While both flow-mediated vasodilation (FMD) in the brachial artery (BA), which measures endothelium-dependent vasodilatation, and intima-media thickness (IMT) in the carotid artery are correlated with the prognosis of coronary artery disease (CAD), it is not clear which modality is a better predictor of CAD. Furthermore, it has not been fully determined whether either of these modalities is superior to conventional ST-segment depression on exercise stress electrocardiogram (ECG) as a predictor. Thus, the goal of the present study was to compare the predictive value of FMD, IMT, and stress ECG for CAD prognosis.A total of 103 consecutive patients  with clinically suspected CAD had FMD and nitroglycerin-induced dilation (NTG-D) in the BA, carotid artery IMT measurement using high-resolution ultrasound, and exercise treadmill testing. The 73 CAD patients and 30 normal coronary patients were followed for 50 ± 15 months. Fifteen patients had coronary events during this period . On Kaplan-Meier analysis, only FMD and stress ECG were significant predictors for cardiac events.Brachial endothelial function as reflected by FMD and conventional exercise stress testing has comparable prognostic value, whereas carotid artery plaque burden appears to be less powerful for predicting future cardiac events. Endothelial function is a sensitive barometer of arterial health and can reflect the status of atheroma such as the presence of vulnerable and/or stable plaque. Several studies have suggested that endothelial vasomotor function testing, such as brachial artery flow-mediated vasodilatation (FMD), has prognostic value -6.Furthermore, the carotid atheroma burden has also been reported to be well correlated with coronary artery disease severity -9. Some Thus, the purpose of this study was to determine the relative prognostic importance of brachial artery endothelial function as determined by FMD, the carotid atheroma burden as determined by IMT, and exercise-induced myocardial ischemia in patients with suspected CAD.A total of 103 consecutive patients who were referred to the Division of Cardiology at the National Defense Medical College due to clinically suspected coronary artery disease and who were subsequently admitted for cardiac catheterization and agreed with study protocol were included in this study. Suspected coronary artery disease was defined as having either typical angina symptoms or atypical chest pain with exercise-induced myocardial ischemia by exercise testing. The patients were enrolled in this study from August 1999 to February 2001. The study population consisted of 79 men and 24 women, whose ages ranged from 35 to 80 years . Exclusion criteria were as follows; the patients present acute illness including acute coronary syndrome, uncompensated phase of chronic illness such as chronic renal failure, chronic heart failure and chronic lung disorders. The patients in whom percutaneous coronary intervention was performed at the time of coronary angiography was included and this percutaneous coronary intervention was not considered as cardiac events. None of the patients had electrocardiogram (ECG) abnormalities (such as bundle-branch block) on resting ECG that would have precluded measurement of ischemic ST or T-wave changes, nor did any patient have ECG evidence of Wolff-Parkinson-White syndrome or left ventricular hypertrophy. The presence of a Q wave > 0.04 sec duration in a lead, and the presence of baseline ST-segment morphology, defined as a depression or an elevation of 1 mm or more as compared to the isoelectric line, were considered for ST-segment depression measurements. Oral medications, including antianginal agents, were discontinued for at least five half-lives prior to FMD, IMT, and exercise testing, but sublingual nitroglycerin was administered during acute anginal episodes. All subjects were aware of the investigative nature of the study and gave their informed consent. The research protocol was approved by the local institutional ethics committee.All ultrasound studies were done at approximately 08:00 in the morning in a temperature-controlled room (25°C) with the fasting subject resting in the supine position. Heavy meals, including a high-fat meal and caffeine-containing beverages, were prohibited from the night before the study. During the ultrasound procedures, blood pressure and heart rate were recorded from the left arm every 3 min using an automatic sphygmomanometer . A 7.5 MHz high-resolution ultrasound  was used to measure carotid artery IMT, using essentially the same method as previously reported,14. IMT FMD was measured using a previously validated technique,17. BracFinally, after a 15 min interval, nitroglycerin-induced vasodilation (NTG-D) was obtained because we put a 15 min interval in our institute to make sure the canceling the effect of reactive hyperemia despite guideline As previExercise treadmill testing was performed to assess exercise-induced myocardial ischemia using the Bruce or modified Bruce protocol. Exercise was continued until the heart rate reached 85% of the estimated maximum age-predicted target heart rate for each patient. If a patient could not exercise to the target heart rate, the patient continued to exercise until exhaustion or until cardiac symptoms, such as precordial discomfort, dyspnea, or palpitations, occurred. Throughout the study, 12-lead ECGs were monitored continuously and recorded at one min intervals using a Marquette CASE 12  and blood pressure was measured by Korotkoff's method at 1-minute interval. ST-segment depression was measured 80 ms after the J point. A