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A practical method to diagnose muscle degradation in normonourished patients with chronic heart failure.

INTRODUCTION

Patients with heart failure often are characterized by muscle wasting and weakness responsible for exercise intolerance and reduced survival. (1,2) One important mechanism that leads to wasting of both muscle mass and function is represented by increased myofibrillar protein degradation (MPD).

The ability of estimating MPD under clinical conditions could be highly desirable. For research purposes, MPD can be assessed by using isotope methods (3) which are impractical in clinical settings. For clinical practices, an estimate of MPD can be made by measuring the amino acid 3-methylhistidine (MEH) levels in plasma or in 24-hour urine output. (4,5) This amino acid is formed by methylation of the histidine t-RNA complex, which occurs only in actin and myosin. After proteolysis, it can not be re-used (6), so is eliminated and quantitatively cleared by the kidney. (7) Therefore, in absence of renal failure, increased 3MEH is an index of myofibrillar (contractile) protein breakdown. (8,9)

Both early and recent investigations have indicated that 3MEH could be a sensitive indicator of MPD in fasting healthy subjects (5), in malnourished children on nutritional support (10), in patients on total parenteral nutrition (9), in intensive care individuals undergoing muscle electrical stimulation (11) and finally in acutely burnt children treated with early enteral support. (12)

To our knowledge, so far no studies have measured 3MEH in patients with CHF. We suspected that there was a high prevalence of MPD in patients with increased plasma levels of 3MEH, given the profound plasma hormonal, and/or metabolic, and/or inflammatory alterations characterising CHF. (13-17) Therefore, the first aim of this study was to document the prevalence of high 3MEH in outpatients with CHF and normal renal function.

As the determination of 3MEH could be both expensive and time-wasting, the secondary aim of the study was to find whether 3MEH could be substituted by a more simple biochemical parameter that is routinely measured during clinical operations. We believe that this parameter could be blood urea level (BU).

This hypothesis relies on the following considerations:

1) plasma levels of 3MEH vary with muscle degradation (5),

2) forearm efflux of 3MEH reflects the MPD in this tissue compartment (18),

3) BU, formed in the liver (gluconeogenesis), is the end product of protein/amino acid oxidation, which occurs most in skeletal muscle,

4) muscle protein metabolism constitutes the bulk of body protein,

5) in patients that are clinically stable, at rest and after overnight fasting, the release of amino acids from muscles is the major contributor of hepatic gluconeogenesis.

If we are correct, we would find a positive correlation between plasma levels of 3MEH and BU. Thus, the ultimate aim of the study was to provide a simple biochemical tool (3MEH or BU) as an indicator of MPD in a clinical setting.

METHODS

Population

We enrolled 38 outpatients with CHF, who were regularly followed up in our institutes' wards. They were selected according to the following criteria:

1) normal body weight or above normal (body mass index, BMI >20Kg/[m.sup.2]), stable over the last year, associated with normal skeletal muscle mass (arm muscle area, AMA>10[degrees] percentile of normal values for age and sex). (19)

2) stable daily energy protein-intake over the past year, providing energy [greater than or equal to]30 Kcal/Kg and proteins >1.1g/Kg. (20)

3) daily physical activity limited to ordinary tasks (dressing, washing, walking etc...).

4) absence of liver insufficiency (normal serum transaminases; prothrombine activity >40%; serum total bilirubine <2mg/dl) and/or renal disease (creatinine clearance >60ml/min), diabetes, insulin resistance (HOMA index >2.4). (21)

5) clinical stability (no evidence of fluid retention, peripheral or pulmonary edema; jugular venous pressure not raised; no changes in medication for at least three months).

Table 1 summarizes the demographic-, antrophometric-, clinical-, functional-, treatment-characteristics of the patients. The patients were comprehensively informed about the aims and methods of the study and gave written consent for their participation. The study was approved by our institutions' ethical scientific committee.

