• View in gallery
    Figure 1—

    Mean ± SEM number of dogs with ascites (A) and tricuspid regurgitant murmur (B) during progression of overpacinginduced heart failure in dogs receiving ramipril (0.125 mg/kg, PO, daily) or no treatment (control group) for 7 weeks (10 dogs/group). *†Significantly (P < 0.05 and P < 0.01, respectively) different from ramipril group.

  • View in gallery
    Figure 2—

    Mean ± SEM values of IVRT (A) and the mitral E wave–to–A wave ratio (B) during progression of overpacinginduced heart failure in dogs receiving ramipril (0.125 mg/kg, PO, daily; squares) or no treatment (control group; triangles) for 7 weeks (10 dogs/group). *†‡Significant (P < 0.05, P < 0.01, P < 0.001, respectively) difference between baseline (week 0) and control group. §II¶Significant (P < 0.05, P < 0.01, P < 0.001, respectively) difference between baseline (week 0) and ramipril group. R/HF = Interaction group time.

  • View in gallery
    Figure 3—

    Mean ± SEM values for RAP (A) and PAPO (B) during progression of overpacing-induced heart failure in dogs receiving ramipril (0.125 mg/kg, PO, daily; squares) or no treatment (control group; triangles) for 7 weeks (10 dogs/group). *Significant (P < 0.001) difference between baseline (week 0) and control group. †‡§Significant (P < 0.05, P < 0.01, P < 0.001, respectively) difference between baseline (week 0) and ramipril group. See Figure 2 for remainder of key.

  • View in gallery
    Figure 4—

    Iohexol plasma clearance versus urinary exogenous ClCr during progression of overpacing-induced heart failure in dogs receiving ramipril (0.125 mg/kg, PO, daily) or no treatment (control group) for 7 weeks (10 dogs/group). A—Linear correlation between plasma ClI and urinary exogenous ClCr. B—Bland-Altman plot between ClI (corrected by use of the formula of ClI by Brochner-Mortensen16 [(ClI-BM]) and ClCr indicating a mean difference of 0.7 mL/kg/min between the 2 methods; the 95% limits of agreement varied from −1.25 to 2.65 mL/kg/min. C—Mean ± SEM values for ClCr measuring the GFR during progression of heart failure. D—Mean ± SEM values for ClI-BM measuring the GFR during progression of heart failure. *Significant (P < 0.001) difference between baseline (week 0) and control group. †Significant (P < 0.001) difference between baseline (week 0) and ramipril group. Triangles = Control group. Squares = Ramipril group.

  • View in gallery
    Figure 5—

    Mean ± SEM values for PAH clearance (ClPAH) measuring RPF (A) and the filtration fraction (B) during progression of overpacing-induced heart-failure in dogs receiving ramipril (0.125 mg/kg, PO, daily; squares) or no treatment (control group; triangles) for 7 weeks (10 dogs/group). *†Significant (P < 0.05 and P < 0.01, respectively) difference between baseline (week 0) and control group. ‡§IISignificant (P < 0.05, P < 0.01, P < 0.001, respectively) difference between baseline (week 0) and ramipril group.

  • View in gallery
    Figure 6—

    Mean ± SEM values for sodium EF (EFNa; A), potassium EF (EFK; B), and the log10(Na+/K+) (C) during progression of overpacing-induced heart failure in dogs receiving ramipril (0.125 mg/kg, PO, daily; squares) or no treatment (control group; triangles) for 7 weeks (10 dogs/group). *†Significant (P < 0.05 and P < 0.01, respectively) difference between baseline (week 0) and control group. ‡§Significant (P < 0.05 and P < 0.01, respectively) difference between baseline (week 0) and ramipril group. R = Effect of ramipril. R/HF = Interaction group-time. See Figure 2 for remainder of key.

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Effects of ramipril on renal function during progressive overpacing-induced heart failure in dogs

Myrielle MathieuLaboratory of Physiology, Faculty of Medicine, Free University of Brussels, Route de Lennik 808, CPI 604, 1070 Brussels, Belgium

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Lynn RayLaboratory of Physiology, Faculty of Medicine, Free University of Brussels, Route de Lennik 808, CPI 604, 1070 Brussels, Belgium

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Anne PensisLaboratory of Physiology, Faculty of Medicine, Free University of Brussels, Route de Lennik 808, CPI 604, 1070 Brussels, Belgium

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Pascale JespersLaboratory of Physiology, Faculty of Medicine, Free University of Brussels, Route de Lennik 808, CPI 604, 1070 Brussels, Belgium

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Serge BrimioulleLaboratory of Physiology, Faculty of Medicine, Free University of Brussels, Route de Lennik 808, CPI 604, 1070 Brussels, Belgium

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Valérie LarouteUnité Mixte de Recherche 181 Physiopathologie et Toxicologie Experimentales, Institut National de la Recherche Agronomique, Ecole Nationale Vétérinaire de Toulouse, 23 Chemin des Capelles, BP 87614, 31076 Toulouse Cedex 3, France

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Abstract

Objective—To investigate the effects of preventive angiotensin converting enzyme inhibitor treatment with ramipril in dogs with progressively severe experimentally induced heart failure.

