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European Journal of Heart Failure 2008 10(7):652-657; doi:10.1016/j.ejheart.2008.05.009
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© 2008 European Society of Cardiology

Reduced in vivo skeletal muscle oxygen consumption in patients with chronic heart failure—A study using Near Infrared Spectrophotometry (NIRS)

Khalid Abozguiaa,*,1, Thanh Trung Phana,1, Ganesh Nallur Shivua, Abdul R. Mahera, Ibrar Ahmeda, Anton Wagenmakersb and Michael P. Frenneauxa

a Department of Cardiovascular Medicine, Medical School, University of Birmingham Edgbaston, Birmingham, B15 2TT, UK
b School of Sport and Exercise Sciences, University of Birmingham Edgbaston, Birmingham, B15 2TT, UK

* Corresponding author. Tel.: +44 121 414 5916; fax: +44 121 414 3713. E-mail address: abozguia{at}gmail.com (K. Abozguia).


   Abstract
Top
 Notes
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Aim: We used Near Infrared Spectrophotometry (NIRS) during arterial occlusion to measure resting skeletal muscle oxygen consumption in chronic heart failure (CHF) patients and in age-matched healthy volunteers (HVs).

Methods: Fifteen CHF patients (ten males) and eleven HVs (six males) had echocardiographic evaluation followed by measurement of the oxygen consumption of the brachioradialis muscle using NIRS. This involved continuous measurement of the oxygenated haemoglobin concentration ([Oxy-Hb]) and deoxy-haemoglobin concentration ([Deoxy-Hb]) with an Oxiplex TS NIRS probe first under basal overnight fasted resting conditions followed by 1 min of forearm arterial occlusion. A linear decline was observed in [Oxy-Hb–Deoxy-Hb] during the arterial occlusion and the oxygen consumption rate was calculated from the initial slope observed.

Results: CHF patients were 59±2.8 years old with Left Ventricular Ejection Fraction (LVEF) 31%±2.2 and the HVs were 52±4.8 years old with LVEF 62%±2.5. The resting muscle oxygen consumption rate was significantly reduced in CHF patients versus HVs (0.04±0.01 mlO2/min/100 g versus 0.07±0.01 mlO2/min/100 g) p<0.005.

Conclusions: There is a significant reduction in resting oxygen consumption per gram of tissue in skeletal muscle of patients with CHF.

Key Words: Chronic heart failure • Skeletal muscle • Oxygen consumption • NIRS

Received December 22, 2007; Revised April 25, 2008; Accepted May 19, 2008


   1. Introduction
Top
 Notes
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
CHF is a common condition and is associated with considerable morbidity and mortality [1]. Clinical features include muscle weakness, general fatigue and dyspnoea [2,3]. It is clear that central haemodynamics correlate poorly with exercise capacity in CHF [3]. Therefore, attention has been focused on peripheral factors such as intrinsic skeletal muscle abnormalities and skeletal muscle underperfusion. Several studies in patients [4-8] and animal models of CHF [9-14] have described skeletal muscle histological abnormalities, including fibre-type transformation toward more fast phenotype, fibre atrophy, and reduced oxidative enzyme activities. Phosphocreatine (PCr) and creatine kinase (CK) are involved in the fine regulation between energy production and energy utilization in muscle cells [15,16]. 31P Magnetic Resonance Spectroscopy (MRS) has revealed a decreased content of mitochondrial CK in skeletal muscle of patients with CHF. However, whether these skeletal muscle abnormalities result in reduced peripheral oxygen consumption has never been directly assessed. The goal of the present study was therefore to examine whether skeletal muscle oxygen consumption is reduced in CHF patients as compared to age-matched HVs.

NIRS is a non-invasive optical technique that is increasingly used to assess changes in tissue oxygenation in skeletal muscle [17]. This technique is based upon the principle that NIRS light easily penetrates skeletal muscle, where it is absorbed by the iron or copper content of haemoglobin and myoglobin [18]. The majority of NIRS light absorption is due to the presence of haemoglobin in the small arterioles, capillaries, and venules of the microcirculation [17]. These features have led to growing interest in the use of NIRS as a non-invasive technique to measure changes in muscle oxygenation and blood flow at rest and during both submaximal and maximal exercise.

