Heart failure: The pivotal role of histone deacetylases

The International Journal of Biochemistry & Cell Biology 45 (2013) 448–453

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Medicine in focus

Heart failure: The pivotal role of histone deacetylases Ruth Hewitsona , James Dargana , David Collisa , Aneta Greena , Narain Moorjanib , Sunil Ohrib , Paul A. Townsendc,∗ a

Cancer Sciences, Faculty of Medicine, Southampton General Hospital, University of Southampton, Southampton SO16 6YD, UK Wessex Cardiac Centre, Southampton General Hospital, University of Southampton, Southampton SO16 6YD, UK Faculty Institute for Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Research Floor, St Mary’s Hospital, Oxford Road, Manchester, M13 9WL, UK b c

a r t i c l e

i n f o

Article history: Received 20 July 2012 Received in revised form 16 October 2012 Accepted 13 November 2012 Available online 22 November 2012 Keywords: Heart failure Hypertrophy Histone deacetylase HDAC

a b s t r a c t Heart failure, a state in which cardiac output is unable to meet the metabolic demands of the tissues, poses a significant health burden; following an initial hospital admission with heart failure, five-year mortality is close to 50%. Cardiac hypertrophy, characterised by increased cardiomyocyte size and protein synthesis, has deleterious effects when prolonged and contributes to heart failure. Cardiac hypertrophy itself increases risk of morbidity and mortality. Histone deacetylases are chromatin modifiers which deacetylate the N-terminal tails of histones and have been implicated in common cardiac pathologies associated with hypertrophy. There are 18 histone deacetylases separated into four classes. Class I histone deacetylases interact with heat shock proteins and are pro-hypertrophic, class IIa histone deacetylases repress hypertrophy by inhibiting the activity of transcription factors such as myocyte enhancer factor 2. Histone deacetylases present an exciting new target in combating cardiac hypertrophy and progression to heart failure. © 2012 Elsevier Ltd. All rights reserved.

1. Introduction: heart failure Key facts • Cardiac hypertrophy is characterised by increased cardiomyocyte size and protein synthesis and contributes to the development of heart failure, which increases morbidity and mortality. • The chromatin modifiers, histone deacetylases (HDACs), exert both pro- and anti-hypertrophic effects on the heart. • Class I histone deacetylases, which interact with heat shock proteins, are pro-hypertrophic. Class IIa histone deacetylases inhibit the activity of transcription factors such as myocyte enhancer factor 2 and repress hypertrophy. • Many HDAC targets are transcription factors that act on the cell cycle; HDAC inhibitor (HDACi) species are used successfully in the treatment of cutaneous T-cell lymphoma and rheumatoid arthritis. Due to involvement of HDACs in cardiac hypertrophy via multiple pathways, HDACis may offer therapeutic benefit in heart disease.

1.1. The burden of heart failure Cardiovascular disease remains the number one cause of mortality worldwide (World Health Organisation, 2012). Common pathologies such as hypertension, ischaemic heart disease and valvular heart disease can ultimately lead to heart failure, a state in which cardiac output is unable to meet the metabolic demands of the tissues. Following an initial hospital admission with heart failure, five-year mortality is close to 50%, highlighting the requirement for more effective strategies to combat heart disease (Lloyd-Jones et al., 2009). Fundamental to heart failure is cardiac remodelling characterised by hypertrophy, cell death and fibrosis (Kee and Kook, 2011). Such events are a consequence of cellular changes that commonly involve the reactivation of foetal genes with consequent cardiac growth and repression of calciumhandling and cardiac contractile proteins (Barry and Townsend, 2010). As many signalling pathways lead to the remodelling integral to heart failure, new therapeutic strategies aim to target the downstream mediators, where many of these pathways converge (McKinsey, 2012). 1.2. The role of hypertrophy in heart failure

∗ Corresponding author. Tel.: +44 (0)161 701 6923; fax: +44 (0)161 701 6919. E-mail address: [email protected] (P.A. Townsend). 1357-2725/$ – see front matter © 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.biocel.2012.11.006

Cardiac hypertrophy, an initial adaptive response to increased pathological stress of the heart, has deleterious effects when

