Boxer cardiomyopathy, or as it is also known, arrhythmogenic right ventricular cardiomyopathy (ARVC), is an adult-onset cardiac disease that affects the cardiac muscle. As the name suggests, it predominantly affects the myocardium of the right ventricle, but on histopathology, has also been shown to involve the intraventricular septum and left ventricle. ARVC in Boxer dogs has many similarities to ARVC in humans, which has been documented as a cause of sudden cardiac death in apparently healthy young athletes (Basso et al, 1996). It was first described in Boxer dogs in 1983 (Harpster, 1983) and has since been shown to be a genetic disease within the breed (Meurs et al, 1999). ARVC has been reported in other breeds of dog (Santilli et al, 2009), in cats (Fox et al, 2000) and in horses (Freel et al, 2010). Studies have shown that ARVC in Boxer dogs is an inherited disease (Meurs et al, 1999), and so family history of sudden death and syncope is useful in supporting a diagnosis of the disease. While it is an uncommon form of heart disease, and typically difficult to diagnose, veterinary nurses should be aware of it, because any Boxer dog that is admitted with episodes of syncope, periods of ventricular tachycardia, or congestive heart failure (CHF) could be at risk of sudden death.
Background
ARVC can have potentially serious side effects on cardiac function. Haemodynamic compromise, progression of concurrent cardiac disease and sudden death may all be seen with ARVC, and these can manifest as haemodynamic compromise, electrical instability, or both (Dennis, 2010).
Haemodynamic instability
The primary role of the cardiovascular system is to provide a normal arterial blood pressure (see Box 1). Normal arterial pressure is vital to maintain adequate perfusion to the organs of the body, especially vital organs, such as the heart, brain, and kidneys. If cardiac output is compromised, arterial pressure falls, and compensatory mechanisms are activated in an attempt to return blood pressure to a more normal level. These compensatory mechanisms include increased fluid retention by the kidneys, vasoconstriction, and stimulation of the heart to increase heart rate and stroke volume (primarily via increased sympathetic tone). Although ultimately beneficial to restore adequate arterial pressures, the ‘trade-off’ is an increase in venous pressures, which if severe enough can cause effusions, such as pulmonary oedema, pleural effusion or ascites. As soon as fluid accumulates, the patient is considered to have developed congestive heart failure (CHF). If arterial pressure cannot be normalised despite maximal activation of compensatory mechanisms, then low output heart failure is present. Affected patients usually have concurrent CHF, unless the fall in output is so acute that compensatory mechanisms have insufficient time to be activated, for example, seen with some arrhythmias. Low output failure can be seen with ARVC because the rhythm disturbance ventricular tachycardia (VT) is a common finding. VT can occur spontaneously, and can compromise cardiac filling, so compensatory mechanisms may not have had time to activate. Patients with low output failure can present collapsed, have cold extremities, and weak pulses. Clinical signs of haemodynamic instability can be seen in Box 2.
Electrical instability
The conduction system allows the spread of electrical activity through the heart, which results in the heart contracting in the most efficient way to maximise stroke volume. The blood pumped out from the ventricles is known as cardiac output (Box 1), and a regular sinus rhythm allows time for the heart to refill with blood once it has contracted, so that it is ready to contract again. It follows therefore, that if the heart rate becomes excessively fast, cardiac output may become compromised because the ventricles do not have time to relax and refill with blood between contractions. Myocardial diseases such as ARVC are predisposed to electrical instability. On electrocardiograms (ECG), Boxer dogs with ARVC have been shown to have many types of heart rhythm disturbances, and in a recent study, Mõtsküla et al (2013) showed that Boxer dogs with more complex ventricular arrhythmias had a poorer prognosis. While electrical instability can be seen with many severe disease processes, some of which may not be life threatening, dogs that are predisposed to cardiomyopathies such as ARVC, might require urgent veterinary surgeon attention due to the haemodynamic and electrical instability of the disease (Dennis, 2010). Table 1 describes the ventricular rhythm disturbances that may be seen with ARVC.
