mixing it up with myxomatous degeneration
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Mobile Cardiology
Mixing it Up With Myxomatous Degeneration Aaron C. Wey, DVM, DACVIM (Cardiology)Upstate Veterinary Specialties, PLLCOctober 10th, 2015
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Mixing it Up With Myxomatous DegenerationNovel Thoughts for an Old DiseaseLecture OverviewIntroductionReview of clinical history/pathophysiologyNew developments in understanding of the diseaseMedical treatment options/clinical trialsHuman experienceInterventional treatment optionsSummaryQ & A
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Mixing it Up With Myxomatous DegenerationClinical HistoryMyxomatous Valvular Degeneration (MVD)Aliases: Degenerative valve diseaseEndocardiosisMitral valve diseaseMost common cardiac disease in dogsEstimated that 1/3 of dogs >10yrs of age have MVDUnknown what percentage progresses to overt symptoms/CHFNo 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 dogsEasy pre-clinical diagnosis Relatively long pre-clinical phaseRare acute exacerbationsClinical presentationsCongestive heart failureBronchial compression
Mixing it Up With Myxomatous DegenerationClinical History
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Mixing it Up With Myxomatous DegenerationClinical HistoryClinical presentationCoughBronchial compressionPulmonary edemaDyspneaPulmonary edemaPleural effusionPulmonary hypertension (PHT)Expiratory airway collapseSyncopeArrhythmias (often atrial origin, rarely ventricular)ExertionalVasovagal Sudden death relatively rare
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Mixing it Up With Myxomatous DegenerationClinical History
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Mixing it Up With Myxomatous DegenerationClinical History
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Mixing it Up With Myxomatous DegenerationClinical History and TreatmentTreatment options: Stage A/B1 (Early/Mild disease) None?Stage B2 (Moderate disease)ACE Inhibitors still under debatePimobendan?Stage C/D (Severe disease)Medical ManagementDiuretics, ACE-inhibitors, pimobendan, other vasodilators, dietary therapy, etc., etc
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Mixing it Up With Myxomatous DegenerationClinical History and Treatment
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Mixing it Up With Myxomatous DegenerationClinical History and TreatmentEPIC Evaluating Pimobendan In Cardiomegaly2010-2015: Enrolled 360 dogs in Stage B2 (Radiographic and echo confirmation of cardiomegaly and a murmur, no symptoms)180 Controls (Placebo)180 PimobendanSize: 4-15kgPrimary endpoint (up to 3 years) radiographic onset of CHFEarly 2015 study termination: Interim analysis revealed statistically different results in favor of pimobendan vs. placebo in prolonging time to congestive heart failure in dogs with moderate to severe MR (Stage B2)
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Mixing it Up With Myxomatous DegenerationWhat Next?Ultimately, we still dont have early interventional therapy to stop/reverse this disease processIf CHF develops, the condition is fatal unless the patient has another life threatening condition end its life firstWill better understanding of pathogenesis offer avenues for prevention/modification of disease?Once a patient gets the condition and it does progress, are there better treatment options to maintain quality of life?
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Blood flowMixing it Up With Myxomatous DegenerationPathogenesisMicroscopic valve anatomy
Valve Endothelial cells (VEC)
Smooth muscle cellElastin
Valvular interstitial cell (VIC)
PG/GAG
Collagen type I
Atrialis
Spongiosa
Fibrosa
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Mixing it Up With Myxomatous DegenerationPathogenesisMyxomatous degeneration Connective tissue disorderLoss of valvular endothelial cells (VEC)Activation of valvular interstitial cell (VIC) - myofibroblastAccumulation of glycosaminoglycans (GAGs)Oxidative damage and breakdown of the extracellular matrix (ECM)Valve thickening and elongation leading to poor valve function
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Mixing it Up With Myxomatous DegenerationPathogenesis
1. Chetboul V et al. JVIM May-June 2007; 21(3): 742-753.
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Mixing it Up With Myxomatous DegenerationPathogenesisGet to the root of the problem GeneticsSmall dog phenotype, certain breeds predominateLikely complex (polymorphic)Madsen MB, et al.1Identification of 2 Loci Associated with Development of Myxomatous Mitral Valve Disease in Cavalier King Charles SpanielsCFA (Configural Frequency Analysis) multivariate analysis of SNPs that make up a phenotype
1. Journal of Heredity, 2011:102(S1), S62-S67
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Mixing it Up With Myxomatous DegenerationPathogenesisGene 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 organsAccumulation of GAG/PG in valve tissue causing valvulopathyCanine Muchopolysaccharidosis 1 (MPS-1)RV vector containing IDUA DNA injected into neonatal dogs decreases the severity of valvular lesions (and other organ abnormalities)1University of Pennsylvania - Dr. Meg Sleeper, DVM, DACVIM(C)
