Plasma adrenomedullin concentration in dogs with myxomatous mitral valvular disease

Adrenomedullin (AM), a peptide identified to have vasodilating and natriuretic effects, is involved in the regulation of the cardiovascular system. To evaluate plasma AM concentration in dogs with myxomatous mitral valvular disease (MMVD), and to investigate the associations between the concentrations of plasma AM and natriuretic peptides and the echocardiographic data, we evaluated plasma AM concentrations in 31 healthy control dogs and 57 dogs with MMVD. Plasma AM concentrations in dogs with MMVD were higher than that in the control subjects. The plasma AM concentration increased in conjunction with the severity of heart failure according to the International Small Animal Cardiac Health Council (ISACHC). The AM concentrations were 25.1 ± 5.0 fmol/ml (ISACHC class Ia), 29.9 ± 11.0 fmol/ml (ISACHC class Ib), 43.4 ± 19.8 fmol/ml (ISACHC class II) and 73.5 ± 21.7 fmol/ml (ISACHC class III) and 7.5 ± 5.1 fmol/ml (control group), respectively. The receiver operating characteristic curve indicated an area of 0.93 (95% CI, 0.8801-0.9889; <0.0001), a cutoff value of 30.5 fmol/ml, a sensitivity of 87.1%, and a specificity of 82.5% for the determination of congestive heart failure. Plasma AM concentrations correlated with atrial natriuretic peptide concentrations, LA/Ao ratio, and left ventricular diameter. In conclusion, AM may be a potential diagnostic marker for canine MMVD and possibly plays a pathophysiological role in collaboration with the other neurohumoral factors such as natriuretic peptides.     

Decreased plasma concentration of nitric oxide metabolites in dogs with untreated mitral regurgitation

Endothelium-dependent (nitric oxide [NO]-mediated) vasodilation is impaired in humans with heart failure. This dysfunction is an important therapeutic target. The plasma concentration of the NO metabolites nitrate and nitrite (collectively referred to as NOx) is a measure of whole-body NO production, provided that the dietary intake of the ions is low. Fifty clinically healthy dogs older than I year (median 5.0 years; interquartile interval 2.6-8.2 years) were studied, including 9 controls of various breeds, 23 Cavalier King Charles Spaniels (CKCSs) with no or minimal mitral regurgitation (MR), 9 CKCSs with mild MR (regurgitant jet occupying 15-50% of the left atrial area), and 9 CKCS with moderate to severe MR (jet >50%) due to myxomatous valve disease. None of the dogs received medication. The dogs were given NOx-free water and a diet with a low concentration of NOx for 96 hours before blood sampling. Multiple linear regression analysis revealed that dog group, but not gender, age, serum creatinine concentration, and platelet count, was associated with NOx concentrations. Control dogs had the same NOx concentration (median 20.0 microM; interquartile interval 15.1-25.5 microM) as CKCSs without MR (median 18.7 microM; interquartile interval 15.5-25.9 microM). Compared to CKCSs without MR, the NOx concentration was lower in CKCSs with mild (median 12.9 microM; interquartile interval 11.0-13.5 microM; P = .04) and moderate to severe (median 11.2 microM; interquartile interval 6.9-17.1 microM; P = .02) MR. In conclusion, CKCSs with mild to severe, clinically silent MR have decreased plasma NOx concentrations, suggesting that endothelial dysfunction develops early in the course of developing MR in dogs.     

Pulmonary function in dogs with mitral valve regurgitation

Mitral valve regurgitation was created in 2 groups of dogs. Groups were selected on absence (group 1) or presence (group 2) of clinical signs of congestive left ventricular failure. Group-2 dogs, in which mean left atrial pressures were greater than 30 mm of Hg, had increases in heart rate, pulmonary arterial mean pressure, left atrial diameter, and left ventricular diastolic diameter. These changes were associated with decreased arterial O2 tension, decreased static and dynamic compliance, reduced lung volumes, and increased pulmonary resistance. Group-1 dogs, in which mean left atrial pressure was less than 30 mm of Hg, had moderate changes in hemodynamics, but no changes in pulmonary function, except during exercise when arterial O2 tension decreased.     

