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Aldosterone breakthrough in dogs with naturally occurring myxomatous mitral valve disease
Journal of Veterinary Cardiology (2017)
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Aldosterone breakthrough in dogs with naturally occurring myxomatous mitral valve disease M.K. Ames, DVM a,*, C.E. Atkins, DVM a, A. Eriksson, DVM a, A.M. Hess, MS, PhD b a
Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, 1060 William Moore Dr. Raleigh, NC, 27607, USA b Department of Statistics, Colorado State University, Ft. Collins, CO, USA Received 19 April 2016; received in revised form 18 March 2017; accepted 27 March 2017
KEYWORDS Angiotensin converting enzyme inhibitor; Mineralocorticoid receptor blocker; Heart failure; Renin angiotensin aldosterone system
Abstract Introduction: Aldosterone breakthrough (ABT) is the condition in which angiotensin converting enzyme inhibitors (ACEIs) and/or angiotensin receptor blockers fail to effectively suppress the activity of the renin angiotensin aldosterone system. The objective of this study was to determine if ABT occurs in dogs with naturally occurring myxomatous mitral valve disease receiving an ACEI, using the urine aldosterone to creatinine ratio (UAldo:C) as a measure of renin angiotensin aldosterone system activation. Animals, Materials and Methods: This study includes 39 dogs with myxomatous mitral valve disease. A UAldo:C cut-off definition (derived from a normal population of healthy, adult, and client-owned dogs) was used to determine the prevalence of ABT in this population. Spearman analysis and univariate logistic regression were used to evaluate the relationship between UAldo:C and ABT (yes/no) and eight variables (age, serum Kþ concentration, serum creatinine concentration, ACEI therapy duration and ACEI dosage, furosemide therapy duration and furosemide dosage, and urine sample storage time). Finally, the UAldo:C in dogs receiving spironolactone, as part congestive heart failure (CHF) therapy, was compared to dogs with CHF that were not receiving spironolactone. Results: The prevalence of ABT was 32% in dogs with CHF and 30% in dogs without CHF. There was no relationship between either the UAldo:C or the likelihood of ABT
Preliminary results were presented at the 2014 American College of Veterinary Internal Medicine Forum, Nashville, TN, USA, June 2014. * Corresponding author. Current address: Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA. E-mail address: [email protected] (M.K. Ames). http://dx.doi.org/10.1016/j.jvc.2017.03.001 1760-2734/ª 2017 Elsevier B.V. All rights reserved.
Please cite this article in press as: Ames MK, et al., Aldosterone breakthrough in dogs with naturally occurring myxomatous mitral valve disease, Journal of Veterinary Cardiology (2017), http://dx.doi.org/10.1016/j.jvc.2017.03.001
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M.K. Ames et al. and the eight variables. Therapy with spironolactone lead to a significant elevation of the UAldo:C. Discussion: Using the UAldo:C and a relatively stringent definition of ABT, it appears that incomplete RAAS blockade is common in dogs with MMVD receiving an ACEI. The prevalence of ABT in this canine population mirrors that reported in humans. While the mechanism of ABT is likely multifactorial and still poorly understood, the proven existence of ABT in dogs offers the potential to improve the prognosis for MMVD with the addition of a mineralocorticoid receptor blocker to current therapeutic regimens. Conclusions: Approximately 30% of dogs being treated for heart disease and CHF satisfied the definition of ABT. Identifying patient subpopulations experiencing ABT may help guide future study design and clinical decision-making. ª 2017 Elsevier B.V. All rights reserved.
Abbreviations ABT ACE ACEI
aldosterone breakthrough angiotensin converting enzyme angiotensin converting enzyme inhibitor ARB angiotensin 1-receptor blocker CHF congestive heart failure MMVD myxomatous mitral valve disease MRB mineralocorticoid receptor blockade/blocker RAAS renin angiotensin aldosterone system RIA radioimmunoassay UAldo:C urine aldosterone to creatinine ratio
Chronic activation of the sympathetic nervous system and renin angiotensin aldosterone system (RAAS) results in sodium and water retention, vasoconstriction (increased preload and afterload), and cardiovascular remodeling. This neurohormonal activation promotes and perpetuates the congestive heart failure (CHF) syndrome. Plasma renin activity and blood concentrations of aldosterone and norepinephrine, which increase as heart disease progresses, are markers and contributors to the hemodynamic derangements of this syndrome [1e5]. Importantly, loopdiuretic therapy, and sodium restriction further stimulate RAAS activation [5e7]. Improved understanding of the pathological consequences of neurohormonal activation has led to beneficial heart failure therapies beyond loop diuretics in veterinary medicine, most notably angiotensin converting enzyme inhibitors (ACEIs) [8e11]. Furthermore, benefits seen with inodilating drugs, such as pimobendan, are likely due, in
part, to reduced circulating neurohormone levels produced by improvements in hepatic and renal perfusion, more efficient metabolism and excretion of these compounds, and reduced stimuli for their release. However, despite improved CHF pharmacotherapy, morbidity, and mortality remain high. When secreted chronically and in excess, aldosterone has been implicated in the increased generation of reactive oxygen species, inflammation, and pathologic remodeling (hypertrophy and fibrosis) in tissues such as myocardium, vascular smooth muscle, and kidneys [12e15]. Aldosterone levels have been found to be increased in people with chronic and acutely decompensated CHF [2,3,6]. It had been presumed that both ACEI and angiotensin 1-receptor blockers (ARB) would effectively blunt aldosterone secretion by reducing the formation of angiotensin II (a major secretagogue of aldosterone). It is now known that ACEI and ARB (alone or in combination) do not always effectively suppress aldosterone secretion in people and this phenomenon is referred to as aldosterone breakthrough (ABT) [16e25]. In humans, ABT is an important, well-accepted, yet poorly understood phenomenon, in those treated with ACEI or ARB for chronic kidney disease, heart failure, and hypertension [16,20,21,25,26]. Despite its acceptance, there is no consensus regarding ABT’s exact definition, timing, and prevalence. Creating a definition of ABT requires a reliable screening tool to evaluate aldosterone levels. As previously described by the authors, the urine aldosterone to creatinine ratio (UAldo:C), using spot urine samples, can be used as a surrogate for 24-h urinary aldosterone excretion, allowing assessment of RAAS activity in dogs [27]. Using the UAldo:C, the authors have demonstrated ABT in normal research dogs where, despite ACEI
Please cite this article in press as: Ames MK, et al., Aldosterone breakthrough in dogs with naturally occurring myxomatous mitral valve disease, Journal of Veterinary Cardiology (2017), http://dx.doi.org/10.1016/j.jvc.2017.03.001
Aldosterone breakthrough in dogs
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Table 1 Demographics for dogs with naturally occurring myxomatous mitral valve disease, grouped on basis of presence/absence of congestive heart failure and by pharmacotherapy. Parameter Group treatment characteristics Interpretation of UAldo:C > 1.0 mg/g Number of dogs per group Age (yr) median (IQR) Sex BW (kg) median (IQR)
CHF group
No CHF group
Spiro group
CHF, standard therapya ABT 22 11.0 (9.8e12.7) 13 SF, 8 CM, 1 M 9.9 (7.3e16.6)
No CHF, receiving ACEI
CHF, standard therapya þ spiro N/A 7 12.4 (9.2e13.1) 4 SF, 3 CM 10.0 (6.8e28.5)
ABT 10 10.3 (9.4e12.5) 4 SF, 6 CM 7.6 (3.3e11.7)
ABT, aldosterone breakthrough; ACEI, angiotensin converting enzyme inhibitor; BW, body weight; CHF, congestive heart failure; CM, castrated male; M, male; IQR, interquartile range; N/A, not applicable; SF, spayed female; Spiro, spironolactone; UAldo:C, urine aldosterone to creatinine ratio. Please see text for detail on group definitions. There were no significant differences in either age or BW between these groups. a Standard therapy for congestive heart failure includes furosemide, pimobendan, and angiotensin converting enzyme inhibitor.