| Rhythm disturbances seen with ARVC | Example of arrhythmia |
|---|---|
|
Ventricular premature complex (VPC)
|
|
|
Ventricular tachycardia (VT)
|
|
|
Ventricular fibrillation (VF)
|
|
The disease
Cardiologists have demonstrated that Boxer ARVC has many similarities to ARVC in humans (Meurs et al, 1999; Basso et al, 2004). Histopathology shows that right ventricular myocytes are replaced with adipose or fibrous tissues. In a study conducted by Basso et al (2004) investigating sudden cardiac death in Boxer dogs, they found left ventricular lesions in 50% of the hearts affected by ARVC. Myocarditis was also found in 70% of dogs, and in 100% of the dogs that died suddenly. This would suggest that inflammation has a role in the disease process.
In 1999, Meurs reported ARVC as an autosomal dominant genetic defect, which means that only one parent need have the defective gene to pass it on to offspring. In the UK, one study showed that hereditary transmission of the disease is limited to three family lines, which interestingly, all have links to American ancestors (Palermo et al, 2011). In studies, males appear to be overrepresented (Harpster, 1983; Harpster, 1991; Palermo et al, 2011; Mõtsküla et al, 2013), and age ranges have been reported from 1–15 years, with a mean age of 8.5 years (Sisson et al, 2000). The most common presenting sign seen with ARVC is syncope (Palermo et al, 2011). It is thought that syncope is associated with ventricular arrhythmias. It is also thought that increased risk of ventricular arrhythmia is associated with sudden cardiac death (Ware, 2007). However, other arrhythmias have also been documented to cause syncope with ARVC, such as bradycardia (Thomanson et al, 2008) and these can also be associated with sudden death. Other clinical signs that have been reported are signs associated with CHF.
In 1991, Harpster outlined three separate categories of ARVC:
Similar categories of disease have been reported in humans with ARVC. These may represent progressive stages of the disease (Thiene and Basso, 2001). This may also be the case in Boxer dogs, but has yet to be proven (Baumwart et al, 2005). There may be geographical differences in the reports of the disease, which may represent genetic or environmental differences. A retrospective paper showed that in the UK most of the dogs had the myocardial dysfunction type of ARVC (Palermo et al, 2011), whereas in a US study, Meurs (2004) found that only a small number of Boxers with tachyarrhythmias also had myocardial dysfunction. However, in the same paper Palermo et al acknowledge that the dogs that were presented to the UK referral centre, were only done so because of clinical signs, and therefore it is impossible to know if they had previously been in the concealed or overt groups. What Palermo et al do conclude in their study, and as previously shown in similar studies (Harpster, 1991), is that prognosis for Boxer dogs with myocardial dysfunction is poor, typically ranging from 3–6 months.
Diagnosis
Unfortunately, ARVC is a difficult disease to diagnose. There are a few reasons for this, but primarily because dogs can be asymptomatic between rhythm disturbances (Caro-Vadillo et al, 2013), and that the disease can mimic other cardiac diseases such as dilated car-diomyopathy (Palermo et al,2011). Another difficulty is that sudden death can be the first (and therefore only) clinical sign.
History
Syncope, weakness or exercise intolerance can occur with ARVC, but may also be present as a result of other cardiac (or non-cardiac) disease. Boxer dogs are also predisposed to aortic stenosis and neurally mediated syncope, both of which can cause syncope (Mõtsküla et al, 2013). Familial history of syncope or sudden death can be clinically relevant. Many affected dogs will have a normal physical examination. A ventricular premature beat may be detected by the veterinary surgeon as a pulse deficit. A heart murmur may be present in dogs with myocardial dysfunction, but Boxer dogs are prone to other cardiac diseases, such as aortic stenosis which can cause a heart murmur, and so other causes need to be ruled out.
