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Departments of Anatomy, Physiology and Kinesiology, Kansas State University, Manhattan, KS 66506-5802, USA
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O2) and, at a given O2 uptake (
O2), lowers microvascular O2 pressures (PmvO2: determined by the O2-to-O2 ratio), which may impair recovery of high-energy phosphates following exercise. Because CHF preferentially decreases O2 to slow-twitch muscles, we hypothesized that recovery PmvO2 kinetics would be slowed to a greater extent in soleus (SOL: 
84% type I fibres) than in peroneal (PER: 14% type I) muscles of CHF rats. PmvO2 dynamics were determined in SOL and PER muscles of control (CON: n= 6; left ventricular end-diastolic pressure, LVEDP: 3 mmHg), moderate CHF (MOD: n= 7; LVEDP: 11 mmHg) and severe CHF (SEV: n= 4; LVEDP: 25 mmHg) following cessation of electrical stimulation (180 s; 1 Hz). In PER, neither the recovery PmvO2 values nor the mean response time (MRT; a weighted average of the time to 63% of the overall response) were altered by CHF (CON: 66.8 ± 8.0, MOD: 72.4 ± 11.8, SEV: 69.1 ± 9.5 s). In marked contrast, SOL PmvO2, at recovery onset, was reduced significantly in the SEV group (6 Torr) and PmvO2 MRT was slowed with increased severity of CHF (CON: 45.1 ± 5.3, MOD: 63.2 ± 9.4, SEV: 82.6 ± 12.3 s; P < 0.05 CON vs. MOD and SEV). These data indicate that CHF slows PmvO2 recovery following contractions and lowers capillary O2 driving pressure in slow-twitch SOL, but not in fast-twitch PER muscle. These results may explain, in part, the slowed recovery kinetics (phosphocreatine and O2) and pronounced fatigue following muscular work in CHF patients.
(Received 27 January 2004;
accepted after revision 30 April 2004; first published online 30 April 2004)
Corresponding author D. C. Poole: Departments of Anatomy, Physiology and Kinesiology, 129 Coles Hall, Kansas State University, Manhattan, KS 66506-5802, USA. Email: poole{at}vet.ksu.edu
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Introduction |
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O2 (Sietsema et al. 1994; Belardinelli et al. 1997; Koike et al. 1998; Tanabe et al. 2000; Myers et al. 2001) are demonstrably slowed compared with control subjects. These findings are of obvious importance to CHF patients, because it suggests that repetitive daily activities will precipitate marked fatigue (Thompson et al. 1995a,; Mitchell et al. 2003) and exercise intolerance (Zelis et al. 1988; Simonini et al. 1996b; Musch et al. 2002) in this population.
In healthy individuals, the recovery of pre-exercise muscle PCr concentration ([PCr]) is acutely dependent upon muscle O2 (Idstrom et al. 1985), vascular O2 pressures (Bylund-Fellenius et al. 1981; Haseler et al. 1999), oxidative capacity (Paganini et al. 1997) and pHi (Arnold et al. 1984). Moreover, the recovery of intramuscular PO2 (Bylund-Fellenius et al. 1981), PmvO2 (McDonough et al. 2004) and pHi (which is modulated by O2 pressures via their effects upon glycolysis; Wilson et al. 1977) are largely dependent upon O2. Therefore, it is likely that the O2 at a given level of metabolism (i.e. the O2-to-O2 ratio; McDonough et al. 2001) plays a deterministic role in the recovery of muscle energetic status following contractions. Indeed, we recently noted that PmvO2 recovery following contractions was markedly slowed in the fast-twitch PER muscle (comprised predominately of type II fibres) compared to the slow-twitch SOL (predominately type I fibres), a finding that was attributed to the much lower recovery O2 in PER (Armstrong & Laughlin, 1983; McDonough et al. 2004).
