Brain natriuretic peptide and right heart dysfunction after heart transplantation.

Heart transplantation (HT) should normalize cardiac endocrine function, but brain natriuretic peptide (BNP) levels remain elevated after HT, even in the absence of left ventricular hemodynamic disturbance or allograft rejection. Right ventricle (RV) abnormalities are common in HT recipients (HTx), as a result of engraftment process, tricuspid insufficiency, and/or repeated inflammation due to iterative endomyocardial biopsies. RV function follow-up is vital for patient management as RV dysfunction is a recognized cause of in-hospital death and is responsible for a worse prognosis. Interestingly, few and controversial data are available concerning the relationship between plasma BNP levels and RV functional impairment in HTx. This suggests that infra-clinical modifications, such as subtle immune system disorders or hypoxic conditions, might influence BNP expression. Nevertheless, due to other altered circulating molecular forms of BNP, a lack of specificity of BNP assays is described in heart failure patients. This phenomenon could exist in HT population and could explain elevated BNP plasmatic levels despite a normal RV function. In clinical practice, intra-individual change in BNP over time, rather than absolute BNP values, might be more helpful in detecting right cardiac dysfunction in HTx.

Reductive stress impairs myoblasts mitochondrial function and triggers mitochondrial hormesis.

Even though oxidative stress damage from excessive production of ROS is a well known phenomenon, the impact of reductive stress remains poorly understood. This study tested the hypothesis that cellular reductive stress could lead to mitochondrial malfunction, triggering a mitochondrial hormesis (mitohormesis) phenomenon able to protect mitochondria from the deleterious effects of statins. We performed several in vitro experiments on L6 myoblasts and studied the effects of N-acetylcysteine (NAC) at different exposure times. Direct NAC exposure (1mM) led to reductive stress, impairing mitochondrial function by decreasing maximal mitochondrial respiration and increasing H2O2production. After 24h of incubation, the reactive oxygen species (ROS) production was increased. The resulting mitochondrial oxidation activated mitochondrial biogenesis pathways at the mRNA level. After one week of exposure, mitochondria were well-adapted as shown by the decrease of cellular ROS, the increase of mitochondrial content, as well as of the antioxidant capacities. Atorvastatin (ATO) exposure (100µM) for 24h increased ROS levels, reduced the percentage of live cells, and increased the total percentage of apoptotic cells. NAC exposure during 3days failed to protect cells from the deleterious effects of statins. On the other hand, NAC pretreatment during one week triggered mitochondrial hormesis and reduced the deleterious effect of statins. These results contribute to a better understanding of the redox-dependant pathways linked to mitochondria, showing that reductive stress could trigger mitochondrial hormesis phenomenon.

Skeletal muscle mitochondrial dysfunction during chronic obstructive pulmonary disease: central actor and therapeutic target.

Muscle dysfunction is a common complication and an important prognostic factor in chronic obstructive pulmonary disease (COPD). As therapeutic strategies are still needed to treat this complication, gaining more insight into the process that leads to skeletal muscle decline in COPD appears to be an important issue. This review focuses on mitochondrial involvement in limb skeletal muscle alterations (decreased muscle mass, strength, endurance and power and increased fatigue) in COPD. Mitochondria are the main source of energy for the cells; they are involved in production of reactive oxygen species and activate an important pathway that leads to apoptosis. In COPD patients, skeletal muscles are characterized by decreased mitochondrial density and biogenesis, impaired activity and coupling of mitochondrial respiratory chain complexes, increased mitochondrial production of reactive oxygen species and, possibly, increased apoptosis. Of particular interest, a sedentary lifestyle, hypoxia, hypercapnia, tobacco smoking, corticosteroid therapy and, possibly, inflammation participate in this mitochondrial dysfunction, which is accessible to conventional therapies, such as exercise and tobacco cessation, as well as, potentially, to more innovative approaches, such as antioxidant treatment and supplementation with polyunsaturated fatty acids.

Opposite effects of statins on mitochondria of cardiac and skeletal muscles: a 'mitohormesis' mechanism involving reactive oxygen species and PGC-1.

