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Cardiovascular Research 2001 52(1):111-119; doi:10.1016/S0008-6363(01)00357-1
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Copyright © 2001, European Society of Cardiology

Cardiac energetics are abnormal in Friedreich ataxia patients in the absence of cardiac dysfunction and hypertrophy: An in vivo 31P magnetic resonance spectroscopy study

Raffaele Lodia,b,*, Bheeshma Rajagopalana, Andrew M Blamirea, J.Mark Cooperc, Crispin H Daviesd, Jane L Bradleyc, Peter Stylesa and Anthony H.V Schapirac,e

aMRC Biochemical and Clinical Magnetic Resonance Unit, Department of Biochemistry, University of Oxford and Oxford Radcliffe Hospital, Oxford, UK
bDipartimento di Medicina Clinica e Biotecnologia Applicata ‘D. Campanacci’, Universita’ di Bologna, Policlinico S. Orsola, Via Massarenti 9, 40138 Bologna, Italy
cUniversity Department of Clinical Neurosciences, Royal Free and University College School of Medicine, University College London, London NW3 2PF, UK
dDepartment of Cardiovascular Medicine, John Radcliffe Hospital, Oxford, UK
eDepartment of Clinical Neurology, Institute of Neurology, London, UK

* Corresponding author. Tel.: +39-051-305-993; fax: +39-051-303-962 lodi{at}med.unibo.it

Received 19 February 2001; accepted 25 May 2001


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Objective: Friedreich ataxia (FRDA), the commonest form of inherited ataxia, is often associated with cardiac hypertrophy and cardiac dysfunction is the most frequent cause of death. In 97%, FRDA is caused by a homoplasmic GAA triplet expansion in the FRDA gene on chromosome 9q13 that results in deficiency of frataxin, a mitochondrial protein of unknown function. There is evidence that frataxin deficiency leads to a severe defect of mitochondrial respiration associated with abnormal mitochondrial iron accumulation. To determine whether bioenergetics deficit underlies the cardiac involvement in Friedreich ataxia (FRDA) we measured cardiac phosphocreatine to ATP ratio non-invasively in FRDA patients. Methods and results: Eighteen FRDA patients and 18 sex- and age-matched controls were studied using phosphorus MR spectroscopy and echocardiography. Left ventricular hypertrophy was present in eight FRDA patients while fractional shortening was normal in all. Cardiac PCr/ATP in FRDA patients as a group was reduced to 60% of the normal mean (P<0.0001). In the sub-group of patients with no cardiac hypertrophy PCr/ATP was also significantly reduced (P<0.0001). Conclusion: Cardiac bioenergetics, measured in vivo, is abnormal in FRDA patients in the absence of any discernible deterioration in cardiac contractile performance. The altered bioenergetics found in FRDA patients without left ventricle hypertrophy implies that cardiac metabolic dysfunction in FRDA precedes hypertrophy and is likely to play a role in its development.

KEYWORDS Energy metabolism; Free radicals; Hypertrophy; Mitochondria; Oxidative phosphorylation


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Friedreich ataxia (FRDA) is the commonest form of inherited ataxia with a frequency of 1 in 50 000 live births. It is an autosomal recessive degenerative disorder, characterised clinically by onset before the age of 25 of progressive gait and limb ataxia, absence of deep tendon reflexes, extensor plantar responses, and loss of position and vibration sense in the lower limbs [1]. Hypertrophic cardiomyopathy is a common clinical feature in FRDA and is present in 39–100% of patients [2–6]. Most FRDA patients show left ventricle (LV) concentric hypertrophy with, in general, normal LV systolic and diastolic function, though abnormalities of both systolic and diastolic function have been reported [4–6].

