Perinatal arrhythmias.

Cardiac arrhythmias are very frequent in fetuses and newborns. The prognosis depends on the nature of the arrhythmias but is most often either spontaneously benign or following short-term medication administration. A correct diagnosis is essential for both management and prognosis. It is based on echocardiography during the fetal period and mainly on history, physical exam, and electrocardiogram after birth, but other modalities are available to record transient arrhythmic events. Irregular rhythms are mostly benign and rarely require therapy. In most fetuses and infants, tachyarrhythmias resolve spontaneously or require short-term administration of antiarrhythmics. Approximately one third of these may recur later on, especially during adolescence. Persistent bradyarrhythmias might require pacemaker implantation when associated with failure to thrive or with risk of sudden death. CONCLUSION: Arrhythmias in fetuses and infants are very common and mostly benign. History, physical exam, and recording of the arrhythmia are essential to make a correct diagnosis and establish an appropriate management for the rare potentially harmful arrhythmias.

Urgences rythmiques [Rhythm emergencies]

Arrhythmias have a high incidence in our population, and since the emergence of new methods in electrophysiology, the mechanism of most tachycardias can be identified. This allows not only to progress in the understanding of their pathophysiology but also in the treatment of arrhythmias, either in an emergency situation or in the chronic phase. The goal of this review is to give some therapeutic advice in case of rhythmic emergencies, keeping in mind that any arrhythmia should be subject to a cardiological work-up to seek specific treatment outside the emergency phase. The proposed therapies in this article are the ones which we are used to apply, but they differ depending on the areas. The final goal is to render service to the patients by trying to be as less damaging as possible, knowing that the understanding of the arrhythmogenic mechanism is not always possible. We hope that the little advice this review contains will be of use for the practitioner and for those who are confronted with patients suffering of acute arrhythmia.

mitoKATP channel activation in the postanoxic developing heart protects E-C coupling via NO-, ROS-, and PKC-dependent pathways.

Whereas previous studies have shown that opening of the mitochondrial ATP-sensitive K(+) (mitoK(ATP)) channel protects the adult heart against ischemia-reperfusion injury, it remains to be established whether this mechanism also operates in the developing heart. Isolated spontaneously beating hearts from 4-day-old chick embryos were subjected to 30 min of anoxia followed by 60 min of reoxygenation. The chrono-, dromo-, and inotropic disturbances, as well as alterations of the electromechanical delay (EMD), reflecting excitation-contraction (E-C) coupling, were investigated. Production of reactive oxygen species (ROS) in the ventricle was determined using the intracellular fluorescent probe 2',7'-dichlorofluorescin (DCFH). Effects of the specific mitoK(ATP) channel opener diazoxide (Diazo, 50 microM) or the blocker 5-hydroxydecanoate (5-HD, 500 microM), the nitric oxide synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 50 microM), the antioxidant N-(2-mercaptopropionyl)glycine (MPG, 1 mM), and the PKC inhibitor chelerythrine (Chel, 5 microM) on oxidative stress and postanoxic functional recovery were determined. Under normoxia, the baseline parameters were not altered by any of these pharmacological agents, alone or in combination. During the first 20 min of postanoxic reoxygenation, Diazo doubled the peak of ROS production and, interestingly, accelerated recovery of ventricular EMD and the PR interval. Diazo-induced ROS production was suppressed by 5-HD, MPG, or L-NAME, but not by Chel. Protection of ventricular EMD by Diazo was abolished by 5-HD, MPG, L-NAME, or Chel, whereas protection of the PR interval was abolished by L-NAME exclusively. Thus pharmacological opening of the mitoK(ATP) channel selectively improves postanoxic recovery of cell-to-cell communication and ventricular E-C coupling. Although the NO-, ROS-, and PKC-dependent pathways also seem to be involved in this cardioprotection, their interrelation in the developing heart can differ markedly from that in the adult myocardium.