Platelet aggregation in dogs with mitral valve regurgitation

OBJECTIVE: To compare platelet aggregation in healthy dogs and dogs with mitral valve regurgitation (MVR) to determine whether regurgitation had an effect on platelet function. ANIMALS: 32 dogs with MVR and 43 healthy dogs. PROCEDURE: Platelet aggregation was measured with an aggregometer, using adenosine 5'-diphosphate as the aggregating agent, and the maximum aggregation and the enhancement of platelet sensitivity (EPS) values were calculated. RESULTS: Platelet count and maximum aggregation were not significantly different between healthy dogs and dogs with MVR. However, EPS values in dogs with MVR were significantly higher than values in healthy dogs. Platelet count and maximum aggregation were not significantly different between dogs classified as New York Heart Association functional class I or II and dogs classified as functional class III or IV; however, EPS values were significantly higher in dogs classified as functional class III or IV. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that platelet aggregation is decreased in dogs with MVR and that the EPS value may be more sensitive to differences in disease severity than in measurement of maximum aggregation.     

Pharmacokinetics of nicorandil in dogs with mild mitral regurgitation

The aim of this study was to examine the pharmacokinetics of nicorandil, a hybrid of an adenosine triphosphate-sensitive potassium channel opener and a nitrate, and to estimate its clinical doses in dogs with mild mitral valve regurgitation (MR). Nicorandil (0.1, 0.3, and 1.0 mg/kg) was administered orally to normal dogs and those with experimentally-induced MR, and its plasma concentrations were analyzed using high-performance liquid chromatography. Plasma concentrations increased dose-dependently after the administration of nicorandil, and were not different between normal dogs and those with MR. Similar to the effective plasma values obtained in cardiac disease in humans, the findings of this pharmacokinetic study may indicate that a dose of 0.3-1.0 mg/kg has the same effectiveness in dogs with cardiac dysfunction.     

Increased pulmonary transit times in asymptomatic dogs with mitral regurgitation

Pulmonary transit time (PTT) normalized to heart rate (nPTT) is a measure of the pulmonary blood volume (PBV) to stroke volume ratio (PBV/SV). It is an index of cardiac performance. To determine the effect of compensated mitral regurgitation (CMR) and decompensated mitral regurgitation (DMR) caused by valvular endocardiosis on the index nPTT, we measured nPTT by first-pass radionuclide angiocardiography and ECG in 13 normal dogs, 18 dogs with CMR, and 13 dogs with DMR. PTT was measured as time between onset of appearance of activity at the pulmonary trunk and the left atrium. In the normal dogs, the relationship between PTT and mean R-R interval (mRR) was PTT = 4.08 x mRR + 0.15 (R2 = 0.71). Normal nPTT was 4.4 +/- 0.6 (SD) (range. 3.6-5.3). in CMR, 6.3 +/- 1.6 (SD) (range, 4.0-9.7). and in DMR, 11.9 +/- 3.4 (SD) (range, 8.0-18.8). The differences among all groups were significant. Heart rates were 110 +/- 22 bpm in normal dogs, 111 +/- 20 in dogs with CMR, and 144 +/- 18 in dogs with DMR (P < .001 for difference between DMR group and normal and CMR groups). Increased nPTT in CMR indicates preclinical heart pump dysfunction. Heart rate-normalized pulmonary transit times may be a useful index of heart function in mitral regurgitation.     

Evaluation of collagenase-induced mitral valve regurgitation in dogs

OBJECTIVE: To investigate the hemodynamic changes induced by injecting collagenase into the mitral valve to induce mitral valve regurgitation (MVR) in dogs. ANIMALS: 9 healthy Beagles. PROCEDURE: Dogs were randomly assigned to 3 groups: control (saline [0.9% NaCl] solution; n = 3), single collagenase injection (C1; 3), and 2 collagenase injections (C2; 3). Open-heart surgery was performed, and saline or collagenase solutions were injected into the mitral valve. Before and weekly for 11 weeks after surgery, radiography, echocardiography, and phonocardiography were performed. Mean pulmonary arterial pressure and mean pulmonary arterial wedge pressure (mPAWP) were measured before and 11 weeks after surgery. Postmortem examinations were performed after dogs were euthanatized. RESULTS: No changes were detected in the control group during the 11-week follow-up period. A systolic murmur and MVR developed 1 week after surgery in groups C1 and C2. The murmur changed from a protosystolic to a pansystolic murmur, and left atrial diameter and the left atrial-to-aortic root diameter ratio increased with time. Mean pulmonary arterial pressure and mPAWP were greater 11 weeks after surgery in groups C1 and C2, compared with presurgery values. During necropsy, tissue loss was detected in the mitral valve at the site of collagenase injection. Degree of regurgitation corresponded to lesion size. CONCLUSIONS AND CLINICAL RELEVANCE: Injection of collagenase into the mitral valve of healthy dogs induced MVR, and dogs with MVR developed progressive hemodynamic changes without acute overload. Collagenase-induced MVR may be an appropriate model for evaluation of prognostic markers of idiopathic MVR in dogs.     