The cause of FRDA in most patients is a homozygous GAA triplet expansion in the first intron of the FRDA gene on chromosome 9q13 [7]. The FRDA gene encodes a widely expressed protein, frataxin, which is located in the mitochondrion [8–10] and is decreased in FRDA patients [8]. The function of frataxin is still unknown but yeast strains carrying a disruption in the frataxin homologue gene (YFH1) showed a severe defect of mitochondrial respiration [9–12] and loss of mitochondrial DNA [11,12] associated with increased sensitivity to oxidative stress and elevated intramitochondrial iron [9,12]. We and others have shown that mitochondrial ATP production rate in FRDA patients measured in skeletal muscle in vivo is reduced [13,14]. In addition, the analysis of post mortem heart samples from patients with FRDA has revealed severe defects of complexes I, II and III [15] which is in agreement with a previous preliminary study of endomyocardial biopsies from two FRDA patients with hypertrophic cardiomyopathy [16]. Taken together these data suggest that a mitochondrial deficit of ATP production may be relevant in the pathogenesis of cardiomyopathy in FRDA.

Elements of myocardial energetics can be measured in vivo by 31P MRS. 31P MRS enables the measurement of the ratio of phosphocreatine (PCr) to ATP which has been shown by 31P MRS or conventional biochemistry to be a good measure of the energetic state of cardiac muscle [17,18]. PCr/ATP is decreased in patients with impaired LV function due to increased workload as in mitral regurgitation, aortic valve disease, hypertension, hypertrophic cardiomyopathy, and also in cases of idiopathic or ischaemic congestive cardiomyopathy [19–22]. Some recent studies have also described abnormal PCr/ATP ratios in conditions with increased workload but without impaired mechanical function [23,24].

To determine if the frataxin defect in FRDA leads to abnormal in vivo cardiac energetics, we measured cardiac PCr/ATP by 31P MRS in 18 FRDA patients all with no signs or symptoms of heart failure. In view of the possible effect of cardiac hypertrophy per se on heart bioenergetics, PCr/ATP in FRDA patients with and without hypertrophy were grouped separately.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1 Subjects
Our study was approved by the Central Oxford Research Ethics Committee and conformed with the principles outlined in the Declaration of Helsinki (Cardiovascular Research 1997;35:2–3); informed consent was obtained. Recognised clinical criteria for the diagnosis of FRDA [1] were used to recruit 18 FRDA patients (eight men and ten women; age range 16–54; 31±9 years, mean±S.D.) (Table 1). We also studied 18 healthy individuals (eight men and ten women; age range 16–51 years; 30±7 years, mean±S.D.) who had no history of heart disease.


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  		Table 1 Clinical and genetic data from FRDA patients

 
2.2 DNA analysis
DNA was extracted from the patients’ blood using the NucleonTM I DNA isolation kit (Scotlab, Strathclyde, UK). A portion of the FRDA gene was amplified using the ExpandTM Long Template PCR system (Boehringer) using the GAAF and GAAR primers previously described [7] and the PCR protocol of: 94°C for 3 min, followed by 94°C for 10 s, 63°C for 30 s and 68°C for 3 min for 30 cycles, with the addition of 20 s per cycle for the elongation step for the last 20 cycles and a final elongation of 72°C for 10 min. The GAA repeat length was calculated according to the size of the PCR product (457+3n bp, n=number of GAA triplets).

2.3 Echocardiography
M-mode and two-dimensional imaging from parasternal and apical windows was performed using a HP-5500. Images were recorded on optical disk for subsequent analysis. Standard M-mode measurements were made using established criteria [25].

2.4 31P MRS study of human subjects
2.4.1 Spectral acquisition
All studies were performed in a 2.0 T whole body magnet. Patients were positioned prone on a custom-made patient bed incorporating a gantry to allow a range of surface coils to be located beneath the subjects’ chest without moving the subject. After optimising the position of the heart from spin-echo images acquired using a double surface coil, the sample volume was shimmed using a 15-cm diameter circular 1H surface coil. Cardiac gated spectra were acquired using an 8-cm diameter 31P surface coil. The liver and skeletal muscle from the chest wall are anatomically close to the heart making accurate spectral localisation crucial in cardiac 31P MRS. A localised one-dimensional chemical shift imaging sequence [26] was employed to provide contiguous slices in the coronal plane (64 encode steps, 64 cm field of view, 12 averages per encode) which separate the signals from the anterior chest wall and heart. The lateral extent of these slices is limited by the active volume of the surface coil but is relatively poorly defined. To improve localisation, skeletal muscle in the chest wall lateral to the heart was identified from the MR images and metabolite signals were eliminated using an oblique pre-saturation slab. To achieve effective saturation with the surface coil, four sinc-shaped pre-saturation pulses were used at two flip-angles ({alpha} and 2{alpha}) which we have previously shown to eliminate >95% of the signal from within the presaturation slab [27]. A selective excitation pulse was also used to define an 8-cm thick axial slice and its’ inferior extent was defined using the proton images to exclude signal from the liver and diaphragm.

