Myxomatous mitral valve disease (MMVD) is the most prevalent acquired heart disease in dogs, accounting for between 75–80% of all cardiac disease (Buchanan, 1977; Mattin et al, 2015). Small dogs are predisposed to MMVD, but larger dogs can also be affected. Increased age is associated with higher risk, with reports of 100% of geriatric dogs diagnosed in predisposed breeds (Whitney, 1974; Chetboul et al 2004). Males are overrepresented in studies, but no statistical risks have been associated with sex (Mattin et al, 2015). Studies have repeatedly shown that the Cavalier King Charles Spaniel (CKCS) has a particularly high incidence of MMVD, and an early onset of the disease, in many different countries, including France, Sweden, Denmark and the UK (Swift et al, 2017). CKCS are also at higher risk of the disease progressing (Mattin et al, 2019).
Two specific UK studies warrant further analysis. The first retrospective study examined data pertaining to 111 967 dogs presenting to primary care veterinary practice and published the following results:
- In total, 405 dogs were diagnosed with MMVD, and a further 3557 dogs were diagnosed with a murmur consistent with MMVD
- Mean age of diagnosis was 9.5 years
- 62.2% were male
- CKCS represented 32.4% (Mattin et al, 2015).
The second study specifically looked at CKCS as part of a breeding scheme from 1991–2010, which became the basis of breeding guidelines for the Kennel Club (Swift et al, 2017). A total of 8860 CKCS were presented for auscultation at a breed show or veterinary practice. The recommendations were:
- CKCS could be bred from if they were 5 years plus, and did not have a murmur
- Dogs over 2.5 years could be bred from, if both parents reached 5 years old without a murmur being detected.
The paper concludes that breeding schemes can be successful because during this period, the average age of diagnosis of a murmur increased from 8.6 years to 9.2 years. However, selective breeding is not without risks. For example, breeding to remove one specific trait could have detrimental effects if other selection criteria are not considered (O'Brien, 2021). It has been suggested that selective breeding could have caused the rise in syringomyelia in this breed (Rusbridge and Knowler, 2004).
MMVD and the genetic link to CKCS
The exact reason for CKCS MMVD prevalence is not known. High levels of heritability have been shown, yet there are difficulties in determining why, not least because nearly all CKCS have MMVD, so a control group for study is difficult to find. Further, the high variability the disease can make predictions difficult. Two loci have been identified and linked to the development of MMVD in CKCS. CFA-13 has 20 genes associated with this region, of and CFA-14 has 11 (Madsen et al, 2011), although this has not been replicated or validated in subsequent studies (Bionda, 2020; O'Brien, 2021). This suggests that MMVD is under a polygenic mode of inheritance. Therefore, if genetic tests are not a viable option, emphasis needs to be placed on early identification and treatment.
Pathophysiology
MMVD is characterised by the deposition of glycosaminoglycans and degeneration of collagen in the mitral apparatus. Degeneration of the valve causes abnormal coaptation (closure) of the valve. This leads to the backflow of blood into the left atrium during systole. This backflow is called mitral regurgitation, and is what causes the classic left-sided apical heart murmur. If the disease progresses, valvular tissue thickens, collagen deteriorates further and glycosaminoglycan infiltration increases causing disruption of valvular interstitial and endothelial cells. Secondary fibrosis occurs in later stages of MMVD, and this can lead to worsening mitral regurgitation. In turn, this causes left-sided dilation, which exacerbates the impact on the incompetent valves, and ultimately can lead to left-sided congestive heart failure. In severe cases, pressure can back up into right side of the heart as well, causing pulmonary hypertension and right-sided congestive heart failure.
Diagnosis
The American College of Veterinary Medicine (ACVIM) published a consensus statement that classified MMVD into different stages (Atkins et al, 2009; Keene et al, 2019), which clarified and simplified diagnosis and gave treatment guidelines. Table 1 shows the stages as identified by the consensus statement.
