1st Degree Atrioventricular Block Research Articles

CARDIAC CONDUCTION DISTURBANCES FOLLOWING TRANSAPICAL «MEDLAB-KT» AORTIC VALVE IMPLANTATION: FIRST RESULTS

Aim: to assess cardiac conduction disturbances after transcatheter aortic valve replacement (TAVR) with the “MedLab-KT” device in early postoperative period.Methods. The study comprised 80 patients (mean age 72,4±5,1 years; 42,5% males) undergoing successful TAVR with the “MedLab-KT”. Before operation, all patients were evaluated with 12-lead ECG and 24-hour Holter monitoring, transthoracic and transesophageal echocardiography, computed tomography, coronarography. In 29 (36,3%) patients cardiac conduction abnormalities were detected before operation: 1st degree atrioventricular (AV) block was found in 17 patients, including concomitant left anterior hemiblock (LAH) in 7 patients, and right bundle branch block (RBBB) in 3 (LAH+RBBB). Second degree AV-block type 1 was found in 1 patient. LAH – in 2, RBBB – in 5, and left bundle branch block (LBBB) – in 4. Post-operative follow-up was limited to hospital stay (13,4±7,4 days).Results. De-novo conduction abnormalities (reversible and irreversible) were detected in 41 patients (51,3%). Post-TAVR complete AV-block was found in 6 (7,5%) patients, and required temporal pacing. In 4 of those patients AV-block was transient and resolved within 1 day. In 2 (2,5%) patients permanent pacing was required due to irreversible distal AV-block. In one case AV-block developed 2 days after TAVR in a patient with pre-existent 1st degree AV-block in combination with LAH+RBBB. Another patient developed complete AV-block at 3d day after TAVR; in this case there was pre-existent 1st degree AV-block plus LAH. Persistent interventricular block was found in 35 patients: complete LBBB - in 17 patients and complete RBBB – in 1 patient. There were no statistically significant predictors of conduction disturbance development following TAVR.

P898Association of acroparesthesias and angiokeratomas with the alpha-galactosidase A gene polymorphisms in females with hypertrophic cardiomyopathy

Abstract Introduction Clinical implications of different single nucleotide polymorphisms (SNPs) in the alpha-galactosidase A gene (α-GLA) as potential cause of symptoms and organ manifestations similarly to those seen in Fabry disease (FD) remain unclear. Purpose To study the prevalence of FD among patients with hypertrophic cardiomyopathy (HCM), as well as to evaluate the impact of polymorphic variants of the α-GLA gene on extracardiac manifestations in females with HCM. Methods The study included 321 patients with left ventricular hypertrophy ≥15 mm. 24 of the 321 patients (males (n=15) and females (n=9)) presented with HCM phenotype and extracardiac features suggestive of FD: acroparesthesias and pain in hands and feet, stroke at a young age, angiokeratomas, kidney damage (microalbuminuria, proteinuria, decreased glomerular filtration rate), suspicion for X-linked inheritance. This patients carried out screening for FD. A combined enzymatic and genetic strategy was used, measuring the activity of α-D-galactosidase A by tandem mass spectrometry (ESI-MS/MS) and genotyping the α-GLA (in females) in dried filter-paper blood spot samples. Results We haven't identified any pathogenic genetic variants in the α-GLA gene. However, in three patients with HCM, the two intronic SNPs within the α-GAL gene (c.640–16A>G [rs2071397] and c.1000–22C>T [rs2071228]) were identified. Patient no. 1, a 64-year-old female, was admitted to our clinic for the diagnosis of obstructive HCM. She also had a transient 2:1 second degree atrioventricular block, an Adams-Stokes attack, angiokeratomas and left median cerebral artery lacunar stroke in middle age. In case no. 2, a 75-year-old female, were verified obstructive HCM, a 1st degree atrioventricular block, paroxysms of nonsustained ventricular tachycardia, acroparesthesia, pain in hands and angiokeratomas. In patient no. 3, a 41-year-old female, were established combined phenotypes (nonobstructive hypertrophic + restrictive), acroparesthesia, pain in hands and angiokeratomas. Conclusions In females with HCM, the intronic SNPs (rs2071397 and rs2071228) in the α-GLA gene can be associated with angiokeratomas and acroparesthesias.

5164New risk prediction score for life-threatening ventricular tachyarrhythmias in laminopathies

Abstract Background An accurate estimation of the risk of life-threatening (LT) ventricular tachyarrhythmia (VTA) in patients with LMNA mutations is crucial to select candidates for implantable cardioverter defibrillator (ICD) implantation. Methods We included 839 adult patients with LMNA mutations, including 660 from a French nationwide registry in the development sample, and 179 from other countries, referred to 5 tertiary centers for cardiomyopathies, in the validation sample. LTVTA was defined as a) sudden cardiac death or b) ICD-treated or hemodynamically unstable VTA. The prognostic model was derived using Fine-Gray's regression model. The net reclassification was compared with current clinical practice guidelines. The results are presented as means (standard deviation) or medians [interquartile range]. Results We included 444 patients 40.6 (14.1) years of age in the derivation sample and 145 patients 38.2 (15.0) years in the validation sample, of whom 86 (19.3%) and 34 (23.4%) suffered LTVTA over 3.6 [1.0–7.2] and 5.1 [2.0–9.3] years of follow-up, respectively. Predictors of LTVTA in the derivation sample were: male sex, non-missense LMNA mutation, 1st degree and higher atrioventricular block, non-sustained ventricular tachycardia, and left ventricular ejection fraction. In the derivation sample, C-index (95% CI) of the model was 0.776 (0.711–0.842). In the external validation sample, the C-index was 0.800 (0.642–0.959) and calibration slope 1.082 (95% CI, 0.643–1.522). A 5-year estimated risk threshold ≥7% predicted 96.2% of LTVTA and net reclassified 28.8% of patients with LTVTA compared with the guidelines-based approach. Conclusions Compared to the current standard of care, this risk prediction model for LTVTA in laminopathies facilitated significantly the choice of ICD candidates. Acknowledgement/Funding AFM Téléthon