2.4.2 Saturation correction
As the interpulse delay is much shorter than the T1 relaxation times for ATP and PCr there is a reduction in measured signal intensity (saturation) which is a function of pulse angle, repetition rate and the T1 of the metabolite. As the T1s of ATP and PCr are different the calculated ratio is altered by changing heart rate. To allow for this effect, correction factors were measured using phosphate phantoms of known T1. The pulse angle at the surface of the coil was similar for equivalent power levels whether the load was a phantom or a human subject. T1s of PCr and ATP were assumed to be 4.3 and 2.52 s, respectively, being the average of published data [28]. As the difference between the correction factors for heart rates of 55 and 100 was only 4–5% the correction factor has little effect on the relative differences between patients and controls. As the correction factors are sensitive to the assumed T1s, the corrected absolute ratios from different reports may vary depending on assumed T1s. We therefore present both the raw and corrected ratios.

2.4.3 Data processing
Spectra from slices identified as cardiac from their position in the proton images (Fig. 1) were analysed using a purpose-written interactive frequency domain fitting program incorporating prior knowledge on chemical shifts and j-coupling constants and similar to a method recently described [29]. After fitting, the ATP signal was corrected for blood contamination based on the amplitude of the 2,3-DPG [20,30] and saturation correction was applied to give the final PCr/ATP.


Figure 1
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  		Fig. 1 (Top) Left: Axial MR image showing the location of the surface coil. Signal localisation was achieved by slice selection (transverse slice), elimination of signal from antero-lateral chest wall skeletal muscles using an oblique presaturation slab (shaded region) and phase encoding into 1-cm thick contiguous coronal slices (dotted lines). Further localisation was provided by the restricted field of view of the surface coil as approximately indicated by extent of the dotted lines. Right: Selected rows from the dataset showing spectra from chest wall muscles and cardiac muscle. The cardiac muscle spectrum was obtained by adding the signal of two 1-cm slices collected from septum, apex and posterior wall. (Bottom) 31P MRS cardiac spectra from a patient with Friedreich ataxia (FRDA) (top) and a sex- and age-matched healthy volunteer (bottom). In the patient the PCr peak (relative to ATP) is decreased to about one-third of the normal subject (after correction for blood contamination and saturation). 2-3-DPG, 2-3-diphosphoglycerate; PCr, phosphocreatine; {gamma}, {alpha} and β, the three phosphate groups of ATP.

 
2.5 Analysis of iron effects on phosphorus metabolites longitudinal relaxation times (T1s)
Accumulation of iron which has been hypothesised to cause mitochondrial damage in FRDA [9,12,16,31] could alter phosphorus metabolite T1s. We therefore investigated the effects of iron on PCr to ATP ratios in solution experiments. Within the cell free iron levels are tightly controlled with most iron being in the ferric form, stored within ferritin [32]. Solutions were prepared as tabulated in Table 3 and studied in the whole body system used in the patient study to avoid field strength differences. A ferritin concentration of 2.5 mg Fe/ml was chosen based upon literature data of the concentration in patients with hepatic iron overload [33] as an extreme case of elevated iron levels. Longitudinal relaxation rates were measured using an inversion recovery sequence under fully relaxed conditions with 16 inversion times from 2 ms to 15 s and data was fitted to the standard three-parameter IR formula.


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  		Table 3 31P MRS solution experiment data

 
2.6 Statistical analysis
Individual results were taken as abnormal when they fell outside the entire range of the control values. The Student’s t-test for unpaired data was used to compare variables from groups and statistical significance was taken as P<0.05. Comparison of variables from more than two groups was done by performing an analysis of variance (ANOVA) followed the Fisher’s PLSD test to discriminate significant differences between group means. Data are reported as mean±S.D.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1 Genetic, echocardiographic and 31P MRS evaluation of FRDA patients
All the 18 FRDA patients were homozygous for the GAA triplet repeat expansion (range 290–950 on the smaller allele; normal values range from seven to 22 repeats [7]) (Table 1). No patient had systemic hypertension, aortic stenosis or clinical symptoms/signs of heart failure.