AIMS: Statins protect against cardiovascular-related mortality but induce skeletal muscle toxicity. To investigate mechanisms of statins, we tested the hypothesis that statins optimized cardiac mitochondrial function but impaired vulnerable skeletal muscle by inducing different level of reactive oxygen species (ROS). METHODS AND RESULTS: In atrium of patients treated with statins, ROS production was decreased and oxidative capacities were enhanced together with an extensive augmentation of mRNAs expression of peroxisome proliferator-activated receptor gamma co-activator (PGC-1) family. However, in deltoid biopsies from patients with statin-induced muscular myopathy, oxidative capacities were decreased together with ROS increase and a collapse of PGC-1 mRNA expression. Several animal and cell culture experiments were conducted and showed by using ROS scavengers that ROS production was the triggering factor responsible of atorvastatin-induced activation of mitochondrial biogenesis pathway and improvement of antioxidant capacities in heart. Conversely, in skeletal muscle, the large augmentation of ROS production following treatment induced mitochondrial impairments, and reduced mitochondrial biogenesis mechanisms. Quercetin, an antioxidant molecule, was able to counteract skeletal muscle deleterious effects of atorvastatin in rat. CONCLUSION: Our findings identify statins as a new activating factor of cardiac mitochondrial biogenesis and antioxidant capacities, and suggest the importance of ROS/PGC-1 signalling pathway as a key element in regulation of mitochondrial function in cardiac as well as skeletal muscles.

Mitochondria of trained skeletal muscle are protected from deleterious effects of statins.

INTRODUCTION: Statins are associated with adverse skeletal muscle effects. Our objective was to determine if muscular adaptations following exercise training prevented deleterious effects of atorvastatin in glycolytic skeletal muscle. METHODS: Twenty rats were divided into 2 groups: a control group (n = 10; Cont) and a 10 days of training group (n = 10; Training). Using the permeabilized fibers technique, we explored mitochondrial function. RESULTS: Exercise training increased V(max) and H(2)O(2) production without altering the free radical leak, and mRNA expression of SOD2 and Cox1 were higher in trained muscle. In the Cont group, atorvastatin exposure increased H(2)O(2) production and decreased skeletal muscle V(max). The decreased V(max) effect of atorvastatin was dose dependent. Interestingly, the half-maximal inhibitory concentration (IC(50)) was higher in the Training group. H(2)O(2) production increased in trained muscle after atorvastatin exposure. CONCLUSIONS: These results suggest that improvements in mitochondrial respiratory and antioxidant capacities following endurance training protected mitochondria against statin exposure.

Isoflurane anesthesia preserves liver and lung mitochondrial oxidative capacity after gut ischemia-reperfusion.

BACKGROUND: Lung and liver dysfunction is involved in gut ischemia-reperfusion (IR)-induced multiple organ failure. We compared the effects of ketamine and isoflurane on liver and lung mitochondrial oxidative capacity after gut IR. METHODS: Adult male Wistar rats were randomized into 4 groups (controls and gut IR receiving either intraperitoneal ketamine or inhaled isoflurane). Maximal oxygen consumption and the activity of respiratory chain complexes were measured on isolated liver and lung mitochondria. RESULTS: Gut IR significantly impaired liver and lung mitochondrial oxidative capacity when using ketamine but not isoflurane. CONCLUSIONS: Isoflurane preserved liver and lung mitochondrial oxidative capacity after gut IR.

Impairment of maximal aerobic power with moderate hypoxia in endurance athletes: do skeletal muscle mitochondria play a role?

This study investigates the role of central vs. peripheral factors in the limitation of maximal oxygen uptake (Vo(2max)) with moderate hypoxia [inspired fraction (Fi(O(2))) =14.5%]. Fifteen endurance-trained athletes performed maximal cycle incremental tests to assess Vo(2max), maximal cardiac output (Q(max)), and maximal arteriovenous oxygen (a-vO(2)) difference in normoxia and hypoxia. Muscle biopsies of vastus lateralis were taken 1 wk before the cycling tests to evaluate maximal muscle oxidative capacity (V(max)) and sensitivity of mitochondrial respiration to ADP (K(m)) on permeabilized muscle fibers in situ. Those athletes exhibiting the largest reduction of Vo(2max) in moderate hypoxia (Severe Loss group: -18 +/- 2%) suffered from significant reductions in Q(max) (-4 +/- 1%) and maximal a-vO(2) difference (-14 +/- 2%). Athletes who well tolerated hypoxia, as attested by a significantly smaller drop of Vo(2max) with hypoxia (Moderate Loss group: -7 +/- 1%), also display a blunted Q(max) (-9 +/- 2%) but, conversely, were able to maintain maximal a-vO(2) difference (+1 +/- 2%). Though V(max) was similar in the two experimental groups, the smallest reduction of Vo(2max) with moderate hypoxia was observed in those athletes presenting the lowest apparent K(m) for ADP in the presence of creatine (K(m+Cr)). In already-trained athletes with high muscular oxidative capacities, the qualitative, rather than quantitative, aspects of the mitochondrial function may constitute a limiting factor to aerobic ATP turnover when exercising at low Fi(O(2)), presumably through the functional coupling between the mitochondrial creatine kinase and ATP production. This study suggests a potential role for peripheral factors, including the alteration of cellular homeostasis in active muscles, in determining the tolerance to hypoxia in maximally exercising endurance-trained athletes.

