Manual De Cardiologia Veterinaria Pdf Editor

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doi: 10.5935/abc.20170032

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PMID: 28380134

Abstract

Background

The knowledge of the variables predicting mortality is important in clinicalpractice and for therapeutic monitoring in mitral valve disease.

Objectives

To determine whether a quality of life score evaluated with the FunctionalEvaluation of Cardiac Health questionnaire would predict mortality in dogswith degenerative mitral valve disease (DMVD).

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Methods

Thirty-six client-owned dogs with mitral valve disease underwent clinical,laboratory, and echocardiographic evaluations at baseline and were monitoredfor 6 months. Cardiovascular death was the primary outcome.

Results

The 36 dogs were classified as survivors or nonsurvivors. Higher values ofthe following variables were obtained at baseline in the nonsurviving group(12 dogs): amino-terminal pro-B-type natriuretic peptide (NT-proBNP) levels,plasma norepinephrine, heart rate, quality of life score, diastolic leftventricular internal dimension to aortic root ratio, systolic leftventricular internal dimension to aortic root ratio, and left atrium toaortic root ratio. NT-proBNP levels and quality life score wereindependently associated with death in the multivariable analysis.

Conclusion

The quality life score was an independent variable for cardiac death in dogswith DMVD. This result is encouraging, as this score is easy to apply anddoes not require any technology, only a veterinarian and an observant owner.

Keywords: Dogs, Quality of Life, Mortality, Heart Valve Diseases, Mitral Valve / abnormalities

Introduction

Degenerative mitral valve disease (DMVD) is the most commonly diagnosed disease inroutine veterinary cardiology in dogs. Therefore, the knowledge of the variablesthat can predict mortality in DMVD is important for the clinical practice and fortherapeutic monitoring of these patients.1

Diagnostic tests, such as electrocardiography, echocardiography, chest radiography,and blood pressure measurement, are routinely used to evaluate these patients andthe effectiveness of their treatments.2 Other tests have been identified as useful in monitoring theprogression of this valvular heart disease. For example, exacerbated activation ofthe sympathetic nervous system developed during heart failure associated with mitralvalve disease can be monitored by measuring the plasma concentration ofnorepinephrine (NE), which is associated with severe symptoms and a higher risk ofdeath., The importance of the amino-terminal pro-B-typenatriuretic peptide (NT-proBNP), an inactive amino-terminal fragment of theprohormone brain natriuretic peptide, has been recognized in recent years. Inveterinary medicine, studies in dogs have suggested that NT-proBNP is a marker ofthe presence and severity of cardiac disease. Cutoff values for the concentrationsof this peptide have been established and used to estimate the risk of the onset ofcongestive heart failure and to predict mortality in dogs with mitral valvedisease.-

In addition to this biochemical marker, the echocardiographic variables leftventricular end-diastolic diameter, left atrial (LA) to aortic root (Ao) ratio(LA/Ao), and E wave transmitral peak velocity are predictors of all-cause mortalityin dogs with DMVD. Thesediagnostic variables may be used to predict mortality in therapeutic management.Nevertheless, several clinical variables, such as respiratory signs, difficultieswith mobility, etc., could together be an important tool to predict death and bevery useful in veterinary clinics where technology is unavailable. The aim of thisstudy was to investigate whether a score obtained with the Functional Evaluation ofCardiac Health, a quality of life questionnaire, could be used as a predictor ofdeath in dogs with DMVD.

Methods

Animals

The dogs included in this prospective study were referred from a privateveterinary ambulatory clinic at the time of their first presentation of signs orsymptoms of congestive heart failure. The inclusion criteria for participationin the study were dogs with mitral regurgitation (MR) and LA enlargement (LA/Ao> 1.2) normal laboratory renal (creatinine < 2.1 mg/dL) and liver functionresults, and no other associated diseases. All dogs underwent a clinicalevaluation consisting of physical examination, electrocardiography, bloodpressure measurement, thoracic radiography, blood cell count, plasma and serumbiochemical analysis, and two-dimensional, M-mode spectral-pulsed Dopplerechocardiography. Therapeutic adjustments were only made when the dogs hadundergone all diagnostic tests and the quality of life questionnaire had beenapplied, which occurred after the selection of the animals.

