No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
New perspective in canine myxomatous mitral valve disease
ResearchGate has not been able to resolve any citations for this publication.
Stress and welfare are important factors to animal production in a context of growing production optimization and scrutiny by the general public. In a context in which animal and human health are intertwined aspects of the one-health concept it is of utmost importance to define markers for stress and welfare. These are important tools for producers, retailers, regulatory agents and ultimately consumers to effectively monitor and assess the welfare state of the producing animal. Proteomics is the science that studies the proteome i.e. the proteins existing in a given tissue or fluid, is therefore of extreme pertinence in such definition. In this review we address this topic by showing clear examples where proteomics has been used to study stress-induced changes at various levels. We adopt a multi-species (cattle, swine, small ruminants, poultry, fish and shellfish) approach under the effect of varied stress inducers (handling, transport, management, nutritional, thermal and exposure to pollutants) clearly demonstrating how Proteomics and Systems Biology are key elements to the study of stress and welfare on farm animals and a powerful tool to animal welfare, health and productivity.
Background:
Cavalier King Charles Spaniels (CKCS) are predisposed to myxomatous mitral valve disease (MMVD). Studies have indicated a strong genetic background.
Objective:
The aim of this study was to evaluate the effect of a breeding scheme involving auscultation and echocardiography.
Animals:
In the Danish Kennel Club mandatory breeding scheme, 997 purebred CKCS were examined during the period 2002-2011. Each dog was evaluated 1-4 times with a total of 1,380 examinations.
Methods:
Auscultation and echocardiography were performed to evaluate mitral regurgitation murmur severity and degree of mitral valve prolapse (MVP). The odds of having mitral regurgitation murmur or MVP > grade 1 in 2010-2011 compared to 2002-2003 were estimated using logistic regression analysis including age and sex as covariates. Odds were estimated for dogs that were products of the breeding scheme (defined as dogs with both parents approved by the breeding scheme before breeding) and non-products of the breeding scheme (defined as dogs with at least 1 parent with unknown cardiac status).
Results:
In 2010-2011, the odds of having mitral regurgitation murmur were 0.27 if dogs were a product of the breeding scheme compared with dogs in 2002-2003, reflecting a 73% decreased risk (P < .0001). If non-products of the breeding scheme examined in 2010-2011 were compared with dogs in 2002-2003, no difference in odds was found (P = .49).
Conclusion and clinical importance:
A mandatory breeding scheme based on auscultation and echocardiography findings significantly decreased the prevalence of MMVD over the 8- to 10-year period. Such a breeding scheme therefore is recommended for CKCS.
Rheumatic heart disease (RHD) affects heart-valve tissue and is the most serious consequence of group A Streptococcus infection. Myxomatous degeneration (MXD) is the most frequent valvopathy in the western world. In the present work, key protein expression alterations in the heart-valve tissue of RHD and MXD patients were identified and characterized, with controls from cadaveric organ donors. Proteins were separated by two-dimensional (2D)-electrophoresis and identified by mass spectrometry. We found 17 differentially expressed protein spots, as compared to control samples. We observed an increased expression of ASAP-2 in the RHD patients' valves, while collagen-VI, haptoglobin-related protein, prolargin, and cartilage oligomeric protein showed reduced expression. Valve tissue of MXD patients, on the other hand, presented lower expression of annexin-A1 and A2, septin-2, SOD (Cu/Zn), and transgelin. Tissue samples from both valvopathies displayed higher expression of apolipoprotein-A1. Biglycan was downexpressed in both diseases. Vimentin and lumican showed higher expression in RHD and lower in MXD. These results suggest that key pathogenetic mechanisms are intrinsically distinct in RHD and MXD.
Crohn's disease (CD) represents a highly debilitating disease of difficult diagnosis and increasing incidence. Serum protein profiling of early stage Crohn's disease (ES) CD was investigated in order to improve the comprehension of the very early pathologic mechanisms and to support the difficult diagnostic procedures currently available. Inflammatory proteins and complement 3 chain C (C3c) were over-represented during ES CD, clusterin, retinol binding protein, α1-microglobulin and transthyretin were under-represented. A C3c isoform was found to be present only during ES CD. By now, lack of specific antibodies to detect isoforms made it impossible to perform alternative validation.
Little is known about genetic basis and proteomics in valvular heart disease (VHD) including rheumatic (RVD) and degenerative (DVD) valvular disease. The present proteomic study examined the hypothesis that certain proteins may be associated with the pathological changes in the plasma of VHD patients.
Differential protein analysis in the plasma identified 18 differentially expressed protein spots and 14 corresponding proteins or polypeptides by two-dimensional electrophoresis and mass spectrometry in 120 subjects. Two up-regulated (complement C4A and carbonic anhydrase 1) and three down-regulated proteins (serotransferrin, alpha-1-antichymotrypsin, and vitronectin) were validated by ELISA in enlarging samples. The plasma levels (n = 40 for each) of complement C4A in RVD (715.8±35.6 vs. 594.7±28.2 ng/ml, P = 0.009) and carbonic anhydrase 1 (237.70±15.7 vs. 184.7±10.8 U/L, P = 0.007) in DVD patients were significantly higher and that of serotransferrin (2.36±0.20 vs. 2.93±0.16 mg/ml, P = 0.025) and alpha-1-antichymotrypsin (370.0±13.7 vs. 413.0±11.6 µg/ml, P = 0.019) in RVD patients were significantly lower than those in controls. The plasma vitronectin level in both RVD (281.3±11.0 vs. 323.2±10.0 µg/ml, P = 0.006) and DVD (283.6±11.4 vs. 323.2±10.0 µg/ml, P = 0.011) was significantly lower than those in normal controls.
