Exercise induces rapid interstitial lung water accumulation in patients with chronic mountain sickness.

BACKGROUND: Chronic mountain sickness (CMS) is a major public health problem in mountainous regions of the world. In its more advanced stages, exercise intolerance is often found, but the underlying mechanism is not known. Recent evidence indicates that exercise-induced pulmonary hypertension is markedly exaggerated in CMS. We speculated that this problem may cause pulmonary fluid accumulation and aggravate hypoxemia during exercise. METHODS: We assessed extravascular lung water (chest ultrasonography), pulmonary artery pressure, and left ventricular function in 15 patients with CMS and 20 control subjects at rest and during exercise at 3,600 m. RESULTS: Exercise at high altitude rapidly induced pulmonary interstitial fluid accumulation in all patients but one (14 of 15) with CMS and further aggravated the preexisting hypoxemia. In contrast, in healthy high-altitude dwellers exercise did not induce fluid accumulation in the majority of subjects (16 of 20) (P = .002 vs CMS) and did not alter arterial oxygenation. Exercise-induced pulmonary interstitial fluid accumulation and hypoxemia in patients with CMS was accompanied by a more than two times larger increase of pulmonary artery pressure than in control subjects (P < .001), but no evidence of left ventricular dysfunction. Oxygen inhalation markedly attenuated the exercise-induced pulmonary hypertension (P < .01) and interstitial fluid accumulation (P < .05) in patients with CMS but had no detectable effects in control subjects. CONCLUSIONS: To our knowledge, these findings provide the first direct evidence that exercise induces rapid interstitial lung fluid accumulation and hypoxemia in patients with CMS that appear to be related to exaggerated pulmonary hypertension. We suggest that this problem contributes to exercise intolerance in patients with CMS. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01182792; URL: www.clinicaltrials.gov.

Familial evaluation in catecholaminergic polymorphic ventricular tachycardia: disease penetrance and expression in cardiac ryanodine receptor mutation-carrying relatives.

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome associated with mutations in the cardiac ryanodine receptor gene (Ryr2) in the majority of patients. Previous studies of CPVT patients mainly involved probands, so current insight into disease penetrance, expression, genotype-phenotype correlations, and arrhythmic event rates in relatives carrying the Ryr2 mutation is limited. METHODS AND RESULTS: One-hundred sixteen relatives carrying the Ryr2 mutation from 15 families who were identified by cascade screening of the Ryr2 mutation causing CPVT in the proband were clinically characterized, including 61 relatives from 1 family. Fifty-four of 108 antiarrhythmic drug-free relatives (50%) had a CPVT phenotype at the first cardiological examination, including 27 (25%) with nonsustained ventricular tachycardia. Relatives carrying a Ryr2 mutation in the C-terminal channel-forming domain showed an increased odds of nonsustained ventricular tachycardia (odds ratio, 4.1; 95% CI, 1.5-11.5; P=0.007, compared with N-terminal domain) compared with N-terminal domain. Sinus bradycardia was observed in 19% of relatives, whereas other supraventricular dysrhythmias were present in 16%. Ninety-eight (most actively treated) relatives (84%) were followed up for a median of 4.7 years (range, 0.3-19.0 years). During follow-up, 2 asymptomatic relatives experienced exercise-induced syncope. One relative was not being treated, whereas the other was noncompliant. None of the 116 relatives died of CPVT during a 6.7-year follow-up (range, 1.4-20.9 years). CONCLUSIONS: Relatives carrying an Ryr2 mutation show a marked phenotypic diversity. The vast majority do not have signs of supraventricular disease manifestations. Mutation location may be associated with severity of the phenotype. The arrhythmic event rate during follow-up was low.

Physiopathologie de l'hypertrophie ventriculaire gauche. [Physiopathology of left ventricular hypertrophy]

Left ventricular hypertrophy (LVH) is an early complication of hypertension. To a certain degree, this process counteracts the parietal stress induced by high blood pressure. Genetic factors, obesity, high salt diet and different growth factors, notably angiotensin II and noradrenaline, can also predispose to hypertrophic cardiomyopathy. Left ventricular mass is increased on echocardiography in about 20% of hypertensive subjects. LVH is initially associated with a change in myocardial diastolic function and later with abnormal systolic function. It is a major risk factor, a cause of cardiac failure, reduction in coronary reserve and of ventricular arrhythmias. Treatment of hypertension is associated with regression of LVH and preservation or improvement in myocardial diastolic and systolic functions. The decrease in left ventricular mass could reduce the incidence of cardiovascular complications in hypertension.