Animals—20 dogs.

Procedures—Dogs were randomly allocated to receive no treatment (control) or ramipril (0.125 mg/kg, PO, daily) for 7 weeks. Physical examination, repetitive catheterization of the right side of the heart, and echocardiography were performed before the study (day 0) and weekly for 7 weeks. Renal plasma flow (RPF) as determined by para-aminohippuric acid clearance and glomerular filtration rate (GFR) as determined by creatinine and iohexol clearances were measured on day 0 and at weeks 4 and 7.

Results—Overpacing induced a progressive increase in right atrial pressure (RAP) and pulmonary artery pressure, occluded (PAPO), with a decrease in systemic arterial pressure. There were progressive alterations of echocardiographic indices of diastolic and systolic ventricular function. The RPF and GFR decreased before cardiac output decreased, and filtration fraction increased. The logarithm of the urinary sodium–to–potassium concentration ratio (log10[Na+/K+]) decreased. Significant effects of ramipril included a delay in clinical signs of heart failure, a late decrease in RAP and PAPO, and increases in the sodium excretion fraction and log10(Na+/K+). There was a satisfactory agreement between the creatinine and iohexol clearance measurements.

Conclusions and Clinical Relevance—Results suggest that, in this rapid-evolving, dilated cardiomyopathy, activation of the renin-angiotensin system contributes to the pathophysiology of heart failure late in the disease and essentially by an activation of renal salt and water retention.

Abstract

Objective—To investigate the effects of preventive angiotensin converting enzyme inhibitor treatment with ramipril in dogs with progressively severe experimentally induced heart failure.

Animals—20 dogs.

Procedures—Dogs were randomly allocated to receive no treatment (control) or ramipril (0.125 mg/kg, PO, daily) for 7 weeks. Physical examination, repetitive catheterization of the right side of the heart, and echocardiography were performed before the study (day 0) and weekly for 7 weeks. Renal plasma flow (RPF) as determined by para-aminohippuric acid clearance and glomerular filtration rate (GFR) as determined by creatinine and iohexol clearances were measured on day 0 and at weeks 4 and 7.

Results—Overpacing induced a progressive increase in right atrial pressure (RAP) and pulmonary artery pressure, occluded (PAPO), with a decrease in systemic arterial pressure. There were progressive alterations of echocardiographic indices of diastolic and systolic ventricular function. The RPF and GFR decreased before cardiac output decreased, and filtration fraction increased. The logarithm of the urinary sodium–to–potassium concentration ratio (log10[Na+/K+]) decreased. Significant effects of ramipril included a delay in clinical signs of heart failure, a late decrease in RAP and PAPO, and increases in the sodium excretion fraction and log10(Na+/K+). There was a satisfactory agreement between the creatinine and iohexol clearance measurements.

Conclusions and Clinical Relevance—Results suggest that, in this rapid-evolving, dilated cardiomyopathy, activation of the renin-angiotensin system contributes to the pathophysiology of heart failure late in the disease and essentially by an activation of renal salt and water retention.

Activation of the renin-angiotensin system contributes to clinical signs and prognosis of heart failure through a complex interaction of effects, which include myocardial and vascular remodeling, renal vasoconstriction with decreases in RPF and GFR, sodium and water retention, potassium depletion, and positive interaction with the sympathetic nervous system.1–5 Accordingly, ACE inhibitors, angiotensin II receptor blockers, and anti-aldosterone treatments reportedly improve clinical state and survival in humans with heart failure.6–9 However, essentially all of these studies have been performed in humans with established disease, and exactly how the renin-angiotensin system contributes to the progression of heart failure is not completely understood.

The purpose of the study reported here was to investigate the effects of preventive ACE inhibitor treatment with ramipril in dogs with progressively severe, experimentally induced heart failure. For this purpose, we used the overpacing-induced heart failure model in dogs, titrated to observe all stages of disease progression during a period of 7 weeks.10 Angiotensin converting enzyme inhibition was induced with ramipril at a dose recommended in veterinary practice.11,12 Cardiac function was monitored by repetitive catheterization of the right side of the heart and echocardiography, and renal function was monitored by RPF, GFR, and plasma and urinary electrolyte determinations. We specifically asked whether, and at what stage of disease progression, ACE inhibition would improve cardiovascular function. We investigated if this improvement was due to changes in renal hemodynamics and in sodium reabsorption or through direct changes in systolic or diastolic function and cardiac output.

