Closing the loop: Novel quantitative fMRI approach for manipulation of the sensorimotor loop in tremor.

Tremor is thought to be an effect of oscillatory activity within the sensorimotor network. To date, the underlying pathological brain networks are not fully understood. Disentangling tremor activity from voluntary motor output and sensorimotor feedback systems is challenging. To better understand the intrinsic sensorimotor fingerprint underlying tremor, we aimed to disentangle the sensorimotor system into driving (motor) and feedback/compensatory (sensory) neuronal involvement, and aimed to pinpoint tremor activity in essential tremor (ET) and tremor-dominant Parkinson's disease (PD) with a novel closed-loop approach. Eighteen ET patients, 14 tremor-dominant PD patients, and 18 healthy controls were included. An MR-compatible wrist manipulator was employed during functional MRI (fMRI) while muscle activity during (in)voluntary movements was concurrently recorded using electromyography (EMG). Tremor was quantified based on EMG and correlated to brain activity. Participants performed three tasks: an active wrist motor task, a passive wrist movement task, and rest (no wrist movement). The results in healthy controls proved that our experimental paradigm activated the expected motor and sensory networks separately using the active (motor) and passive (sensory) task. ET patients showed similar patterns of activation within the motor and sensory networks. PD patients had less activity during the active motor task in the cerebellum and basal ganglia compared to ET and healthy controls. EMG showed that in ET, tremor fluctuations correlated positively with activity in the inferior olive region, and that in PD tremor fluctuations correlated positively with cerebellar activity. Our novel approach with an MR-compatible wrist manipulator, allowed to investigate the involvement of the motor and sensory networks separately, and as such to better understand tremor pathophysiology. In ET sensorimotor network function did not differ from healthy controls. PD showed less motor-related activity. Focusing on tremor, our results indicate involvement of the inferior olive in ET tremor modulation, and cerebellar involvement in PD tremor modulation.

[Molecular genetics of human hypertension]. / Molekulargenetik der humanen Hypertonie.

A genetic influence on blood pressure was demonstrated more than 100 years ago and a simple Mendelian inheritance was initially presumed. Platt and Pickering conducted a lively debate on this topic. Platt favored the idea that a single gene or only a few genes were responsible for high blood pressure. Pickering presented research results, which supported the assumption that many genes exerted an influence on blood pressure. This was all in a period when it was not even known what genes were. Genome-wide association studies (GWAS) according to the Pickering model have identified > 500 blood pressure relevant gene loci, which are distributed over the whole genome. Each individual gene exerts only a small effect on blood pressure. The dark horses of hypertension research are the secondary causes. In pheochromocytoma, primary aldosteronism, Cushing's syndrome and even fibromuscular dysplasia (renovascular hypertension) the results indicate that a genetic cause regularly underlies secondary hypertension. This would therefore also partially confirm Platt's theory. In the meantime, a multitude of forms of hypertension have been described with a genetic inheritance according to Mendel. Each of these genetic variants exerts a considerable influence on blood pressure. A multitude of novel physiological mechanisms were explained by this. These findings will become therapeutically important. Therefore, it is incumbent upon clinicians to be optimally informed about these research results.

Branched-chain amino acid catabolism rather than amino acids plasma concentrations is associated with diet-induced changes in insulin resistance in overweight to obese individuals.

BACKGROUND & AIMS: 3-Hydroxyisobutyrate (3-HIB), a catabolic intermediate of the BCAA valine, which stimulates muscle fatty acid uptake, has been implicated in the pathogenesis of insulin resistance. We tested the hypothesis that circulating 3-HIB herald insulin resistance and that metabolic improvement with weight loss are related to changes in BCAAs and 3-HIB. METHODS AND RESULTS: We analyzed plasma and urine in 109 overweight to obese individuals before and after six months on hypocaloric diets reduced in either carbohydrates or fat. We calculated the homeostasis model assessment index (HOMA-IR) and whole body insulin sensitivity from oral glucose tolerance tests and measured intramyocellular fat by magnetic resonance spectroscopy. BCAAs and 3-HIB plasma concentrations were inversely related to insulin sensitivity but not to intramyocellular fat content at baseline. With 7.4 ± 4.5% weight loss mean BCAA and 3-HIB plasma concentrations did not change, irrespective of dietary macronutrient content. Individual changes in 3-HIB with 6-month diet but not BCAAs were correlated to the change in whole body insulin sensitivity and HOMA-IR independently of BMI changes. CONCLUSIONS: 3-HIB relates to insulin sensitivity but is not associated with intramyocellular fat content in overweight to obese individuals. Moreover, changes in 3-HIB rather than changes in BCAAs are associated with metabolic improvements with weight loss. Registration number for clinical trials: ClinicalTrials.gov Identifier: NCT00956566.

