Adult Onset Valvular Heart Disease

Question 1

Briefly describe the genetic basis to MMVD and mode of inheritance

Answer 1

• MMVD has a polygenic mode of inheritance
• MMVD is a multifactorial, polygenic, threshold trait
• Early onset MMVD in CKCS is likely different to the late onset disease and has been shown to be highly heritable.
  
  • Two loci on chromosomes 13 and 14 have been shown to be associated with the early onset disease in CKCS
• Males have been shown more susceptible - lower threshold for disease development
• No specific genetic tests exist

Question 2

Outline breeding recommendations based on known inheritance models of early onset MMVD in CKCS

Answer 2

• Significant heritability has been shown for early onset MMVD in CKCS
  
  • Early onset - before 5 years of age.
• Auscultation of the heart serves as a minimum requirement, with any grade murmur resulting in removal from a breeding program.
• Early onset MMVD usually presents a heart murmur before 5 years of age. Breeding before this age is commonplace - so tracing of both sire and dam is essential
• Early detection of mitral valve prolapse is an indicator of progression to mitral valve insufficiency within 3 years.
  
  • Echo examination at a younger age may be more sensitive to early detection of early onset MMVD than auscultation alone
  • Early echo examination is likely to have a reduced specificity and sensitivity when compared to the same study performed at 4-5 years of age.

Question 3

Describe the gross changes seen in the myxomatous mitral valve

Answer 3

• Thickening starts in the areas of apposition, often worse at the insertions of the chordae
• The free edge becomes thickened and irregular and can balloon or bulge towards the LA
• Myxomatous change may also affect the chordae tendinae
• In late stages, fibrosis can cause contraction of the leaflets or chordae.
• Atrial endocardial lesions can be seen (jet lesions)
• In severe cases, varying degrees of atrial rupture may be seen - endomyocardial splits

Question 4

Describe the histopathological changes seen in the myxomatous mitral valve

Answer 4

• Myxomatous degeneration is the hallmark of the disease
  
  • Disorganisation and weakening of the connective tissue
  • Spongiosa is usuallyt prominent
  • Collagen in the fibrosa layer is disorganised
• Increased amounts of mucopolysaccharides and glycosaminoglycans are seen within affected valves
• Endothelial cell damage, pleomorphism or lass may be present - this exposes the underlying basement membrane and subendothelial matrix
• Myocardial fibrosis and intramyocardial arteriosclerosis may be seen with advanced disease (especially in the papilliary muscles).

Question 5

Discuss the role of serotonin in the progressive nature of MMVD in CKCS

Answer 5

Note: Little is known about the progressive thickening and degeneration of the leaflets

• With disease progression, endothelial cells become damaged or lost, exposing the subendothelial matrix and valvular interstitial cells (VICs).
• Endothelial cell damage induces release of endothelin-1
• Endothelin-1 may be involved in transformation of valvular interstitial cells from fibroblast to myofibroblast / smooth muscle cell phenotypes
• This transformation of VIC’s may be initiated by 5-HT (serotonin)
• Serum concentrations of serotonin has been shown to be elevated in CKCS compared to other breeds
• Serotonin has also been shown to be increased in LV myocardial and valvular tissue in dogs with MMVD
• Further, expression of 5-HT receptors are altered in diseased mitral valve leaflets.

Question 6

Briefly describe the pathophysiological changes due to MMVD in dogs leading up to congestive heart failure.

Answer 6

1. Mitral valve distortion initially causes valve prolapse
   
   • No effective left ventricular stroke volume decrease at this point.
2. Mitral valve thickening progresses to enable mitral regurgitation
   
   • The degree of regurgitation is directly dependent on the MV orifice area and the systolic pressure gradient
3. MR is accepted by the LA and stroke volume is maintained. LA slowly dilated to normalise LA pressures
   
   • This slow increase in LA size is dependent on appropriate compliance. This is protective to the pulmonary venous circulation
4. Increased LV diastolic filling leads to a volume overload and eccentric dilatation - this can further enlarge the mitral orifice for regurgitation
5. Reduced afterload leads to increased measures of contractility
6. Increased LA pressures with disease progression confer increased hydrostatic pressures to the pulmonary venous circulation
   
   • Pulmonary venous congestion leads to pulmonary oedema
7. With chronic low grade pulmonary congestion (prior to oedema formation) lymphatics expand to enhance vascular drainage
8. The increased pressures can also affect the pulmonary capilliary bed leading to pulmonary arterial hypertension
9. Left ventricular dilatation occurs secondary to increased preload and in response to locally produced ATII

