Heart Failure and Mouse Models

Disease Models & Mechanisms 3, 138-143 (2010) doi:10.1242/dmm.005017 CLINICAL PUZZLE © 2010. Published by The Company of Biologists Ltd Heart failure and mouse models Ross Breckenridge1,* Heart failure is a common, complex condition with a poor prognosis and increasing couraged in heart failure for many years on the basis of studies showing increased mor- incidence. The syndrome of heart failure comprises changes in electrophysiology, tality when given to acutely unwell patients contraction and energy metabolism. This complexity, and the interaction of the (Braunwald and Chidsey, 1965). Subse- clinical syndrome with very frequently concurrent medical conditions such as quently, blockers have been found to be diabetes, means that animal modelling of heart failure is difficult. The current animal beneficial when used in relatively low doses models of heart failure in common use do not address several important clinical in stable heart failure patients (CIBIS, 1999). problems. There have been major recent advances in the understanding of cardiac An increasingly commonly recognised biology in the healthy and failing myocardium, but these are, as yet, unmatched variant of heart failure is ‘diastolic’ or ‘sys- tolic function preserved’ heart failure, char- by advances in therapeutics. Arguably, the development of new animal models acterised by resistance to ventricular filling of heart failure, or at least adaptation of existing models, will be necessary to fully rather than defective contraction (Dodek et translate scientific advances in this area into new drugs. This review outlines the al., 1972; Zile et al., 2004). As the com- DMM mouse models of heart failure in common usage today, and discusses how monest causes of diastolic heart failure are adaptations in these models may allow easier translation of animal experimentation ischaemia, obesity, hypertension, diabetes into the clinical arena. and ageing (Owan and Redfield, 2005), the incidence of this condition is expected to increase with time. Fundamentally, the Heart failure: the medical problem the case study. Our understanding of the mechanisms underlying this variant of heart Heart failure is an increasingly common heart failure disease phenotype is not yet failure are unknown. diagnosis, with a dismal prognosis that is sufficient to appreciate whether aspects of There have been major recent advances worse even than many types of cancer (Ho the final heart failure syndrome differ with in the clinical assessment of heart failure et al., 1993). There are few therapeutic the causative aetiologies. Preliminary evi- patients – the aim being earlier diagnosis options. The estimated cost of heart failure dence, however, demonstrates that different and risk stratification (i.e. the identification is currently between 1-2% of the total gene expression patterns (Huang et al., of high-risk patients). Clinical scoring based healthcare spend in developed economies 2005) and prognoses (Felker et al., 2000) are on a patient’s assessment of their own exer- and is expected to rise (McMurray and associated with heart failure resulting from cise capacity and basic clinical observations Stewart, 2000). differing causes. has proved of use in identifying high-risk Clinical presentation may be insidious or Heart failure comprises changes in car- patients and guiding therapy (Goldman et Disease Models & Mechanisms acute, with decreased exercise tolerance diac contractility, electrical conduction and al., 1981). More recently, imaging technol- and shortness of breath. Cardiac arrhyth- energy metabolism, leading to an inability ogy has been used to improve diagnosis and mias may accompany heart failure, leading of the heart to meet circulatory demands prognostication in heart failure. Echocar- to high rates of sudden death. Current treat- (Jessup and Brozena, 2003; Stanley et al., diography has been the historical ‘gold stan- ment includes simultaneous administration 2005). This activates neurohormonal com- dard’ for non-invasive evaluation of the fail- of angiotensin-converting enzyme (ACE) pensatory mechanisms, such as vasocon- ing heart, and is safe and relatively cheap. inhibitors (acting principally by vasodilata- striction, which are thought to be helpful in The recent development of tissue Doppler tion), blockers (slowing the heart rate) and maintaining general organ perfusion in the measurement to evaluate myocardial strain spironolactone (vasodilatation and diure- short term, but maladaptive with respect to has improved sensitivity with respect to sis). This combination reduces death result- long-term cardiac function. In this way, the early detection of abnormalities. Further ing from heart failure, but these drugs do physiological and gene expression changes adaptations, such