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prolonged and contributes to heart failure (Barry and Townsend, 2010). Characterised by increased cardiomyocyte size, protein synthesis and organisation of the sarcomere, hypertrophy is associated with volume and pressure overload states, myocardial infarction, cardiomyopathies and myocarditis (Kee and Kook, 2011). Though the heart enlarges to compensate for increased demand, the cardiomyocytes are structurally and functionally inadequate to accommodate these changes leading to loss of cardiomyocytes via apoptosis or necrosis with subsequent fibrosis. In contrast, physiological cardiac hypertrophy, witnessed in pregnant women and athletes, is associated with normal cardiac structure. Cardiomyocyte hypertrophy and enhanced sarcomere synthesis without pathological remodelling permits normal or enhanced cardiac function (McMullen and Jennings, 2007). In pathological hypertrophy, impaired contraction leads to a reduced ejection fraction during systole and impaired relaxation results in inadequate filling during diastole. Thus, cardiomyocyte death poses further stress on the heart, perpetuating the deleterious cycle with progression to cardiac failure (Green et al., 2012). Hypertrophy itself also increases risk of morbidity and mortality and as such represents a significant target in limiting the progression of heart disease (Vakili et al., 2001). 2. Pathogenesis: mechanisms of hypertrophy 2.1. Transcriptional regulation of hypertrophy Nuclear factor of activated T cells (NFAT), GATA, serum response factor (SRF), calmodulin-binding transcription factor (CAMTA) and myocyte enhancing factor 2 (MEF2) are master regulators common to most hypertrophic pathways (Barry and Townsend, 2010; Davis et al., 2003; Song et al., 2006). MEF2, a MADS-box transcription factor, is potently pro-hypertrophic and drives expression of several cardiac genes including atrial natriuretic peptide (ANP) and troponins (Barry and Townsend, 2010). In pressure overload models, reduced expression of MEF2D decreases left ventricular dilation, myocyte hypertrophy and fibrosis whereas over-expression induces severe cardiac hypertrophy (Kim et al., 2008). Many signals integrate to induce activation of MEF2 including those from MAPKs and calcium handling; one major mechanism of regulation is the epigenetic control of MEF2 by chromatin modifiers. In particular, the proteins governing acetyvlation status of histones appear most significant in MEF2-related hypertrophic changes (Barry and Townsend, 2010). 2.2. Chromatin modification Histones are subject to post-translational modifications owing to long N-terminal tails (Kee and Kook, 2011); acetylation status is central to gene expression and is controlled by two opposing protein families; histone acetyl transferases (HATs) and HDACs. The former acetylates lysine residues on histones, relaxing chromatin structure and permitting access of transcription factors to DNA. HDACs, the opposing regulators of histone acetylation, remove acetyl groups from lysine residues and have been implicated in a variety of cardiac diseases including arrhythmias, acute coronary syndromes and heart failure. They have been demonstrated to play a role in autophagy, fibrosis, contractility and energy metabolism and influence both the development and repression of cardiac hypertrophy (McKinsey, 2012).

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cytoplasm and nucleus and are more tissue specific. Class III HDACs, more commonly known as sirtuins, are known to exist in the nucleus, cytoplasm and mitochondria of the cell. Class II HDACs are further divided into two groups: IIa (HDAC4, 5, 7 and 9) and IIb (HDAC6 and 10). Evidence from murine models demonstrates that classes I and IIa HDACs are pro- and anti-hypertrophic respectively via distinct molecular pathways, and that both can play a potentially significant role in cardiovascular disease (Kee and Kook, 2011). 2.3.1. Class I HDACs A significant body of evidence implicates class I HDACs in cardiac cell growth and proliferation, pathological hypertrophy, ischaemic heart disease and arrhythmia. Embryonic lethality is witnessed in HDAC1 deficient mice due to cardiac proliferation defects (Lagger et al., 2002) and HDAC2 deficient mice initially appeared to be resistant to hypertrophic stimuli using a gene trap technique (Trivedi et al., 2007). However, the results were disputed by Montgomery et al. (2007) who demonstrated a conditional knock-out of cardiac HDAC2 was insufficient to block hypertrophy. The latter also indicated that global deletion of HDACs 1 or 2 cause embryologic or perinatal mortality. Suggesting that the LacZ insertion lines of Trivedi et al. (2007) were creating a hypomorphic allele rather than a true null, the remaining levels of HDAC2 were sufficient for murine viability. Montgomery et al. also showed that there was no phenotype associated with a single cardiac specific HDAC knockout (Montgomery et al., 2007). This suggests a greater role for class I HDACs in non-cardiac specific progression of hypertrophy. HDAC3 suppresses hypertrophy while enhancing proliferation; mice over-expressing HDAC3 have ventricular and septal thickening at neonatal day 1 but at 2 months do not have an increased proliferation index (Trivedi et al., 2008). Recently, HDAC1 presence has been demonstrated on sarcomeres in hypertrophied cardiomyocytes. This could contribute to a reduction in cardiac contraction following deacetylation of sarcomeric proteins and loss of molecular regulation (Green et al., 2012). 2.3.2. The pro-hypertrophic mechanism of HDAC2 In response to hypertrophic stresses it has been found that HSP70 activates HDAC2 with subsequent hypertrophy. Conversely, HSP70 knock-out mice do not recruit HDAC2 and hypertrophy is reduced (Kee et al., 2008). Therefore the interaction between HDAC2 and HSP70 appears critical in the pro-hypertrophic signalling cascade. An important downstream target of HDAC2 is Inpp5f which mediates cardiac hypertrophy via the phosphatidylinoditol 3kinase (PI3 K) Akt-Gsk3␤ pathway. HDAC2 levels augmented by HSP70 reduce Inpp5f expression causing a build-up of inositol3,4,5-triphosphate (PIP3 ). Accumulated PIP3 activates Akt which suppresses Gsk3␤, relieving pro-hypertrophic pathways like ␤catenin from inhibition (Trivedi et al., 2008). Inpp5f knock-out mice have a greater hypertrophic response and mice over-expressing Inpp5f are resistant to hypertrophy (Zhu et al., 2009). Enzymatic activation of HDAC2 precedes hypertrophy in response to hypertrophic stimuli, and hypertrophy is not observed with mutant HDAC2 (Kee et al., 2008). However, certain HDACs regulate hypertrophy independent of catalytic activity. A splice variant of HDAC9, MEF2 interacting transcription repressor (MITR), has anti-hypertrophic potential but lacks the deacetylase domain suggesting that its existence alone is effective in this role (Kee and Kook, 2011).