Chagas disease: what is known and what is needed - A background article

Chagas disease began millions of years ago as an enzootic disease of wild animals and started to be transmitted to man accidentally in the form of an anthropozoonosis when man invaded wild ecotopes. Endemic Chagas disease became established as a zoonosis over the last 200-300 years through forest clearance for agriculture and livestock rearing and adaptation of triatomines to domestic environments and to man and domestic animals as a food source. It is estimated that 15 to 16 million people are infected with Trypanosoma cruzi in Latin America and 75 to 90 million people are exposed to infection. When T. cruzi is transmitted to man through the feces of triatomines, at bite sites or in mucosa, through blood transfusion or orally through contaminated food, it invades the bloodstream and lymphatic system and becomes established in the muscle and cardiac tissue, the digestive system and phagocytic cells. This causes inflammatory lesions and immune responses, particularly mediated by CD4+, CD8+, interleukin-2 (IL) and IL-4, with cell and neuron destruction and fibrosis, and leads to blockage of the cardiac conduction system, arrhythmia, cardiac insufficiency, aperistalsis, and dilatation of hollow viscera, particularly the esophagus and colon. T. cruzi may also be transmitted from mother to child across the placenta and through the birth canal, thus causing abortion, prematurity, and organic lesions in the fetus. In immunosuppressed individuals, T. cruzi infection may become reactivated such that it spreads as a severe disease causing diffuse myocarditis and lesions of the central nervous system. Chagas disease is characterized by an acute phase with or without symptoms, and with entry point signs (inoculation chagoma or Romaña's sign), fever, adenomegaly, hepatosplenomegaly, and evident parasitemia, and an indeterminate chronic phase (asymptomatic, with normal results from electrocardiogram and x-ray of the heart, esophagus, and colon) or with a cardiac, digestive or cardiac-digestive form. There is great regional variation in the morbidity due to Chagas disease, and severe cardiac or digestive forms may occur in 10 to 50% of the cases, or the indeterminate form in the other asymptomatic cases, but with positive serology. Several acute cases have been reported from Amazon region most of them by T. cruzi I, Z3, and a hybrid ZI/Z3. We conclude this article presenting the ten top Chagas disease needs for the near future.

Gap junction reduction in cardiomyocytes following transforming growth factor-β treatment and Trypanosoma cruzi infection

Gap junction connexin-43 (Cx43) molecules are responsible for electrical impulse conduction in the heart and are affected by transforming growth factor-β (TGF-β). This cytokine increases during Trypanosoma cruzi infection, modulating fibrosis and the parasite cell cycle. We studied Cx43 expression in cardiomyocytes exposed or not to TGF-β T. cruzi, or SB-431542, an inhibitor of TGF-β receptor type I (ALK-5). Cx43 expression was also examined in hearts with dilated cardiopathy from chronic Chagas disease patients, in which TGF-β signalling had been shown previously to be highly activated. We demonstrated that TGF-β treatment induced disorganised gap junctions in non-infected cardiomyocytes, leading to a punctate, diffuse and non-uniform Cx43 staining. A similar pattern was detected in T. cruzi-infected cardiomyocytes concomitant with high TGF-β secretion. Both results were reversed if the cells were incubated with SB-431542. Similar tests were performed using human chronic chagasic patients and we confirmed a down-regulation of Cx43 expression, an altered distribution of plaques in the heart and a significant reduction in the number and length of Cx43 plaques, which correlated negatively with cardiomegaly. We conclude that elevated TGF-β levels during T. cruzi infection promote heart fibrosis and disorganise gap junctions, possibly contributing to abnormal impulse conduction and arrhythmia that characterise severe cardiopathy in Chagas disease.

Rescue treatment with terlipressin in children with refractory septic shock: a clinical study

INTRODUCTION Refractory septic shock has dismal prognosis despite aggressive therapy. The purpose of the present study is to report the effects of terlipressin (TP) as a rescue treatment in children with catecholamine refractory hypotensive septic shock. METHODS We prospectively registered the children with severe septic shock and hypotension resistant to standard intensive care, including a high dose of catecholamines, who received compassionate therapy with TP in nine pediatric intensive care units in Spain, over a 12-month period. The TP dose was 0.02 mg/kg every four hours. RESULTS Sixteen children (age range, 1 month-13 years) were included. The cause of sepsis was meningococcal in eight cases, Staphylococcus aureus in two cases, and unknown in six cases. At inclusion the median (range) Pediatric Logistic Organ Dysfunction score was 23.5 (12-52) and the median (range) Pediatric Risk of Mortality score was 24.5 (16-43). All children had been treated with a combination of at least two catecholamines at high dose rates. TP treatment induced a rapid and sustained improvement in the mean arterial blood pressure that allowed reduction of the catecholamine infusion rate after one hour in 14 out of 16 patients. The mean (range) arterial blood pressure 30 minutes after TP administration increased from 50.5 (37-93) to 77 (42-100) mmHg (P < 0.05). The noradrenaline infusion rate 24 hours after TP treatment decreased from 2 (1-4) to 1 (0-2.5) microg/kg/min (P < 0.05). Seven patients survived to the sepsis episode. The causes of death were refractory shock in three cases, withdrawal of therapy in two cases, refractory arrhythmia in three cases, and multiorgan failure in one case. Four of the survivors had sequelae: major amputations (lower limbs and hands) in one case, minor amputations (finger) in two cases, and minor neurological deficit in one case. CONCLUSION TP is an effective vasopressor agent that could be an alternative or complementary therapy in children with refractory vasodilatory septic shock. The addition of TP to high doses of catecholamines, however, can induce excessive vasoconstriction. Additional studies are needed to define the safety profile and the clinical effectiveness of TP in children with septic shock.