Bulk O2 to the working limbs is reduced in CHF, but this effect is highly variable between individual muscles (Musch & Terrell, 1992). In particular, O2 is reduced to the greatest degree in those muscles with the highest percentage of oxidative fibres, such that these muscles (i.e. SOL; primarily oxidative fibres) exhibit marked decrements, whereas others (i.e. PER; primarily glycolytic) exhibit essentially no deficits in O2 in CHF (Musch & Terrell, 1992). One explanation for the marked variability in CHF-induced reductions in O2 is differences in the reactivity of the arterioles feeding these muscles (Didion & Mayhan, 1997), an effect that appears to be endothelium-dependent (Kubo et al. 1991). Specifically, Hirai et al. (1995) noted that the response to nitric oxide synthase inhibition was severely blunted in the SOL muscle of rats with CHF, yet essentially unaltered in the PER, suggesting that the endothelial defects reside primarily in those individual muscles with the highest percentage of oxidative fibres (i.e. types I and IIa). Therefore, if CHF reduces O2 during recovery from exercise preferentially in oxidative fibres, this would provide a putative mechanism for the exercise intolerance in individuals with CHF because type I and IIa fibres are recruited predominately during low-to-moderate intensity exercise.
Given the above, the most direct way to determine if fibre type, per se, plays a deterministic role in the recovery of cellular energetic status following contractions in CHF is to examine muscles that are polar opposites with respect to their fibre type composition. Two muscles that fit the above criteria are the SOL (84% type I, 7% type IIa, and 9% type IIb and d/x) and PER (14% type I, 19% type IIa, and 67% type IIb and d/x), which demonstrate similar oxidative capacity, yet exhibit a fibre type composition that is essentially the opposite of one another (Delp & Duan, 1996). To help elucidate the mechanisms through which the re-establishment of muscle energetic status is impaired following muscular work in CHF, we tested the following hypotheses: (1) that PmvO2 recovery kinetics would be slowed by CHF to a greater degree in SOL than in PER; (2) that PmvO2 (and thus capillary O2 driving pressure) would be reduced in CHF animals during recovery (i.e. lower absolute value during the majority of the contractions off-transient) in SOL, but not in PER; and (3) that PmvO2 recovery kinetics would be prolonged in SOL in relation to the severity of CHF.
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Methods |
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Female Sprague–Dawley rats (291 ± 4 g; n= 11) were given a myocardial infarction (MI) as previously described (Musch et al. 1986; Musch & Terrell, 1992). Briefly, rats were anaesthetized (5% isoflurane/O2 mixture), intubated and connected to a rodent respirator (Harvard Model 680). The anaesthetic plane was maintained on a 2% isoflurane/O2 mixture. A left thoracotomy was performed (fifth intercostal space; 1.5 cm in length) to expose the heart. The pericardial sac was opened and the heart exteriorized. A 6-O suture was then used to ligate the left main coronary artery (2–4 mm distal to its origin). Following this procedure, the lungs were hyperinflated and the ribs approximated (3-O gut), the muscles of the thorax sewn together (4-O gut) and the skin incision closed (3-O silk). To reduce the chance of infection, antibiotics were administered (Ampicillan, 200 mg kg–1). Anaesthesia was then withdrawn, and the rat was extubated and monitored for 8–12 h after surgery. Because we had previously noted no significant haemodynamic differences between Control and Sham operated animals (Symons et al. 1999), we chose to use non-infarcted control animals (CON; n= 6) to reduce the number of animals undergoing survival recovery procedures. All procedures were conducted according to National Institutes of Health guidelines and approved by the Kansas State University Institutional Animal Care and Use Committee (IACUC).
Cardiac haemodynamics
Six to 10 weeks following MI procedures, the rats were anaesthetized (pentobarbital sodium; 30 mg kg–1I.P., supplemented as needed) and a 2-French catheter-tip pressure manometer (Millar Instruments) was introduced into the right carotid artery. The catheter was then advanced into the left ventricle in a retrograde fashion to measure LVEDP and the rate of pressure change within the chamber (LV dP/dt). Following these measurements, the manometer was replaced with a fluid-filled catheter (PE-50) to monitor arterial blood pressure for the duration of the experiment (Digi-Medical BPA Model 200). In addition, the fluid-filled catheter was used for the administration of additional anaesthesia, sampling of arterial blood and to provide a route of access for infusion of the phosphorescent probe [R2: palladium meso-tetra(4-carboxyphenyl)porphine dendrimer; 15 mg kg–1].