2.3. Histone deacetylases (HDACs) There are 18 HDACs divided into four subclasses: class I HDACs (HDAC1, 2, 3 and 8) are nuclear proteins ubiquitously expressed in cells, whereas classes II and IV HDACs are found in both the

2.3.3. Class IIa HDACs There is much evidence in the literature highlighting class IIa HDACs as negative regulators of hypertrophy in cardiac disease. HDAC5 knockout mice develop hypertrophy in response to

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pressure overload and correspondingly, over-expression blocks hypertrophy in response to the same stimuli (Chang et al., 2004). Similarly, HDAC9 deficient mice with thoracic aortic banding develop cardiac hypertrophy more readily and a mutant form of HDAC9 confers cardiac hypertrophy with advancing age (Zhang et al., 2002). Knocking out both HDAC5 and HDAC9 gives an even greater hypertrophic phenotype (Chang et al., 2004). 2.3.4. Class IIa HDACs and MEF2 Collective research demonstrates that class IIa HDACs exert their anti-hypertrophic effects via repression of MEF2. Class IIa HDACs associate with MEF2 in the cell nucleus, inhibiting HDAC activity. However, in the presence of kinases such as protein kinase C (PKC), protein kinase D (PKD) and calcium/calmodulin-dependent protein kinase (CaMK), they are phosphorylated and exported from the nucleus to the cytoplasm, with subsequent MEF2 activation and hypertrophy (Kee and Kook, 2011). The presence of PKC and PKD are dependent upon G-protein coupled receptors for catecholamines, angiotensin, endothelin, the activation of G protein Gaq/11 and the secondary messengers phospholipase C (PLC) and diacylglycerol (DAG) (Shah and Mann, 2011). Movement of HDAC4 and 5 from the cytosol into the nucleus, induced by silencing mediator for retinoic acid and thyroid hormone receptors (SMRT), has been shown to lead to the repression of MEF2 (Barry and Townsend, 2010). HDAC4 and 5, but not MEF2 levels, are lower in nuclear fractions of left ventricular specimens taken from human failing heart compared to non-failing control. Further, CaMK, PKD1 kinase and HDAC kinase are found at higher levels in failing hearts. Thus, in the human failing heart, class II HDACs are exported from the nucleus due to increased phosphorylation activity and the action of chaperone protein 14-3-3 (Calalb et al., 2009). As well as controlling MEF2 activity via nuclear association, HDAC4 also induces phosphorylation of MEF2 by the kinase Cdk5, which further represses its activity (Barry and Townsend, 2010). Further investigation by Backs et al. (2011) revealed an equilibrium in the healthy heart. Acute ␤-adrenoceptor (␤AR) stimulation activates protein kinase A (PKA) which, through proetolysis of HDAC4, produces HDAC4-NT (HDAC4 1-201). HDAC4-NT is a selective repressor of MEF2, preventing stress induced cardiac remodelling, while sparing SRF which maintains cardiac myocyte integrity. This prevents a hypertrophic response to a nonpathological stressor such as exercise (Fig. 1a). In chronic ␤AR stimulation, seen in heart failure, PKA activation decreases but CaMKII signalling is activated. In addition to the translocation of HDAC4 and the loss of its MEF2 repressor qualities, the accumulation of HDAC4 in the cytosol has pathological consequences and is associated with increased apoptosis. HDAC4 has been shown to be cleaved by caspases at Asp-289 (Liu et al., 2004) to form HDAC4 1–289, which represses SRF leading to cardiomyopathy and chronic hypertrophy (Backs et al., 2011) (Fig. 1b). CaMKII␦ knock-out models are resistant to heart failure (Ling et al., 2009), hypertrophy and cardiac remodelling (Backs et al., 2009) suggesting a more significant role for this isoform in cardiac disease. CaMKII activation has also been shown to cause the transphosphorylation and exportation of HDAC5 to the cytosol through its direct association and oligomerisation with HDAC4, also increasing the loss of HDACIIa MEF2 repressor function (Backs et al., 2008). Therefore HDAC4 is acting as a bipolar integrator of PKA and CaMKII and its effects on cardiac gene expression are modulated through MEF2 and SRF. There has been a recent focus on the interactions of HDACs and MicroRNA (miR), specifically miR-1 which has been shown to inhibit MEF2A and the resulting pro-hypertophic calmodulin–calcineurin–NFAT signalling pathway (Ikeda et al., 2007).