Question 7

Describe the deliterious effects of cardiac remodelling triggered by MMVD in dogs

Answer 7

• The major remodelling changes include left atrial dilatation and left ventricular eccentric hypertrophy
  
  • Initially, these changes sever to protect the pulmonary vascular from increased pressure and preserve systolic function respectively
• As the left atrium enlarges, compliance slowly decreases
  
  • With severe enlargement, endomyocardial splits or tearing of the pectinate muscles may occur leading to haemopericardium
  • Increased LA pressures leads to pulmonary venous congestion, the major trigger for the development of pulmonary oedema
• LV eccentric hypertrophy will further separate the mitral annulus and increase the regurgitant fraction
• As LV hypertrophy progresses, systolic function slowly declines
• Myocardial fibrosis further inhibits both diastolic function and contractility
• Despite progressive systolic dysfunction, clinical signs due to pulmonary congestion predominate the clinical picture.

Question 8

Discuss the pathophysiological consequences of TR secondary to tricuspid valve endocardiosis

Answer 8

• In most dogs, TVE occurs concurrently to MMVD and often to a lesser extent or at least a less clinical extent
• Pathological changes in the TV are identical to those in the MV.
• Regurgitation in TVE occurs due to a combination of valvular conformational changes and increase in pulmonary arterial pressures
  
  • In most cases, if pulmonary pressures are normal, mild to moderate TR is well tolerated
• RV enlargement occurs with concominant RA enlargement
  
  • Annular stretch can further increase TR
• RA enlargement predisposes to supraventricular arrhythmia
• Increased RA pressures can lead to increased systemic venous hydrostatic pressure and effusion (pericardial, pleural - especially cats, peritoneal) or congestion of the abdominal organs.

Question 9

Describe the major pathophysiological changes that may precipitate the development of clinical signs due to MMVD

Answer 9

1. Increase left atrial pressures leads to pulmonary venous congestion. This can cause interstitial oedema and eventually overt pulmonary oedema with intra-alveolar fluid accumulation
2. Reduced LV stroke volume leads to signs of forward failure - weakness and exercise intolerance
   
   • Development of a supraventricular arrhythmia including AFib can contribute to forward flow failure
3. Increase RA and systemic venous pressures leading to R CHF - ascites, pleural effusion
4. Acute decompensation - most often due to chordae rupture, atrial rupture or sudden ventricular arrhythmia

Question 10

List the various clinical signs and physical exmination findings that can be attributed to decompensated MMVD

Answer 10

1. tachypnoea
2. Weakness / lethargy
3. Syncope / collapse
4. Anxiousness / restlessness
5. Heart murmur - typically loud or radiating
6. Increased lung sounds - end inspiratory crackles
   
   • differentiation from primary small airway disease can be difficult. If due to oedema, then tachypnoea should be present
7. Mucous membrane palour or cyanosis
8. Ascites
9. Dull thoracic sounds with pleural effusion
10. Dull cardiac sounds with pericardial effusion
11. Weak pulses or arrhythmia

Question 11

Describe the abnormalities seen on routine cardiac diagnostic tests

Answer 11

• ECG - limited clinical use unless there is an arrhythmia
  
  • ECG changes are non-specific to underlying cause and may reflect changes in chamber size
• Radiology (thoracic)
  
  • Left atrial enlargement is the earliest and most consistent abnormality.
    
    • If LA enlargement is not present with pulmonary changes, consider primary respiratory disease, though correlation is poor
  • Pulmonary congestion with clinical progression
    
    • Increased size of the pulmonary veins
    • Interstitial oedema may impair delineation of the pulmonary vasculature
  • Pulmonary oedema
    
    • Interstitial changes occur initially and can mimic those of chronic primary respiratory disease
    • Changes around the perihilar / dorsocaudal lung fields is common in dogs
    • Changes can be patchy, variable in location and ill-defined in cats
• Echocardiography
  
  • Non-invasive gold standard for diagnosis of MMVD and associated chamber changes
    
    • No diagnostic for documenting progression to congestive heart failure
  • Identify thickening and prolapse of the MV and TV
  • Identify and quantify left atrial enlargement
  • Quantify left ventricular size and (systolic function)
    
    • Systolic function estimates can be confounded in MVD dogs - LVd may be the best estimate
  • Valve regurgitation and vena contracta width can be semi-quantified and measured respecitively
  • Assess the tricuspid valve and for right sided changes