We have for the first time identified alterations of 14 differential proteins or polypeptides in the plasma of patients with various VHD. The elevation of plasma complement C4A in RVD and carbonic anhydrase 1 in DVD and the decrease of serotransferrin and alpha-1-antichymotrypsin in RVD patients may be useful biomarkers for these valvular diseases. The decreased plasma level of vitronectin - a protein related to the formation of valvular structure - in both RVD and DVD patients might indicate the possible genetic deficiency in these patients.
Cardioproteomics (Cardiovascular proteomics) is fast becoming an indispensible technique in deciphering changes in signaling pathways that occur in cardiovascular diseases (CVDs). The quality and availability of the instruments and bioinformatics software used for cardioproteomics continues to improve, and these techniques are now available to most cardiovascular researchers either directly or indirectly via university core centers. The heart and aorta are specialized tissues which present unique challenges to investigate. Currently, the diverse range of proteomic techniques available for cardiovascular research makes the choice of the best method or best combination of methods for the disease parameter(s) being investigated as important as the equipment used. This review focuses on proteomic techniques and their applications which have advanced our understanding of the signaling mechanisms involved in CVDs at the levels of protein complex/protein-protein interaction, post-translational modifications and signaling induced protein changes.
Myxomatous mitral valve disease (MMVD) is the most common heart disease in dogs. It is characterized by chronic progressive degenerative lesions of the mitral valve. The valve leaflets become thickened and prolapse into the left atrium resulting in mitral regurgitation (MR). MMVD is most prevalent in small to medium sized dog breeds, Cavalier King Charles Spaniels (CKCS) in particular. The onset of MMVD is highly age dependent, and at the age of 10 years, nearly all CKCS are affected. The incidence of a similar disease in humans-mitral valve prolapse-is 1-5%. By defining CKCSs with an early onset of MMVD as cases and old dogs with no or mild signs of MMVD as controls, we conducted a genome-wide association study (GWAS) to identify loci associated with development of MMVD. We have identified a 1.58 Mb region on CFA13 (P(genome) = 4.0 × 10(-5)) and a 1.68 Mb region on CFA14 (P(genome) = 7.9 × 10(-4)) associated with development of MMVD. This confirms the power of using the dog as a model to uncover potential candidate regions involved in the molecular mechanisms behind complex traits.
A breeding program with the aim of reducing the prevalence of mitral regurgitation (MR) caused by myxomatous mitral valve disease (MMVD) in Cavalier King Charles Spaniels (CKCS) is currently ongoing in Sweden. In this investigation 353 CKCS were selected as a sample of the population and 150 were examined by auscultation for heart murmurs when they reached the age of six years in 2007 and 2009. The aim with this investigation was to study the prevalence of heart murmurs in six-year-old CKCS and to estimate if prevalence has decreased since the breeding program was introduced 2001. The effect of the breeding program was evaluated by comparing the prevalence of heart murmurs in the two groups. In 2007, the prevalence of heart murmurs was 52% (50% for females and 54% for males) and in 2009, the prevalence was 55% (44% for females and 67% for males). No significant difference was found in the prevalence of heart murmurs between 2007 and 2009 (P=0.8). For all six-year-old CKCS, the prevalence of heart murmur was 53% (females 46% and males 61%), which is higher than previous Swedish investigations.
ACVIM Consensus Statement Consensus Statements of the American College of Veterinary Internal Medicine (ACVIM) provide the veterinary community with up-to-date information on the pathophysiology, diagnosis, and treatment of clinically important animal diseases. The ACVIM Board of Regents oversees selection of relevant topics, identification of panel members with the expertise to draft the statements, and other aspects of assuring the integrity of the process. The statements are derived from evidence-based medicine whenever possible and the panel offers interpretive comments when such evidence is inadequate or contradictory. A draft is prepared by the panel, followed by solicitation of input by the ACVIM membership, which may be incorporated into the statement. It is then submitted to the Journal of Veterinary Internal Medicine, where it is edited prior to publication. The authors are solely responsible for the content of the statements. © 2009 by the American College of Veterinary Internal Medicine.
Indices for M-mode measurements in dogs usually have been based on the assumption that a linear relationship exists between these measurements and body weight (BW) or body surface area (BSA). The relationships between the geometry of 3-dimensional objects do not support this assumption. The purposes of this study were to retrospectively examine M-mode data from a large number of dogs of varying sizes and breeds that were examined by a large number of ultrasonographers, to use the allometric equation to determine the appropriate BW exponent required to predict these cardiac dimensions, and to determine normal mean values and prediction intervals for common M-mode variables. Linear regression analyses of data from 494 dogs (2.2-95 kg) revealed a good correlation between M-mode measurements and BW after logarithmic transformation of the data (r2 = .55-.88). Most variables were most closely related to an index of body length, BW(1/3), although the exponent that best predicted diastolic and systolic left ventricular wall thicknesses was closer to 0.25. No variable indexed well to BW or BSA. With these data, appropriate mean values and prediction intervals were calculated for normal dogs, allowing veterinarians to correctly and appropriately index M-mode values. The equations developed from this study appear to be applicable to adult dogs of most breeds.