therapy, aldosterone levels rise during RAAS activation with either a diuretic or vasodilator [27e30]. Plasma angiotensin converting enzyme (ACE) activity was measured in three of these studies and was found to decrease significantly within 1 day of oral ACEI administration [27], yet the incidence of ABT in these studies was found to be as high as 60%. Although these experiments involved normal dogs in subacute studies, they raised the question as to whether ABT occurs in dogs with naturally occurring heart disease. Myxomatous mitral valve disease (MMVD) is the most common acquired cardiovascular disease and the most common cause of CHF in dogs. Angiotensin converting enzyme inhibitor are indicated once a patient is in CHF (American College of Veterinary Internal Medicine [ACVIM] stage C), yet it remains controversial as to whether they confer benefit, prior to the onset of CHF (ACVIM stage B1 and B2) [31]. Identification of subpopulations of dogs with MMVD, experiencing ABT, may help guide future study design and clinical decision-making. The goal of this study was to use the UAldo:C to determine both the existence and frequency of ABT in dogs with naturally occurring MMVD. This study also sought to investigate the mechanism of ABT by evaluating the relationships between UAldo:C and ABT (yes/no) and eight variables (age, serum Kþ concentration, serum creatinine concentration, ACEI therapy duration and dosage, furosemide therapy duration and dosage, and urine sample storage time). The first seven variables were chosen, as they are hypothesized to play a role in the mechanisms of ABT. The variable ‘sample storage time’ was chosen to determine if duration of sample freezing affects aldosterone concentration. Finally, the UAldo:C from dogs
receiving spironolactone as part of CHF therapy was compared to that of dogs with CHF, not receiving spironolactone.
Materials and methods Animals Dogs with MMVD that presented to the cardiology and emergency services of the North Carolina State University College of Veterinary Medicine and Colorado State University College of Veterinary Medicine and Biomedical Sciences were enrolled into this study between 6/2012 and 6/ 2014. In this study, CHF was defined as the presence of cardiogenic pulmonary edema, necessitating furosemide administration. A board certified cardiologist (MA or CA) confirmed the diagnosis of MMVD and of CHF, when present. Dogs already receiving therapy for MMVD were prospectively placed into three groups, based on the presence/absence of a proven history of CHF and their pharmacotherapy (Table 1). Dogs with MMVD and CHF receiving ‘standard therapy’ (furosemide, pimobendan, and ACEI) were included in the CHF group. An ACEI (enalapril or benazepril) was required to have been used for greater than one day for dogs to be enrolled in the study. Dogs with MMVD and CHF, receiving ‘standard therapy’ (ACEI, furosemide, and pimobendan) and spironolactone, were included in the Spiro group. Dogs with MMVD without CHF, that were receiving an ACEI, were placed in the no CHF group. The authors prospectively collected the data from all recruited and enrolled dogs, and then allocated them to their respective treatment groups. The
Please cite this article in press as: Ames MK, et al., Aldosterone breakthrough in dogs with naturally occurring myxomatous mitral valve disease, Journal of Veterinary Cardiology (2017), http://dx.doi.org/10.1016/j.jvc.2017.03.001
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M.K. Ames et al.
investigators did not impose treatment regimens, rather accepted or rejected cases from the study, based in part on their therapies. Concurrent medications (cardiac and non-cardiac), other than ARB, were allowed. Dogs with controlled systemic hypertension or endocrine disease were permitted. Patients were excluded if they did not fit the criteria of one of the three groups or if their urine sample was not handled per the study protocol. The Institutional Animal Care and Use Committees approved this study at both institutions.
normal, >5-year-old dogs (mean UAldo:C of 0.49 mg/g, 0.27).e Only 1 of these 55 dogs (a dog in the <6-year-old group) had a UAldo:C greater than 1.0 mg/g. From these historical data, it appears that the UAldo:C usually does not exceed 1.0 mg/g, and the UAldo:C does not appear to change significantly with age in normal dogs. The mean þ 2 SD of the UAldo:C of the older dogs from Colorado State University was 1.0 mg/g and this value was used to determine our cut-off definition for ABT (UAldo:C > 1.0 ug/g).
Urine aldosterone to creatinine ratio (UAldo:C)
Statistical analysis
About 2e5 mL of a free-catch urine sample was collected from each dog, immediately refrigerated and then frozen at 70 C, within 24 h of collection. Samples were submitted for determination of UAldo:C. If blood work was deemed necessary by the primary clinician, as part of the dog’s medical and treatment plan, then a sample was taken for serum biochemical analysis. The blood samples were taken on the same day as the urine collection and were obtained via venipuncture (jugular, cephalic, or saphenous) with the dog gently restrained in a sitting or lateral position. The timing of urine collection was not standardized for these clinical patients, presenting at various times of the day to both the cardiology and emergency services. A radioimmunoassay (RIA) that has been validated in dogsc was used to measure urine aldosterone concentration. Urine creatinine concentration was measured via a standard colorimetric assay. For all samples, these two components of the UAldo:C were performed by a veterinary diagnostic laboratory.d The same RIA assay was used for all analyses and the assay performed per the manufacturer’s directions, as described elsewhere [28]. Briefly, this assay measures free aldosterone and one of its two major metabolites, aldosterone b-glucuronide (after acid hydrolysis to aldosterone).
Definition of ABT The normal (baseline) UAldo:C has been studied (using an RIAc to measure urine aldosterone) in 34 healthy, <6-year-old laboratory dogs (mean UAldo:C of 0.40 0.21 mg/g) and 21 client-owned,
c Coat-a-count aldosterone (RIA), Siemens Medical Diagnostic Solutions, Los Angeles, CA, USA. d Michigan State University Center for Population and Animal Health, Lansing, MI, USA.
The D’AgostinoePearson omnibus procedure was used to test for normality. Data are presented as median and interquartile range (median; IQR). There were 32 dogs receiving an ACEI without spironolactone (CHF, no CHF groups) included in the analysis for ABT. The occurrence of ABT is presented as a percentage. The Spearman test was used to evaluate the relationship between UAldo:C ratio vs. eight variables (age, serum Kþ concentration, serum creatinine concentration, ACEI therapy duration and dosage, furosemide therapy duration and dosage, and urine sample storage time). All 32 dogs receiving an ACEI were included in this analysis. Sample storage time was defined as the time from collection to analysis. Univariate logistic regression was used to look at the relationship between ABT (yes/no, using the definition of UAldo:C > 1.0 mg/g) and each of the eight variables above for those same 32 dogs. The BenjaminieHochberg procedure was used to adjust pvalues for multiple testing. The mean age, body weight, UAldo:C, and ACEI dosages and durations were compared between the three groups (CHF, no CHF, and Spiro) using the KruskaleWallace test with Dunn’s adjustment for multiple comparisons. The ManneWhitney U test was used to compare the furosemide dosages and durations between the CHF and Spiro groups. The ManneWhiney U test was also used to compare ACEI type (enalapril vs. benazepril) and UAldo:C for dogs in the CHF and no CHF groups. The Fisher’s exact test was used to determine if there was a relationship between ABT and presence of CHF. The criteria for statistical significance was set to a ¼ 0.05. Analyses were performed using the
e Ames MK, Atkins CE, Webb K. The urine aldosterone to creatinine ratio (UALDO:C) determined by radioimmunoassay (RIA) in normal dogs greater than 5 years of age. J Vet Intern Med 2015; 29: 1148 (abstract).