Question 12

Describe the ACVIM MMVD staging recommendations

Answer 12

1. Stage A:
   
   • At risk of developing MMVD but without a strucural abnormality
2. Stage B
   
   • B1: Heart murmur, mild MR but without significant cardiac remodelling (no cardiomegaly)
   • B2: Asymptomatic dogs with haemodynamically significant MR and findings consistent with cardiomegaly (enlarged LA on echo or radiographs)
3. Stage C
   
   • Dogs with past or current signs of CHF associated with known MMVD and structural heart changes (LA enlargement, eccentric LV hypertrophy
4. Stage D
   
   • Advanced CHF caused by MVD and caridac structural changes that is refractory to standard CHF therapy.

Question 13

Detail the various medications that have been assessed for benefit in dogs with stage B2 mitral valve disease

Comment on the strength of recommendation for each medication

Answer 13

1. ACEI - enalapril most studied
   
   • Results from SVEP and VETPROOF trials failed to demonstrate a significant delay in progression to CHF in dogs with variable stage B1 and B2 MMVD
2. Calcium channel blockers - eg. Amlodipine, diltiazem
   
   • Amlodipine has been shown to reduce regurgitant stroke volume
   • Concurrent 3-fold increase in aldosterone levels due to RAAS activation
   • Not to be used without concurrent ACEI or ARB
   • May have benefit in acute decompensation or chronic advanced disease where LA pressures are significantly elevated
3. Beta-blockers
   
   • Experimentally improve the haemodynamic consequences of MR
   • No studies have shown beneficial preventative effect
4. Inodilators (eg. pimobendan)
   
   • treatment with pimobendan once left atrial enlargement is noted (B2 disease) has been shown beneficial with significant prolongation of the time to CHF - 1228 days versus 766

Question 14

List the major pathophysiological mechanisms the occur during progression to stage C (CHF) MMVD

Answer 14

1. Increased venous pressure - systemic for right sided CHF, pulmonary for left sided CHF
2. cardiac output is reduced
3. Cardiac workload is increased (due to regurgitation)
4. Neurohormonal windup progresses, especially sympathetic drive

Question 15

In early or mild stage C MMVD (early CHF), describe the therapies used and there effect on the pathophysiological consequences of CHF

Answer 15

1. Frusemide: diuretic primarily used to reduce pre-load and venous pressures
2. Pimobendan: Vasodilatory effects especially in the pulmonary vasculature reduces afterload and preload by arterial and venous dilatory effects. Inotropic effects improves forward stroke volume. MR is reduced by this combination
3. ACEI drugs: Reduce systemic arterial pressures and afterload. These help to reduce the cardiac work required to maintain forward flow. May also reduce the regurgitant volume. Reduces RAAS activation

Question 16

Define the expected prognosis after progression to stage C MMVD.

Identify the various prognostic indicators that may underlie a less favourable prognosis

Answer 16

• Not well defined in the literature.
  
  • QUEST suggests pimobendan increases the time to 1st treatment intensification to 98 days (cf 59 days with benazepril)
• Survival time decreases with
  
  • Increased frusemide maintenance dose
  • worsening exercise tolerance
  • severity of mitral valve prolapse
  • increased cardiac size
  • worsening systolic function
  • decreaseing serum creatinine concentration (suggested marker of cachexia)\
  • Development of complications including arrhythmia, renal failure, concurrent bronchial disease, pulmonary hypertension

Question 17

Briefly discuss the aetiology of infective endocarditis

Answer 17

1. Transient or persistent bacteremia must be present
   
   • Note that the origin of that bacteraemia may not be detectable clinically
2. Bacteria must infect the endocardium, generally of the aortic or mitral valve
   
   • Direct contact or within the valvular capilliaries
3. Predisposing factors must be present
   
   • primary valvular damage
     
     • exposure of extracellular matrix proteins, thromboplastin and tissue factor
   • Coagulum forms on the damage valve
4. Bacteria with MSCRAMMS adhere to the coagulum
   
   • microbial surface components recognizing adhesive matrix molecules
5. Bacteria then stimulate further tissue factor release and platelet activation leading to enlargement of the vegetation
6. Fibrinous vegetative lesion is inherently resistant to antibiotic penetration
7. Some bacteria includine Staph. aureus and Bartonella can be internalised within endothelial cells, escaping immune surveillance.

