Mixing it up with Myxomatous Degeneration

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Mixing it Up With Myxomatous
DegenerationAaron C. Wey, DVM, DACVIM
(Cardiology)
Upstate Veterinary Specialties, PLLC
October 10th, 2015

+ Mixing it Up With Myxomatous
Degeneration
Novel Thoughts for an Old Disease
 Lecture Overview
 Introduction
 Review of clinical history/pathophysiology
 New developments in understanding of the disease
 Medical treatment options/clinical trials
 Human experience
 Interventional treatment options
 Summary
 Q & A

Degeneration
Clinical History
 Myxomatous Valvular Degeneration
(MVD)
 Aliases:
 Degenerative valve disease
 Endocardiosis
 Mitral valve disease
 Most common cardiac disease in dogs
 Estimated that 1/3 of dogs >10yrs of age
have MVD
 Unknown what percentage progresses to
overt
symptoms/CHF
 No cure for the condition currently

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 Myxomatous Valvular Degeneration (MVD)
 Older, small breed dogs (inherited?)
 Age exception – Cavalier King Charles Spaniel (Others?)
 Can affect old, large breed dogs
 Easy pre-clinical diagnosis
 Relatively long pre-clinical phase
 Rare acute exacerbations
 Clinical presentations
 Congestive heart failure
 Bronchial compression
Degeneration
Clinical History

Degeneration
Clinical History
Clinical presentation
 Cough
 Bronchial compression
 Pulmonary edema
 Dyspnea
 Pulmonary edema
 Pleural effusion
 Pulmonary hypertension (PHT)
 Expiratory airway collapse
 Syncope
 Arrhythmias (often atrial origin,
rarely ventricular)
 Exertional
 Vasovagal
 Sudden death relatively rare

Degeneration
Clinical History

Degeneration
Clinical History and Treatment
 Treatment options:
 Stage A/B1 (Early/Mild disease)
 None?
 Stage B2 (Moderate disease)
 ACE Inhibitors – still under debate
 Pimobendan?
 Stage C/D (Severe disease)
 Medical Management
 Diuretics, ACE-inhibitors, pimobendan, other
vasodilators, dietary therapy, etc., etc…

Degeneration

Degeneration
 EPIC – Evaluating Pimobendan In
Cardiomegaly
 2010-2015: Enrolled 360 dogs in Stage B2
(Radiographic and echo confirmation of cardiomegaly
and a murmur, no symptoms)
 180 Controls (Placebo)
 180 Pimobendan
 Size: 4-15kg
 Primary endpoint (up to 3 years) – radiographic onset of
CHF
 Early 2015 – study termination: “Interim analysis
revealed statistically different results in favor of

Degeneration
What Next?
 Ultimately, we still don’t have early
interventional therapy to stop/reverse this
disease process
 If CHF develops, the condition is fatal unless
the patient has another life threatening
condition end it’s life first…
 Will better understanding of pathogenesis
offer avenues for prevention/modification of
disease?
 Once a patient gets the condition and it does

Degeneration
Pathogenesis
 Microscopic valve anatomy
Valvular interstitial cell (VIC)
PG/GAG
Collagen type I

Degeneration
Pathogenesis
 Myxomatous degeneration
 Connective tissue disorder
 Loss of valvular endothelial cells (VEC)
 Activation of valvular interstitial cell (VIC) -
myofibroblast
 Accumulation of glycosaminoglycans (GAGs)
 Oxidative damage and breakdown of the extracellular
matrix (ECM)
 Valve thickening and elongation leading to poor valve
function

Degeneration
Pathogenesis
1. Chetboul V et al. JVIM May-June 2007; 21(3): 742-753.