Chronic phase of Chagas disease: why should it be treated? A comprehensive review

The pathogenesis and evolutive pattern of Chagas disease suggests that the chronic phase should be more widely treated in order to (i) eliminate Trypanosoma cruzi and prevent new inflammatory foci and the extension of tissue lesions, (ii) promote tissue regeneration to prevent fibrosis, (iii) reverse existing fibrosis, (iv) prevent cardiomyopathy, megaoesophagus and megacolon and (v) reduce or eliminate cardiac block and arrhythmia. All cases of the indeterminate chronic form of Chagas disease without contraindications due to other concomitant diseases or pregnancy should be treated and not only cases involving children or recently infected cases. Patients with chronic Chagas cardiomyopathy grade II of the New York Heart Association classification should be treated with specific chemotherapy and grade III can be treated according to medical-patient decisions. We are proposing the following new strategies for chemotherapeutic treatment of the chronic phase of Chagas disease: (i) repeated short-term treatments for 30 consecutive days and interval of 30-60 days for six months to one year and (ii) combinations of drugs with different mechanisms of action, such as benznidazole + nifurtimox, benznidazole or nifurtimox + allopurinol or triazole antifungal agents, inhibition of sterol synthesis.

New electrocardiographic criteria for discriminating between Brugada types 2 and 3 patterns and incomplete right bundle branch block.

OBJECTIVES: The aim of this study was to evaluate new electrocardiographic (ECG) criteria for discriminating between incomplete right bundle branch block (RBBB) and the Brugada types 2 and 3 ECG patterns. BACKGROUND: Brugada syndrome can manifest as either type 2 or type 3 pattern. The latter should be distinguished from incomplete RBBB, present in 3% of the population. METHODS: Thirty-eight patients with either type 2 or type 3 Brugada pattern that were referred for an antiarrhythmic drug challenge (AAD) were included. Before AAD, 2 angles were measured from ECG leads V(1) and/or V(2) showing incomplete RBBB: 1) α, the angle between a vertical line and the downslope of the r'-wave, and 2) β, the angle between the upslope of the S-wave and the downslope of the r'-wave. Baseline angle values, alone or combined with QRS duration, were compared between patients with negative and positive results on AAD. Receiver-operating characteristic curves were constructed to identify optimal discriminative cutoff values. RESULTS: The mean β angle was significantly smaller in the 14 patients with negative results on AAD compared to the 24 patients with positive results on AAD (36 ± 20° vs. 62 ± 20°, p < 0.01). Its optimal cutoff value was 58°, which yielded a positive predictive value of 73% and a negative predictive value of 87% for conversion to type 1 pattern on AAD; α was slightly less sensitive and specific compared with β. When the angles were combined with QRS duration, it tended to improve discrimination. CONCLUSIONS: In patients with suspected Brugada syndrome, simple ECG criteria can enable discrimination between incomplete RBBB and types 2 and 3 Brugada patterns.

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.

A new look at atrial fibrillation: lessons learned from drugs, pacing, and ablation therapies.

Atrial fibrillation (AF) is the most common arrhythmia and among the leading causes of stroke and heart failure in Western populations. Despite the increasing size of clinical trials assessing the efficacy and safety of AF therapies, achieved outcomes have not always matched expectations. Considering that AF is a symptom of many possible underlying diseases, clinical research for this arrhythmia should take into account their respective pathophysiology. Accordingly, the definition of the study populations to be included should rely on the established as well as on the new classifications of AF and take advantage from a differentiated look at the AF-electrocardiogram and from increasingly large spectrum of biomarkers. Such an integrated approach could bring researchers and treating physicians one step closer to the ultimate vision of personalized therapy, which, in this case, means an AF therapy based on refined diagnostic elements in accordance with scientific evidence gathered from clinical trials. By applying clear-cut patient inclusion criteria, future studies will be of smaller size and thus of lower cost. In addition, the findings from such studies will be of greater predictive value at the individual patient level, allowing for pinpointed therapeutic decisions in daily practice.

Suivi cardiologique d'un patient oncologique [Cardiologic follow up of an oncologic patient]

Recent progress in cancer therapy has dramatically modified the course and prognosis of some malignancies. Chemo and radiotherapy, along with newer targeted treatments, are given to control symptoms, postpone relapse, or attempt cure. However, many of these regimens are associated with adverse cardiovascular effects such as impaired left ventricular function, myocardial ischemia, hypertension, and arrhythmia. Awareness of potential cardiotoxicity is important, as it may allow practitioners to recognize early signs of cardiac complications and to adapt therapy in order to limit detrimental effects. Diagnosis of cardiovascular complications may iustify the introduction of cardiologic therapies, and may require the reassessment of risk/benefit ratios related to specific cancer therapy. Screening and follow up strategies are proposed.