The definitive diagnosis of DMVD was obtained during an echocardiographicexamination performed by a veterinary specialist who was blinded to the qualityof life questionnaire and laboratory results. The dogs were classified as havinggrade I to IV DMVD according to the New York Heart Association functional classscoring system modified for veterinary use.9 Briefly, functional class I was defined as a heartmurmur of mitral origin with no signs of heart enlargement and no limitation tophysical activity, class II included slight limitation to physical activity withvarying degrees of heart enlargement without clinical signs, class III includedmarked limitation of physical activity with radiologic signs of congestive heartfailure, and class IV comprised severe limitation of physical activity withradiologic signs of congestive heart failure.

Before enrollment in the study, 17 animals were already being treated withdiuretics, inotropic agents, and/or angiotensin converting enzyme inhibitors.The drugs administered at the beginning of the study were adjusted according tothe severity of the disease and included angiotensin converting enzymeinhibitors, inotropic agents, diuretics, and beta-blockers (when welltolerated). During the 6-month follow-up period, the treatment was adjustedwhenever necessary. The owners of the dogs were asked to inform the researcherin case a cardiac-related death occurred outside of the hospital. None of thedogs were euthanized.

An informed written consent was obtained from each dog owner, and the study wasapproved by the Ethics Committee Heart Institute (InCor), University ofSão Paulo Medical School (number 072/05).

The variables of the survivors and nonsurvivors at baseline were compared beforeany therapeutic adjustment was made. The significance of the variables that wereclinically relevant in predicting death was analyzed after 6 months offollow-up.

Assessment of quality of life

A total of 36 client-owned dogs were chosen by convenience for our study. Aspreviously described, the Functional Evaluation of Cardiac Health quality oflife questionnaire was developed based on widely accepted clinical signs ofcardiac disease in dogs. Thequestionnaire consists of 17 questions answered by the dog owner, who grades theseverity of symptoms on a scale from 0 to 5, in which 0 = few symptoms and 5 =several symptoms , with higher scores indicating a poorer health-related qualityof life. The questions are mainly related to respiratory signs, difficultieswith mobility (such as walking and climbing stairs), physical activity,irritability, appetite, sleepiness, and frequency of urination and vomiting. Thescore was established using information obtained from the owner by aveterinarian during the anamnesis.

Laboratory measurements

Blood samples were obtained early in the morning for measurement of plasmaconcentrations of NE, NT-proBNP, and other biochemical variables. Anappropriately sized heparinized catheter was inserted into the saphenous vein ofeach dog. The dog was then placed in lateral recumbency on a table with minimalrestraint for 20 minutes.The first mL of blood collected from the catheter was discarded. The subsequent3 to 5 mL of blood were collected and immediately transferred to ice-chilledtubes containing a mixture of ethylene glycol tetraacetic acid - glutathione (20µL of anticoagulant/mL of blood) for NE analysis.Other samples were collected from the same catheter and transferred to an EDTAtube for NT-proBNP measurement and into a plain tube for other biochemicalanalyses. Within 1 hour of blood collection, the plasma and serum were separatedand immediately frozen at -70°C. NE levels were determined by high-performanceliquid chromatography with an electrochemical detector, (Model 515, Waters Corp,Milford, MA, USA) and sodium (Na) levels were analyzed with a selectiveelectrode (Dimension RXL, Dade Behring, Newark, DE, USA). Specific kits forautomated equipment were used to measure urea and creatinine levels (DimensionRXL). The concentrations of plasma NT-proBNP were measured in duplicate using acommercial ELISA kit specific for canine NT-proBNP (Vet Sign Canine CardioSCREENNT- Pro-BNP kit, Guildhay, UK).

Echocardiographic and electrocardiographic evaluation

The arterial blood pressure was measured indirectly by vascular Doppler (MedmegaDV-610, Medmega, São Paulo, Brazil) while the dogs were in lateralrecumbency. The cuff width was approximately 40% of the limb circumference. Eachsystolic and diastolic arterial blood pressure value was calculated as the meanof three to four measurements.