Ginseng administration protects skeletal muscle from oxidative stress induced by acute exercise in rats

Enzymatic activity was analyzed in the soleus, gastrocnemius (red and white) and plantaris muscles of acutely exercised rats after long-term administration of Panax ginseng extract in order to evaluate the protective role of ginseng against skeletal muscle oxidation. Ginseng extract (3, 10, 100, or 500 mg/kg) was administered orally for three months to male Wistar rats weighing 200 ± 50 g before exercise and to non-exercised rats (N = 8/group). The results showed a membrane stabilizing capacity of the extract since mitochondrial function measured on the basis of citrate synthase and 3-hydroxyacyl-CoA dehydrogenase activities was reduced, on average, by 20% (P < 0.05) after exercise but the activities remained unchanged in animals treated with a ginseng dose of 100 mg/kg. Glutathione status did not show significant changes after exercise or treatment. Lipid peroxidation, measured on the basis of malondialdehyde levels, was significantly higher in all muscles after exercise, and again was reduced by about 74% (P < 0.05) by the use of ginseng extract. The administration of ginseng extract was able to protect muscle from exercise-induced oxidative stress irrespective of fiber type.

Comparison of sweat rate during graded exercise and the local rate induced by pilocarpine

Centrally stimulated sweat rate produced by graded exercise until exhaustion was compared to the local sweat rate induced by pilocarpine, often used as a sweating index for healthy individuals. Nine young male volunteers (22 ± 4 years) were studied in temperate environment in two situations: at rest and during progressive exercise with 25 W increases every 2 min until exhaustion, on a cycle ergometer. In both situations, sweating was induced on the right forearm with 5 ml 0.5% pilocarpine hydrochloride applied by iontophoresis (1.5 mA, 5 min), with left forearm used as control. Local sweat rate was measured for 15 min at rest. During exercise, whole-body sweat rate was calculated from the body weight variation. Local sweat rate was measured from the time when heart rate reached 150 bpm until exhaustion and was collected using absorbent filter paper. Pharmacologically induced local sweat rate at rest (0.4 ± 0.2 mg cm-2 min-1) and mean exercise-induced whole-body sweat rate (0.4 ± 0.1 mg cm-2 min-1) were the same (P > 0.05) but were about five times smaller than local exercise-induced sweat rate (control = 2.1 ± 1.4; pilocarpine = 2.7 ± 1.2 mg cm-2 min-1), indicating different sudorific mechanisms. Both exercise-induced whole-body sweat rate (P < 0.05) and local sweat rate (P < 0.05) on control forearm correlated positively with pilocarpine-induced local sweat rate at rest. Assuming that exercise-induced sweating was a result of integrated physiological mechanisms, we suggest that local and whole-body sweat rate measured during graded exercise could be a better sweating index than pilocarpine.

Induction of chagasic-like arrhythmias in the isolated beating hearts of healthy rats perfused with Trypanosoma cruzi-conditioned medium

Chagas' myocardiopathy, caused by the intracellular protozoan Trypanosoma cruzi, is characterized by microvascular alterations, heart failure and arrhythmias. Ischemia and arrythmogenesis have been attributed to proteins shed by the parasite, although this has not been fully demonstrated. The aim of the present investigation was to study the effect of substances shed by T. cruzi on ischemia/reperfusion-induced arrhythmias. We performed a triple ischemia-reperfusion (I/R) protocol whereby the isolated beating rat hearts were perfused with either Vero-control or Vero T. cruzi-infected conditioned medium during the different stages of ischemia and subsequently reperfused with Tyrode's solution. ECG and heart rate were recorded during the entire experiment. We observed that triple I/R-induced bradycardia was associated with the generation of auricular-ventricular blockade during ischemia and non-sustained nodal and ventricular tachycardia during reperfusion. Interestingly, perfusion with Vero-infected medium produced a delay in the reperfusion-induced recovery of heart rate, increased the frequency of tachycardic events and induced ventricular fibrillation. These results suggest that the presence of parasite-shed substances in conditioned media enhances the arrhythmogenic effects that occur during the I/R protocol.

Central release of nitric oxide mediates antinociception induced by aerobic exercise

Nitric oxide (NO) is a soluble gas that participates in important functions of the central nervous system, such as cognitive function, maintenance of synaptic plasticity for the control of sleep, appetite, body temperature, neurosecretion, and antinociception. Furthermore, during exercise large amounts of NO are released that contribute to maintaining body homeostasis. Besides NO production, physical exercise has been shown to induce antinociception. Thus, the present study aimed to investigate the central involvement of NO in exercise-induced antinociception. In both mechanical and thermal nociceptive tests, central [intrathecal (it) and intracerebroventricular (icv)] pretreatment with inhibitors of the NO/cGMP/KATP pathway (L-NOArg, ODQ, and glybenclamide) prevented the antinociceptive effect induced by aerobic exercise (AE). Furthermore, pretreatment (it, icv) with specific NO synthase inhibitors (L-NIO, aminoguanidine, and L-NPA) also prevented this effect. Supporting the hypothesis of the central involvement of NO in exercise-induced antinociception, nitrite levels in the cerebrospinal fluid increased immediately after AE. Therefore, the present study suggests that, during exercise, the NO released centrally induced antinociception.