Changes in platelet life span in dogs with mitral valve regurgitation

Platelet life span was measured in dogs with experimentally-induced mitral regurgitation (MR) by using an in vitro whole-blood biotinylation technique to evaluate the effects of shear stress induced by MR. Mitral regurgitation was created in healthy dogs by ablation of the mitral valve chordae tendineae. Mitral regurgitation was identified by auscultation and postoperative color Doppler echocardiography. Platelets were biotinylated. and derivatized blood was reinfused into the dogs. Biotinylated platelet disappearance was measured over time to determine platelet life span. Pre- and postablation platelet life span was compared in each dog. Platelet life span was shorter in dogs with experimentally induced MR. Shear stress from MR was postulated to shorten platelet life span. Alternations in platelet function and life span may contribute to the progression of cardiovascular disease in dogs with MR. Further studies are required to determine if platelet dysfunction is related to disease progression in these patients.     

Acute hemodynamic effects of hydralazine in dogs with chronic mitral regurgitation

The hemodynamic response to hydralazine administration was evaluated in 6 conscious small dogs with chronic mitral regurgitation. All dogs underwent invasive and noninvasive hemodynamic monitoring before and after hydralazine administration. Cardiac output and pulmonary capillary wedge pressure were measured with a Swan-Ganz thermodilution catheter. Systemic arterial blood pressure (AP) was measured directly by inserting a needle into the femoral artery. Standard M-mode echocardiograms and thoracic radiographs were obtained. Other hemodynamic variables were calculated. Base-line hemodynamic variables were altered severely in all dogs. Hydralazine decreased mean arterial blood pressure from 104 +/- 18 (mean +/- SD) to 78 +/- 12 mm of Hg (P less than 0.005), total systemic resistance index from 2,946 +/- 625 to 1,261 +/- 420 dynes-s-cm-5m2 (P less than 0.005), and pulmonary capillary wedge pressure from 40 +/- 5 to 26 +/- 3 mm of Hg, (P less than 0.005). Cardiac index increased from 2.92 +/- 0.72 to 5.36 +/- 1.67 L/min/m2 of body surface area (P less than 0.005). Mixed venous oxygen tension (PvO2) increased from 28.4 +/- 4.3 to 41.2 +/- 5.2 mm of Hg (P less than 0.001). Pulmonary edema resolved, as determined on thoracic radiographs. Mixed venous oxygen tension correlated well with the cardiac index (r = 0.92; P less than 0.001). It was concluded that hydralazine administration caused a small decrease in end diastolic diameter (4.8 +/- 0.9 to 4.5 +/- 0.8 cm, P less than 0.05) and end systolic diameter (2.6 +/- 0.8 to 2.3 +/- 0.7 cm, P less than 0.05). Fractional shortening and heart rate did not change.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma L-carnitine concentration in healthy dogs and dogs with hepatopathy

BACKGROUND: L-Carnitine has an essential role in lipid metabolism. Disturbances of L-carnitine metabolism can influence the energy supply of the organism. L-Carnitine is synthesized exclusively in the liver. Hence, we hypothesized that liver disease can influence L-carnitine metabolism. OBJECTIVES: The goal of this study was to compare plasma L-carnitine concentrations in dogs with different liver diseases of differing severity with the plasma L-carnitine concentrations of healthy dogs. METHODS: Sixteen dogs with inflammatory liver disease and 12 dogs with liver neoplasia were included in the study. Liver disease was diagnosed by clinical chemistry, ultrasonography, and histology of liver biopsy specimens. L-Carnitine concentration was measured in plasma samples using mass spectrometry, and compared among groups using unpaired Student's t-tests. RESULTS: Compared with healthy controls (24.4 +/- 8.4 micromol/L), the plasma L-carnitine concentration in dogs with liver disease (44.2 +/- 23.7 micromol/L) was significantly higher (P<.0001). The difference in L-carnitine concentration between dogs with moderate (n=8; 33.6 +/- 13.7 micromol/L) and severe (n=8; 57.4 +/- 22.9 micromol/L) hepatitis was also significant (P=.02). No difference in plasma L-carnitine concentration was found between dogs with hepatitis and those with liver tumors. CONCLUSIONS: Liver disease in dogs was accompanied by elevated plasma L-carnitine concentration. The severity of hepatitis appears to influence L-carnitine concentration.     