Please cite this article in press as: Ames MK, et al., Aldosterone breakthrough in dogs with naturally occurring myxomatous mitral valve disease, Journal of Veterinary Cardiology (2017), http://dx.doi.org/10.1016/j.jvc.2017.03.001
ACEI, furosemide, and spironolactone: dosage and duration The number of dogs receiving each type of ACEI (enalapril or benazepril) in the CHF, and no CHF groups and the average dosages are shown in Fig. 1. The median (IQR) durations of ACEI administration for dogs in the CHF, no CHF, and Spiro groups were 86 (12e233), 297 (15e713), and 787 (164e1,661) days, respectively. Three of the 39 (7.7%) had been receiving an ACEI for less than one week. There were no differences in ACEI dosages between the three groups (p¼0.8). The median (IQR) dosages of furosemide for dogs in the CHF and Spiro groups were 3.7 (1.8e4.2) and 3.4 (1.9e6.7) mg/kg/day and the median (IQR) durations of furosemide administration were 28 (7e110) and 229 (91e792) days, respectively. Both the mean dosage and duration of furosemide therapy were significantly greater in the Spiro group (p¼0.0001 and p¼0.02, respectively). Within the CHF group, 6 dogs had received furosemide for <2 weeks and 16 dogs had received furosemide for >2 weeks. Dogs in the Spiro group received a dosage of spironolactone (median [IQR]) of 1.7 (1.0e1.8) mg/kg/day. All dogs
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Forty-one dogs were enrolled into this study and 39 dogs were included, as they fit the criteria for one of the groups described in Table 1. Twenty-nine of these 39 dogs had a serum biochemistry performed on the same day as their urine sample collection. The CHF group was made up of 22 dogs with both acute (<2 weeks of furosemide therapy; n ¼ 10) and chronic (>2 weeks of furosemide therapy; n ¼ 12) CHF. The no CHF group was made up of 10 dogs, all but one of which was placed in ACVIM stage B2 MMVD. One dog, in stage B1 MMVD, was on amlodipine and an ACEI as chronic therapy for systemic hypertension. There were seven dogs in the Spiro group. There were no differences in age or body weight between the three groups (p¼0.64 and p¼0.28, respectively).
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ACEI dosage (mg/kg/day)
Aldosterone breakthrough in dogs
Figure 1 Angiotensin converting enzyme inhibitor (ACEI) type and dosage shown as a scatter dot plot (median and interquartile range) in dogs with myxomatous mitral valve disease (MMVD). CHF B, 4 dogs with congestive heart failure (CHF), receiving benazepril as part of standard CHF therapy (ACEI, furosemide, and pimobendan); CHF E, 18 dogs with CHF, receiving enalapril, as part of standard CHF therapy; no CHF B, 4 dogs with MMVD, without CHF, receiving benazepril; no CHF E, 6 dogs with MMVD, without CHF, receiving enalapril. There were no significant differences between these groups. Red dots indicate dogs with UAldo:C > 1.0 mg/g (ABT).
receiving spironolactone had received it for more than one week.
Urine aldosterone to creatinine ratio Urine samples from the 39 dogs were submitted for analysis of UAldo:C. The majority of samples were collected between the hours of 9 am and 5 pm. The UAldo:C results from the three groups are shown in Fig. 2. The median (IQR) UAldo:C results in the Spiro group were 2.3 (1.3e5.7) mg/g. None of the eight variables (age, serum Kþ concentration, serum creatinine concentration, ACEI duration and dosage, furosemide duration and dosage, and urine sample storage time) were significantly correlated with UAldo:C (p-values all 0.49). The UAldo:C for dogs with MMVD receiving spironolactone (Spiro group; n ¼ 7) was significantly greater than that for dogs with MMVD and CHF, not receiving spironolactone (CHF group, p<0.05) and dogs with MMVD, not in CHF (no CHF group, p<0.05). There was no difference in UAldo:C between the CHF and no CHF groups (p>0.05).
ABT and RAAS activation f g
SAS, version 9.4, SAS Institute Inc, Cary, North Carolina, USA. GraphPad Prism v6.0 La Jolla, CA, USA.
The percentages of ABT in the CHF and no CHF groups were 32% and 30% respectively (Table 2 and
Please cite this article in press as: Ames MK, et al., Aldosterone breakthrough in dogs with naturally occurring myxomatous mitral valve disease, Journal of Veterinary Cardiology (2017), http://dx.doi.org/10.1016/j.jvc.2017.03.001
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CHF groups, when the enalapril dosage was compared between dogs with ABT and those without ABT, there was no difference (p¼0.23, Fig. 3).
UAldo:C (μg/g)
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Figure 2 Urine aldosterone to creatinine ratio (UAldo:C) as a scatter dot plot (median and interquartile range) in dogs with myxomatous mitral valve disease (MMVD), with and without congestive heart failure (CHF). Dogs receiving spironolactone (Spiro), in addition to standard therapy (furosemide, pimobendan, and an ACEI), demonstrated significantly higher UAldo:C than dogs in the other groups. Individual dogs experiencing aldosterone breakthrough (ABT) were 7 of 22 (CHF group, receiving standard therapy) and 3 of 10 (no CHF group, receiving ACEI). Six of 7 dogs in the Spiro group (receiving standard therapy plus spironolactone) had a UAldo:C > 1.0 mg/g. Red line denotes upper limit of normal UAldo:C (>1.0 mg/g).
Fig. 2). Within the CHF group, the percentage of ABT in dogs with subacute (<2 weeks of furosemide therapy) and chronic (>2 weeks of furosemide therapy) CHF was 50% and 25%, respectively. Based on univariate regression analysis, none of the eight variables (age, serum Kþ concentration, serum creatinine concentration, ACEI duration and dosage, furosemide duration and dosage, and urine sample storage time) were predictive of ABT (p-values all 0.63). Similarly, in the CHF and no
From these results, it appears that ABT is a common occurrence in dogs with naturally occurring MMVD, being treated with ACEI. Aldosterone break through occurred in 32% in dogs with CHF and 30% in dogs that were not yet in CHF. The definition of ABT used in this study is stringent, as compared to human medical definitions of ABT, which often only require that the value of blood aldosterone be either greater than the mean of a normal population, greater than the upper limit of a reference interval for a normal population, or greater than an individual’s baseline value. Overall, it appears that approximately 30% of dogs in this study had inadequate RAAS blockade. No correlation was found between ACEI dosage and therapy duration and either the UAldo:C or the presence of ABT. In regards to ACEI dosage, the results of this study are similar to those of small studies in people with CHF [22] and dogs with experimental RAAS activation [28], which have not shown that higher dosages of ACEI prevent ABT. It is, however, noteworthy that, although there were dogs receiving enalapril at dosages of less than 0.5mg/kg/day that did not experience ABT, no dog receiving enalapril at a dosage greater than 1mg/ kg/day experienced ABT (Fig. 3). The relationship between duration of ACEI therapy and ABT has not been well studied in either man or dog. The dogs in this study had been receiving an ACEI for varying durations, including three dogs in the CHF and no CHF groups that had received less than one week’s therapy. Of interest, 1 of 3 dogs (33%) demonstrated ABT, a percentage similar to that of dogs
Table 2 The mean UAldo:C for each myxomatous mitral valve disease group is presented with the incidence of aldosterone breakthrough. Parameter MMVD: ACVIM stage UAldo:C (mg/g) median (IQR) UAldo:C > 1.0 mg/g Percent ABT
CHF group
No CHF group
Spiro group
C 0.44 (0.27e1.65)* 7/22 31.8
B1 (1) and B2 (9) 0.63 (0.20e1.35)y 3/10 30.0
C and D 2.54 (0.63e4.13)*y 6/7 N/A
ABT, aldosterone breakthrough; ACEI, angiotensin converting enzyme inhibitor; CHF, congestive heart failure; MMVD, myxomatous mitral valve disease; N/A, not applicable; Spiro, spironolactone; UAldo:C, urine aldosterone to creatinine ratio (normal <1 mg/g); IQR, interquartile range. MMVD stage is based on the ACVIM consensus statement. A single dog with controlled systemic hypertension and stage B1 MMVD receiving and ACEI was included. Please see text for detail on group definitions.