Echocardiographic findings are summarised in Table 2. Eight patients (patients 11–18) showed left ventricular hypertrophy (LVH) as defined on the basis of a posterior wall (PWd) and/or septal (IVSd) thickness equal or >1.1 cm in diastole (1.24±0.15 and 1.22±0.21, respectively), while in the other ten (patients 1–10), PWd and IVSd thickness was <1.1 cm (0.95±0.11 and 0.93±0.09, respectively). End-systolic and end-diastolic LV dimensions were normal in all patients except case 9 who showed values just above the normal limit. Fractional shortening (FS) was normal in all 18 FRDA patients (lower limit of normal in our institution 25%). GAA repeat length on the smaller allele was higher in FRDA patients with LVH (668±194) compared to those without hypertrophy (560±188), but it did not reach statistical significance (P=0.2). Subjects’ age, age at onset, duration of disease and LV dimensions were not statistically different between the two group of patients (data not shown). Patients without LVH had a similar FS (37±10%) as those with hypertrophy (36±7%) (P=0.7).


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  		Table 2 31P MRS and echocardiography data from FRDA patients

 
Cardiac PCr to ATP ratios in the FRDA group as a whole were significantly reduced compared to age- and sex-matched controls (FRDA 1.46±0.53, controls 2.39±0.13; P<0.0001) (Table 2 and Fig. 2). The Fisher’s PLSD test showed significantly reduced PCr/ATP ratios in both groups of FRDA patients with normal (1.44±0.54) and hypertrophic heart (1.47±0.55) compared to controls (P<0.0001 for both groups) (Fig. 2), and similar mean ratios in the two patient groups (P=0.85). No correlation was found between FS and cardiac PCr/ATP (P=0.4). Only two FRDA patients, one without LVH (case 9), and one with LVH (case 14), showed PCr/ATP ratios within the normal range (Table 2). No correlation was found between GAA repeat number on the smaller allele and cardiac PCr/ATP (P=0.9).


Figure 2
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  		Fig. 2 Cardiac PCr/ATP in Friedreich ataxia patients (FRDA) with no LVH (n=10), in FRDA patients with LVH (n=8), and in 18 healthy volunteers. * P<0.0001.

 
3.2 31P MRS solution experiments
As our human studies were performed under partially saturated conditions, the potential influence of iron overload [15,34] in FRDA hearts, on PCr and ATP T1s and its effect on PCr/ATP were investigated. Table 3 shows that longitudinal relaxation rates of PCr and {gamma}-ATP were both reduced on addition of ferritin (T1 decreases proportionally by about the same amount). From these data we conclude that iron effect on PCr to ATP ratios would be negligible (less than 5%).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
Our results show that in FRDA patients the GAA repeat expansion on the FRDA gene is associated with abnormal in vivo cardiac bioenergetics in the absence of any discernible deterioration in contractile performance. The bioenergetic deficit is also present in FRDA patients without LV thickening, implying that cardiac metabolic dysfunction in FRDA precedes the development of the hypertrophic process and it is not a consequence of it. This study represents the first evidence in humans of abnormal in vivo cardiac bioenergetics in the absence of increased workload, vascular problems or hypertrophic cardiomyopathy.