as ultrasonographic track- not ‘cure’ the condition. There are no truly observed in heart failure are not constantly ing of acoustic markers (‘speckle tracking’) ‘disease modifying’ drugs for heart failure. ‘adaptive’ or ‘maladaptive’ (and are, thus, not and intravascular ultrasound contrast (Flu Many conditions eventually lead to heart easily amenable to pharmacological modu- et al., 2009), have shown promise at their failure (Table 1), several of which are asso- lation). This has introduced therapeutic relatively early stage of development. Car- ciated with each other, such as hyperten- confusion over the years. For example, use diac magnetic resonance imaging (cMRI) is sion, obesity and diabetes, as exemplified in of -adrenoceptor antagonists was dis- increasingly used in heart failure and, as well as being the most accurate method to deter- 1MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London, NW7 1AA, UK mine left ventricular mass (an important *Author for correspondence ([email protected]) clinical measurement in certain types of car- 138 dmm.biologists.org Heart failure and mouse models CLINICAL PUZZLE legal difficulties in obtaining high-quality Case study biopsies from relevant patient groups have A 72-year-old man was admitted to hospital complaining of a progressive three-day history of been addressed by a working group of the shortness of breath at rest, exacerbated by lying flat. He had suffered a myocardial infarction four American Heart Association and European years earlier, which was treated by primary angioplasty. His past medical history was significant for Society of Cardiology (Cooper et al., 2007). hypertension, hypercholesterolaemia, and type II diabetes, which was diagnosed at the time of his In the absence of widely available biopsy infarct. Following the angioplasty, he was prescribed a blocker, an ACE inhibitor, a statin, anti- platelet agents (all of which have been shown to reduce mortality following myocardial infarction) material, clinical trials and medical practice and oral anti-diabetic medication. He had remained well in the intervening four years. On have relied on the use of biomarkers that examination, he was found short of breath at rest with crackles audible in both lung fields, consistent are essentially unvalidated. A comparison of with left ventricular failure. Echocardiography was performed, revealing a significantly depressed left the gene expression changes in animal mod- ventricular ejection fraction and normal valvular function. He was treated with intravenous diuretics els and human failing hearts is vital for val- to good symptomatic effect, and had the doses of his other cardiac medications increased. Over the idating the findings from animal models of next six months, he had two further admissions with left ventricular failure, both of which were heart failure, and eventually for assaying treated with diuretics. biomarkers used in humans. diomyopathy and heart failure), can also niques are still experimental in that they Unanswered clinical questions in determine the cause of heart failure by have not yet been proven to predict clini- heart failure quantifying microvascular perfusion, cal events. It is largely unknown whether the individ- myocardial iron and fibrosis (Karamitsos et The gene expression changes that lead to ual changes in gene expression and physi- al., 2009). Diagnostic imaging of the heart failure are not definitively known. ology that are observed in heart failure myocardium using radio- or nanoparticle- Many changes in gene expression have been patients are adaptive or maladaptive, and labelled probes (‘molecular imaging’) is an described in biopsies taken from human how this changes with the evolution of the DMM area of active development (Saraste et al., heart failure patients. However, biopsies disease. Further questions include whether 2009) and is potentially one of the quickest are necessarily small and usually taken there are novel biomarkers (Lainscak and ways to translate advances in basic science blindly through the endocardial route via a Anker, 2009), and which imaging modali- into the clinical arena. Many of these tech- vascular catheter. The logistical, ethical and ties are optimal that will facilitate clinical decision-making in heart failure patients. Two obvious deficiencies are hindering Table 1. Commonest documented causes of heart failure the development of new heart failure ther- Cause of heart failure apies: (1) high-resolution, longitudinal phe- No single identifiable cause found in 50% of cases notyping of heart failure patients (i.e. at sev- Ischaemia eral stages in the evolution of the condition) has not yet been carried out; and (2) the Pressure overload Hypertension development

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