Objectives
The objectives of this study were (1) to assess the potential effect of body weight (BW), age, and gender on the most commonly used echocardiographic and conventional Doppler variables in a large population of healthy Cavalier King Charles Spaniels (CKCS), and (2) to establish the corresponding reference intervals (RI).
Animals
134 healthy adult CKCS.
Methods
Ultrasound examinations were performed by trained observers in awake dogs. M-mode variables included left ventricular (LV) end-diastolic and end-systolic diameters, LV free wall and interventricular septal thicknesses at end-diastole and end-systole, and LV fractional shortening (FS%). The left atrium (LA) and aortic (Ao) diameters were measured using a 2D method, and the LA/Ao was calculated. Pulsed-wave Doppler variables included peak systolic aortic and pulmonary flow velocities, mitral E and A waves, and E/A ratio. Effects of BW, age, and gender on these 15 variables were tested using a general linear model, and RIs were determined by applying the statistical procedures recommended by the Clinical and Laboratory Standards Institute.
Results
A significant BW effect was observed for all variables, except LA/Ao, FS%, and mitral E/A ratio. A significant but negligible effect of gender and age was also observed for 5/15 and 4/15 of the tested variables, respectively. Only the BW effect on M-mode variables was considered as clinically relevant and the corresponding regression-based RIs were calculated.
Conclusions
Body weight should be taken into account when interpreting echocardiographic values in CKCS, except for LA/Ao, FS%, and mitral E/A ratio.
Congenital heart disease (CHD) is the most common birth defect in newborns. Plasma proteins may serve as indicators of disease and are a rich source for biomarker discovery, but little has been studied in CHD. We examined the hypothesis that plasma proteins may be altered and related to the pathologic changes of CHD.
Differential protein analysis was performed in the plasma of patients with tetralogy of Fallot, isolated ventricular septal defect, and normal controls by using two-dimensional electrophoresis and mass spectrometry. Candidate proteins that might be related to disease processes were further confirmed by enzyme-linked immunosorbent assay in the new samples (n = 40).
Identified were 18 differentially expressed protein spots and 10 corresponding proteins or polypeptides. Among those, 2 downregulated proteins, gelsolin, ficolin-3, with significant clinical relevance, were further analyzed for validation. The plasma levels of gelsolin (76.30 ± 4.42 vs 131.80 ± 23.46 μg/mL in control; p = 0.025, n = 40 in each group) and ficolin-3 (4.93 ± 0.36 vs 10.58 ± 1.58 μg/mL in control; p = 0.001, n = 40 in each group) in tetralogy patients were significantly lower than those in normal controls. The ficolin-3 plasma level was also lower in the patients with isolated VSD (5.55 ± 0.34 vs 10.58 ± 1.58 μg/mL in control μg/mL; p = 0.003, n = 40 in each group).
We used proteomic methods to demonstrate for the first time the plasma protein changes in CHD patients that may reveal the possible mechanisms for the prolonged bleeding time in tetralogy patients and the susceptibility to pulmonary infections in patients with CHDs. These findings have strong clinical implications.
Unlabelled:
Mitral regurgitation (MR) is a common valvular lesion frequently caused by mitral valve prolapse (MVP). Surgical intervention in MVP patients with significant MR is predicated on symptoms and measures of left ventricular dysfunction. Because these indicators may be subjective or imprecise, serological biomarkers of disease could be a valuable adjunct to standard evaluation. This study aimed to identify such biomarkers by a proteomics approach. Two pooled plasma samples from 24 MVP subjects with MR (MVP/MR) and 24 non-MVP individuals were treated with the combinatorial peptide ligand library (CPLL) beads prior to iTRAQ labeling and ESI-MS/MS. Lower levels of haptoglobin, platelet basic protein (PBP), and complement component C4b were observed in the MVP/MR as compared to the control sample. These findings were verified by ELISA testing of each of the 24 paired samples, and another 42 matched cases and controls. The AUC values, sensitivities and specificities for (i) haptoglobin, (ii) PBP, (iii) C4b, and (iv) all 3 proteins in combination were (i) 0.813, 76%, 74%; (ii) 0.721, 56%, 77%; (iii) 0.689, 83%, 49%; and (iv) 0.840, 89%, 67%, respectively. In conclusion, haptoglobin, PBP, and C4b are down-regulated in MVP/MR. Their value as serological biomarkers of valvular pathology should be further explored.
Biological significance:
We report the first study that performed comparative proteomics of clinical human plasma samples to identify novel diagnostic biomarkers for mitral valve prolapse (MVP) patients with moderate to severe mitral regurgitation (MR). MR is a common valvular lesion that can be complicated by heart failure, sudden death and atrial fibrillation, yet many patients with severe MR are asymptomatic. Our results revealed reduced levels of haptoglobin, platelet basic protein (PBP), and complement component C4b in the MVP/MR patients as compared to the matched control cases. The plasma proteomics findings were subsequently confirmed by ELISA. Each of these candidate biomarkers has a putative role in the pathophysiology of MVP/MR, further supporting their roles in detection and possibly surveillance and prognostication of this disease.
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.
Background:
Hemopexin, an acute phase protein, can downregulate the angiotensin (ang) II type 1 receptor (AT1-R) in vitro. Whether hemopexin is involved in the responsiveness to ang II in vivo is unknown. Therefore, we tested whether variations in endogenous hemopexin activity are associated with the responsiveness of blood pressure to ang II in healthy volunteers.
