We evaluated the hypotheses that endurance training decreases arterial lactate concentration ([lactate](a)) during continuous exercise by decreasing net lactate release () and appearance rates (R(a)) and increasing metabolic clearance rate (MCR). Measurements were made at two intensities before [45 and 65% peak O(2) consumption (VO(2 peak))] and after training [65% pretraining VO(2 peak), same absolute workload (ABT), and 65% posttraining VO(2 peak), same relative intensity (RLT)]. Nine men (27.4 +/- 2.0 yr) trained for 9 wk on a cycle ergometer, 5 times/wk at 75% VO(2 peak). Compared with the 65% VO(2 peak) pretraining condition (4.75 +/- 0.4 mM), [lactate](a) decreased at ABT (41%) and RLT (21%) (P < 0.05). decreased at ABT but not at RLT. Leg lactate uptake and oxidation were unchanged at ABT but increased at RLT. MCR was unchanged at ABT but increased at RLT. We conclude that 1) active skeletal muscle is not solely responsible for elevated [lactate](a); and 2) training increases leg lactate clearance, decreases whole body and leg lactate production at a given moderate-intensity power output, and increases both whole body and leg lactate clearance at a high relative power output.

In idiopathic dilated cardiomyopathy, functional improvement related to treatment with beta-blockers is associated with changes in myocardial gene expression.

To evaluate the effects of endurance training on the expression of monocarboxylate transporters (MCT) in human vastus lateralis muscle, we compared the amounts of MCT1 and MCT4 in total muscle preparations (MU) and sarcolemma-enriched (SL) and mitochondria-enriched (MI) fractions before and after training. To determine if changes in muscle lactate release and oxidation were associated with training-induced changes in MCT expression, we correlated band densities in Western blots to lactate kinetics determined in vivo. Nine weeks of leg cycle endurance training [75% peak oxygen consumption (VO(2 peak))] increased muscle citrate synthase activity (+75%, P < 0.05) and percentage of type I myosin heavy chain (+50%, P < 0.05); percentage of MU lactate dehydrogenase-5 (M4) isozyme decreased (-12%, P < 0.05). MCT1 was detected in SL and MI fractions, and MCT4 was localized to the SL. Muscle MCT1 contents were consistent among subjects both before and after training; in contrast, MCT4 contents showed large interindividual variations. MCT1 amounts significantly increased in MU, SL, and MI after training (+90%, +60%, and +78%, respectively), whereas SL but not MU MCT4 content increased after training (+47%, P < 0.05). Mitochondrial MCT1 content was negatively correlated to net leg lactate release at rest (r = -0.85, P < 0.02). Sarcolemmal MCT1 and MCT4 contents correlated positively to net leg lactate release at 5 min of exercise at 65% VO(2 peak) (r = 0.76, P < 0.03 and r = 0. 86, P < 0.01, respectively). Results support the conclusions that 1) endurance training increases expression of MCT1 in muscle because of insertion of MCT1 into both sarcolemmal and mitochondrial membranes, 2) training has variable effects on sarcolemmal MCT4, and 3) both MCT1 and MCT4 participate in the cell-cell lactate shuttle, whereas MCT1 facilitates operation of the intracellular lactate shuttle.

Patients with atherosclerotic peripheral arterial disease (PAD) of the lower extremities have impaired walking ability due to exercise-induced muscle ischemia and the resultant pain of intermittent claudication. To evaluate the benefit of exercise training as a treatment for patients with PAD, as well as possible mechanisms associated with improvement, we randomly assigned 19 men with disabling claudication to treated and control groups. Treatment consisted of supervised treadmill walking (1 hr/day, 3 days/wk, for 12 weeks) with progressive increases in speed and grade as tolerated. Graded treadmill testing was performed to maximal toleration of claudication pain on entry and after 12 weeks of training to define changes in peak exercise performance. After 12 weeks, treated subjects had increased their peak walking time 123%, peak oxygen consumption 30%, and pain-free walking time 165% (all p<0.05). Control subjects had no change in peak oxygen consumption, but after 12 weeks, peak walking time increased 20% (p<0.05). In treated subjects, maximal calf blood flow (measured by a plethysmograph) increased 38+45% (p<0.05), but the change in flow was not correlated to the increase in peak walking time. Elevated plasma concentrations of acylcarnitines have been associated with the functional impairment of PAD and may reflect the metabolic state of ischemic skeletal muscle. In treated subjects, a 26% decrease in resting plasma short-chain acylcarnitine concentration was correlated with improvement in peak walking time (r= -0.78, p <0.05). Thus, 12 weeks of exercise training for patients with PAD improved peak exercise performance and claudication pain severity, which in part may be due to an improvement in skeletal muscle oxidative metabolism. (Circulation 1990;81:602-609) A therosclerotic peripheral arterial disease (PAD) of the lower extremities, when associated with intermittent claudication, results in a moderate-to-severe impairment in walking ability. Patients with PAD are unable to walk more than a short distance on level ground and have a severely limited peak exercise capacity during graded treadmill exercisel-4 in a range that allows for only very light to light activities.5 As a result, the energy requirements of many leisure-and work-related tasks exceed the peak exercise capacity of these patients.Exercise training has been shown to improve walking ability on level ground6-8 and during constant-