horizontal or downsloping ST-segment depression of at least 1.0 mm was considered significant for exercise-induced ischemia. Stress ECGs were interpreted visually by expert cardiologists blinded to the clinical information and any clinical parameters, including the FMD and IMT measurements. Exercise treadmill testing was performed within two days of the FMD and IMT studies.Coronary angiography was conducted using the standard Judkins femoral approach method. Coronary angiographic findings were interpreted visually by at least three expert cardiologists blinded to the results of the FMD and IMT measurements. Significant coronary artery disease was defined as the presence of vessel luminal diameter stenosis > 70% in a major branch of the coronary arteries.Clinical long-term follow-up was done and confirmed by reviewing death certificates, hospital records, telephone conversations with the local treating physicians, the patients, or the patients' relatives. During follow-up, the time to the occurrence of cardiac events was assessed. Cardiac events were defined as cardiac death, myocardial infarction, and hospital readmission for unstable angina and acute heart failure due to documented ischemia such as the presence of significant ischemic ECG changes. Myocardial infarction was defined as new ST elevations (> 0.1 mV) in 2 contiguous leads or an elevation of creatine kinase levels > 2 times the upper limit of normal. Since aspirin, β-blocking agents, angiotensin-converting enzyme (ACE) inhibitors, and statins might affect either endothelial vasodilator function or disease progression, the use of these medical therapies was documented during follow-up. The clinical long-term follow up analyses were performed in the entire population as well as CAD group only.t-test for continuous variables and the chi-square or Fisher's exact test for non-continuous variables, as appropriate. Survival was determined using Kaplan-Meier curves, and outcomes were compared using the log-rank test. A receiver operating characteristic (ROC) curve was used to acquire appropriate sensitivity and specificity of FMD, IMT and stress ECGs for the diagnosis of adverse outcome during follow up period. Multiple logistic regression analysis was performed to identify the independent variables for predicting cardiac events. In order to determine the predictive value of FMD, IMT, and stress ECG, multiple logistic regression analysis for all the cardiac events was applied to these variables and they were compared with the other factors including conventional clinical variables. Baseline clinical characteristics, such as coronary risk factors, the information on follow-up medication, the number of coronary artery diseased vessels, the presence of the baseline revascularization procedures, and left ventricular ejection fractions, were included as independent variables. Univariate predictors which had P < 0.1 were included into multiple logistic regression analysis. All of these statistical analyses were performed using SPSS version 11.0 . Statistical significance was set at the P < 0.05 level.All data are presented as the means ± SD and a 95% confidence interval (CI) or frequency (%), unless otherwise stated. The baseline clinical characteristics of the groups were compared using the two-tailed Student's The clinical characteristics of the study population are summarized in Table The heart rate, blood pressure, baseline brachial artery diameter, blood flow in the brachial artery, and reactive hyperemia were not significantly different between the CAD and NCAD groups Table . FMD wasThe mean follow-up period was 50 ± 15 months. During this period, 15 patients suffered from cardiac events: 1 cardiac death, 2 non-fatal myocardial infarctions, 3 acute heart failures, and 9 unstable anginas , and Kaplan-Meier cardiac event-free survival curves were compared Figures  to 4. PaThe same Kaplan-Meier cardiac event-free survival curves were compared in CAD group only Figures  to 7. AsIn order to compare the predictive value of FMD, IMT, and stress ECG with conventional clinical variables, we did a multiple logistic regression analysis for all the cardiac events. Baseline clinical characteristics, such as coronary risk factors, the number of coronary artery diseased vessels, the presence of the baseline revascularization procedures, and left ventricular ejection fractions, were included as independent variables. The information on follow-up medication was also included. We found that the univariate predictors for cardiac events included: the number of diseased coronary arteries, diabetes mellitus, HDL-cholesterol level, FMD, IMT, and stress ECG. However, FMD, IMT, and stress ECG were the only multivariate predictors for cardiac events Table .The main findings in our results demonstrate that brachial artery endothelial function (FMD) and conventional exercise stress testing have comparable prognostic power for predicting adverse outcome in patients with suspected CAD. However, the carotid atheroma burden as reflected by IMT does not strongly predict cardiac events. Event-free survival analyses showed that impaired FMD and marked exercise-induced myocardial ischemia were significantly correlated with increased cardiac events, whereas increased IMT tended to be associated with increased cardiac events, but this trend was not statistically significant.Since the endothelium is the major regulator of vascular homeostasis, endothelial function could be a very sensitive barometer of the functional state of atheroma. It is known that endothelial function rapidly responds to pro-atherogenic or