Method:
Healthy men (n = 33, age 26 ± 9) were studied in balance on low sodium (50 mmol Na per 24 h) and high sodium (200 mmol Na per 24 h) diet, respectively. After baseline measurements of blood pressure, ang II was infused at 0.3, 1 and 3 ng/kg per min for 1 h per dose. Hemopexin activity was measured at baseline in EDTA-plasma samples by an amidolytic assay with a chromogenic substrate suitable for hemopexin activity evaluation.
Results:
During high sodium the hemopexin activity was lower; 1.6 × 10 (0.6 × 10 - 4.7 × 10) versus 2.8 × 10 (1.1 × 10 - 5.1 × 10) arbitrary units (P < 0.01) and the pressor response to 3 ng ang II/kg per minute larger than during low sodium (17.6 ± 6.5 versus 14.6 ± 6.9 mmHg, P < 0.01). Hemopexin activity negatively correlated with the pressor response to ang II during either type of sodium intake (high sodium: r = 0.42, P < 0.05; low sodium: r = 0.35, P < 0.05).
Conclusion:
These in-vivo data obtained in healthy individuals support recent in-vitro data showing that active hemopexin downregulates the availability of the AT1-R. Therefore, activated hemopexin might be considered as a factor mediating ang II effects upon blood pressure by modulating AT1-R availability.
Cardiac fibroblasts are the most prevalent cell type in the heart and play a key role in regulating normal myocardial function and in the adverse myocardial remodeling that occurs with hypertension, myocardial infarction and heart failure. Many of the functional effects of cardiac fibroblasts are mediated through differentiation to a myofibroblast phenotype that expresses contractile proteins and exhibits increased migratory, proliferative and secretory properties. Cardiac myofibroblasts respond to proinflammatory cytokines (e.g. TNFα, IL-1, IL-6, TGF-β), vasoactive peptides (e.g. angiotensin II, endothelin-1, natriuretic peptides) and hormones (e.g. noradrenaline), the levels of which are increased in the remodeling heart. Their function is also modulated by mechanical stretch and changes in oxygen availability (e.g. ischaemia–reperfusion). Myofibroblast responses to such stimuli include changes in cell proliferation, cell migration, extracellular matrix metabolism and secretion of various bioactive molecules including cytokines, vasoactive peptides and growth factors. Several classes of commonly prescribed therapeutic agents for cardiovascular disease also exert pleiotropic effects on cardiac fibroblasts that may explain some of their beneficial outcomes on the remodeling heart. These include drugs for reducing hypertension (ACE inhibitors, angiotensin receptor blockers, beta-blockers), cholesterol levels (statins, fibrates) and insulin resistance (thiazolidinediones). In this review, we provide insight into the properties of cardiac fibroblasts that underscores their importance in the remodeling heart, including their origin, electrophysiological properties, role in matrix metabolism, functional responses to environmental stimuli and ability to secrete bioactive molecules. We also review the evidence suggesting that certain cardiovascular drugs can reduce myocardial remodeling specifically via modulatory effects on cardiac fibroblasts.
Chronic mitral valve disease due to myxomatous degeneration (MMVD) is the most common cardiovascular disease in dogs and has been known to cause congestive heart failure for more than 100 years. This article presents an historical perspective of the disease and reviews the most updated data on epidemiology and natural history of MMVD in dogs.
Degenerative mitral valve disease (MVD), the most common acquired heart disease in small-sized dogs, is characterized by valvular degeneration resulting in systolic mitral valve regurgitation (MR). Worsening of MR leads to several combined complications including cardiac remodeling, increased left ventricular filling pressure, pulmonary arterial hypertension, and myocardial dysfunction. Conventional two-dimensional, M-mode, and Doppler examination plays a critical role in the initial and longitudinal assessment of dogs affected by MVD, providing information on mitral valve anatomy, MR severity, left ventricular (LV) size and function, as well as cardiac and vascular pressures. Several standard echocardiographic variables have been shown to be related to clinical outcome. Some of these markers (e.g., left atrium to aorta ratio, regurgitation fraction, pulmonary arterial pressure) may also help in identifying asymptomatic MVD dogs at higher risk of early decompensation, which remains a major issue in practice. However, both afterload and preload are altered during the disease course. This represents a limitation of conventional techniques to accurately assess myocardial function, as most corresponding variables are load-dependent. Recent ultrasound techniques including tissue Doppler imaging, strain and strain rate imaging, and speckle tracking echocardiography, provide new parameters to assess regional and global myocardial performance (e.g., myocardial velocities and gradients, deformation and rate of deformation, and mechanical synchrony). As illustration, the authors present new data obtained from a population of 91 dogs (74 MVD dogs, 17 age-matched controls) using strain imaging, and showing a significant longitudinal systolic alteration at the latest MVD heart failure stage.
Myxomatous mitral valve disease (MMVD) is the most commonly diagnosed cardiovascular disease in the dog accounting for more than 70% of all cardiovascular disease in dogs. As are most canine diseases with genetic underpinnings, risk of MMVD is greatly increased in a subset of breeds. What is uncommon is that the vast majority of the breeds at elevated risk for MMVD are small or toy breeds with average adult weights under 9 kg. These breeds appear to have little in common other than their diminutive size. In the following review we propose a number of mechanisms by which relatively unrelated small breeds may have developed a predisposition for chronic valvular disorders. Although factors such as age are key in the expression of MMVD, taking a comprehensive look at the commonalities, as well as the differences, between the susceptible breeds may assist in finding the causal variants responsible for MMVD and translating them to improved treatments for both dogs and humans.