Branched-chain and aromatic amino acids, insulin resistance and liver specific ectopic fat storage in overweight to obese subjects.

BACKGROUND & AIMS: Amino acids may interfere with insulin action, particularly in obese individuals. We hypothesized that increased circulating branched-chain and aromatic amino acids herald insulin resistance and ectopic fat storage, particularly hepatic fat accumulation. METHODS AND RESULTS: We measured fasting branched-chain and aromatic amino acids (tryptophan, tyrosine, and phenylalanine) by mass spectrometry in 111 overweight to obese subjects. We applied abdominal magnetic resonance imaging and spectroscopy to assess adipose tissue distribution and ectopic fat storage, respectively. Plasma branched-chain amino acids concentrations were related to insulin sensitivity and intrahepatic fat independent from adiposity, age and gender, but not to abdominal adipose tissue or intramyocellular fat. CONCLUSIONS: In weight stable overweight and obese individuals, branched-chain amino acid concentrations are specifically associated with hepatic fat storage and insulin resistance.

[Resistant hypertension : What is it?]. / Resistente Hypertonie : Was ist das?

When blood pressure is poorly controlled despite treatment with a diuretic and two antihypertensive drugs at adequate doses, the hypertension is termed resistant. The prevalence of resistant hypertension is increasing. Once pseudo-resistance due to poor compliance, secondary forms of hypertension, and massive salt consumption have been excluded, some authorities maintain that blood pressure can be invariably lowered using minoxidil or mineralocorticoid receptor blockade. I also adhered to this belief until we encountered a patient who despite treatment with seven antihypertensive agents, electrical carotid sinus stimulation, and catheter-based renal denervation continued to exhibit extraordinarily high blood pressure values. I am now convinced that resistant hypertension does indeed exist. The prevalence of such patients can be substantially reduced by means of a thorough history and physical examination, determining drug serum concentrations, and excluding secondary causes.

[Iatrogenic electrolyte disorders]. / Iatrogene Elektrolytstörungen.

The maintenance of water and electrolyte homeostasis is of enormous importance for the functioning of cells and tissues. A number of therapeutic procedures intentionally or unintentionally influence important regulatory mechanisms of these interdependent balanced systems. Excessive salt intake doesn't only expand the extracellular volume; it can also cause a considerable increase in tonicity. Owing to its insulin-dependent duality of action, glucose can represent an effective or an ineffective osmolyte. This fact has to be considered in patients with diabetic ketoacidosis. Diuretics reduce the volume expansion via renal excretion of sodium (and water); however, in addition to hypokalemia, diuretics can also cause severe alkalosis. Nowadays, hemodialysis is a routine procedure-but even routine procedures can deliver undesirable surprises. Can dialysis cause an increase in calcium levels, or does the procedure remove therapeutically administered radioactive iodine? The current article presents a series of cases we have come across in recent years. These case reports illustrate common, but also rare iatrogenic situations. The discussion of these cases is aimed at raising awareness of the issues involved in a pathophysiological approach to clinical problems.

Distensibility of the anal canal in patients with systemic sclerosis: a study with the functional lumen imaging probe.

AIM: Systemic sclerosis (SSc) is a generalized connective tissue disease that affects smooth muscle cells. Patients with SSc often have faecal incontinence caused by fibrotic degeneration of the internal anal sphincter (IAS). The functional lumen imaging probe (FLIP) is a novel method that allows the segmental biomechanical properties of the anal canal to be dynamically evaluated. The aim of the present study was to compare the segmental biomechanical properties of the anal canal in incontinent SSc patients and healthy controls. We hypothesized that the FLIP would reveal weaknesses of the IAS in the SSc patients. METHOD: We performed FLIP distensions, endoanal ultrasonography and standard anal manometry on 14 incontinent SSc patients [11 women, median age 60 years (range 35-80)] and 15 healthy volunteers [12 women, median age 54 years (range 33-67)]. The anal canal was divided into three parts for the biomechanical analysis: upper (surrounded by the IAS and the puborectalis), middle (IAS and external anal sphincter) and lower (external sphincter only). RESULTS: The middle anal canal was the segment most resistant to distension in all of the subjects, but it was less resistant in the SSc patients than in the controls (P < 0.01). Correspondingly, the endoanal ultrasonography showed that the IAS of the SSc patients was thinner than normal (P < 0.05), and the anal resting and squeeze pressures were lower (P < 0.05). Only minor distensibility differences were found in the upper anal canal. No changes were found in the lower anal canal. CONCLUSION: Faecal incontinence in SSc patients is associated with poor IAS function, causing increased distensibility of the middle anal canal.

