Valvular Disease
Daniel Hall, VMD
September 23, 2010
Valvular Disease - Outline
• Pathophysiology of canine degenerative mitral
valve disease (DMVD)
• Literature review
• Current treatment recommendations based on
ACVIM Consensus Statement (2009)
Degenerative Mitral Valve Disease (DMVD)
• Myxomatous
– No inflammatory component
within valve tissue*
– Genetic
• Cavaliers
• Dachsunds
– Metabolic
• Serotonin
• Other mediators?
– Environmental?
• Carcinoid plaques
Normal Mitral Valve Anatomy
• Atrialis
– Elastic tissue
– Type I & III collagen fibers
• Spongiosa
– Mostly proteoglycans
– Modest collagen
– Valvular interstitial cells (VIC)
A
S
F
• Fibrosa – main structural layer
– Dense collagen
– Few elastic fibers
– Extends into chordae
• Ventricularis
– Collagen fibers
*Valvular endothelial cells cover the valve surface*
V
A Little More About VICs
• Normally quiescent, fibroblast-like
cells evenly distributed throughout
valve tissue
• Differentiation and activation into
“active myofibroblast” cells
mediated by:
PDGF, TGFβ, FGF, Thrombin, Fibronectin
• Active myofibroblasts cause
spongiosa expansion and fibrosa
destruction via expression of:
Actin, collagenases, fibronectin, MMPs,
chondroitin, cathepsin D, GAGs, etc.
Han et al. AJVR 2008
Biomechanical Forces
1. Flexure
2. Shear
In vitro studies suggest
that canine VICs have
receptors sensitive to
tensile forces that lead to
signaling involved in the
pathogenesis of DMVD
3. Tension/Compression
Progression of DMVD
• Mild
↑ extracellular matrix (ECM) of atrialis, ↓ collagen organization of
fibrosa, ↑ valvular endothelial cell proliferation
• Moderate
Coalescing nodules of proteoglycans & basement membrane
material, further disorder/lack of fibrosa collagen
• Severe
↑↑ ECM within spongiosa, disorganized fibrosa collagen,
endothelial cell denuding
Main changes:
VIC activation, Spongiosa expansion
Fibrosa [collagen] destruction, GAG infiltration
Histologic Changes in DMVD
A) Normal mitral valve
Oyama et al. JVIM 2010
B) DMVD
Initiation and Progression of Myxomatous Changes
• Initiating cause(s) still unknown
– Most feel initial valve injury/insult a key factor
– Morphologic changes usually start at leaflet tips
• Key players?
– ↑ circulating 5-HT
• Small dogs with CVD, CKCS without CVD
– ↑ 5-HT signaling
• ↑ 5-HT receptors, ↓ serotonin transmembrane transporter
(SERT), ↑ tryptophan hydroxylase 1 (TPH1) expression
– Other factors/pathways implicated
• TGFβ, endothelin, IGF, nitric oxide
– Pro-inflammatory state? - ↑ C reactive protein
A Little More About 5-HT
• RLS in synthesis
catalyzed by THP1
• Majority of circulating
5-HT stored in dense
granules of platelets
• At least 5 different 5-HT
receptor types in CV
tissue
• Elevated levels cause
carcinoid syndrome
(plaques)
Proposed 5-HT Relation to DMVD
Oyama et al. JVIM 2010
Pathophysiology
What are the main factors that determine
the severity of valvular regurgitation?
1. Regurgitant orifice area (ROA)
2. Transvalvular pressure gradient
From the James W. Buchanan library
Pathophysiology - Hemodynamics
Sympathetic N.S. &
RAAS activation
↑ MR
+
-
↓ LV SV
(↓ CO)
↑ plasma volume,
cardiac remodeling
↑ Preload → ↑ CO
DMVD - Disease Progression
Left atrial size
Severe LAE
CHF
Mod LAE
Mild LAE
Normal
Time (Years)
Can Disease Progression Be Altered?
