Effect of furosemide on comprehensive renin-angiotensin-aldosterone system activity of Thoroughbred horses.

BACKGROUND: Furosemide, a commonly used diuretic, activates the renin-angiotensin-aldosterone system (RAAS) in other species. Little is known about RAAS peptide activation in horses. HYPOTHESIS/OBJECTIVES: To evaluate equilibrium analysis as a practical method for RAAS quantification in horses and describe the RAAS response to a single dose of furosemide. We hypothesize that furosemide would cause transient increase in RAAS peptides in horses. ANIMALS: 14 healthy adult thoroughbreds from a university teaching herd. METHODS: Horses received either furosemide (1 mg/kg IV) or saline IV in a crossover study design. Protease-inhibited samples were compared with equilibrium analysis samples with Deming regression analysis. Renin-angiotensin-aldosterone system hormones were evaluated at 0, 0.25, 0.5, 4, and 24 hours postadministration, via equilibrium analysis. Values were compared with a mixed effects model. RESULTS: Correlation between protease inhibition and equilibrium analysis was high for angiotensin I peptide (AngI) and angiotensin II peptide (AngII) (r = .92 and .95, respectively). Baseline RAAS peptide concentrations were below the limit of detection except AngII (median, 7.5 [range, 3.5-14.0] pmol/L). Furosemide administration resulted in an increase in AngI (8.0 [0.5-15.5] pmol/L, P = .03), AngII (33.7 [9.6-57.9] pmol/L, P = .0008), angiotensin III peptide (AngIII) (2.9 [0.9-4.9] pmol/L, P = .0005), angiotensin IV peptide (AngIV) (2.0 [0.6-3.4] pmol/L, P = .0005), and angiotensin 1-5 peptide (Ang1-5) (5.6 [1.2-5.9] pmol/L, P = .003) at 4 hours. Differences are reported as difference in the mean (95% confidence interval [CI]). CONCLUSIONS AND CLINICAL IMPORTANCE: Furosemide produced an increase in hormones associated with both the classical and alternative RAAS pathways. Serum equilibrium analysis is practical for RAAS analysis in horses.

Characterization of the circulating markers of the renin-angiotensin-aldosterone system in telmisartan- or enalapril-treated dogs with proteinuric chronic kidney disease.

BACKGROUND: Effects of the renin-angiotensin-aldosterone system (RAAS) inhibitors enalapril and telmisartan on circulating RAAS in dogs with proteinuric chronic kidney disease (pCKD) are undescribed. OBJECTIVES: To characterize the RAAS in untreated dogs with pCKD compared to healthy, life-stage- and sex-matched controls, and in dogs with pCKD after 30 days of treatment with enalapril or telmisartan. ANIMALS: Dogs with pCKD (n = 36) and healthy controls (n = 20). METHODS: Retrospective study of banked samples and previously collected data. Day 0 serum equilibrium concentrations of angiotensin I, II, III, IV, 1-5, and 1-7, and aldosterone, and urinary aldosterone-to-creatinine ratio (UACR) from pCKD dogs were compared to values on day 30 of treatment with enalapril (0.5 mg/kg PO q12) or telmisartan (1 mg/kg PO q24h) and to those of healthy dogs. Data were analyzed using linear mixed models. RESULTS: Compared with healthy dogs, pCKD dogs had significantly higher Ang I, III, 1-5, and 1-7 concentrations, and UACR. Relative to pretreatment values, day 30 Ang II concentrations were significantly increased and decreased in telmisartan- and enalapril-treated pCKD dogs, respectively (both P < .001). Mean (95% confidence interval) percentage change from pretreatment value in serum Ang 1-7 concentration was significantly greater in telmisartan- (753% [489%-1134%]) versus enalapril-treated (149% [69%-268%]) dogs (P < .001). Serum aldosterone decreased with treatment (P = .02 for enalapril, P < .001 for telmisartan), with no difference between groups at day 30. CONCLUSIONS AND CLINICAL IMPORTANCE: Circulating RAAS activity is higher in dogs with pCKD. Compared with enalapril, treatment with telmisartan caused significantly greater increases in the presumed beneficial peptide Ang 1-7.