Endocrine heart after lung transplantation: increased brain natriuretic peptide is related to right ventricular function.

Brain natriuretic peptide (BNP) increases in proportion to the extent of right ventricular dysfunction in pulmonary hypertension and after heart transplantation. No data are available after lung transplantation. Clinical, biological, respiratory, echocardiographic characteristics and circulating BNP and its second messenger cyclic guanosine monophosphate (cGMP) were determined in thirty matched subjects (10 lung-, 10 heart-transplant recipients (Ltx, Htx) and 10 healthy controls). Eventual correlations between these parameters were investigated. Heart rate and pulmonary arterial blood pressure were slightly increased after transplantation. Creatinine clearance was decreased. Mean of forced expiratory volume in 1 s was 76.6 +/- 5.3% and vital capacity was 85.3 +/- 6.4% of the predicted values in Ltx. BNP was similarly increased in Ltx and Htx, as compared with control values (54.1 +/- 14.2 and 45.6 +/- 9.2 vs. 6.2 +/- 1.8 pg/ml, respectively). Significant relationships were observed between plasma BNP and cGMP values (r = 0.62; P < 0.05 and r = 0.75; P < 0.01, in Ltx and Htx) and between BNP and right ventricular fractional shortening and tricuspid E/Ea ratio in Ltx (r = -0.75 and r = 0.93; P < 0.01, respectively). BNP is increased after lung transplantation, like after heart transplantation. The relationships observed suggest that the cardiac hormone might counterbalance possible deleterious effects of lung-transplantation on right functioning of patient's heart.

Contralateral leg as a control during skeletal muscle ischemia-reperfusion.

BACKGROUND: Recent data demonstrated that hind limb ischemia induces skeletal muscle mitochondrial dysfunctions. Improvement of such metabolic myopathy improves patient's symptomatology, supporting the development of experimental models focused on mitochondrial function analysis. However, although the nonischemic contralateral leg is often used as a control during unilateral leg ischemia, whether it might be useful when assessing ischemia-induced mitochondrial dysfunction remains to be investigated. MATERIALS AND METHODS: Both ischemic (IR) and nonischemic contralateral legs (CTL) of rats (n=13) submitted to 5 h ischemia induced by a rubber band tourniquet applied on the root of the hind limb were studied and compared to that of sham-operated animals (SHAM, n=13). Maximal oxidative capacities (V(max)) and complexes I, II and IV activities of the gastrocnemius mitochondrial respiratory chain were determined, using glutamate-malate, succinate (Vs) and TMPD-ascorbate (V(TMPD)) substrates. RESULTS: V(max) was decreased in IR (4.6+/-0.4 microM/min/g dry weight) compared to both SHAM and CTL muscles (8.5+/-0.5 and 7.1+/-0.4 microM/min/g dry weight, -46% and -36%, P<0.001, respectively). V(S) and V(TMPD) were reduced in IR muscle (-56% and -48% for V(S); and -25% and -24% for V(TMPD), P<0.001) as compared to SHAM and CTL). V(S) and V(TMPD) were similar in SHAM and CTL muscles. CONCLUSIONS: Five hours ischemia-reperfusion significantly impaired complexes I, II and IV of the ischemic skeletal muscle mitochondrial respiratory chain. Interestingly, only V(max) was slightly altered in the contralateral leg, supporting that the nonischemic leg might be used as a control when assessing mitochondrial function in the experimental setting of unilateral hind limb ischemia.

Lack of endothelial dysfunction in patients under tacrolimus after orthotopic liver transplantation.