anti-atherogenic stimuli -20. The Exercise-induced myocardial ischemia is related to both functional and morphological atherosclerotic changes. The pathophysiology of exercise-induced myocardial ischemia has been extensively investigated,22. FixeHowever, we could not determine why the carotid atheroma burden, as reflected by IMT, did not predict cardiac events. Since IMT represents a morphological change, dynamic function testing, such as FMD or exercise testing, theoretically does not reflect the IMT. Some studies show that IMT is more predictive of stroke than of cardiac events, while IStudy limitations: This study had several limitations. First, medications were discontinued before the FMD and IMT studies, as well as before exercise treadmill testing. This is the definitive limitation when our study findings are applied to the clinical practice. Since FMD and exercise testing may be affected by various medications, the therapeutic impact on the relationship among FMD, IMT, and exercise testing with respect to CAD prognostication should be investigated in future studies. Second, we did not use an exercise diagnostic score, such as the Duke exercise scoring system,22 whichNotwithstanding all these limitations, the data suggest that endothelial dysfunction, carotid atheroma burden, and exercise stress testing appear to reflect prognosis in patients with suspected CAD. However, our results indicate that brachial endothelial function, as reflected by FMD, and conventional exercise stress testing are comparable with respect to prognostic value, whereas carotid artery plaque burden might be less powerful for predicting future cardiac events, even though it may still be a possible prognostic predictor.The authors declare that they have no competing interests.YM carried out the patient enrollment and each parameter's measurement. AU, MI and AK participated in the design of the study. BT conceived of the study, and participated in its design and coordination.


Circulating TGFβ1 levels, procollagen type III levels, microalbuminuria, and left ventricular geometry and function were evaluated in all the hypertensives with LVH subgrouped according to T29C TGFβ1 gene polymorphism. Circulating TGFβ1 was evaluated by ELISA technique, procollagen type III by a specific radioimmunoassay, microalbuminuria by radioimmunoassay, and left ventricular geometry and function by echocardiography. All groups were comparable for gender, age, and sex. Regarding T29C TGFβ1 gene polymorphism, prevalence of TC or CC genotypes was significantly (P < .05) higher in hypertensives with LVH than hypertensives without LVH TC and CC LVH hypertensives were characterized by a higher prevalence of subjects with microalbuminuria (P < .05 TC and CC versus TT), by increased levels of TGFβ1, procollagen type III, urinary albumin excretion, LVM, LVM/h2.7, and lower values of left ventricular ejection fraction (P < .05 TC and CC versus TT). Our data suggest that T29C TGFβ1 gene polymorphism was associated with clinical characteristics adequate to recognize a subset of LVH hypertensives with a higher severity of hypertension.The distribution of the T29C TGF Hypertension represents the most common powerful risk factor for cardiovascular morbidity and mortality . High bl The disproportional accumulation of fibrous tissue is the major characteristic of the adverse structural remodelling of cardiac tissue in hypertensives promoting systolic and diastolic dysfunction –5.β1 (TGFβ1) is a multifunctional cytokine and its gene has been found in position 19q13.2, 19q13.1 on chromosome 19 and it has 7 exons and the length of the whole gene is 17.52 kb. Transforming growth factor β1 overproduction acts on cardiomyocytes as well as on cardiac fibroblasts inducing cardiac fibrosis and hypertrophy [β1 through a block of the renin-angiotensin system (RAS) was reported to be associated with an improvement of renal function and a reversion in LVH [β, through a novel orally specific inhibitor of the TGFβ receptor 1, results in significant improvement of deleterious cardiac remodelling after infarction [TGFertrophy , 7. In an in LVH , 9. Morefarction . β1 is in part under genetic control [s) have been described in TGFβ1 gene and related to its production and to hypertension and cardiovascular disease [s are located at positions 29 and 74 of the translated sequence of TGFβ1 and give rise to amino acid substitutions at positions 10 (Leu10→Pro) and 25 (Arg25→  Pro) in the signal peptide of TGFβ1, respectively [β1 mRNA in peripheral blood mononuclear cells and serum levels of TGFβ1, and the G74C was found to be related to TGFβ1 production in peripheral blood leukocytes [25 allele was associated with risk of hypertension in the normotensives [25 allele. On the contrary, no studies have been addressed the evaluation of the role of T29 → C polymorphism of TGFβ1 gene on left ventricular geometry and function in hypertensive patients [Production of TGF control . Eight s disease , 12. Twoectively . The T29ukocytes , 14. In tensives  and withtensives  comparedpatients .