Fig. 1. (a) MEF2 regulation by class II HDACs. Class IIa HDACs, especially HDAC4, associate with the strongly hypertrophic transcription factor MEF2, maintaining its inactivity through nuclear association and the inhibitory actions of Cdk5. Acute ␤AR activation leads to HDAC4 cleavage by PKA to form HDAC4-NT (HDAC201). HDAC4NT selectively represses MEF2 while sparing the cardioprotective functions of SRF. Thus preventing cardiac remodelling and heart failure. (b) The effects of chronic ␤AR signalling. CaMKII, PKC and PKD signalling cause the activation of MEF2 via phosphorylation of HDAC4. CaMKII and HDAC4 transphosphorylate HDAC5 and are translocated to the cytosol by chaperone protein 14-3-3 (C). HDAC4 is cleaved by caspase 3 at Asp-289 to form HDAC4 1–289 which inhibits SRF. Activation of MEF2 and inhibition of SRF leads to pro-hypertrophic transcription and heart failure.

The cardio-specific miR-208 negatively regulates systemic energy homeostasis through MED13, leading to obesity, hypercholesterolaemia, hyperglycaemia and reduced cardiac function due to pathological cardiac remodelling (Grueter et al., 2012). In addition to MEF2, GATA4 and NFAT are both repressed by association with the class II HDACs. Further, SRF-mediated transcriptional activity and hypertrophy is repressed by its association with HDAC4 in the nucleus. Hypertrophic stimuli such