Resting skeletal muscle oxygen consumption is the ultimate measure of resting muscle metabolic rate, and is affected by environmental temperature, body temperature, the microvascular blood flow and nutrition [19]. In the absence of blood flow, the oxygen content of the tissue diminishes as oxygen is consumed by the mitochondria. Therefore oxygen consumption can be determined by measuring the decline in oxygen saturation of haemoglobin and myoglobin following total arterial occlusion. Assuming the duration of occlusion is insufficient to cause a significant shift to anaerobic glycolysis, this will be a reliable indicator of resting oxygen consumption.

This work represents a clinical application of a non-invasive technique to assess and compare resting skeletal muscle oxygen consumption in CHF patients and HVs using NIRS.


   2. Methods
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
Fifteen CHF patients (ten males) and eleven HVs (six males), who provided written informed consent, were included in the study. Characteristics and treatment of participants are shown in Table 1. The experiment was approved by the local Research Ethics Committee at the University of Birmingham, UK and the investigation conforms to the principles outlined in the Declaration of Helsinki. All CHF patients had a history of dyspnoea on exertion (NYHA II-III) with LVEF≤50% and had been in a stable clinical condition over the last 3 months. All HVs had no history or symptoms of any medical illness with normal ECG and echocardiogram (LVEF≥55%). CHF patients and HVs were matched for age, sex and body surface area. All study participants had an ECG, echocardiographic evaluation and measurement of oxygen consumption using NIRS.


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  		Table 1 Baseline characteristics and treatments for chronic heart failure (CHF) patients and healthy volunteers (HVs)

 
2.1. Resting echocardiography
Echocardiography was performed with participants in the left lateral decubitus position using a Vivid 7 echocardiographic machine and a 2.5-MHz transducer. Measurements were averaged for 3 beats. Resting scans were acquired in standard echocardiographic windows for LVEF. LV volumes were obtained by biplane echocardiography, and LVEF was derived from a modified Simpson's formula. Studies were stored digitally and analyzed off-line.

2.2. NIRS
Subjects were investigated in the overnight fasted state. The hair was removed from the forearm of participants using a disposable shaver and the skin thickness was measured using skin callipers. Skeletal muscle oxygenated haemoglobin concentration [Oxy-Hb], deoxygenated haemoglobin concentration [Deoxy-Hb] and total haemoglobin concentration [HbT] were measured with the OxiplexTS Near Infrared tissue oximeter (ISS Inc., Champaign, IL, USA). This is a frequency domain multi-distance NIRS using 4 laser-diode light sources at two wavelengths (692 and 834 nm) and one detector. The NIRS probe used had source-detector distances of 3.0-4.4 cm to limit the contribution of skin and subcutaneous non-muscle tissue and was placed over the brachioradialis muscle. The absorbances measured represent the sum of haemoglobin in the microvasculature and myoglobin in the myocytes. NIRS exploits the difference in optical absorption spectra between the [HbT] and [Deoxy-Hb]. At a wavelength of 834 nm, [Oxy-Hb] and [Deoxy-Hb] exhibit similar absorption coefficients. Therefore, absorption of light at this wavelength is proportional to [HbT] in the muscle under examination. At a wavelength of 692 nm, absorption is primarily by the deoxygenated Hb. Therefore, changes in light absorption at 692 nm provide assessment of changes in [Deoxy-Hb]. The difference between absorption at 834 and 692 nm gives the [Oxy-Hb]. A blood pressure cuff was applied around the proximal part of the arm as described previously [20]. The experiment involved continuous measurements of [Oxy-Hb], [Deoxy-Hb] and [HbT] at rest for 2 min. Then the cuff was inflated to 220 mm Hg for 1 min, to induce forearm arterial occlusion. [Oxy-Hb], [Deoxy-Hb] and [HbT] were again recorded continuously during the 1 min of forearm arterial occlusion (Fig. 1). The resting muscle oxygen consumption rate was determined by the rate of decline of the difference between [Oxy-Hb] and [Deoxy-Hb] during occlusion and was then expressed per 100 g of forearm muscle tissue. The conversion of oxygen consumption rate to mlO2/min/100 g was performed as previously described [21,22]. Initially, the oxygen consumption NIRS value ({varepsilon}mol/l/s) was converted into minutes. 1.04 kg/l was used for muscle density to convert 1 l to 100 g of skeletal muscle. One mole of Hb carries four moles of O2. Then, 1 mol of gas was converted into 1 l with value of 1 mol gas=22.4 L standard temperature and pressure, dry (STPD) conditions. Oxygen saturation was calculated from the ratio between [Oxy-Hb] and [HbT].