BACKGROUND: Endothelial dysfunction is a significant cause of vascular and end-organ damage after solid organ transplantation. The aim of this study was to compare endothelial function in healthy controls and in patients who received tacrolimus for immunosuppression after orthotopic liver transplantation (OLT). METHODS: Eight OLT patients and eight age- and BMI-matched healthy subjects were included in the study. Apart from hemodynamic parameters, enzymatic liver function, fasting plasma glucose levels, creatinine, cholesterol, nitric oxide and endothelin-1 levels were measured. Flow-mediated dilatation (FMD) in the brachial artery was determined by bi-mode ultrasound. RESULTS: Systolic and diastolic blood pressure and heart rate were higher in OLT recipients compared with the control group, but remained within normal limits. Blood results did not differ significantly between the groups. Circulating nitric oxide (152.2 +/- 29.7 vs. 180.6 +/- 40.1 micromol/L) and endothelin-1 (20.5 +/- 1.0 vs. 18.9 +/- 1.3 pmol/L) values were similar, and the FMD was normal in both groups (10.29 +/- 0.89 vs. 9.86 +/- 2.43% in controls and OLT recipients, respectively). There was a significant positive correlation between plasma tacrolimus levels after OLT and FMD (r = 0.72, p < 0.05). CONCLUSION: As assessed by both laboratory and functional approaches, endothelial function was unaltered in patients taking tacrolimus after OLT. The positive correlation between tacrolimus plasma levels and FMD suggest that tacrolimus might have beneficial effects on endothelial function after OLT.

Can the six-minute walk test predict peak oxygen uptake in men with heart transplant?

OBJECTIVE: To determine whether the six-minute walk test (6MWT) might predict peak oxygen consumption (VO2peak) after heart transplantation. DESIGN: Case-control prospective study. SETTING: Public hospital. PARTICIPANTS: Patients with heart transplant (n=22) and age-matched sedentary male subjects (n=13). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Exercise performance using a maximal exercise test, distance walked using the 6MWT, heart rate, and VO2peak. RESULTS: Compared with controls, exercise performance was decreased in patients with heart transplant with less distance ambulated (516+/-13m vs 592+/-13m; P<.001) and a decrease in mean VO2peak (23.3+/-1.3 vs 29.6+/-1mL x min(-1) x kg(-1); P<.001). Patients with heart transplant showed an increased resting heart rate, a response delayed both at the onset of exercise and during recovery. However, the patient's heart rate at the end of the 6MWT was similar to that obtained at the ventilatory threshold. The formula did not predict measured VO2, with a weak correlation observed between the six-minute walk distance and both VO2peak (r=.53; P<.01) and ventilatory threshold (r=.53; P<.01) after heart transplantation. Interestingly, when body weight was considered, correlations coefficient increased to .74 and .77, respectively (P<.001). CONCLUSIONS: In heart transplant recipients, the 6MWT is a safe, practical, and submaximal functional test. The distance-weight product can be used as an alternative method for assessing the functional capacity after heart transplantation but cannot totally replace maximal VO2 determination.

Effects of a High Fat Meal Associated with Water, Juice, or Champagne Consumption on Endothelial Function and Markers of Oxidative Stress and Inflammation in Young, Healthy Subjects.

Endothelial dysfunction (ED), often linked to hypertriglyceridemia, is an early step of atherosclerosis. We investigated, in a randomized cross-over study, whether high-fat meal (HFM)-induced ED might be reduced by fruit juice or champagne containing polyphenols. Flow-mediated dilatation (FMD) and biological parameters (lipid profile, glycemia, inflammation, and oxidative stress markers) were determined before and two and three hours after the HFM in 17 healthy young subjects (24.6 ± 0.9 years) drinking water, juice, or champagne. Considering the entire group, despite significant hypertriglyceridemia (from 0.77 ± 0.07 to 1.41 ± 0.18 mmol/L, p < 0.001) and a decrease in Low Density Lipoprotein (LDL), the FMD was not impaired. However, the FMD decreased in 10 subjects (from 10.73 ± 0.95 to 8.1 3± 0.86 and 8.07 ± 1.16%; p < 0.05 and p < 0.01; 2 and 3 hours, respectively, after the HFM), without concomitant change in concentration reactive protein or reactive oxygen species, but with an increase in glycemia. In the same subjects, the FMD did not decrease when drinking juice or champagne. In conclusion, HFM can impair the endothelial function in healthy young subjects. Fruit juice, rich in anthocyanins and procyanidins, or champagne, rich in simple phenolic acids, might reduce such alterations, but further studies are needed to determine the underlying mechanisms, likely involving polyphenols.