Background-We studied a large family affected by an autosomal dominant cardiac conduction disorder associated with sinus node dysfunction, arrhythmia, and right and occasionally left ventricular dilatation and dysfunction. Previous linkage analysis mapped the disease phenotype to a 30-cM region on chromosome 3p22-p25 (CMD1E). This region also contains a locus for right ventricular cardiomyopathy (ARVD5) and the cardiac sodium channel gene (SCN5A), mutations that cause isolated progressive cardiac conduction defect (Lenègre syndrome), long-QT syndrome (LQT3), and Brugada syndrome. Methods and Results-Family members were studied, and the positional candidate gene SCN5A was screened for mutations. We identified, by direct sequencing, a heterozygous G-to-A mutation at position 3823 that changed an aspartic acid to asparagine (D1275N) in a highly conserved residue of exon 21. This mutation was present in all affected family members, was absent in 300 control chromosomes, and predicted a change of charge within the S3 segment of domain III. Conclusions-Our findings expand the clinical spectrum of disorders of the cardiac sodium channel to include cardiac dilation and dysfunction and support the hypothesis that genes encoding ion channels can be implicated in dilated cardiomyopathies. Key Words: genetics Ⅲ cardiomyopathy Ⅲ conduction Ⅲ arrhythmia Ⅲ heart block I n 1986, Greenlee et al 1 reported a peculiar form of dilated cardiomyopathy (DCM) after studying a large pedigree of German and Swiss ancestry. The affected phenotype included sinus node dysfunction in adolescence, supraventricular tachyarrhythmia, and a progressive atrioventricular (AV) and intraventricular conduction delay that led to permanent pacing in most cases. The phenotype was also characterized by a progression toward atrial dilatation, frequently followed by right ventricular dilatation and, in some cases, left ventricular dilatation and dysfunction. 1 Subsequent linkage analysis mapped the disease locus to chromosome 3p22-p25 (CMD1E; OMIM %601154), which contains the voltagegated ␣-subunit of the cardiac sodium channel (SCN5A) gene. 2 SCN5A mutations have been associated with progressive cardiac conduction defect (Lenègre syndrome), isolated cardiac conduction disease, AV conduction block, sick sinus syndrome, sudden infant death syndrome, long-QT syndrome, and Brugada syndrome. [3][4][5][6][7][8][9] This chromosomal region also contains a locus for right ventricular cardiomyopathy (ARVD5). 10 We hypothesized that SCN5A mutations might be responsible for causing the conduction-related phenotype within this family (pedigree DN-ADFDC3; Figure 1A) and report the identification of an SCN5A mutation associated with the disease phenotype. Methods Clinical InvestigationInformed written consent was obtained from participants according to our protocol approved by the Colorado Multiple Institutional Review Board. The proband (IV-2 in Figure 1A) in the present study and his first-degree relatives (III-4, III-5, IV-1, and IV-4 in Figure 1A) were evaluated at t...

Persons with type II diabetes mellitus (DM), even without cardiovascular complications have a decreased maximal oxygen consumption (VO2 max) and submaximal oxygen consumption (VO2) during graded exercise compared with healthy controls. We evaluated the hypothesis that change in the rate of VO2 in response to the onset of constant-load exercise (measured by VO2-uptake kinetics) was slowed in persons with type II DM. Ten premenopausal women with uncomplicated type II DM, 10 overweight, nondiabetic women, and 10 lean, nondiabetic women had a VO2 max test. On two separate occasions, subjects performed 7-min bouts of constant-load bicycle exercise at workloads below and above the lactate threshold to enable measurements of VO2 kinetics and heart rate kinetics (measuring rate of heart rate rise). VO2 max was reduced in subjects with type II DM compared with both lean and overweight controls (P < 0.05). Subjects with type II DM had slower VO2 and heart rate kinetics than did controls at constant workloads below the lactate threshold. The data suggest a notable abnormality in the cardiopulmonary response at the onset of exercise in people with type II DM. The findings may reflect impaired cardiac responses to exercise, although an additional defect in skeletal muscle oxygen diffusion or mitochondrial oxygen utilization is also possible.