Presence of Leishmania sp. and Dirofilaria immitis in Cutaneous Canine Transmissible Venereal Tumor

Background: Canine Transmissible Venereal Tumor (CTVT) is a neoplasm transmitted by implantation of its cells into genital and extragenital organs, while Heartworm and Visceral Leishmaniasis are zoonosis transmitted by hematophagous insects that are often underdiagnosed in asymptomatic animals. Coinfection by the agents of these parasitosis is well documented, however, the association of both diseases with the CTVT is still unusual. Thus, it was aimed to report a case of incidental identification of microfilariae of D. immitis and amastigotes forms of Leishmania sp. in cutaneous CTVT by cytology in an asymptomatic dog for the parasitosis.Case: A 6-year-old, male, mongrel, sexually intact dog from the city of Patos, Paraiba, Brazil, was presented with a cutaneous circumscribed tumoral lesion in a region adjacent to the right olecranon, with an ulcerated surface of reddish color, having areas of necrosis inside and larvae (myiasis), draining bloody secretion. The material was collected for cytological analysis, which proved to be Canine Transmissible Venereal Tumor (CTVT) with the presence of amastigote forms of Leishmania sp. and microfilariae of D. immitis among neoplastic cells. Blood count, serum urea, creatinine and albumin, ALT, AST, FA, CK, Na+, K+, Ca++, CK-MB, Troponin I (cTnI), Snap 4Dx Plus (Idexx®), Snap Leishmania (Idexx®), and Knott's test were performed, plus chest radiography, blood pressure measurements and electrocardiogram (ECG). The alterations found corresponded to normochromic normocytic anemia, thrombocytopenia, hypoalbuminemia, microfilariae in the Knott test, increase of CK, CK-MB and cTnI, positivity for Erlichia sp., Anaplasma sp., Leishmania sp. and Dirofilaria immitis. Furthermore cardiomegaly on radiographs and sinus arrhythmia associated with atrioventricular block (AVB) of the first degree on the ECG. Euthanasia was performed after necropsy, in which adult worms were observed in the right heart chambers.Discussion: The coexistence of neoplastic diseases and infectious microorganisms is often detected only incidentally in asymptomatic animals and complementary tests are important tools to support clinical suspicions, as was observed in the present case. The fact that the animal is not neutered, be in full sexual activity and have unrestricted life habit, favored his involvement by CTVT due to greater contact with other whole canines. Coinfection by Dirofilaria sp. and Leishmania sp., identified in this case, has already been confirmed in several countries, suggesting the presence of distinct vectors in the same geographical area and the imminent exposure of humans to these agents. Despite the studies evidencing the systemic infection by the two parasites, there are no reports of mutual parasitism by the pathogens mentioned in canine neoplasms, especially in the cutaneous extragenital form of the CTVT, making the present case uncommon. The cytological examination was fundamental not only to show that the cutaneous lesion was a CTVT, but also to have evidenced the parasites Leishmania sp. and Dirofilaria immitis, whose infections remained hidden. The changes present in hematology are commonly present in the diseases diagnosed in this case, and elevation of CK, CK-MB and cTnI denote damage to cardiomyocytes due to the action of both parasites. Cardiomegaly on radiographs and 1st degree AVB on the ECG also correspond to secondary changes in the presence of worms in the animal's cardiovascular system. Thus, the presence of a dog autochthonously infected by parasites with a zoonotic potential reveals the susceptibility of other animals and humans in the region to infections.

SAT-278 Changes in Biochemical and Electrocardiographic Findings During Insulin Tolerance Test

BACKGROUND : The insulin tolerance test (ITT) is the most sensitive test for evaluation of growth hormone and cortisol deficiency. However, this test has risks of hypoglycemia and its associated complications. Therefore, it is limitedly performed in pediatric patients in clinical practice. This study investigated the changes of serum levels of electrolytes and calcium, and findings on electrocardiography (EKG) during ITT. Methods : We recruited 88 short stature patients who hospitalized the Severance Children’s Hospital for combined pituitary function test between July 2017 and June 2018. The changes in EKG and serum level of electrolytes and calcium were analyzed when the patients were in hypoglycemia during ITT. Results : The mean age of patients at evaluation was 6.33±2.58 years. The height of all patients were below the 3 rd percentile on the Korean children and adolescents growth standard, and mean yearly growth rate was 4.5±1.5cm/yr. Hypoglycemia (serum glucose level of <50 mg/dL) increased heart rate (90.82/min at euglycemia; 109.82/min at hypoglycemia; p <0.001) and corrected QT (QTc) interval (427 ms at euglycemia; 445 ms at hypoglycemia; p <0.001). Hypokalemia was observed in 53 (61.63%) of patients at hypoglycemia and the serum level of potassium decreased from 4.32±0.35 mmol/L to 3.34±0.60 mmol/L (p<0.001). The serum level of calcium did not show any difference. Therefore, additional subgroup analysis was performed to compare the prolongation of QTc in patients with normokalemia and hypokalemia during ITT. The number of patients with prolonged QTc interval (>500ms) was found to be statistically increased in the hypokalemic group compared to the normokalemic group (45.83%(n=22) vs 19.35%(n=6), p=0.016). Among 88 patients, cardiac arrhythmia (1st degree atrioventricular block) was found in 2 patients during hypoglycemia CONCLUSION : Statistically significant differences were noted in serum level of potassium and QTc interval before and after ITT. This study also showed the relationship between prolonged QTc interval (>500ms) and decreased serum level of potassium. Therefore it is important to monitor the changes in EKG continuously during ITT and perform electrolyte tests before and after ITT to ensure the pediatric patient’s safety.