Study procedures

After enrolment, the patients were asked to continue with their usual alimentation but to abstain from meat ingestion over the day preceding blood sampling. Then, at 8 am, after overnight fasting, plasma concentrations of 3MEH and serum creatinine (CR) as well as BU were measured from peripheral venous blood samples.

The concentration of 3MEH in the plasma was determined by using an AminoQuant II aminoacid analyzer based on the HP 1090 HPLC system with fully automated pre-column derivatization. Both ortho-phthalaldehyde (OPA) and 9-fluorenylmethyl-chloroformate (FMOC) reaction chemistries were used according to the manufacture's protocol.

Detection was performed by measuring the UV absorbance at 338 and 262, respectively. We used the following procedure: 2-ml samples of plasma were deproteinized by adding 500[micro]L samples of 0.5N HCl and after centrifugation at 5,000 g for 10min at 5[degrees]C, the supernatant was concentrated up to 200[micro]L under a nitrogen stream and then filtered on a 0.45-[micro]m Millipore filter. Aliquots (1[micro]L each) were automatically transferred to the reaction coil and the derived serum was stored at -20[degrees]C. The analyses were performed in duplicate and the value reported for 3MEH was the mean of two independent results. The average minimum detectable level of 3MEH was 3 to 5 pmol for each microliter of material injected. Amino acid concentrations were expressed as micromoles per litre ([micro]mol/L).

After completing this procedure, the patients were connected to a system for respiratory gas analysis to measure resting oxygen consumption (V[O.sub.2];ml/kg/min) as described elsewhere. (22)

Seventeen voluntary healthy subjects (13 males and 4 females), free from any endocrinological, metabolic, cardiovascular disease, with sedentary daily activity (aerobic exercise<60min/week) matched for age, sex, body mass index and served as a control group. The control healthy subjects were submitted to the same procedures as the patients except for the respiratory gas analysis.

Statistical analysis

Unpaired t test was used to compare intergroup differences in 3MEH, BU, and CR variables. The data were reported as mean [+ or -] standard deviation (mean[+ or -]SD). The indication of statistical significance was defined as p<0.05. The ability of the urea parameter to discriminate between patients with MPD and normal cases was evaluated using the Receiver Operating Characteristic (ROC) curve analysis. The sensitivity and specificity of the test was graphically and numerically assessed at different cut-off points using the 3MEH level as reference parameter. Patients with 3MEH less than 6 (mean+1.96 SD in healthy subjects) was assumed to be free from muscle damage. The best discriminating threshold in urea parameter was chosen by privileging sensitivity in order to avoid underestimating damage. Positive and negative predictive values (PPV and NPV respectively) were estimated on the basis of the chosen threshold. The area under the ROC curve and 95% confidence intervals (95%CI) were also calculated.

Simple regression analysis was used to show possible correlations among the variables considered in the study.

RESULTS

The results of the study showed that blood urea concentration (BU), serum CR and 3MEH levels were significantly higher in patients with CHF than in healthy subjects (table 2). The mean value of 3MEH in CHF was 154% higher than in healthy individuals (table 2). Supporting our initial hypothesis, 3MEH and BU were positively correlated (r=+0.49; p< 0.001) (fig. 1).

The ROC curve analysis estimated an area under the curve equal to 0.81 (95%CI: 0.70-0.92), being 81% the probability that a randomly selected individual from the patient group has an urea test larger than that of a randomly chosen normal case. The best discriminating threshold for BU between patients with MPD and healthy subjects was 38 mg/dl, reflecting the normal parameters for the general population. For this threshold, sensitivity and specificity of urea test were 70% and 68%, whereas PPV and NPV were 68% and 69%, respectively.

Twenty-seven of the 38 patients (71%) had BU levels above the threshold 38 mg/dl whereas patients with 3MEH>6[micro]mol/L were 33/38 (86.8%). The results showed that 3MEH correlated with resting oxygen consumption (V[O.sub.2]/Kg)(n=24, r=+0.48; p=0.02), NYHA functional class (r=+0.32;p<0.05) and tended to be negatively linked to muscle mass (AMA) (r=-0.26;p=0.1). No correlation was found between 3MEH and body mass (BMI).

