Usefulness of inducible ventricular tachycardia to predict long-term adverse outcomes in arrhythmogenic right ventricular cardiomyopathy

The role of the electrophysiologic (EP) study for risk stratification in patients with arrhythmogenic right ventricular cardiomyopathy is controversial. We investigated the role of inducible sustained monomorphic ventricular tachycardia (SMVT) for the prediction of an adverse outcome (AO), defined as the occurrence of cardiac death, heart transplantation, sudden cardiac death, ventricular fibrillation, ventricular tachycardia with hemodynamic compromise or syncope. Of 62 patients who fulfilled the 2010 Arrhythmogenic Right Ventricular Cardiomyopathy Task Force criteria and underwent an EP study, 30 (48%) experienced an adverse outcome during a median follow-up of 9.8 years. SMVT was inducible in 34 patients (55%), 22 (65%) of whom had an adverse outcome. In contrast, in 28 patients without inducible SMVT, 8 (29%) had an adverse outcome. Kaplan-Meier analysis showed an event-free survival benefit for patients without inducible SMVT (log-rank p = 0.008) with a cumulative survival free of an adverse outcome of 72% (95% confidence interval [CI] 56% to 92%) in the group without inducible SMVT compared to 26% (95% CI 14% to 50%) in the other group after 10 years. The inducibility of SMVT during the EP study (hazard ratio [HR] 2.99, 95% CI 1.23 to 7.27), nonadherence (HR 2.74, 95% CI 1.3 to 5.77), and heart failure New York Heart Association functional class II and III (HR 2.25, 95% CI 1.04 to 4.87) were associated with an adverse outcome on univariate Cox regression analysis. The inducibility of SMVT (HR 2.52, 95% CI 1.03 to 6.16, p = 0.043) and nonadherence (HR 2.34, 95% CI 1.1 to 4.99, p = 0.028) remained as significant predictors on multivariate analysis. This long-term observational data suggest that SMVT inducibility during EP study might predict an adverse outcome in patients with arrhythmogenic right ventricular cardiomyopathy, advocating a role for EP study in risk stratification.

The RYR2-encoded ryanodine receptor/calcium release channel in patients diagnosed previously with either catecholaminergic polymorphic ventricular tachycardia or genotype negative, exercise-induced long QT syndrome: a comprehensive open reading frame mutational analysis.

OBJECTIVES This study was undertaken to determine the spectrum and prevalence of mutations in the RYR2-encoded cardiac ryanodine receptor in cases with exertional syncope and normal corrected QT interval (QTc). BACKGROUND Mutations in RYR2 cause type 1 catecholaminergic polymorphic ventricular tachycardia (CPVT1), a cardiac channelopathy with increased propensity for lethal ventricular dysrhythmias. Most RYR2 mutational analyses target 3 canonical domains encoded by <40% of the translated exons. The extent of CPVT1-associated mutations localizing outside of these domains remains unknown as RYR2 has not been examined comprehensively in most patient cohorts. METHODS Mutational analysis of all RYR2 exons was performed using polymerase chain reaction, high-performance liquid chromatography, and deoxyribonucleic acid sequencing on 155 unrelated patients (49% females, 96% Caucasian, age at diagnosis 20 +/- 15 years, mean QTc 428 +/- 29 ms), with either clinical diagnosis of CPVT (n = 110) or an initial diagnosis of exercise-induced long QT syndrome but with QTc <480 ms and a subsequent negative long QT syndrome genetic test (n = 45). RESULTS Sixty-three (34 novel) possible CPVT1-associated mutations, absent in 400 reference alleles, were detected in 73 unrelated patients (47%). Thirteen new mutation-containing exons were identified. Two-thirds of the CPVT1-positive patients had mutations that localized to 1 of 16 exons. CONCLUSIONS Possible CPVT1 mutations in RYR2 were identified in nearly one-half of this cohort; 45 of the 105 translated exons are now known to host possible mutations. Considering that approximately 65% of CPVT1-positive cases would be discovered by selective analysis of 16 exons, a tiered targeting strategy for CPVT genetic testing should be considered.