Degeneration
Pathogenesis
 Get to the root of the
problem – Genetics
 “Small dog” phenotype,
certain breeds
predominate
 Likely complex
(polymorphic)
 Madsen MB, et al.1
 Identification of 2 Loci
Associated with
Development of
Myxomatous Mitral Valve
Disease in Cavalier King
Charles Spaniels
 CFA (Configural Frequency
Analysis) – multivariate
analysis of SNPs that
1. Journal of Heredity, 2011:102(S1), S62-S67

Degeneration
Pathogenesis
 Gene therapies –
 Lysosomal storage diseases (LSDs)
 Group of diseases in which enzymatic contents of
lysosomes are deficient and cause an accumulation of
byproducts within cells of many organs
 Accumulation of GAG/PG in valve tissue causing
valvulopathy
 Canine Muchopolysaccharidosis 1 (MPS-1)
 RV vector containing IDUA DNA injected into neonatal
dogs decreases the severity of valvular lesions (and
other organ abnormalities)1
 University of Pennsylvania - Dr. Meg Sleeper, DVM,
DACVIM(C)
1. Traas AM, et al. Mol Ther. 2007;15:1423–1431.

Degeneration
Pathogenesis
 Gene therapy not available yet – what next?
 Focus on pathophysiology

Degeneration
Pathogenesis
1. Orton EC et al. J. Vet Card. 2012:14, 7-17

Degeneration
Pathogenesis
 Serotonin (5-hydroxytriptamine, 5-HT)
 95% produced by enterochromaffin cells in the gut
 Most metabolized quickly in the lungs, largest stores in
platelets
 Interact with 5-HT receptors (5-HT2B-R in valvular tissue)
to elicit subcellular actions
 Uptake by serotonin transporter (SERT) and metabolized
(MOA)
 Serotonin and valvular disease
 Lab animals injected with 5-HT develop valvular lesions
typical of MVD
 Humans with carcinoid tumors that secrete 5-HT develop
valvulopathy
 Intake of seritonergic drugs or toxins causes valvulopathy
 Fenfluramine, pergolide

Degeneration
Pathogenesis
Supportive evidence:
• Increased transcript
levels in dogs with
MVD
• Chronic
administration
decreased [SERT]
in rats
• Increased
expression in
human and canine
degenerative valves
• Increased
ppERK/ERK in dogs
with MVD

Degeneration
Pathogenesis
 Transforming growth factor b (TGF-b)
 Three isoforms, TGF-b1 implicated in valvular
degeneration
 Binds to components of ECM through two receptors
(R1, R11)
 Through a series of phosphorylation events, actives
other proteins that translocate into the nucleus and
effects gene transcription
 Mediates myofibroblast transformation (VICs)
 Increases collagen synthesis
 TGF-b1 induces GAG synthesis in cultured VICs

Degeneration
Pathogenesis
 Platelets function and MVD
 Roughly 1 article/yr in the past 15 years related to
platelets in CKCS, half of these suggest altered
platelet function with MVD
 Primary site for circulating 5-HT in the body, released
with aggregation/activation
 Loss of valvular endothelial cells (VEC) on atrial side
of A-V valves with myxomatous degeneration
 Are platelets the source of serotonin that
contributes to valvular degeneration?

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 Serotonin Concentrations in Platelets, Plasma,
Mitral Valve Leaflet, and Left Ventricular
Myocardial Tissue in Dogs with Myxomatous
Mitral Valve Disease1
 [5-HT] in platelet rich plasma was
higher in CKCS (with and without
MVD) and other breeds with
MVD compared with controls
 [5-HT] in valve tissue and LV
myocardium in dogs with valve
disease compared to controls
Degeneration
Pathogenesis
1. Cremer SE, et al. JVIM 2014;28:1524-1540

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 Serotonin Concentrations in Platelets, Plasma,
Mitral Valve Leaflet, and Left Ventricular
Myocardial Tissue in Dogs with Myxomatous
Mitral Valve Disease1
Degeneration
Pathogenesis
1. Cremer SE, et al. JVIM 2014;28:1524-1540