Left atrial size
Severe LAE
Mod LAE
Mild LAE
Normal
New intervention?
Time (Years)
Degenerative Mitral Valve Disease
Clinical Syndromes
• No clinical signs (asymptomatic murmur or click)
• Left sided congestive heart failure (chronic LCHF)
May progress to right-sided or biventricular HF secondary to
development of pulmonary hypertension
• Left mainstem bronchus compression by LA  cough
• Ruptured chordae tendinae (acute LCHF)
Incidence ~15% (70% of dogs with severe CHF)
• Syncope
Vasovagal syncope, arrhythmias, “tussive” syncope,
pulmonary hypertension
• Endocardial split/LA rupture – hemopericardium,
acquired atrial septal defect
Clinical Assessment of DMVD
Physical Exam
• Mid systolic click in most
• Left apical holo- or
pansystolic murmur
• Pulse quality – usually normal*
• HR/rhythm
– Sinus arrhythmia to tachycardia
– Variable arrhythmias
• Respiratory
– Eupnic to tachypneic and/or dyspneic, +/- cough, crackles
• Body condition - variable
• Evidence of pulmonary hypertension/right CHF?
– Loud/split S2, jugular distension, ascites
– Rarely pleural/pericardial effusion
Clinical Assessment
Cardiac or Respiratory Dyspnea?
Murmur
Duration of signs
Body condition
HR & rhythm
Lung sounds
Other heart sounds
BNP
DMVD
Respiratory
≥ III/VI
Variable
*usually ≤ 1 month
≥ months
Normal to ↓
Normal to ↑
Sinus tachycardia
Sinus arrhythmia
“Do you really want to hear my answer to that?”
S3 gallop?
Loud/split S2?
↑↑↑
Normal to ↑
Treatment Options
Depends on Disease Stage/Severity
“This is a surgical disease” BJB
• ACE inhibitors
• Diuretics
– Furosemide
– Spironolactone
– HCTZ, torsemide?
• Pimobendan
• Vasodilators
– Hydralazine
– Amlodipine
– Nitrates
•
•
•
•
•
•
•
•
•
β blockers
Digoxin
Antiarrhythmics
Sildenafil
Bronchodilators
Cough suppressants
Tranquilizers/sedatives
n-3 fatty acids
AT receptor blockers?
Onto some literature…
Survival Characteristics and Prognostic Variables of Dogs with
Mitral Regurgitation Attributable to Myxomatous Valve Disease
Borgarelli et al. JVIM 2008
558 dogs with DMVD of varying severity
302 (54%) ISACHC Class I
157 (28%) ISACHC Class II
99 (18%) ISACHC Class III
33 mo.
28 mo.
9 mo.
All cause mortality
9 mo.
Cardiac related deaths
Borgarelli et al continued.
Negative Prognostic Indicators
All cause mortality
Age
Dyspnea
Furosemide Rx
Cardiac-related deaths
Age
Dyspnea
Furosemide Rx
Syncope
Arrhythmia
ESV-I > 30 mL/m2
HR > 140
ISACHC Class
LA/Ao > 1.7
MV Evel > 1.2 m/s
E
Syncope
Arrhythmia
ESV-I > 30 mL/m2
MV Evel > 1.2 m/s
HR > 140
ISACHC Class
LA/Ao > 1.7
EDV-I > 100 mL/m2
Overall, multivariate analysis:
Syncope
LA/Ao > 1.7
A
MV Evel > 1.2 m/s
Decreased Systolic Function and Inadequate
Hypertrophy in Large and Small Breed Dogs with
Chronic Mitral Valve Insufficiency (CMVI)
Borgarelli et al. JVIM 2007
• Examined indices of LV diameter, contractile function and wall thickness in:
– Small and large breed normal dogs
– Small and large breed dogs with CMVI and CHF
• Small and large breed dogs with CMVI and CHF had evidence of systolic
dysfunction, possibly secondary to inadequate LV hypertrophy
Fractional shortening
ESVI (ml/m2)
ESD/ESDe
Normal SB
40.1%
21.2
0.89
CMVI SB
45.6%
30.0
1.11
Relative wall thickness
0.53
0.41
Normal LB CMVI LB
27.3%
33.6%
36.4
83.2
1.13
1.30
0.47
0.38
All differences were significant (P < 0.05)
ESVI = end systolic volume index. ESD = end systolic diameter. ESDe = expected end diastolic
diameter for weight. Relative wall thickness = LV free wall thickness/LV diameter in diastole.