Dystrophic cardiomyopathy: role of TRPV2 channels in stretch-induced cell damage

Aims Duchenne muscular dystrophy (DMD), a degenerative pathology of skeletal muscle, also induces cardiac failure and arrhythmias due to a mutation leading to the lack of the protein dystrophin. In cardiac cells, the subsarcolemmal localization of dystrophin is thought to protect the membrane from mechanical stress. The absence of dystrophin results in an elevated stress-induced Ca2+ influx due to the inadequate functioning of several proteins, such as stretch-activated channels (SACs). Our aim was to investigate whether transient receptor potential vanilloid channels type 2 (TRPV2) form subunits of the dysregulated SACs in cardiac dystrophy. Methods and results We defined the role of TRPV2 channels in the abnormal Ca2+ influx of cardiomyocytes isolated from dystrophic mdx mice, an established animal model for DMD. In dystrophic cells, western blotting showed that TRPV2 was two-fold overexpressed. While normally localized intracellularly, in myocytes from mdx mice TRPV2 channels were translocated to the sarcolemma and were prominent along the T-tubules, as indicated by immunocytochemistry. Membrane localization was confirmed by biotinylation assays. Furthermore, in mdx myocytes pharmacological modulators suggested an abnormal activity of TRPV2, which has a unique pharmacological profile among TRP channels. Confocal imaging showed that these compounds protected the cells from stress-induced abnormal Ca2+ signals. The involvement of TRPV2 in these signals was confirmed by specific pore-blocking antibodies and by small-interfering RNA ablation of TRPV2. Conclusion Together, these results establish the involvement of TRPV2 in a stretch-activated calcium influx pathway in dystrophic cardiomyopathy, contributing to the defective cellular Ca2+ handling in this disease.

Diabetic cardiomyopathy and post-infarct ventricular remodelling : Effects of levosimendan in a rodent model of type II diabetes

Type 2 diabetes is a risk factor for the development of cardiovascular disease. Recently, the term diabetic cardiomyopathy has been proposed to describe the changes in the heart that occur in response to chronic hyperglycemia and insulin resistance. Ventricular remodelling in diabetic cardiomyopathy includes left ventricular hypertrophy, increased interstitial fibrosis, apoptosis and diastolic dysfunction. Mechanisms behind these changes are increased oxidative stress and renin-angiotensin system activation. The diabetic Goto-Kakizaki rat is a non-obese model of type 2 diabetes that exhibits defective insulin signalling. Recently two interconnected stress response pathways have been discovered that link insulin signalling, longevity, apoptosis and cardiomyocyte hypertrophy. The insulin-receptor PI3K/Ak pathway inhibits proapoptotic FOXO3a in response to insulin signalling and the nuclear Sirt1 deacetylase inhibits proapoptotic p53 and modulates FOXO3a in favour of survival and growth. --- Levosimendan is a calcium sensitizing agent used for the management of acute decompensated heart failure. Levosimendan acts as a positive inotrope by sensitizing cardiac troponin C to calcium and exerts vasodilation by opening mitochondrial and sarcolemmal ATP-sensitive potassium channels. Levosimendan has been described to have beneficial effects in ventricular remodelling after myocardial infarction. The aims of the study were to characterize whether diabetic cardiomyopathy associates with cardiac dysfunction, cardiomyocyte apoptosis, hypertrophy and fibrosis in spontaneously diabetic Goto-Kakizaki (GK) rats, which were used to model type 2 diabetes. Protein expression and activation of the Akt FOXO3a and Sirt1 p53 pathways were examined in the development of ventricular remodelling in GK rats with and without myocardial infarction (MI). The third and fourth studies examined the effects of levosimendan on ventricular remodelling and gene expression in post-MI GK rats. The results demonstrated that diabetic GK rats develop both modest hypertension and features similar to diabetic cardiomyopathy including cardiac dysfunction, LV hypertrophy and fibrosis and increased apoptotic signalling. MI induced a sustained increase in cardiomyocyte apoptosis in GK rats together with aggravated LV hypertrophy and fibrosis. The GK rat myocardium exhibited decreased Akt- FOXO3a phosphorylation and increased nuclear translocation of FOXO3a and overproduction of the Sirt1 protein. Treatment with levosimendan decreased cardiomyocyte apoptosis, senescence and LV hypertrophy and altered the gene expression profile in GK rat myocardium. The findings indicate that impaired cardioprotection via Akt FOXO3a and p38 MAPK is associated with increased apoptosis, whereas Sirt1 functions in counteracting apoptosis and the development of LV hypertrophy in the GK rat myocardium. Overall, levosimendan treatment protects against post-MI ventricular remodelling and alters the gene expression profile in the GK rat myocardium.