AN UNUSUAL CAUSE OF PALPITATIONS DURING PREGNANCY

The majority of arrhythmias in pregnancy are benign, but recognizing high-risk features is critical to appropriate management. A 35-year-old gravida 1, para 0, woman at 22 weeks gestation presented for follow-up of 1st degree atrioventricular block. Two years prior, her electrocardiogram (ECG) was

Electrocardiogram in Bitches Submitted to Unilateral Total Mastectomy

Background: The frequency of oncological diseases in companion animals has increased in recent years, mainly due to the longer longevity of dogs. The neoplasms are not only open by the presence of the tumor and its location, but also by paraneoplastic syndromes, which are disorders that occur due to the production of substances by the tumor that cause. In addition to causing local changes and damages, oncological diseases may also result in injuries at distant sites, such as paraneoplastic syndromes, which, if untreated, may result in death of animals. The present study aimed to investigate whether female dogs with mammary tumors demonstrate electrocardiographic changes, and if so, to investigate whether these cease after removal of the tumor, and to relate the type of tumor with the occurrence of arrhythmias. Materials, Methods &amp; Results: Eighteen female dogs, aged between 4 and 14 years, underwent electrocardiogram 24 h prior to undergoing a total unilateral mastectomy. After removal of the tumor, electrocardiograms were again performed 24 (M24), 48 (M48), and 72 (M72), as well as 14 days (M14d) after surgery. Histological analysis of the neoplasms showed that 55% of the tumors were benign, with predominance of adenoma (38%), and 45% were malignant, with predominance of adenocarcinoma (22%). The following rhythms and arrhythmias were observed: normal sinus rhythm (37.2%), sinus arrhythmia (62.8%), wandering pacemaker (26%), 1st degree atrioventricular block (AVB; 5%), premature ventricular complex (PVC; 10%), and T-wave &gt; 25% of R-wave (25%); more than one change could occur simultaneously. Out of the evaluated electrocardiographic parameters, a significant difference was observed in the QT interval between the following timepoints: M24 (204 ± 18), M48 (204 ± 22), and M72 (203 ± 23), as well as Mbasal (192 ± 15) and M14d (178 ± 43).Discussion: Regarding the observed rhythms, arrhythmias, and changes, respiratory sinus arrhythmia was the normal predominant rhythm, followed by sinus rhythm. Wandering pacemaker in conjunction with respiratory sinus arrhythmia is widely observed in dogs; these conditions occur due to vagal predominance, without hemodynamic consequences. PVC is the premature depolarization originating in ectopic foci of the ventricular tissue, and is considered the most common type of ventricular arrhythmia in small animals. Two animals demonstrated PVC, one in Mbasal and the other in M14d. The former presented with a tumor diagnosed as an adenocarcinoma, which could be related to the paraneoplastic syndrome. The later presented with a tumor diagnosed as an adenoma, indicating that PVC may have occurred due to stress at that time. The T-wave occurs after ventricular depolarization, and is usually up to 25% of the amplitude of the R-wave. This change was observed at all times for the animal that was histologically diagnosed as having mammary adenocarcinoma, and may have been related to the neoplasm or be an individual change. The 1st degree AVB occurred in Mbasal, and was therefore related to increased vagal tonus. The significant differences in the QT interval were negatively correlated with decreased heart rate (HR), i.e., the QT interval increased when HR decreased. This must have been related to the acclimatization of the animals to the tests. Owing to the high number of animals with early-stage mammary tumors in this study, the observed electrocardiographic changes could not be correlated with tumor presence and type.