Heart involvement in FRDA is an important prognostic factor since complications of cardiomyopathy are a frequent cause of premature death in FRDA patients. The frequency of cardiomyopathy increases with the size of the GAA expansion in intron 1 of the FRDA gene, though a large overlap between patients with and without cardiomyopathy is present [4,6]. The GAA expansion results in a reduction in the levels of frataxin, the FRDA gene product, and this is likely to be the primary cause of cardiomyopathy in FRDA patients [7]. About 44% of our patients showed echocardiographic signs of LVH, while all 18 cases had normal LV systolic function and only one patient showed end-diastolic and end-systolic LV dimensions just above the normal limit (Table 2). Despite normal LV function, low PCr to ATP ratio in our FRDA patients clearly indicates reduced cardiac energy reserve in these patients. Iron deposits have been found in the myocardium of FRDA patients [34] which, depending on their sub-cellular distribution could potentially alter the metabolite spin-lattice relaxation times (T1) and alter the observed PCr to ATP ratios in the FRDA patients. Frataxin deficiency is associated with cellular iron re-distribution rather than total cellular increase with a selective accumulation into mitochondria as shown in yeast strains carrying a disruption in the FRDA homologue gene [9,12,16], and in fibroblasts [31] and post-mortem cardiac samples from FRDA patients [15]. The high viscosity within the mitochondrial matrix leads to very rapid signal decay (short spin–spin relaxation times,T2) which under our experimental conditions eliminates all signal from mitochondrial PCr and ATP. Were there to be significant iron accumulation within the cytosol, our solution experiments (Table 3) clearly show that although absolute metabolite T1 relaxation times would be reduced, they would not result in any substantial effect on PCr to ATP ratios. Although we do not know absolute PCr and ATP concentrations, reduced cardiac [PCr] associated with unchanged [ATP] or ATP reduced to a lesser extent than PCr, is the most likely cause of reduced PCr/ATP in our patients. A recent study, demonstrating that overexpression of frataxin in mammalian cells results in elevated ATP content, would predict reduced levels of ATP in FRDA patients’ tissues [35]. If ATP content were reduced in the heart of our FRDA patients the PCr content, derived from PCr/ATP, would be even lower. Fully quantitative spectral acquisition could directly address whether reduced PCr/ATP is due to changes in PCr or ATP (or differential changes in both). However, absolute quantitation requires accurate measurement of the tissue volume contributing to each spectrum, assumptions or measurement of intra-cellular and extra-cellular water content, assumption of uniform metabolite distribution within the tissue, correction for surface coil properties and reference of all data to external standards. Acquisition of all of the data required to address each of these factors was not possible within a duration which could be tolerated by this patient population.

PCr is a central metabolite in the biochemical pathways that supply high-energy phosphates for muscle contraction. Through the creatine-kinase reaction PCr is in equilibrium with ADP [36]. Thus, assuming unchanged total creatine, low PCr/ATP in our FRDA patients leads to an increase in [ADP] which is the major driving force of mitochondrial ATP production [37,38]. Low [PCr] and high [ADP] is a typical finding in skeletal muscle [39] and brain [40] of patients with mitochondrial encephalomyopathies due to a deficit of oxidative phosphorylation caused by mutations within mitochondrial DNA. In mitochondrial encephalomyopathies as well as in FRDA, high cellular [ADP] represents an increased stimulus for ATP production in the presence of malfunctioning oxidative phosphorylation. In view of the mitochondrial localisation of frataxin and the effects on oxidative phosphorylation of its deficit demonstrated in the FRDA yeast knock out model (see below) and in the skeletal muscle of FRDA patients [13,14], mitochondrial dysfunction is the most likely cause of low cardiac PCr/ATP in FRDA. This interpretation is supported by our recent finding of reduced cardiac PCr/ATP in patients with the mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome [41] which is caused by the A3243G mutation of mitochondrial DNA and is associated with a profound deficit of respiratory chain complex I activity. However, decrease in total cardiac creatine (PCr+Cr) concentration may contribute to PCr/ATP reduction which could further impair the ability to deliver ATP to energy-consuming systems.