Table 1. Classification of myxomatous mitral valve disease adapted from the ACVIM Consensus Statement (Keene et al, 2019)
| Stage | Classification criteria | Description |
|---|---|---|
| A | At risk but no disease present | Dogs that fall into this stage are at high risk of developing heart disease, because of their breed. There is no disease present at this stage, therefore no heart murmur |
| B | Pre-clinical stage: heart disease is present but no heart failure | Dogs in this stage will have a heart murmur, but no clinical signs. There are two distinct categories in this stage:
|
| C | Disease has progressed to heart failure and the dog will display clinical signs | Either past or current heart failure. A wide group ranging from chronic outpatient to acute, life-threatening heart failure |
| D | Refractory heart failure | Routine heart failure medication has ceased to be effective |
Physical examination
Cardiac auscultation is the simplest diagnostic tool if a dog is suspected of having MMVD. Mitral regurgitation causes an audible sound that can be detected by stethoscope during systole. The MMVD murmur is best heard between the 4th and 5th rib at the level of the costochondral junction on the left side of the thorax. The loudness of the sound is linked to severity (Mattin, 2018), and a murmur of grade III or above increases the risk of developing congestive heart failure (Eriksson et al, 2014; Mattin, 2018). One UK study linked murmur severity to increased risk of cardiac-related death (López-Alvarez et al, 2015). Table 2 shows the murmur grading system.
Table 2. Murmur grading system
| Grade | Murmur |
|---|---|
| I | Very soft murmur. Only heard in quiet surroundings after careful auscultation |
| II | Soft murmur, but easily heard |
| III | Moderate intensity murmur |
| IV | Loud murmur without a palpable precordial thrill |
| V | Loud murmur with a palpable precordial thrill |
| VI | Very loud murmur that can be heard with the stethoscope lifted away from the chest. Precordial thrill present |
Increased heart rate has been associated with adverse outcome in dogs with preclinical MMVD (Eriksson et al, 2014; Boswood et al, 2016), and with those in heart failure (Häggström et al, 2008; Borgarelli et al, 2008; Mattin et al, 2018). However, while a strong correlation between heart rate and disease outcomes has been identified, it is important to note that heart rate can be increased for different reasons, such as pain or stress.
Clinical signs
The presence of a cough has been linked to increased risk of disease progression (Borgarelli et al, 2012; Mattin, 2018). A cough can be caused by compression of the bronchi by atrial enlargement, and also from pulmonary oedema. Table 3 shows clinical signs associated with heart failure.
Table 3. Clinical signs of heart failure
| Left-sided congestive heart failure – pulmonary congestion | Right-sided congestive heart failure – system venous congestion |
|---|---|
| Increased respiratory rate and effort | Increased respiratory rate and effort |
| Tachypnoea | Tachypnoea |
| Respiratory distress | Dyspnoea |
| Pulmonary oedema | Ascites |
| Cough | Pleural and/or pericardial effusion |
| Reduced exercise tolerance | Jugular distention |
| Syncope | Reduced exercise tolerance |
| Anorexia | Syncope |
| Weight and muscle loss |
Echocardiography
Echocardiography is the gold standard method of diagnosing MMVD. It allows visualisation of cardiac chambers, providing assessment of dilation and contractility, analysis of the mitral valve and measurement of mitral regurgitation. Figure 1a shows a right parasternal long axis 4 chamber view which shows normal-sized chambers. In comparison, Figure 1b is the same view, but shows a CKCS heart at stage B2. Note the increased left atrium and left ventricular dimensions, thickened mitral valve leaflet and that the leaflets do not close properly.
One way to assess progression of MMVD is to assess left atrium enlargement in a short axis view. If the left atrium is more than 1.5 times wider than the aorta, left atrium enlargement is present. Figure 2a shows the left atrium and aorta in short axis, and measuring a normal ratio. Figure 2b shows a CKCS with significant left atrium enlargement.
Systolic function can also be assessed, by a short axis M-mode view. The percentage change in left ventricular diameter during systole is called fractional shortening. Fractional shortening is increased with increased mitral regurgitation; however, it can return to normal with myocardial failure. Figure 3a shows an example of normal fractional shortening in a dog in short axis M-mode view. Figure 3b shows fractional shortening in a CKCS with MMVD.
Colour flow Doppler is an excellent way of determining abnormal blood flow patterns through the mitral valve, and can be measured to assess severity. In a healthy dog, there should be no mitral regurgitation. Figure 4 shows a regurgitant jet in the right parasternal long axis view. The red colour is blood flow towards the probe; blue is away, and any yellow/green colour is turbulent blood flow.
Further information on how to obtain these views can be found in Luis Fuentes (2010).
Thoracic radiography
Chest radiographs can show heart enlargement if a dog is suspected to have MMVD. It will not, however, give any indication on the competence of the mitral valve itself, and if mitral regurgitation is mild, there may be no changes to the cardiac silhouette. However, radiography can show the lungs, pulmonary vessels and airways, which can be useful to rule out concurrent disease. Radiography is still seen as the gold standard for assessing for pulmonary oedema, and can be used to obtain a vertebral heart score. Details of how to perform vertebral heart score can be found in Summerfield (2018).