Cardiomyopathy and Diastolic Dysfunction in the Embryo and Neonate of a Type 1 Diabetic Mouse Model

Objective: The purpose of this study was to examine the effect of maternal type 1 diabetes on the structure and function of the embryonic and neonatal mouse heart.

Methods: Type 1 diabetes was induced in female C57BL6/J mice using streptozotocin. Embryonic (n = 105) and neonatal hearts (n = 46) were examined using high-frequency ultrasound (US) and a cohort of E18.5 (n = 34) and 1-day-old pup hearts (n = 27) underwent histological examination.

Results: Global cardiac hypertrophy in late gestation (E18.5) was evident on US in the diabetic group compared to controls with increased interventricular septal (IVS) thickness (0.44 ± 0.08 mm vs 0.36 ± 0.08 mm, P < .05) and increased left ventricular wall thickness (0.38 ± 0.04 mm vs 0.29 mm ± 0.05, P < .01). Isovolumetric relaxation time was initially prolonged in the diabetic group but resolved by E18.5 to control values. Histological examination at E18.5 demonstrated increased transverse measurements (2.42 ± 0.72 mm/g vs 1.86 ± 0.55 mm/g, P < .05) and increased IVS thickness (0.64 ± 0.20 mm/g vs 0.43 ± 0.15 mm/g, P < .05) in diabetic embryos compared to control embryos.

Conclusion: Maternal hyperglycemia has severe effects on offspring with evidence of cardiac impairment and cardiac hypertrophy in the embryo. These effects persisted in the 1-day old but attenuated in the 1-week old suggesting cardiac remodeling after the hyperglycemic milieu of pregnancy is removed

Dilated cardiomyopathy and impaired cardiac hypertrophic response to angiotensin II in mice lacking FGF-2.

FGF-2 has been implicated in the cardiac response to hypertrophic stimuli. Angiotensin II (Ang II) contributes to maintain elevated blood pressure in hypertensive individuals and exerts direct trophic effects on cardiac cells. However, the role of FGF-2 in Ang II-induced cardiac hypertrophy has not been established. Therefore, mice deficient in FGF-2 expression were studied using a model of Ang II-dependent hypertension and cardiac hypertrophy. Echocardiographic measurements show the presence of dilated cardiomyopathy in normotensive mice lacking FGF-2. Moreover, hypertensive mice without FGF-2 developed no compensatory cardiac hypertrophy. In wild-type mice, hypertrophy was associated with a stimulation of the c-Jun N-terminal kinase, the extracellular signal regulated kinase, and the p38 kinase pathways. In contrast, mitogen-activated protein kinase (MAPK) activation was markedly attenuated in FGF-2-deficient mice. In vitro, FGF-2 of fibroblast origin was demonstrated to be essential in the paracrine stimulation of MAPK activation in cardiomyocytes. Indeed, fibroblasts lacking FGF-2 expression have a defective capacity for releasing growth factors to induce hypertrophic responses in cardiomyocytes. Therefore, these results identify the cardiac fibroblast population as a primary integrator of hypertrophic stimuli in the heart, and suggest that FGF-2 is a crucial mediator of cardiac hypertrophy via autocrine/paracrine actions on cardiac cells.

Postpacing abnormal repolarization in catecholaminergic polymorphic ventricular tachycardia associated with a mutation in the cardiac ryanodine receptor gene.

BACKGROUND Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an arrhythmogenic disease for which electrophysiological studies (EPS) have shown to be of limited value.OBJECTIVE This study presents a CPVT family in which marked postpacing repolarization abnormalities during EPS were the only consistent phenotypic manifestation of ryanodine receptor (RyR2) mutation carriers.METHODS The study was prompted by the observation of transient marked QT prolongation preceding initiation of ventricular fibrillation during atrial fibrillation in a boy with a family history of sudden cardiac death (SCD). Family members underwent exercise and pharmacologic electrocardiographic testing with epinephrine, adenosine, and flecainide. Noninvasive clinical test results were normal in 10 patients evaluated, except for both epinephrine- and exercise-induced ventricular arrhythmias in 1. EPS included bursts of ventricular pacing and programmed ventricular extrastimulation reproducing short-long sequences. Genetic screening involved direct sequencing of genes involved in long QT syndrome as well as RyR2.RESULTS Six patients demonstrated a marked increase in QT interval only in the first beat after cessation of ventricular pacing and/or extrastimulation. All 6 patients were found to have a heterozygous missense mutation (M4109R) in RyR2. Two of them, presenting with aborted SCD, also had a second missense mutation (I406T- RyR2). Four family members without RyR2 mutations did not display prominent postpacing QT changes.CONCLUSION M4109R- RyR2 is associated with a high incidence of SCD. The contribution of I406T to the clinical phenotype is unclear. In contrast to exercise testing, marked postpacing repolarization changes in a single beat accurately predicted carriers of M4109R- RyR2 in this family.