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 Plasma and serum serotonin concentrations
and surface-bound platelet serotonin
expression in Cavalier King Charles Spaniels
with myxomatous mitral valve disease1
 Compared serum/plasma [5-HT] in dogs with Class
A/B1 (n=33) to dogs with Class B2/C1-2 disease (n=29)
 Dogs with no/mild disease had higher serum [5-HT] than
dogs with severe disease
 No differences in surface bound platelet serotonin
expression or activation were found between groups
 Platelets may not be the smoking gun…
 Local serotonin production?
Degeneration
Pathogenesis
1. Cremer SE et al, AJVR 2015;76(6):520-31

Degeneration
Pathogenesis
1. Oyama MA and Levy RJ, JVIM 2010;24:27-36
Serotonin? Stay
tuned…..

Degeneration
Pathogenesis Endothelial dysfunction/Oxidative damage
 Emerging pathogenic mechanisms in human myxomatous
mitral valve: lessons from past and novel data. Hulin A et
al. Cardiovasc Pathol. 2013;22(4): 245-50
 Biopterin status in dogs with myxomatous mitral valve
disease is associated with disease severity and
cardiovascular risk factors. Reimann MJ et al. JVIM
2014;28(5):1520-26.
 Increased [BH4] and [BH2] in dogs with MVD/CHF
 Veterinary Medicine and Multi-Omics Research for Future
Nutrition Targets: Metabolomics and Transcriptomics of the
Common Degenerative Mitral Valve Disease in Dogs. Li Q,
et al. OMICS 2015;19(8):461-70.
 Higher levels of ADMA, oxidize glutathione, other markers of
oxidative stress

Degeneration
Pathogenesis Would free radical scavengers and other anti-
oxidants be helpful in treating MVD?
 To date, no long term placebo controlled clinical trials
evaluating anti-oxidants in patients with MVD
 Omega-3 Fatty Acids:
 DHA: 25mg/kg/day
 EPA: 40mg/kg/day
 Other free radical scavengers?
 Dietary therapy?
No current evidence of
efficacy at preventing
progression of MVD

Degeneration
Interventional Therapy
 Dreisbaugh KH and Oyama MA., 2015 ACVIM
Proc.

Degeneration
 Surgical Correction of Primary
Mitral Valve Disease in Humans
 May include :
 Valve replacement – bioprosthesis or
mechanical valve
 Valvuloplasty with plication or direct
suturing of the valve
 Annuloplasty with internal reduction
in annulus size
 Chordal substitution, reattachment,
or shortening
 All of these require
cardiopulmonary bypass
 All require specialized technical
abilities

Degeneration
 Circumferential Suture of the Mitral Annulus
for Correction of Mitral Regurgitation in Dogs1
1. Buchanan JW and Sammarco CD. Vet Surg 1998;27:182-193

Degeneration
 Circumferential Suture of the Mitral Annulus
for Correction of Mitral Regurgitation in Dogs1
 Attempted placement in 15 dogs
 9 dogs died in perioperative period
 Satisfactory suture placement in
6 dogs…
 Only 3 dogs were long term
survivors (>6 months)
1. Buchanan JW and Sammarco CD. Vet Surg 1998;27:182-193

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Degeneration
 Partial external mitral
annuloplasty in dogs with
myxomatous mitral valve
degeneration and
congestive heart failure:
Outcome in 9 cases1
 9 Dogs with severe
disease/CHF (Stage C)
 4 died during or
immediately after surgery
 4/5 surviving dogs had no
reduction in LA size or
regurgitant fraction
1.DeAndrade JN et al. J Vet Card. 2011;13(3): 197-201

Degeneration
 Is open surgical repair feasible in dogs?
 Griffiths LG, Orton EC, Boon JA. Evaluation of
techniques and outcomes of mitral valve repair in
dogs. JAVMA 2004;224(12): 1941-1945.
 Variety of repair techniques (annuloplasty, chordal
repair/replacement, valve replacement or end-to-end
repair)
 18 dogs, 66% operative survival, most dogs
surviving surgery had good long term survival
 Expensive/Technically demanding
 Required travel to Colorado
 Eventually not supported by the University
 Redirection to research less invasive techniques