Biomarkers
N-Terminal pro B-type natriuretic peptide (NTproBNP) and cardiac troponin I (cTnI) are biomarkers that can be used to assess cardiac disease severity. NTproBNP is released in response to atrial and ventricular myocardial stretch, and cardiac troponins are a protein found when myocardial cells have been damaged or have died. Increased NTproBNP levels have been linked with progression to congestive heart failure in dogs with preclinical MMVD (Chetboul et al, 2009; Reynolds et al, 2012). cTnI is not a specific biomarker for cardiac disease, but values increase in severe cases, and it has been linked to mortality in dogs in congestive heart failure (Linklater et al, 2007; Mattin, 2018).
While echocardiography is the best way to assess MMVD, it is a challenging skill to master. Therefore, if an experienced cardiologist is not available, a few things, done together, can help diagnosis and prognosis (Mattin et al, 2018). These are:
- Heart rate
- Heart murmur intensity
- NTproBNP measurement.
Treatment
Until 2016, treatment had only been proven to work when a dog reached heart failure (stage C). Since then, however, pimobendan has been licensed for stage B2. This relies upon diagnosis and staging of MMVD. The aims of treatment are:
- Improve contractility of the ventricles
- Diuresis to remove excess fluid
- Neurohormonal blockade
- Reduction of heart rate in cases with atrial fibrillation
- Surgical intervention if appropriate.
1. Improving contractility
Pimobendan is a positive inotrope, and has a dual mechanism; firstly, it increases myocardial contractility by increasing sensitisation of calcium to troponin C. Secondly, it has vasodilatory effects which counteract reninangiotensin aldosterone system (RAAS) activation. It has been shown that administration of pimobendan at stage B2 prolongs the pre-clinical period by on average 15 months (Boswood et al, 2016). It is the only drug recommended before the onset of clinical signs, but if treatment has not been initiated before, it should be started when congestive heart failure is present. Pimobendan should be administered an hour before feeding to maximise drug bioavailability. Pimobendan is generally well tolerated in dogs.
2. Diuresis
Furosemide
Furosemide is a first-line medication at the onset of congestive heart failure. It is a potent drug that acts on the loop of Henle, and blocks absorption of sodium, chloride and water. Doses are usually titrated to the minimum effective dose, allowing room to manoeuvre upwards when more is needed. There is no evidence to prove the efficacy of furosemide, but it is considered irreplaceable in the treatment of congestive heart failure.
Torasemide
Torasemide is also a loop diuretic. It is more potent and has longer bioavailability than furosemide. It is useful to add to treatment regimes if a patient becomes refractory to furosemide.
Spironolactone
Spironolactone is a potassium sparing diuretic that works on the collecting duct. Spironolactone also has aldosterone agonist properties, and therefore is also used for neurohormonal blockade.
Adverse effects of diuresis include polyuria, polydipsia, hypokalaemia, increased urea and creatinine, continuous activation of RAAS.
3. Neurohormonal blockade
Angiotensin-converting enzyme inhibitors (ACEI)
ACEIs vasodilate blood vessels and block neurohormonal messages to retain sodium. Therefore, ACEIs are indicated in most cases where furosemide is prescribed. Examples of ACE inhibitors are enalapril and benazepril.
Aldosterone antagonists
Aldosterone release is another part of neurohormonal compensation. It has similar vasoconstriction and sodium retention effects as angiotensin II. An example of an aldosterone antagonist is spironolactone, which is also used for its potassium-sparing diuretic properties.
Adverse effects of neurohormonal blockade include azotaemia and hypotension.
4. Anti-arrhythmics
Arrhythmias can occur in the later stages of MMVD. The most common is atrial fibrillation, due to atrial myocardial stretch. Digoxin and/or diltiazem may be prescribed.
Digoxin decreases heart rate allowing for an improvement in cardiac filling. It has a narrow therapeutic window. Adverse effects include gastrointestinal symptoms, bradyarrhythmias and tachyarrhythmias. Blood digoxin levels should be monitored regularly.
Diltiazem is a class IV anti-arrhythmic. It is a calcium channel blocker that targets the sinus rate and AV node conduction. It is used to treat atrial tachycardias, and is available in different forms, including short- or long-term release. Caution should be used with both drugs, and regular monitoring is required.
5. Surgery
Some referral centres offer surgical repair of the mitral valve. This requires cardiac bypass and can be restrictive to some clients due to cost.