Effects of pimobendan for mitral valve regurgitation in dogs

Pimobendan has a dual mechanism of action: it increases myocardial contractility by increasing calcium sensitization to troponin C and it promotes vasodilation by inhibiting PDEIII. This study examined the effects of pimobendan on cardiac function, hemodynamics, and neurohormonal factors in dogs with mild mitral regurgitation (MR). The dogs were given 0.25 mg/kg of pimobendan orally every 12 hr for 4 weeks. With pimobendan, the heart rate and stroke volume did not change, but the systolic blood pressure gradually decreased and the degree of mitral valve regurgitation tended to decrease. Renal blood flow was significantly increased and the glomerular filtration rate was slightly increased at 2 and 4 weeks. Furthermore, over the 4-week period, the plasma norepinephrine concentration decreased significantly, the systolic index increased slightly, the left atrial diameter and the left ventricular diameters decreased significantly, and the heart size improved. Given these results, pimobendan appears to be useful for treating MR in dogs. However, further long-term studies of pimobendan involving a larger number of dogs with mild and moderate MR are needed to establish the safety of pimobendan and document improvements in quality of life.     

Spectral analysis of heart rate variability in dogs with mild mitral regurgitation

OBJECTIVE: To assess autonomic function in dogs with mild mitral regurgitation (MR) that did not have clinical signs of the condition. ANIMALS: 6 healthy adult Beagles. PROCEDURE: Mild MR was experimentally induced. A 24-hour ambulatory ECG was recorded before and after induction of MR. Heart rate variability was analyzed in frequency domains by use of the ambulatory ECG. Low-frequency (LF) and high-frequency (HF) power were calculated by integrating over their frequency intervals, and the ratio of LF to HF was also calculated. Measurements of frequency domains were analyzed for 4 time periods (midnight to 6 AM, 6 AM to noon, noon to 6 PM, and 6 PM to midnight). RESULTS: Dogs with experimentally induced MR were classified as International Small Animal Cardiac Health Council class Ia. The HF power of dogs with MR was significantly decreased between 6 AM and noon. The ratio of LF to HF in dogs with MR was significantly increased for the periods between midnight and 6 AM, 6 AM and noon, and noon and 6 PM. CONCLUSIONS AND CLINICAL RELEVANCE: Compensatory response through autonomic modulation was observed in dogs with mild MR that did not have abnormalities, except for cardiac murmur, during clinical examination. This result suggests that treatment during the early stages of mild MR may be beneficial. Additional studies are necessary to determine whether such treatment will delay the onset of congestive heart failure and prolong survival in dogs affected with mild MR.     

R-R interval variations influence the degree of mitral regurgitation in dogs with myxomatous mitral valve disease

Mitral regurgitation (MR) due to myxomatous mitral valve disease (MMVD) is a frequent finding in Cavalier King Charles Spaniels (CKCSs). Sinus arrhythmia and atrial premature complexes leading to R-R interval variations occur in dogs. The aim of the study was to evaluate whether the duration of the R-R interval immediately influences the degree of MR assessed by echocardiography in dogs. Clinical examination including echocardiography was performed in 103 privately-owned dogs: 16 control Beagles, 70 CKCSs with different degree of MR and 17 dogs of different breeds with clinical signs of congestive heart failure due to MMVD. The severity of MR was evaluated in apical four-chamber view using colour Doppler flow mapping (maximum % of the left atrium area) and colour Doppler M-mode (duration in ms). The influence of the ratio between present and preceding R-R interval on MR severity was evaluated in 10 consecutive R-R intervals using a linear mixed model for repeated measurements.MR severity was increased when a short R-R interval was followed by a long R-R interval in CKCSs with different degrees of MR (P < 0.005 when adjusted for multiple testing). The relationship was not significant in control dogs with minimal MR and in dogs with severe MR and clinical signs of heart failure. In conclusion, MR severity increases in long R-R intervals when these follow a short R-R interval in CKCSs with different degrees of MR due to asymptomatic MMVD. Thus, R-R interval variations may affect the echocardiographic grading of MR in CKCSs.     