Materials and Methods

The study was approved by the Animal Care and Use Committee of the Free University of Brussels and was conducted in accordance with the Guide for the Care and Use of Laboratory Animals.13

Dogs—Twenty male Beaglesa weighing between 13 and 17 kg were included in the study. Dogs had free access to water and were fed a dry maintenance dietb; sodium was not restricted. During general anesthesia, a bipolar pacemaker lead was surgically inserted in theright jugular vein and implanted in the right ventricular apex during fluoroscopy. A multiprogrammable pulse generatorc was inserted in the subcutaneous tissues of the cervical region and connected to the pacemaker lead.d

Experimental design—The experiment was a longitudinal repeated-measures study. The dogs underwent a modified pacing protocol with a stepwise increase of stimulation frequencies. After a 2-week period of recovery, the multiprogrammable pulse generator was activated on day 0. The rate of stimulation was 180 beats/min and was continued for 1 week (week 1), followed by 200 beats/min during the second week (week 2), 220 beats/min during the third week (week 3), and finally, 240 beats/min during the last 4 weeks (weeks 4 to 7). Dogs were randomly allocated to receive ramiprile (0.125 mg/kg, PO, daily beginning on day 0) or no treatment (control group). All investigations were performed when dogs were in sinus rhythm with the pacemaker turned off and after a stabilization period of 30 minutes. A physical examination, Doppler echocardiography, and catheterization of the right side of the heart were performed on day 0, before the start of overpacing, and then weekly until week 7. Measurements of RPF, GFR, and plasma and urinary electrolytes were obtained on day 0 and at weeks 4 and 7. At the end of the study, dogs were euthanized by IV injection of pentobarbitalf (200 mg/kg).

Physical examinations—Physical examinations included evaluation of general clinical signs (such as lethargy and anorexia) and clinical signs of heart failure (edema, ascites, pulmonary rales, and heart murmurs), as well as measurements of heart rate, respiratory rate, and blood pressure (measured with a Doppler sphygmomanometerg).

Doppler echocardiography—Doppler echocardiographyh was performed during continuous ECG monitoring with a 3.5- to 5-MHz sector probe, as described.10 All measurements were performed in triplicate irrespective of the respiratory phase. End diastolic and systolic left ventricular internal diameters were measured from the M-mode right short-axis view of the left ventricle at the level of the chordae tendinae to calculate FS of the left ventricle. The E-point septal separation was measured from the M-mode right short-axis view of the left ventricle at the level of the mitral valve. The LAD and Ao were measured from the 2-dimensional short-axis view. To calculate their ratio, the PEP and the LVET were measured from the left side by pulsed Doppler examination of the aortic flow. Mitral peak flow velocities of the E and A waves were measured from the left apical position by pulsed Doppler examination of the mitral flow, and the mitral E wave–to–A wave ratio was calculated. The IVRT of the left ventricle was measured from the left apical position by simultaneous pulsed Doppler examination of the aortic and mitral flows.

Hemodynamics—A pediatric 5-F thermodiltion Swan-Ganz catheteri was inserted via the left jugular vein during fluoroscopy for measurements of pulmonary artery pressure, PAPO, RAP, and cardiac index.

Renal function and hydroelectrolytic balance assessment—All clearance measurements were performed on conscious dogs trained to rest calmly on a table with minimal handling. The GFR was estimated by the ClCr and ClI, and RPF was estimated by the ClPAH. These 3 clearance procedures were performed simultaneously on the same dog. Creatininej (50 mg/mL) and PAHk (12.5 mg/mL) were dissolved in sterile water and stored at −20°C until use. For ClCr and the ClPAH, a 1-minute IV bolus (creatinine, 50 mg/kg; PAH, 2 mg/kg) followed by a 2-hour constant infusion (creatinine, 0.3 mg/kg/min; PAH, 0.1 mg/kg/min at a rate of 0.4 mL/min) were administered with lactated Ringer's solution at a rate of 3 mL/min. For ClI, a 1-minute IV bolus of iohexoll at a dose of 240 mg/kg was injected. After an equilibration period of 50 minutes, a rubber catheter was placed to empty and rinse the urinary bladder 3 times with 10 mL of sterile water. Three successive urine collection periods of 20 minutes were performed; a 5-mL sample of venous blood was obtained at the midpoint of each period. The bladder was carefully rinsed with sterile water (10 mL) after each period, and the rinsing solution was added to the urine volume of the preceding collection. To measure ClI, blood samples were obtained 2, 3, and 4 hours after iohexol injection and placed in tubesm containing sodium heparin.