β1 gene polymorphism (rs1800470), LVH and clinical severity of hypertension. The aim of this study was to investigate the relationship between T29C TGFβ1, procollagen type III levels, microalbuminuria, left ventricular geometry and function were evaluated in hypertensive patients and related to genotype profile.In particular, circulating TGFSubjects eligible for the study were screened at the antihypertensive center of the Department of Internal Medicine, University of Palermo . The study population consisted of hypertensive subjects with age ≤65 years. Each patient gave a written consent after received a detailed description of study procedure. The study was approved by Ethics Committee of our Institution. Subjects under antihypertensive treatment or with a casual blood pressure (SBP) ≥140 mmHg and/or with casual diastolic blood pressure (DBP) ≥90 mmHg obtained with a standard sphygmomanometer after 5 minute of rest at three independent occasions with patients sitting were considered hypertensives. Exclusion criteria included secondary hypertension, endocrinal disease and diabetes mellitus, cardiovascular diseases , severe chronic renal failure, alcoholism and psychiatric problems.2.7≥50 g/m2.7for men and ≥47 g/m2.7for women were considered to have LVH [433 hypertensive subjects fulfilled the inclusion criteria and they were grouped according to the presence or absence of LVH, following standard echocardiographic criteria. In particular all the hypertensives with LVM/hhave LVH . AccordiGenotyping was performed by investigators blinded to clinical status.Peripheral venous blood was collected in EDTA from all the patients and stored at −70°C.β1. The PCR approach was used to analyze SNP in the coding regions of TGFβ1 polymorphism was done by analyzing the sequence. The polymorphism is on exon 1 at +869 from the beginning of the transcription and generate an amino acid substitution in position 10 (Leu → Pro). This study analyzed the genotypes derived from this substitutions. The study of the TGB PCR was performed on purified DNA obtained using the GenElute Blood Genomic Dna Kit by Sigma: which provided sequence-specific oligonucleotide primers T869C: Forward 5′-TTCCCTCGAGGCCCTCCTA -3′Reverse 5′-GCCGCAGCTTGGACAGGAT-3′μL containing approximately 5 μL of genomic DNA(0.1 μg/μL), 2 μL of forward and reverse primers (100 ng/μL), 5 μL of 10 × reaction buffer (160 mM (NH4)2SO4, 670 mM Tris-HCl , 15 mM MgCl2, 0, 1% Tween 20), 4 μL of 2 mM dNTPs (invitrogen), 4 μL of DMSO, 0, 1u of Taq Polymerase.Briefly, PCR reactions were carried out in a total volume of 50-Amplification was carried out in a Robocycler using cycle parameters of 3 minutes and 30 seconds at 95°C , 35 cycles of 95°C for 45 seconds (denaturation), 62°C for 30 seconds  and a final extension for 10 minutes at 72°C.T869C: the PCR generated amplicons with a fragment size of 294 Bp.μL of ethidium bromide  and from sequence electropherograms was analysed the presence of single-nucleotide polymorphisms T869C in all the subjects , cholesterol by routine laboratory methods.β1 levels were determined by using a solid-phase specific sandwich ELISA technique  as previously described [β1 were 8% and 6%, respectively. The sensitivity, hence minum level of detection of TGFβ1 by sandwich ELISA, was 5 pg/mL. Peripheral venous blood was obtained from each patient and the sera were isolated and stored at −70°C. TGF escribed . The intTo determine amino-terminal PIIIP, blood samples were taken from each patient and stored at 40°C until manipulation. PIIIP were determined by using a specific radioimmunoassay (Orion Diagnostic Finland), as previously described . The senTo eliminate the intra-individual day-to-day variability of UAE, three consecutive 24-hour urine collections were used. In addition, to assess the completeness of a 24 hours urine collection, measurements of urinary rate of clearance of creatinine were evaluated. UAE was measured by radioimmuno-assay . Microalbuminuric patients were defined as a level of UAE ≥20 and <300 mg/24 hours.All patients underwent an echocardiography examination M and B-mode, by a computerized echocardiography  for the determination of following parameters: left ventricular telediastolic internal diameter (LVIDd), interventricular septum (IVSTd), and posterior wall thickness (PWTd). The Penn convention was used to calculate left ventricular mass (LVM). LVM was normalized for height to the 2.7 power . The relLV relaxation and filling were evaluated by pulsed-wave Doppler interrogation of the LV inflow tract from the apical four-chamber view, with the sample volume placed at the tips of the mitral valve. After a stable signal of the transmitral flow velocity was obtained, the Doppler cursor was moved toward the LV outflow tract in the apical five-chamber view for recording both mitral and aortic signals, including the closing click of the aortic valve and the opening click of the mitral valve. Doppler signals were recorded at high speed (80–120 mm/s) with the subjects in held expiration. An average of five beats was used for analysis. E), peak late transmitral flow velocity (A), and the deceleration time of E velocity (DTE) were measured at the tips of mitral leaflets at the maximum amplitude of E velocity. DTE was measured as the time from peak E velocity to the time when E wave descent intercept the zero line.Isovolumic relaxation time (IVRT) was calculated as the time from the closure click of the aortic valve to the opening click of the mitral valve. When either the closing or opening click was not identified, the time from the end of the aortic flow to the onset of mitral flow from the continuous wave interrogation of the LV inflow-outflow tract was used. Peak early transmitral flow velocity , and TC plus CC (P = .0466) genotypes, was significantly higher in hypertensives with LVH than hypertensives without LVH . The distribution of T29C genotypes in both hypertensive groups has been reported in Genotype frequency distribution in the two groups of hypertensives occurred according to Hardy-Weinberg proportions.Since genotype frequency distribution was not significant different in hypertensives