Preclinical myxomatous mitral valve degeneration (MMVD) includes a heterogeneous group of dogs. Therefore, identifying risk factors for progression of the disease is of clinical importance.
To investigate survival time and risk factors for clinical and echocardiographic variables taken at initial examination for clinical progression in preclinical MMVD dogs.
A total of 256 dogs with stage B1 or B2 MMVD.
Medical records of 256 dogs with preclinical MMVD were reviewed retrospectively. Long-term outcome was assessed by telephone interview. Dogs alive at the time of phone interview were asked to return to the hospital for re-evaluation of their cardiac status.
Seventy of 256 (27.3%) dogs died during the observation period. The median survival time, regardless of cause of death, was 588 (range 75-1,668) days. The presence of a murmur was associated with an increased risk of death (AHR 2.14; 95% CI 1.12, 4.11; P = 0.022). Thirty (12%) deaths were considered cardiac related. LA/Ao > 1.4 was the only negative predictor (AHR 2.64; 1.13, 6.13; P = 0.024) for cardiac-related deaths. Eighty-three dogs were re-examined, of which 34 progressed to a more advanced stage of MMVD. The presence of Emax > 1.2 (AHR 2.75; 95% CI 1.01, 7.48; P = 0.047) and cough (AHR 7.89; 95% CI 3.18, 20.07; P < 0.001) were significant in the multivariate analysis.
Preclinical MMVD represents a relatively benign condition in dogs. Clinicians might find stratification of this dog population according to risk factors based on clinical and echocardiographic findings helpful in determining treatment.
Valvular heart disease accounts for over 20 000 deaths and 90 000 hospitalizations yearly in the United States. Myxomatous valve disease (MVD) is the most common disease of the mitral valve in humans and dogs. MVD is pathologically identical in these species and its pathogenesis is poorly understood. The objectives of this study were to (i) develop proteomic methodology suitable for analysis of extracellular matrix-rich heart valve tissues and (ii) survey over- and under-expressed proteins that could provide mechanistic clues into the pathogenesis of MVD. Normal, early-stage, and late-stage myxomatous mitral valves from dogs were studied. A shotgun proteomic analysis was used to quantify differential protein expression. Proteins were classified by function and clustered according to differential expression patterns. More than 300 proteins, with 117 of those being differentially expressed, were identified. Hierarchical sample clustering of differential protein profiles showed that early- and late-stage valves were closely related. This finding suggests that proteome changes occur in early degeneration stages and these persist in late stages, characterizing a diseased proteome that is distinct from normal. Shotgun proteome analysis of matrix-rich canine heart valves is feasible, and should be applicable to human heart valves. This study provides a basis for future investigations into the pathogenesis of MVD.
To review medications that can affect serum calcium concentrations.
The literature was reviewed for articles pertaining to medications that affect calcium concentrations.
The serum calcium concentration is tightly regulated because of the importance of this mineral in diffuse cellular processes. Many medications have been reported to cause changes in serum calcium levels by influencing intestinal calcium absorption, renal calcium resorption, and bone remodeling or through altering parathyroid or 1,25-dihydroxyvitamin D-mediated regulation. Some medications are used specifically to alter serum calcium as a therapeutic intervention. With others, the calcium disturbances are viewed as a side effect of the treatment.
It is important to be aware of the influence that medications can have on serum calcium levels when evaluating patients with disorders of calcium homeostasis.
The left ventricular (LV) dilatation of isolated mitral regurgitation (MR) is associated with an increase in chymase and a decrease in interstitial collagen and extracellular matrix. In addition to profibrotic effects, chymase has significant antifibrotic actions because it activates matrix metalloproteinases and kallikrein and degrades fibronectin. Thus, we hypothesize that chymase inhibitor (CI) will attenuate extracellular matrix loss and LV remodeling in MR.
We studied dogs with 4 months of untreated MR (MR; n=9) or MR treated with CI (MR+CI; n=8). Cine MRI demonstrated a >40% increase in LV end-diastolic volume in both groups, consistent with a failure of CI to improve a 25% decrease in interstitial collagen in MR. However, LV cardiomyocyte fractional shortening was decreased in MR versus normal dogs (3.71±0.24% versus 4.81±0.31%; P<0.05) and normalized in MR+CI dogs (4.85±0.44%). MRI with tissue tagging demonstrated an increase in LV torsion angle in MR+CI versus MR dogs. CI normalized the significant decrease in fibronectin and FAK phosphorylation and prevented cardiomyocyte myofibrillar degeneration in MR dogs. In addition, total titin and its stiffer isoform were increased in the LV epicardium and paralleled the changes in fibronectin and FAK phosphorylation in MR+CI dogs.
These results suggest that chymase disrupts cell surface-fibronectin connections and FAK phosphorylation that can adversely affect cardiomyocyte myofibrillar structure and function. The greater effect of CI on epicardial versus endocardial titin and noncollagen cell surface proteins may be responsible for the increase in torsion angle in chronic MR.