| Number of VPCs per 24 hours | Classification |
|---|---|
| 0–20 | Within normal limits |
| 20–100 | Indeterminate. Repeat in 6–12 months |
| 100–300 (grade 1–2) |
Suspicious. Consider not breeding for 1 year |
| 100–300 (grade 3–4) |
Likely affected |
| 300–1000 (grade 1–2) |
Likely affected |
| > 1000 | Affected. Consider treatment |
From Lown (1975) and Meurs (2004)
Screening
There have been several genetic mutations found in the human form of the disease. A recent study in the United States found strong evidence of a striatin mutation in Boxer dogs with ARVC (Meurs, 2013). There are always limitations to any genetic test as often more than one genetic mutation is a cause for a disease; however, this recent development is significant.
Echocardiography
Echocardiography can be useful in ruling out any other cardiac disease, particularly for the concealed and overt forms of the disease. Echocardiography can show systolic dysfunction, which would be seen in the myocardial dysfunction form of ARVC, but this is not definitive of ARVC, as findings can be similar to those observed with other forms of dilated cardiomyopathy.
ECG
ARVC has characteristic ventricular arrhythmias on an ECG trace. The predominant rhythm in ARVC is sinus rhythm, with a characteristic type of ventricular premature complex (VPC) (see Table 1). In ARVC, VPCs are wide and bizarre and often positive (upright) in leads II and III. This morphology of VPC is associated with a right ventricular origin. With ARVC, VPCs can occur singularly, in pairs, in bigeminal or trigeminal pattern, in short runs or as sustained VT (Ware, 2007). Boxers with ARVC can also have polymorphic (multiform) VPCs, meaning that there is disease affecting multiple sites within the ventricle. One review concludes that looking at VPCs alone is a fairly non-specific diagnostic aid, because VPCs can be found in many dogs without cardiac disease, and that ECG traces are characteristically taken over a period of a couple of minutes only (Palermo et al, 2011). This means that it would not be able to assess the frequency of VPCs for a very long period, or assess electrical stability when the heart is under stress, such as during exercise or excitement.
24-hour ambulatory ECG Holter monitoring
A 24-hour ambulatory Holter monitor device is a reliable diagnostic test for arrhythmias in Boxers with ARVC. Holter monitoring allows dogs to continue their normal behaviour during continual monitoring of the heart rhythm. A 24-hour monitor allows cardiologists to evaluate the number of VPCs detected, study the complexity of the arrhythmias found, and match that with a diary that the owners keep documenting the dog's activity while wearing the recorder (Figure 1). A 24-hour monitor can then be used to monitor disease progression and if necessary, response to medical therapy.
Meurs (2004) proposed a list as a screening tool for Boxers with ARVC. This list evaluates the number of VPCs shown in a 24-hour period and is shown in Table 2.
While the use of 24-hour ambulatory Holter monitors are useful, it still not conclusive proof of ARVC. Spier et al (2004) showed that there could be up to an 83% difference in day-to-day numbers of VPCs in Boxer dogs with ARVC. Furthermore, there have been other rhythm disturbances reported with ARVC, which can make diagnosis even more difficult. Su-praventricular arrhythmias, such as atrial fibrillation, have been reported (Harpster, 1991; Baumwart et al, 2005). This could be as a result of atrial dilation that can occur with CHF, if the dog has the myocardial dysfunction form of the disease, or as a result of the myocardial disease process.
Biopsy
Ante-mortem myocardial biopsies have shown to be accurate for diagnosis of ARVC in humans (Asimaki et al, 2009), but this has yet to be described in living Boxer dogs.
Histopathology
It is widely accepted that histopathology is still the best way to diagnose the disease. The classic appearance of ARVC in human and Boxer dogs is of fibrofatty replacement of the right ventricular myocardium. However, the usefulness of this is limited because the diagnosis is post mortem.