Left ventricular remodeling in preclinical experimental mitral regurgitation of dogs

Dogs with experimental mitral regurgitation (MR) provide insights into the left ventricular remodeling in preclinical MR. The early preclinical left ventricular (LV) changes after mitral regurgitation represent progressive dysfunctional remodeling, in that no compensatory response returns the functional stroke volume (SV) to normal even as total SV increases. The gradual disease progression leads to mitral annulus stretch and enlargement of the regurgitant orifice, further increasing the regurgitant volume. Remodeling with loss of collagen weave and extracellular matrix (ECM) is accompanied by stretching and hypertrophy of the cross-sectional area and length of the cardiomyocyte. Isolated ventricular cardiomyocytes demonstrate dysfunction based on decreased cell shortening and reduced intracellular calcium transients before chamber enlargement or decreases in contractility in the whole heart can be clinically appreciated. The genetic response to increased end-diastolic pressure is down-regulation of genes associated with support of the collagen and ECM and up-regulation of genes associated with matrix remodeling. Experiments have not demonstrated any beneficial effects on remodeling from treatments that decrease afterload via blocking the renin-angiotensin system (RAS). Beta-1 receptor blockade and chymase inhibition have altered the progression of the LV remodeling and have supported cardiomyocyte function. The geometry of the LV during the remodeling provides insight into the importance of regional differences in responses to wall stress.     

Echocardiographic estimation of systemic systolic blood pressure in dogs with mild mitral regurgitation

BACKGROUND: Systemic hypertension is likely underdiagnosed in veterinary medicine because systemic blood pressure is rarely measured. Systemic blood pressure can theoretically be estimated by echocardiography. According to the modified Bernoulli equation (PG = 4v(2)), mitral regurgitation (MR) velocity should approximate systolic left ventricular pressure (sLVP), and therefore systolic systemic blood pressure (sSBP) in the presence of a normal left atrial pressure (LAP) and the absence of aortic stenosis. The aim of this study was to evaluate the use of echocardiography to estimate sSBP by means of the Bernoulli equation. HYPOTHESIS: Systemic blood pressure can be estimated by echocardiography. ANIMAL: Seventeen dogs with mild MR. No dogs had aortic or subaortic stenosis, and all had MR with a clear continuous-wave Doppler signal and a left atrial to aorta ratio of < or = 1.6. METHODS: Five simultaneous, blinded continuous-wave measurements of maximum MR velocity (Vmax) and indirect sSBP measurements (by Park's Doppler) were obtained for each dog. Pressure gradient was calculated from Vmax by means of the Bernoulli equation, averaged, and added to an assumed LAP of 8 mm Hg to calculate sLVP. RESULTS: Calculated sLVP was significantly correlated with indirectly measured sSBP within a range of 121 to 218 mm Hg (P = .0002, r = .78). Mean +/- SD bias was 0.1 +/- 15.3 mm Hg with limits of agreement of -29.9 to 30.1 mm Hg. CONCLUSION: Despite the significant correlation, the wide limits of agreement between the methods hinder the clinical utility of echocardiographic estimation of blood pressure.     

The effect of furosemide on left atrial pressure in dogs with mitral valve regurgitation