1. Traas AM, et al. Mol Ther. 2007;15:14231431.
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Mixing it Up With Myxomatous DegenerationPathogenesisGene therapy not available yet what next?Focus on pathophysiology
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Mixing it Up With Myxomatous DegenerationPathogenesis
1. Orton EC et al. J. Vet Card. 2012:14, 7-17
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Mixing it Up With Myxomatous DegenerationPathogenesisSerotonin (5-hydroxytriptamine, 5-HT)95% produced by enterochromaffin cells in the gutMost metabolized quickly in the lungs, largest stores in plateletsInteract with 5-HT receptors (5-HT2B-R in valvular tissue) to elicit subcellular actionsUptake by serotonin transporter (SERT) and metabolized (MOA)Serotonin and valvular diseaseLab animals injected with 5-HT develop valvular lesions typical of MVDHumans with carcinoid tumors that secrete 5-HT develop valvulopathyIntake of seritonergic drugs or toxins causes valvulopathyFenfluramine, pergolide
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Mixing it Up With Myxomatous DegenerationPathogenesis
1. Orton EC et al. J. Vet Card. 2012:14, 7-17Supportive evidence:
Increased transcript levels in dogs with MVDChronic administration decreased [SERT] in ratsIncreased expression in human and canine degenerative valvesIncreased ppERK/ERK in dogs with MVDOverexpression of TGFb isoforms in canine degenerative mitral valves
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Mixing it Up With Myxomatous DegenerationPathogenesisTransforming growth factor b (TGF-b)Three isoforms, TGF-b1 implicated in valvular degenerationBinds 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 transcriptionMediates myofibroblast transformation (VICs)Increases collagen synthesisTGF-b1 induces GAG synthesis in cultured VICs1. Orton EC et al. J. Vet Card. 2012:14, 7-17
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Mixing it Up With Myxomatous DegenerationPathogenesis1. Orton EC et al. J. Vet Card. 2012:14, 7-17
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Mixing it Up With Myxomatous DegenerationPathogenesis1. Orton EC et al. J. Vet Card. 2012:14, 7-17
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Mixing it Up With Myxomatous DegenerationPathogenesisPlatelets function and MVDRoughly 1 article/yr in the past 15 years related to platelets in CKCS, half of these suggest altered platelet function with MVDPrimary site for circulating 5-HT in the body, released with aggregation/activationLoss 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
Mixing it Up With Myxomatous DegenerationPathogenesis1. 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
Mixing it Up With Myxomatous DegenerationPathogenesis1. 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 disease1Compared 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 diseaseNo differences in surface bound platelet serotonin expression or activation were found between groupsPlatelets may not be the smoking gunLocal serotonin production? Mixing it Up With Myxomatous DegenerationPathogenesis1. Cremer SE et al, AJVR 2015;76(6):520-31
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Mixing it Up With Myxomatous DegenerationPathogenesis
1. Oyama MA and Levy RJ, JVIM 2010;24:27-36?Serotonin? Stay tuned..
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Mixing it Up With Myxomatous DegenerationPathogenesisEndothelial dysfunction/Oxidative damageEmerging pathogenic mechanisms in human myxomatous mitral valve: lessons from past and novel data. Hulin A et al. Cardiovasc Pathol. 2013;22(4): 245-50Biopterin 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/CHFVeterinary 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
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Mixing it Up With Myxomatous DegenerationPathogenesisWould 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 MVDOmega-3 Fatty Acids:DHA: 25mg/kg/dayEPA: 40mg/kg/dayOther free radical scavengers? Dietary therapy?
No current evidence of efficacy at preventing progression of MVD
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Mixing it Up With Myxomatous DegenerationInterventional TherapyDreisbaugh KH and Oyama MA., 2015 ACVIM Proc.