Please cite this article in press as: Ames MK, et al., Aldosterone breakthrough in dogs with naturally occurring myxomatous mitral valve disease, Journal of Veterinary Cardiology (2017), http://dx.doi.org/10.1016/j.jvc.2017.03.001
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Enalapril dosage (mg/kg/day)
Aldosterone breakthrough in dogs
Figure 3 Scatter dot plot (median and interquartile range) of angiotensin converting enzyme inhibitor (enalapril) dosage and aldosterone breakthrough (ABT) status in 24 dogs receiving enalapril for the management of myxomatous mitral valvular disease with (CHF group) and without (no CHF group) congestive heart failure. None of these 24 dogs received spironolactone. The dogs are divided into 2 groupsdthose that experienced aldosterone breakthrough (ABT) and those that did not (no ABT). These enalapril dosages were not significantly different.
receiving chronic therapy. As it may take weeks for the maximal beneficial effects of ACEI to be realized [32,33], elevated urinary aldosterone levels during the first month of therapy may be temporary. It can be argued, however, that incomplete RAAS blockade for the first weeks/months of therapy is suboptimal, and that its recognition may be clinically useful. There does not appear to be a relationship between the presence of ABT and the presence of CHF. Additionally, ABT may occur both before and after the onset of CHF. Finally, there was no correlation between either UAldo:C or the presence of ABT and age, serum Kþ concentration, serum creatinine concentration, duration and dosage of furosemide therapy, or urine sample storage time. Once spironolactone is administered, the UAldo:C is difficult to interpret as blockade of the mineralocorticoid receptor leads to an increase in circulating and urine aldosterone concentrations, presumably due to receptor occupation and the failure of an aldosterone-generated negative feedback loop to lower renin secretion from the juxtaglomerular apparatus [34]. The consequences of high levels of free, circulating aldosterone are still unknown in such patients, but the mineralocorticoid receptor-mediated effects of aldosterone are inhibited [35,36]. The nonereceptormediated effects of aldosterone, however, remain under investigation. Based on the mortality benefit
attributed to spironolactone in people with heart failure and low ejection fraction [37e39] and in dogs with MMVD [40] that are treated with spironolactone, the pathophysiologic impact of high levels of aldosterone with concurrent mineralocorticoid receptor blockade, do not appear to negatively impact outcome on a population basis. The study presented here was designed to prove the existence and determine the rate of occurrence of ABT in canine veterinary patients, but not designed to evaluate the impact of ABT on survival. However, the aforementioned study in dogs with heart failure due to MMVD has already demonstrated a survival benefit, when mineralocorticoid receptor blockade/blocker (MRB) was added to standard heart failure therapy (including an ACEI) [40]. There is no consensus regarding the definition of ABT in people, and clinical definitions are usually based on spot blood aldosterone concentrations, using either a baseline definition (a patient’s blood aldosterone concentration increases despite ACEI/ ARB therapy) or a cut-off definition (while receiving an ACEI/ARB, a patient’s blood aldosterone concentration is greater than the mean or mean þ 2 standard deviations of a normal population). A baseline definition can be used when pre-treatment samples are available, allowing ‘individualization’ and monitoring of ‘anti-RAAS’ therapy in a way that is independent of the aldosterone assay used. A cut-off definition is the only option; however, when baseline data are unavailable (i.e. the patient is already on ACEI or ARB therapy). Furthermore, while controversy exists regarding the use of ACEI in MMVD prior to the onset of CHF, pre-treatment assessment of UAldo:C, would help to clarify the potential benefit of anti-RAAS therapy at this stage. In human CHF patients, treatment with the MRBs, spironolactone and eplerenone, is associated with an improved prognosis, on a population basis. The mechanism is thought to be through combatting ABT [37e39]. Increased aldosterone levels in heart disease/ failure results not only from increased secretion (RAAS stimulation) but also through decreased neurohormone metabolism and clearance (due to decreased hepatic and renal perfusion) [41,42]. Circulating ACE activity is reduced by label dosages of the ACEI, benazepril, and enalapril, in both healthy dogs receiving furosemide as a RAAS stimulant, and in dogs with naturally occurring MMVD and CHF [29,30,43,44]. As ABT has been documented to occur despite the reduction in ACE activity that attends ACEI administration, mechanisms other than failure of ACE-inhibition likely
Please cite this article in press as: Ames MK, et al., Aldosterone breakthrough in dogs with naturally occurring myxomatous mitral valve disease, Journal of Veterinary Cardiology (2017), http://dx.doi.org/10.1016/j.jvc.2017.03.001
8 occur. NoneACE-dependent pathways for angiotensin II production, other stimuli for aldosterone release, and decreased aldosterone metabolism and clearance have all been hypothesized as mechanisms for ABT [16,18]. Along with angiotensin II, blood potassium concentration is a key regulator of aldosterone secretion [13]. An elevated potassium concentration, secondary to ACEI or other cause, may contribute to ABT. This role of this hypothesis in ABT in the studied population, however, is not supported by our data. Another possible mechanism for ABT is the excessive production of renin, associated with the use of ACEI, wherein excess renin secretion ‘overwhelms’ the actions of the ACEI, allowing aldosterone production [18]. In none of the dogs, described herein, was plasma renin concentration measured and it is therefore unknown if renin upregulation contributed to the observed ABT. Three additional possibilities for ABT in clinical patients may be related to the therapy of heart failure. The first is potentiation of RAAS activation by diuretics, salt restriction, and vasodilators, which are commonly used in the pharmacotherapy of heart failure [44e47]. Second, activation of the sympathetic nervous system with heart failure may be potentiated by the use of certain cardiac medications, as has been documented with the administration of amlodipine in humans with systemic hypertension [48]. Finally, compliance is a major problem in patients, both human and animal, and might be expected to worsen with length of time under treatment, due to cost, patient or owner fatigue, and drug side-effects. Failure to take/give the ACEI would be associated with ACEI ‘failing’ to suppress aldosterone, mimicking breakthrough. These proposed explanations are not mutually exclusive. This study has several limitations related to its small sample size. First, it was not designed to evaluate survival and there is only minimal evidence that ABT influences survival in dogs with naturally occurring heart disease.h There is, however, evidence supporting an influence of elevated aldosterone levels and/or ABT on cardiorenal outcomes in people [49,50]. An antecedent study in dogs, however, has shown that an MRB (spironolactone), added to ACEI in dogs with MMVD, confers an added benefit in survival [40]. This historical study, along with the present study,
h Hezzell MJ, Boswood A, Elliott J. Relationships between serum and urinary aldosterone, ventricular remodeling and outcome in dogs with mitral valve disease. J Vet Intern Med 2010; 24(3):672 (abstract).
M.K. Ames et al. supports the existence and importance of ABT in dogs and suggest a potential benefit with additional RAAS blockade in the form of an MRB. Second, a firm conclusion cannot be made regarding correlation between the UAldo:C or ABT and the eight variables studied herein. Therefore, the mechanism(s) of ABT remain unknown. Additionally, the absence of measurement of RAAS hormonal elements, other than ACE activity and UAldo:C, make answering some mechanistic questions impossible. Despite these limitations, our results show that ABT occurs in approximately 30% of dogs receiving an ACEI for MMVD, mirroring the findings in humans with cardiovascular disease, and those in our experimental model of ABT. The mechanism of ABT is likely multifactorial and variable between individuals. Further study should be undertaken to determine if ABT is correlated to worsened prognosis, to evaluate its permanence and consistency in a given patient, and to elucidate its mechanism(s). Finally, a priori identification of patient subpopulations experiencing or expected to experience ABT may help guide future study design and clinical decision-making, as whether to initiate MRB therapy in an individual patient.
Conflicts of Interest The authors do not have any conflicts of interest to disclose.
Acknowledgments This study was supported by the Jane Lewis-Seaks Endowment and Ceva Sante Animale. The authors would like to thank Allison Klein, Petra Vasilik, and Susan Beyerlein for their technical assistance.