Surgical preparation for experiments
Following measurement of cardiac haemodynamics, the SOL and PER were exposed in the manner detailed previously (Behnke et al. 2003). The exposed tissue was superfused with a Krebs–Henseleit bicarbonate-buffered solution (38°C, equilibrated with 5% CO2, N2 balance) and body temperature (rectal thermister catheter) was maintained at 37°C using a heating pad.
Contraction protocol
Prior to beginning the experimental protocol the R2 probe was infused (via the arterial catheter). Approximately 15 min later, the SOL or PER (random order) was stimulated (stainless-steel electrodes attached to the distal and proximal ends of the muscle) at 1 Hz for 3 min (2–4 V, 2 ms pulse duration) using a Grass S88 stimulator (Quincy, MA, USA; for further detail, see Behnke et al. 2004). Following stimulation, recovery data were gathered for at least 3 min or until baseline values (i.e. a clear plateau) were reached. This contraction protocol has been shown in our laboratory to increase muscle blood flow significantly, while not changing arterial acid–base status or elevating plasma lactate concentrations (Behnke et al. 2003). Thus, in this regard, it resembles moderate-intensity exercise and as such interpretation of the recovery data should not be complicated by acidaemia (McDonough et al. 2004). All animals were killed with an overdose of pentobarbitol sodium (> 80 mg kg–1, I.A.) following the conclusion of the experimental protocol.
Principle and measurement of phosphorescence quenching
The basic principles of phosphorescence quenching have been detailed previously (Poole et al. 1995; McDonough et al. 2001; Behnke et al. 2003); however, a concise outline follows. The Stern–Volmer relationship (Rumsey et al. 1988) describes the relationship between probe phosphorescence and PmvO2:
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| (1) |
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| (2) |
For the R2 probe t0 is 601 µs and kQ 409 Torr s–1 (Lo et al. 1997) and as the phosphorescent characteristics of R2 do not change over the normal range of temperatures and pH extant in the rat, the sole variable that can alter the phosphorescence lifetime is molecular O2 pressure (Rumsey et al. 1988; Lo et al. 1997). Therefore, PmvO2 is wholly dependent upon the lifetime of the phosphorescence decay, which is inversely proportional to the prevailing PmvO2.
Importantly, the R2 phosphorescent probe is restricted to the intravascular space within the muscle, which allows measurement of PmvO2 (Poole et al. 2003). To measure PmvO2, a PMOD 1000 Frequency Domain Phosphorimeter (Oxygen Enterprises, Ltd, Philadelphia, PA, USA) was employed, with the light guide placed 2–4 mm above the medial portion of the muscle and focused on a circular area of exposed muscle of 2 mm diameter. Within this area (principally composed of capillary blood, as this compartment constitutes the majority of intramuscular blood volume; Poole et al. 1995), a sample is obtained up to 500 µm deep. The PMOD 1000 modulates the excitation frequencies between 100 Hz and 20 kHz, which can measure PmvO2 values from 0 to 240 Torr. PmvO2 was measured continuously with data reported at 2 s intervals throughout recovery.
Curve fitting and statistical analysis
For the PmvO2 data, curve fitting was accomplished using KaleidaGraph software (version 3.5; Synergy Software, Reading, PA, USA) and was performed on the off-transient using a one-component model:
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1 and 2 are the amplitudes of the fast and slow recovery components, TD1 and TD2 are the independent time delays and 
1 and 2 are the time constants for each component. Goodness of fit was determined by three criteria: (1) the coefficient of determination (i.e. r2), (2) the sum of the squared residuals and (3) visual inspection and analysis of the residual fit to a linear model. MRT was calculated using the formula of MacDonald et al. (1997):
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1 and 2, TD1 and TD2 and 1 and 2 are as defined above. In addition, to normalize the rate of recovery to the amplitude of the response, the relative rate of PmvO2 recovery (dPO2/dt) was calculated by dividing the delta PmvO2 by the time constant of the response for both the fast and the slow components of PmvO2 recovery (McDonough et al. 2004).