The heart rate (HR) and cardiac rhythm were evaluated using a short-termelectrocardiographic recorder (Ecafix model E.C.G.-6, Ecafix , São Paulo,Brazil).13,14 The echocardiographicexamination was performed using an ultrasound system with a 5-MHz microconvextransducer (Aloka SSD 650 Ultrasound System, Aloka Inc., Tokyo, Japan).

The M-mode echocardiographic variables studied were the diastolicinterventricular septal thickness (IVSd), diastolic left ventricular wallthickness (LVWd), diastolic ventricular internal dimension (LVIDd), systolicventricular internal dimension (LVIDs), fractional shortening (FS), Ao, and LAdimension. The left ventricular dimensions and the LA were indexed to the Ao. FSvalues were calculated using the equation FS = [(LVIDd - LVIDs) / LVIDd] X 100.The intraobserver variability of the M-mode echocardiographic variables wascalculated using 15 measurements of each variable (obtained from threerecordings measured five times each) in five dogs (the coefficients of variationranged from 2.6% to 6.5%).

The severity of the MR was estimated with spectral-pulsed Doppler ultrasonographybased on the percentage of the LA occupied by the regurgitant jet (mild <20%, moderate 20 to 50%, severe > 50%).16,

Statistical analysis

Data with normal distribution are expressed as mean ± standard deviation(SD), while those with non-normal distribution are shown as median andinterquartile range (IQR). The Kolmogorov-Smirnov normality test was used totest for the normality of the data. When the data were normally distributed, theparametric Student's t test for independent samples was used,as displayed in Table 1. When the datawere not normally distributed, the nonparametric Mann-Whitney Utest for independent samples (Table 2)and Kruskal-Wallis test (NT-proBNP) were used. In addition, the chi-square testand Fishers' exact test were used when the groups were evaluated in relation totheir proportions. The Spearman test was used to measure the statisticalassociation between two variables.

Table 1

Baseline characteristics of 36 dogs with degenerative mitral valvedisease (DDMV) categorized as survivors or nonsurvivors. Variables withnormal distribution, described as mean and standard deviation (SD)

AllMortality
VariablesDMVD dogs (n = 36)Surviving dogs (n = 24)Nonsurviving dogs (n = 12)p
Age (SD) yrs10.7 (2.0)10.5 (2.2)11.0 (1.5)0.478
Male, n (%)23 (63.9)12 (50.0)11 (91.7)0.025
FC III-IV, n (%)15 (41.7)6 (25.0)9 (75.0)0.004
FETCH (SD)14.9 (10.5)10.5 (7.9)23.7 (10.0)< 0.001
Na (SD) mEq/L147.0 (4.00)147.2 (4.19)146.4 (3.60)0.550
HR (ECG),(SD),bpm144.3 (33.8)137.3 (36.6)158.3 (22.5)0.041
SBP (SD) mmHg135.5 (24.8)134.8 (26.2)136.7 (23.0)0.831
DBP (SD) mmHg80.1 (16.9)79.3 (15.3)81.9 (21.1)0.689
LVIDd/Ao (SD)2.23 (0.44)2.07 (0.39)2.54 (0.36)0.0014
LVIDs/Ao (SD)1.17 (0.28)1.07 (0.23)1.36 (0.28)0.0025
FS (%)47.7 (6.7)48.5 (7.0)45.9 (6.0)0.277

FC: functional classification; FETCH: Functional Evaluation ofCardiac Health; Na: sodium; HR: heart rate; SBP: systolic bloodpressure; DBP: diastolic blood pressure; LVIDd/Ao: diastolic leftventricular internal dimension/aortic root ratio; LVIDs/Ao: systolicleft ventricular internal dimension/aortic root ratio; FS:fractional shortening.