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[45] Atkins CE, Rausch WP, Gardner SY, DeFrancesco TC, Keene BW, Levine JF. The effect of amlodipine and the combination of amlodipine and enalapril on the reninangiotensin-aldosterone system in the dog. J Vet Pharmacol Ther 2007;30:394e400. [46] Lantis AC, Atkins CE, DeFrancesco TC. Effects of furosemide and the combination of furosemide and the labeled dosage of pimobendan on the circulating reninangiotensin-aldosterone system in clinically normal dogs. Am J Vet Res 2011;72:1646e51. [47] Lovern CS, Swecker WS, Lee JC, Moon ML. Additive effects of a sodium chloride restricted diet and furosemide administration in healthy dogs. Am J Vet Res 2001;62: 1793e6. [48] Champlain J de, Karas M, Assouline L, Nadeau R, LeBlanc AR, Dube ´ B, Larochelle P. Effects of valsartan or amlodipine alone or in combination on plasma catecholamine levels at rest and during standing in hypertensive patients. J Clin Hypertens 2007;9:168e78. [49] Deo R, Yang W, Khan AM, Bansal N, Zhang X. Serum aldosterone and death, end-stage renal disease, and cardiovascular events in blacks and whites. Hypertension 2014;64:103e10. [50] Girerd N, Pang PS, Swedberg K, Fought A, Kwasny MJ, Subacius H, Konstam MA, Maggioni A, Gheorghiade M, Zannad F. Serum aldosterone is associated with mortality and re-hospitalization in patients with reduced ejection fraction hospitalized for acute heart failure: analysis from the EVEREST trial. Eur J Heart Fail 2014;15:1228e35.
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Aldosterone breakthrough in dogs with naturally occurring myxomatous mitral valve disease M.K. Ames, DVM a,*, C.E. Atkins, DVM a, A. Eriksson, DVM a, A.M. Hess, MS, PhD b a
Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, 1060 William Moore Dr. Raleigh, NC, 27607, USA b Department of Statistics, Colorado State University, Ft. Collins, CO, USA Received 19 April 2016; received in revised form 18 March 2017; accepted 27 March 2017
KEYWORDS Angiotensin converting enzyme inhibitor; Mineralocorticoid receptor blocker; Heart failure; Renin angiotensin aldosterone system
Abstract Introduction: Aldosterone breakthrough (ABT) is the condition in which angiotensin converting enzyme inhibitors (ACEIs) and/or angiotensin receptor blockers fail to effectively suppress the activity of the renin angiotensin aldosterone system. The objective of this study was to determine if ABT occurs in dogs with naturally occurring myxomatous mitral valve disease receiving an ACEI, using the urine aldosterone to creatinine ratio (UAldo:C) as a measure of renin angiotensin aldosterone system activation. Animals, Materials and Methods: This study includes 39 dogs with myxomatous mitral valve disease. A UAldo:C cut-off definition (derived from a normal population of healthy, adult, and client-owned dogs) was used to determine the prevalence of ABT in this population. Spearman analysis and univariate logistic regression were used to evaluate the relationship between UAldo:C and ABT (yes/no) and eight variables (age, serum Kþ concentration, serum creatinine concentration, ACEI therapy duration and ACEI dosage, furosemide therapy duration and furosemide dosage, and urine sample storage time). Finally, the UAldo:C in dogs receiving spironolactone, as part congestive heart failure (CHF) therapy, was compared to dogs with CHF that were not receiving spironolactone. Results: The prevalence of ABT was 32% in dogs with CHF and 30% in dogs without CHF. There was no relationship between either the UAldo:C or the likelihood of ABT
Preliminary results were presented at the 2014 American College of Veterinary Internal Medicine Forum, Nashville, TN, USA, June 2014. * Corresponding author. Current address: Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA. E-mail address: [email protected] (M.K. Ames). http://dx.doi.org/10.1016/j.jvc.2017.03.001 1760-2734/ª 2017 Elsevier B.V. All rights reserved.
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M.K. Ames et al. and the eight variables. Therapy with spironolactone lead to a significant elevation of the UAldo:C. Discussion: Using the UAldo:C and a relatively stringent definition of ABT, it appears that incomplete RAAS blockade is common in dogs with MMVD receiving an ACEI. The prevalence of ABT in this canine population mirrors that reported in humans. While the mechanism of ABT is likely multifactorial and still poorly understood, the proven existence of ABT in dogs offers the potential to improve the prognosis for MMVD with the addition of a mineralocorticoid receptor blocker to current therapeutic regimens. Conclusions: Approximately 30% of dogs being treated for heart disease and CHF satisfied the definition of ABT. Identifying patient subpopulations experiencing ABT may help guide future study design and clinical decision-making. ª 2017 Elsevier B.V. All rights reserved.
Abbreviations ABT ACE ACEI
aldosterone breakthrough angiotensin converting enzyme angiotensin converting enzyme inhibitor ARB angiotensin 1-receptor blocker CHF congestive heart failure MMVD myxomatous mitral valve disease MRB mineralocorticoid receptor blockade/blocker RAAS renin angiotensin aldosterone system RIA radioimmunoassay UAldo:C urine aldosterone to creatinine ratio
Chronic activation of the sympathetic nervous system and renin angiotensin aldosterone system (RAAS) results in sodium and water retention, vasoconstriction (increased preload and afterload), and cardiovascular remodeling. This neurohormonal activation promotes and perpetuates the congestive heart failure (CHF) syndrome. Plasma renin activity and blood concentrations of aldosterone and norepinephrine, which increase as heart disease progresses, are markers and contributors to the hemodynamic derangements of this syndrome [1e5]. Importantly, loopdiuretic therapy, and sodium restriction further stimulate RAAS activation [5e7]. Improved understanding of the pathological consequences of neurohormonal activation has led to beneficial heart failure therapies beyond loop diuretics in veterinary medicine, most notably angiotensin converting enzyme inhibitors (ACEIs) [8e11]. Furthermore, benefits seen with inodilating drugs, such as pimobendan, are likely due, in
part, to reduced circulating neurohormone levels produced by improvements in hepatic and renal perfusion, more efficient metabolism and excretion of these compounds, and reduced stimuli for their release. However, despite improved CHF pharmacotherapy, morbidity, and mortality remain high. When secreted chronically and in excess, aldosterone has been implicated in the increased generation of reactive oxygen species, inflammation, and pathologic remodeling (hypertrophy and fibrosis) in tissues such as myocardium, vascular smooth muscle, and kidneys [12e15]. Aldosterone levels have been found to be increased in people with chronic and acutely decompensated CHF [2,3,6]. It had been presumed that both ACEI and angiotensin 1-receptor blockers (ARB) would effectively blunt aldosterone secretion by reducing the formation of angiotensin II (a major secretagogue of aldosterone). It is now known that ACEI and ARB (alone or in combination) do not always effectively suppress aldosterone secretion in people and this phenomenon is referred to as aldosterone breakthrough (ABT) [16e25]. In humans, ABT is an important, well-accepted, yet poorly understood phenomenon, in those treated with ACEI or ARB for chronic kidney disease, heart failure, and hypertension [16,20,21,25,26]. Despite its acceptance, there is no consensus regarding ABT’s exact definition, timing, and prevalence. Creating a definition of ABT requires a reliable screening tool to evaluate aldosterone levels. As previously described by the authors, the urine aldosterone to creatinine ratio (UAldo:C), using spot urine samples, can be used as a surrogate for 24-h urinary aldosterone excretion, allowing assessment of RAAS activity in dogs [27]. Using the UAldo:C, the authors have demonstrated ABT in normal research dogs where, despite ACEI
Please cite this article in press as: Ames MK, et al., Aldosterone breakthrough in dogs with naturally occurring myxomatous mitral valve disease, Journal of Veterinary Cardiology (2017), http://dx.doi.org/10.1016/j.jvc.2017.03.001
Aldosterone breakthrough in dogs
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Table 1 Demographics for dogs with naturally occurring myxomatous mitral valve disease, grouped on basis of presence/absence of congestive heart failure and by pharmacotherapy. Parameter Group treatment characteristics Interpretation of UAldo:C > 1.0 mg/g Number of dogs per group Age (yr) median (IQR) Sex BW (kg) median (IQR)
CHF group
No CHF group
Spiro group
CHF, standard therapya ABT 22 11.0 (9.8e12.7) 13 SF, 8 CM, 1 M 9.9 (7.3e16.6)
No CHF, receiving ACEI
CHF, standard therapya þ spiro N/A 7 12.4 (9.2e13.1) 4 SF, 3 CM 10.0 (6.8e28.5)
ABT 10 10.3 (9.4e12.5) 4 SF, 6 CM 7.6 (3.3e11.7)
ABT, aldosterone breakthrough; ACEI, angiotensin converting enzyme inhibitor; BW, body weight; CHF, congestive heart failure; CM, castrated male; M, male; IQR, interquartile range; N/A, not applicable; SF, spayed female; Spiro, spironolactone; UAldo:C, urine aldosterone to creatinine ratio. Please see text for detail on group definitions. There were no significant differences in either age or BW between these groups. a Standard therapy for congestive heart failure includes furosemide, pimobendan, and angiotensin converting enzyme inhibitor.
