Severe Myxomatous Mitral Valve Disease Research Articles

Genetic Variants at the Nebulette Locus Are Associated with Myxomatous Mitral Valve Disease Severity in Cavalier King Charles Spaniels.

The most common cardiovascular disease in domestic dogs is myxomatous mitral valve disease (MMVD), accounting for 75% of all cardiac disease. An increase in age is generally associated with increased incidence of the disease, but Cavalier King Charles Spaniels (CKCS) exhibit an unusually high prevalence of early-onset MMVD, and thus, potentially greater cardiac morbidity and mortality compared to other breeds. Previous research has suggested that selected candidate risk alleles for MMVD are fixed in CKCSs, including six locations within the Nebulette (NEBL) gene on CFA2. The current study analysed genotypes of 180 Australian CKCSs at the identified risk loci. Of these, 178 were phenotyped for severity of disease by echocardiographic measurements of left atrium to aortic root ratio (LA:Ao) and weight normalised left ventricular end diastolic diameter (LVIDdN). Genotyping array markers correctly predicted the genotype at the risk-variant loci in the CKCS population, and the NEBL1, NEBL2 and NEBL3 variants were observed to be in perfect linkage disequilibrium in this cohort. The CKCS cohort included 6/178 dogs being heterozygous for the protective/wild-type alleles at the NEBL locus. The mean LA:Ao and LVIDdN scores of these dogs heterozygous at NEBL1-3 variants were significantly smaller, and with significantly lower variance compared to age-matched CKCSs that were homozygous for risk alleles. The lower cardiac measurements in the heterozygous dogs indicate a significantly reduced risk of severe MMVD disease. Our analysis suggests that despite relative fixation of the NEBL risk alleles, healthy reference alleles at NEBL1-3 exist in low frequency in the CKCS breed and can be used to reduce MMVD severity and mortality.

Mitral valvuloplasty with left atrial appendage closure and pacemaker implantation in a dog with severe myxomatous mitral valve degeneration: a case report

BackgroundMitral valvuloplasty (MVP) has been widely recognized as a treatment option for myxomatous mitral valve disease (MMVD). However, postoperative complications such as thromboembolism, arrhythmia, and pancreatitis in some cases have resulted in death. We treated a dog with severe MMVD complicated by impaired sinus function with MVP and pacemaker implantation. Also, due to an intrinsic procoagulant state and severe arrhythmia after the MVP, left atrial appendage (LAA) closure was performed to reduce the postoperative risk of thrombosis.Case presentationAn 11-year-old castrated 7.5-kg male Miniature Schnauzer with a history of congestive heart failure was brought to Shiraishi Animal Hospital for MMVD surgical treatment. Echocardiography revealed an enlarged left atrium and ventricle secondary to MMVD. Sinus arrest with 2 to 3-second periods of asystole was identified by electrocardiogram. Mitral valvuloplasty was performed with cardiopulmonary bypass to treat the MMVD. After coronary reperfusion, there was no spontaneous electrical activity. Cardiac arrest continued. Based on this surgical outcome, a permanent pacemaker was implanted. In addition, LAA closure with an AtriClip was performed to prevent intra-atrial thrombus formation. Cardiac remodeling and congestion were ameliorated after surgery. Sinus rhythm was restored 5 days postoperatively; however, the patient continued pacemaker dependent. All cardiac drugs were discontinued 3 months after surgery. The owner reported no postoperative complications (i.e., thrombosis), and the patient was brought for a check-up 4 months after the operation in good health.ConclusionsFor surgical MMVD cases complicated with impaired sinus function, the chances of spontaneous sinus rhythm are low, requiring pacemaker implantation. LAA closure may be considered to protect against decreased atrial function after mitral valvuloplasty and prevent intra-atrial thrombus formation.

Exhaustive echocardiographic phenotyping of mitral valve prolapse in a single center: ‘Severe myxomatous mitral valve disease’ as a specific entity?