Dysautonomia in a Bitch with Hypothyroidism

Background: Thyroid hormones have important effects on the cardiovascular system, of which the main ones are the increase in the heart response to the autonomic sympathetic nervous system. Heart rate variability is a non-invasive method of assessing autonomic heart modulation, thus being an important form of evaluation in patients with thyroid dysfunctions. This study aimed to report electrocardiographic and heart rate variability data of a dog with hypothyroidism that presented a parasympathetic dysfunction.Case: A 7-year-old female Dalmatian dog was admitted for clinical evaluation in Fortaleza, Brazil. According to the owner, she had been apathetic for a year, had gained weight, always had a sad expression, and her hair was generally brittle and opaque. On physical examination, skin lesions were observed at the end of the spine, extending to the tail region, with the latter showing total alopecia. Low T4 levels confirmed the diagnosis of primary hypothyroidism. Then, a 24-h Holter monitoring was performed, which showed that the animal had sinus arrhythmia associated with moments of second-degree sinoatrial block and rare moments of sinus tachycardia. In addition, moments of premature multifocal ventricular extrasystoles and 1st-degree atrioventricular block were observed. Based on the Holter results, heart rate variability (HRV) was calculated. Regarding the HRV in the frequency domain, 32.16 was obtained in the low frequency (LF) band, 67.84 in the high frequency (HF) band, and the LF / HF ratio was 0.46, with a total power of 5205. As for the HRV in the time domain, RMSSD was 117, pNN50 was 62.64 and SDNN was 384. This showed an increase in the parasympathetic activity of the heart and, due to this increased activity, a second-degree sinoatrial block occurred, which is a sinus function disturbance resulting from the exacerbated parasympathetic activity.Discussion: Beta-adrenergic receptors have their expression and activity altered by thyroid hormones. The sympathetic stimulation on the heart through the activation of these receptors originates a positive inotropic, lusitropic, dromotropic and chronotropic effect. Therefore, in the absence of thyroid hormones, there is a decrease in this stimulation, thus allowing a preponderant parasympathetic tone. In the present report, the increase in the parasympathetic tonus, observed in hypothyroidism, resulted in a reduction in the frequency of sinus firing, slowing of intranodal and sinoatrial conduction, and shortening of the effective refractory period, a combination of factors that led to decreased HR observed in the Holter monitoring. Previous studies have shown that thyroid hormones increase sympathetic activity, mainly in the heart, since they do not act by increasing the production or release of catecholamines, but rather increasing catecholamine response on the heart, due to a positive regulation of Ca2+-ATPase channels of the sarcoplasmic reticulum and beta1-adrenergic receptors. Thus, the observed result was already expected, because in hypothyroidism there is a decrease in these hormones that increase the sympathetic activity on the heart and so, the parasympathetic tone was very evident. The study of heart rate variability allows the simple assessment of the autonomic nervous system imbalance, and may be extremely important in the follow-up of diseases that affect this balance, such as hypothyroidism. Hence, more studies are required to verify the effect of such diseases on heart rate variability, aiming to define associations between the diseases and the alterations, as well as to define parameters of normality for such examinations.

Insuficiência cardíaca grave de etiologia amiloidótica

A amiloidose é uma doença sistêmica causada pela deposição extracelular de fibrilas insolúveis de proteínas de baixo peso molecular em diversos tecidos. Pode ser classificada nas formas: primária, secundária, hereditária e sistêmica senil. Relatamos o caso de um paciente masculino, 75 anos, que deu entrada em emergência cardiológica com quadro progressivo de edema em membros inferiores iniciado há quatro meses. Trinta dias antes do internamento passou a apresentar dispneia de médios para pequenos esforços, evoluindo para dispneia ao repouso e em decúbito (insuficiência cardíaca – classe funcional IV). Ao exame físico apresentou-se em estado geral regular, consciente, taquidispneico, afebril, hidratado, hipocorado (1+/4+), ictérico (2+/4+), acianótico e presença de estase jugular a 45°. O ritmo cardíaco era regular em dois tempos e bulhas, normofonéticas, com sopro sistólico em foco mitral (2+/6+) desdobramento fixo da segunda bulha; pressão arterial de 80x40 mmHg e frequência cardíaca de 84 bpm. O eletrocardiograma de admissão mostrou ritmo sinusal regular, bloqueio atrioventricular de 1º grau, baixa voltagem em derivações de plano frontal, zona eletricamente inativa em região ântero-septal e distúrbio de condução pelo ramo esquerdo do feixe de His. Radiografia de tórax com área cardíaca aumentada, padrão de congestão pulmonar e derrame pleural bilateral, mais acentuado à esquerda. Também foi realizado ecocardiograma transtorácico que evidenciou câmaras cardíacas aumentadas à direita, função sistólica de ventrículo direito levemente deprimida, insuficiência tricúspide moderada a importante, hipertensão pulmonar moderada, hipertrofia de ventrículo esquerdo, disfunção de ventrículo esquerdo e achado de ecogenicidade granular brilhante. Ultrassonografia de abdome mostrou fígado e baço com textura heterogênea, sugestivo de doença granulomatosa. Posteriormente foi realizada biópsia hepática que confirmou a hipótese de doença infiltrativa determinada pela amiloidose cardiovascular. Paciente evoluiu com rebaixamento de nível de consciência e insuficiência renal aguda, sendo realizada hemodiálise e transferência para Unidade Coronariana, onde apresentou parada cardiorrespiratória e evolução para óbito.

Postnatal undernutrition in mice causes cardiac arrhythmogenesis which is exacerbated when pharmacologically stressed.

Growth restriction caused by postnatal undernutrition increases risk for cardiovascular disease in adulthood with the potential to induce arrhythmogenesis. Thus, the purpose was to determine if undernutrition during development produced arrhythmias at rest and when stressed with dobutamine in adulthood. Mouse dams were fed (CON: 20% protein), or low-protein (LP: 8%) diet before mating. A cross-fostering model was used where pups nursed by dams fed LP diet in early [EUN; postnatal day (PN) 1-10], late (LUN; PN11-21) and whole (PUN; 1-21) phases of postnatal life. Weaned pups were switched to CON diets for the remainder of the study (PN80). At PN80, body composition (magnetic resonance imaging), and quantitative electrocardiogram (ECG) measurements were obtained under 1% isoflurane anesthesia. After baseline ECG, an IP injection (1.5 µg/g body weight) of dobutamine was administered and ECG repeated. Undernutrition significantly (P<0.05) reduced body weight in LUN (22.68±0.88 g) and PUN (19.96±0.32 g) but not in CON (25.05±0.96 g) and EUN (25.28±0.9207 g). Fat mass decreased in all groups compared with controls (CON: 8.00±1.2 g, EUN: 6.32±0.65 g, LUN: 5.11±1.1 g, PUN: 3.90±0.25 g). Lean mass was only significantly reduced in PUN (CON: 17.99±0.26 g, EUN: 17.78±0.39 g, LUN: 17.34±0.33 g, PUN: 15.85±0.28 g). Absolute heart weights were significantly less from CON, with PUN having the smallest. ECG showed LUN had occurrences of atrial fibrillation; EUN had increases of 1st degree atrioventricular block upon stimulation, and PUN had increased risk for ventricular depolarization arrhythmias. CON did not display arrhythmias. Undernutrition in early life resulted in ventricular arrhythmias under stressed conditions, but undernutrition occurring in later postnatal life there is an increased incidence of atrial arrhythmias.