Mixed model analysis of 1252 records of cardiac auscultation of 4- to 5-year-old Cavalier King Charles spaniels (CKCS) from 1991 to 2008 in conjunction with the Kennel Club pedigree records of all dogs registered from the mid 1980s to September 2007 was used to estimate variance parameters of premature mitral valve disease (MVD). Data were limited to dogs ≥4 and <5 years of age to ensure diagnostic distinction between early and late onset MVD. Cardiac murmurs were detected in 108/1252 (8.6%) dogs. Heritability estimates of 0.67 (standard error, SE 0.071) for the grade of murmur and 0.33 (SE 0.072) for the presence/absence of murmur were calculated. The variance due to clinician was 0.02 (SE 0.012) for grade and 0.03 (SE 0.017) for presence/absence of murmur. These results indicate that the presence and severity of MVD, as assessed by cardiac auscultation, in 4- to 5-year-old CKCS is highly heritable and that selection against the disease should be successful.
To evaluate the influence of heart disease and heart failure on 9 parameters: the serum sodium, potassium, chloride, creatinine and urea concentrations, heart rate, vaso-vagal tonus index (VVTI), red cell number and hematocrit.
Previous studies have demonstrated that heart disease, heart failure and their treatment are associated with changes in laboratory and electrocardiographic parameters.
Data were retrieved from 92 client-owned dogs with naturally occurring heart disease. Dogs were classified according to the severity of their heart disease and or the presence of heart failure. The effects of heart disease, the progression into heart failure, the initiation of successful therapy and the administration of diuretics on these parameters were determined.
Worse heart failure was characterized by the following changes: a significant fall in serum sodium and chloride concentrations and VVTI, and a significant increase in the serum urea concentration and heart rate. The onset of heart failure was characterized by a fall in VVTI and chloride concentration. The successful treatment of heart failure was characterized by a fall in heart rate, an increase in creatinine and sodium concentrations. Dogs receiving diuretics had higher heart rates, lower VVTI, higher urea concentrations, lower potassium, sodium and chloride concentrations.
Numerous complex alterations in some of the studied parameters are associated with heart disease, heart failure and their treatment. Further consideration of these changes may improve our skills in diagnosis, prognostication and treatment.
Recommendations are presented for standardized imaging planes and display conventions for two-dimensional echocardiography in the dog and cat. Three transducer locations ("windows") provide access to consistent imaging planes: the right parasternal location, the left caudal (apical) parasternal location, and the left cranial parasternal location. Recommendations for image display orientations are very similar to those for comparable human cardiac images, with the heart base or cranial aspect of the heart displayed to the examiner's right on the video display. From the right parasternal location, standard views include a long-axis four-chamber view and a long-axis left ventricular outflow view, and short-axis views at the levels of the left ventricular apex, papillary muscles, chordae tendineae, mitral valve, aortic valve, and pulmonary arteries. From the left caudal (apical) location, standard views include long-axis two-chamber and four-chamber views. From the left cranial parasternal location, standard views include a long-axis view of the left ventricular outflow tract and ascending aorta (with variations to image the right atrium and tricuspid valve, and the pulmonary valve and pulmonary artery), and a short-axis view of the aortic root encircled by the right heart. These images are presented by means of idealized line drawings. Adoption of these standards should facilitate consistent performance, recording, teaching, and communicating results of studies obtained by two-dimensional echocardiography.
To study the relationship between parental cardiac status in Cavalier King Charles Spaniels and development of chronic valvular disease (CVD) in offspring.
Historical cohort.
54 female and 53 male Cavalier King Charles Spaniel offspring.
7 sires, selected on the basis of their liability to develop CVD, were screened for clinical signs of CVD and assigned to 1 of 3 groups (late, intermediate, and early onset of CVD). The mates of these sires (30 dams) were selected and classified likewise, and 107 offspring produced in 1988 from matings between these parents were screened for clinical signs of CVD at a mean age of 5.3 +/- 0.3 years.
55% of the offspring were free from clinical signs of CVD, whereas 45% had cardiac murmurs of low or moderate intensity. The proportion of offspring with heart murmurs and the intensity of murmurs were significantly greater with increased parental classification. More males than females had developed murmurs, and murmurs of moderate intensity also were more prevalent in males. Results of multiple-regression analysis indicated that mean parental classification and sex had significant effects on proportion of offspring with murmurs and their intensity. Additionally, age affected disease prevalence and severity, despite the narrow range in age of offspring examined.
Parental CVD status is an important factor influencing the probability of heart murmurs and their intensity in offspring. The results of this study indicate that CVD development is a polygenic threshold trait and that sex of the offspring influences threshold levels.
M., GheorghiadeF., FollathP., PonikowskiJ. H., BarsukJ. E. A., BlairJ. G., ClelandK., DicksteinM. H., DraznerG. C., FonarowT., JaarsmaG., JondeauJ. L., SendonA., MebazaaM., MetraM., NieminenP. S., PangP., SeferovicL. W., StevensonD. J., van VeldhuisenF., ZannadS. D., AnkerA., RhodesJ. J. V., McMurrayG., Filippatos. (2010) Assessing and grading congestion in acute heart failure: a scientific statement from the Acute Heart Failure Committee of the Heart Failure Association of the European Society of Cardiology and endorsed by the European Society of Intensive Care Medicine. European Journal of Heart Failure 12, 423-433
CrossRef
Mutations in the gene G4.5 result in a wide spectrum of severe infantile cardiomyopathic phenotypes, including isolated left ventricular noncompaction (LVNC), as well as Barth syndrome (BTHS) with dilated cardiomyopathy (DCM). The purpose of this study was to investigate patients with LVNC or BTHS for mutations in G4.5 or other novel genes.