Serum Serotonin Concentrations in Dogs
with Degenerative Mitral Valve Disease
Arndt et al. JVIM 2009
Serum 5-HT concentration higher in dogs with DMVD, dogs
predisposed to DMVD, CKCS predisposed to DMVD
C-Reactive Protein Concentration in
Dogs with Chronic Valvular Disease
Rush et al. JVIM 2006
C-reactive protein concentration higher in dogs with DMVD
compared to healthy controls; no relation to CHF or murmur grade
P < 0.001
P = 0.49
Chordae Tendineae Rupture in Dogs with Degenerative
Mitral Valve Disease: Prevalence, Survival, and Prognostic
Factors (114 Cases, 2001–2006)
Serres et al. JVIM 2007
• MST 425 days
• 58% survival > 1 yr
• Negative prognostic
indicators:
–
–
–
–
–
–
ISACHC class
Ascites
Dyspnea
HR
BUN
LA size
Doppler Echocardiography–Derived Evidence of
Pulmonary Arterial Hypertension in Dogs with
Degenerative Mitral Valve Disease: 86 cases (2001–2005)
Serres et al. JAVMA 2006
• Prevalence of PHT
–
–
–
–
ISACHC Class Ia = 3.0%
ISACHC Class Ib = 16.9%
ISACHC Class II = 26.7%
ISACHC Class III = 72.2%
• 18 dogs with mild PHT
had normal 2D LA/Ao
– 2 had moderate MR
– 16 had severe MR
Azotemia and Glomerular Filtration Rate
in Dogs with Chronic Valvular Disease
Nicolle et al. JVIM 2007
• 124 dogs (retrospective)
– 50% azotemic
– Azotemia increased with increasing
NYHA HF class
• 24 dogs (prospective)
– 8/24 azotemic
– 15 NYHA Class I-II: GFR 3.1 ml/kg/m
– 9 NYHA Class III-IV: GFR 1.7 ml/kg/m
Left Atrial Rupture in Dogs: 14 cases (1990-2005)
Reineke et al. JVECC 2008
• Most common presenting
complaints:
– Collapse (13)
– Cough (9)
– Dyspnea (8)
• 5/14 survived to discharge
– 3 euthanized within 35 days
• Acquired ASD is a rare
manifestation of LA tear
Treatments…
VETPROOF TRIAL
Results of the veterinary enalapril trial to prove reduction in onset
of heart failure in dogs chronically treated with enalapril alone for
compensated, naturally occurring mitral valve insufficiency
Atkins et al, et al. JAVMA 2007
• Primary endpoint
– Onset of CHF  58 mo.
• Secondary endpoints
– Time to combined CHFall cause death
– #dogs free of CHF at 500,
1000, 1500 days and
study end
– Mean # CHF-free days
All dogs (n = 139)
Enalapril administered at ~0.5 mg/kg SID
VETPROOF, cont.
• Chronic Rx defined as ≥
60 days
• 15% benefit in reduction
to onset of CHF (P = .06)
Chronically treated dogs (n = 124)
VETPROOF, cont.
