Thinking outside the box

The cardiac disease of dogs that we now refer to as “dilated cardiomyopathy” has been recognized for nearly 50 years since first being described as “congestive cardiomyopathy” in the late 1960s (Ettinger et al. 1970, Buchanan 2013). It is a condition characterized by progressive and (currently) unexplained dysfunction of the ventricular myocardium. It frequently affects large breeds of dog and in a recent, large retrospective study of this condition in the UK the three breeds that were seen most commonly were the Dobermann, boxer and great Dane (Martin et al. 2009). The Dobermann is so frequently affected by this condition that it has become the archetype. Different populations of Dobermanns have been studied in North America and Europe and a similar picture of prevalence and progression of disease has emerged (Calvert et al. 1997, O'Grady & O'Sullivan 2004, Wess et al. 2010). The disease appears to be characterized by three stages. In the earliest stage of the disease the dog appears completely healthy; in fact one could argue that in the early stage of the disease the dog does not have the disease! What is known as a result of studies of affected families and recent genetic discoveries (Meurs et al. 2012, Owczarek-Lipska et al. 2013) is that some dogs are at increased risk of going on to develop the disease. The second stage of the disease is characterized by electrical instability and mechanical dysfunction of the heart; some dogs demonstrating one of these traits, some both. At this stage, the animal is outwardly normal, however if performed, diagnostic tests such as echocardiography or Holter electrocardiography may reveal abnormalities of cardiac rhythm or contractile function. This is described as the “occult” stage of the disease because although present, the disease is hidden. The majority of dogs with occult disease will progress on to develop overt clinical signs. These are either signs associated with abnormalities of cardiac rhythm such as syncope and collapse, or signs of congestive heart failure. For up to a third of these dogs, the first and only clinical sign is sudden death. Sadly the prognosis for Dobermanns with dilated cardiomyopathy, and for dogs with cardiomyopathy in general, is depressingly poor. A recent large study of dogs in the UK suggested a median survival time of less than 6 months from diagnosis to death (Martin et al. 2009). These data were corroborated by a prospective clinical trial of symptomatic Dobermanns that found a median survival time of approximately 19 weeks (130 days) in the group that did significantly better in the study (O'Grady et al. 2008). To put this in context, these are survival times similar to those expected for some patients with cancer. Over recent decades, the diagnostic techniques at our disposal have improved and proliferated and we are able to confidently diagnose the disease earlier in its course. Holter electrocardiography and echocardiography have become standard “screening” techniques and the prevalence and natural history of the disease are increasingly well understood (Wess et al. 2010). More recently, the potential for circulating concentrations of biomarkers to help identify these dogs has also been demonstrated (Singletary et al. 2012). One of the hopes inevitably raised with earlier diagnosis of a condition is that this will lead to an improved ability to treat the disease and an improved outcome for patients that participate in screening studies. Ideally, intervention before the patient is showing signs should allow the onset of signs to be delayed (or prevented altogether) and through slowing the progression of the disease, the patient should live longer. In 2009, O'Grady et al. published a retrospective study suggesting that early intervention with benazepril may be of benefit. In 2012, the results of the PROTECT study, a prospective, randomized, placebo-controlled, blinded clinical trial, (Summerfield et al. 2012) were reported demonstrating an improvement in survival associated with the administration of pimobendan in the occult stage of the disease. Although the progress represented by these therapeutic studies is to be applauded, the reality is that they show we can delay the progression of the disease, but we cannot currently arrest its development or cure it. The difference in survival demonstrated in the PROTECT study showed that pimobendan may prolong life on average by about 20 weeks (Summerfield et al. 2012). That is a great result but it is not a cure. Various surgical attempts have been made to delay progression of dilated cardiomyopathy including latissimus dorsi flaps (Moreira et al. 1990), the Batista procedure (Batista et al. 1996) and other extracardiac supports. With such surgical techniques, initial enthusiasm has usually been followed by disappointing long-term outcomes and realistically the only long-term surgical solution currently widely accepted for generalized myocardial failure in human patients is transplantation (Hunt 1998), a technique that for various reasons is never likely to be a serious consideration in veterinary patients. All of this means that if we are going to have a greater impact on this disease we are going to have to think outside the box. If the problem in the heart is degeneration leading to the observable malfunction can we prevent the heart from degenerating further – or better still get the heart to regenerate? We are entering the realm of regenerative medicine and stem-cell therapy. Regenerative medicine attempts to manipulate the body's own capacity for repair to bring about the growth of tissues capable of restoring the function of diseased organs. There are many choices and challenges that face researchers attempting to apply such therapy to myocardial disease (Segers & Lee 2008): From where should stem cells be isolated? How should they be delivered to the myocardium? When introduced to the myocardium will they differentiate appropriately, survive and proliferate? Finally, will the cells integrate into the myocardium and exhibit normal electrical and mechanical function? Currently, many (almost all) of these questions remain unanswered and no single accepted and successful technique has been described experimentally, let alone clinically. There have been many experiments that appear to have demonstrated benefits in terms of improved myocardial function (Nagaya et al. 2005) but controversy continues to rage about the interpretation of the results from such studies (Anversa et al. 2007). In this issue of the journal, Pogue et al. (2013) report the results of a clinical study in which commercially obtained mesenchymal stem cells of adipose origin were used via coronary venous delivery for injection into the myocardium of a group of Dobermanns with dilated cardiomyopathy, the majority of which were at the occult stage of the disease. On one level the results are disappointing. The outcome for the treated dogs was not apparently different to that reported in the literature for similar untreated dogs at a similar stage of the disease. There are, however, other ways to view the study more positively. Firstly, I applaud the authors (and the journal) for publishing a study with negative results; this is a relative rarity. The article, despite having negative results, is informative on many levels. We now know that this is an area of active research and the authors have shared their technique so that others may learn from their experience. They have demonstrated that their technique is feasible and (at least in the majority of cases) tolerated by dogs with this disease. The treated dogs did no better, but they also did no worse than would be expected so in most cases (at least for the dogs with occult disease) it appears to be safe. Thus, although the outcome is disappointing the study still gives us some grounds for optimism with reason to hope that further refinements may lead to improved outcomes in future. Whether further study in this area will result in more positive outcomes cannot be confidently predicted, but what one can say with certainty is that if we do not try we will never find a way to more effectively manage this debilitating and distressing condition. Even if the road to more effective management is going to be long, it is reassuring to know that at least the first tentative steps are being taken. Adrian graduated from the University of Cambridge in 1989. In 1990, following a brief period in general practice, he joined the RVC as an intern and has remained there since then. He is now Professor of Cardiology and a European Specialist in Companion Animal Cardiology. His clinical and research interests include the diagnosis and medical management of cardiac disease and failure. He has a particular interest in biomarkers and the diagnosis and management of degenerative mitral valve disease in dogs.