Treatment
Treatment of ARVC is also complicated. There are many reasons for this, primarily because a definitive diagnosis is difficult, but also because patients vary greatly in presentation and clinical signs (Mõtsküla et al, 2013). There is no recognised treatment protocol, due to conflicting or unconvincing data. To confuse this situation even further, any antiarrhythmic drug has the potential to be proarrhythmic and/or increase the likelihood of syncope or sudden death. Furthermore, there is no evidence that the use of antiarrhythmic drugs changes the risk of sudden death in affected Boxer dogs (Meurs et al, 2004). Therefore treatment is aimed at:
However, while these treatment aims seem logical, there has been no study assessing the effects of treatment on the risk of sudden death.
When antiarrhythmic medication is started, doses are usually introduced slowly and titrated to effect, using Holter monitoring and owner history to guide the best dose for the particular patient. This requires regular Holter monitoring and good communication with the owners. In addition, some of the antiarrhythmic drugs used can also have other side effects, such as loss of appetite and gastrointestinal problems. If a patient has signs of systolic dysfunction and CHF, this will also need to be treated with heart failure medication.
Supplementation
There has been some research into the role of supplements and ARVC. One study looked at supplementation of L-carnitine in Boxer dogs with low levels of myocardial carnitine, and showed improvement after supplementation (Keene et al, 1991). However, it is expensive and there has been no evidence to show that it is beneficial for patients that do not have carnitine deficiency (Freeman, 1998). Alternatively, Omega-3 fatty acids have shown beneficial effects. As previously mentioned, it is thought that the disease process with ARVC, has an inflammatory component, and Omega-3 fatty acids have an anti-inflammatory effect. Smith et al (2007) showed that the use of fish oils in Boxer dogs with ARVC reduced the number of VPCs on a 24-hour ECG.
Implantable cardioverter defibrillator (ICD)
One other treatment method worthy of mention, is the use of an implantable cardioverter defibrillator (ICD), which has become commonplace in human medicine. It involves placement of a device, similar to a pacemaker that can detect excessively high heart rates and deliver a targeted electric shock to the heart when the heart rate reaches a pre-programmed limit. One case report looked at the placement of an ICD in a Boxer dog (Nelson et al, 2007). While this has become a successful treatment option in human medicine, preventing sudden cardiac death, Nelson's case study showed the dog received many inappropriate shocks. The maximal setting on the ICD used in this case report was 240 beats/minute, and for human heart rate to reach 240 beats/minute, would be highly indicative of a tachyarrhythmia. However, a dog can reach 240 beats/minute with a normal sinus rhythm when exercising, so the high heart rate triggered the ICD. Different techniques and further research are required before this becomes an accepted method of treatment.
Prognosis
Despite the many advances in veterinary medicine, dogs with ARVC are still at risk of sudden death. As previously discussed, complexity of ventricular arrhythmia can signal a poor prognosis. Mòtsküla et al (2013) reported that if the patient had systolic dysfunction and CHF, then prognosis was equally poor. However, both Mòtsküla et al (2013) and Meurs (2004) showed that some affected dogs can be asymptomatic and live for years, often with, but sometimes without, antiarrhythmic medication.
Role of the veterinary nurse
The role of the veterinary nurse and patients with suspected ARVC is a challenging one. Any Boxer dog with a history of syncope should be treated with caution, and stress kept to a minimum. If a patient has presented at the veterinary practice collapsed, an intravenous catheter should be placed and crash box or trolley ready. An ECG should also be taken, in combination with a record of pulse rate and quality. If the patient is being treated with anti-arrhythmic medication, the veterinary nurse should be communicating with owners to discuss the progress of the patient, exercise tolerance, and any other potential side effects such as anorexia or gastrointestinal problems.
Conclusion
ARVC is a difficult disease to diagnose and treat. The variety of different presentations, lack of research carried out on treating dogs with the disease, and conflicting data make it difficult to understand the disease while dogs are living. The best advice for veterinary nurses would be to maintain good communication with owners and treat suspected patients with caution and avoid over exertion and stress in the veterinary practice.