Dietary management
Recent research has focused on the role of metabolomics and MMVD, and the hope is to create a tailored diet that supports cardiac function and prolongs the preclinical phase of MMVD. Cardiac tissue and serum samples have shown cellular and metabolic changes with MMVD (Li et al, 2019). These changes are classified into:
- Alterations in energy metabolism
- Oxidative stress
- Inflammation
- Extracellular matrix homeostasis pathways.
The healthy canine heart takes approximately 70% of its energy from mitochondrial oxygenation of long chain fatty acids. However, MMVD causes mitochondrial dysfunction which results in restricted fatty acid oxidation and ketosis. To counteract this, the heart uses anaerobic glycolysis, which is much less efficient and results in myocardial energy deprivation (Li et al, 2019). A diet containing medium-chain triglycerides, fish oils to reduce inflammation, antioxidants and other key nutrients, was tested on 36 dogs living in a controlled environment, and diagnosed with early stage MMVD. Results showed reduced left atrial size at 3 and 6 months (Li et al, 2019). However, another study investigated 101 client-owned dogs, and found no difference in the control and test groups (Oyama et al, 2023). Specialised nutrition for dogs with MMVD is still in its infancy, but hopefully, an effective diet will come.
The ACVIM guidelines recommend mild sodium restriction at stage B2, and provision of a highly palatable diet, including adequate protein and calories, to maintain optimal body condition. Cardiac cachexia is a term used to describe loss of muscle or lean body mass resulting from heart failure, and may or may not be associated with weight loss. Cachexia is a significant negative prognostic indicator, and so awareness of this is paramount (Keene et al, 2019). Stage C recommendations include adequate protein content and modest sodium restriction, which should include all foods, including that used to give medication. Calorie intake is recommended at 60 kcal/kg bodyweight, and if anorexia occurs, usual techniques such as warming food and offering different types should be tried. Weight loss with congestive heart failure occurs often, so bodyweight and body condition scores should be taken at each visit. Episodes of anorexia should be specifically investigated with the owner. At stage D, sodium should be restricted further, as long as appetite is not compromised.
Table 4 summarises diagnostic and treatment recommendations from the ACVIM guidelines, including nursing considerations and recommendations to owners.
Table 4. Summary of diagnostic, treatment, nursing and owner recommendations. Adapted from ACVIM guidelines (Keene et al, 2019)
| Stage | Diagnostic tests | Treatment | Nursing care | Recommendation to owners |
|---|---|---|---|---|
| A | Regular health checks, with annual auscultation | N/A | N/A | Breeders or Cavalier King Charles Spaniel (CKCS) owners may wish to attend annual screening conducted by board certified cardiologists, or events at breed shows |
| B1 |
|
N/A | N/A | Re-evaluation every 6-12 months. Preferably echocardiographic evaluation. If not available, radiography acceptable. |
| B2 | Grade III/VI murmur or above Echocardiographic measurements:
|
Pimobendan recommended (0.25–0.3 mg/kg PO q12h)Surgical intervention if costs and access to a referral centre are viable | N/A | Dietary recommendation: mild sodium restriction; highly palatable diet with adequate protein and calories to maintain optimal body condition |
| C | Physical examination: signs of left-sided congestive heart failure including tachypnoea, respiratory distress, cough and/or restlessness Loud heart murmur (grade III or above)Thoracic radiography: assess heart failureEchocardiography:
|
Acute management:
|
Optimal nursing care to include:
|
Chronic management:
|
| D | As for stage CBlood pressure needs to be closely monitored to avoid hypotension | As for stage CIf not used previously, torsemide (0.1-0.2 mg/kg q12h-q24h)Sildenafil if pulmonary hypertension presentOther options include:
|
As for stage C.Client support is crucial at this point | As for stage C, except further sodium restriction if tolerated. |
Conclusions
Whilst MMVD is prevalent amongst CKCS, cases are easy to identify, and so the client–practice relationship can be developed early. Prognosis is still approximately 11–12 months from onset of congestive heart failure to death, despite recent progress made at prolonging the pre-clinical phase of the disease. Early intervention can be beneficial, if pimobendan is started at stage B2. Advancement in medication protocols will hopefully be followed by dietary advances.
KEY POINTS
- Cavalier King Charles Spaniels (CKCS) are predisposed to myxomatous mitral valve disease (MMVD), are more likely to have an earlier onset, and for the disease to progress
- American College of Veterinary Medicine guidelines have classified MMVD into four groups. These can help with diagnosis, treatment and management
- Pimobendan can prolong the preclinical phase if used at stage B2
- Echocardiography is the best method to assess MMVD, but is a challenging technique
- Heart rate, heart murmur intensity and NTproBNP can be used if echocardiography is not an option