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as angiotensin II and ionomycin disturb the SRF/HDAC4 interaction and HDAC4 translocates to the cytoplasm with subsequent pro-hypertrophic transcription (Davis et al., 2003). Thus, several transcription factors responsible for cardiac hypertrophy are controlled by HDAC location (Barry and Townsend, 2010). In fact, excluding HDAC3 which modifies MEF2 directly, deacetylase activity is not critical for the repression of hypertrophy by class IIa HDACs (Gregoire et al., 2007). 2.3.5. Class III HDACs The class III HDACs are members of the silencing information regulator 2 (Sir2) family of proteins. There are seven Sir2 family members in mammalian cells known as SIRT1-7, or sirtuins, and these deacetylases are intrinsic to the regulation of chromatin structure. Distinct from other HDAC classes, sirtuins are not modulated by many of the inhibitor species of the classes I, II and IV HDACs, such as TSA. In addition sirtuins require the presence of the metabolic cofactor NAD+ to facilitate deacetylation, this differs mechanistically from classes I and II HDACs which utilise a zinc ion for acetyl group hydrolysis in deacetylation (Barry and Townsend, 2010). Sirtuin activity is linked to many distinct metabolic and stress response pathways. Recent research suggests sirtuin modulation may have beneficial effects in the treatment of a number of human diseases, including heart failure (Villalba and Alcain, 2012; Chong et al., 2012). Of the seven sirtuin types SIRT1 and SIRT3 have been most extensively investigated in the cardiovascular system, with emerging evidence suggesting they play a protective role in the progression of heart failure. Their biological function includes regulation of energy production, detoxification of oxidative stress, intracellular signalling and Ca2+ handling, the promotion of angiogenesis and autophagy and suppression of cell death. Derangement of these physiological processes underlies heart failure progression and through pharmacologic activation of SIRT1 and/or SIRT3 disease amelioration has recently been achieved in animal models (Tanno et al., 2012). Recent work on SIRT6 has shown how favourable modification of cellular processes through deacetylation slows heart failure progression. In vitro studies have suggested SIRT6 suppresses cardiomyocyte hypertrophy via its interaction with nuclear factor kappa-B (NF-␬B). This protective activity occurs through SIRT6 acting to inhibit NF-␬B transcriptional activity (Yu et al., 2012). Our understanding of sirtuins role in cardiac cell biology requires much further work, though preliminary research suggests a sirtuin-activating compound could be a promising future therapeutic in the treatment of heart failure. 2.3.6. The effect of acetylation status on non-histone proteins HDACs influence hypertrophy by association with and deacetylation of several other non-histone proteins. ␣-Tubulin, which is deacetylated by HDAC6, is increased in an animal model of heart failure and represents a marker of hypertrophy (Kee and Kook, 2011). Cytosolic HDAC4 has also been implicated in the regulation of cardiac myofilament contraction through interactions with the Z-disc-associated muscle LIM protein (Gupta et al., 2008). Further, the significance of connexin 43 acetylation status has recently been investigated. GAP junctions, which facilitate electrical impulse transmission between individual cardiac myocytes, are comprised of two connexon hemi-channels in adjacent cardiomyocyte membranes. Connexons themselves are formed of six connexins, of which connexin 43 (Cx43) is most abundant in the heart. In the Duchenne’s Muscular Dystophy Mouse Heart Model (mdx), acetylation of Cx43 by histone acetylases is enhanced in conjunction with lateralisation and gap junction dissociation. Such effects are reversed with anacardic acid, an histone acetylase inhibitor. Fittingly, treatment with the HDACi, suberoylanilide

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hydroxamic acid, causes Cx43 dissociation from the gap junction and reduced cell permeability. Thus, the pivotal role of Cx43 in effective electrical conduction within the heart via cardiomyocyte coupling may be, in part, governed by its acetylation status (Colussi et al., 2011). Non-histone targets of HDACs can also be master transcriptional regulators; HDAC3 deacetylates STAT3 and E2F1, which controls initial cell cycle progression, is deacetylated by HDAC1. Furthermore, HDAC1 acetylates the p53 tumour suppressor gene (Kee and Kook, 2011). Such information has contributed to the successful development and use of HDACis in certain cancers (see Section 3.1). 3. Pharmacological implications 3.1. HDAC inhibitors The impact of HDACis has been proven pharmacologically and genetically. An older style HDACi, sodium valproate, inhibits progression of hypertrophy and fibrosis in rats with right ventricular hypertrophy following pulmonary artery banding (Cho et al., 2010). A more recent hydroxymate, trichostatin A (TSA), confers similar protection in an aortic banding model of left ventricular hypertrophy in mice (Kong et al., 2006). Class I HDAC-specific inhibition attenuates heart failure and mortality induced by thoracic aortic constriction in mice (Gallo et al., 2008). A potential role for HDACis in acute coronary syndromes has also been demonstrated using a murine model of ischaemia-reperfusion injury, HDAC inhibition was found to reduce infarct size and enhanced ventricular recovery (Granger et al., 2008). TSA and valproate are non-selective HDACis; given that non-specific inhibitors confer anti-hypertrophic effects on the myocardium and class II HDACs are considered protective against hypertrophy, class I HDACs are strongly implicated in the prohypertrophic mechanism. 3.2. Current use of HDAC inhibitors There are four main classes of HDACis: hydroxamic acids, benzamides, short-chain fatty acids, and cyclic peptides. The zincchelating activity of the hydroxamic acids confers broad inhibitory activity whereas benzamides are selective for HDACs 1, 2 and 3. The varied selectivity profiles provide the potential for closer investigation of the significance that HDAC isoforms play in the pathology of different diseases (McKinsey, 2012). HDACis are used successfully in the treatment of cancer by targeting the transcription factors required to successfully complete the S and M phases of the cell cycle, preventing neoplastic replication and inducing apoptosis. Vorinostat, a broad inhibitor of zinc dependent HDACs, was approved in 2006 for the treatment of cutaneous T-cell lymphoma (Duvic et al., 2007). Recently, HDACis have been demonstrated to attenuate the invasion of thyroid cancer cells (Borbone et al., 2010) and induce apoptosis in colorectal cancer cells (Wilson et al., 2010). TF2357, a broad-spectrum HDAC inhibitor, is efficacious in reducing inflammation at low doses in patients with systemic onset juvenile idiopathic arthritis (McKinsey, 2012). Furthermore, it has recently emerged that HDACis can suppress bone loss in rheumatoid arthritis (Joosten et al., 2011). Efficacy at low doses supports a role for HDACis in the treatment of chronic disease (McKinsey, 2012). 3.3. HDAC inhibitors for the treatment of heart failure Due to the plethoric ways in which HDACs control the development of hypertrophy, HDACis will have multiple mechanisms of