without LVH, only hypertensives with LVH were further subdivided into three groups, according to T/C genotypes.P < .05 TC and CC versus TT).The association between genotypes and clinical characteristics in the three groups of hypertensives with LVH have been reported in No significant difference in the prevalence and duration of antihypertensive drugs utilized was observed among the groups Tables  and 2. Iβ1, PIIIP, LVM and LVM/h2.7levels were significantly (P < .05) higher and left ventricular ejection fraction values were significantly (P < .05) lower in LVH hypertensives with TC or CC genotype than those detectable in LVH hypertensives homozygous for allele T  on left ventricular geometry and function in hypertensive patients. Our data indicate a higher prevalence of TC and CC Leu10→Pro polymorphism in hypertensives with LVH than hypertensives without LVH, associated to some unfavorable clinical characteristics of hypertension. In fact, LVH hypertensive subjects with TC or CC genotype were characterized by a higher prevalence of subjects with microalbuminuria, higher value of LVM and lower left ventricular ejection fraction. In our opinion, this association doesn't reflect unknown differences in population ancestry between the two hypertensive groups. We consider the probability of false positive inference attributable to population studied rather small because the two hypertensive groups were recruited from an ethnically homogenous population. In this context recent results from Xu et al. [β1 + 915 Arg → Pro at codon 25 polymorphism with LVH in a Chinese hypertensive population, while the codon 10 genotypes did not show any association to LVH. Even if in this study we have analyzed only TGFβ1 Leu → Pro at codon 10 polymorphism, our recent unpublished data indicated no association between TGFβ1 + 915 Arg → Pro at codon 25 polymorphism and hypertension in a Caucasian hypertensive population. These contrasting data may be explained by ethnicity of two hypertensive populations considered (Caucasian and Chinese).To our knowledge this is the first study to investigate the impact of TGFu et al.  revealedAlthough changes in the heart caused by hypertension are well known, the effective mechanisms are not entirely clarified. Despite the role of hemodynamic effects and growth factors have been largely reported, other metabolic and inflammatory factors have to be also considered .β1 in hypertensives. Moreover, hypertensives with target organ damage (TOD) have higher circulating levels of TGFβ1 than hypertensives without TOD. This finding seems to attribute an important role to TGFβ1 overproduction in the pathophysiology of essential hypertension and its sequelae [β1 overproduction in hypertension may be explained by the effects of various factors, such as elevated angiotensin II, increased fluid shear stress and a differential expression of TGFβ1 linked to DNA polymorphisms in the promoter [β1 is predominantly under genetic control (heritability estimate 0.54). Up regulation of TGFβ1 system in monocytes of hypertensive patients and association of TGFβ1 gene polymorphism with risk of hypertension suggests that quantitative difference in TGFβ1 production may determine the intensity of the process of vascular remodelling and therefore influence overall susceptibility to the development of hypertension [β1 overproduction, as evidenced by collagen formation, may represent a pathophysiological molecular mechanism in hypertension [β1 Arg25-Pro polymorphism might be associated with hypertension but does not address the issue of quantitative phenotypes related to TGFβ1 production in relation to hypertension. On the contrary no study has been addressed the evaluation of the role of Leu-to-Pro polymorphism at codon 10 to explain whether the substitution has functional and biological importance, or it could affect protein transport. In view of this we have now shown that the serum concentration of TGFβ1 was significantly different in LVH hypertensives subgrouped according to T29 → C polymorphism. It is possible that the T29 → C polymorphism of the TGFβ1 gene is linked to some other genes that are actually responsible for the development of hypertension.Literature data and the results of our previous studies indicate an overproduction of circulating TGFsequelae , 25. Thepromoter . Plasma rtension . On the rtension , 28. Thertension  suggest β1 values among LVH hypertensive groups indicated that TC or CC genotypes could be able to induce quantitative change in the production of the cytokine and it might affect also the function of signal peptide, perhaps influencing intracellular trafficking or export efficiency of preprotein [Moreover, the significant change in circulating TGFeprotein .β1 may contribute to the progression of renal and cardiovascular damage in obese and/or hypertensive subjects. In particular, the present study emphasizes the unfavourable effects of TGFβ1 overproduction on left ventricular geometry and function that might be mediated by an higher collagen production [β1 is a susceptibility locus for hypertension. A potential limit of this study was to have computed no a priori evaluation of the β error and consequently the power of our statistical analysis. However this involves considerations only about the sample size. Accordingly the negative results of our study has needed further evaluations.In addition, our data suggest some clinical considerations. First, LVH hypertensive subjects with TC or CC genotypes were characterized by a higher value of microalbuminuria, LVM and by a systolic left ventricular dysfunction. This might