Background: The effects of furosemide on left atrial pressure (LAP) in dogs with mitral regurgitation (MR) have not been documented in a quantitative manner and between different routes of administration. Objective: To document LAP and echocardiographic parameters in MR dogs administered furosemide IV or PO, in order to document changes in LAP after furosemide treatment. Animals: Five healthy Beagle dogs (3 males and 2 females; aged 2 years) were used. Methods: Experimental, cross‐over, and interventional study. LAP was measured before the administration of furosemide, and 30 minutes, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours after administration. Furosemide 1, 2, or 4 mg/kg IV, PO or placebo was administered. Results: LAP was significantly decreased with all administrations of furosemide but not after placebo (P < .05, respectively). The max reduction was observed 1 hour (1 mg/kg IV, 15.04 ± 7.02 mmHg), 3 hours (2, 4 mg/kg IV, 13.28 ± 8.01, 9.23 ± 4.92 mmHg), 4 hours (1 mg/kg PO, 14.68 ± 11.51 mmHg), and 5 hours (2, 4 mg/kg PO, 13.19 ± 10.52, 10.70 ± 7.69 mmHg). E wave and E/Ea were significantly decreased corresponding to the reduction of LAP after administration of 2 and 4 mg/kg (P < .05, respectively). Conclusions and Clinical Importance: LAP was decreased in proportion to the dosage of furosemide, which did not significantly differ between IV and PO of the same dosages. E wave and E/Ea might be useful for the treatment evaluation of furosemide.     

Echocardiographic estimation of left atrial pressure in beagle dogs with experimentally-induced mitral valve regurgitation

Non-invasive and immediate estimation of left atrial pressure (LAP) is very useful for the management of mitral regurgitation (MR), and many reports have assessed echocardiographic estimations of LAP to date. However, it has been unclear of which examination and evaluate article possess the best accuracy for the MR severity. The present research aims to establish the echocardiographic estimation equation of LAP that is well applicable for clinical MR dogs. After the chordae tendineae rupture was experimentally induced via left atriotomy in six healthy beagle dogs (three males and three females, two years old, weighing between 9.8 to 12.8 kg), a radio telemetry transmitter catheter was inserted, which allows the continuous recordings of LAP without the use of sedation. Approximately 5 weeks after the surgery, echocardiographic examination, indirect blood pressure measurement, measurement of plasma atrial natriuretic peptide (ANP) and LAP measurement by way of the radio telemetry system was performed simultaneously. Subsequently, simple linear regression equations between LAP and each variable were obtained, and the equations were evaluated whether to be applicable for clinical MR dogs. As a result, the ratio of early diastolic mitral flow to early diastolic lateral mitral annulus velocity (E/Ea) had the strongest correlation as maximum LAP=7.03*(E/Ea)-54.86 (r=0.74), and as mean LAP=4.94*(E/Ea)-40.37 (r=0.70) among the all variables. Therefore, these two equations associated with E/Ea should bring more precise and instant estimations of maximum and mean LAP in clinical MR dogs.     

Circulating concentrations of insulin-like growth factor-1 in dogs with naturally occurring mitral regurgitation

Insulin-like growth factor-1 (IGF-1), which mediates most effects of growth hormone, has effects on cardiac mass and function, and plays an important role in the regulation of vascular tone. In humans, an inverse relationship between degree of heart failure (HF) and circulating IGF-1 concentrations has been found in several studies. In dogs with HF, few studies have focused on IGF-1. We examined circulating IGF-1 concentrations in dogs with mitral regurgitation (MR) caused by myxomatous mitral valve disease. Study 1 included 88 Cavalier King Charles Spaniels (CKCSs) with a broad range of asymptomatic MR (median serum IGF-1: 76.7 microg/L; 25-75 percentile, 59.8-104.9 microg/L). As expected, standard body weight and percentage under- or overweight correlated directly with IGF-1. MR (assessed in 4 different ways) did not correlate with IGF-1. In study 2, 28 dogs with severe MR and stable, treated congestive HF had similar serum IGF-1 concentrations (median, 100.8 g/L; 25-75 percentile, 74.9-156.5 microg/L) as 11 control dogs (79.6 microg/L; 25-75 percentile, 64.1-187.4 microg/L; P = .84). In study 3, the plasma IGF-1 concentration of 15 untreated CKCSs with severe MR was 16.4 +/- 24.2 microg/L lower (P = .02) at the examination when decompensated HF had developed (80.8 +/- 30.9 microg/L) than at a visit 1-12 months earlier (97.2 +/- 39.8 microg/L), possibly in part due to an altered state of nutrition. The studies document that circulating IGF-1 concentrations are not altered before development of congestive HF in dogs with naturally occurring MR, but decrease by approximately 20% with the development of untreated HE In treated HF, circulating IGF-1 concentrations apparently return to within the reference range.