Severe autosomal dominant hypertension and brachydactyly in a unique Turkish kindred maps to human chromosome 12.

Finding genes that cause human hypertension is not straightforward, since the determinants of blood pressure in primary hypertension are multifactorial. One approach to identifying relevant genes is to elucidate rare forms of monogenic hypertension. A relevant mutation may provide a rational starting point from which to analyse the pathophysiology of a condition affecting 20% of the world's population. In 1973 a family with autosomal dominantly inherited brachydactyly and severe hypertension, where the two traits cosegregated completely, was described. We have now re-examined this kindred, and localized the hypertension and brachydactyly locus to chromosome 12p in a region defined by markers D12S364 and D12S87. As the renin-angiotensin-system and sympathetic nervous system respond normally in this form of hypertension, the condition resembles essential hypertension. This feature distinguishes this form of hypertension from glucocorticoid remediable aldosteronism and Liddle's syndrome, which are salt-sensitive forms of monogenic hypertension with very low plasma renin activity. We suggest that identification of the gene involved in hypertension and brachydactyly and its mutation will be of great relevance in elucidating new mechanisms leading to blood pressure elevation.

Thiazolidinedione response in familial lipodystrophy patients with LMNA mutations: a case series.

Type 2 familial partial lipodystrophy (FPLD2) patients show impaired glucose and lipid metabolism resulting from lipodystrophic 'lipid pressure' and an intrinsic defect in skeletal muscle metabolism. Since mutated lamin A may interfere with peroxisome proliferator activator gamma (PPARγ) expression, we hypothesized that PPARγ stimulation improves fat distribution and metabolic abnormalities in these patients. 5 nondiabetic FPLD2 patients were treated with rosiglitazone over 12 months. We assessed body composition, body fat distribution, and skinfold thickness/subcutaneous tissue thickness. We also determined venous glucose, insulin, and free fatty acid (FFA) concentrations, and respiratory quotient (RQ) before and during oral glucose tolerance testing. Adipose tissue and muscle fasting and postprandial metabolism were studied by microdialysis. Within 12 months treatment, hip circumference increased from 93.6±2.78 cm to 96.2±2.3 cm (p<0.05). Rosiglitazone reduced fasting glucose levels and liver transaminases. Baseline and postprandial FFA concentrations were significantly lower after 12 months treatment. RQ and muscle interstitial pyruvate and lactate did not respond to treatment. We conclude that PPARγ stimulation with rosiglitazone modestly improves glucose metabolism in FPLD2 patients presumably through proximal adipose tissue expansion. The intrinsic muscular metabolic defect does not respond to rosiglitazone.

Influence of dietary fat ingestion on asymmetrical dimethylarginine in lean and obese human subjects.

BACKGROUND AND AIMS: Asymmetrical dimethylarginine (ADMA) may contribute to hypertension and cardiovascular disease by decreasing NO formation. In diabetic patients, a high fat meal acutely increased plasma ADMA while impairing endothelial function. We hypothesized that chronic and acute increases in dietary fat intake augment ADMA also in lean and in obese subjects without diabetes. METHODS AND RESULTS: Seventeen lean and twelve obese volunteers were randomized to two weeks of isocaloric diets with approximately 20% or >40% calories from fat in a cross-over fashion. At the end of the high and low fat periods, volunteers received corresponding test meals. ADMA was measured by GC-MS/MS using a deuterated standard. Mean fasting plasma ADMA concentration was 0.52 (0.49-0.54; 95% CI) µmol/l in lean and 0.53 (0.50-0.55) µmol/l in obese subjects (p = 0.55). The two week high fat diet did not influence ADMA. Both test meals elicited a 6%increase in circulating ADMA in lean subjects. In obese subjects, plasma ADMA concentration did not change with the low fat meal, and decreased by approximately 4% with the high fat meal. CONCLUSION: Our findings challenge the idea that obesity and dietary fat intake have a major effect on plasma ADMA, at least in subjects without overt cardiovascular and metabolic disease. This finding is important with regard to dietary recommendations for weight loss. Overestimation of the influence of dietary fat intake and obesity on circulating ADMA in previous reports was most likely due to methodological issues concerning ADMA measurements.