indicate that hypertension in these subjects has to be considered more severe. Another aspect of our study that seems to be interesting is related to the higher collagen production in LVH hypertensive subjects with TC or CC genotype than in those homozygous for allele T. This finding is further supported by analysis of logistic regression indicating that PIIIP may be considered the most important marker associated to T and C alleles. In fact, analysis of odd ratio indicates that the risk of association with T or C allele increases eight fold for each PIIIP quintile variation. In our opinion this finding might further support our previous results , 23 indioduction , 24, 29.10  → Pro polymorphism, rs 1800470) might be considered a particular subset of LVH hypertensives with a more severity of hypertension. However, the present results require verifications in other populations, since it is well known that hypertension is under the control of many genes that contribute modest individual effects, and TGFβ1 may act in concert with other hypertension susceptibility loci.In conclusion our data are attractive to indicate that LVH hypertensive subjects with TC or CC genotypes (Leu


Cardiac tamponade is a condition whereby fluid accumulation in the pericardial sac surrounding the heart causes elevation and equilibration of pericardial and cardiac chamber pressures, reduced cardiac output, changes in hemodynamics, partial chamber collapse, pulsus paradoxus, and arterio-venous acid-base disparity. Our large-scale model of the human cardiovascular-respiratory system (H-CRS) is employed to study mechanisms underlying cardiac tamponade and pulsus paradoxus. The model integrates hemodynamics, whole-body gas exchange, and autonomic nervous system control to simulate pressure, volume, and blood flow.th-order Runge-Kutta numerical integration scheme. MATLAB is employed for waveform analysis.We integrate a new pericardial model into our previously developed H-CRS model based on a fit to patient pressure data. Virtual experiments are designed to simulate pericardial effusion and study mechanisms of pulsus paradoxus, focusing particularly on the role of the interventricular septum. Model differential equations programmed in C are solved using a 52 due to hypoperfusion, and we explore implications of respiratory pattern in tamponade.The H-CRS model simulates hemodynamic and respiratory changes associated with tamponade clinically. Our model predicts effects of effusion-generated pericardial constraint on chamber and septal mechanics, such as altered right atrial filling, delayed leftward septal motion, and prolonged left ventricular pre-ejection period, causing atrioventricular interaction and ventricular desynchronization. We demonstrate pericardial constraint to markedly accentuate normal ventricular interactions associated with respiratory effort, which we show to be the distinct mechanisms of pulsus paradoxus, namely, series and parallel ventricular interaction. Series ventricular interaction represents respiratory variation in right ventricular stroke volume carried over to the left ventricle via the pulmonary vasculature, whereas parallel interaction (via the septum and pericardium) is a result of competition for fixed filling space. We find that simulating active septal contraction is important in modeling ventricular interaction. The model predicts increased arterio-venous COOur modeling study of cardiac tamponade dissects the roles played by septal motion, atrioventricular and right-left ventricular interactions, pulmonary blood pooling, and the depth of respiration. The study fully describes the physiological basis of pulsus paradoxus. Our detailed analysis provides biophysically-based insights helpful for future experimental and clinical study of cardiac tamponade and related pericardial diseases. PERI) which is conventionally defined as a liquid pressure. In a healthy subject, PPERI is approximately equal to the pleural pressure (PPL). PPERI rises with increasing effusion and may equalize to diastolic right atrial (RA) and right ventricular (RV) pressures, and at higher levels of effusion to diastolic left atrial (LA) and left ventricular (LV) pressures. Heightened pericardial pressure may lead to partial chamber collapse for a portion of the cardiac cycle [PERI exceeds chamber pressure. Clinical cardiac tamponade occurs when there is significant component of decreased cardiac output, stroke volume, systemic blood pressure, attendant tachycardia, and manifestation of pulsus paradoxus .Cardiac tamponade may present as an acute clinical emergency or in a less emergent fashion that requires timely intervention . Low-preparallel interaction occurs whereby expansion of the RV during inspiration compresses the LV; likewise, a smaller RV volume during expiration allows more blood to be drawn into the LV [series form of ventricular interaction occurs in tamponade when an augmented right heart volume upon inspiration travels to the left heart within two to three beats, contributing to an increase in LV stroke volume (LVSV) at the expiratory phase of respiration [Pericardial effusion leads to increased chamber interaction. A o the LV -10. The o the LV -14. Locao the LV ,15 aidinpiration ,17. Parapiration ,9,16-18 piration  causes sLarge-scale integrated cardiovascular-respiratory closed-loop models provide informative analysis of normal and diseased human physiology ,12,20-27Sun et al.  have modIn this work, we first examine the model-generated predictions of cardiovascular pressures, volumes, and flows in tamponade, with particular focus on the role