DNA was isolated from 2 families and 3 individuals with isolated LVNC or LVNC with congenital heart disease (CHD), as well as 4 families with BTHS associated with LVNC or DCM, and screened for mutations by single-strand DNA conformation polymorphism analysis and DNA sequencing. In 1 family with LVNC and CHD, a C-->T mutation was identified at nucleotide 362 of alpha-dystrobrevin, changing a proline to leucine (P121L). Mutations in G4.5 were identified in 2 families with isolated LVNC: a missense mutation in exon 4 (C118R) in 1 and a splice donor mutation (IVS10+2T-->A) in intron 10 in the other. In a family with cardiomyopathies ranging from BTHS or fatal infantile cardiomyopathy to asymptomatic DCM, a splice acceptor mutation in exon 2 of G4.5 (398-2 A-->G) was identified, and a 1-bp deletion in exon 2 of G4.5, resulting in a stop codon after amino acid 41, was identified in a sporadic case of BTHS.
These data demonstrate genetic heterogeneity in LVNC, with mutation of a novel gene, alpha-dystrobrevin, identified in LVNC associated with CHD. In addition, these results confirm that mutations in G4.5 result in a wide phenotypic spectrum of cardiomyopathies.
Cavalier King Charles Spaniels (CKCS) often have idiopathic asymptomatic thrombocytopenia. In affected dogs, the thrombocytes often are large, and it has been speculated that the condition could be an inherited macrothrombocytopenia. The aim of this study was to examine the inheritance of idiopathic, asymptomatic thrombocytopenia in CKCS. Sixteen families (both parents and > or = 3 offspring) of privately owned CKCS were included. There were 105 clinically healthy dogs (50 from Denmark and 55 from Sweden): 81 offspring and 26 parents (2 dogs had both roles). Because autoanalyzers have difficulty counting large platelets, the platelets were counted manually, with a counting chamber. Platelet counts were not influenced by age, gender, or heart murmur status. Thrombocytopenia (< or = 100,000 platelets/microL) was found in 46% of the parents. The pedigrees indicated that thrombocytopenia segregated as an autosomal recessive trait and that 100,000 platelets/microL was appropriate as a lower limit of normal. Affected offspring were found in all families, showing that all of the included parents were at least carriers. Therefore, the expected segregation ratios (which were in good accordance with the observed ones) were 1:0, 1:1, and 1:3 for the 3 crosses: affected x affected, normal x affected, and normal x normal. Within a given cross, the mean parental platelet count had no influence on the platelet counts of the offspring. We conclude that idiopathic, asymptomatic thrombocytopenia in CKCS is inherited in an autosomal recessive manner. The condition most likely constitutes an inherited macrothrombocytopenia in dogs.
Two-dimensional (2-D) echocardiographic measurement of the left atrium (LA) has the potential to be more accurate than the standard M-mode method, because the LA body can be measured. We evaluated a 2-D method for measuring LA and aorta (AO) in a right parasternal short-axis view and compared it to the M-mode method. An index for LA size (LA/AO) was calculated in 166 cavalier King Charles spaniels, 56 normal and 110 dogs with mitral regurgitation (MR) of varying degrees secondary to chronic valvular disease. In normal dogs, the AO-2-D and LA/AO-2-D did not correlate to body weight (BW) or BW2; whereas, all M-mode values and the LA-2-D were significantly (p < .05) related to both BW parameters. In normal dogs, there was no difference between M-mode and 2-D indices. For all dogs (normal and dogs with MR) there was an 11% bias between the M-mode and 2-D index with the LA/AO-2-D being higher than the LA/AO-M. The association between the mean and the difference of the indices demonstrated a quadratic relationship. Dogs with a mean LA/AO of 2.0-2.5 showed the largest difference between the two indices. Small values for the 2-D coefficients of variation for respiration and stage of diastole were found; 3.4 and 3.1%, respectively. The 2-D index is more sensitive to LA enlargement than the M-mode index.
The aim of this study was to describe the clinical, functional, and morphologic characteristics of platelets in Cavalier King Charles Spaniel dogs (Cavaliers).
Blood from 69 clinically normal Cavaliers was collected and anticoagulated with ethylenediamine-tetraacetic acid (EDTA) and citrate. Automated and manual platelet counts were obtained. Percent platelet aggregation in response to ADP (2, 4, 8, 16, and 32 microM) was determined. Electron microscopy was performed to examine platelet internal morphology and dense granule distribution. A cardiologist recorded the quality of murmurs.
Thrombocytopenia (<100,000/microL) was present in 51.43% (36/69) of Cavaliers. Macrothrombocytes (>3 microm) were present in 33.33% (22/69). Mean manual platelet count was 118,770/microL. Manual (EDTA blood) and automated (EDTA and citrated blood) methods of platelet counting were correlated. Prevalence of cardiac murmurs was 38% (26/69). There was no association between affected dogs and murmur, signalment, or coat color. Mean percent platelet aggregation was significantly higher in controls than in Cavaliers (79% vs 38%, p=0.001). Response to ADP was unaffected by thrombocytopenia, macrothrombocytes, murmur, or any combination thereof. Platelet electron microscopy showed normal and giant sized platelets with normal internal morphology.
