Jorge Pinto Ribeiro

The acute administration of L-arginine (L-arg), a nitric oxide (NO) precursor, reduces lactate (LAC) concentration after exercise in healthy individuals. Lower concentration of L-arg may enhance the action of some inflammatory cytokines in HIV-1 infected patients. We tested the hypothesis that acute L-arg administration may reduce post-exercise blood LAC and inflammatory cytokines levels in HIV-infected patients. 10 HIV-infected men performed 2 maximal incremental cardiopulmonary exercise tests, separated by one week. 30 min before each test, patients received oral placebo or 20 g of L-arg, in random order. Blood LAC, tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-10 (IL-10) were measured before and up to 60 min after exercise. L-arg administration had no significant effect on exercise performance. Compared to placebo, L-arg administration reduced maximal post-exercise blood LAC from 8.7±0.6 to 6.9±0.4 mmol.L⁻¹ (p−1; L-arg=63±8 pg.mL⁻¹; p<0.05). In HIV-1 infected men, acute administration of L-arg reduces post-exercise blood LAC and increases IL-6 levels, suggesting the activation of the L-arg-NO pathway, with possible anti-inflammatory consequences.

Background: Adrenocortical carcinomas (ACCs) are among the most common childhood cancers occurring in infants affected with the Li-Fraumeni and Li- Fraumeni-like (LFS/LFL) syndromes, which are caused by dominant germline mutations in the TP53 gene. In Brazil, a particular mutation, occurring in the tetramerisation domain of the gene, p.R337H, is exceedingly common due to a founder effect and is strongly associated with ACC. In this report, we describe the phenotype and long-term clinical follow-up of a female child diagnosed with ACC and homozygous for the TP53 p.R337H founder mutation. Case presentation: At age 11 months, the patient was diagnosed with a virilising anaplastic adrenal cortical tumour, which was completely excised without disturbing the adrenal capsule. Family history was consistent with an LFL tumour pattern, and genotyping identified the TP53 p.R337H mutation in both alleles in genomic DNA from lymphocytes and fibroblasts. Haplotype analysis confirmed the occurrence of the mutation in the same founder haplotype previously described in other Brazilian patients. No other germline or somatic TP53 mutations or rearrangements were identified. At age 9 years, the child was asymptomatic and had no evidence of endocrine derangements. Full body and brain magnetic resonance imaging (MRI) failed to detect any suspicious proliferative lesions, and cardiopulmonary exercise testing results were within the normal reference for the child’s age, ruling out a major exercise capacity deficiency. Conclusion: This is the first clinical and aerobic functional capacity documentation of a patient who carries two mutant TP53 alleles and no wild-type allele. Our results support the hypothesis that TP53 p.R337H, the most common TP53 mutation ever described in any population, is a conditional mutant. Furthermore, our observations over a long period of clinical follow-up suggest that TP53 p.R337H homozygotes do not have a more severe disease phenotype than do heterozygote carriers of the same mutation. Patients with the homozygous TP53 p.R337H genotype will require careful surveillance for lifetime cancer risk and for effects on metabolic capacity later in life.

Background: A single aerobic exercise session increases blood flow and vascular reactivity in remote vascular areas in chronic heart failure (CHF). We hypothesized that CHF patients would present increased vascular reactivity after a resistance exercise session. Methods: Ten CHF patients and 10 healthy controls participated in three experiments, on different days: (1) 25-min rest (control); (2) 25-min lower-limb resistance exercises with vascular measurements in the calf (RELL); and (3) 25-min lower-limb resistance exercises with vascular measurements in the forearm (REUL). Heart rate (HR), blood pressure (BP), forearm blood flow (FBF), and calf blood flow (CBF) were measured at baseline, immediately, and 10, 30, and 60 min after the interventions. Calf and forearm reactive hyperaemia (RH) were measured at baseline and at 10, 30, and 60 min post interventions. Results: Mean BP was unchanged throughout the protocols in CHF patients, whereas healthy controls had postexercise reduction up to 60 and 10 min after RELL and REUL sessions, respectively. Forearm RH (30- min post exercise) indicated remote effects and was increased by 36% and 43% (p < 0.05) in CHF patients and controls, respectively. Both groups increased postexercise calf RH (local effect) up to 60 min; however, healthy controls presented larger responses compared with patients (73% vs. 39%, p < 0.05). Conclusion: Patients with CHF present blunted vascular responses in the exercised areas, but remote vascular reactivity responses are similar to those observed in healthy individuals, suggesting that resistance exercise may remotely contribute to vascular adaptation in nontrained vasculatures.