A particular phenotype of mitral valve prolapse (MVP) was identified as linked to sudden-death (SD) associating myxomatous, bi-leaflet and prolapse with mitral annular disjunction (MAD), so called ‘severe myxomatous mitral valve disease’ (SMMVP). Description of the prevalence and the echocardiographic characteristics of SMMVP in a cohort of MVP patients. From a single center echocardiographic database, patients with MVP were retrospectively enrolled from January 2016 to December 2017 and echocardiographic characteristics, based for all patients on reports and additional measurement, were reported. Results Among 101 patients included (female, n = 50; 59 ± 16 years), we reported 71 patients with myxomatous MVP and 30 patients with fibro-elastic deficiency (FED). All patients with MAD ( n = 22/101) had myxomatous bi-leaflet MVP (i.e. SMMVP). Compared to FED, SMMVP patients were younger (52 ± 13 vs. 68 ± 13 years, P = 0.02), without flail leaflet (0 vs.7 patients, P < 0.0001), with lower left ventricle (LV) ejection fraction (65 ± 9% vs. 76 ± 5%, P = 0.002) and greater LV end-systolic diameter (31 ± 5 mm vs. 25 ± 5 mm, P = 0.005) as systolic mitral annulus diameter (43 ± 7 vs. 33 ± 4 mm, P = 0.0009). SMMVP patients had, compared to FED and Barlow groups, a deeper MVP (6.5 ± 2.1 mm vs. 3.8 ± 1.2 mm, P = 0.0096; vs. 4.4 ± 1.4 mm, P = 0.009) with thicker distal posterior mitral leaflet (5.5 ± 1.2 mm vs. 3.4 ± 0.8 mm, P 0.004; vs. 4.3 ± 1.6 mm, P = 0.01) and lower mitral regurgitation (MR) (3/22 vs. 22/30 vs. 24/49 patients with severe MR, P < 0.0001). Among 101 MVP, 5 had SD history, all had a SMMVP. SMMVP patients with SD had larger MAD (10.3 ± 1.5 vs. 6.9 ± 1.7 mm, P = 0.007), deeper MVP (8.8 ± 2. vs. 5.1 ± 1.9 mm, P = 0.04) and larger systolic annulus diameter (48 ± 2 vs. 40 ± 6 mm, P = 0.02) than the other SMMVP. Among MVP population, SMMVP is an independent MVP entity. This phenotype is all the more specific because it is linked to SD, associating severe deep myxomatous bi-leaflet prolapse with large MAD.

Anatomic regurgitant orifice area obtained using 3D-echocardiography as an indicator of severity of mitral regurgitation in dogs with myxomatous mitral valve disease

ObjectivesTo determine feasibility and repeatability of measuring the anatomic regurgitant orifice area (AROA) using real-time three-dimensional transthoracic echocardiography (RT3DE) in dogs with myxomatous mitral valve disease (MMVD), and to investigate differences in the AROA of dogs with different disease severity and in different American College of Veterinary Internal Medicine (ACVIM) stages. AnimalsSixty privately-owned dogs diagnosed with MMVD. MethodsThe echocardiographic database of our institution was retrospectively searched for dogs diagnosed with MMVD and RT3DE data set acquisition. Dogs were classified into mild, moderate, or severe MMVD according to a Mitral Regurgitation Severity Score (MRSS), and into stage B1, B2 or C according to ACVIM staging. The RT3DE data sets were imported into dedicated software and a short axis plane crossing the regurgitant orifice was used to measure the AROA. Feasibility, inter- and intra-observer variability of measuring the AROA was calculated. Differences in the AROA between dogs in different MRSS and ACVIM stages were investigated. ResultsThe AROA was measurable in 60 data sets of 81 selected to be included in the study (74%). The inter- and intra-observer coefficients of variation were 26% and 21%, respectively. The AROA was significantly greater in dogs with a severe MRSS compared with dogs with mild MRSS (p=0.045). There was no difference between the AROA of dogs in different ACVIM clinical stages. ConclusionsObtaining the AROA using RT3DE is feasible and might provide additional information to stratify mitral regurgitation severity in dogs with MMVD. Diagnostic and prognostic utility of the AROA deserves further investigation.