Case report: Chylopericardium secondary to dialysis catheter related jugular venous thrombosis in two dogs receiving long-term hemodialysis.

Chylopericardium is a rare entity in veterinary medicine. In this report we document the development of chylopericardium in two dogs undergoing chronic hemodialysis. An 11-year-old female spayed Labrador retriever (Case 1) presented with acute coughing and lethargy 2 months following initial dialysis catheter placement and initiation of dialysis therapy for severe azotemia. Echocardiography demonstrated severe pericardial effusion and cardiac tamponade. Pericardial fluid analysis was consistent with chylous effusion. The dog underwent a subtotal pericardiectomy with thoracic duct ligation, and a PleuralPort™ was placed. The patient continued to receive outpatient hemodialysis therapy after pericardiectomy for several months until she died acutely at home. A 4-year-old male neutered Doberman (Case 2) was being treated for 2 months with outpatient hemodialysis for management of chronic kidney disease. On presentation for the 17th hemodialysis treatment, the patient had increased respiratory rate. Echocardiography demonstrated pleural and pericardial effusions, and fluid analysis in both cavities was consistent with chylous effusion. Use of tissue plasminogen activator (TPA), clot removal and replacement of the catheter was attempted; however pleural and pericardial effusion continued. The patient was euthanized after 25 hemodialysis sessions as owners elected not to pursue more procedures. In both cases, the cause of the chylopericardium was suspected to be secondary to catheter-associated thrombosis and/or stenosis based on multiple imaging modalities. Despite use of rivaroxaban and clopidogrel concurrently in each case, the chylous effusion persisted. This case report describes clinical details of a rare complication of long-term indwelling dialysis catheters in two dogs.

Beyond Angiotensin-Converting Enzyme Inhibitors: Modulation of the Renin-Angiotensin-Aldosterone System to Delay or Manage Congestive Heart Failure.

The renin-angiotensin-aldosterone system (RAAS) consists of bioactive angiotensin peptides, enzymatic pathways, receptors, and the steroid hormone aldosterone. The RAAS regulates blood pressure, sodium, and electrolyte homeostasis and mediates pathologic disease processes. Within this system is an alternative arm that counterbalances the vasoconstrictive, sodium and water retentive, and pro-fibrotic and inflammatory effects of the classical arm. Improved biochemical methodologies in RAAS quantification are elucidating how this complex system changes in health and disease. Future treatments for cardiovascular and kidney disease will likely involve a more nuanced manipulation of this system rather than simple blockade.

The classical and alternative circulating renin-angiotensin system in normal dogs and dogs with stage B1 and B2 myxomatous mitral valve disease.

BACKGROUND: The behavior of the comprehensive circulating renin-angiotensin system (RAS) in dogs with myxomatous mitral valve disease (MMVD) before to the onset of congestive heart failure remains largely unexplored. HYPOTHESIS/OBJECTIVES: The classical and alternative RAS activity and aldosterone concentrations will be significantly higher in dogs with American College of Veterinary Internal Medicine (ACVIM) stage B2 MMVD compared to normal dogs and dogs with ACVIM stage B1 MMVD. ANIMALS: One-hundred seventeen client-owned dogs (normal = 60; B1 = 31; B2 = 26). METHODS: Prospective observational study. Angiotensin peptides (AP) and aldosterone concentrations were measured using liquid chromatography and mass spectrometry. Angiotensin converting enzymes 1 and 2 (ACE, ACE2) and renin activity surrogates were calculated from AP concentrations. Equilibrium dialysis (ED) and immediate protease inhibition (PI) methods of AP quantification were compared in 14 healthy dogs. RESULTS: Core RAS activity and aldosterone concentrations did not differ among the 3 groups. However, the balance between the alternative and classical RAS differed, with dogs with stage B2 MMVD having significantly higher ACE2 activity surrogate (ACE2surr ) when compared to normal dogs (adjusted P = .02; ratio of medians for ACE2surr [B2:normal], 1.89; 95% confidence interval [CI]: 1.4-2.6). The ED and PI methods of AP quantification were highly correlated (AngI, r = .9, P < .0001; AngII, r = .8, P = .001). CONCLUSIONS AND CLINICAL IMPORTANCE: Circulating alternative RAS activity, specifically the surrogate measure of ACE2 activity, was increased in dogs with stage B2 MMVD as compared to normal dogs. Equilibrium dialysis results are analogous to immediate protease inhibition in dogs.