Rats were separated into groups based on the severity of lung congestion (lung weight to body weight ratio: LW/BW) and right ventricular (RV) hypertrophy (RV to body weight ratio: RV/BW). Using cardiac indices derived from both anatomical dissection and morphology, MI rats were divided into two groups prior to analysis of PmvO2 profiles: rats with a LW/BW and RV/BW greater than 4 S.D. above the mean for CON (n= 6) were placed in SEV (n= 4) CHF group, and the remaining MI rats were placed in the MOD (n= 7) CHF group. PmvO2 values during resting and steady-state contractions (e.g. baseline and end contraction) as well as modelling dependent (e.g. TD, , MRT) results were analysed using a two-way ANOVA to test for the effects of disease severity (CON, MOD, SEV) and muscle type (SOL and PER). As no interactions were found between muscle type and disease severity, a one-way ANOVA was employed to investigate the effect of disease severity, and an unpaired t test was utililised to study between-muscle effects. When a significant F value was demonstrated by the ANOVA, a Student–Newman–Keuls (SNK) procedure was performed to determine differences among mean values. Pearson product-moment correlations were performed upon select variables. Statistical significance was accepted at P < 0.05.
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Results |
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Evidence of heart failure
The criteria for inclusion in the CON or MOD and SEV CHF groups were previously reported for these animals (Behnke et al. 2004). Briefly, based on LW/BW and RV/BW ratios, the rats were separated into MOD and SEV CHF. Those animals with a LW/BW and RV/BW greater than 4 S.D. above the mean for CON were placed in the SEV group, and the other infarcted animals were placed in the MOD group. RV/BW (0.61 ± 0.03, 0.74 ± 0.02 and 1.44 ± 0.12; CON < MOD < SEV, P < 0.05) and LVEDP (2.9 ± 0.6, 11.0 ± 3.6 and 24.5 ± 6.8; CON < MOD < SEV, P < 0.05) were significantly different between experimental groups, whereas LV dP/dt (7410 ± 580, 5217 ± 444 and 5100 ± 513; CON > MOD = SEV, P < 0.05) was reduced in both CHF groups (no difference between CHF groups) compared with CON. LW/BW (3.9 ± 0.1, 4.1 ± 0.2 and 10.3 ± 2.0; CON = MOD < SEV, P < 0.05) was increased for SEV CHF only compared with MOD (which was not different from CON). Furthermore, citrate synthase activity (CSa) was not different between muscles for CON (25.5 ± 1.8 vs. 20.2 ± 1.8 µmol g–1 min–1; SOL vs. PER) or MOD (22.4 ± 2.4 vs. 16.5 ± 1.7 µmol g–1 min–1; SOL vs. PER) and no difference was noted for either muscle between CON and MOD CHF. However, CSa was significantly different between SOL (19.6 ± 1.5 µmol g–1 min–1) and PER (13.0 ± 0.8 µmol g–1 min–1; P < 0.05) for the SEV CHF group and in both SOL and PER, CSa was significantly reduced in SEV CHF compared with MOD CHF and CON (P < 0.05).
Microvascular PO2 during recovery in CHF
Following contractions, PmvO2 rose, following a short delay (Table 1), in all conditions for both muscles (Figs 1 and 2). However, specific differences were noted for the PmvO2 recovery profiles both within and between muscles. Moreover, as we have noted previously (McDonough et al. 2004) the data for both SOL and PER were better fit by the more complex two-component (2-comp) model [based on r2 and chi-squared residual term (
2)] than the one-component (1-comp) model (SOL r2: 1-comp: 0.989 ± 0.003 and 2-comp: 0.993 ± 0.002, 2: 1-comp: 8.27 ± 2.1 and 2-comp: 7.76 ± 2.1; PER r2: 1-comp: 0.988 ± 0.007 and 2-comp: 0.990 ± 0.007, 2: 1-comp: 8.47 ± 1.7 and 2-comp: 6.3 ± 1.5; all P < 0.05).
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1 generally increased with CHF severity in SOL), but not for PER (as 1 generally decreased with CHF in PER) in CHF rats vs. CON. Finally, the initial rate of recovery (dPO2/dt fast) was significantly slower for the CHF rats vs. CON for SOL (Table 1), such that the relative speed of recovery for PmvO2 was significantly slowed in SOL, but remained unchanged in PER for CHF animals compared to CON (Figs 1 and 2).
