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Background: The clinical outcome of dogs affected by degenerative mitral valve disease (MVD) without overt clinical signs is still poorly defined, and criteria for identification of animals that are at a higher risk of early decompensation have not yet been determined.
Hypothesis: N-terminal pro-B-type natriuretic peptide plasma concentration (NT-proBNP) is correlated with mitral regurgitation (MR) severity and can predict disease progression in dogs with asymptomatic MVD.
Animals: Seventy-two dogs with asymptomatic MVD, with or without heart enlargement (International Small Animal Cardiac Health Council: ISACHC classes 1a and 1b), and a control group of 22 dogs were prospectively recruited.
Methods: Severity of MR was quantitatively assessed from the regurgitation fraction (RF) by the proximal isovelocity surface area method. Consequences of MR were evaluated from measurements of the left atrium/aorta ratio (LA/Ao), fractional shortening (FS), end-diastolic and end-systolic left ventricular volumes indexed to body surface area (EDVI and ESVI). The relevance of these echo-Doppler indices and NT-proBNP for prediction of outcome at 12 months was studied.
Results: A significant correlation was found between NT-proBNP and RF, LA/Ao, FS, and EDVI (P < .05). NT-proBNP was higher in dogs with MVD (ISACHC classes 1a and 1b) compared with the control group (P= .025 and < .001, respectively). The difference was not significant when only dogs from ISACHC class 1a with RF < 30% were considered. Lastly, NT-proBNP was higher in dogs that underwent MVD decompensation at 12 months (P < .05).
Conclusions and Clinical Importance: NT-proBNP is correlated with MVD severity and prognosis in dogs with asymptomatic MVD.
Degenerative mitral valve disease (MVD) is the most commonly acquired heart disease of dogs and results in systolic mitral regurgitation (MR) with potential complex neurohormonal and hemodynamic consequences.1,2 Although most dogs with MVD remain asymptomatic for years and even for life (International Small Animal Cardiac Health Council [ISACHC] class 1),3–7 severe complications can occur including exercise intolerance, cough, and dyspnea caused by the development of left-sided congestive heart failure (CHF), and ascitis or pleural effusion as signs of right-sided CHF secondary to pulmonary arterial hypertension (PAH). These complications can lead to death or euthanasia because of worsening or unresponsive clinical signs.8–10
Criteria for the identification of dogs in ISACHC class 1 that risk decompensation remain a major issue in practice. Various factors have been hypothesized to influence the time to onset of CHF. It is generally accepted that, as in humans,11 MR severity is a major determinant of natural disease progression and the clinical outcome in asymptomatic dogs.12 In 1 study dedicated to the quantification of MR in canine MVD by the proximal isovelocity surface area (PISA) method,12 dogs without clinical signs exhibited a wide range of regurgitation fractions (RF), and approximately one third of them showed moderate to severe RF (ie, > 50%). Such MR can in turn lead to cardiac remodeling and development of CHF. Several complications including PAH,13chordae tendinae rupture,14 renal impairment,15 and cardiac arrhythmiasa can also contribute to accelerate cardiac decompensation of dogs with asymptomatic MVD. It might therefore be hypothesized that the detection of such complications, along with echo-Doppler markers of MR severity, could be used to identify dogs from ISACHC class 1 that are likely to progress to the symptomatic phase. Several biomarkers, especially natriuretic peptides, which are involved in volume homeostasis and cardiovascular remodeling,16 might also be useful in detecting dogs at risk of CHF.
To date, B-type natriuretic peptides, including both brain natriuretic peptide (BNP) and its inactive aminoterminal portion (N-terminal pro-B-type natriuretic peptide [NT-proBNP]), are considered as among the most reliable neurohormonal markers of human heart diseases.17 BNP is produced and stored as pro-BNP in response to wall stretch, mainly in ventricular cardiomyocytes, and to a lesser extent, in atrial cardiomyocytes.16,17 Inactive pro-BNP is then cleaved into the circulating biologically active BNP and the inactive NT-proBNP.16,17 NT-proBNP is a more stable biomarker than BNP, making its measurement more practical in clinical settings.16
Studies on BNP and NT-proBNP in the dog have mostly focused on their accuracy to discriminate between CHF and primary respiratory diseases18,19 or to assess disease severity,20,21,b but not on their prognostic ability, particularly in compensated heart diseases. The potential interest of BNP for the diagnosis of occult heart disease was described in 1 report using a canine model of dilated cardiomyopathy,22 but its ability to identify asymptomatic dogs at risk for decompensation was not studied. Moreover, in dogs with ISACHC class 1a MVD, correlation between NT-proBNP and MR regurgitation severity or MR progression remains unclear,c although NT-proBNP has been recently shown to be increased in Cavalier King Charles Spaniels (CKC) with preclinical MVD and severe MR compared with both controls and CKC with no, minimal, or moderate MR assessed by color flow mapping.21 Therefore, to the best of our knowledge, evidence is still lacking regarding the usefulness of NT-proBNP as a prognostic biomarker of asymptomatic MVD, and more specifically its ability to identify dogs that are at high risk for MVD complications and cardiac decompensation.