Prevalence of aldosterone breakthrough in dogs receiving renin-angiotensin system inhibitors for proteinuric chronic kidney disease.

BACKGROUND: The influence of aldosterone breakthrough (ABT) on proteinuria reduction during renin-angiotensin system (RAS) inhibition for spontaneous proteinuric chronic kidney disease (CKDP ) has not been determined in dogs. OBJECTIVES: Determine whether ABT occurs in dogs with CKDP and if it is associated with decreased efficacy in proteinuria reduction during RAS inhibitor treatment. ANIMALS: Fifty-six client-owned dogs with CKDP and 31 healthy client-owned dogs. METHODS: Prospective, multicenter, open-label clinical trial. Dogs were treated with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker alone or in combination at the attending clinician's discretion and evaluated at 5 time points over 6 months. Healthy dogs were used to determine the urine aldosterone-to-creatinine ratio cutoff that defined ABT. The relationship of ABT (present at ≥50% of visits) and proteinuria outcome (≥50% reduction in urine protein-to-creatinine ratio from baseline at ≥50% of subsequent visits) was evaluated. Mixed effects logistic regression was used to evaluate the relationship between clinical variables and outcomes (either successful proteinuria reduction or ABT). RESULTS: Thirty-six percent (20/56) of dogs had successful proteinuria reduction. Between 34% and 59% of dogs had ABT, depending on the definition used. Aldosterone breakthrough was not associated with proteinuria outcome. Longer duration in the study was associated with greater likelihood of successful proteinuria reduction (P = .002; odds ratio, 1.6; 95% confidence interval [CI], 1.2-2.2). CONCLUSIONS AND CLINICAL IMPORTANCE: Aldosterone breakthrough was common in dogs receiving RAS inhibitors for CKDp but was not associated with proteinuria outcome.

Treatment of dogs with severe heartworm disease.

Fortunately, the majority of dogs diagnosed with heartworm infection are asymptomatic (or have only mild symptoms such as intermittent cough) and go through adulticide therapy without complication. Complications occurring with heartworm infection and during its treatment most often directly reflect the pulmonary vascular and parenchymal injury inflicted by Dirofilaria immitis. Clinical signs may include exercise intolerance, frequent cough, hemoptysis, tachypnea, and dyspnea. Severe manifestations such as heart failure and caval syndrome may prove fatal. Acute hypersensitivity reactions after initiation of macrocyclic lactone preventive therapy in microfilaremic dogs or after melarsomine injection during adulticide therapy do occur, but are uncommon. This article reviews complications associated with heartworm infection.

Non-Arsenical heartworm adulticidal therapy using topical moxidectin-imidacloprid and doxycycline: A prospective case series.