Degeneration
 Uechi M, et al. Mitral valve repair under cardiopulmonary
bypass in small breed dogs: 48 cases (2006-2009).
JAVMA 2012;240(10): 1194-1201

Degeneration
 Uechi M, et al. Mitral valve repair under cardiopulmonary
bypass in small breed dogs: 48 cases (2006-2009).
JAVMA 2012;240(10): 1194-1201
 Initially small dogs (all <5kg)
 93% success rate (survival >6 months after surgery)
 Now recommending earlier intervention (Stage B2 and early C)
 Success prompted international invitations to help found other
surgical centers
 London
 Cornell University
 Michigan State University

Degeneration
 Case Study: “Benson”, 8.5yr MC Maltese/Poodle cross
 8/2013: Diagnosed with MVD, severe MR, and early CHF
 Furosemide, pimobendan, enalapril, potassium supplement
 Slowly increasing renal values
 Stable for almost 1.5yrs, then decompensation after increased
water intake
 2/2015: Hospitalized for acute CHF management – ruptured chord
 Higher furosemide, pimobendan, benazepril, amlodipine, hydrocodone...
 Over next 3 months progressive cardiomegaly and azotemia but no
hospitalization.
 BUN 56/Cr 2.9
 Owner elects to pursue surgery
with Dr. Uechi at Cornell

Degeneration

Degeneration
 Case Study: “Benson”, 8.5yr MC Maltese/Poodle cross
 5/6/2015 – Surgery
 Post-operative complications
 Acute renal failure
 Systemic hypertension/pulmonary hypertension
 Acute vestibular symptoms presumed to be thromboembolic event
 Discharged 5/18/2015
 Sildenafil, pimobendan, clopidogrel, benazepril
 Recheck 9/22/2015
 BUN 17/Creat 2.1
 Off all medications other than benazepril

Degeneration
 Concerns with surgery
 Longevity of repair
 Underlying myxomatous change progresses
 Durability of artificial chordae
 Postoperative complications
 Reduced with experience
 Start over in new Sx center
 Cost:
 $30-$35,000

Degeneration
 Veterinary patients need alternatives:
 Widely available
 Economical
 Durable
 Safe/Easy to perform
 Ideal valve repair procedure
 Avoid cardiopulmonary bypass
 Avoid anticoagulation
 No specialized equipment
 Simple to learn; Safe/Easy to perform

Degeneration
 Epicardial Annuloplasty Device
 Mitral Touch (Maquet Cardiovascular, LLC)
 Mitrex Device (Infiniti Medical)
www.cavalierhealth.org

Degeneration
 Epicardial Annuloplasty
www.cavalierhealth.org

Degeneration
 MitraClip Device (Abbott)
 Based on a surgical procedure first described >20yrs
ago
 Ottavio Alfieri – “Alfieri Stitch”
 Edge-to-edge apposition of the mitral leaflets

Degeneration
 MitraClip®Device (Abbott)
 http://mitraclip.com/hcp/tmvr_mitraclip_ther
apy

Degeneration
 Mitral Seal® Avalon Medical/CSU
 Based on surgical mitral prostheses
 Hybrid procedure
 Eliminate concerns about progressive
disease
 Requires anticoagulation

Degeneration
 Mitral Seal® Avalon Medical/CSU
 https://www.youtube.com/watch?v=SbEBsejE
J1I

Degeneration
Novel Thoughts for an Old Disease
 Summary
 Myxomatous valvular degeneration remains a
common, incurable disease
 Advances in medical therapy are helping to maintain
quality of life for longer in affected patients
 New basic research is beginning to shed light on the
pathophysiology of the disease
 Many new interventional techniques are either
available or under investigation to more effectively
treat this disease

Degeneration
Novel Thoughts for an Old Disease Questions?

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Mixing it up with Myxomatous Degeneration

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