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Mixing it Up With Myxomatous DegenerationInterventional TherapySurgical Correction of Primary Mitral Valve Disease in HumansMay include : Valve replacement bioprosthesis or mechanical valveValvuloplasty with plication or direct suturing of the valveAnnuloplasty with internal reduction in annulus sizeChordal substitution, reattachment, or shorteningAll of these require cardiopulmonary bypassAll require specialized technical abilities
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Mixing it Up With Myxomatous DegenerationInterventional TherapyCircumferential Suture of the Mitral Annulus for Correction of Mitral Regurgitation in Dogs1
1. Buchanan JW and Sammarco CD. Vet Surg 1998;27:182-193
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Mixing it Up With Myxomatous DegenerationInterventional TherapyCircumferential Suture of the Mitral Annulus for Correction of Mitral Regurgitation in Dogs1
Attempted placement in 15 dogs9 dogs died in perioperative periodSatisfactory suture placement in 6 dogsOnly 3 dogs were long term survivors (>6 months)
1. Buchanan JW and Sammarco CD. Vet Surg 1998;27:182-193
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Mixing it Up With Myxomatous DegenerationInterventional Therapy
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 surgery4/5 surviving dogs had no reduction in LA size or regurgitant fraction
1.DeAndrade JN et al. J Vet Card. 2011;13(3): 197-201
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Mixing it Up With Myxomatous DegenerationInterventional TherapyIs 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 survivalExpensive/Technically demandingRequired travel to ColoradoEventually not supported by the University Redirection to research less invasive techniques
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Mixing it Up With Myxomatous DegenerationInterventional TherapyUechi M, et al. Mitral valve repair under cardiopulmonary bypass in small breed dogs: 48 cases (2006-2009). JAVMA 2012;240(10): 1194-1201
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Mixing it Up With Myxomatous DegenerationInterventional TherapyUechi M, et al. Mitral valve repair under cardiopulmonary bypass in small breed dogs: 48 cases (2006-2009). JAVMA 2012;240(10): 1194-1201
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Mixing it Up With Myxomatous DegenerationInterventional TherapyUechi M, et al. Mitral valve repair under cardiopulmonary bypass in small breed dogs: 48 cases (2006-2009). JAVMA 2012;240(10): 1194-1201Initially small dogs (all 6 months after surgery)Now recommending earlier intervention (Stage B2 and early C)Success prompted international invitations to help found other surgical centersLondonCornell UniversityMichigan State University
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Mixing it Up With Myxomatous DegenerationInterventional TherapyCase Study: Benson, 8.5yr MC Maltese/Poodle cross8/2013: Diagnosed with MVD, severe MR, and early CHFFurosemide, pimobendan, enalapril, potassium supplementSlowly increasing renal valuesStable for almost 1.5yrs, then decompensation after increased water intake2/2015: Hospitalized for acute CHF management ruptured chordHigher furosemide, pimobendan, benazepril, amlodipine, hydrocodone...Over next 3 months progressive cardiomegaly and azotemia but no hospitalization. BUN 56/Cr 2.9Owner elects to pursue surgery with Dr. Uechi at Cornell
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Mixing it Up With Myxomatous DegenerationInterventional Therapy
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Mixing it Up With Myxomatous DegenerationInterventional Therapy
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Mixing it Up With Myxomatous DegenerationInterventional TherapyCase Study: Benson, 8.5yr MC Maltese/Poodle cross5/6/2015 SurgeryPost-operative complicationsAcute renal failureSystemic hypertension/pulmonary hypertensionAcute vestibular symptoms presumed to be thromboembolic eventDischarged 5/18/2015Sildenafil, pimobendan, clopidogrel, benazeprilRecheck 9/22/2015BUN 17/Creat 2.1Off all medications other than benazepril
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Mixing it Up With Myxomatous DegenerationInterventional Therapy
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Mixing it Up With Myxomatous DegenerationInterventional TherapyConcerns with surgeryLongevity of repairUnderlying myxomatous change progressesDurability of artificial chordaePostoperative complicationsReduced with experienceStart over in new Sx centerCost:$30-$35,000
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Mixing it Up With Myxomatous DegenerationInterventional TherapyVeterinary patients need alternatives:Widely availableEconomicalDurableSafe/Easy to performIdeal valve repair procedureAvoid cardiopulmonary bypassAvoid anticoagulationNo specialized equipmentSimple to learn; Safe/Easy to perform
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Mixing it Up With Myxomatous DegenerationInterventional TherapyEpicardial Annuloplasty Device
Mitral Touch (Maquet Cardiovascular, LLC)Mitrex Device (Infiniti Medical)www.cavalierhealth.org
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Mixing it Up With Myxomatous DegenerationInterventional TherapyEpicardial Annuloplasty
www.cavalierhealth.org
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Mixing it Up With Myxomatous DegenerationInterventional TherapyMitraClip Device (Abbott) Based on a surgical procedure first described >20yrs ago Ottavio Alfieri Alfieri StitchEdge-to-edge apposition of the mitral leaflets
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Mixing it Up With Myxomatous DegenerationInterventional TherapyMitraClipDevice (Abbott) http://mitraclip.com/hcp/tmvr_mitraclip_therapy
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Mixing it Up With Myxomatous DegenerationInterventional TherapyMitral Seal Avalon Medical/CSU
Based on surgical mitral prostheses
Hybrid procedure
Eliminate concerns about progressive disease
Requires anticoagulation
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Mixing it Up With Myxomatous DegenerationInterventional TherapyMitral Seal Avalon Medical/CSUhttps://www.youtube.com/watch?v=SbEBsejEJ1I
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Mixing it Up With Myxomatous DegenerationNovel Thoughts for an Old DiseaseSummaryMyxomatous valvular degeneration remains a common, incurable diseaseAdvances in medical therapy are helping to maintain quality of life for longer in affected patientsNew basic research is beginning to shed light on the pathophysiology of the diseaseMany new interventional techniques are either available or under investigation to more effectively treat this disease
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Mixing it Up With Myxomatous DegenerationNovel Thoughts for an Old DiseaseQuestions?
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