The PCr to ATP ratios were reduced to 60% of the mean control value in the group of ten FRDA patients with normal echocardiographic features (Table 2). This represents the first evidence that cardiac PCr/ATP can be reduced in the absence of both failing contractile function and hypertrophy in humans [19–24]. A low PCr/ATP in FRDA patients with no signs of LVH suggests that the hypertrophic process may be compensatory and that the bioenergetic deficit, which is known to stimulate myocyte hypertrophy [42], may contribute to or initiate it. We have previously shown a negative correlation between the maximum rate of mitochondrial ATP production (Vmax), measured using in vivo 31P MRS, and the number of GAA repeats in the smaller allele in skeletal muscle of FRDA patients: the higher the number of repeats the lower the mitochondrial Vmax [13]. The lack in the present study of correlation in FRDA patients between the number of GAA repeats and heart PCr/ATP is difficult to explain. The spectral acquisition protocol we used is robust as demonstrated by S.D. just above 5% of the mean PCr/ATP in the heart of normal subjects. One possible explanation is that cardiac hypertrophy compensates for the metabolic dysfunction, as shown by normal cardiac function, in our patients with LVH. Compensatory LV thickening may also occur in patient with PWd and IVSd below the upper normal limits (i.e. without cardiac hypertrophy) and, if this is the case, influence the cardiac levels of PCr/ATP for a given cardiac workload. Eventually, when compensation fails, the heart may dilate as has been described in previous echocardiographic studies in FRDA patients [4–6] and this may be associated with further reduction in cardiac PCr/ATP. The hypothesis that a defect of energy metabolism can contribute to the development of heart hypertrophy in FRDA is supported by the frequent finding of hypertrophic cardiomyopathy in patients with deficit of oxidative phosphorylation due to mutations of mitochondrial DNA [43]. Moreover, animal studies showed that low cardiac PCr/ATP can precede cardiac hypertrophy in the {alpha}MCH 403/+ mouse [44]. Low PCr/ATP has been also described in mice lacking glucose transporter GLUT4 where preserved contractile function is associated with the development of compensated cardiac hypertrophy [45]. This was interpreted as secondary to reduced substrate supply due to GLUT4 lack [45].

The sequence of events leading to oxidative phosphorylation deficit in FRDA is still undefined. The findings of a preliminary study, showing reduced activity of the mitochondrial respiratory chain complexes I, II and III in endomyocardial biopsies from two FRDA patients with hypertrophic cardiomyopathy [16], where later confirmed by our post-mortem study of the heart of nine FRDA patients [15]. Knockout of the yeast homologue YFH1 gene led to a striking increase in intramitochondrial iron content which was associated with increased sensitivity to oxidative stress and reduced oxidative phosphorylation rate [9,12]. Iron accumulation has been reported not only in the cardiac tissue [15,34] but also in liver and spleen of FRDA patients [15] and could well contribute to oxidative damage and mitochondrial dysfunction. This is supported by decreased aconitase activity in hearts [15,16] as well as in skeletal muscle and dorsal root ganglia [15] from FRDA patients, an activity which is extremely sensitive to inhibition by superoxide and peroxynitrite [46]. The Fe–S centres of respiratory chain complex I, II, and III are a critical target for oxygen free radicals and this would contribute to their deficiency, though decreased frataxin levels might also impair Fe–S assembly. Recent evidence of up-regulation of mitochondrial respiration rate in mammalian cells overexpressing frataxin suggests that frataxin deficit would primarily result in an impairment of mitochondrial ATP production and that mitochondrial iron metabolism dysfunction would be secondary to the energy metabolism deficit [35].

The present study shows that cardiac PCr/ATP, an indicator of bioenergetic status, is decreased in FRDA patients and strongly supports mitochondrial involvement in the pathogenesis of cardiomyopathy in FRDA. Further studies, using 31P MRS and other techniques assessing cardiac metabolism in vivo (e.g. positron emission tomography), are needed to define the prognostic value of the cardiac bioenergetic deficit found in FRDA patients and its possible association with functional cardiac impairment when increased cardiac output is required. In contrast to other neurodegenerative disorders where evidence of oxidative damage has been found [47], FRDA can be diagnosed by genetic analysis in the early stage of disease, possibly before central nervous system and cardiac damage become established. Our findings provide a strong rationale for longitudinal studies assessing the clinical effect of treatments aimed to enhance mitochondrial function and reduce toxic radical production in FRDA patients. This is now further supported by a preliminary study that showed a decrease in LV mass index in three FRDA patients treated with idebenone, a short chain quinone analogue acting as a powerful free-radical scavenger [48].

Time for primary review 23 days.


   Acknowledgements
 
We are indebted to all the patients and their families for participating in the study. We would like to thank Dr J. Crilley for some of the echocardiographic studies and E. Gower and Ruth Cooper for helping in their organisation. This work was supported by the Medical Research Council and the Friedreich’s Ataxia Group (UK). RL is supported by CNR grant #97.01029.PF49, MURST 60%, and by Fondazione Cassa di Risparmio in Bologna.


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

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