The aims of this prospective study were therefore (1) to determine the correlation between NT-proBNP and various echo-Doppler variables reflecting MR severity in a large population of dogs with asymptomatic MVD (ISACHC classes 1a and 1b), and (2) to evaluate the comparative ability of all these markers to predict outcome at 12 months in the same population of dogs.
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The clinical outcome of MVD-affected dogs without overt clinical signs is still poorly defined, and criteria for identification of dogs in ISACHC class I that are at a higher risk of early decompensation remain a major issue in veterinary cardiology. This report demonstrates the ability of NT-proBNP together with several imaging variables to help in predicting 12-month evolution of heart disease in dogs from various breeds with asymptomatic MVD.
The present study has several advantages. First, all the animals were prospectively investigated in the same hospital according to a well-standardized protocol by well-trained observers using the same echocardiographic and Doppler methods. Second, the number of recruited animals with asymptomatic MVD was high with a wide range of MR severity, and comparison with an age-matched control group was performed. Third, in the present report, MR severity was assessed by the PISA method with calculation of RF. Previous studies of NT-proBNP in canine MVD did not use the PISA method, but rather the color Doppler mapping technique with calculation of the area of regurgitant jet relative to the left atrial area (ARJ/LAA),b,c,21 and ARJ/LAA, as a semiquantitative index, presents several limitations.12
In the current study, epidemiologic characteristics of the asymptomatic MVD population were in accordance with previous reports, with a predominance of male aged adult small-breed dogs. The overrepresentation of English Toy Spaniels in Group 1 is in accordance with previous results.29,30 This unbalanced breed distribution between Groups C and 1, which represents a limitation of the present study, may somewhat explain the difference in body weight between the 2 groups, with a higher weight for dogs with MVD compared with healthy controls. Its potential impact on the present results is unknown, as the influence of breed on NT-proBNP plasma levels has not been studied in the dog as yet.
Numerous studies focusing on the diagnostic interest of BNP and NT-proBNP in humans have been published. NT-proBNP is now widely recognized as a powerful marker for diagnostic purpose, especially to distinguish patients with dyspnea of cardiac and noncardiac origin,31 which has also been demonstrated in the dog.18,19 More recent reports have emphasized the prognostic usefulness of B-type NP in both symptomatic and asymptomatic human patients. In a large cohort of asymptomatic persons, plasma BNP level was recently shown to predict a wide range of cardiovascular outcomes such as CHF, atrial fibrillation, and cardiac death after adjustment for traditional risk factors.32 Little evidence exists on the prognostic value of such biomarkers in veterinary cardiology, and more particularly on their ability to predict worsening of an asymptomatic heart disease. In a recent study performed in 1 single canine breed (CKC), plasma concentrations of NT-proBNP at reexamination could predict progression in regurgitant jet size in dogs with asymptomatic MVD. However, the ability of NT-proBNP to predict clinical outcome could not be evaluated.21
The present study first demonstrates that plasma NT-proBNP concentration varies according to the clinical status. NT-proBNP, indexed or not to plasma creatinine concentration, was shown to be significantly higher in dogs with ISACHC class 1 MVD compared with healthy dogs. Additionally, dogs from ISACHC class 1b had significantly higher plasma NT-proBNP concentrations than those from ISACHC class 1a. Similarly, in a recent study,20 NT-proBNP was shown to discriminate healthy dogs from dogs with MVD, and asymptomatic dogs with heart enlargement (corresponding to ISACHC class 1b) had significantly higher NT-proBNP concentration than dogs with heart disease but no heart enlargement (ISACHC class 1a); however, these groups were not compared with a healthy control group. Similar results were also obtained by Drourr and colleagues, who demonstrated a significant increase in NT-proBNP values in dogs with MVD from ISACHC class 1b compared with those from ISACHC class 1a.b In the present report and in comparison with the latter studies, a further distinction within the asymptomatic MVD stage was made with 2 new subsets of animals, ie, those without heart enlargement (ISACHC class 1a) and mild MR (RF ≤ 30%) and those without heart enlargement (ISACHC 1a) but moderate to severe MR (RF > 30%). The latter subgroup had significantly higher NT-proBNP values than the former and than dogs from the control group, thus suggesting that MR severity is one of the major determinants of MVD severity. Similarly, in the present study, a significant correlation was found between plasma NT-proBNP concentration and various markers of MVD severity including RF, LA/Ao, FS, and EDVI. However, these correlations were weak (as shown by the low r values), thus suggesting that other factors were probably involved in elevating plasma NT-proBNP concentration.