Creatinine concentrations in urine and serum were determined according to the Jaffe method.14 Urine and serum concentrations of PAH were analyzed by a spectrophotometric assay, whereas plasma concentrations of iohexol were determined by high-performance liquid chromatography.

Calculations—The ClCr was calculated by use of the following equation:

article image
where UCr and PCr are urinary and serum concentrations of creatinine, respectively, and UO is urinary output. Urinary output was calculated as UO = urinary volume/(body weight × time of collection). The GFR of creatinine (GFRCr) was calculated as the mean of 3 successive clearances.

The ClI was calculated by use of the following equation:

article image
where D is the dose of iohexol injected and AUC is the area under the curve. The area under the curve was calculated by use of the following mono-compartmental model:
article image
where Co is the plasma iohexol concentration at zero time as determined by extrapolation of the line of best fit from 120-, 180-, and 240-minute samples, and k is the elimination rate constant (slope) of the decay curve.15 An R2 value of ≥ 0.97 for the 3-point elimination phase was required for acceptance of the clearance value on each dog. The GFR of iohexol (GFRI) was then corrected by use of the Brochner-Mortensen formula16 as follows:
article image

The ClPAH was calculated by use of the following equation:

article image
where UPAH and PPAH are urinary and serum concentrations of PAH, respectively. The RPF was calculated as the mean of 3 successive clearances.

The filtration fraction (FF) was calculated as FF = (GFRCr/RPF). The EFs and log10(Na+/K+) were calculated by use of the following equations:

article image
where x is the molecule Na+, K+, or urea excreted.

The ClOsm and ClH2O were calculated by use of the following equations:

article image
where UOsm and POsm are urinary and plasma osmolalities, respectively.

Statistical analysis—All values are reported as mean ± SEM. Results of a Shapiro-Wilk test indicated that the variables were normally distributed. The correlation between ClCr and CI was calculated by use of a least squares linear regression, and the agreement between ClCr and ClI was determined by plotting the differences between the 2 methods against the mean and calculation of the 95% limits of agreement from the mean difference and SD.17

Continuous variables were tested by a 2-factor ANOVA for repeated measures. When a time effect was detected, as a result of induction of the disease, we compared week 0 to 7 (for cardiac variables) and weeks 4 and 7 to week 0 (for renal parameters) with a modified t test (ie, ttest computed by use of the residual variance of the ANOVA).18 When a group effect was detected, as a result of treatment, or when the interaction group time was significant, the 2 groups were then compared week by week with a modified t test.18 All comparisons were performed at a 1-sided significance level of P = 0.05. Time and treatment effects were tested for discontinuous variables with a χ2 test.18

Results

Physical examination findings indicated progressive increases in heart and respiratory rates and a progressive decrease in blood pressure (Table 1). Clinical signs of congestive heart failure such as weakness, apathy, cachexia, heart murmurs, pulmonary crackles, and ascites were detected from weeks 4 to 5. Tricuspid regurgitant murmurs and ascites developed during weeks 4 and 5, respectively (Figure 1).

Table 1—

Mean ± SEM values for physical examination and hemodynamic parameters during progression of overpacing-induced heart failure in dogs receiving ramipril (0.125 mg/kg, PO, daily; n = 10) or no treatment (control group; 10) for 7 weeks.

ParameterGroupBaselinePacing activation
Week 0Week 1Week 2Week 3Week 4Week 5Week 6Week 7
SAP (mm Hg)Control152±8.0138±8.0126±9124±8122±7126±5126±5124±5
Ramipril159±9.7138±10*139±15*123±8114±6123±12117±11119±11
HR (beats/min)Control103±6.9128±7130±8143±9140±3141±6150±4149±6
Ramipril106±6.7129±7138±6145±6141±6150±8152±10160±8
RR (breaths/min)Control24±2.226±2.623±1.628±3.033±4*37±450±547±6
Ramipril21±2.024±1.626±2.227±3.235±430±1*39±543±4
PAPs (mm Hg)Control20.5±1.317.6±1.1*20.7±1.019.5±1.322.3±1.225.0±1.527.0±2.231.0±2.2
Ramipril19.5±1.918.6±1.519.6±1.420.6±1.123.1±1.223.7±0726.0±1.027.4±1.7
PAPd (mm Hg)Control10±1.011±1.111±0.912±0.5*14±0.716±0.617±1.219±1.0
Ramipril9±1.210±1.310±0.812±0.913±0.814±0.914±1.116±1.6
PAPm (mm Hg)Control14.3±1.113.3±1.014.7±1.014.6±1.217.3±1.118.8±0.920.6±1.623.4±1.8
Ramipril14.5±1.113.6±1.413.8±1.115.1±0.916.9±1.0*17.3±0.818.7±1.220.1±1.7
CI (L/min/m2)Control3.6±0.23.7±0.33.4±0.13.1±0.13.1±0.13.1±0.23.1±0.23.0±0.2
Ramipril4.1±0.23.4±0.13.2±0.13.1±0.23.1±0.13.0±0.13.2±0.23.1±0.2

Significantly (P 0.05, P 0.01, and P 0.001, respectively) different from baseline.