Conduction Abnormalities and Permanent Pacemaker Implantation After Transcatheter Aortic Valve Replacement Using the Repositionable LOTUS Device: The United Kingdom Experience

ObjectivesThe authors report the incidence of pacemaker implantation up to hospital discharge and the factors influencing pacing rate following implantation of the LOTUS bioprosthesis (Boston Scientific, Natick, Massachusetts) in the United Kingdom. BackgroundTranscatheter aortic valve replacement (TAVR) is associated with a significant need for permanent pacemaker implantation. Pacing rates vary according to the device used. The REPRISE II (Repositionable Percutaneous Replacement of Stenotic Aortic Valve Through Implantation of Lotus Valve System) trial reported a pacing rate of 29% at 30 days after implantation of the LOTUS device. MethodsData were collected retrospectively on 228 patients who had the LOTUS device implanted between March 2013 and February 2015 across 10 centers in the United Kingdom. Twenty-seven patients (12%) had pacemakers implanted pre-procedure and were excluded from the analysis. ResultsPatients were aged 81.2 ± 7.7 years; 50.7% were male. The mean pre-procedural QRS duration was 101.7 ± 20.4 ms. More than one-half of the cohort (n = 111, 55%) developed new left bundle branch block (LBBB) following the procedure. Permanent pacemakers were implanted in 64 patients (32%) with a median time to insertion of 3.0 ± 3.4 days. Chief indications for pacing were atrioventricular (AV) block (n = 46, 72%), or LBBB with 1st degree AV block (n = 11, 17%). Amongst those who received a pacemaker following TAVR the pre-procedural electrocardiogram findings included: No conduction disturbance (n = 41, 64%); 1st degree AV block (n = 10, 16%); right bundle branch block (n = 6, 9%) and LBBB (n = 5, 8%). LBBB (but not permanent pacemaker) occurred more frequently in patients who had balloon aortic valvuloplasty before TAVR (odds ratio [OR]: 1.25; p = 0.03). Pre-procedural conduction abnormality (composite of 1st degree AV block, hemiblock, right bundle branch block, LBBB) was independently associated with the need for permanent pacemaker (OR: 2.54; p = 0.048). The absence of aortic valve calcification was also associated with a higher pacing rate (OR: 0.55; p = 0.031). Multivariate regression analysis did not show an independent association between depth of implant, valve oversizing, balloon post-dilatation, and the need for pacing post-procedure. ConclusionsFollowing implantation of the repositionable LOTUS valve, 55% of patients developed LBBB and 32% of patients required a pacemaker during their index hospital admission. Patients with pre-procedural conduction disturbance and non-calcified aortic valves were more likely to need pacing. No other anatomic features were identified with increased pacing requirement with the LOTUS device.

Congenital heart defect causing mutation in Nkx2.5 displays in vivo functional deficit

The Nkx2.5 gene encodes a transcription factor that plays a critical role in heart development. In humans, heterozygous mutations in NKX2.5 result in congenital heart defects (CHDs). However, the molecular mechanisms by which these mutations cause the disease remain unknown. NKX2.5-R142C is a mutation that was reported to be associated with atrial septal defect (ASD) and atrioventricular (AV) block in 13-patients from one family. The R142C mutation is located within both the DNA-binding domain and the nuclear localization sequence of NKX2.5 protein. The pathogenesis of CHDs in humans with R142C point mutation is not well understood. To examine the functional deficit associated with this mutation in vivo, we generated and characterized a knock-in mouse that harbours the human mutation R142C. Systematic structural and functional examination of the embryonic, newborn, and adult mice revealed that the homozygous embryos Nkx2.5R141C/R141C are developmentally arrested around E10.5 with delayed heart morphogenesis and downregulation of Nkx2.5 target genes, Anf, Mlc2v, Actc1 and Cx40. Histological examination of Nkx2.5R141C/+ newborn hearts showed that 36% displayed ASD, with at least 80% 0f adult heterozygotes displaying a septal defect. Moreover, heterozygous Nkx2.5R141C/+ newborn mice have downregulation of ion channel genes with 11/12 adult mice manifesting a prolonged PR interval that is indicative of 1st degree AV block. Collectively, the present study demonstrates that mice with the R141C point mutation in the Nkx2.5 allele phenocopies humans with the NKX2.5 R142C point mutation.

Consciousness disorders from cardiological view

Consciousness disorders may have many causes, mainly cardiac arrhythmias. The incidence of bradyarrhythmias (BA) in patients with acute coronary syndrome (ACS) is 0.3-18 % and caused by sinus node dysfunction (SND), high degree atrioventricular (AV) block or bundle branch blocks. SND are sinus bradycardia or sinus arrest. 1st degree AV-block occurs in 4-13 % of patients with ACS caused by rhythm disturbances in atrium, AV node, bundle of His or the Tawara system. 1st or 2nd degree AV block is seen very frequently within 24 hours after beginning of ACS and these arrhythmias are frequently transient and no more present after 72 hours. 3rd degree AV blocks are also frequently transient in pts with infero-posterior myocardial infarction (MI) and permanent in anterior MI patients. Left anterior fascicular block occurs in 5 % of ACS, left posterior fascicular block is observed less frequently (incidence < 0.5 %). Complete bundle branch block is present in 10-15 % of ACS patients and right bundle branch block is more often (2/3) present than left bundle branch block (1/3). In patients with BA atropine i. v. (1-3 mg) is helpful in 70-80 % of ACS patients and will lead to an increased heart rate. The need of pacemaker stimulation (PS) is different in patients with inferior (IMI) or anterior MI (AMI). Tachyarrhythmias are ventricular tachycardia, ventricular flutter or ventricular fibrillation in pts with ACS and it is necessary to terminate these arrhythmias as soon as possible by direct current cardioversion or defibrillation. Other causes of consciousness disorders are valvular heart diseases (aortic stenosis, hypertrophic obstructive cardiomyopathy), myxoma or ion-channel diseases (Brugada syndrome, long and short QT-syndromes). In all cases, a detailed cardiological evaluation is necessary in order to initiate a proper treatment.