The present report also demonstrates the prognostic value of NT-proBNP in the asymptomatic phase of MVD in dogs. Dogs from ISACHC class 1 that either died or developed clinical signs of CHF within the next 12 months after admission had significantly higher initial plasma NT-proBNP concentrations than the others. These dogs that underwent MVD progression and thus belonged to the D group were also characterized by significantly worse echocardiographic and Doppler alterations than dogs with a stable state belonging to the S group. These imaging alterations included higher MR, LA, and LV dilation, and apparent ventricular performance (as assessed by RF, LA/Ao, EDVI, ESVI, and FS, respectively), as well as higher mitral E wave and SPAP. These data suggest that activation of the natriuretic peptide system occurs in a subset of dogs with asymptomatic MVD concomitantly with morphological and functional cardiac changes owing to the increase in MR severity. We can hypothesize that these cardiac alterations (ie, LA and LV dilation) are responsible for an increased pro-BNP production by cardiomyocytes in response to wall stretch.16,17 This could explain why, in the present study (Table 5), both NT-proBNP and several echo-Doppler indices were able to identify asymptomatic dogs at high risk for MVD worsening. Plasma NT-proBNP measurement may therefore be used to complement ultrasound-imaging techniques and help stratify and monitor MR severity during the asymptomatic phase of canine MVD. Detecting dogs with the most severe MR or that are at a higher risk of decompensation could have a therapeutic impact5,6 that needs to be accurately assessed in further studies.
Lastly, the present study provides additional evidence that ISACHC class 1 is not a homogeneous stage but rather includes several degrees of MVD severity according to both echocardiographic and Doppler alterations and plasma NT-proBNP levels. These data are in accordance with previous reports published by our group, which have demonstrated that ISACHC class 1 MVD may include more severely affected animals than clinically suspected, with moderate or even severe MR, chordae tendinae rupture, and PAH.12,13,28 In the present report, respectively, 54, 11, and 55% of dogs from Group 1 showed moderate to severe MR, chordae tendinae rupture, and PAH. This dispersion of MVD severity, which is confirmed by and correlated with the heterogeneity of NT-proBNP values, provides a new approach to the MVD asymptomatic stage and underlines the usefulness of complementary examinations during this apparently silent phase of the disease.
This study presents several limitations. First, the present protocol only referred to 1 absolute NT-proBNP value at admission. Therefore, possible daily variations of plasma NT-proBNP concentrations were not taken into consideration. Another limitation regarding the present study is that the prognostic usefulness of NT-proBNP was studied through only a single sampling at the time of diagnosis, and not through its progression over time using serial measurements. NT-proBNP reduction percentage, rather than its absolute value at admission, has been demonstrated to be the best predictor of cardiovascular death during the follow-up period in human patients with acutely decompensated CHF.33 The age difference between Group C and subgroup 1-b as well as the larger number of affected dogs compared with the control dogs are other limitations of the present study. Moreover, only 10 dogs reached the decompensation endpoint at 12 months. Nevertheless, this small number provided significant results in terms of outcome predictors. Splitting subgroup 1-a into dogs with moderate to severe MR and those with mild MR was a posthoc comparison, which is another limitation of the present study. Lastly, more than 40% of dogs with asymptomatic MVD were receiving one or more treatments at the time of diagnosis, including at least an angiotensin-converting enzyme inhibitor, which could have influenced both the MVD outcome5,6 and plasma NT-proBNP concentrations.
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aO'Sullivan ML, O'Grady MR, Walker C. Frequency of ventricular ectopy in dogs with chronic mitral valve disease and congestive heart failure treated with pimobendan or benazepril. Presented at the 25th Annual ACVIM Forum Seattle, WA, June 6–9, 2007. J Vet Intern Med 2007;21:587 (abstract)
bDrourr LT, Gordon SG, Roland RM, et al. NT-Pro-BNP concentration in preclinical (ISACHC 1b & 1b) chronic degenerative atrioventricular valve disease. Presented at the 26th Annual ACVIM Forum San Antonio, TX, June 4–7, 2008. J Vet Intern Med 2008;22:758 (abstract)
cTarnow I, Pedersen HD, Kvart C, et al. Natriuretic peptides are elevated in Cavalier King Charles Spaniels with congestive heart failure but not in dogs with clinically inapparent mitral valve disease. Presented at the 25th Annual ACVIM Forum Seattle, WA, June 6–9, 2007. J Vet Intern Med 2007;21:587 (abstract)
dVivid 7, General Electric Medical System, Waukesha, WI
eEchopac Dimension, General Electric Medical System
fVETSIGN Canine CardioSCREEN Nt-proBNP, Guildhay Ltd, Guildford, UK
gZieba M, Beardow A, Carpenter C, et al. Analytical validation of a commercially available canine N-terminal prohormone Brain natriuretic peptide elisa. Presented at the 26th Annual ACVIM Forum San Antonio, TX, June 4–7, 2008. J Vet Intern Med 2008;22:717 (abstract)
hMedcalc, Medcalc Software, Mariakerke, Belgium