Functional luminal imaging probe: a new technique for dynamic evaluation of mechanical properties of the anal canal.

BACKGROUND: The muscle structures surrounding the anal canal are of major importance in maintaining continence but their anatomy and function vary along its length. Standard manometry does not provide detailed information about mechanical properties of the anal canal. A new functional luminal imaging probe (FLIP) has been developed for this purpose. The aim of our study was to investigate whether FLIP allows detailed evaluation of dynamic biomechanical properties along the length of the anal canal. METHODS: The in vitro validity and reproducibility of the FLIP system were tested. Fifteen healthy volunteers (age 32-65 years, mean 51 years), of whom 12 were females, were investigated. The integrity and dimensions of the anal sphincter apparatus were evaluated with endoanal ultrasonography and standard anal manometry. During standardized distensions with the FLIP, 16 cross-sectional areas of the anal canal were measured at 5-mm intervals. Distensibility of the following three segments was evaluated: upper anal canal (surrounded by the internal anal sphincter and the puborectalis muscle), mid-anal canal (surrounded by the internal anal sphincter and the external anal sphincter) and lower anal canal (surrounded by the external anal sphincter). Color contour plots were generated from the FLIP-based dynamic recordings of serial cross-sections. RESULTS: In vitro tests confirmed the validity and reproducibility of the FLIP system. The luminal geometry during distension and the biomechanical properties of the anal canal differed at the three levels. Both at rest and during squeeze the mid-anal canal was significantly less distensible than the upper (p < 0.01) and the lower (p < 0.05) anal canal. CONCLUSIONS: FLIP is a promising method for evaluation of the nonhomogeneous biomechanical properties along the length of the anal canal.

Directionality of corticomuscular coupling in essential tremor and cortical myoclonic tremor.

OBJECTIVE: A role of the motor cortex in tremor generation in essential tremor (ET) is assumed, yet the directionality of corticomuscular coupling is unknown. Our aim is to clarify the role of the motor cortex. To this end we also study 'familial cortical myoclonic tremor with epilepsy' (FCMTE) and slow repetitive voluntary movements with a known cortical drive. METHODS: Directionality of corticomuscular coupling (EEG-EMG) was studied with renormalized partial directed coherence (rPDC) during tremor in 25 ET patients, 25 healthy controls (mimicked) and in seven FCMTE patients; and during a self-paced 2 Hz task in eight ET patients and seven healthy controls. RESULTS: Efferent coupling around tremor frequency was seen in 33% of ET patients, 45.5% of healthy controls, all FCMTE patients, and, around 2 Hz, in all ET patients and all healthy controls. Ascending coupling, seen in the majority of all participants, was weaker in ET than in healthy controls around 5-6 Hz. CONCLUSIONS: Possible explanations are that tremor in ET results from faulty subcortical output bypassing the motor cortex; rate-dependent transmission similar to generation of rhythmic movements; and/or faulty feedforward mechanism resulting from decreased afferent (sensory) coupling. SIGNIFICANCE: A linear cortical drive is lacking in the majority of ET patients.

The use of small molecule high-throughput screening to identify inhibitors of the proteinase 3-NB1 interaction.

Anti-neutrophil cytoplasmic antibodies (ANCA) to proteinase 3 (PR3) are found in patients with small-vessel vasculitis. PR3-ANCA bind strongly to membrane PR3 (mPR3) that is presented by the NB1 receptor. We performed high-throughput screening using a small molecule library to identify compounds that inhibit PR3-NB1 binding. We established a human embryonic kidney (HEK293) cell-based system, where approximately 95 +/- 2% of the NB1-transfected cells expressed the NB1 receptor on the cell surface. Addition of 0.1 microg/ml human PR3 to 10(4) NB1-expressing HEK293 cells resulted in PR3 binding that was detected by immunofluorescence using a fluorescence plate reader assay. We identified 13 of 20 000 molecules that inhibited PR3 binding by >70%. Seven of 13 substances showed reproducible inhibition in four additional validation experiments. Two selected compounds (27519 and 27549) demonstrated a dose-dependent inhibition over a range from 6.25 to 100 microM as measured by the plate reader assay. We used flow cytometry as a second assay, and found that both compounds reproducibly inhibited PR3 binding to NB1-transfected HEK293 cells at 50 microM (inhibition to 42 +/- 4% with compound 27519 and to 47 +/- 6% with compound 27549 compared to the dimethylsulphoxide control). Furthermore, compounds 27519 and 27549 also inhibited binding of exogenous PR3 to human neutrophils. In contrast, the compounds did not decrease mPR3 expression on resting neutrophils, but reduced the tumour necrosis factor-alpha-mediated mPR3 increase on NB1(pos) neutrophils when present continuously during the assay. The findings suggest that small inhibitory compounds provide a potential therapeutic tool to reduce mPR3 by preventing its binding to NB1.

