Treatment and management options
The ultimate aim of treatment is to cure disease, but this is currently not always possible. When a cure is not available, treatment of disease is aimed at reducing the impact of the disease, extending lifespan, and maintaining quality of life.
Treatment of DCM in people is focused primarily on managing symptoms if at the overt stage of disease or, if presented with a preclinical case, prolonging the time between diagnosis and congestive heart failure [35]. Due to the predisposition of certain canine breeds, preclinical cardiac screening can help diagnose early abnormal findings, leading to a more successful diagnosis and potentially a management and treatment regime [36], in addition to possibly altering breeding programmes and preferences for some owners/breeders.As with human DCM, in veterinary cases the ultimate aim is to minimise the effect of heart failure with attempts to delay disease progression depending on the stage of diagnosis [37]. Strategic treatments presently include vasodilators, angiotensin-converting enzyme (ACE) inhibitors, diuretics and positive inotropes. With atypical breeds or American cocker spaniels and Golden retrievers, dietary supplementation of taurine and L-carnitine is usually recommended if the suspected aetiology of DCM is diet-related [38-40].
In regards to treating earlier stages of DCM, there is often a focus on the prevention of further myocardial dysfunction by using the cardioprotective effect of ACE inhibitors [41]. These interventions focus on the vasodilation of blood vessels by reducing angiotensin II effects within the renin-angiotensin-aldosterone system (RAAS), a system heavily associated with severe heart disease through aldosterone release [42]. ACE inhibitors currently approved for veterinary purposes include benazepril, enalapril, imidapril and Ramipril, with the former being used to treat initial stages of heart failure and the latter three for more progressive stages [43].
Furosemide and spironolactone are both recommended diuretics, with the former inhibiting the re-absorption of sodium and chloride in the thick ascending loop of Henle to promote natriuresis. The latter is a weak potassium-sparing diuretic which works as an aldosterone antagonist. Monotherapy of these diuretics are not recommended [44] as they reduce plasma volume, further stimulating RAAS activity [42]. Therefore, diuretics are often used in combination with ACE inhibitors.
In Ref. to the undetermined link between canine DCM and atrial fibrillation (AF), for these patients, positive inotropes such as digoxin are particularly effective by increasing vagal tone, hence, decreasing heart rate [45]. Another drug often used is diltiazem, a calcium channel blocker also slowing conduction through the atrioventricular node. Although it is in fact a negative inotrope, it is particularly effective in dogs with AF by increasing diastolic filling time and therefore improving cardiac output [46]. Even though both of these drugs can be used individually, research indicates that using these drugs in combination can prove to be more effective [47]. With digoxin having a narrow therapeutic index, digoxin toxicity can occur and gradual withdrawal should take place if clinical signs such as depression, anorexia and vomiting are seen [45]. In addition, pimobendan has been investigated in relation to prolonging the onset of coronary heart failure due to DCM by having similar effects to digoxin whilst advantageously keeping myocardial oxygen demand to a minimum [42]. Pimobendan has also been shown to increase the survival rate in Dobermans [36] and we can assume it offers similar benefits to other breeds.
Although the majority of canine DCM treatments focus on managing the condition whilst optimising quality of life, diet-associated DCM can be potentially reversible with certain supplements such as taurine and L-carnitine [40]. Taurine deficiency is a prime cause of DCM in cats, evidence suggests micronutrient shortages (e.g.
selenium, iron) are linked to human DCM, and there are some trials suggesting there may be a link in certain canine breeds, including American cocker spaniels, Golden retrievers [38, 40]. Accumulating research indicates that nutrient imbalances may cause or exacerbate DCM due to reduced myocardial expenditure [48]. There are minimal to no side-effects of taurine supplementation in dogs [49], therefore treating American cocker spaniels, Golden retrievers and atypical breeds presenting with DCM with taurine pending the results of blood testing may be prudent. Furthermore, alongside nutraceuticals such as taurine and L-carnitine, omega-3 fatty acids have been shown to significantly reduce muscle loss and prostaglandin E2 production, and these results also correlate with increased survival rate [50]. However, these supplementary products are very expensive, especially when prescribed for larger breed dogs, so finding the possible aetiology for the disease is vital to determine the efficacy of these products [49].Beta-blockers such as carvedilol have shown to have positive impacts for people with DCM [51-53]. Although carvedilol is a popular choice in humans with DCM and congestive heart failure [54, 55], there is limited evidence to date that these are beneficial in canine breeds with DCM [56]. Where used, careful monitoring should be ensured and treatment is best tolerated in dogs during the early stages of DCM [42].