of an active septum. We then analyze the contributory role of breathing pattern, and by introducing artificial isolation of the right and left hearts, dissect the separate contributions of serial and parallel ventricular interactions. Lastly, we analyze the important role of the septum as an active, tertiary pump assisting both systolic ejection and diastolic filling, and demonstrate the relevance of this previously neglected component in the physiology of cardiac tamponade.2, CO2, and N2) at the lung and in major tissues of the body at the capillary level . The neural control system model includes baroreceptor control of heart rate, contractility, and vasomotor tone, and chemoreceptor control of heart rate and vasomotor tone [Our H-CRS model ,12,24-26tor tone .th-order Cash-Karp Runge-Kutta method [Differential equations for the H-CRS model were programmed in C and solved numerically using a 5a method . TypicalTPERI) vs. pericardial effusion volume (VPERI) relationship, where PTPERI is defined as PPERI minus PPL. A nonlinear least-squares parameter estimation method [PERI vs. VPERI data from a clinical case reported by Reddy et al. [TPERI was calculated from this data under the assumption of a constant mean PPL of -3.0 mmHg. This new PTPERI-VPERI relationship is given by Eq. 1, where P0 (= 4.24e-7 mmHg) is the PPERI coefficient, λ (= 0.0146 ml-1) the pericardial stiffness parameter, VPERI the effusion volume, VH the total heart volume, and V0 (=159.36 ml) the volume offset:The H-CRS model  is updatn method  was usedy et al. . EffusioThe new and old transmural pressure-volume characteristics of the pericardial space differ in that their slopes in the normal range of volumes are approximately the same, however at high volumes, the new characteristic develops significantly greater pressures.PL -3.0 mmHg. This pseudo-human respiratory waveform has PPL range estimated from [Apart from gas exchange modeled in the lung and airways , time-vated from .Three septal models were compared: two passive septa, whose P-V relationship was fixed at either end-systolic or end-diastolic behavior throughout the cardiac cycle, and an active septum for which the P-V relationship is modulated by a time-dependent activation function in synchrony with free wall contraction, thereby undergoing biphasic operation. The passive septum models are used only for this comparison study – all simulations of control and tamponade employ the active septum model detailed previously ,12.Tamponade was simulated by graded increases in pericardial volume. Following each step-increase, the model was brought to steady-state and data was analyzed using MATLAB . EffusioPL.To analyze ventricular interaction, we tracked a fixed volume of blood as it was transported from the right atrium to left ventricle. In Experiment 1 (see Results section), we simulated an inspiratory increase in venous return to the right heart by delivering a triangular pulse volume to the vena cava within a period of two seconds at fixed PPERI constant. To study parallel interaction, the pulmonary venous volume was held constant thus creating an independent left heart venous return, thereby eliminating series interaction. Parallel and series ventricular interactions were analyzed and compared based on a triangular pulse of venous return to the right atrium such as in Experiment 1, and PPL was held constant.In Experiment 2, to dissect the relative importance of each type of ventricular interaction, the model was modified to eliminate one type of interaction at a time (see Experiment 2 in Results section). To study series interaction, parallel interactions via the septum and pericardium were respectively eliminated by increasing the septal stiffness parameter λ by 100× from 0.05 to 5.0, and holding PPERI in response to increases of effusion volume. At VPERI of 800 ml, there is > 2 mmHg increase in PPERI. At 950 ml fluid accumulation, pulsus paradoxus is seen with an 11% variation in systolic blood pressure with respiration. At 1050 ml, all chamber pressures equilibrate within 2 mmHg of each other. We define a "chamber collapse index" as the mean percentage of a cardiac cycle in which PPERI exceeds chamber pressure, averaged over several cardiac cycles covering both the inspiratory and expiratory phases of respiration. At 1100 ml, RA collapse occurs over 34% of the cardiac cycle and LA over 20%.To simulate tamponade, we modeled graded increases in pericardial fluid . Figure PERI is accompanied by decreases in cardiac output (CO), mean arterial pressure (MAP), and associated activation of the baroreceptor reflex manifested as an increase in heart rate (HR). Figure PERI. Measured data points from the patient whose pericardium we have modeled [Above 700 ml, progressive increases in V modeled  are showPL is set to the mean, thus simulating breath-holding. The atrium may be envisioned as a contractile storage chamber with an inflow from the vena cava compartment and an outflow through the tricuspid valve to the RV chamber. Diastole is defined as the interval between tricuspid valve opening and closure [To examine the right heart hemodynamics in tamponade without overlying respiratory variations, P closure .RA), i.e., the x-descent. Systolic filling of the RA consists of a fast and slow component as is seen in the RA volume (VRA) curve   in Figure Figure e Figure  and in Pe Figure . The fasC Figure . In earl) Figure  equivaleA Figure . In thisC Figure  and the C Figure . This isC Figure  and 4G, A Figure  and incrPERI waveform reveals key alterations during the cardiac cycle which may actively participate in the