therapy, aldosterone levels rise during RAAS activation with either a diuretic or vasodilator [27e30]. Plasma angiotensin converting enzyme (ACE) activity was measured in three of these studies and was found to decrease significantly within 1 day of oral ACEI administration [27], yet the incidence of ABT in these studies was found to be as high as 60%. Although these experiments involved normal dogs in subacute studies, they raised the question as to whether ABT occurs in dogs with naturally occurring heart disease. Myxomatous mitral valve disease (MMVD) is the most common acquired cardiovascular disease and the most common cause of CHF in dogs. Angiotensin converting enzyme inhibitor are indicated once a patient is in CHF (American College of Veterinary Internal Medicine [ACVIM] stage C), yet it remains controversial as to whether they confer benefit, prior to the onset of CHF (ACVIM stage B1 and B2) [31]. Identification of subpopulations of dogs with MMVD, experiencing ABT, may help guide future study design and clinical decision-making. The goal of this study was to use the UAldo:C to determine both the existence and frequency of ABT in dogs with naturally occurring MMVD. This study also sought to investigate the mechanism of ABT by evaluating the relationships between UAldo:C and ABT (yes/no) and eight variables (age, serum Kþ concentration, serum creatinine concentration, ACEI therapy duration and dosage, furosemide therapy duration and dosage, and urine sample storage time). The first seven variables were chosen, as they are hypothesized to play a role in the mechanisms of ABT. The variable ‘sample storage time’ was chosen to determine if duration of sample freezing affects aldosterone concentration. Finally, the UAldo:C from dogs
receiving spironolactone as part of CHF therapy was compared to that of dogs with CHF, not receiving spironolactone.
Materials and methods Animals Dogs with MMVD that presented to the cardiology and emergency services of the North Carolina State University College of Veterinary Medicine and Colorado State University College of Veterinary Medicine and Biomedical Sciences were enrolled into this study between 6/2012 and 6/ 2014. In this study, CHF was defined as the presence of cardiogenic pulmonary edema, necessitating furosemide administration. A board certified cardiologist (MA or CA) confirmed the diagnosis of MMVD and of CHF, when present. Dogs already receiving therapy for MMVD were prospectively placed into three groups, based on the presence/absence of a proven history of CHF and their pharmacotherapy (Table 1). Dogs with MMVD and CHF receiving ‘standard therapy’ (furosemide, pimobendan, and ACEI) were included in the CHF group. An ACEI (enalapril or benazepril) was required to have been used for greater than one day for dogs to be enrolled in the study. Dogs with MMVD and CHF, receiving ‘standard therapy’ (ACEI, furosemide, and pimobendan) and spironolactone, were included in the Spiro group. Dogs with MMVD without CHF, that were receiving an ACEI, were placed in the no CHF group. The authors prospectively collected the data from all recruited and enrolled dogs, and then allocated them to their respective treatment groups. The
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investigators did not impose treatment regimens, rather accepted or rejected cases from the study, based in part on their therapies. Concurrent medications (cardiac and non-cardiac), other than ARB, were allowed. Dogs with controlled systemic hypertension or endocrine disease were permitted. Patients were excluded if they did not fit the criteria of one of the three groups or if their urine sample was not handled per the study protocol. The Institutional Animal Care and Use Committees approved this study at both institutions.
normal, >5-year-old dogs (mean UAldo:C of 0.49 mg/g, 0.27).e Only 1 of these 55 dogs (a dog in the <6-year-old group) had a UAldo:C greater than 1.0 mg/g. From these historical data, it appears that the UAldo:C usually does not exceed 1.0 mg/g, and the UAldo:C does not appear to change significantly with age in normal dogs. The mean þ 2 SD of the UAldo:C of the older dogs from Colorado State University was 1.0 mg/g and this value was used to determine our cut-off definition for ABT (UAldo:C > 1.0 ug/g).
Urine aldosterone to creatinine ratio (UAldo:C)
Statistical analysis
About 2e5 mL of a free-catch urine sample was collected from each dog, immediately refrigerated and then frozen at 70 C, within 24 h of collection. Samples were submitted for determination of UAldo:C. If blood work was deemed necessary by the primary clinician, as part of the dog’s medical and treatment plan, then a sample was taken for serum biochemical analysis. The blood samples were taken on the same day as the urine collection and were obtained via venipuncture (jugular, cephalic, or saphenous) with the dog gently restrained in a sitting or lateral position. The timing of urine collection was not standardized for these clinical patients, presenting at various times of the day to both the cardiology and emergency services. A radioimmunoassay (RIA) that has been validated in dogsc was used to measure urine aldosterone concentration. Urine creatinine concentration was measured via a standard colorimetric assay. For all samples, these two components of the UAldo:C were performed by a veterinary diagnostic laboratory.d The same RIA assay was used for all analyses and the assay performed per the manufacturer’s directions, as described elsewhere [28]. Briefly, this assay measures free aldosterone and one of its two major metabolites, aldosterone b-glucuronide (after acid hydrolysis to aldosterone).
Definition of ABT The normal (baseline) UAldo:C has been studied (using an RIAc to measure urine aldosterone) in 34 healthy, <6-year-old laboratory dogs (mean UAldo:C of 0.40 0.21 mg/g) and 21 client-owned,
c Coat-a-count aldosterone (RIA), Siemens Medical Diagnostic Solutions, Los Angeles, CA, USA. d Michigan State University Center for Population and Animal Health, Lansing, MI, USA.
The D’AgostinoePearson omnibus procedure was used to test for normality. Data are presented as median and interquartile range (median; IQR). There were 32 dogs receiving an ACEI without spironolactone (CHF, no CHF groups) included in the analysis for ABT. The occurrence of ABT is presented as a percentage. The Spearman test was used to evaluate the relationship between UAldo:C ratio vs. eight variables (age, serum Kþ concentration, serum creatinine concentration, ACEI therapy duration and dosage, furosemide therapy duration and dosage, and urine sample storage time). All 32 dogs receiving an ACEI were included in this analysis. Sample storage time was defined as the time from collection to analysis. Univariate logistic regression was used to look at the relationship between ABT (yes/no, using the definition of UAldo:C > 1.0 mg/g) and each of the eight variables above for those same 32 dogs. The BenjaminieHochberg procedure was used to adjust pvalues for multiple testing. The mean age, body weight, UAldo:C, and ACEI dosages and durations were compared between the three groups (CHF, no CHF, and Spiro) using the KruskaleWallace test with Dunn’s adjustment for multiple comparisons. The ManneWhitney U test was used to compare the furosemide dosages and durations between the CHF and Spiro groups. The ManneWhiney U test was also used to compare ACEI type (enalapril vs. benazepril) and UAldo:C for dogs in the CHF and no CHF groups. The Fisher’s exact test was used to determine if there was a relationship between ABT and presence of CHF. The criteria for statistical significance was set to a ¼ 0.05. Analyses were performed using the
e Ames MK, Atkins CE, Webb K. The urine aldosterone to creatinine ratio (UALDO:C) determined by radioimmunoassay (RIA) in normal dogs greater than 5 years of age. J Vet Intern Med 2015; 29: 1148 (abstract).