Differences in atrial fibrillation properties under vagal nerve stimulation versus atrial tachycardia remodeling

Fond : Le substrat de fibrillation auriculaire (FA) vagale et celui secondaire à remodelage par tachycardie auriculaire (RTA) partagent beaucoup des caractéristiques : période réfractaire efficace (PRE) réduite, hétérogénéité accrue de PRE et quelques mécanismes moléculaires communs. Cette étude a comparé les 2 substrats à une abréviation comparable de PRE. Méthodes : Chez chacun de 6 chiens de groupe de stimulation vagal (SV), les paramètres de stimulation cervicale bilatérale de nerves vagaux ont été ajustés pour produire la même PRE moyenne (calculé à 8 sites des oreillettes gauche et droite) avec 6 chiens de groupe de RTA assorti à sexe et poids. Des paramètres électrophysiologiques, la durée moyenne de la fibrillation auriculaire (DAF) et les fréquences dominantes (FD) locales ont étés calculés. Résultats : En dépit des PREs assorties (SV: 80±12msec contre RTA: 79±12msec) la DAF était plus longue (*), l’hétérogénéité de conduction était plus élevée (*), la FD était plus rapide (*) et la variabilité de FD plus grande (*) chez les chiens SV. Les zones de maximum FD qui reflètent les zones d’origine de FA étaient à côté de ganglions autonomes chez les chiens SV. Conclusions : Pour un PRE atriale comparable, la FA secondaire à SV est plus rapide et plus persistante que la FA avec un substrat de RTA. Ces résultats sont consistants avec des modèles de travail suggérant que l'hyperpolarisation SV-induite contribue de façon important à la stabilisation et à l'accélération des rotors qui maintiennent la FA. La similitude de la distribution de FD du groupe vagal avec la distribution des lésions d’ablation après cartographie des électrogrammes atriales fragmentés suggère des nouvelles techniques d’ablation. La distribution des FD entre le SV et le RTA fournit de nouvelles idées au sujet de possible rémodelage neuroreceptorial et indique des différences importantes entre ces substrats de FA superficiellement semblables.

Lesions of the commissural subnucleus of the nucleus of the solitary tract increase isoproterenol-induced water intake

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

Atrophic Cardiac Remodeling Induced by Taurine Deficiency in Wistar Rats

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

AV3V-LESION IMPAIRS RESPONSES INDUCED BY CHOLINERGIC ACTIVATION OF SFO IN RATS

This study was performed to investigate the effect of lesion of the anteroventral third ventricle (AV3V) region on the pressor, bradycardic, dipsogenic, natriuretic, kaliuretic, and antidiuretic responses induced by cholinergic activation of the subfornical organ (SFO) in rats. Male Holtzman rats with sham or electrolytic AV3V lesion were implanted with a stainless steel cannula directly into the SFO. Microinjection of the cholinergic agonist carbachol (2 nmol) into the SFO of sham rats induced natriuresis (563 +/- 70 mueq/120 min), kaliuresis (205 +/- 13 mueq/120 min), antidiuresis (10.4 +/- 0.5 ml/120 min), water intake (9.3 +/-1.4 ml/h), bradycardia (-42 +/- 11 beats/min), and increased mean arterial pressure (53 +/- 3 mmHg). In AV3V-lesioned rats (1-5 and 14-18 days), there was a reduction of natriuresis (23 +/-11 and 105 +/- 26 mueq/120 min, respectively), kaliuresis (92 +/- 16 and 100 +/- 17 mueq/120 min), water intake (2.5 +/- 0.9 and 1.8 +/- 1.0 ml/h), and arterial pressure increase (17 +/- 2 and 16 +/- 2 mmHg) induced by carbachol into the SFO. Increased antidiuresis (6.0 +/- 1.0 and 5.2 +/- 0.7 ml/120 min, respectively) and tachycardia (39 +/- 4 and 15 +/- 12 beats/min) instead of bradycardia were also observed in both groups of AV3V-lesioned rats. These results show that cholinergic activation of the rat SFO produces marked natriuresis and kaliuresis in addition to the well-known pressor and dipsogenic responses. They also show that the AV3V region plays an important role in the cardiovascular, fluid, and electrolytic changes induced by cholinergic activation of the SFO in rats.