High-resolution electrocardiography in dogs under doxorubicin-induced cardiomyopathy

Determinaram-se a ocorrência de potencial tardio em cães com cardiomiopatia induzida pela doxorrubicina e sua relação com o desenvolvimento de arritmias ventriculares ou morte súbita. Sete cães adultos, sem raça definida, de ambos os sexos foram utilizados. A cardiomiopatia foi induzida por infusão venosa lenta de doxorrubicina (30mg/m²) em intervalos de 21 dias, até uma dose total cumulativa de 240mg/m². Os animais foram monitorados ecocardiograficamente. Após a confirmação da cardiomiopatia, foi feito o registro da eletrocardiografia de alta resolução. Potenciais tardios foram observados em dois animais que morreram subitamente poucos dias após.

Holter electrocardiography in dogs showing doxorubicin-induced dilated cardiomyopathy

O estudo consistiu na identificação precoce da ocorrência de arritmias em cães com cardiomiopatia dilatada experimental induzida pela doxorrubicina (DOX). Utilizaram-se 10 cães adultos, sadios, distribuídos nos grupos A (n=5) e B (n=5). O grupo B recebeu 30mg/m² de DOX, via intravenosa, a cada 21 dias, até a dose cumulativa de 180 ou 240mg/m². No grupo A (controle), administrou-se solução salina 0,9%, via intravenosa, nos mesmos intervalos do grupo B. Ao se evidenciar o quadro de disfunção miocárdica nos cães do grupo B, caracterizado pela fração de encurtamento menor que 20%, aumento da separação septal do ponto E acima de 0,7cm e aumento do índice volumétrico do ventrículo esquerdo ao final da sístole (61,4ml/m²), realizaram-se os eletrocardiogramas por 24 horas. Os resultados demonstraram aumentos de 44,6% e 41,7% nas freqüências cardíacas mínima e média, respectivamente, e presença, com maior freqüência, de arritmias supraventriculares do que ventriculares nos animais do grupo B. Concluiu-se que o Holter é eficaz e demonstra, com precocidade e melhor definição, as alterações da freqüência e do ritmo cardíaco de cães com disfunção miocárdica induzida pela doxorrubicina.

Ventricular Systolic Reserve in Asymptomatic Children Previously Treated With Low Doses of Anthracyclines

Doppler echocardiography has been used for the diagnosis of anthracycline-induced cardiotoxicity. However, few data are available that include asymptomatic children previously treated with a low cumulative dose of this drug and therefore have a low risk of cardiac dysfunction. The aim of this study was to evaluate after-exercise cardiac function in asymptomatic children previously treated with a low cumulative dose of anthracycline and no clinical or laboratory evidence of cardiotoxicity. Doppler echocardiography was performed before and immediately after physical exercise in 29 children aged 5 to 17 years (anthracycline [ADRIA] group). All had finished cancer treatment with anthracycline derivatives for ≥1 year (cumulative dose 100 mg/m2). Results were compared with those from age- and gender-matched healthy children (control group; n = 26) using the Mann-Whitney rank test. Exercise-induced cardiac function changes within groups were analyzed using Wilcoxon's signed-rank test. Exercise induced significant increases in left ventricular systolic function indexes in both groups. However, the ADRIA group had significantly lower changes in left ventricular ejection fraction (ADRIA group 0.71 ± 0.02 vs 0.80 ± 0.04 and control group 0.71 ± 0.02 vs 0.89 ± 0.05, p = 0.0017) and end-systolic stress-volume index (ADRIA group 4.59 ± 0.69 vs 6.4 ± 2.0 g.cm-2/ml.m-2 and control group 5.49 ± 0.98 vs 11.54 ± 2.86 g.cm-2/ml.m-2; p <0.0001), indicating decreased functional systolic reserve. In conclusion, asymptomatic children previously treated with low cumulative doses of anthracycline had decreased functional systolic reserve evidenced by exercise, suggesting a nonclinically manifested cardiotoxicity. © 2007 Elsevier Inc. All rights reserved.