Effects of pimobendan on myocardial perfusion and pulmonary transit time in dogs with myxomatous mitral valve disease: a pilot study.

To describe pulmonary transit time (nPTT) and myocardial perfusion (nMP) normalised to heart rate in dogs with stable ACVIM stage C myxomatous mitral valve disease (MMVD) and to assess short-term effects of pimobendan on these variables. We hypothesised that nPTT and nMP would increase in dogs with MMVD compared with normal dogs. Additionally, we hypothesised that treatment with pimobendan would decrease nMP and nPTT in dogs with MMVD. Prospective, single-blind study involving 6 normal dogs and 12 dogs with MMVD. Dogs with MMVD were treated with enalapril and furosemide for at least 1 month prior to examination. All dogs underwent standard and contrast echocardiographic examinations at the beginning of the study (T0). At this time, MMVD dogs were randomly assigned to receive either pimobendan (0.4-0.6 mg/kg) or not. All dogs with MMVD were re-evaluated by standard and contrast echocardiography after 1 week (T1) and nPTT and nMP were measured. nPTT was significantly increased in dogs with MMVD (P = 0.0063), compared with normal dogs. It was significantly decreased at T1 in dogs receiving pimobendan (P = 0.0250). The nMP was not significantly different in dogs with MMVD, compared with healthy dogs (P = 0.2552), and it was not significantly different at T1 in the treatment group (P = 0.8798). Contrast echocardiography was a valid, complementary tool for echocardiographic analysis of dogs with MMVD. Pimobendan decreased nPTT in dogs affected by MMVD. Myocardial perfusion was not different in dogs with severe MMVD.

Comparison of cellular changes in Cavalier King Charles spaniel and mixed breed dogs with myxomatous mitral valve disease

IntroductionThe aim of this study was to determine if there are differences in cellular changes in Cavalier King Charles spaniel (CKCS) myxomatous mitral valves compared to non-CKCS dogs. AnimalsCavalier King Charles spaniels (n = 6) and age-matched mixed breed (n = 6) with severe myxomatous mitral valve disease (MMVD), and normal mixed breed (n = 4) dogs. Materials and MethodsImmunohistochemistry staining and qualitative and quantitative analysis of mitral valves sections, examining for the presence of CD11c and CD45, vimentin, alpha smooth muscle actin (α-SMA) and embryonic smooth muscle myosin heavy chain (Smemb), von Willebrand factor and CD31 and Ki-67. ResultsVimentin positive cell numbers were increased in the MMVD dogs and distributed throughout the valve with greatest density close to the endothelium. There were no significant differences in cell marker expression for the two diseased groups, but cell numbers were significantly increased compared to controls for α-SMA (CKCS only) and Smemb (CKCS and mixed breed: p < 0.05). Alpha smooth muscle actin+ cells were primarily located at the valve edge, with Smemb+ cells similarly located, but also present throughout the valve stroma. A small number of cells close to the valve edge co-expressed α-SMA and Smemb. Endothelial von Willebrand factor expression was identified in all valves, with evidence of disrupted endothelium in the diseased, but was also found in diseased valve stroma. There was no staining for CD11c, CD45 or CD31 in any valve. Ki-67+ cells formed linear clusters at the leaflet tip and were sparsely distributed throughout both myxomatous valve groups. ConclusionsThe cellular changes notes with advanced stage MMVD appear similar for CKCS when compared to mixed breed dogs.

Plasma and serum serotonin concentrations and surface-bound platelet serotonin expression in Cavalier King Charles Spaniels with myxomatous mitral valve disease.