Early repolarization, acute emotional stress and sudden death.

We herein report the case of a 36-year-old man who died suddenly after a fight with another man. Forensic investigations included unenhanced computed tomography, postmortem angiography, autopsy, histology, neuropathology, toxicology, and biochemistry and allowed a traumatic cause of death to be excluded. An electrocardiogram recorded some years prior to death revealed the presence of an early repolarization pattern. Based on the results of all investigations, the cause of death was determined to be cardiac arrhythmia and cardiac arrest during an emotionally stressful event associated with physical assault. Direct third party involvement, however, was excluded, and the manner of death was listed as natural. The case was not pursued any further by the public prosecutor.

Amyloïdose cardiaque: une urgence diagnostique [Echocardiographic analysis in cardiac amyloidosis]

Systemic amyloidosis with cardiac involvement may clinically be suspected in the presence of heart failure or arrhythmia of unknown origin. Herein two cases of cardiac amyloidosis are described with a clinical presentation of heart failure refractory to usual treatment. The key role of echocardiography in the diagnosis and prognosis evaluation of cardiac amyloidosis is discussed. A treatment targeted against the generation of amyloid fibril should ideally be initiated before apparition of heart failure.

n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia.

BACKGROUND: The use of n-3 fatty acids may prevent cardiovascular events in patients with recent myocardial infarction or heart failure. Their effects in patients with (or at risk for) type 2 diabetes mellitus are unknown. METHODS: In this double-blind study with a 2-by-2 factorial design, we randomly assigned 12,536 patients who were at high risk for cardiovascular events and had impaired fasting glucose, impaired glucose tolerance, or diabetes to receive a 1-g capsule containing at least 900 mg (90% or more) of ethyl esters of n-3 fatty acids or placebo daily and to receive either insulin glargine or standard care. The primary outcome was death from cardiovascular causes. The results of the comparison between n-3 fatty acids and placebo are reported here. RESULTS: During a median follow up of 6.2 years, the incidence of the primary outcome was not significantly decreased among patients receiving n-3 fatty acids, as compared with those receiving placebo (574 patients [9.1%] vs. 581 patients [9.3%]; hazard ratio, 0.98; 95% confidence interval [CI], 0.87 to 1.10; P=0.72). The use of n-3 fatty acids also had no significant effect on the rates of major vascular events (1034 patients [16.5%] vs. 1017 patients [16.3%]; hazard ratio, 1.01; 95% CI, 0.93 to 1.10; P=0.81), death from any cause (951 [15.1%] vs. 964 [15.4%]; hazard ratio, 0.98; 95% CI, 0.89 to 1.07; P=0.63), or death from arrhythmia (288 [4.6%] vs. 259 [4.1%]; hazard ratio, 1.10; 95% CI, 0.93 to 1.30; P=0.26). Triglyceride levels were reduced by 14.5 mg per deciliter (0.16 mmol per liter) more among patients receiving n-3 fatty acids than among those receiving placebo (P<0.001), without a significant effect on other lipids. Adverse effects were similar in the two groups. CONCLUSIONS: Daily supplementation with 1 g of n-3 fatty acids did not reduce the rate of cardiovascular events in patients at high risk for cardiovascular events. (Funded by Sanofi; ORIGIN ClinicalTrials.gov number, NCT00069784.).

Pharmacokinetic-pharmacodynamic profile of angiotensin II receptor antagonists.

The pharmacokinetic and pharmacodynamic properties of nonpeptide angiotensin antagonists in humans are reviewed in this paper. Representatives of this new therapeutic class share common features: lipophilia, intermediate bioavailability, high affinity for plasma proteins and liver metabolism; some have active metabolites. Angiotensin II antagonists block the blood pressure response to exogenous angiotensin II in healthy volunteers, decrease baseline blood pressure in both normal and hypertensive patients, produce a marked rise in plasma renin activity and endogenous angiotensin II and increase renal blood flow without altering glomerular filtration rate. These effects are dose-dependent, but their time course varies between the drugs owing to pharmacokinetic and pharmacodynamic differences. Additionally, the extent of blood pressure reduction is dependent on physiological factors such as sodium and water balance. The characterisation of their pharmacokinetic-pharmacodynamic relationships deserves further refinement for designing optimal therapeutic regimens and proposing dosage adaptations in specific conditions.