P < .03
Mean # CHF-free days
Combined endpoint
P = .05
Effect of Benazepril on Survival and Cardiac Events in
Dogs with Asymptomatic Mitral Valve Disease: A
Retrospective Study of 141 Cases
Pouchelon, et al. JVIM 2008
• Dogs with compensated MVD and moderate to severe MR
• Benazepril (n = 66) vs. untreated (n = 75)
Prior ACE Inhibitor Studies
PRE-CHF:
• The SVEP trial. JVIM 2002; 16: 80-88
CHF:
• The IMPROVE study group. JVIM 1995; 9: 234–242
• The COVE study group. JVIM 1995; 9: 243–252
• The LIVE study group. JAVMA 1998; 213: 1573–1577
• The BENCH study group. J Vet Card 1999; 1: 7–18
Comparative Adverse Cardiac Effects of Pimobendan and
Benazepril Monotherapy in Dogs with Mild Degenerative Mitral
Valve Disease: A Prospective, Controlled, Blinded, and
Randomized Study
Chetboul, et al. JVIM 2007
• 12 beagles with asymptomatic DMVD, grade I-II/VI murmur,
and normal LA and LV dimensions received pimobendan (n=6)
or benazepril (n=6)
• Followed via echo during treatment
• Sacrificed with valvular histopathology at 512 days
Systolic function
MR grade
Valvular lesions
Pimo
↑
↑
↑
Benazepril
NS ∆
NS ∆
NS ∆
Effect of Pimobendan on Echocardiographic Values in
Dogs with Asymptomatic Mitral Valve Disease
Ouellet, et al. JVIM 2009
• Hypothesis: The addition of pimobendan to treatment
decreases the regurgitant fraction (RF) in dogs with
asymptomatic MVD
• 24 dogs with asymptomatic DMVD and LA:Ao > 1.6
– 19 pimobendan
– 5 control
• Echo parameters monitored at day 0, 30, 90, 180
• Nonsustained increased in ejection fraction and decrease
in systolic LV diameter
• No significant change in regurgitant fraction
THE QUEST STUDY
Effect of Pimobendan or Benazepril Hydrochloride on Survival
Times in Dogs with Congestive Heart Failure Caused by Naturally
Occurring Myxomatous Mitral Valve Disease
Haagstrom et al, et al. JAVMA 2007
• Primary endpoint
– Composite of cardiac
death, euthanized for
CHF, treatment failure
• Pimobendan (n = 124)
– 267 days
• Benazepril (n = 128)
– 140 days
Evaluation of Pimobendan and N-Terminal Probrain Natriuretic
Peptide in the Treatment of Pulmonary Hypertension Secondary
to Degenerative Mitral Valve Disease in Dogs
Atkinson, et al. JVIM 2009
Efficacy of Spironolactone on Survival in Dogs with Naturally
Occurring Mitral Regurgitation Caused by Myxomatous Mitral
Valve Disease
Bernay, et al. JVIM 2010
• 212 dogs with Class II (190) and Class III (22) DMVD
• Composite endpoint: cardiac death, euthanasia or worsening MR
11 % spironolactone (2 mg/kg SID) group, 26% control group
Greater withdrawls in spironolactone (56/102) vs control (38/110)
BNP
Clinical utility of serum N-terminal pro-B-type natriuretic
peptide concentration for identifying cardiac disease in dogs
and assessing disease severity
Oyama, et al. JAVMA 2008
• NT-proBNP correlated with murmur grade and ISACHC
class in patients with DMVD (n = 119) as well multiple
echo and radiographic markers of cardiac size
Association of Plasma N-Terminal Pro-B-Type Natriuretic Peptide
Concentration with Mitral Regurgitation Severity and Outcome in
Dogs with Asymptomatic Degenerative Mitral Valve Disease
Chetboul, et al. JVIM 2010
• Prospective study of 72 dogs with subclinical
(ISACHC Ia & Ib) DMVD and 22 control dogs
• NT-proBNP correlated with:
• Regurgitant fraction (R = 0.54)
• LA/Ao (R = 0.33)
• FS% (R = 0.34)
• EDVI (R = 0.31)
• Development of
CHF by 12 months
(D = decompensation)
(S = stable)
Surgery
Griffiths et al. JAVMA 2004
Evaluation of techniques and outcomes of mitral valve repair in dogs
Griffiths, et al. JAVMA 2004
• 18 dogs with severe MR and CHF
• 12 survived surgery
• 4/4 congenital disease
• 8/14 with DMVD
• Predictive of death due to ↓ CO:
• BW <10 kg
• CHF > 6 mo.