Abstract 12805: Postnatal Progressive Atrioventricular Block By Heterozygous Nkx2-5 Homeodomain Missense Mutation With Atrioventricular Nodal Atrophy

Introduction: Heterozygous human NKX2-5 homeodomain (DNA binding domain) missense mutations are highly penetrant for varied cardiac anomalies and progressive atrioventricular block (AVB). We replicated many elements of the cardiac anomalies in a murine heterozygous knock-in model (Nkx2-5+/R52G, hereafter Nkx2-5-KI) in a 129/Sv background. Hypothesis: We hypothesized that Nkx2-5-KI mice demonstrate progressive AVB during postnatal life similar to human patients. Methods: Nkx2-5-KI mouse model and control Nkx2-5+/+ mice were analyzed by histopathology, surface and telemetry ECG, and in vivo electrophysiology studies (EPS), and compared at postnatal day 1 (P1) to 17 months. We re-evaluated a pedigree of a human family having Arg52(189)Gly mutation in 5 generations. Results: Nkx2-5-KI mice demonstrated PR-prolongation (1st degree AVB) at 4 weeks, 7 months, and 17 months of age but not at P1 (control n=35, mutant n=38). Advanced AVB was occasionally observed. EPS showed that AV node function, and right ventricular effective refractory period were impaired in Nkx2-5-KI mice, while sinus node function was normal. AV node size was significantly smaller in Nkx2-5-KI mice relative to control mice (maximum area size 2.4 ± 0.2 vs. 1.6 ± 0.1 x 10-2 mm2, 36% reduction; calculated volume 1.50 ± 0.1 vs. 1.11 ± 0.03 x 10-4 mm3, 24% reduction, n=6 each) at 4 weeks of age but not P1, similar to age-dependence of PR-prolongation. AV node in mutant mice was composed of smaller cardiomyocytes without fibrosis, suggesting in part, that conduction abnormalities are the result of an AV node that becomes morphologically atrophic during postnatal life. All 6 genotype-positive humans demonstrated AVB (1st, 2nd, and 3rd degree). QRS prolongation was uniquely demonstrated in Nkx2-5-KI mice from the neonatal stage onward but not in human patients, suggesting substantial discordance in ventricular conduction system between mouse and human. Conclusion: Highly penetrant and progressive AVB similar to that seen in humans with heterozygous NKX2-5 homeodomain missense mutations was replicated in mice by knocking-in a comparable missense mutation. The progressive AVB phenotype is likely due to an AV node composed of smaller cardiomyocytes that becomes atrophic during postnatal life.

Cardiac sarcoidosis, the complete atrioventricular block of which was completely recovered by intravenous steroid pulse therapy

Atrioventricular block (AVB) in individuals with cardiac sarcoidosis (CS) is one of the major complications caused by inflammation of the conducting system of the heart, as a sign of worse prognosis. We report the case of a 53-year-old Japanese woman whose electrocardiogram showed complete AVB by the clinical diagnosis of CS. We administered intravenous methylpredonisolone (1g/day) for 3 days. On the second day of steroid pulse therapy, the complete AVB improved to sinus rhythm of 1st degree AVB and complete right bundle branch block. Normal sinus rhythm was then observed after oral steroid therapy. These results suggest that in cases of complete AVB, steroid pulse therapy with a strong anti-inflammatory effect may be recommended first.<Learning objective: This case illustrates a typical case of CS with complete AVB, but the cardiac contraction was normal. In this setting, steroid pulse therapy may be effective when (1) the active inflammation of the conduction system can be suppressed by steroid pulse therapy; (2) the time to start steroid therapy is short enough to recover.>

The prevalence of abnormal ECG in trained sportsmen

BackgroundCompetitive sports training causes structural and conductive system changes manifesting by various electrocardiographic alterations. We undertook this study to assess the prevalence of abnormal ECG in trained Indian athletes and correlate it with the nature of sports training, that is endurance or strength training. MethodsWe evaluated a standard resting, lying 12 lead Electrocardiogram (ECG) in 66 actively training Indian athletes. Standard diagnostic criteria were used to define various morphological ECG abnormalities. Results33/66 (50%) of the athletes were undertaking endurance training while the other 33 (50%) were involved in a strength-training regimen. Overall 54/66 (81%) sportsmen had significant ECG changes. 68% of these changes were considered as normal training related features, while the remaining 32% were considered abnormal. There were seven common training related ECG changes–Sinus Bradycardia (21%), Sinus Arrhythmia (16%), 1st degree Atrioventricular Heart Block (6%), Type 1 2nd-degree Atrioventicular Heart Block (3%), Incomplete Right bundle branch block (RBBB) (24%), Early Repolarization (42%), Left Ventricular Hypertrophy (LVH) (14%); while three abnormal ECG changes--T-wave inversion (13%), RBBB(4%), Right ventricular hypertrophy (RVH) with strain (29%) were noted. Early repolarization (commonest change), sinus bradycardia, and incomplete RBBB were the commoner features noticed, with a significantly higher presence in the endurance trained athletes. ConclusionA high proportion of athletes undergoing competitive level sports training are likely to have abnormal ECG recordings. Majority of these are benign, and related to the physiological adaptation to the extreme levels of exertion. These changes are commoner during endurance training (running) than strength training (weightlifting).