Effect of AV3V lesion on the cardiovascular, fluid, and electrolytic changes induced by activation of the lateral preoptic area

In this study we investigated the effect of the anteroventral third ventricle (AV3V) lesion on the pressor, bradycardic, natriuretic, kaliuretic, and dipsogenic responses induced by the injection of the cholinergic agonist carbachol into the lateral preoptic area (LPOA) in rats. Male Holtzman rats with sham or electrolytic AV3V lesion were implanted with stainless steel cannula directly into the LPOA. Injection of carbachol (7.5 nmol) into the LPOA of sham rats induced natriuresis (405 ± 66 μEq/120 min), kaliuresis (234 ± 44 μEq/120 min), water intake (9.5 ± 1.7 ml/60 min), bradycardia (-47 ± 11 bpm), and increase in mean arterial pressure (28 ± 3 mmHg). Acute AV3V lesion (1-5 days) reduced the natriuresis (12 ± 4 μEq/120 min), kaliuresis (128 ± 27 μEq/120 min), water intake (1.7 ± 0.9 ml/60 min), and pressor responses (14 ± 4 mmHg) produced by carbachol into the LPOA. Tachycardia instead of bradycardia was also observed. Chronic (14-18 days) AV3V lesion reduced only the pressor response (10 ± 2 mmHg) induced by carbachol. These results showed that acute, but not chronic, AV3V lesion reduced the natriuretic, kaliuretic, and dipsogenic responses to carbachol injection into the LPOA. The pressor response was reduced in acute or chronic AV3V-lesioned rats. The results suggest that the lateral areas may control the fluid and electrolyte balance independently from the AV3V region in chronic AV3V-lesioned rats. © 1992.

Clinical applications and methemoglobinemia induced by dapsone

Dapsona é uma sulfona sintética que é utilizada como um antibiótico em seres humanos e animais para prevenir e tratar doenças, incluindo hanseníase, tuberculose, malária, e pneumonia por Pneumocystis carinii e encefalites por Toxoplasma gondii em pacientes com síndrome da imunodeficiência adquirida (AIDS), bem como em doenças anti-inflamatórias como dermatite herpetiforme. No entanto, este fármaco também está associado com vários efeitos adversos, incluindo a hemólise relacionada com a dose, metemoglobinemia, psicose, neuropatia periférica, agranulocitose, anemia aplástica, síndrome de hipersensibilidade, síndrome de sulfona, e outros. Destes efeitos, a metemoglobinemia é o mais comum efeito adverso da dapsona, que leva a anemia funcional e hipóxia celular com sintomas de cianose, dores de cabeça, fadiga, taquicardia, fraqueza e tonturas. Assim, esta revisão sumariza informações relevantes sobre a estrutura, mecanismo de ação, indicação clínica, e reações adversas de dapsona.

Assesment of the TEI index of myocardial performance in dogs with doxorubicin-induced cardiomiopathy

The development of a dose-dependent cardiomyopathy is the main limitation for the use of doxorubicin in chemotherapy protocols in both humans and animals. In this setting, the global myocardial function may be compromised resulting in signs of congestive heart failure. In this study, we investigated the ability of the Tei index of myocardial performance to identify myocardial dysfunction in healthy dogs receiving doxorubicin to a cumulative dose of 210 mg/m(2) over 147 days, comparing it with other standard echocardiographic indicators of systolic and diastolic function. Our results indicated that the Tei index, the isovolumic relaxation time, pre-ejection period and the pre-ejection period-to-left ventricular ejection time ratio were able to identify the cardiotoxic effects of doxorubicin on cardiac function when only 60 mg/m(2) had been administered, while the standard systolic and diastolic parameters, including left ventricular diameter at systole, ejection fraction, and fractional shortening needed at least 120 mg/mg(2) to deteriorate. We concluded that prolonged anthracycline therapy compromises both systolic and diastolic functions, which may be documented earlier by including the Tel index evaluation to the standard echocardiographic assessment of animals receiving doxorubicin.