The cardiovascular electrophysiologic basis for the action of pyridostigmine, an acetylcholinesterase inhibitor, has not been investigated. The objective of the present study was to determine the cardiac electrophysiologic effects of a single dose of pyridostigmine bromide in an open-label, quasi-experimental protocol. Fifteen patients who had been indicated for diagnostic cardiac electrophysiologic study underwent two studies just before and 90-120 min after the oral administration of pyridostigmine (45 mg). Pyridostigmine was well tolerated by all patients. Wenckebach nodal anterograde atrioventricular point and basic cycle were not altered by pyridostigmine. Sinus recovery time (ms) was shorter during a 500-ms cycle stimulation (pre: 326 ± 45 vs post: 235 ± 47; P = 0.003) but not during 400-ms (pre: 275 ± 28 vs post: 248 ± 32; P = 0.490) or 600-ms (pre: 252 ± 42 vs post: 179 ± 26; P = 0.080) cycle stimulation. Pyridostigmine increased the ventricular refractory period (ms) during the 400-ms cycle stimulation (pre: 238 ± 7 vs post: 245 ± 9; P = 0.028) but not during the 500-ms (pre: 248 ± 7 vs post: 253 ± 9; P = 0.150) or 600-ms (pre: 254 ± 8 vs post: 259 ± 8; P = 0.255) cycle stimulation. We conclude that pyridostigmine did not produce conduction disturbances and, indeed, increased the ventricular refractory period at higher heart rates. While the effect explains previous results showing the anti-arrhythmic action of pyridostigmine, the clinical impact on long-term outcomes requires further investigation.

Inspiratory muscle weakness (IMW) is prevalent in patients with chronic heart failure (CHF) caused by left ventricular systolic dysfunction, which contributes to reduced exercise capacity and the presence of dyspnea during daily activities. Inspiratory muscle strength (estimated by maximal inspiratory pressure) has independent prognostic value in CHF. Overall, the results of trials with inspiratory muscle training (IMT) indicate that this intervention improves exercise capacity and quality of life, particularly in patients with CHF and IMW. Some benefit from IMT may be accounted for by the attenuation of the inspiratory muscle metaboreflex. Moreover, IMT results in improved cardiovascular responses to exercise and to those obtained with standard aerobic training. These findings suggest that routine screening for IMW is advisable in patients with CHF, and specific IMT and/or aerobic training are of practical value in the management of these patients.

We have previously shown that post-exercise inspiratory resistive loading (IRL) reduces blood lactate ([Lac ⁻_b ]). In this study, we tested the hypothesis that IRL during recovery could improve subsequent exercise performance. Eight healthy men underwent, on different days, two sequential 30-s, cycle ergometer Wingate tests. During the 10-min recovery period from test 1, subjects breathed freely or through an inspiratory resistance (15 cm H₂O) with passive leg recovery. Arterialized [Lac ⁻_b ] values, perceptual scores (Borg), cardiac output by impedance cardiography (QT), and changes in the deoxygenation status of the M. vastus lateralis by near-infrared spectroscopy (ΔHHb), were recorded. [Lac ⁻_b ] was significantly reduced after 4 min of recovery with IRL (peak [Lac ⁻_b ] 12.5 ± 2.3 mmol l⁻¹ with free-breathing vs. 9.8 ± 1.5 mmol l⁻¹ with IRL). Effort perception was reduced during late recovery with IRL compared with free-breathing. Cardiac work was increased with IRL, since heart rate and QT were elevated during late recovery. Peripheral muscle reoxygenation, however, was significantly impaired with IRL, suggesting that post-exercise convective O₂ delivery to the lower limbs was reduced. Importantly, IRL had a dual effect on subsequent performance, i.e., improvement in peak and mean power, but increased fatigue index (P < 0.05). Our data demonstrate that IRL after a Wingate test reduces post-exercise effort perception and improves peak power on subsequent all-out maximal-intensity exercise.