BACKGROUND Peripheral arterial disease (PAD) is associated with an impairment in exercise performance and muscle function that is not fully explained by the reduced leg blood flow during exercise. This study characterized the effects of PAD on muscle function, histology, and metabolism. METHODS AND RESULTS Twenty-six patients with PAD and six age-matched control subjects were studied. Ten of the PAD patients had unilateral disease, which permitted paired comparisons between their diseased and nonsymptomatic legs. All PAD patients had a lower peak treadmill walking time and peak oxygen consumption than controls. Vascular disease (diseased leg in unilateral patients and the most severely diseased leg in bilateral patients) was associated with decreased calf muscle strength compared with control values. In patients with unilateral disease, the diseased legs had a greater percentage of angular fibers (indicating chronic denervation) and a decreased type II fiber cross-sectional area (expressed as percent of total fiber area) compared with the nonsymptomatic, or control, legs. In diseased legs, gastrocnemius muscle strength was correlated with the total calf cross-sectional area (r = 0.78, p < 0.05) and type II fiber cross-sectional area (r = 0.63, p < 0.05). Activities of citrate synthase, phosphofructokinase, and lactate dehydrogenase in all 26 PAD patients (most diseased leg) did not differ from control values. Despite a wide range in citrate synthase activity in PAD patients, activity of this enzyme was not correlated with muscle strength or treadmill exercise performance. CONCLUSIONS In patients with PAD, gastrocnemius muscle weakness is associated with muscle fiber denervation and a decreased type II fiber cross-sectional area. In contrast, the PAD patients displayed substantial heterogeneity in muscle enzyme activities that was not associated with exercise performance. Denervation and type II fiber atrophy may contribute to the muscle dysfunction in patients with PAD and further confirm that the pathophysiology of chronic PAD extends beyond arterial obstruction.

BACKGROUND In patients with intermittent claudication, a supervised walking exercise program increases peak exercise performance and community-based functional status. Patients with peripheral arterial disease also have muscle weakness in the affected extremity that may contribute to the walking impairment. However, the potential benefits of training modalities other than walking exercise, such as strength training, have not been critically evaluated in this patient population. The present study tested the hypothesis that a strength training program would be as effective as treadmill walking exercise and that combinations of strengthening and walking exercise would be more effective than either alone in improving exercise performance. METHODS AND RESULTS Twenty-nine patients with disabling claudication were randomized to 12 weeks of supervised walking exercise on a treadmill (3 h/wk at a work intensity sufficient to produce claudication), strength training (3 h/wk of resistive training of five muscle groups of each leg), or a nonexercising control group. Graded treadmill testing was performed to maximally tolerated claudication pain to define changes in peak exercise performance. After 12 weeks, patients in the treadmill training program had a 74 +/- 58% increase in peak walking time as well as improvements in peak oxygen consumption (VO2) and the onset of claudication pain. Patients in the strength-trained group had a 36 +/- 48% increase in peak walking time but no change in peak VO2 or claudication onset time. Control subjects had no changes in any of these measures over the 12-week period. After the first 12 weeks, patients in the initial walking exercise group continued for 12 more weeks of supervised treadmill training. This resulted in an additional 49 +/- 53% increase in peak walking time (total of 128 +/- 99% increase over the 24 weeks). After the initial 12 weeks, patients in the strength-trained group began 12 weeks of supervised treadmill training, and patients in the control group participated in a 12-week combined program of strengthening and treadmill walking exercise. The combined strength and treadmill training program and treadmill training after 12 weeks of strength training resulted in increases in peak exercise performance similar to those observed with 12 weeks of treadmill training alone. CONCLUSIONS A supervised treadmill walking exercise program is an effective means to improve exercise performance in patients with intermittent claudication, with continued improvement over 24 weeks of training. In contrast, 12 weeks of strength training was less effective than 12 weeks of supervised treadmill walking exercise. Finally, strength training, whether sequential or concomitant, did not augment the response to a walking exercise program.