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ACEI, furosemide, and spironolactone: dosage and duration The number of dogs receiving each type of ACEI (enalapril or benazepril) in the CHF, and no CHF groups and the average dosages are shown in Fig. 1. The median (IQR) durations of ACEI administration for dogs in the CHF, no CHF, and Spiro groups were 86 (12e233), 297 (15e713), and 787 (164e1,661) days, respectively. Three of the 39 (7.7%) had been receiving an ACEI for less than one week. There were no differences in ACEI dosages between the three groups (p¼0.8). The median (IQR) dosages of furosemide for dogs in the CHF and Spiro groups were 3.7 (1.8e4.2) and 3.4 (1.9e6.7) mg/kg/day and the median (IQR) durations of furosemide administration were 28 (7e110) and 229 (91e792) days, respectively. Both the mean dosage and duration of furosemide therapy were significantly greater in the Spiro group (p¼0.0001 and p¼0.02, respectively). Within the CHF group, 6 dogs had received furosemide for <2 weeks and 16 dogs had received furosemide for >2 weeks. Dogs in the Spiro group received a dosage of spironolactone (median [IQR]) of 1.7 (1.0e1.8) mg/kg/day. All dogs
B F H
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Forty-one dogs were enrolled into this study and 39 dogs were included, as they fit the criteria for one of the groups described in Table 1. Twenty-nine of these 39 dogs had a serum biochemistry performed on the same day as their urine sample collection. The CHF group was made up of 22 dogs with both acute (<2 weeks of furosemide therapy; n ¼ 10) and chronic (>2 weeks of furosemide therapy; n ¼ 12) CHF. The no CHF group was made up of 10 dogs, all but one of which was placed in ACVIM stage B2 MMVD. One dog, in stage B1 MMVD, was on amlodipine and an ACEI as chronic therapy for systemic hypertension. There were seven dogs in the Spiro group. There were no differences in age or body weight between the three groups (p¼0.64 and p¼0.28, respectively).
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Aldosterone breakthrough in dogs
Figure 1 Angiotensin converting enzyme inhibitor (ACEI) type and dosage shown as a scatter dot plot (median and interquartile range) in dogs with myxomatous mitral valve disease (MMVD). CHF B, 4 dogs with congestive heart failure (CHF), receiving benazepril as part of standard CHF therapy (ACEI, furosemide, and pimobendan); CHF E, 18 dogs with CHF, receiving enalapril, as part of standard CHF therapy; no CHF B, 4 dogs with MMVD, without CHF, receiving benazepril; no CHF E, 6 dogs with MMVD, without CHF, receiving enalapril. There were no significant differences between these groups. Red dots indicate dogs with UAldo:C > 1.0 mg/g (ABT).
receiving spironolactone had received it for more than one week.
Urine aldosterone to creatinine ratio Urine samples from the 39 dogs were submitted for analysis of UAldo:C. The majority of samples were collected between the hours of 9 am and 5 pm. The UAldo:C results from the three groups are shown in Fig. 2. The median (IQR) UAldo:C results in the Spiro group were 2.3 (1.3e5.7) mg/g. None of the eight variables (age, serum Kþ concentration, serum creatinine concentration, ACEI duration and dosage, furosemide duration and dosage, and urine sample storage time) were significantly correlated with UAldo:C (p-values all 0.49). The UAldo:C for dogs with MMVD receiving spironolactone (Spiro group; n ¼ 7) was significantly greater than that for dogs with MMVD and CHF, not receiving spironolactone (CHF group, p<0.05) and dogs with MMVD, not in CHF (no CHF group, p<0.05). There was no difference in UAldo:C between the CHF and no CHF groups (p>0.05).
ABT and RAAS activation f g
SAS, version 9.4, SAS Institute Inc, Cary, North Carolina, USA. GraphPad Prism v6.0 La Jolla, CA, USA.
The percentages of ABT in the CHF and no CHF groups were 32% and 30% respectively (Table 2 and
Please cite this article in press as: Ames MK, et al., Aldosterone breakthrough in dogs with naturally occurring myxomatous mitral valve disease, Journal of Veterinary Cardiology (2017), http://dx.doi.org/10.1016/j.jvc.2017.03.001
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CHF groups, when the enalapril dosage was compared between dogs with ABT and those without ABT, there was no difference (p¼0.23, Fig. 3).
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Figure 2 Urine aldosterone to creatinine ratio (UAldo:C) as a scatter dot plot (median and interquartile range) in dogs with myxomatous mitral valve disease (MMVD), with and without congestive heart failure (CHF). Dogs receiving spironolactone (Spiro), in addition to standard therapy (furosemide, pimobendan, and an ACEI), demonstrated significantly higher UAldo:C than dogs in the other groups. Individual dogs experiencing aldosterone breakthrough (ABT) were 7 of 22 (CHF group, receiving standard therapy) and 3 of 10 (no CHF group, receiving ACEI). Six of 7 dogs in the Spiro group (receiving standard therapy plus spironolactone) had a UAldo:C > 1.0 mg/g. Red line denotes upper limit of normal UAldo:C (>1.0 mg/g).
Fig. 2). Within the CHF group, the percentage of ABT in dogs with subacute (<2 weeks of furosemide therapy) and chronic (>2 weeks of furosemide therapy) CHF was 50% and 25%, respectively. Based on univariate regression analysis, none of the eight variables (age, serum Kþ concentration, serum creatinine concentration, ACEI duration and dosage, furosemide duration and dosage, and urine sample storage time) were predictive of ABT (p-values all 0.63). Similarly, in the CHF and no
From these results, it appears that ABT is a common occurrence in dogs with naturally occurring MMVD, being treated with ACEI. Aldosterone break through occurred in 32% in dogs with CHF and 30% in dogs that were not yet in CHF. The definition of ABT used in this study is stringent, as compared to human medical definitions of ABT, which often only require that the value of blood aldosterone be either greater than the mean of a normal population, greater than the upper limit of a reference interval for a normal population, or greater than an individual’s baseline value. Overall, it appears that approximately 30% of dogs in this study had inadequate RAAS blockade. No correlation was found between ACEI dosage and therapy duration and either the UAldo:C or the presence of ABT. In regards to ACEI dosage, the results of this study are similar to those of small studies in people with CHF [22] and dogs with experimental RAAS activation [28], which have not shown that higher dosages of ACEI prevent ABT. It is, however, noteworthy that, although there were dogs receiving enalapril at dosages of less than 0.5mg/kg/day that did not experience ABT, no dog receiving enalapril at a dosage greater than 1mg/ kg/day experienced ABT (Fig. 3). The relationship between duration of ACEI therapy and ABT has not been well studied in either man or dog. The dogs in this study had been receiving an ACEI for varying durations, including three dogs in the CHF and no CHF groups that had received less than one week’s therapy. Of interest, 1 of 3 dogs (33%) demonstrated ABT, a percentage similar to that of dogs
Table 2 The mean UAldo:C for each myxomatous mitral valve disease group is presented with the incidence of aldosterone breakthrough. Parameter MMVD: ACVIM stage UAldo:C (mg/g) median (IQR) UAldo:C > 1.0 mg/g Percent ABT
CHF group
No CHF group
Spiro group
C 0.44 (0.27e1.65)* 7/22 31.8
B1 (1) and B2 (9) 0.63 (0.20e1.35)y 3/10 30.0
C and D 2.54 (0.63e4.13)*y 6/7 N/A
ABT, aldosterone breakthrough; ACEI, angiotensin converting enzyme inhibitor; CHF, congestive heart failure; MMVD, myxomatous mitral valve disease; N/A, not applicable; Spiro, spironolactone; UAldo:C, urine aldosterone to creatinine ratio (normal <1 mg/g); IQR, interquartile range. MMVD stage is based on the ACVIM consensus statement. A single dog with controlled systemic hypertension and stage B1 MMVD receiving and ACEI was included. Please see text for detail on group definitions.