This prospective case series evaluated the adulticidal efficacy of topical 10 % moxidectin/2.5 % imidacloprid (M/I; Advantage Multi®, Bayer, Shawnee Mission, KS, USA) and doxycycline in dogs with naturally occurring heartworm infection (HWI). Twenty-two dogs with HWI whose owners declined melarsomine were treated with M/I at the preventive dosage twice monthly for 90 days then monthly thereafter and doxycycline (median [interquartile range; IQR] dosage 12.6 [12.0-16.1] mg/kg/day) for the first 15 days. Although strict activity restriction was not imposed, owners were asked to prevent their dogs from exercising strenuously. This protocol was referred to as the MOXY protocol. Antigen testing was performed every 30-60 days, until dogs had 'no antigen detected' (NAD). Twenty-one of the 22 dogs ultimately converted to NAD by 434 days (median [IQR]), 234 (179-303). One dog remained positive 701 days after MOXY initiation and was considered a treatment failure. All sera which converted to NAD on HW antigen testing were retested after heat-treatment. Twelve dogs had NAD on the heat-treated test on the same day as having their first NAD on the conventional test. Six of 9 dogs testing positive after heat-treatment were retested and all 6 had NAD on a heat-treated test within 2-3 months. Microfilaremia was cleared in all 8 dogs re-tested. Four dogs required treatment for cough, thought due to heartworm (HW) death, an average of 89 days after initiation of MOXY. This cough was most likely due to pneumonitis with heartworm-pulmonary thromboembolism. One dog required hospitalization for 24 -h and recovered fully with corticosteroid therapy and supportive care and 2 dogs were treated in an outpatient fashion with steroids. The MOXY protocol was tolerated and 96 % (21/22) of dogs converted to NAD, though 2 dogs required greater than 1 year to achieve this result. Nonaresenical-adulticide therapy may result in pneumonitis and heartworm-pulmonary thromboembolism at unpredictable times, potentially months after initiation of macrocyclic lactone therapy and exercise restriction should be considered when using a nonarsenical protocol. Although not currently recommended by the American Heartworm Society (AHS), non-arsenical strategies are in use and the goal of this study was to evaluate the efficacy, duration of therapy, and safety of an accelerated dosing protocol of M/I with doxycycline.

The renin-angiotensin-aldosterone system and its suppression.

Chronic activation of the renin-angiotensin-aldosterone system (RAAS) promotes and perpetuates the syndromes of congestive heart failure, systemic hypertension, and chronic kidney disease. Excessive circulating and tissue angiotensin II (AngII) and aldosterone levels lead to a pro-fibrotic, -inflammatory, and -hypertrophic milieu that causes remodeling and dysfunction in cardiovascular and renal tissues. Understanding of the role of the RAAS in this abnormal pathologic remodeling has grown over the past few decades and numerous medical therapies aimed at suppressing the RAAS have been developed. Despite this, morbidity from these diseases remains high. Continued investigation into the complexities of the RAAS should help clinicians modulate (suppress or enhance) components of this system and improve quality of life and survival. This review focuses on updates in our understanding of the RAAS and the pathophysiology of AngII and aldosterone excess, reviewing what is known about its suppression in cardiovascular and renal diseases, especially in the cat and dog.

Evaluation of subacute change in RAAS activity (as indicated by urinary aldosterone:creatinine, after pharmacologic provocation) and the response to ACE inhibition.

OBJECTIVE: The objective of this study was to evaluate subacute changes in renin-angiotensin-aldosterone system (RAAS) activity during angiotensin-converting enzyme inhibitor (ACEI) therapy in dogs with experimental RAAS activation. METHODS: Analysis of data (urine aldosterone:creatinine ratio (UAldo:C) and serum angiotensin-converting enzyme activity), in 31 healthy dogs with furosemide or amlodipine-activated RAAS that received an ACEI. When furosemide or amlodipine activation of RAAS preceded ACEI administration, incomplete RAAS blockade (IRB) was defined as a UAldo:C greater than (a) the dog's 'activated' baseline value or (b) a population-derived cut-off value (mean + 2 SD (>1.0 µg/g) of pretreatment UAldo:C from our population of research dogs). In studies where RAAS activation occurred concurrently with ACEIs, IRB was defined as (a) a UAldo:C greater than either twofold the dog's prestimulation baseline value or (b) 1.0 µg/g. Dogs were followed for 7-17 days. RESULTS: Serum angiotensin-converting enzyme activity was measured in 19 dogs and was significantly reduced (P<0.0001) after ACEI administration. The overall incidence of IRB, when RAAS activation preceded ACEI administration, was 33% and 8% for definitions (a) and (b), respectively. The overall incidence of IRB, when ACEIs were concurrent with RAAS activation, was 65% and 61% for definitions (a) and (b), respectively. CONCLUSION: Increases in UAldo:C, despite ACEI administration, is evidence of IRB in this subacute model of experimental RAAS activation and suppression.