A benign inherited giant platelet disorder affects approximately 50% of Cavalier King Charles Spaniels. It is characterized by thrombocytopenia, macrothrombocytes, or decreased platelet aggregation in response to ADP. Platelet ultrastructure is normal. Citrated or EDTA blood provides accurate platelet counts. Further studies are indicated to determine platelet glycoprotein structure and any association with mitral endocardiosis. Cavaliers may be useful models of inherited giant platelet disorders.
Systolic dysfunction associated with chronic mitral valve insufficiency (CMVI) has been demonstrated in experimental animal models and large breed (LB) dogs but has been reported as an uncommon finding in small breed (SB) dogs with naturally occurring disease. It has been suggested the myocardial failure could be, in part, because of an insufficient increase in left ventricular mass.
To test if SB and LB dogs with CMVI and moderate heart failure have systolic dysfunction and if they have adequate eccentric hypertrophy.
Data from 38 SB and 18 LB dogs affected with CMVI were compared retrospectively with results from 2 groups of normal dogs (17 SB and 32 LB).
Systolic function was investigated echocardiographically by using percentage fractional shortening (FS), the ratio between observed and expected end-systolic diameter (ESD/ESDe), and end-systolic volume index (ESVI). Left ventricular hypertrophy was estimated by using the ratio between the thickness of the left ventricular free wall and the radius in diastole (h/R).
Both affected SB and LB dogs had a significantly increased FS and ESVI (FS% SB 45.6 + 8.04 versus 40.06 + 8.9, P < .05; FS% LB 33.64 + 8.61 versus 27.3 + 7.3 P < .05; ESVI SB 30.0 +/- 2.3 mL/m2 versus 21.18 +/- 13.9 mL/m2, P < .05; ESVI LB 83.22 +/- 43.84 mL/m2 versus 36.43 +/- 13.30 mL/m2 versus P < .001). The h/R in affected animals was decreased (0.53 +/- 0.11 versus 0.41 +/- 0.12, P < .05 SB; 0.47 +/- 0.11 versus 0.38 +/- 0.09, P < .05, LB).
Data from this study indicate that dogs with moderate heart failure caused by CMVI have systolic dysfunction. Inadequate hypertrophy of the left ventricle may be, in part, responsible for this finding.
The purpose of this study was to compare platelet concentration in cavalier King Charles spaniels (CKCS) measured by different methods commonly used in veterinary hospitals and commercial laboratories.
Blood samples obtained from 41 CKCS [corrected] were analysed by impedance cell counter, laser cell counter and microscopic estimation. Quantitative buffy coat analysis was performed only on 17 samples, selected from CKCS [corrected] that had low platelet counts detected by cell counters. Platelet counts, platelet estimations and platelet parameters using these different methods were compared.
The median platelet number was lower when estimated using impedance cell counter (1363x10(9)/I) with respect to laser cell counter (1723x10(9)/I), microscopic estimation (238x10(9)/I) [corrected] or quantitative buffy coat analyser (292x10(9)/I) [corrected] (P<0.01). Although impedance cell counter, laser cell counter and microscopic estimation were positively correlated, there was no acceptable agreement among methods. CKCS [corrected] with macrothrombocytes in blood smears had significantly lower counts on impedance cell counter, laser cell counter and microscopic estimation. The percentages of CKCS [corrected] with platelet count < 100x10(9)/I [corrected] were 34.1 per cent (impedance cell counter), 26.8 per cent (laser cell counter), 22.0 per cent (microscopic estimation) (not statistically different) and 5.8 per cent (quantitative buffy coat analyser) (P<0.05).
CKCS [corrected] with macrothrombocytosis have low platelet counts on impedance cell counters, laser cell counters and microscopic estimation. CKCS [corrected] with low platelet counts may have a normal platelet crit detected by a quantitative buffy coat analyser and thus a normal circulating platelet mass.
Consensus Statements of the American College of Veterinary Internal Medicine (ACVIM) provide veterinarians with guidelines regarding the pathophysiology, diagnosis, or treatment of animal diseases. The foundation of the Consensus Statement is evidence-based medicine, but if such evidence is conflicting or lacking, the panel provides interpretive recommendations on the basis of their collective expertise. The Consensus Statement is intended to be a guide for veterinarians, but it is not a statement of standard of care or a substitute for clinical judgment. Topics of statements and panel members to draft the statements are selected by the Board of Regents with input from the general membership. A draft prepared and input from Diplomates is solicited at the ACVIM Forum and via the ACVIM Web site and incorporated in a final version. This Consensus Statement was approved by the Board of Regents of the ACVIM before publication.
Fundamentals of Veterinary Clinical Phatology
- S L Stockham
- M A Scott
Stockham SL, Scott MA. Fundamentals of Veterinary Clinical Phatology.
2nd ed. Victoria: Blackwell Publishing ltd; 2008.
Plasma hemopexin as a potential regulator of vascular responsiveness to angiotensin II
- W W Bakker
- F Spaans
- L El Bakkali
- T Borghuis
- H Van Goor
- E Van Dijk
- J Buijnink
- M M Faas
Bakker WW, Spaans F, el Bakkali L, Borghuis T, van Goor H, van Dijk E,
Buijnink J, Faas MM. Plasma hemopexin as a potential regulator of vascular
responsiveness to angiotensin II. Reprod Sci. 2013;20:234-7.