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Figure 3 Scatter dot plot (median and interquartile range) of angiotensin converting enzyme inhibitor (enalapril) dosage and aldosterone breakthrough (ABT) status in 24 dogs receiving enalapril for the management of myxomatous mitral valvular disease with (CHF group) and without (no CHF group) congestive heart failure. None of these 24 dogs received spironolactone. The dogs are divided into 2 groupsdthose that experienced aldosterone breakthrough (ABT) and those that did not (no ABT). These enalapril dosages were not significantly different.
receiving chronic therapy. As it may take weeks for the maximal beneficial effects of ACEI to be realized [32,33], elevated urinary aldosterone levels during the first month of therapy may be temporary. It can be argued, however, that incomplete RAAS blockade for the first weeks/months of therapy is suboptimal, and that its recognition may be clinically useful. There does not appear to be a relationship between the presence of ABT and the presence of CHF. Additionally, ABT may occur both before and after the onset of CHF. Finally, there was no correlation between either UAldo:C or the presence of ABT and age, serum Kþ concentration, serum creatinine concentration, duration and dosage of furosemide therapy, or urine sample storage time. Once spironolactone is administered, the UAldo:C is difficult to interpret as blockade of the mineralocorticoid receptor leads to an increase in circulating and urine aldosterone concentrations, presumably due to receptor occupation and the failure of an aldosterone-generated negative feedback loop to lower renin secretion from the juxtaglomerular apparatus [34]. The consequences of high levels of free, circulating aldosterone are still unknown in such patients, but the mineralocorticoid receptor-mediated effects of aldosterone are inhibited [35,36]. The nonereceptormediated effects of aldosterone, however, remain under investigation. Based on the mortality benefit
attributed to spironolactone in people with heart failure and low ejection fraction [37e39] and in dogs with MMVD [40] that are treated with spironolactone, the pathophysiologic impact of high levels of aldosterone with concurrent mineralocorticoid receptor blockade, do not appear to negatively impact outcome on a population basis. The study presented here was designed to prove the existence and determine the rate of occurrence of ABT in canine veterinary patients, but not designed to evaluate the impact of ABT on survival. However, the aforementioned study in dogs with heart failure due to MMVD has already demonstrated a survival benefit, when mineralocorticoid receptor blockade/blocker (MRB) was added to standard heart failure therapy (including an ACEI) [40]. There is no consensus regarding the definition of ABT in people, and clinical definitions are usually based on spot blood aldosterone concentrations, using either a baseline definition (a patient’s blood aldosterone concentration increases despite ACEI/ ARB therapy) or a cut-off definition (while receiving an ACEI/ARB, a patient’s blood aldosterone concentration is greater than the mean or mean þ 2 standard deviations of a normal population). A baseline definition can be used when pre-treatment samples are available, allowing ‘individualization’ and monitoring of ‘anti-RAAS’ therapy in a way that is independent of the aldosterone assay used. A cut-off definition is the only option; however, when baseline data are unavailable (i.e. the patient is already on ACEI or ARB therapy). Furthermore, while controversy exists regarding the use of ACEI in MMVD prior to the onset of CHF, pre-treatment assessment of UAldo:C, would help to clarify the potential benefit of anti-RAAS therapy at this stage. In human CHF patients, treatment with the MRBs, spironolactone and eplerenone, is associated with an improved prognosis, on a population basis. The mechanism is thought to be through combatting ABT [37e39]. Increased aldosterone levels in heart disease/ failure results not only from increased secretion (RAAS stimulation) but also through decreased neurohormone metabolism and clearance (due to decreased hepatic and renal perfusion) [41,42]. Circulating ACE activity is reduced by label dosages of the ACEI, benazepril, and enalapril, in both healthy dogs receiving furosemide as a RAAS stimulant, and in dogs with naturally occurring MMVD and CHF [29,30,43,44]. As ABT has been documented to occur despite the reduction in ACE activity that attends ACEI administration, mechanisms other than failure of ACE-inhibition likely
Please cite this article in press as: Ames MK, et al., Aldosterone breakthrough in dogs with naturally occurring myxomatous mitral valve disease, Journal of Veterinary Cardiology (2017), http://dx.doi.org/10.1016/j.jvc.2017.03.001
8 occur. NoneACE-dependent pathways for angiotensin II production, other stimuli for aldosterone release, and decreased aldosterone metabolism and clearance have all been hypothesized as mechanisms for ABT [16,18]. Along with angiotensin II, blood potassium concentration is a key regulator of aldosterone secretion [13]. An elevated potassium concentration, secondary to ACEI or other cause, may contribute to ABT. This role of this hypothesis in ABT in the studied population, however, is not supported by our data. Another possible mechanism for ABT is the excessive production of renin, associated with the use of ACEI, wherein excess renin secretion ‘overwhelms’ the actions of the ACEI, allowing aldosterone production [18]. In none of the dogs, described herein, was plasma renin concentration measured and it is therefore unknown if renin upregulation contributed to the observed ABT. Three additional possibilities for ABT in clinical patients may be related to the therapy of heart failure. The first is potentiation of RAAS activation by diuretics, salt restriction, and vasodilators, which are commonly used in the pharmacotherapy of heart failure [44e47]. Second, activation of the sympathetic nervous system with heart failure may be potentiated by the use of certain cardiac medications, as has been documented with the administration of amlodipine in humans with systemic hypertension [48]. Finally, compliance is a major problem in patients, both human and animal, and might be expected to worsen with length of time under treatment, due to cost, patient or owner fatigue, and drug side-effects. Failure to take/give the ACEI would be associated with ACEI ‘failing’ to suppress aldosterone, mimicking breakthrough. These proposed explanations are not mutually exclusive. This study has several limitations related to its small sample size. First, it was not designed to evaluate survival and there is only minimal evidence that ABT influences survival in dogs with naturally occurring heart disease.h There is, however, evidence supporting an influence of elevated aldosterone levels and/or ABT on cardiorenal outcomes in people [49,50]. An antecedent study in dogs, however, has shown that an MRB (spironolactone), added to ACEI in dogs with MMVD, confers an added benefit in survival [40]. This historical study, along with the present study,
h Hezzell MJ, Boswood A, Elliott J. Relationships between serum and urinary aldosterone, ventricular remodeling and outcome in dogs with mitral valve disease. J Vet Intern Med 2010; 24(3):672 (abstract).
M.K. Ames et al. supports the existence and importance of ABT in dogs and suggest a potential benefit with additional RAAS blockade in the form of an MRB. Second, a firm conclusion cannot be made regarding correlation between the UAldo:C or ABT and the eight variables studied herein. Therefore, the mechanism(s) of ABT remain unknown. Additionally, the absence of measurement of RAAS hormonal elements, other than ACE activity and UAldo:C, make answering some mechanistic questions impossible. Despite these limitations, our results show that ABT occurs in approximately 30% of dogs receiving an ACEI for MMVD, mirroring the findings in humans with cardiovascular disease, and those in our experimental model of ABT. The mechanism of ABT is likely multifactorial and variable between individuals. Further study should be undertaken to determine if ABT is correlated to worsened prognosis, to evaluate its permanence and consistency in a given patient, and to elucidate its mechanism(s). Finally, a priori identification of patient subpopulations experiencing or expected to experience ABT may help guide future study design and clinical decision-making, as whether to initiate MRB therapy in an individual patient.
Conflicts of Interest The authors do not have any conflicts of interest to disclose.
Acknowledgments This study was supported by the Jane Lewis-Seaks Endowment and Ceva Sante Animale. The authors would like to thank Allison Klein, Petra Vasilik, and Susan Beyerlein for their technical assistance.
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Please cite this article in press as: Ames MK, et al., Aldosterone breakthrough in dogs with naturally occurring myxomatous mitral valve disease, Journal of Veterinary Cardiology (2017), http://dx.doi.org/10.1016/j.jvc.2017.03.001