Figure 01
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  		Fig. 1 Oxygen consumption in healthy volunteers (HVs) and chronic heart failure (CHF) patients. This graph shows continuous NIRS measurements at rest, during 1 min of arterial occlusion and during recovery in HVs (white circles) and CHF patients (black circles). The resting skeletal muscle oxygen consumption rate was determined by the rate of decline of the difference between [Oxy-Hb] and [Deoxy-Hb] during arterial occlusion. A) represents the start of arterial occlusion whereas B) represents the end of arterial occlusion.

 
2.3. Statistics
Comparison of oxygen consumption in HVs with CHF patients was determined by a 2-sided Student's t-test. Data were analyzed with SPSS 14 for Windowsxp and expressed as mean±standard error of mean. Variances of data sets were determined using F-test. A p value of <0.05 was taken to indicate statistical significance.


   3. Results
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
CHF patients and HVs were well matched with respect to age and sex (Table 1). However, LVEF was significantly lower in CHF patients (Table 2).


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  		Table 2 Baseline investigations of chronic heart failure (CHF) patients and healthy volunteers (HVs)

 
Resting NIRS measurements showed no significant difference in resting oxygen saturation in CHF patients versus HVs (62.85±1.96 versus 64.18±2.50%, p=0.67). However the resting [HbT] was significantly lower in CHF patients (47.86±4.27 µmol) versus HVs (59.66±4.46 µmol, p<0.05). The [Oxy-Hb] was also significantly lower in CHF patients (30.13±2.95 vs 37.68±2.45 µmol, p<0.05). There was a non-significant trend towards a lower [Deoxy-Hb], probably as a result of lower [HbT] (17.73±1.68 vs 21.97±2.88 µmol, p=0.094) (Table 2). Oxygen consumption at rest in CHF patients was significantly reduced versus HVs (0.04±0.01 mlO2/min/100 g versus 0.07±0.01 mlO2/min/100 g) pgreater double equals0.005. There were no correlations between oxygen consumption and LVEF in patients with CHF (r=0.09, p=0.74) (Fig. 2). Measurements of oxygen consumption correlated positively with [Oxy-Hb] (r=0.59, p=0.001), [Deoxy-Hb] (r=0.71, p<0.001) and [HbT] (r=0.73, p<0.001) (Fig. 3). However, there was no significant correlation between oxygen consumption and oxygen saturation (r=0.28, p=0.17) (Fig. 3).


Figure 02
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  		Fig. 2 Correlation between skeletal muscle oxygen consumption and LVEF in chronic heart failure (CHF) patients. There is no correlation between peripheral oxygen consumption, as expressed in ml/100 g/min, and LVEF in patients with CHF.

 


Figure 03
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  		Fig. 3 Correlation between skeletal muscle oxygen consumption and resting NIRS measurements. There was a positive correlation between peripheral oxygen consumption and resting [Oxy-Hb] (graph A), [Deoxy-Hb] (graph B) and [HbT] (graph C). However, there was no significant correlation between peripheral oxygen consumption and resting oxygen saturation (graph D).

 

   4. Discussion
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
In the present study, we have used a non-invasive tool (NIRS) to measure peripheral oxygen consumption in CHF patients and age-matched HVs. Whilst a reduction in peak oxygen consumption during exercise is a hallmark of heart failure, our finding of reduced resting oxygen consumption is to the best of our knowledge novel. Both central and skeletal muscle factors play a role in exercise limitation in CHF, though the relative importance of each has been controversial [23,24].

Skeletal muscle underperfusion is a recognized feature in CHF patients [25]. This leads to a reduction in oxygen supply to skeletal muscle that might result in adaptation of the skeletal muscle to consume less oxygen at rest. NIRS measurement of [Oxy-Hb] and [HbT] had been used as a surrogate measurement of skeletal muscle blood flow [25,26]. Our resting data of [Oxy-Hb] and [HbT] were reduced at rest in CHF patients as compared to age-matched HVs (Table 2), which is in agreement with Wilson and co-workers [25]. Interestingly, Massie and co-workers [27] showed no relationship between skeletal muscle blood flow and the metabolic findings in CHF patients. However, it is important to note that we measured skeletal muscle oxygen consumption under conditions of temporary circulatory occlusion; therefore reduction in oxygen delivery cannot be the direct cause of the observed reduction in skeletal muscle oxygen consumption. Chronic skeletal muscle hypoperfusion may nevertheless induce adaptive changes in skeletal muscle function that are responsible for the reduced oxygen consumption. Furthermore, it is important to note that the oxygen consumption measurements are expressed per 100 ml forearm tissue therefore these findings cannot be explained in terms of a reduced skeletal muscle mass in heart failure patients. The mechanisms that may lead to this reduction in resting oxygen consumption are discussed below.