DISCUSSION

The primary findings from this investigation were that more than 80% of patients with CHF may have MPD as suggested by increased circulating 3MEH and that BU may be a proxy for 3MEH. Therefore BU may be used as an useful and simple indicator of MPD in clinical situations.

Moreover, BU level of 38 mg/dl has to be considered an alert value for muscle damage in a population with expected high prevalence of MPD.

It is reasonable that the high blood level of 3MEH found in CHF patients may be due to heart failure per se given that patients had normal renal function and that 3MEH was independent of body mass. Minimal renal dysfunction (i.e. from diuretic therapy) as responsible for increased 3MEH, may be excluded since patients with normal BU (13-38 mg/dl) had 3MEH higher than controls (data not shown).

[FIGURE 1 OMITTED]

The relation between 3MEH and BU found in the study patients suggests that MPD and non-contractile protein oxidation, leading to gluconeogenesis, may share common causal mechanism(s). Two main factors may support this hypothesis. Firstly, two thirds of muscle proteins are contained in myofribrillar components. (23) Secondly, possible cytokine overproduction demonstrated in CHF (14) may bring about both myofibrillar and somatic proteolysis. (24-27) Alternatively or in addition to cytokine over-production, elevated blood cortisol levels found in CHF patients (15,20) may be another factor leading to both MPD and non-contractile protein breakdown. (28)

Possible dependence of MPD on activated systemic inflammation might partially explain in the study the link between MPD and the severity of CHF (NYHA class). This finding parallels an investigation that showed the negative association between myosin heavy chain protein content and NYHA class. (27)

Increased MPD puts a patient with CHF at increased risk of lower physical performance and reduced muscle mass and function.

Indeed the muscle tension (i.e. static effort), suggested by increased blood 3MEH, may reduce the capacity of developing muscle force and it may also be responsible for excess energy consumption and contractile protein strain by muscle groups that, even if not directly involved in movement, serve for body posture and stabilization. Consequently, patients may suffer reduced performance and onset of early fatigue during both static work (for instance, holding a weight or carrying a load, tested with a dynamometer) and dynamic tasks in which there is always a static component.

Increased MPD, moreover, may be a potentially threatening biochemical situation to maintain muscle contractile content (27,29), function (30) and force generation. (29,30) Indeed, given that actin-myosin bridging is an energy consumption reaction, if muscle energy formation remains constant, less energy would be available for essential processes such as protein synthesis.

In this biochemical context it could be anticipated that an inadequate protein intake might exalt MPD since it has been shown that protein feeding rapidly reduces 3MEH release. (31,32)

Thus in patients with MPD the need for an adequate diet in both energy and protein content in order to sustain baseline myofibril turnover is mandatory. To confirm this, the study patients with adequate nutritional intake maintained their body weight and muscle mass despite MPD.

We believe that the variability of both MPD/protein synthesis ratio and concurrent energy-protein intakes in CHF patients may explain both the variability in protein metabolism (33) of CHF and the selective reduction of muscle tissue found in subgroups of patients with normal weight. (15,20)

Energy consumption needed for the actin-myosin bridging reaction may explain the mild but significant correlations found in the study between 3MEH on the one hand and oxygen consumption and serum creatinine on the other hand. Indeed, we have to consider that serum creatinine is an end-product of increased creatin phosphate formation by aerobic metabolism.

Clinical implications

For clinical practices, the possibility of estimating the presence of MPD by 3MEH or BU enables the physician/general practitioner to easily diagnose and monitor overtime the impact of heart failure on one important feature of muscle metabolism as well as to plan preventive measures to reduce the risk of muscle deterioration as much as possible over time. This may be particularly important for out patients.

The study suggests the usefulness of interpreting very simple blood measurements such as BU and CR as indicators of metabolic processes, in absence of renal dysfunction.