Training at high exercise intensity promotes qualitative adaptations of mitochondrial function in human skeletal muscle.

This study explored mitochondrial capacities to oxidize carbohydrate and fatty acids and functional optimization of mitochondrial respiratory chain complexes in athletes who regularly train at high exercise intensity (ATH, n = 7) compared with sedentary (SED, n = 7). Peak O(2) uptake (Vo(2max)) was measured, and muscle biopsies of vastus lateralis were collected. Maximal O(2) uptake of saponin-skinned myofibers was evaluated with several metabolic substrates [glutamate-malate (V(GM)), pyruvate (V(Pyr)), palmitoyl carnitine (V(PC))], and the activity of the mitochondrial respiratory complexes II and IV were assessed using succinate (V(s)) and N,N,N',N'-tetramethyl-p-phenylenediamine dihydrochloride (V(TMPD)), respectively. Vo(2max) was higher in ATH than in SED (57.8 +/- 2.2 vs. 31.4 +/- 1.3 ml.min(-1).kg(-1), P < 0.001). V(GM) was higher in ATH than in SED (8.6 +/- 0.5 vs. 3.3 +/- 0.3 micromol O(2).min(-1).g dry wt(-1), P < 0.001). V(Pyr) was higher in ATH than in SED (8.7 +/- 1.0 vs. 5.5 +/- 0.2 micromol O(2).min(-1).g dry wt(-1), P < 0.05), whereas V(PC) was not significantly different (5.3 +/- 0.9 vs. 4.4 +/- 0.5 micromol O(2).min(-1).g dry wt(-1)). V(S) was higher in ATH than in SED (11.0 +/- 0.6 vs. 6.0 +/- 0.3 micromol O(2).min(-1).g dry wt(-1), P < 0.001), as well as V(TMPD) (20.1 +/- 1.0 vs. 16.2 +/- 3.4 micromol O(2).min(-1).g dry wt(-1), P < 0.05). The ratios V(S)/V(GM) (1.3 +/- 0.1 vs. 2.0 +/- 0.1, P < 0.001) and V(TMPD)/V(GM) (2.4 +/- 1.0 vs. 5.2 +/- 1.8, P < 0.01) were lower in ATH than in SED. In conclusion, comparison of ATH vs. SED subjects suggests that regular endurance training at high intensity promotes the enhancement of maximal mitochondrial capacities to oxidize carbohydrate rather than fatty acid and induce specific adaptations of the mitochondrial respiratory chain at the level of complex I.

ACE inhibition prevents myocardial infarction-induced skeletal muscle mitochondrial dysfunction.

Heart failure is associated with alterations in cardiac and skeletal muscle energy metabolism resulting in a generalized myopathy. We investigated the molecular and cellular effects of angiotensin-converting enzyme inhibition (ACEi) on skeletal muscle metabolism in infarcted animals. Myocardial infarction (MI) was obtained by left descending coronary artery ligation. Sham, MI, and MI-treated rats (perindopril, 2 mg.kg(-1).day(-1) given 7 days after MI) were studied 1 and 4 mo after surgery. Oxygen consumption of white gastrocnemius (Gas) muscle was studied in saponin-permeabilized fibers, using the main substrates of mitochondrial respiration. mRNA expression of nuclear factors (PGC-1alpha, NRF-2alpha, and mtTFA), involved in the transcription of mitochondrial proteins, and of MCIP1, a marker of calcineurin activation, were also determined. Echocardiographic left ventricular fractional shortening was reduced in both MI and perindopril group after 1 and 4 mo, whereas systemic blood pressure was reduced by 16% only in the MI group after 4 mo. The capacity of Gas to oxidize glutamate-malate, glycerol-triphosphate, or pyruvate (-30%, P < 0.01; -32%, P < 0.05; -33%, P < 0.01, respectively), was greatly decreased. Furthermore, PGC-1alpha (-54%), NRF-2alpha (-45%), and MCIP1 (-84%) gene expression were significantly downregulated. ACEi improved survival, left ventricular function, and blood pressure. Perindopril protected also totally the Gas mitochondrial function and preserved the mRNAs concentration of the mitochondrial transcriptional factors. Moreover, PGC-1alpha correlated with Gas oxidative capacity (r = 0.48), mitochondrial cytochrome-c oxidase (r = 0.65), citrate synthase (r = 0.45) activities, and MCIP1 expression (r = 0.44). Thus ACEi totally prevented MI-induced alterations of skeletal muscle mitochondrial function and protein expression, halting the development of this metabolic myopathy.