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1) and MRT were significantly longer in PER vs. SOL for CON, but not for animals with either MOD or SEV CHF. Asymmetry between on- and off-transient
For PER, a marked asymmetry was noted between the on- and off-transient for all conditions (CON, MOD and SEV; Fig. 3). In other words, the off-transient MRT was significantly longer than the corresponding on-transient value for all treatment conditions in PER. However, for SOL, a completely different pattern was noted. Specifically, whereas an on–off symmetry was noted for CON, a significant on–off asymmetry that increased with disease severity was noted for CHF animals (Fig. 3).
Relationship between end-exercise PmvO2 and recovery MRT
The overall time course (i.e. MRT) of the off-transient was significantly and inversely related to the end-exercise PmvO2 (Fig. 4) for both SOL (r =–0.82; P < 0.05) and PER (r =–0.65; P < 0.05).
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Discussion |
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2) the slow component (Table 1). In marked contrast, in PER, recovery PmvO2 kinetics were not appreciably altered by CHF (cf. Figs 1 and 2; Table 1). The effect of CHF was such that whereas the MRT for PmvO2 recovery was much slower in PER vs. SOL for CON, it was not different between PER and SOL for either MOD or SEV conditions. In addition, whereas PmvO2 was significantly higher in SOL vs. PER throughout the majority of recovery in CON and MOD (Table 2), PmvO2 was not different between PER and SOL throughout recovery for SEV. This is an important finding because end-exercise PmvO2 was found to be significantly and inversely correlated to the MRT of PmvO2 recovery in both muscles (Fig. 4). Thus, with respect to PmvO2 and its kinetics, CHF induces changes within the slow-twitch SOL that make it respond both during contractions (Behnke et al. 2004) and during recovery (current study) in a similar fashion to the fast-twitch PER. Recovery of cellular energetic status following contractions: putative mechanisms
The speed with which precontraction muscle cellular energetic state (note: for this study we will consider [PCr] as a direct marker (Meyer, 1988) and, through its effect on [PCr], PmvO2 as an indirect marker (Bylund-Fellenius et al. 1981; Haseler et al. 1999)) is re-established is thought to be determined (both directly and indirectly) by several factors that include oxidative capacity, pHi, muscle fibre type and oxygen delivery (Idstrom et al. 1985; Iotti et al. 1993; Simonini et al. 1996b; Paganini et al. 1997). Irrespective of the exact controlling mechanism(s), it is clear that recovery of cellular energetic status is markedly slowed in CHF patients (Sietsema et al. 1994; Belardinelli et al. 1997). As CHF has been shown to induce changes in all of the prospective controllers listed above, it is likely that one or more of these factors is responsible for the slowing of the recovery process in these patients. However, it is not known which factor(s) predominate.
Oxidative capacity.
Oxidative capacity has been posited (Paganini et al. 1997) as a key controller of [PCr] recovery. Indeed, Paganini et al. (1997) noted that in the rat gastrocnemius–plantaris complex, the rate constant for [PCr] recovery was strongly correlated (r = 0.84) with muscle oxidative capacity (CSa) in endurance-trained, control and diseased (chemical thyroidectomy) animals. This relationship appears to be preserved in rats with CHF, as Thompson et al. (1995a, b) noted reductions in oxidative capacity and the maximal rate of ATP re-synthesis concomitant with reductions in the rate of [PCr] recovery. However, the range of values used in the Paganini study (85% reduction in CSa from trained to diseased) is much greater than that typically found in CHF (20–30%; Thompson et al. 1995a; Simonini et al. 1996a; Delp et al. 1997; Pfeifer et al. 2001; Diederich et al. 2002; Behnke et al. 2003). In addition, we recently demonstrated that PmvO2 recovery was significantly prolonged in healthy PER compared with SOL (McDonough et al. 2004), two muscles of near-identical oxidative capacity (as measured by CSa). In the current study, CSa was reduced significantly with SEV CHF in both muscles, but PmvO2 recovery was slowed only in SOL. Thus, whereas oxidative capacity can impact the speed of the recovery of cellular energy state following contractions, it is unlikely to be responsible for the results noted herein.