Limitations

The knowledge of plasma cytokine levels, which were not determined in this study, would have strengthened the discussion. The amino acid 3MEH can be measured in plasma and in 24hr urine collection. Usually, the nutritional investigation uses 3MEH in urine to quantify muscle breakdown over a day. We used plasma samples due to our different aim, as we wanted to document whether patients with CHF had high MPD at rest. Using plasma 3MEH, moreover, has the advantage of avoiding excess of day to day variation of urine flow frequently observed in CHF and potentially influencing the constancy of the measure. Even in healthy subjects, the range of 3MEH excretion is large, despite comparable conditions of evaluation. (4) On the contrary, it has been documented that formed 3MEH plasma levels vary with muscle degradation (5) as the body pool of 3MEH is modest. (5)

Increased BU might follow an excess of protein intake (>2g/day) (34) but this was not the case in our patients, who were ingesting protein 1.2 gr/Kg body weight. For the aims of the study, patients with comorbidities such as renal insufficiency, diabetes/insulin resistance or who were undernourished were excluded. Given that 3MEH is cleared by the kidney, in patients with renal insufficiency, representing 45% of our CHF population, theoretically, it would be not possible to estimate MPD. For clinical purposes, however, this is a false problem as renal insufficiency per se induces muscle wasting. (35) Therefore, the presence of renal insufficiency aggravates MPD in CHF patients. Patients with altered glucose control need a well planned investigation considering muscle alterations primed by metabolic glucose abnormalities.

Our study did not investigate undernourished patients with CHF. This may be particularly interesting because it could lead to a better understanding of the relation between MPD and body wasting over time. Lastly, additional research will be addressed to find out differences in 3MEH in relation to gender, even though these differences were not apparent here (data not shown).

ACKNOWLEDGEMENTS

We would like to thank Prof. Robert Coates (Centro Linguistico, Bocconi University, Milano, Italy), medical writer, for his linguistic revision.

Conflict of interest: None declared.

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(12.) Gottschlich MM, Jenkins ME, Mayes T, Khoury J, Kagan RJ, Warden GD. An evaluation of the safety of early vs delayed enteral support and effects on clinical, nutritional and endocrine outcomes after severe burns. J Burn Care Rehabil 2002; 23: 401-15.

(13.) Niebauer J, Pflaum CD, Clark AL, Strasburger CJ, Hooper J, Poole-Wilson PA, et al. Deficient insulin-like growth factor I in chronic heart failure predicts altered body composition, anabolic deficiency, cytokine and neurohormonal activation. J Am Coll Cardiol 1998; 32(2): 393-7.

(14.) Anker SD, Clark AL, Kemp M, Salsbury C,. Teixeira M, Hellewell PF,et al. Tumor necrosis factor and steroid metabolism in chronic heart failure: possible relation to muscle wasting. J Am Coll Cardiol 1997; 30: 997-1001.

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(17.) Aquilani R, Opasich C, Gualco A, Verri M, Testa A, Pasini E, et al. Adequate Energy protein intake is not enough to improve nutritional and metabolic status in muscle-depleted patients with chronic heart failure. Eur J Heart Fail 2008, 10(11):1127-35.

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(29.) Szentesi P, Bekedam MA, van Beek-Harmsen BJ, van der Laarse WJ, Zaremba R, Boonstra A, et al. Depression of force production and ATPase activity in different types of human skeletal muscle fibers from patients with chronic heart failure. J Appl Physiol 2005; 99(6): 2189-95.