Renal hyporesponsiveness to brain natriuretic peptide: both generation and renal activity of cGMP are decreased in patients with pulmonary hypertension.

We examined the mechanisms of renal resistance to atrial and brain natriuretic peptides (ANP and BNP) in pulmonary hypertension (PH). Compared to eight controls, nine PH patients showed a reduced ability to excrete an acute sodium load despite increased circulating ANP, BNP and cyclic guanosine monophosphate (cGMP), their second messenger. Patients' reduced urinary cGMP/BNP and natriuresis/urinary cGMP ratios demonstrated impaired generation of and reduced renal response to cGMP, respectively. Therefore, PH patients hyporesponsiveness to cardiac natriuretic peptides is likely located both upstream and downstream cGMP generation. Natriuretic peptide signalling pathway disruptions might be accessible to therapy.

Reduced pulsatility does not explain renal hyporesponsiveness to cardiac natriuretic peptides in pulmonary hypertension.

A pulsatile secretory pattern is assumed to improve hormonal efficiency. We examined the short-term time courses of circulating atrial (ANP) and brain natriuretic peptides (BNP) in patients with pulmonary hypertension (PH) and reduced renal efficiency of ANP-BNP, reflected by low natriuresis/ANP or BNP ratios. Compared to controls, we observed a persistence of ANP and BNP pulsatility in PH patients with a similar periodicity of 20min. Pulse amplitude increased proportionally to the rise in mean plasma level observed in patients (around 27%). In PH patients, the decrease in ANP-BNP renal efficiency is not attributable to a loss of the rhythmic pulsatility of these hormones.

Left Ventricular Transmural Gradient in Mitochondrial Respiration Is Associated with Increased Sub-Endocardium Nitric Oxide and Reactive Oxygen Species Productions.

OBJECTIVE: Left ventricle (LV) transmural gradient in mitochondrial respiration has been recently reported. However, to date, the physiological mechanisms involved in the lower endocardium mitochondrial respiration chain capacity still remain to be determined. Since, nitric oxide (NO) synthase expression in the heart has spatial heterogeneity and might impair mitochondrial function, we investigated a potential association between LV transmural NO and mitochondrial function gradient. METHODS: Maximal oxidative capacity (VMax) and relative contributions of the respiratory chain complexes II, III, IV (VSucc) and IV (VTMPD), mitochondrial content (citrate synthase activity), coupling, NO (electron paramagnetic resonance), and reactive oxygen species (ROS) production (H2O2 and dihydroethidium (DHE) staining) were determined in rat sub-endocardium (Endo) and sub-epicardium (Epi). Further, the effect of a direct NO donor (MAHMA NONOate) on maximal mitochondrial respiratory rates (Vmax) was determined. RESULTS: Mitochondrial respiratory chain activities were reduced in the Endo compared with the Epi (-16.92%; P = 0.04 for Vmax and -18.73%; P = 0.02, for Vsucc, respectively). NO production was two-fold higher in the Endo compared with the Epi (P = 0.002) and interestingly, increasing NO concentration reduced Vmax. Mitochondrial H2O2 and LV ROS productions were significantly increased in Endo compared to Epi, citrate synthase activity and mitochondrial coupling being similar in the two layers. CONCLUSIONS: LV mitochondrial respiration transmural gradient is likely related to NO and possibly ROS increased production in the sub-endocardium.

Heart rate variability and intensity of habitual physical activity in middle-aged persons.