Intracellular acidaemia. pHi has also been significantly correlated with the recovery of [PCr] (Paganini et al. 1997). However, whereas low pHi slows [PCr] recovery (Arnold et al. 1984; Iotti et al. 1993; Thompson et al. 1995a; Kemp et al. 1996), there is evidence in the human gastrocnemius that this effect is negligible for pHi > 6.95 (Iotti et al. 1993). Thus, although pHi can appreciably affect [PCr] recovery (Kushmerick, 1983), the fact that the contraction protocol employed in the current investigation is of moderate intensity and does not appreciably alter acid/base status (Behnke et al. 2003; McDonough et al. 2004) suggests that changes in pHi are not the major factor responsible for the results noted herein.
Muscle fibre type
Our previous work suggested a relationship between muscle fibre type and PmvO2 recovery, as PmvO2 recovery was markedly slower in control PER (primarily type II fibres) than in control SOL (primarily type I fibres; McDonough et al. 2004). These findings, in combination with the results of the current study, suggest that fibre type shifts (particularly in SOL) may be responsible for the findings reported herein. However, the literature is equivocal on whether CHF actually causes fibre type shifts (cf. Simonini et al. 1996b; Delp et al. 1997) and when the do occur, they are typically small in scale (Simonini et al. 1996b; Delp et al. 1997; Spangenburg et al. 2002). It is unlikely that small changes in muscle fibre type populations, per se, are responsible for the slowed recovery noted in the current study. Notwithstanding the above, it is important to note the work of several investigators (Crow & Kushmerick, 1982; Kuznetsov et al. 1996; Burelle & Hochachka, 2002), which suggest that intrinsic differences in mitochondrial function may exist between muscles of differing fibre type and similar oxidative capacities. In particular, Kuznetsov et al. (1996) noted that the Km for ADP-stimulated respiration was much lower in both the presence and the absence of creatine in fast-twitch vs. slow-twitch muscle. Thus, in the face of reduced oxidative capacity (as in CHF), slow-twitch muscle will probably be less sensitive to large changes in cellular energy state (as occur in CHF) than fast-twitch muscle, a scenario that may have contributed to the observed results. Whether this is the case remains to be determined.
Oxygen delivery.
Several researchers (Bylund-Fellenius et al. 1981; Idstrom et al. 1985; Haseler et al. 1999, 1998) have noted that [PCr] and the recovery of both vascular and intracellular O2 pressures are intimately dependent upon O2 availability (Bylund-Fellenius et al. 1981; Hogan et al. 1992; Haseler et al. 1998, 1999). This agrees with our previous work (i.e. O2 differences are largely responsible for the differences in PmvO2 recovery; McDonough et al. 2004) and agrees nicely with the known differences in blood flow regulation between fibre types (Hirai et al. 1994; Thomas et al. 1994; Wunsch et al. 2000; Woodman et al. 2001; Aaker & Laughlin, 2002; McAllister, 2003). Specifically, a greater reliance upon endothelium-dependent vasodilation in muscles with a high proportion of oxidative (i.e. type I and IIa) fibres has been noted (Hirai et al. 1994; Woodman et al. 2001; McAllister, 2003), whereas a greater reliance upon sympatholysis is noted in those muscles with a high percentage of glycolytic (i.e. type IIb; Thomas et al. 1994) fibres. As CHF-induced decrements in endothelial function occur primarily in muscles with a high percentage of oxidative fibres (Hirai et al. 1995), the results of the current study and those of Behnke et al. (2004) suggest strongly a greater reduction in O2 in those muscles with the highest percentage of oxidative fibres, which is corroborated by the data of Musch & Terrell (1992). The finding that CHF progressively slows PmvO2 recovery in SOL towards that seen in PER is consistent with a selectively (i.e. fibre-type-dependent) blunted blood flow response to exercise in CHF (Hirai et al. 1994, 1995) in SOL but not in PER (Musch & Terrell, 1992; McAllister et al. 1993).