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fatigue and thrombocytopoenia seen in up to 50% of phase II trials (Subramanian et al., 2010). 4. Concluding remarks HDAC inhibition has been successful in repressing hypertrophy in rodent models, and given that HDACis are well-tolerated as oncological treatment at higher concentrations than would be administered for chronic disease, it may be that HDAC inhibition represents an exciting new strategy in the treatment of heart disease and prevention of heart failure. However, little is known about the relative contribution and involvement of the different HDAC isoforms in human heart failure and the various cardiac pathologies associated with hypertrophy. HDAC isoform-selective inhibitors for the treatment of specific cardiac diseases would be desirable; the next step in this strategy involves discerning which HDACs are associated with which cardiac pathologies. Fig. 2. Possible mechanisms of anti-hypertrophic HDACis. In response to hypertrophic stimuli, HDACs 1 and 2 initiate pro-hypertrophic mechanisms. It is thought that HDACis may repress cardiac hypertrophy by disrupting these mechanisms. This may occur via HDACis encouraging the activity of anti-hypertrophic transcription factors, such as kruppel-like factor 4 (KLF4), through reducing the inhibition of these factors that is exerted by HDACs 1 and 2. Further, HDACis may suppress cardiac hypertrophy via reducing sodium-calcium exchanger 1 (NCX1) expression, by blocking the HDAC-induced deacetylation of NKX2.5.

action on many cells. That HDACs also influence cell death, inflammation, fibrosis and contractility serves only to increase the ways in which HDACis can protect against heart failure (McKinsey, 2012). One suggested anti-hypertrophic mechanism of HDACis is via increased expression of kruppel-like factor 4 (KLF4). In cultured cardiomyocytes, over-expression of this anti-hypertrophic transcription factor protects against agonist-induced hypertrophy (Kee and Kook, 2009). Conversely, repression of certain factors also represents an anti-hypertrophic mechanism. During cardiac hypertrophy, HDAC1 deacetylates the Nkx2.5 transcription factor which stimulates sodium–calcium exchanger (NCX1) expression. In the presence of TSA, Nkx2.5 is acetylated and there is reduced NCX1 transcription (Fig. 2) (Chandrasekaran et al., 2009). How efficacious HDACis might be in the treatment of human heart failure will depend on their cardiac-isoform selectivity, and as yet there is little literature published on this topic (McKinsey, 2012). Pan HDACi, such as vorinostat, show little selectivity. HDAC I inhibition selectivity is demonstrated by the short chain fatty acids and aminobenzides show selectivity towards HDACs 1–3. No high selectivity between HDACs 1 or 2 has been witnessed by HDAC class I selective compounds (Bush and McKinsey, 2010). 3.4. HDAC inhibitors and side-effects Despite HDACis anti-neoplastic and anti-hypertrophic effects, early controversy implicated HDACis in arrhythmogenesis inducing prolonged QT intervals (Olsen et al., 2007) associated with both Torsades de Points and sudden cardiac death. Similar initial research also suggested a role of HDACis in promoting atherosclerosis and subsequent heart failure (Choi et al., 2005). However, a more recent review of phases I and II trials has suggested HDACis in isolation are not arrhythmogenic and that ECG changes seen with HDACi treatment are clinically insignificant (Subramanian et al., 2010). Further research in rodent models has shown HDACis reduce hypertension and inflammation (Cardinale et al., 2010). This may reduce the rate of atherogenesis and offer greater cardioprotection. HDACis have also been associated with a variety of non-cardiac side effects. The most common of these are transient and reversible

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