PURPOSE: In the middle-aged, it has been shown that moderate physical activity is associated with increased global HR variability (HRV) and vagal-related HRV indexes. However, the relative effect of quantity and intensity of physical activity on HRV is still unknown. The purpose of this study was to compare HRV indexes in three groups of subjects presenting different long-term physical activity profiles: sedentary subjects (SED) with low-energy expenditure (PAEE) and two groups of subjects with equivalent moderate PAEE, but differing in terms of intensity of physical activity (active (ACT) and sportive (SP) individuals). METHODS: Forty-three middle-aged subjects (61.2 +/- 4.3 yr) were divided into the three groups on the basis of a physical activity questionnaire (Modified Baecke Questionnaire for Older Adults). Physical activity was evaluated by accelerometry for 1 wk. Time and frequency domain HRV indexes were determined during quiet periods in the morning on 5-min stationary R-R interval segments under controlled breathing. Quality of life was evaluated using the SF-36 Health Survey Questionnaire. RESULTS: SP spent more time in moderate to very high activities than ACT (2.1 +/- 0.1 vs 0.6 +/- 0.1 h.wk(-1); P < 0.05) and less time in very light to light activities (62.8 +/- 2.0 vs 73.7 +/- 1.7 h.wk(-1); P < 0.05). SP presented higher vagal-related HRV indexes than SED (P < 0.05), whereas increases in ACT were less marked. ACT and SP had similar health status scores, which were higher than for SED (P < 0.05). CONCLUSIONS: In older adults with different lifestyles, habitual moderate PAEE is associated with better self-estimated overall health status and higher vagal-related HRV indexes compared with subjects with low PAEE, especially when moderate- to very high-intensity physical activities are undertaken.

Is slow wave sleep an appropriate recording condition for heart rate variability analysis?

Heart rate variability (HRV) analysis holds increasing interest but electrocardiographic (ECG) recordings are strongly disturbed by body movements, changes in environment and respiration. Here we give arguments for the use of slow wave sleep (SWS) as an appropriate recording condition. Sixteen healthy subjects aged 21-31 years (10 males, 6 females) underwent polygraphic sleep, ECG, and respiratory recordings during one experimental night. HRV was analyzed in 5-min SWS segments and compared to data collected during quiet wake in the morning with controlled breathing, using for each individual the same respiratory frequency as that recorded during SWS. SWS has two major advantages. First, it is a quiet sleep period, free of any external confounding events and is characterized by fewer body movements or arousals that cause abrupt heart rate (HR) increases which disrupt the ECG signal. Second, SWS avoids the deleterious effect of controlled breathing on HRV. Respiratory cycles were spontaneously more regular during SWS than during generally used wake (Standard deviation (SD) of the respiratory cycles was 0.27+/-0.02 s during SWS vs 0.42+/-0.07 s during wake under controlled breathing; p<0.01). Compared to quiet wake, the SD of normal R-R intervals reflecting global variability was significantly lower during SWS (54.3+/-4.7 vs 78.8+/-6.1 ms; p<0.001) and the normalized high frequency power was increased (0.57+/-0.04 vs 0.51+/-0.03; p<0.05), suggesting a higher parasympathetic control of the heart. Thus, SWS offers a "self-controlled" and undisturbed moment of observation for assessing time and frequency domain HRV indexes. Its relevance as an optimal ECG recording condition has to be confirmed in various experimental conditions.

L-arginine: an ultradian-regulated substrate coupled with insulin oscillations in healthy volunteers.

OBJECTIVE: Coupled oscillations of 50-110 min in insulin and glucose have been found previously in healthy men under continuous enteral nutrition. Because L-arginine induces insulin release as glucose does, we tested the hypothesis that L-arginine can also display such an ultradian rhythm. RESEARCH DESIGN AND METHODS: Seven healthy male subjects participated in one experimental night during which blood was sampled every 10 min from 2300 to 0700. Plasma glucose, C-peptide, and L-arginine levels were measured simultaneously. The insulin secretion rate (ISR) was calculated from plasma C-peptide levels by a deconvolution procedure. RESULTS: Plasma glucose followed the recognizable profiles, with oscillations closely linked to similar changes in the ISR. Pulse analysis of L-arginine profiles revealed significant oscillations linked to glucose and ISR oscillations, with the highest cross-correlation coefficients at time lag 0 ranging from 0.380 to 0.680 for glucose and L-arginine and from 0.444 to 0.726 for ISR and L-arginine (P < 0.01). The mean period of L-arginine oscillations was 77.2 +/- 6.2 min, and their mean amplitude was 19.9 +/- 1.7%, similar to that of glucose (17.0 +/- 1.9%), when expressed as the percentage of mean overnight levels. CONCLUSIONS: This newly discovered ultradian rhythm of L-arginine and its coupling with glucose and ISR oscillations sheds new light on the regulation of L-arginine, the substrate of numerous metabolic pathways, including nitric oxide synthesis. These oscillations may be of significance in conditions of hyperinsulinemia or abnormal glucose tolerance.