytes contraction

Variable: decreased Ca2+ sensitivity: disruption of sarcolemmal integrity and ion function; impaired force transmission due to cytoskeletal damage; altered gene expression; apoptosis

Early diagnosis treatment as in other forms of systolic dysfunction.

Symptomatic. Corticosteroids, ACE inhibitors/beta blockers to prevent systolic dysfunction, non-invasive ventilation and removing secretions Antiarrythmics, banning of intense physical activity, ICD implantation

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Dilated CM

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Hypertrophic CM

Duchenne/Becker Muscular Dystrophy (DMD)

X-linked inheritance: Dystrophin gene mutations

disruption of sarcolemmal and cytoskeletal structure and function

Arrhythmogenic CM

Mutations in the genes that encode for the desmosomal proteins which are responsible for cell to cell adhesion

Impaired adhesion and electrical conductance between adjacent cardiomyocytes

- Ca2+ homeostasis: Blebbistatin, parvalbumin adenoviral delivery of SERCA2a, dialtiazem - Gene transfer: recombinant viral vectors of cMyBPC - Diversion of myocardial substrate utilization: perhexilin, trimetazidine, ranolazine - Preventing fibrosis: Aldosterone/ARB blocakade: Spironolactone, eplerenone, losartan, candesartan - Immune system modulation: immunoabsorption, COR-1 cyclopeptide - N-3 polyunsaturated fatty acids (nPUFA) - Gene-therapy: SERCA2 gene - Intracoronary stem cells transplantation (CD34+ cells) - Tissue repair and regeneration: Ixmyelocel-T - Ca2+ sensitization: levosimendan, pimobendan, EMD 53998, MCI-154 - Cardiac myosin activators: omecamtiv mecarbil - Gene-therapy: Dystrophin or utrophin, SERCA2a - Reading frame restoration: Antisense Oligo-Nucleotide (AON) - ‘Read through’ therapy: ataluren - Proteasome inhibitors

- Wall stress reduction: combining afterload reduction and diuretics - Mineralocorticoid therapy - Wnt / β–catenin signaling pathway - PPAR-ɣ

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Cardiomyocyte dysfunction and death due to storage, arrested autophagy, energetic deficit and ROS damage

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Autosomal recessive, x-linked or maternal (in mitochondrial diseases). Caused by enzyme deficiency or defects in oxidative phosphorylation

Symptomatic treatment for heart failure, arrhythmias and hypotension

- Fibrosis attenuation - Small interference RNA - Prevention of TTR fibril formation: tafamidis meglumine, diflunisal - Removal of TTR amyloid deposits: doxycycline plus TUDCA Clearance of serum amyloid protein (SAP): CPHAP

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Wall stiffening due to intracellular or extracellular substrate accumulation, or myocardial fibrosis

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Metabolic CM

Mutations in sarcomere genes causing severe fibrosis or gene defects that cause intracellular or extracellular accumulation of various substances (e.g., desmin, glycolipid, iron, amyloid protein)

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Restrictive CM

Substrate modification, substrate supplementation, enzyme replacement therapy, antioxidants

- Novel enzyme replacement therapy: PRX-102 - Pharmacological chaperone: Migalastat HCl - Enhancers of pharmacological chaperones: Ambroxol, Rosiglitazone Mitochondrial protectors

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Figure 1