Abstract CT329: Phase I study of the PI3Kβ/δ inhibitor AZD8186 in patients with advanced castration resistant prostate cancer, triple negative breast cancer, squamous non-small cell lung cancer or PTEN deficient solid tumors: update from dose-finding

Abstract Background: A frequent mechanism of dysregulation of the PI3K/AKT/mTOR pathway, commonly altered in cancer, is loss of function of the tumour suppressor PTEN, leading to increased PI3K signalling, particularly through the PI3Kβ isoform. AZD8186 is a potent and selective inhibitor of PI3Kβ/δ with significant activity in PTEN-deficient preclinical models. We report the dose-finding portion of the study, assessing the safety/tolerability of an intermittent dosing schedule of AZD8186. Trial design and eligibility criteria: AZD8186 tablets were administered twice daily 5 days on treatment, 2 days off (5/2 schedule) in 3 week cycles. Escalating doses of AZD8186 were evaluated in cohorts of 3-6 evaluable patients treated until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. A safety review committee reviewed all available safety data and dose limiting toxicities (DLTs) prior to each dose modification. The dose/schedule finding, safety and activity will be updated at time of presentation. Adult patients were recruited with tumor types known to be PTEN deficient or to have prevalent PTEN loss, such as castration-resistant prostate cancer (CRPC), triple negative breast cancer, squamous non-small cell lung cancer or, that had relapsed and/or were refractory to suitable therapies. Results: As of 25 Oct, 32 patients have received treatment (30 mg n = 7, 60 mg n = 6, 120 mg n = 5; 240 mg n = 6, 360 mg n = 6; 300 mg n = 2). Pharmacokinetic parameters show that systemic exposures to parent drug and its major active metabolite increased in a dose proportional manner and exceeded preclinical exposures that have demonstrated robust anti-tumour activity in PTEN deficient xenograft models. DLTs of maculopapular rash (CTCAE Grade 3) were observed at 360 mg (in 2/6 patients) and at 300 mg (2/2 patients). Additional AEs occurring in &amp;gt;10% of patients included diarrhea, nausea, vomiting, fatigue, rash, decreased appetite and QTc prolongation. AEs of ≥ grade 3 included: rash, hypophosphatemia, hypokalemia, diarrhea elevated aspartate transaminase and 1st degree atrioventricular block; there were no grade 5 events. Overall, 11 patients remained on study for at least 60 days; one CRPC patient remained on study for more than 160 days with minor PSA response, symptomatic improvement and stable disease by CT and bone scan. Conclusions: AZD8186 is a potent oral inhibitor of PI3Kβ/δ, with potential for treatment of PTEN-deficient tumors. Investigation of the safety/tolerability of the 5/2 schedule is continuing. This agent may hold potential for treatment of PTEN deficient tumors. Citation Format: Lillian L. Siu, Johann De Bono, Kari B. Wisinski, Celestia S. Higano, Natalie Cook, Maria Jose De Miguel Luken, Rajiv Kumar, Joshua Lang, Gurkamal S. Chatta, Sara M. Tolaney, Stefan M. Symeonides, Gilmour Morrison, Patrick D. Mitchell, David G. Brooks, Geoffrey I. Shapiro. Phase I study of the PI3Kβ/δ inhibitor AZD8186 in patients with advanced castration resistant prostate cancer, triple negative breast cancer, squamous non-small cell lung cancer or PTEN deficient solid tumors: update from dose-finding. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT329. doi:10.1158/1538-7445.AM2015-CT329

Whole exome sequencing identifies the TNNI3K gene as a cause of familial conduction system disease and congenital junctional ectopic tachycardia

We report familial cardiac conduction disease (FCCD) in a 3-generation pedigree, including some family members with congenital junctional ectopic tachycardia (JET) (Fig. 1A). The proband presented during a febrile illness at 3.5-years of age with variable atrio-ventricular (AV) block (1st, 2nd, and 3rd degrees) together with left anterior fascicular block (LAFB) and right bundle branch block (RBBB) (Fig. 1B). Viral studies and echocardiogram were normal and he received a pacemaker; he subsequently developed clinical junctional tachycardia. Family history revealed a maternal grandmother with RBBB diagnosed at 5 years of age. The electrocardiogram (ECG) from the proband's mother revealed sinus rhythm (SR), 1st degree AV block and a nonspecific intraventricular conduction delay. Clinical genetic testing of SCN5A did not reveal any disease-associated mutations. Subsequently she gave birth to identical twin girls. Both girls had rapid JET in the immediate post-natal period that was initially difficult to control. There was rate dependent RBBB and LAFB in both children prior to use of antiarrhythmic drugs. The arrhythmia has resolved in one twin but persists in the other as a catecholamine dependent accelerated junctional rhythm/congenital JET that is modified by propranolol therapy (Fig. 1C). The resting ECGs now both show LAFB and intermittent incomplete RBBB. The mother has subsequently developed symptomatic palpitations and shows electrocardiographic features consistent with typical atrioventricular nodal re-entrant tachycardia (AVNRT) on symptom-rhythm correlation observed on loop recorder. Thus, the conduction defects in this family were of varying severity and the relationship to congenital JET in the three children is important as it is well recognized that congenital JET may progress to heart block [ 1 Henneveld H. Hutter P. Bink-Boelkens M. et al. Junctional ectopic tachycardia evolving into complete heart block. Heart. 1998; 80: 627-628 Crossref PubMed Scopus (23) Google Scholar , 2 Villain E. Vetter V.L. Garcia J.M. et al. Evolving concepts in the management of congenital junctional ectopic tachycardia. A multicenter study. Circulation. 1990; 81: 1544-1549 Crossref PubMed Scopus (211) Google Scholar ]. At this stage the conduction abnormalities are minor in the twins who presented with the JET and have not progressed.