To investigate serum and plasma serotonin concentrations, percentage of serotonin-positive platelets, level of surface-bound platelet serotonin expression (mean fluorescence intensity [MFI]), and platelet activation (CD62 expression) in platelet-rich plasma from Cavalier King Charles Spaniels with myxomatous mitral valve disease (MMVD). Healthy dogs (n = 15) and dogs with mild MMVD (18), moderate-severe MMVD (19), or severe MMVD with congestive heart failure (CHF; 10). Blood samples were collected from each dog. Serum and plasma serotonin concentrations were measured with an ELISA, and surface-bound platelet serotonin expression and platelet activation were determined by flow cytometry. Dogs with mild MMVD had higher median serum (746 ng/mL) and plasma (33.3 ng/mL) serotonin concentrations, compared with MMVD-affected dogs with CHF (388 ng/mL and 9.9 ng/mL, respectively), but no other group differences were found. Among disease groups, no differences in surface-bound serotonin expression or platelet activation were found. Thrombocytopenic dogs had lower serum serotonin concentration (482 ng/mL) than nonthrombocytopenic dogs (731 ng/mL). In 26 dogs, a flow cytometry scatterplot subpopulation (FSSP) of platelets was identified; dogs with an FSSP had a higher percentage of serotonin-positive platelets (11.0%), higher level of surface-bound serotonin expression (MFI, 32,068), and higher platelet activation (MFI, 2,363) than did dogs without an FSSP (5.7%, 1,230, and 1,165, respectively). An FSSP was present in 93.8% of thrombocytopenic dogs and in 29.5% of nonthrombocytopenic dogs. A substantive influence of circulating serotonin on MMVD stages prior to CHF development in Cavalier King Charles Spaniels was not supported by the study findings. An FSSP of highly activated platelets with pronounced serotonin binding was strongly associated with thrombocytopenia but not MMVD.

Short-term effect of granulocyte colony-stimulating factor in dogs with severe myxomatous mitral valve disease

Background: Use of granulocyte colony-stimulating factor (G-CSF) to treat damaged myocardium is a relatively new concept. Clinical beneficial and safety outcomes are still controversial.Objective: The aim of this study was to evaluate recruitment of hematopoietic stem cells and therapeutic efficacy of G-CSF in the treatment of myxomatous mitral valve disease (MMVD) of dogs.Animals and methods: Thirty client-owned MMVD dogs with clinical signs of heart failure were enrolled in a prospective double-blind, randomized, placebo-controlled study to compare the short-term effect of G-CSF (n = 17) with control group (n = 13) for identical periods. Clinical, hematological, and cardiovascular assessments were performed on days 0, 1, 3, and 7. Follow-up examination was conducted four weeks after the study.Results: Dogs treated with G-CSF had a significantly elevated white blood cell (WBC) (×103/μL) count at day 3 compared with baseline (from 10.23 ± 4.42 to 42.84 ± 11.84; P = .000). The WBC population was also changed (elevated neutrophils and decreased lymphocytes) and the numbers of CD34+ cells in the peripheral blood were also increased at day 3. However, the results of clinical, laboratory, and echocardiographic assessments did not differ significantly between the G-CSF treatment and control groups after four weeks.Conclusions: G-CSF administration elevated the peripheral WBC count, especially neutrophils, and recruited hematopoietic stem cells. However, positive effects of G-CSF on cardiac function were not detected during short-term monitoring.

Serum Serotonin Concentration Is Associated with Severity of Myxomatous Mitral Valve Disease in Dogs