4.1. Possible mechanisms underlying reduced skeletal muscle oxygen consumption in CHF patients
Heart failure is associated with altered metabolism within the skeletal muscle [28] with a reduction in mitochondrial density and oxidative enzymes resulting in reduced aerobic capacity [4,29,30]. Evidence of a reduction in mitochondrial density originates from studies showing that CHF patients had increased PCr breakdown, intracellular acidosis [31], decreased rate of ATP resynthesis during exercise and recovery [31,32] and decreased activity of selected oxidative enzymes [33,34]. Furthermore, other studies have shown that abnormal skeletal muscle metabolism contributes to the reduced functional capacity in CHF patients [31,32,35]. Further studies are required to examine the contribution of these mitochondrial factors to the observed reduction in skeletal muscle oxygen consumption in CHF patients.

Previous reported studies have shown that skeletal muscle energetic status at rest is not significantly impaired in heart failure, in contrast there is accelerated PCr depletion and slower recovery of PCr following exercise [36]. These indicate a reduced ability to generate ATP during the increased demands associated with exercise. Accordingly our observations can only be explained either by a reduced metabolic rate in skeletal muscle (i.e. a reduced resting requirement for ATP production) or by an increase in metabolic efficiency (i.e. an increase in ATP production per unit oxygen consumption). The former paradigm would imply a situation analogous to ‘hibernation’ seen in cardiac muscle in which repetitive myocardial stunning induces a downregulation of basal metabolic processes. Heart muscle contractile function can be recruited to hibernating myocardium by the infusion of low dose Dobutamine but further increments in Dobutamine infusion rate result in a loss of contractile function again [37]. In the same way, it is possible to conceive of a reduction in basal metabolic rate with a capacity to upregulate metabolism during low level exercise but rapid fatigue at higher exercise loads. The second paradigm (increased metabolic efficiency) might theoretically be explained by a change in substrate utilization. Skeletal muscle is capable of using various sources to generate energy such as carbohydrates, fats (including ketones derived from fats) and proteins. The oxidation of glucose generates approximately 12% more ATP per unit oxygen consumption than the oxidation of fats [15,16]. At rest in the fasting state skeletal muscle metabolizes principally free fatty acids (FFAs) and they are also the main form of substrate during low to medium intensity exercise [38]. However, Sidossis and colleagues showed that FFA oxidation is limited during high-intensity exercise, which suggests a shift to an energy efficient substrate such as glucose [38]. Theoretically a shift towards greater glucose utilization might result in greater metabolic efficiency, which leads to less oxygen consumed to generate same molecule of ATP as compared to FFAs. However, this shift could not on its own explain the magnitude of the difference in oxygen consumption that we observed.

4.2. Skeletal muscle atrophy and fibrosis
In the present study, both CHF and HVs groups had comparable body mass index (Table 2). There was an insignificant small increase in the forearm skin thickness in CHF patients as compared to HVs (8.01 mm±3.10 vs. 6.50 mm±4.30, respectively). However, the NIRS probe used in this study had source-detector distances of 30-44 mm to limit the contribution of skin and subcutaneous non-muscle tissue. Skeletal muscle atrophy has been observed in patients with CHF [32,39], which may result from different mechanisms such as inactivity, inflammation, apoptosis and an imbalance in catabolic/anabolic processes [40]. Our measurement of oxygen consumption was expressed per 100 g of forearm muscle tissue. Therefore, skeletal muscle atrophy and increased interstitial fat content and fibrosis in CHF patients may contribute to the reduction in oxygen consumption, but seems unlikely to explain the magnitude of the difference.

4.3. Implication and future research
In this study we used NIRS to provide a non-invasive assessment of peripheral oxygen kinetics in CHF patients. NIRS has the potential to be an important clinical tool for assessing the severity of skeletal muscle metabolic impairment, the progression and also response to treatment in heart failure. In this study, we showed that there is a significant reduction in resting oxygen consumption per gram of tissue in skeletal muscle of patients with CHF. This could be due to a combination of intrinsic factors such as mitochondrial dysfunction, altered skeletal muscle substrate utilisation and skeletal mass composition. Further studies are warranted to examine the underlying mechanisms responsible for these observations.


   Acknowledgements
 
This study was funded by the British Heart Foundation. We would like to thank Erika Cerri for her helpful support.


   Notes
Top
 Notes
Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
1 Both authors contributed equally to this work. Back


   References
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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