Table 2

Baseline characteristics of 36 dogs with degenerative mitral valvedisease (DDMV) categorized as survivors or nonsurvivors. Variableswithout normal distribution, described as median and interquartile range(IQR)

AllMortality
VariablesDMVD dogs (n = 36)Surviving dogs (n = 24)Nonsurviving dogs (n = 12)p
Weight (IQR) kg6.2 (4.5-9.9)6.2 (4.6-9.9)6.0 (4.3-10.0)0.920
NT-proBNP (IQR) pmol/L1282 (699-2477)859 (619-1345)4055 (2070-6452)< 0.001
NE (IQR) pg/mL386 (250-574)293 (214-430)574 (357-998)0.017
Creatinine (IQR) mg/dL0.85 (0.70-1.00)0.80 (0.70-1.00)0.90 (0.80-1.10)0.119
IVSd (IQR) cm0.60 (0.50-0.70)0.60 (0.50-0.70)0.60 (0.50-0.70)0.890
LA/Ao (IQR)1.56 (1.38-2.00)1.44 (1.30-1.65)2.09 (1.70-2.28)< 0.001

NT-proBNP: amino-terminal pro-B-type natriuretic peptide; NE:norepinephrine; IVSd: diastolic interventricular septal thickness;LA/Ao: left atrium dimension/aortic root ratio.

We performed a multivariable logistic analysis in a forward stepwise approachconsidering death at 6 months as the dependent variable. The independentvariables were functional classification, LA/Ao, creatinine, quality of lifescore, ranked NT-proBNP, and dichotomized HR as ≤ 130 bpm or > 130bpm. NT-proBNP values were ranked in units of 1,000 pmol/L, in order to make iteasier to interpret the results. Only variables with p < 0.1 were included in themultivariable regression model.

Receiver operating characteristic (ROC) analyses were performed to determine theoptimal cutoff values for selected variable. Odds ratios (OR) were calculated as part of thelogistic regression analysis. The significance level adopted for the statisticaltests was 5%. Statistical analyses were performed using the Statistical AnalysisSystem (SAS) software program for Windows, version 9.2 (SAS Institute Inc.,1989-1996, Cary, NC, USA).

Results

The following breeds of dogs were enrolled in the study: 23 Poodles, five mixed-breeddogs, one Basset hound, one Beagle, one Cocker Spaniel, one Dachshund, one LhasaApso, and three Pinschers. The baseline characteristics of the 36 DMVD dogs arepresented in Tables 1 and and2.2. The dogs were classified as having mild (n =4), moderate (n = 18), or severe (n = 14) MR.

We investigated the correlation between laboratory, electrocardiographic,echocardiographic, and clinical variables obtained at baseline. A positivecorrelation was identified between quality of life scores and the followingvariables: functional classification of the dog (r = 0.729, p < 0.0001), LA/Ao (r= 0.591, p = 0.0001), and plasma NE (r = 0.430, p = 0.009).

NT-proBNP concentrations correlated positively with LA/Ao (r = 0.615, p < 0.001),LVIDd/Ao (r = 0.502, p = 0.0018), and LVIDs/Ao (r = 0.622, p = 0.0001) andnegatively with FS (r = -0.386, p = 0.020). The only clinical and biochemicalvariables that correlated positively with NT-proBNP levels were the quality lifescore (r = 0.537, p = 0.001) and the plasma NE levels (r = 0.383, p = 0.021).

Dogs with mild (n = 4), moderate (n = 18), and severe (n = 14) MR had NT-proBNPvalues of 751 pmol/L (IQR 539 - 1017 pmol/L), 1183 pmol/L (IQR 701 - 1850 pmol/L),and 2070 pmol/L (IQR 878 - 5461 pmol/L), respectively (Kruskal-Wallis test, p =0.0849).

The 36 DMVD dogs were further classified as survivors and nonsurvivors. We comparedthe clinical, laboratory, and echocardiographic variables of the dogs in both groupsto identify factors predictive of death (Tables1 and and2).2). The following variableswere significantly higher among the animals that did not survive when compared withthose that survived: NT-proBNP, NE, HR, quality of life score, LVIDd/Ao, LVIDs/Ao,and LA/Ao. Additionally, most nonsurvival dogs were male (91.7%) and had functionalclasses III-IV (75.0%).

On multivariable logistic analysis, the variables independently associated with deathwere NT-proBNP (OR = 2.29, 95% confidence interval [95%CI] 1.24 - 4.2, p = 0.008)and quality of life score (OR = 1.22, 95%CI 1.02 - 1.45, p = 0.027).