• Cardiac arrest > 120 min
• 9/12 survivors achieved CHF
resolution for median duration of
1 year (4 mo. – 3 yr.)
• LV EDVI and ESVI predictive for
CHF resolution
Technique and outcome of mitral valve replacement in dogs
Orton, et al. JAVMA 2005
• 8 dogs; 7 DMVD, 1 DCM
• 7/8 survived; 6/6 surviving dogs
with DMVD had resolution of CHF
• 6/7 later died of acute CHF;
thrombosis of valve prosthesis
The ACVIM Consensus Panel (2009)
Guidelines for the Diagnosis and Treatment of Canine Chronic
Valvular Heart Disease. JVIM 2009; 23:1142-1150
ACVIM 2009 Consensus
• Classic heart failure scoring systems
– Modified New York Heart Association (NYHA)
– International Small Animal Cardiac Health Council (ISACHC)
• ACVIM/ECVIM classification system
Stage A = dogs at risk without structural heart disease
ex/ asymptomatic Cavalier King Charles Spaniel
Stage B = structural disease with no history of clinical signs
B1 = no cardiomegaly
B2 = cardiomegaly
Stage C = dogs with past or current signs of CHF
Stage D = dogs with end-stage CHF refractory to standard Rx
ACVIM 2009 Consensus
Stage A – At risk with no structural dz
• Consensus reached
Yearly ausculation
Can participate in yearly
screening programs
No diet or drug
recommendations
Discontinue breeding if MR
identified early during normal
breeding age
ACVIM 2009 Consensus
Stage B – Structural dz with no clinical signs
• Consensus reached
Thoracic rads
Baseline
Hemodynamic significance
Blood pressure
Echo for any large breed
Echo any small breed in which
hemodynamic questions not
answered through auscultation
and CXR
Basic labs: Hct, TP, Creatinine, UA
ACVIM 2009 Consensus
Stage B, cont.
• B1 – no cardiomegaly
No diet/drug Rx
Yearly re-evaluation
Ao
Some felt sooner in large breeds
• B2 – cardiomegaly
LA
Majority:
ACEi for LA enlargement or increasing LA size over time
Mild sodium restriction with adequate protein and calories
Minority:
β blockade
Other Rx under specific circumstances (pimobendan,
digoxin, amlodipine, spironolactone)
ACVIM 2009 Consensus
Stage C & D (heart failure) – acute vs. chronic Rx
• Acute Rx
Optimize: preload, afterload,
contractility, HR
Relieve signs of congestive or low
output CHF
↓ MR if possible
• Chronic Rx
As above plus improve QOL, slow
progression
ACVIM 2009 Consensus
Stage C – Past or current CHF
DIAGNOSTIC CONSIDERATIONS:
• Consensus reached
Small breed older coughing dog + loud murmur
doesn’t always = CHF
Thoracic rads, basic labs, echo
History and physical exam helpful
sinus arrhythmia? weight loss?
Complete database (CBC/Chem/UA) in older dogs
“NT-proBNP likely to be increasingly useful but no consensus of PPV”
ACVIM 2009 Consensus
Stage C – Acute Therapy
• Consensus reached
Initial lasix bolus (1-4 mg/kg IV)
*repeat if needed or start CRI
Lasix CRI @ 1 mg/kg/h for life
threatening CHF /failure to
respond to bolus(es) w/in 2 hr
Start pimobendan @ 0.25-0.3
mg/kg PO q12
Treat anxiety; most → butorphanol
Nitroprusside CRI up to 48 hours
for life threatening /nonresponsive
ACVIM 2009 Consensus
Stage C – Acute Therapy, cont.