How CHF alters the recovery of cellular energy state
CHF causes myriad peripheral (e.g. altered arteriolar vasoreactivity and reduced oxidative capacity; Kubo et al. 1991; Musch & Terrell, 1992; McAllister et al. 1993; Simonini et al. 1996a,b; Delp et al. 1997; Didion & Mayhan, 1997; Kindig et al. 1999; Richardson et al. 2003) and central (e.g. reduced cardiac output and stroke volume; Musch et al. 1986; Musch & Terrell, 1992; Drexler & Coats, 1996) adaptations that become more marked as CHF severity increases (Musch & Terrell, 1992). In general, these adaptations serve to reduce O2 both to (Musch & Terrell, 1992; McAllister et al. 1993; Hirai et al. 1995) and within (Kindig et al. 1999) the working muscles, as well as reducing the muscle's ability to use that O2 (Simonini et al. 1996a; Kindig et al. 1999; Nusz et al. 2003; Richardson et al. 2003; Behnke et al. 2004). Germane to the current investigation, CHF has been shown to induce reductions in skeletal muscle blood flow (and O2) that are far greater in SOL than in PER. Indeed, Musch & Terrell (1992) noted that blood flow was markedly reduced to the SOL with CHF (30%), whereas BF to the PER was unaltered during moderate intensity exercise, a finding that appears to be due to a reduction in endothelium-dependent vasodilation in SOL (Behnke et al. 2004).
In addition to reductions in O2, evidence exists that O2 demand is altered inequitably in CHF (Simonini et al. 1996a,b). Indeed, the reduction in oxidative capacity from CON was greater in PER than in SOL for SEV CHF (
36 vs.23%, respectively), such that CSa was significantly lower for PER than for SOL in SEV CHF animals. Thus, in CHF, the relative under-perfusion during contractions in SOL (i.e. large in O2) coupled with a modest decrease in oxidative demand (i.e. moderate CSa) will cause the O2/O2 ratio (due to sluggish O2 dynamics relative to those of O2; Behnke et al. 2002) and PmvO2 and the blood-tissue O2 pressure gradient to fall to a much greater degree in SOL of CHF animals (Table 2). The effects of a reduction in the blood-tissue O2 gradient will probably be exacerbated by the reduction in diffusing capacity that attends CHF (Kindig et al. 1999; Nusz et al. 2003; Richardson et al. 2003). Furthermore, the correlation between end-contraction PmvO2 and MRT is much stronger for SOL than for PER (Fig. 4), which suggests that the combined sequelae of CHF (which cause a greater fall in PmvO2 during the on-transient; Behnke et al. 2004) conspire to prolong the recovery of PmvO2 in SOL (and by association [PCr]; Bylund-Fellenius et al. 1981) following contractions.
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Summary and conclusions |
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O2 (Musch & Terrell, 1992; Tanabe et al. 2000) and O2 during peak exercise (Musch et al. 1986; Belardinelli et al. 1997) and a prolongation of PCr and O2 recovery time (Thompson et al. 1995b; Belardinelli et al. 1997). The results of the current study (recovery) and those of Behnke et al. (2004) suggest that much of this maladaptive response to CHF is located within the slow-twitch, oxidative fibres. This is in agreement with previous work showing that much of the O2 deficits noted during exercise were located in such fibres (Musch & Terrell, 1992; Hirai et al. 1995). In the context of the current study, CHF results in vascular and metabolic adaptations that reduce the O2/O2 ratio and thus PmvO2 following contractions in slow-twitch, oxidative fibres. As slow-twitch fibres (i.e. SOL) are chiefly responsible for sustaining most activities of daily living and moderate exercise in humans, the slowing of recovery PmvO2 kinetics in SOL, but not in PER, in those individuals with SEV CHF supports a schema wherein reductions in O2 will lead to slowed PmvO2 recovery kinetics and consequently to slowed O2 and PCr recovery kinetics in these patients. This in turn will probably contribute to the fatigue incurred by CHF patients while performing the repetitive activities of daily living or the exercise component of a cardiac rehabilitation programme.
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References |
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Author's present address
Paul McDonough: University of Texas Southwestern Medical Center, Pulmonary & Critical Care Medicine, Department of Internal Medicine, 5323 Harry Hines Boulevard, Dallas, TX 75390-9034, USA.
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