SAP = Systolic artery pressure. HR = Heart rate. RR = Respiratory rate. PAPs = Systolic pulmonary artery pressure. PAPd = Diastolic pulmonary artery pressure. PAPm = Mean pulmonary artery pressure. CI = Cardiac index.

Figure 1—
Figure 1—

Mean ± SEM number of dogs with ascites (A) and tricuspid regurgitant murmur (B) during progression of overpacinginduced heart failure in dogs receiving ramipril (0.125 mg/kg, PO, daily) or no treatment (control group) for 7 weeks (10 dogs/group). *†Significantly (P < 0.05 and P < 0.01, respectively) different from ramipril group.

Citation: American Journal of Veterinary Research 67, 7; 10.2460/ajvr.67.7.1236

Doppler echocardiography of the heart revealed a progressive decrease in FS and an increase in the PEP-to-LVET ratio starting at week 1, with progressive increases in LAD and in the LAD-to-Ao ratio (Table 2). Indicesof diastolic function (ie, the mitral E wave–to–A wave ratio and IVRT) indicated a progressive evolution with decreased relaxation starting at week 1, a pseudonormalmitral inflow and IVRT at the fourth week, and a restrictive pattern with an increased mitral E wave–to–A wave ratio from the fifth to seventh weeks (Figure 2).

Table 2—

Mean±SEM values for Doppler echocardiographic variables during progression of overpacing-induced heart failure in dogs receiving ramipril (0.125 mg/kg, PO, daily; n = 10) or no treatment (control group; 10) for 7 weeks.

ParameterGroupBaselinePacing activation
Week 0Week 1Week 2Week 3Week 4Week 5Week 6Week 7
FS (%)Control36±1.3227±1.0*22±1.4*21±0.9*17±1.1*18±1.2*17±0.9*18±1.2*
Ramipril35±1.3728±1.0*24±2.1*23±1.4*22±1.0*21±1.3*20±2.1*19±2.2*
PEP:LVETControl0.33±0.020.41±0.01*0.44±0.01*0.46±0.02*0.56±0.02*0.57±0.02*0.62±0.03*0.63±0.02*
Ramipril0.30±0.010.41±0.030.43±0.02*0.43±0.02*0.48±0.03*0.54±0.03*0.54±0.03*0.57±0.05*
LAD (cm)Control2.1±0.081.9±0.102.1±0.082.3±0.132.5±0.07*2.8±0.12*3.2±0.09*3.2±0.05*
Ramipril2.0±0.072.0±0.042.0±0.052.1±0.082.6±0.13*2.6±0.19*2.8±0.15*3.0±0.10*
LAD:AoControl1.1±0.021.0±0.051.1±0.041.2±0.071.3±0.06*1.5±0.07*1.7±0.04*1.8±0.03*
Ramipril1.1±0.041.1±0.031.1±0.031.2±0.041.4±0.06*1.5±0.07*1.5±0.08*1.7±0.05*

Significantly (P < 0.001) different from baseline.

Figure 2—
Figure 2—

Mean ± SEM values of IVRT (A) and the mitral E wave–to–A wave ratio (B) during progression of overpacinginduced heart failure in dogs receiving ramipril (0.125 mg/kg, PO, daily; squares) or no treatment (control group; triangles) for 7 weeks (10 dogs/group). *†‡Significant (P < 0.05, P < 0.01, P < 0.001, respectively) difference between baseline (week 0) and control group. §II¶Significant (P < 0.05, P < 0.01, P < 0.001, respectively) difference between baseline (week 0) and ramipril group. R/HF = Interaction group time.

Citation: American Journal of Veterinary Research 67, 7; 10.2460/ajvr.67.7.1236

Results of hemodynamic measurements indicated an increase in PAPO from the third to the seventh weeks, whereas RAP increased from the fourth to the seventh weeks (Figure 3). There was a progressive decrease in the cardiac index and a progressive increase in mean pulmonary arterial pressure (Table 1).

Figure 3—
Figure 3—

Mean ± SEM values for RAP (A) and PAPO (B) during progression of overpacing-induced heart failure in dogs receiving ramipril (0.125 mg/kg, PO, daily; squares) or no treatment (control group; triangles) for 7 weeks (10 dogs/group). *Significant (P < 0.001) difference between baseline (week 0) and control group. †‡§Significant (P < 0.05, P < 0.01, P < 0.001, respectively) difference between baseline (week 0) and ramipril group. See Figure 2 for remainder of key.