Question 18

List the known predisposing factors for the development of infective endocarditis

Answer 18

• Subaortic stenosis
  
  • Suspected to predispose due to the development of damage to the ventricular aspect of the valve
• Large breed dogs
  
  • May be some link with the occurrence of subaortic stenosis in these breeds
  • The condition is extremely rare in small breed dogs - no association with MMVD
• No direct link to dental prophylaxis

Question 19

List the various factors that contribute to the pathophysiological consequences of infectious endocarditis

Answer 19

1. Virulence of the infective agent
2. Site of infection
   
   • Aortic valve
   • Mitral valve
3. Degress of valvular damage
4. Influence of the infection of valvular function
5. Production or endo- or exo-toxins
6. Development of immune complexes
   
   • Therefore, development of immune complex diseases including polyarthritis
7. Develpment of thromboembolism and metastatic infection

Question 20

List the historical and clinical signs most often associated with infective endocarditis

Answer 20

• note: the history and signs are non-specific and easily overlooked

1. Recent surgery, immunosuppressive treatment, indwelling catheter use or known infections
2. Lameness is the most frequent historical complaint
3. General lethargy, fever, anorexia, weakness, respiratory issues, weight loss and GI disturbances are all possible

• Clinical examination:
  
  • Pain from inflammatory (or septic) joint disease
  • A new heart murmur, often soft (especially if the aortic valve is involved) - 59% in Sykes et al.
  • Arrhythmia is common - 45% in Sykes et al 2006, 62% in Sisson et al 1984
  • Abdominal or muscular pain
  • Neurological disturbances

Question 21

List the various diagnostic tests used to help confirm a diagnosis of infective endocardititis, including the sensitivity / specific of each as appropriate.

Answer 21

1. Echocardiography
   
   • With appropriate operator experience, highly sensitive
   • 57/59 dogs were accurately diagnosed with IE in Sykes et al 2006.
   • vegetations can be identified together with associated regurgitation/insufficiency
   • Useful for both diagnosis and estimating the severity of secondary cardiac dysfunction
2. Electrocardiography
   
   • Arrhythmia is a common finding with 2/3 being ventricular in origin.
   • ~ 40-65% of dogs with IE will have an arrhythmia, but these abnormalities are not specific.
3. Blood cultures
   
   • A positive culture is essential for establishing a diagnosis.
   • Sensitivity is ~ 60-70%
   • PCR may be used as an adjuct but is not any more sensitive than culture alone (requirement of only 1 sample may be beneficial).
4. Basic Laboratory Tests
   
   • Mild non-regenerative anaemia (chronic disease): ~ 60%. Occasionally regenerative anaemia was seen
   • Leukocytosis: neutrophilia and monocytosis in ~ 80%
   • Thrombocytopenia in ~ 50%
   • Hypoalbuminaemia in 95% of dogs (Sykes et al)
   • ALT/ALKP may be increased due to circulating endotoxins (~ 70%)
   • BUN / creatinine may be increased with infarction
   • Hypoglycaemia may be present
   • Coombs Test positive in some cases
   • Urinalysis - pyuria in 60%, haematuria in 62%, bacteriuria in 10%. Cultures??
5. Radiographs
   
   • Generally do not provide additional information relevant to the diagnosis.
   • May help stage secondary cardiac disease and CHF
6. Abdominal Ultrasound:
   
   • Abnormalities are common, the findings are however, typically non-specific.

Question 22

Discuss the Modified Duke’s Criteria for the diagnosis of Infective Endocarditis in Dogs.

Answer 22

• Duke’s criteria involves the inclusion of both major and minor criteria.
  
  • Definitive diagnosis:
    
    • Valvular histopathology
    • 2 major criteria
    • 1 major criteria and 2 minor criteria
  • Possible diagnosis
    
    • 1 major and 1 minor criteria
    • 3 minor criteria
• Major Criteria:
  
  1. Positive echocardiogram
  2. New valvular insufficiency
     
     • more than a mild aortic insufficiency without SAS
  3. Positive blood culture
     
     • at least 2 positive cultures or 3 if a common skin contaminant
• Minor criteria
  
  1. Fever
  2. Medium to large breed dog (> 15kgs)
  3. Concurrent SAS
  4. Documented thromboembolic disease
  5. Concurrent immune mediated disease
     
     • polyarthritis
     • glomerulonephritis
  6. Positive blood culture (not meeting major criteria)
  7. Bartonella serology > 1:1024