The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) has recently been suggested to play a role in the development of naturally acquired myxomatous mitral valve disease (MMVD) in dogs. To investigate the association between serum 5-HT concentration and MMVD severity in dogs, and to assess potential associations between serum 5-HT concentrations and dog characteristics, echocardiographic variables, heart rate, systolic blood pressure, presence of macrothrombocytosis, and plateletcrit. A total of 120 client-owned dogs. Dogs were prospectively recruited and were classified by standard echocardiography into healthy (dogs of breeds predisposed to MMVD, but without echocardiographic evidence of the disease), mild, moderate, or severe MMVD groups. Serum 5-HT concentrations were analyzed using an ELISA. Dogs with severe MMVD had lower serum 5-HT concentrations than healthy dogs (P = .0025) and dogs with mild MMVD (P = .0011). Unilinear and multiple regression analyses showed that serum 5-HT concentrations decreased with increasing left atrial to aortic root ratio (LA/Ao), were higher in Cavalier King Charles Spaniel (CKCS) dogs compared to dogs of other breeds, and were higher in female dogs than in male dogs. The LA/Ao was the variable most strongly associated with serum 5-HT concentration. The finding of higher serum 5-HT concentrations in dogs of breeds predisposed to the early onset of MMVD (CKCS) and dogs with mild MMVD suggests that alterations in 5-HT signaling might play a role in progression of early stages of MMVD.

Minimally invasive mitral valve repair in patients with severe myxomatous valve degeneration (M. Barlow) is feasible and safe

Objective: Severe myxomatous mitral valve disease (M. Barlow) is frequently seen in patients with degenerative mitral valve disease, often associated with bileaflet prolapse. Repair of Barlow valves affords multiple techniques including artificial chordae. While minimally invasive mitral valve repair (MIS MVR) is meanwhile established as a routine procedure for non-myxomatous degenerative mitral valve disease it is controversely discussed if it is also safe and feasible in patients with Barlow's disease. Here we report about a series of Barlow patients who underwent MIS MVR through small lateral mini-thoracotomies under videoscopic vision at our center.

Assessment of Global and Regional Left Ventricular Volume and Shape by Real‐Time 3‐Dimensional Echocardiography in Dogs with Myxomatous Mitral Valve Disease

Left ventricular (LV) remodeling occurs in response to chronic volume overload. Real-time 3-dimensional (RT3D) echocardiography offers new modalities for LV assessment. To investigate LV changes in shape and volume in response to different severities of naturally acquired myxomatous mitral valve disease (MMVD) in dogs by RT3D echocardiography. Sixty-five client-owned dogs. Prospectively recruited dogs were classified by standard echocardiography into healthy, mild, moderate, and severe MMVD groups. Endocardial border tracking of LV RT3D dataset was performed, from which global and regional (automatically acquired basal, mid, and apical segments based on LV long-axis length) end-diastolic (EDV) and end-systolic volumes (ESV), LV long-axis length, and sphericity index were obtained. Global and regional EDV and ESV (indexed to body weight) were most prominently increased in dogs with severe MMVD. All 3 regional LV segments contributed to increased global EDV and ESV with increasing MMVD severity, but mid-EDV contributed the most to the global EDV increase. Furthermore, LV long-axis length and LV sphericity index increased with increasing MMVD severity. Basal and apical EDV segments displayed the strongest association with sphericity index (P < .0001). The most prominent LV volume expansion was found in dogs with severe MMVD. Increased EDV, primarily in the mid-segment, leads to rounding of LV apical and basal segments in response to increasing MMVD severity. Assessment of LV volume and shape potentially could allow early detection of dogs at risk for rapid progression into congestive heart failure.

Brain-natriuretic peptide and cyclic guanosine monophosphate as biomarkers of myxomatous mitral valve disease in dogs

Elevations in the plasma concentrations of natriuretic peptides correlate with increased severity of myxomatous mitral valve disease (MMVD) in dogs. This study correlates the severity of MMVD with the plasma concentrations of the biomarkers N-terminal fragment of the pro-brain-natriuretic peptide (NT-proBNP) and its second messenger, cyclic guanosine monophosphate (cGMP). Furthermore, the L-arginine:asymmetric dimethylarginine (ADMA) ratio was measured as an index of nitric oxide availability. The study included 75 dogs sub-divided into five groups based on severity of MMVD as assessed by clinical examination and echocardiography. Plasma NT-proBNP and cGMP concentrations increased with increasing valve dysfunction and were significantly elevated in dogs with heart failure. The cGMP:NT-proBNP ratio decreased significantly in dogs with heart failure, suggesting the development of natriuretic peptide resistance. Although the l-arginine:ADMA ratio decreased with increasingly severe MMVD, this was largely due to the older age of the dogs with heart failure.