Citation: American Journal of Veterinary Research 67, 7; 10.2460/ajvr.67.7.1236

There was a significant correlation between ClCr and ClI, with a satisfactory agreement between these 2 methods; the mean difference between the 2 methods was −0.7 mL/kg/min, and the 95% limits of agreement varied from −1.25 to 2.65 mL/kg/min (Figure 4). Heart failure was associated with a decrease in GFR, which was of the same magnitude using the 2 methods of measurement at weeks 4 and 7 (ClCr evolution vs ClI evolution; the value of P was not significant). Renal plasma flow decreased proportionally more, increasing the filtration fraction (Figure 5).

Figure 4—
Figure 4—

Iohexol plasma clearance versus urinary exogenous ClCr during progression of overpacing-induced heart failure in dogs receiving ramipril (0.125 mg/kg, PO, daily) or no treatment (control group) for 7 weeks (10 dogs/group). A—Linear correlation between plasma ClI and urinary exogenous ClCr. B—Bland-Altman plot between ClI (corrected by use of the formula of ClI by Brochner-Mortensen16 [(ClI-BM]) and ClCr indicating a mean difference of 0.7 mL/kg/min between the 2 methods; the 95% limits of agreement varied from −1.25 to 2.65 mL/kg/min. C—Mean ± SEM values for ClCr measuring the GFR during progression of heart failure. D—Mean ± SEM values for ClI-BM measuring the GFR during progression of heart failure. *Significant (P < 0.001) difference between baseline (week 0) and control group. †Significant (P < 0.001) difference between baseline (week 0) and ramipril group. Triangles = Control group. Squares = Ramipril group.

Citation: American Journal of Veterinary Research 67, 7; 10.2460/ajvr.67.7.1236

Figure 5—
Figure 5—

Mean ± SEM values for PAH clearance (ClPAH) measuring RPF (A) and the filtration fraction (B) during progression of overpacing-induced heart-failure in dogs receiving ramipril (0.125 mg/kg, PO, daily; squares) or no treatment (control group; triangles) for 7 weeks (10 dogs/group). *†Significant (P < 0.05 and P < 0.01, respectively) difference between baseline (week 0) and control group. ‡§IISignificant (P < 0.05, P < 0.01, P < 0.001, respectively) difference between baseline (week 0) and ramipril group.

Citation: American Journal of Veterinary Research 67, 7; 10.2460/ajvr.67.7.1236

Serum creatinine concentrations remained unchanged, whereas serum urea concentrations increased; both were within reference ranges (Table 3). The EF of potassium increased, and the EF of sodium and log10(Na+/K+) decreased (Figure 6). Urinary output, ClOsm, ClH2O, and the EF of urea all decreased from weeks 4 to 7 (Table 4).

Table 3—

Mean±SEM values for serum urea and creatinine concentrations during progression of overpacing-induced heart failure in dogs receiving ramipril (0.125 mg/kg, PO, daily; n = 10) or no treatment (control group;10) for 7 weeks.

ParameterGroupBaselinePacing activation
Week 0Week 1Week 2Week 3Week 4Week 5Week 6Week 7
Urea (mg/dL)Control32±235±336±240±344±248±445±348±3
Ramipril31±337±2*44±343±240±238±2*39±241±2
Creatinine (mg/dL)Control0.83±0.040.93±0.060.84±0.040.94±0.070.98±0.070.99±0.060.94±0.050.97±0.04
Ramipril0.82±0.030.88±0.030.99±0.060.90±0.030.87±0.050.88±0.060.88±0.030.91±0.04

Significantly (P < 0.05, P < 0.01, and P < 0.001, respectively) different from baseline.

Table 4—

Changes (mean ± SEM) in hydroelectrolytic parameters during progression of overpacing-induced heart failure in dogs receiving ramipril (0.125 mg/kg, PO, daily) or no treatment (control group)

ParameterBaselinePacing activation
Group (n = 10)Week 0Week 4Week 7
UO (mL/kg/min)Control0.071±0.0120.023±0.0030.019±0.003*
Ramipril0.0612±0.0100.0316±0.010.038±0.012
ClOsm (mL/kg/min)Control0.123±0.0170.056±0.0060.056±0.005
Ramipril0.121±0.0150.064±0.0070.063±0.016
ClH2O (mL/min)Control–0.117±0.017–0.054±0.006–0.055±0.005
Ramipril–0.112±0.015–0.062±0.006–0.064±0.014
EFurea (mL/kg/min)Control0.60±0.040.50±0.050.44±0.03
Ramipril0.62±0.010.51±0.02*0.54±0.03

Significantly (P < 0.05, P < 0.01, and P < 0.001, respectively) different from baseline.