• Consensus reached
O2 therapy, thoraco- or
abdominocentesis if indicated
Optimal nursing care and free
access to water
• No consensus
BP monitoring and respiratory
response to narcotics/tranquilizers
Nitroglycerin ointment (12 h on/off)
ACEi (enalapril 0.5 mg/kg q12)
Evidence that ACEi + lasix decreases
PCWP more than lasix alone
ACVIM 2009 Consensus
Stage C – Chronic Therapy
• Consensus reached
Lasix usually around 2 mg/kg q12
Range: 1-2 mg/kg q12 to 4-6 mg/kg q8
> 6 mg/kg q12 → probably Stage D
ACEi – most use 0.5 mg/kg q12
Check creatinine and electrolytes 3-7d
Continue pimobendan
Client education important to
optimize compliance, drug doses
Monitor BW, resting RR, HR, appetite
ACVIM 2009 Consensus
Stage C – Dietary Considerations
• Consensus
Adequate calorie intake
Address/inquire about anorexia
Monitor weight
Avoid low protein diets
*unless severe renal disease
Modify Na intake, avoid processed
and other salty foods
Monitor K+ and consider
supplementation if low (?), or if
arrhythmias noted
ACVIM 2009 Consensus
Stage C – Dietary Considerations
• No consensus
Monitor Mg and consider
supplementing if low and
arrhythmias noted
Give n-3 fatty acids, especially
with decreased appetite, cachexia
or arrhythmias
ACVIM 2009 Consensus
Stage D – Refractory Heart Failure
• Before entering Stage D, the patient should
be on maximum tolerated/recommended
amounts of pimobendan, ACEi, furosemide,
AND be treated with any indicated antiarrhythmic(s) to maintain sinus rhythm or
ventricular response rate between 80-160
• Difficult to come up with additional concrete
recommendations for class D due to lack of
studies within this population
ACVIM 2009 Consensus
Stage D – Acute Therapy
• Consensus
Additional IV lasix bolus(es) or CRI if
Creatinine  3.0
Free access to water, thoraco- or
abdominocentesis as needed
Mechanical ventilation may be
needed to allow time for effect of Rx
Additional afterload reducers if
tolerated
Nitroprusside
Hydralazine
Amlodipine
ACVIM 2009 Consensus
Stage D – Acute Therapy
• No Consensus
↑ Pimobendan to 0.3 mg/kg TID
If patient too sick to wait for benefits
of other therapies, start nitroprusside
and/or dobutamine
Sildenafil 1-2 mg/kg q12, even in
absence of pulmonary hypertension
Bronchodilators (minority)
ACVIM 2009 Consensus
Stage D – Chronic Therapy
• Consensus
↑ lasix as allowed by renal
function
*consider injectable
Give spironolactone
Don’t start β blockade unless
CHF controlled as discussed
previously
↓ Na further in face of
refractory fluid accumulation,
if tolerated
ACVIM 2009 Consensus
Stage D – Chronic Therapy
• No consensus
Start hydrochlorthiazide
↑ Pimobendan to TID
Digoxin for Afib, or if no contraindications
Sildenafil if pulmonary hypertension is present
Don’t stop β blocker but may need to decrease
Add β blocker once CHF stabilized
Add cough suppressants, bronchodilators
Take Home Points – Canine DMVD
• Surgical repair is the definitive long term treatment
for severe DMVD
• ACEi Rx may modestly delay the onset of CHF, and
improves survival and QOL once CHF is present
• Pimobendan improves survival and QOL in dogs with
CHF, greater than benazepril alone, but may have
adverse effects in mild, subclinical DMVD
• Serotonin and other factors likely play a role in the
onset and/or progression of DMVD
• NT pro BNP increases with increasing severity of
DMVD, but is also increased with renal disease and
pulmonary hypertension