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Corresponding author: Dr. Federica BOSCHI Department of Experimental and Applied Pharmacology University of Pavia V.le Taramelli, 14, 27100 Pavia-Italy Tel: ++39 0382 987398, Fax ++39 0382 987405 e-mail: federica.boschi@unipv.it

Roberto Aquilani [1], Cristina Opasich [2], Alessandra Gualco [2], Paola Baiardi [3], Evasio Pasini [4], Amidio Testa [5], Simona Viglio [6], Paolo Iadarola [6], Manuela Verri [7], Luca D'Agostino [8], Federica Boschi [9]

[1] Metabolic Service and Nutrition Pathophysiology, S.Maugeri Foundation, IRCCS Scientific Institute of Montescano, Pavia, Italy

[2] Cardiology Division, S.Maugeri Foundation,IRCCS Scientific Institute of Pavia, Italy

[3] Consortium for Biological and Pharmacological evaluations, S.Maugeri Foundation and University of Pavia, Pavia, Italy

[4] Cardiology Division, S.Maugeri Foundation, IRCCS Scientific Institute of Lumezzane, Brescia, Italy

[5] Rehabilitation Center "E.Spalenza", Don Gnocchi Foundation, Rovato, Brescia, Italy

[6] Department of Biochemistry "A.Castellani", University of Pavia, Italy

[7] Department of Legal Medicine, Forensic and Pharmacotoxicological Sciences "A. Fornari", Section of Pharmacological and Toxicological Sciences, University of Pavia, Italy

[8] S.Maugeri Foundation, IRCCS Scientific Institute of Pavia, Italy

[9] Department of Experimental and Applied Pharmacology, University of Pavia, Italy
Table 1. Demographic-, anthropometric-, clinical-,
functional-, treatment characteristics of study patients.

Number (n) 38
Age (yrs) 56.4 [+ or -] 10.6
Men/women 30/8
Arm Muscle Area (cm2) 54.9 [+ or -] 13
Body weight (Kg) 75.7 [+ or -] 14.2
Creatinine clearance (ml/min) 88.5 [+ or -] 22.6

Aetiology

Coronary artery disease 16 (42.1%)
Valvular heart disease 5 (13.2%)
Idiopathic 17 (44.7%)

Duration of disease (months)

<18 10
>18 28
NYHA Class
I 2 (5.26%)
II 19 (50%)
III 15 (39.48%)
IV 2 (5.26%)
Left ventricular ejection fraction 34.2 [+ or -] 10.5%

Medication

ACE inhibitors 33 (86.8%)
[beta]-blockers 31 (81.6%)
Digoxin 14 (36.8%)
Diuretics 38 (100%)

Table 2. Anthropometric and biohumoral variables in healthy
subjects (controls) and patients with CHF (mean [+ or -] SD).

 Controls
 n=17

Age (yr) 57.2 [+ or -] 5.9
Weight (Kg) 82.8 [+ or -] 12.2
Body Mass Index (Kg/[m.sup.2]) 28.7 [+ or -] 2.5
Blood Urea Levels (mg/dl) 29.9 [+ or -] 9.8 (nv 13-38)
Serum Creatinine (mg/dl) 0.89 [+ or -] 0.15 (nv 0.7-1.3)
Plasma 3MEH ([micro]mol/L) 3.74 [+ or -] 1.07 (nv 0-4)

 CHF
 n=38

Age (yr) 56.4 [+ or -] 10.6
Weight (Kg) 75.7 [+ or -] 14
Body Mass Index (Kg/[m.sup.2]) 26.8 [+ or -] 4.2
Blood Urea Levels (mg/dl) 45.6 [+ or -] 13
Serum Creatinine (mg/dl) 1.04 [+ or -] 0.16
Plasma 3MEH ([micro]mol/L) 9.5 [+ or -] 4.8

 p

Age (yr) ns
Weight (Kg) ns
Body Mass Index (Kg/[m.sup.2]) ns
Blood Urea Levels (mg/dl) <0.001
Serum Creatinine (mg/dl) =0.002
Plasma 3MEH ([micro]mol/L) <0.001

3MEH= 3-methylistidine nv = normal value of our laboratory
p = statistical significance
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Title Annotation:ORIGINAL ARTICLE
Author:Aquilani, Roberto; Opasich, Cristina; Gualco, Alessandra; Baiardi, Paola; Pasini, Evasio; Testa, Ami
Publication:Archives: The International Journal of Medicine
Article Type:Report
Geographic Code:4EUIT
Date:Apr 1, 2009
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