UO = Urinary output. EFurea = Urea EF.

Figure 6—
Figure 6—

Mean ± SEM values for sodium EF (EFNa; A), potassium EF (EFK; B), and the log10(Na+/K+) (C) during progression of overpacing-induced heart failure in dogs receiving ramipril (0.125 mg/kg, PO, daily; squares) or no treatment (control group; triangles) for 7 weeks (10 dogs/group). *†Significant (P < 0.05 and P < 0.01, respectively) difference between baseline (week 0) and control group. ‡§Significant (P < 0.05 and P < 0.01, respectively) difference between baseline (week 0) and ramipril group. R = Effect of ramipril. R/HF = Interaction group-time. See Figure 2 for remainder of key.

Citation: American Journal of Veterinary Research 67, 7; 10.2460/ajvr.67.7.1236

Ramipril delayed the development of tricuspid regurgitant murmurs and ascites (Figure 1) and limited the increases in RAP and PAPO beginning at the fourth and the fifth weeks, respectively (Figure 3). Ramipril had no effect on GFR and RPF, but did increase the EF of sodium and the log10(Na+/K+) (Figures 4–6).

Discussion

Results of the study reported here indicated that preventive ACE inhibition with ramipril in overpacinginduced heart failure in dogs improves advanced clinical signs, renal sodium and water handling, and cardiac preload, suggesting an effective but limited and late contribution of the renin-angiotensin system in this heart failure model.

The overpacing-induced heart failure model in dogs is characterized by development, within a few weeks, of dilated cardiomyopathy with impaired cardiac systolic and diastolic function and increased cardiac and pulmonary vascular pressures, with neurohormonal and renin-angiotensin system activation.10,19–21 We adapted the pacing rate such as to detect all stages of heart failure during a period of 7 weeks.21 Results of our study verify the early subclinical development of marked alterations in ventricular function as assessed by echocardiography, confirming results of another study22 in which invasive techniques were used. After only 1 week of pacing in dogs with clinical signs, the Doppler echocardiography revealed a delayed relaxation pattern, with a decreased mitral E wave–to–A wave ratio and an increased IVRT. This was accompanied by early systolic dysfunction as assessed by a decrease in FS and an increase in the PEP-to-LVET ratio. In mild to moderate heart failure, systolic dysfunction further deteriorated, whereas a pseudonormal pattern of diastolic function developed. This is explained by the fact that the decrease in left ventricular relaxation is compensated by an increase in left atrial pressure, confirmed by an increase in PAPO, leading to an increase in the early diastolic left atrial to left ventricular pressure gradient. In dogs with severe heart failure detected after 6 to 7 weeks of pacing, the restrictive left ventricular filling pattern with increased peak early filling rate and early filling deceleration rate indicated a major alteration in diastolic function and filling pressures. Results of our study thus confirm the validity of the overpacing-induced heart failure model for studies of clinical, Doppler echocardiograpic, and hemodynamic stages of the disease during a reasonable period of several weeks.

The renin-angiotensin system is known to aggravate heart failure through a complex interaction of effects, which include myocardial and vascular remodeling, renal vasoconstriction with decreases in both RPF and GFR, sodium and water retention, potassium depletion, and positive interaction with the sympathetic nervous system.1–3,5,20,21,23,24 An increased release of angiotensin II is believed to play a major role in the marked decrease in renal perfusion, which develops early in patients with heart failure.25 In the study reported here, both RPF and GRF were decreased after only 4 weeks of overpacing in the presence of still unchanged cardiac output, confirming neurohormonal activation-mediated early alteration in renal hemodynamics. There was an avid sodium and water retention state as indicated by decreased urinary output, ClOsm, EF of sodium, and log10(Na+/K+); an increased ClH2O in the presence of an unchanged cardiac output; and marked decreases in RPF and GFR, all of which suggest activation of intense hypertensive hormones and the sympathetic nervous system.23–26

The administration of ACE inhibitors has been found to improve clinical state and survival in patients with heart failure.4,6,7,11 The improved survival appears to be essentially attributed to a decreased risk of arrhythmia-related sudden death,27 but exactly how and when renin-angiotensin system activation affects the evolution of heart failure from early to late stages is not completely understood.28 Results of our study are in agreement with the notion that beneficial effects of ACE inhibitors in rapidly evolving heart failure, such as in overpacing-induced cardiomyopathy, may be essentially attributed to an improvement in renal function, with a predominant limitation in tubular handling of sodium and water.3 However, this result may not be transposable to chronic and slowly evolving heart failure models or diseases, in which angiotensin II and aldosterone, in combination with activation of the sympathetic nervous system, are more likely to contribute to the disease by major myocardial and arterial remodelling effects.