Background Patients with chronic heart failure (CHF) have abnormal vascular responses to acute exercise; however, regular aerobic training improves endothelial function in these patients. We hypothesized that, because of their attenuated vascular responses, CHF patients would present abnormal endothelium-dependent vasodilatation after a single exercise session. Methods Thirteen CHF patients and 13 healthy controls participated in two experiments, on different days, using a crossover design: (i) control (25-min seated at rest), and (ii) a submaximal exercise session (25-min cycling). Measurements of heart rate, blood pressure (BP), venous occlusion plethysmography forearm blood flow (FBF), and reactive hyperemia were made before and after (immediately, 10, 30, 60 min, and 24 h) each experimental condition. Results CHF patients had no changes in the mean BP throughout the protocols, whereas mean BP was reduced up to 60 min after exercise in controls. In CHF patients, FBF was increased and forearm vascular resistance was reduced up to 10 min after exercise, whereas these changes were sustained up to 30 min after exercise in controls. Reactive hyperemia was significantly increased up to 30 min after exercise in both groups. Conclusion Patients with CHF have increased postexercise FBF and decreased forearm vascular resistance; however, these responses last longer in healthy individuals. Despite the attenuated postexercise vascular responses, patients with CHF respond to a single-cycle exercise session with improved forearm endothelium-dependent vasodilation. Eur J Cardiovasc Prev Rehabil 16:53-59 © 2009 The European Society of Cardiology

With and without ischemia as detected by myocardial perfusion scintigraphy. Methods: Eighty-seven patients referred to exercise myocardial perfusion scintigraphy were also evaluated with incremental treadmill cardiopulmonary exercise testing. One investigator prospectively identified patients who presented transient exercise-induced perfusion defects on 99mTc sestamibi myocardial scintigraphies. Another investigator evaluated the response of oxygen pulse to incremental exercise testing without knowledge of electrocardiographic response or scintigraphic findings. Results: Exercise myocardial perfusion scintigraphy detected transient perfusion defects in 36% of the patients. Compared with patients with normal perfusion studies, patients with exercise-induced ischemia presented similar peak double product, peak oxygen uptake, and anaerobic threshold. Oxygen pulse at 25% of peak (ischemia: 9.7 ± 2 mL per beat; no ischemia: 9.3 ± 2 mL per beat), 50% of peak (11.2 ± 3 vs 10.8 ± 3 mL per beat), 75% of peak (12.5 ± 3 vs 11.9 ± 3 mL per beat), and at peak exercise (13 ± 4 vs 13 ± 4 mL per beat) were not different in exercise-induced ischemia and normal groups, respectively. However, patients who presented extensive transient perfusion defects during exercise had a lower peak oxygen pulse (12.8 ± 3.8 vs 16.4 ± 4.6 mL per beat; P < 0.05). Conclusion: The analysis of the oxygen pulse response to incremental exercise test does not identify mild myocardial ischemia. Flattening of oxygen pulse response during incremental exercise might be present only with extensive myocardial ischemia....