Effects of exercise training on stress-induced vascular reactivity alterations: role of nitric oxide and prostanoids

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

[Suddenly occurring exercise intolerance]

In this case report, the differencial diagnosis of exercise intolerance associated with dyspnea and the diagnostic approach with cardio-pulmonary exercise testing with detection of an exercise induced second-degree atrio-ventricular block as a cause of chronotropic incompetence is described.

Genetic of catecholaminergic polymorphic ventricular tachycardia: basic concepts.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a cardiac channelopathy characterized by altered intracellular calcium handling resulting in ventricular arrhythmias and high risk of cardiac sudden death in young cases with normal structural hearts. Patients present with exertional syncope and the trademark dysrhythmia is polymorphic and/or bidirectional ventricular tachycardia during exercise or adrenergic stimulation. Early detection of CPVT is crucial because opportune medical intervention prevents sudden cardiac death. Mutations in the ryanodine receptor RYR2 explain nearly 70% of the CPVT cases and cause the autosomic dominant form of the disease. Mutations in calsequestrin 2 causes a recessive form and explain less than 5% of all cases. Genetic screening in CPVT, besides providing early detection of asymptomatic carriers at risk, has provided important insights in the mechanism underlying the disease. Mutational analysis of RYR2 has been a challenge due to the large size of the gene, 105 exons encoded for 4,967 amino-acids. In this review we analyze general concepts of the disease, differential diagnosis and strategies for genetic screening.

Cellular hyper-excitability caused by mutations that alter the activation process of voltage-gated sodium channels.

Voltage-gated sodium channels (Nav) are widely expressed as macro-molecular complexes in both excitable and non-excitable tissues. In excitable tissues, the upstroke of the action potential is the result of the passage of a large and rapid influx of sodium ions through these channels. NaV dysfunction has been associated with an increasingly wide range of neurological, muscular and cardiac disorders. The purpose of this review is to summarize the recently identified sodium channel mutations that are linked to hyper-excitability phenotypes and associated with the alteration of the activation process of voltage gated sodium channels. Indeed, several clinical manifestations that demonstrate an alteration of tissue excitability were recently shown to be strongly associated with the presence of mutations that affect the activation process of the Nav. These emerging genotype-phenotype correlations have expanded the clinical spectrum of sodium channelopathies to include disorders which feature a hyper-excitability phenotype that may or may not be associated with a cardiomyopathy. The p.I141V mutation in SCN4A and SCN5A, as well as its homologous p.I136V mutation in SCN9A, are interesting examples of mutations that have been linked to inherited hyperexcitability myotonia, exercise-induced polymorphic ventricular arrhythmias and erythromelalgia, respectively. Regardless of which sodium channel isoform is investigated, the substitution of the isoleucine to valine in the locus 141 induces similar modifications in the biophysical properties of the Nav by shifting the voltage-dependence of steady state activation toward more negative potentials.

Blocking effects of polyunsaturated fatty acids on Na+ channels of neonatal rat ventricular myocytes.

Recent evidence indicates that polyunsaturated long-chain fatty acids (PUFAs) prevent lethal ischemia-induced cardiac arrhythmias in animals and probably in humans. To increase understanding of the mechanism(s) of this phenomenon, the effects of PUFAs on Na+ currents were assessed by the whole-cell patch-clamp technique in cultured neonatal rat ventricular myocytes. Extracellular application of the free 5,8,11,14,17-eicosapentaenoic acid (EPA) produced a concentration-dependent suppression of ventricular, voltage-activated Na+ currents (INa). After cardiac myocytes were treated with 5 or 10 microM EPA, the peak INa (elicited by a single-step voltage change with pulses from -80 to -30 mV) was decreased by 51% +/- 8% (P < 0.01; n = 10) and 64% +/- 5% (P < 0.001; n = 21), respectively, within 2 min. Likewise, the same concentrations of 4,7,10,16,19-docosahexaenoic acid produced the same inhibition of INa. By contrast, 5 and 10 microM arachidonic acid (AA) caused less inhibition of INa, but both n - 6 and n - 3 PUFAs inhibited INa significantly. A monounsaturated fatty acid and a saturated fatty acid did not. After washing out EPA, INa returned to the control level. Raising the concentration of EPA to 40 microM completely blocked INa. The IC50 of EPA was 4.8 microM. The inhibition of this Na+ channel was found to be dose and time, but not use dependent. Also, the EPA-induced inhibition of INa was voltage dependent, since 10 microM EPA produced 83% +/- 7% and 29% +/- 5% inhibition of INa elicited by pulses from -80 to -30 mV and from -150 to -30 mV, respectively, in single-step voltage changes. A concentration of 10 microM EPA shifted the steady-state inactivation curve of INa by -19 +/- 3 mV (n = 7; P < 0.01). These effects of PUFAs on INa may be important for their antiarrhythmic effect in vivo.