In the study reported here, administration of ramipril had no effect on RPF or GFR, suggesting limited participation of angiotensin II in altered renal hemodynamics in the overpacing-induced heart failure model. Ramipril was given at a dose previously found to effectively inhibit ACE in dogs and is recommended for treatment of heart failure in dogs. In addition, ramipril treatment was associated with a marked improvement in the EF of sodium and log10(Na+/K+), which are valid indices of the effects of aldosterone on the renal tubules.29 The delayed development of clinical signs of congestive heart failure and the decrease in ventricular filling pressures may be considered direct consequences of the beneficial effects of ramipril on the hydroelectrolytic balance. We therefore believe that the absence of renal hemodynamic effects of ramipril in our study could be explained by insufficient dosage or absorption.

In the study reported here, GFR was measured by use of 2 methods (ClCr and ClI). Mean values of 3.1 mL/kg/min for ClI and 4.1 mL/kg/min for ClCr in healthy dogs are in agreement with previously reported reference values in dogs.30–32 However, the correlation between the 2 clearances, although significant, was weak, and results of the Bland-Altman analysis revealed that ClI underestimated ClCr by approximately 0.7 mL/kg/min, with a difference of as much as 0.98 mL/kg/min, indicating only moderate precision. This may have been attributable to the small number of plasma iohexol concentration measurements used to construct the plasma elimination curve.33 Nevertheless, it is of interest that both ClCr and CI determinations lead to similar estimations of the mean decrease in GFR (2- and 2.3-fold, respectively) in dogs with heart failure, where-as serum urea and creatinine concentrations remained within reference ranges. Additionally, the use of 2 measurements of clearances confirms the observation that ramipril had no effect on GFR in dogs with moderate and severe overpacing-induced heart failure.

Results of our study indicated that cardiac and renal function can be monitored by repetitive catheterization of the right side of the heart and Doppler echocardiography and by use of clearance and electrolyte measurements in dogs with overpacing-induced heart failure. Angiotensin converting enzyme inhibition in this particular type of congestive heart failure has only moderate and late beneficial effects, which appear essentially associated with decreased renal tubular sodium and water reabsorption.

ABBREVIATIONS

RPF

Renal plasma flow

GFR

Glomerular filtration rate

ACE

Angiotensin converting enzyme

FS

Fraction shortening

LAD

Left atrial diameter

Ao

Aortic root diameter

PEP

Pre-ejection period

LVET

Left ventricular ejection time

IVRT

Isovolumetric relaxation time

PAPO

Pulmonary artery pressure, occluded

RAP

Right atrial pressure

Clcr

Creatinine clearance

ClI

Iohexol clearance

ClPAH

Para-aminohippuric acid clearance

log10(Na+/K+)

Logarithm of the urinary sodium–to–potassium concentration ratio

ClOsm

Osmolar clearance

ClH2O

Free water clearance

EF

Excretion fraction

a.

Harlan Netherlands BV, Horst, The Netherlands.

b.

Eukanuba maintenance small and medium breed formula, Laroy-Duvo SA, Wondelgem, Belgium.

c.

Insigna I Plus Model 1298, Guidant, Brussels, Belgium.

d.

Thin Line EZ model 438-10, Guidant, Brussels, Belgium.

e.

Vasotop, 2.5 mg, Intervet, Mechelen, Belgium.

f.

Nembutal, 60 mg/100 mL, Sanofi, Diegem, Belgium.

g.

Model 811-BTS, Parks Medical Electronics, Aloka, Ore.

h.

Pandion, Pie Medical Benelux, Zaventem, Belgium.

i.

Swan-Ganz 5F, 110 cm, Baxter Healthcare Corp, Deerfield, Ill.

j.

Creatinine powder, 100 g, VWR International, Leuven, Belgium.

k.

Para-aminohippuric acid sodium crystalline powder, 25 g, Sigma Chemical Co, Leuven, Belgium.

l.

OmnipaqueTM, 300 mg/mL, Amersham Health, Oslo, Norway.

n.

Na-Heparin tubes, 10 mL, Terumo Venoject, Leuven, Belgium.

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Contributor Notes

Supported by the Foundation for Cardiac Surgery, Belgium, and a grant from Intervet International.

Presented in abstract form at the 13th European College of Veterinary Internal Medicine–Companion Animals Congress, Uppsala, Sweden, September 2003.

The authors thank Suzanne Foulon and Patrick Broeckaert for technical assistance.

Address correspondence to Dr. Mathieu.