Neurohumoral and metabolic response to exercise in water.

Atrial natriuretic peptide (ANP) stimulates lipid mobilization and lipid oxidation in humans. The mechanism appears to promote lipid mobilization during exercise. We tested the hypothesis that water immersion augments exercise-induced ANP release and that the change in ANP availability is associated with increased lipid mobilization and lipid oxidation. In an open randomized and cross-over fashion we studied 17 men (age 31+/-3.6 years; body mass index 24+/-1.7 kg/m(2); body fat 17+/-6.7%) on no medication. Subjects underwent two incremental exercise tests on a bicycle ergometer. One test was conducted on land and the other test during immersion in water up to the xiphoid process. In a subset (n=7), we obtained electromyography recordings in the left leg. We monitored gas exchange, blood pressure, and heart rate. In addition, we obtained blood samples towards the end of each exercise step to determine ANP, norepinephrine, epinephrine, lactate, free fatty acids, insulin, and glucose concentrations. Heart rate, systolic blood pressure, and oxygen consumption at the anaerobic threshold and during peak exercise were similar on land and with exercise in water. The respiratory quotient was mildly reduced when subjects exercised in water. Glucose and lactate measurements were decreased whereas free fatty acid concentrations were increased with exercise in water. Water immersion attenuated epinephrine and norepinephrine and augmented ANP release during exercise. Even though water immersion blunts exercise-induced sympathoadrenal activation, lipid mobilization and lipid oxidation rate are maintained or even improved. The response may be explained by augmented ANP release.

Determinants of exercise-induced fat oxidation in obese women and men.

Endurance training at an intensity eliciting maximal fat oxidation may have a beneficial effect on body weight and glucose metabolism in obese patients. However, the exercise intensity at which maximal fat oxidation occurs and the factors limiting fat oxidation are not well studied in this population. Obese, otherwise healthy men (n=38) and women (n=91) performed an incremental exercise test up to exhaustion on a cycle ergometer. Substrate oxidation was estimated using indirect calorimetry. Magnetic resonance tomography and spectroscopy were conducted to assess body fat distribution and intramyocellular fat content. We determined the exercise intensity at which maximal body fat oxidation occurs and assessed whether body composition, body fat distribution, intramyocellular fat content, or oxidative capacity predict exercise-induced fat oxidation. Maximal exercise-induced fat oxidation was 0.30+/-0.02 g/min in men and 0.23+/-0.01 g/min in women (p<0.05). Exercise intensity at the maximum fat oxidation was 42+/-2.2% VO (2 max) in men and 43+/-1.7% VO (2 max) in women. With multivariate analysis, exercise-induced fat oxidation was related to fat-free mass, percent fat mass, and oxidative capacity, but not to absolute fat mass, visceral fat, or intramyocellular fat content. We conclude that in obese subjects the capacity to oxidize fat during exercise appears to be limited by skeletal muscle mass and oxidative capacity rather than the availability of visceral or intramyocellular fat.

Loss of caveolae, vascular dysfunction, and pulmonary defects in caveolin-1 gene-disrupted mice.

Caveolae are plasma membrane invaginations that may play an important role in numerous cellular processes including transport, signaling, and tumor suppression. By targeted disruption of caveolin-1, the main protein component of caveolae, we generated mice that lacked caveolae. The absence of this organelle impaired nitric oxide and calcium signaling in the cardiovascular system, causing aberrations in endothelium-dependent relaxation, contractility, and maintenance of myogenic tone. In addition, the lungs of knockout animals displayed thickening of alveolar septa caused by uncontrolled endothelial cell proliferation and fibrosis, resulting in severe physical limitations in caveolin-1-disrupted mice. Thus, caveolin-1 and caveolae play a fundamental role in organizing multiple signaling pathways in the cell.

Antihypertensive therapy with aliskiren.