In patients with severe autonomic dysfunction, water ingestion elicits an acute pressor response. Hypertension may be associated with changes in cardiovascular autonomic modulation, but there is no information on the acute effects of water ingestion in patients with hypertension. In this study, we compared the effect of acute water ingestion on haemodynamic and autonomic responses of hypertensive and normotensive individuals. Eight patients with mild hypertension were compared to 10 normotensive individuals. After 30 min resting in the supine position all subjects ingested 500 ml of water. At baseline and after water ingestion, venous blood samples for plasma volume determination were collected, and electrocardiographic tracings, finger blood pressure, forearm blood flow and muscle sympathetic nerve activity (MSNA) were obtained. Water ingestion resulted in similar and minor reduction in plasma volume. Systolic and diastolic blood pressure increased in both hypertensive (means.d.: 19/146/3 mm Hg) and normotensive subjects (17/146/3 mm Hg). There was an increase in forearm vascular resistance and in MSNA. Heart rate was reduced (hypertensive: 51 beats/min, normotensive: 56 beats/min) and the high-frequency component of heart rate and systolic blood pressure variability was increased. In hypertensive and normotensive individuals, acute water ingestion elicits a pressor response, an effect that is most likely determined by an increased vasoconstrictor sympathetic activity, and is counterbalanced by an increase in blood pressure and heart rate vagal modulation.

OBJETIVO: Testar a hipótese, por meio de ensaio clínico randomizado, de que a administração de cimetidina altera a resposta cronotrópica ao exercício. MÉTODOS: Foram selecionados 24 indivíduos saudáveis, com idade entre 20 e 68 anos, não-atletas, os quais concordaram em ser submetidos a testes cardiopulmonares, após uso de placebo e de cimetidina, 400 mg, duas vezes ao dia, durante uma semana. Os testes foram realizados em esteira rolante, com protocolo de rampa com análises diretas dos gases expirados. Foi avaliada freqüência cardíaca máxima atingida, além da freqüência cardíaca de repouso e do limiar anaeróbico. RESULTADOS: Os indivíduos estudados foram igualmente distribuídos por sexo, com idade média (± desvio padrão) de 43 ±11 anos. Os exames com placebo e com cimetidina tiveram igual duração (578±90 seg vs 603±131 seg) e igual VO2 pico (35±8 ml/kg.min vs 35±8 ml/kg.min). A administração de cimetidina não apresentou efeito significativo na freqüência cardíaca de repouso (75±10 vs 74±8 bpm), no pico do esforço (176±12 vs 176±11 bpm) e, da mesma forma, também não houve diferença entre as variações das freqüências cardíacas (pico - repouso), nos dois estudos (101±14 vs 101±13 bpm). CONCLUSÃO: A administração de cimetidina por sete dias não altera a resposta cronotrópica ao exercício. OBJECTIVE: To test the hypothesis that the administration of cimetidine will modify the chronotropic response to exercise testing through a random clinical trial. METHODS: The study selected 24 eligible healthy subjects, ages between 20 and 68 years, not athletes, who agreed to undergo cardiopulmonary exercise testing after the administration of placebo and 400 mg of cimetidine twice a day for one week. The tests were performed on a treadmill using a ramp protocol and direct analysis of the expired gases. Peak, resting and anaerobic threshold heart rate were recorded. RESULTS: The twenty subjects studied were equally distributed across sex with mean (± SD) age 43 ± 11 years. Tests on placebo and on cimetidine presented similar duration (578 ± 90 sec vs 603 ± 131 sec) and similar peak oxygen uptake (35 ± 8 ml/kg.min vs 35 ± 8 ml/kg.min). Cimetidine administration had no significant effect on resting heart rate (75 ± 10 bpm vs 74 ± 8 bpm), heart rate at peak exercise (176 ± 12 bpm vs 176 ± 11 bpm), and on the difference between the peak and the resting heart rates - delta HR (101 ± 14 bpm vs 101 ± 13 bpm). CONCLUSION: The administration of cimetidine for 7 days has no significant effect on the chronotropic response to exercise testing