The area under the curve, sensitivity, and specificity (obtained from ROC curves) ofthe univariate models associating NT-proBNP (cutoff = 1850 pmol/L) and the qualityof life score (cutoff = 17) with death were 0.91 (95%CI 0.77 - 0.98, standard error[SE] = 0.05, p < 0.0001), 0.83 and 0.88, respectively, and 0.86 (95%CI 0.70 -0.95, SE = 0.06, p < 0.0001), 0.75 and 0.79, respectively.

Finally, ROC curves were developed for the multivariable model with NT-proBNP and thequality of life score as predictors (Figure1).

Receiver operating characteristic (ROC) curves for the comparison of theFunctional Evaluation of Cardiac Health (FETCH) score and NT-proBNPlevels.

Discussion

The dogs enrolled in this study had mainly MR, LA enlargement, and preserved renalfunction. According to our results, the quality of life scores correlated with thefunctional classification and NE concentrations, while NT-proBNP values correlatedwith the quality of life score, NE concentrations, and certain echocardiographicfindings. On multivariable regression analysis, NT-proBNP concentrations and qualityof life score emerged as independent predictors of death after a follow-up period of6 months. We were also able to calculate the NT-proBNP levels and the quality oflife score cutoff values that best predicted mortality.

The association between quality of life scores and NE values with the severity ofmitral valve disease has been previously described in the veterinaryliterature., The positive correlation betweenthese variables suggests that dogs with mitral valve disease that develop heartfailure and experience increased sympathetic activity have a decreased quality oflife.

The correlation between natriuretic peptide levels and the echocardiographicvariables LVIDd/Ao, LVIDs/Ao, LA/Ao, and FS observed in this study have beenpreviously reported by other investigators,- confirming thatthis peptide is a marker of cardiac remodeling and left ventricular dysfunction indogs with mitral valve disease.

Furthermore, animals with higher concentrations of NT-proBNP or a higher quality oflife score had a higher risk of death. The prognostic value of NT-proBNP has beendiscussed by other investigators. Chetboul et al. demonstrated the ability of NT-proBNP to predictthe transition from asymptomatic mitral insufficiency to a symptomatic disease indogs. In a prospective study of dogs with symptomatic mitral valve disease over a6-month follow-up period, Serres et al. demonstrated that NT-proBNP was a good predictor ofsurvival.

Questionnaires assessing the health-related quality of life of dogs have beenvalidated for a variety of diseases, including cardiac disease, diabetes,neuropathic pain, and skin diseases.,- The questionnaire used in the present study hasbeen already validated in dogs with heart failure. All studies recommend using the owner-perceivedquality of life score for disease management.

In the multivariable regression model, both NT-proBNP concentrations and quality oflife score were equally significant and independent predictors of mortality. Still,our most interesting finding was the quality of life score as a predictor of risk ofmortality. This result is encouraging, as this questionnaire is easy to apply anddoes not require any technology, only a veterinarian and an observant owner.

One limitation of our study was the small sample size, which may limit the validityof the results. Another limitation was that the dogs were at different stages of thedisease, as shown by their different functional classification. Finally, it ispossible that the owner-reported data may have introduced subjectivity into theevaluation.

Conclusion

The quality of life score was an independent predictor of cardiac death in dogs withDMVD.

Acknowledgements

The present work was supported by and performed at Sena Madureira VeterinaryHospital, São Paulo, Brazil and at the Clinical Laboratory, Heart Institute(InCor), University of São Paulo, Medical School.

Footnotes

Author contributions

Conception and design of the research:Strunz CMC; Acquisition ofdata:Marcondes-Santos M, Fragata FS; Analysis and interpretation of the data andCritical revision of the manuscript for intellectual content:Strunz CMC,Marcondes-Santos M, Takada JY, Fragata FS, Mansur AP; Statistical analysis:Takada JY, Mansur AP; Obtaining financing:Strunz CMC, Marcondes-Santos M;Writing of the manuscript:Strunz CMC.

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Sources of Funding

This study was funded by Laboratório Clínico do Instituto doCoração (InCor) e Hospital Veterinário Sena Madureira.

Study Association

This article is part of the thesis of Doctoral submitted by MárioMarcondes-Santos, from Faculdade de Medicina da Universidade de SãoPaulo.

References

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