Aliskiren represents the first member in a new class of antihypertensive drugs. Inhibiting the renin-angiotensin system at its rate-limiting step is an idea that has been pursued for >30 years; however, earlier compounds failed because of problems related to efficacy, bioavailability, and/or side effects. Aliskiren, a 610 Da nonpeptide molecule, has exceptional affinity for the human renin enzymatic site and a half-life of about 40 h, which make its 3% bioavailability clinically unimportant with continued administration. The drug is not metabolized by CYP P450 enzymes and is excreted >90% unchanged by the fecal route. No adjustments are necessary for renal function, liver function, age, ethnicity, or other prescribed drugs. Blood pressure reductions are similar to those provided by other monotherapies. Interestingly, aliskiren combined with angiotensin receptor blocker or angiotensin-converting enzyme inhibitor therapy leads to a further blood pressure reduction as does combination with a diuretic or calcium channel blocker. The fact that plasma renin activity is reduced to low levels with aliskiren could provide a theoretical advantage over other treatments, while increases in total renin (prorenin) after the drug poses additional food for thought. Studies with primary cardiovascular and renal end points to address these possibilities are in progress.

Neutrophil surface presentation of the anti-neutrophil cytoplasmic antibody-antigen proteinase 3 depends on N-terminal processing.

The neutrophil serine protease proteinase 3 (PR3) is a main autoantigen in anti-neutrophil cytoplasmic antibody-associated vasculitis. PR3 surface presentation on neutrophilic granulocytes, the main effector cells, is pathogenically important. PR3 is presented by the NB1 (CD177) glycoprotein, but how the presentation develops during neutrophil differentiation is not known. An N-terminally unprocessed PR3 (proPR3) is produced early during neutrophil development and promotes myeloid cell differentiation. We therefore investigated if PR3 presentation depended on NB1 during neutrophil differentiation and if PR3 and proPR3 could both be presented by NB1. In contrast to mature neutrophils, differentiating neutrophils showed an early NB1-independent PR3 surface display that was recognized by only two of four monoclonal anti-PR3 antibodies and occurred in parallel with proPR3, but not PR3 secretion, suggesting that the NB1-independent surface PR3 was proPR3. PR3 gene expression preceeded NB1. When the NB1 receptor was detected on the surface, a mode of PR3 surface display similar to mature neutrophils developed together with the degranulation system. Ectopic expression studies showed that NB1 was a sufficient receptor for PR3 but not proPR3. ProPR3 display on the plasma membrane may influence the bone marrow microenvironment. NB1-mediated PR3 presentation depended on PR3 N-terminal processing implicating the PR3-N-terminus as NB1-binding site.

Determinants of fast marathon performance: low basal sympathetic drive, enhanced postcompetition vasodilatation and preserved cardiac performance after competition.

OBJECTIVE: To test the hypothesis that enhanced postexercise vasodilatation is related to sympathetic drive to resistance vessels and to fast marathon performance. DESIGN: Prospective field study before and after running a marathon. PARTICIPANTS: 51 healthy amateur runners who volunteered to participate. The fastest competitor finished fourth, the slowest 1290 th out of 1324 participants. INTERVENTIONS: None. MAIN OUTCOME MEASUREMENTS: Competition time, beat-to-beat blood pressure by the vascular unloading technique, oscillometric blood pressure, beat-to-beat stroke volume by impedance cardiography, total peripheral resistance changes calculated from blood pressure and stroke volume changes, sympathetic modulation of vasomotor tone and parasympathetic modulation of sinus node function by spectral analysis of blood pressure and heart rate variability, baroreceptor reflex sensitivity by the sequence method. RESULTS: Slow performers, in contrast to fast performers, exhibited a higher 0.1 Hz band of diastolic blood pressure variability before the competition (0.1 Hz BPV) (40.0 (SD 2.39) vs 54.9 (2.47), p<0.001), diminished vasodilatation (-11.3 (4.78) vs -29.4 (3.23), p<0.01) and a decrease in stroke index (-14.9 (3.55) vs +0.9 (3.37), p<0.001) in response to the race. Single and multiple regression analyses further corroborated the findings. CONCLUSIONS: Fast performance in the marathon is associated with low sympathetic modulation of vasomotor tone, maintained stroke index postcompetition and enhanced exercise-induced vasodilatation. We postulate that maintaining a low level of sympathetic modulation to resistance vessels during the course of training may indicate its appropriateness, thus enabling fast performance by optimal postexercise vasodilatation and by prevention of postcompetition cardiac dysfunction. This will have to be tested in future longitudinal studies.