Effects of high doses of enalapril and benazepril on the pharmacologically activated renin-angiotensin-aldosterone system in clinically normal dogs.

OBJECTIVE: To determine whether high doses of enalapril and benazepril would be more effective than standard doses of these drugs in suppressing the furosemide-activated renin-angiotensin-aldosterone system (RAAS). ANIMALS: 6 healthy Beagles. PROCEDURES: 2 experiments were conducted; each lasted 10 days, separated by a 2-week washout period. In experiment 1, all dogs received furosemide (2 mg/kg, PO, q 12 h) and enalapril (1 mg/kg, PO, q 12 h) for 8 days (days 0 through 7). In experiment 2, dogs received furosemide (2 mg/kg, PO, q 12 h) and benazepril (1 mg/kg, PO, q 12 h) for 8 days. Effects on the RAAS were determined by assessing serum angiotensin-converting enzyme (ACE) activity on days -1, 3, and 7; serum aldosterone concentration on days -2, -1, 1, 3, and 7; and the urinary aldosterone-creatinine ratio (UAldo:C) in urine collected in the morning and evening of days -2, -1, 1, 3, and 7. RESULTS: High doses of enalapril and benazepril caused significant reductions in serum ACE activity on all days but were not more effective than standard doses used in other studies. Mean UAldo:C remained significantly higher on days 2 through 7, compared with baseline values. Serum aldosterone concentration also increased after drug administration, which mirrored changes in the UAldo:C. CONCLUSIONS AND CLINICAL RELEVANCE: In this study, administration of high doses of enalapril and benazepril significantly inhibited ACE activity, yet did not prevent increases in mean urine and serum aldosterone concentrations resulting from furosemide activation of RAAS. This suggested that aldosterone breakthrough from ACE inhibition was a dose-independent effect of ACE inhibitors.

Case-control study of the effects of pimobendan on survival time in cats with hypertrophic cardiomyopathy and congestive heart failure.

OBJECTIVE: To assess survival time and adverse events related to the administration of pimobendan to cats with congestive heart failure (CHF) secondary to hypertrophic cardiomyopathy (HCM) or hypertrophic obstructive cardiomyopathy (HOCM). DESIGN: Retrospective case-control study. ANIMALS: 27 cats receiving treatment with pimobendan and 27 cats receiving treatment without pimobendan. PROCEDURES: Medical records between 2003 and 2013 were reviewed. All cats with HCM or HOCM treated with a regimen that included pimobendan (case cats) were identified. Control cats (cats with CHF treated during the same period with a regimen that did not include pimobendan) were selected by matching to case cats on the basis of age, sex, body weight, type of cardiomyopathy, and manifestation of CHF. Data collected included signalment, physical examination findings, echocardiographic data, serum biochemical values, and survival time from initial diagnosis of CHF. Kaplan-Meier survival curves were constructed and compared by means of a log rank test. RESULTS: Cats receiving pimobendan had a significant benefit in survival time. Median survival time of case cats receiving pimobendan was 626 days, whereas median survival time for control cats not receiving pimobendan was 103 days. No significant differences were detected for any other variable. CONCLUSIONS AND CLINICAL RELEVANCE: The addition of pimobendan to traditional treatment for CHF may provide a substantial clinical benefit in survival time for HCM-affected cats with CHF and possibly HOCM-affected cats with CHF.

Primary cardiac spindle cell tumor in a dog.