Cardiac Troponin I Is Associated with Severity of Myxomatous Mitral Valve Disease, Age, and C‐Reactive Protein in Dogs

Concentrations of cardiac troponin I (cTnI) and C-reactive protein (CRP) might be associated with cardiac remodeling in dogs with myxomatous mitral valve disease (MMVD). Age- and sex-dependent variations in cTnI concentration have been described. To investigate whether plasma concentrations of cTnI and CRP are associated with severity of MMVD, and investigate potential associations of dog characteristics on cTnI and CRP concentrations. Eighty-one client-owned dogs with MMVD of varying severity. Dogs were prospectively recruited for the study. Dogs were classified according to severity of MMVD. Plasma cTnI was analyzed by a high sensitivity cTnI assay with a lower limit of detection of 0.001 ng/mL, and plasma CRP was analyzed by a canine-specific CRP ELISA. Higher cTnI concentrations were detected in dogs with moderate (0.014 [interquartile range 0.008-0.029] ng/mL, P = .0011) and severe (0.043 [0.031-0.087] ng/mL, P < .0001) MMVD, compared with healthy dogs (0.001 [0.001-0.004]ng/mL). Dogs with severe MMVD also had higher cTnI concentrations than dogs with mild (0.003 [0.001-0.024] ng/mL, P < .0001) and moderate (P = .0019) MMVD. There were significant associations of age, CRP, heart rate, and left ventricular end-diastolic diameter, on cTnI concentration C-reactive protein did not differ among severity groups, but was significantly associated with cTnI, breed, and systolic blood pressure on CRP concentration. Analysis of cTnI concentration has potential to increase knowledge of overall cardiac remodeling in dogs with MMVD. However, effect of age on cTnI needs consideration when assessing cTnI.

Folding Valvuloplasty Without Leaflet Resection: Simplified Method for Mitral Valve Repair

Standard repair techniques can prove challenging in patients with severe myxomatous mitral valve disease when there is a broad-based mid-portion of the posterior leaflet and small medial and lateral scallops. We describe a new surgical technique in which the mitral valve repair was accomplished by simple folding the prolapsed segment of the posterior leaflet and by insertion of the flexible annuloplasty ring.

Brain natriuretic peptide concentration in dogs with heart disease and congestive heart failure.

Plasma brain natriuretic peptide concentration ([BNP]) is high in humans with cardiac disease and is further increased with congestive heart failure (CHF). The hypotheses of this study were that dogs with moderate to severe mitral regurgitation due to myxomatous mitral valve disease (MVD) would have increased plasma [BNP] compared to normal dogs, that plasma [BNP] would be higher in dogs with CHP, and that plasma [BNP] would predict premature death from cardiovascular disease. The study population consisted of 34 dogs: 9 normal dogs and 25 dogs with MVD. Patients were divided into 4 groups: group 1-10 dogs with moderate to severe MVD and no radiographic evidence of CHF; group II--6 dogs with severe MVD and mild CHF; group III--7 dogs with severe MVD and moderate CHF; and group IV--2 dogs with severe MVD and severe CHF. Diagnostic tests included thoracic radiographs, an echocardiogram, a serum chemistry profile, and the measurement of plasma [BNP] by a canine-specific radioimmunoassay. There was a significant positive correlation between the plasma [BNP] and heart disease/failure groups (P = .0036). Plasma [BNP] increased with progressively increasing severity of MVD and CHE Group I dogs had higher plasma [BNP] than did control dogs (P < .0001), and plasma [BNP] was higher in dogs with CHF (groups II-IV versus group I; P = .012). Plasma [BNP] was also weakly positively correlated with left atrial size (r = 0.43, P = .04). For every 10-pg/mL increase in plasma [BNP], the mortality rate over 4 months' time increased approximately 44%.