Atrial pacing site and atrioventricular conduction in patients paced for sinus node disease.

Unnecessary ventricular pacing in sinus node disease (SND) must be avoided. To test the hypothesis that in SND, with or without 1st degree atrioventricular (AV) block, cumulative percent ventricular pacing (cum%VP) can be limited by low right atrial septal (LRAS) instead of right atrial appendage (RAA) pacing. We studied 102 dual-chamber pacemaker recipients with SND. The PQ interval on 12-lead electrocardiogram and the atrial paced to ventricular sensed interval (Ap-Vs) during LRAS and RAA pacing were measured and compared at implantation, 3 months and 1 year of follow-up. Group 1 included 62 patients with baseline PQ interval <200milliseconds during LRAS (n = 28) versus RAA (n = 34) pacing. Group 2 included 40 patients with baseline PQ ≥200 milliseconds during LRAS (n = 20) versus RAA (n = 20) pacing. cum%VP were measured at 3 months and 1 year. The characteristics and AV conduction properties were similar and the Ap-Vs interval was significantly shorter in the LRAS than in the RAA pacing group up to 1 year (193 ± 32 milliseconds vs. 220 ± 27 milliseconds in Group 1; P = 0.003, 222 ± 41 milliseconds vs. 281 ± 30 milliseconds in Group 2; P < 0.001). While cumulative percent atrial pacing was consistently similar, cum%VP was significantly smaller during LRAS than RAA pacing (1 ± 1% vs. 8 ± 18% in Group 1; P = 0.03, 7 ± 10% vs. 48 ± 38% in Group 2; P < 0.001). Similar observations were made with or without left atrial (LA) enlargement. Compared with RAA, LRAS pacing showed shorter AV interval in SND patients with or without 1st degree AV block and LA enlargement. This beneficial effect persisted through 1-year follow-up, and decreased cum%VP significantly.

Coronary Artery to Right Atrium Fistula Associated With First Degree Atrioventricular Block: A Rare Association.

A 40 year-old man with no significant past history except for asymptomatic 1st degree heart block presented for general health screen. Clinical examination revealed a loud continuous murmur with diastolic accentuation in the left precordium, noncollapsing pulse, and no differential pulses in the upper and lower limbs. The ECG showed normal sinus rhythm with PR interval of 220 milliseconds. Transthoracic echocardiogram (Figure ​(Figure1)1) showed a dilated right coronary artery that was enlarged, forming multiple saccular aneurysms distally that drain into the roof of right atrium. The right heart was normal in size and function. CT angiogram (Figure ​(Figure2)2) later confirmed the presence of a coronary artery fistula from the right coronary artery draining into the right atrium. Right coronary artery is dilated and the distal segment of the RCA is tortuous and aneurismal. Nuclear myocardial perfusion imaging showed no inducible ischemia during exercise stress. He declined cardiac catheterization, and was advised for corrective surgery. This case illustrated a rare saccular aneurysm formation in a right coronary artery to right atrium (coronary-cameral) fistula associated with 1st degree atrioventricular (AV) block. Coronary arteriovenous fistula (CAVF) arises as a persistence of sinusoidal connections between the lumens of the primitive tubular heart in the early embryologic period. It is reported in 0.1%–0.2% of all cases of selective coronary angiography[1]. Most fistulae originate from the right coronary artery (60%) and terminate in the right side of the heart such the right ventricle or atrium, coronary sinus, and pulmonary vasculature. Most often congenital, a CAVF may rarely arise as a consequence of surgical complication, endomyocardial biopsy, invasive procedures[2, 3] or penetrating trauma. It could cause myocardial stealing due to run-off from the coronary vasculature to a low-pressure receiving cavity. Coronary artery that feeds the fistula progressively dilates, leading to complications of frank aneurysmal formation and mural thrombosis. Hence, all CAVF ought to be closed except for trivial ones. The evolution of 1st degree AV block in our case may reflect a flow limitation to atrioventricular (AV) node directly caused by the CAVF. CT angiogram has now emerged as an excellent imaging technique to delineate the lesion anatomy[4-6] CAVF generally requires closure. Transcatheter embolization techniques using coils, bags, or other devices can be performed successfully and safely, and are now the treatment modality of choice [7]. CAVFs with multiple connections, circuitous routes, and acute angulations may however be better treated surgically. Figure 1. Transthoracic echocardiogram performed showed the tubular structure coming off the right coronary cusp (bold arrow, image A); saccular formations adjacent to the aortic root in short axis and apical 4 chamber view (bold arrows, image B and C); as well as predominantly diastolic turbulent flow within the saccular formations (image D). Figure 2. Cardiac multidetector computed tomography (MDCT) angiogram volume rendering reconstruction of cardiac structures (images A-B) and multiplanar reconstruction images (images C-D) showed a dilated, tortuous right coronary artery (RCA) that eventually gave off a fistulous connection into the right atrium (RA).