An adult Labrador retriever dog was presented with respiratory signs and heart murmur. Echocardiography and thoracic radiographs revealed a heart base mass infiltrating the left atrial wall. Microscopically, neoplastic tissues consisted of spindle cells and abundant extracellular matrix. Based on histochemical stain and immunohistochemistry, a diagnosis of primary cardiac sarcoma was made.

Tumeur cardiaque primaire à cellules fusiformes chez un chien. Un chien Labrador Retriever adulte a été présenté avec des signes respiratoires et un souffle cardiaque. L'échocardiographie et les radiographies thoraciques ont révélé une masse à la base du cœur infiltrant la paroi atriale gauche. Au microscope, les tissus néoplasiques se composaient de cellules fusiformes et d'une matrice extracellulaire abondante. En se fondant sur la coloration histochimique et l'immunohistochimie, un diagnostic de sarcome cardiaque primaire a été posé.(Traduit par Isabelle Vallières).

Effect of furosemide and high-dosage pimobendan administration on the renin-angiotensin-aldosterone system in dogs.

OBJECTIVE: To determine whether a high dosage of pimobendan, when administered concurrently with moderate-dosage furosemide to healthy dogs, would activate the renin-angiotensin-aldosterone system (RAAS) more than furosemide alone. ANIMALS: 12 healthy dogs. PROCEDURES: 6 dogs received furosemide (2.0 mg/kg, PO, q 12 h) only, as an RAAS activator, for 10 days. The other 6 dogs received furosemide (2.0 mg/kg, PO, q 12 h) and pimobendan (0.6 mg/kg, PO, q 12 h) for 10 days. The effect of these drugs on the RAAS was determined by measurement of the aldosterone-to-creatinine ratio (A:C) in urine collected in the morning and evening of study days -2, -1, 1, 5, and 10. RESULTS: Although there was an increase in the urine A:C during the study period in both groups, it was significant only for dogs that received both drugs. The urine A:C only differed significantly between groups on day 1, at which time A:C was greater in the group that received both drugs. CONCLUSIONS AND CLINICAL RELEVANCE: High-dosage pimobendan administration neither substantially suppressed nor potentiated the RAAS when administered with furosemide in healthy dogs.

Successful treatment of pacemaker-induced stricture and thrombosis of the cranial vena cava in two dogs by use of anticoagulants and balloon venoplasty.

CASE DESCRIPTION: 2 castrated male Labrador Retrievers (dogs 1 and 2) were evaluated 3 to 4 years after placement of a permanent pacemaker. Dog 1 was evaluated because of a large volume of chylous pleural effusion. Dog 2 was admitted for elective replacement of a pacemaker. CLINICAL FINDINGS: Dog 1 had mild facial swelling and a rapidly recurring pleural effusion. Previously detected third-degree atrioventricular block had resolved. Cranial vena cava (CVC) syndrome secondary to pacemaker-induced thrombosis and stricture of the CVC was diagnosed on the basis of results of ultrasonography, computed tomography, and venous angiography. Dog 2 had persistent third-degree atrioventricular block. Intraluminal caval stricture and thrombosis were diagnosed at the time of pacemaker replacement. Radiographic evidence of pleural effusion consistent with CVC syndrome also was detected at that time. TREATMENT AND OUTCOME: Dog 1 improved after treatment with unfractionated heparin and a local infusion of recombinant tissue-plasminogen activator. Balloon venoplasty was performed subsequently to relieve the persistent caval stricture. In dog 2, balloon dilatation of the caval stricture was necessary to allow for placement of a new pacing lead. Long-term anticoagulant treatment was initiated in both dogs. Long-term (> 6 months) resolution of clinical signs was achieved in both dogs. CLINICAL RELEVANCE: Thrombosis and stricture of the CVC are possible complications of a permanent pacemaker in dogs. Findings suggested that balloon venoplasty and anticoagulation administration with or without thrombolytic treatment can be effective in the treatment of dogs with pacemaker-induced CVC syndrome.