In latter stages of DCM, the last resort for treating human heart disease includes transplants or inserting cardiac assist devices such as pacemakers [37], but these are far less realistic for canine patients due to cost, disease prognosis and surgical risk for the animal. Therefore, medical management based on symptomatic relief is the only current option for these patients [37].
Given that identifying, preventing, managing, and treating canine DCM is still a clinical challenge, new approaches are still needed. One new approach focusses on therapeutic gene transfer to target underlying molecular defects of ventricular dysfunction.
Gene therapy could replace a defective gene, or part of a gene, with a functional one, resulting in effective amounts of a certain protein being produced that was once deficient [57, 58]. Evidence suggests Ca2+ handling is damaged in a heart with cardiac failure, and experiments involving altering calcium-handling protein levels in rodents through cardiac gene therapy have been successful [59]. Although achieving myocardial transduction in larger animal models presents many difficulties, therapeutic gene transfer may be a viable option in the future to treat canine DCM regardless of underlying cause. Another example of gene therapy is the use of vascular endothelial growth factor-B167 (VEGF-B167), which was administered via an intracoronary route in a study of 10 dogs with DCM [60]. The method was well tolerated by the canine patients. VEGF-B has anti-apoptotic and cardioprotective effects, so could be used to mitigate progression of DCM. Naturally many genes are associated with cardiomyopathy or in the drug and gene pathways [27, 61, 62], and additionally multiple genetic associations have been associated with the disorder [20] which potentially increases the complexity of gene therapy interventions.Another of the requirements of gene therapy is understanding which mutations cause DCM in which species/breeds, therefore large trials are necessary in order to understand the basics, in addition to understanding the best methods of introducing gene therapy itself. For example gene therapy trials into dystrophin delivery via viral vectors has been promising but cardiovascular tissue is more complex than skeletal muscle, even when delivered via intravenous injection in dogs [63, 64]. Therefore gene therapy may be a very promising avenue of research, but the impact of gene associations and delivery methods may need to be taken into account for differing individuals and/or breeds.
Other new approaches being researched currently include myocardial regeneration therapies such as the use of resident cardiac stem cells, bone marrow stem cells, and skeletal myoblasts via transplantation therapies [65].
Cellular cardiomyoplasty has been explored via transplants of skeletal muscle cells into myocardium of canine DCM hearts. In early trials three of five dogs died early of tachyarrhythmias and pulmonary embolism, however two dogs survived and showed improved function of the heart [66]. Further investigation into this method is needed to understand the mechanisms and to prove if it can be successfully used in the clinic. Previous research on hamsters using smooth muscle cell transplants also showed clinical improvement in heart function [67], therefore this method could be developed for dogs and other species.The use of cardiosphere-derived stem cells (CDCs) from adult dog hearts has also been trialled [68]. These cells can differentiate into cardiomyocytes in vitro and a study in Doberman pinschers diagnosed with DCM detailed patients given an infusion of canine CDCs via the coronary vessels [68, 69]. There was no rejection of the cells, and no adverse reactions were reported [69]. It has been suggested that therapy using CDCs can slow down ventricular enlargement and the effects of DCM such as systolic dysfunction. Studies on larger sample sizes need to be undertaken.
2-deoxyadenosine triphosphate (dATP) is an energy substrate that can be used by myosin instead of ATP during formation of cross-bridges in myocardial contraction. A study discovered that substituting ATP with dATP in both normal and DCM hearts leads to increased activity of myofilaments and increased systolic function [70]. Another potential pharmaceutical method is active myosin using drugs such as danicamtiv, which has undergone in vitro and in vivo trials in dogs, people and other mammals [71].
Transvenous electrical cardioversion of AF involves the placement of electrode coils in the vasculature of the heart, with the right atrium acting as the anode, and the left pulmonary artery acting as the cathode. A connection with a defibrillator is made and electrical shocks are given in time with the R wave. In a study of two canine cases affected by DCM, treatment resulted in the heartbeat returned to a normal sinus rhythm [72]. There is therefore potential for this therapy to be used to reduce the risk of AF leading to DCM development.
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