clinically observed features of tamponade. Under control conditions, PPERI is low relative to PRA and tracks the PPL  as observed in canine measurements [RA occurring in RV systole  and QTC (outflow from RA) and the large decline in the D component of QVC in tamponade is responsible for the smaller decrease in VRA during the early diastole phase. As the tricuspid E-wave declines, VRA continues to decline at a slower rate. When the RA contracts (a-wave feature in PRA), it produces a strong tricuspid flow , providing some relief from pericardial constraint. Subsequently, PPERI increases slowly due to a very limited diastolic venous return continuing into the systolic interval. This slow return delays the occurrence of the x-descent. Model measurements of common clinical indices are given in Table Examination of the PL Figure . It is ie Figure  serving urements ,19. We be Figure . With tam Figure  and 4J. l Figure , PRA sepe Figure  and 4E. e Figure  and 4F. e Figure . In lateLA)   is elevated in tamponade  indicating that the RV is compressed to a much higher degree than the LV.The pre-ejection period for the LV (LPEP) is normally slightly longer than that for the RV (RPEP) as noted in  compare. This asRA at the end of the systolic interval, but a substantially decreased VRA at end-diastole related to a reduction in diastolic venous return. Diastolic left heart venous return volume has both reduced influx and a significantly reduced reversal flow  the pericardial pressure tracks the chamber pressures and not the pleural pressure; 2) RA filling is delayed and diminished such that the x-descent occurs after the onset of RV ejection, rather than at the onset of RV isovolumic contraction; 3) the early diastolic filling (E-wave) is diminished and the late filling (A-wave) assumes greater proportion, due to a markedly decreased vena cava D-component; 4) atrial filling is restricted significantly to ventricular systole, in contrast to the normal filling during both ventricular systole and diastole, leading to a diminished or absent y-descent. The left heart hymodynamics are altered in parallel. Informative findings of these changes in tamponade are well visualized with atrial and ventricular P-V loops. There is evidence >11% pulsus paradoxus and atrial collapse . The CO and MAP are compromised and there is demonstration of baroreflex activation and tachycardia.Importantly, the pericardial pressure waveform in tamponade reflects local volumetric changes in the heart chambers, in particular the diastolic and systolic dips in pressure, which in turn influence the filling capability of the chambers. As a result of this pericardial constraint, venous return to the atria is progressively higher in systole rather than in diastole, as the ventricles are contracted and the heart occupies less volume, producing atrioventricular interaction that largely determines the heart's filling volume.PERI due to effusion creates a competition for filling space, which increases interaction between the ventricles. During the inspiratory increase in systemic venous return, filling of the left heart is compromised, lowering LVSV and aortic pressure [During inspiration, there is an increase in venous return to the right atrium. Lowered intrathoracic pressure on inspiration lowers pressure in intrathoracic systemic veins, pericardium, and cardiac chambers. Consequently, flow from extrathoracic systemic veins is increased and more blood flows to the right heart. This augmented blood flow appears in the left heart two to three beats later (during expiration for a person at rest), i.e., the "transit time" for blood to travel through the pulmonary vasculature ,17. In spressure ,6,17,33.PL on inspiration, overall respiratory variations increase. In the control case  have much greater respiratory variation than the left . For example, at different levels of respiratory effort, the flow variations at the tricuspid valve (QTC) range from 23–43%, whereas the flow variations at the mitral valve (QM) range from 5–13%. With severe tamponade, the flow variations at the tricuspid valve range from 21–40%, but the flow variations at the mitral valve increase its range to 12–37%  were used in the model and the percentage variation between expiration and inspiration for inlet, outlet, and transvalvular flows was calculated. Figure e Figure , right h% Figure . The incPA) is increased and shows less pressure excursion due to the increase in pulmonary blood pooling (discussed below), but PAO is decreased due to the decline in cardiac output and the respiratory variation increases. Hence, there are opposing effects with pericardial constraint on the pulmonary and aortic pressures. However, increased respiratory variation increases pressure variation at both sides  relationship for the septal compliant compartment, linear in systole, nonlinear in diastole. Secondly, the septum undergoes active contraction synchronized with RV and LV free wall contraction in systole, behaving as a third pump. Septal activation and the trans-septal pressure gradient both shape septal motion.The septal model we have employed encompasses septal motion for the complete cardiac cycle, mimicking biphasic motion as noted by others ,14. As dn Figure , where pSPT independent of time, whereas case c treats the septum as an active pump synchronous to the active RV and LV free wall pumps. Figure SPT for the three cases. With passive septum case a, the septum is highly non-compliant and approximately fixed at neutral position  a linear P-V relationship as observed in end-systole  and heldn Figure . Systolimentally ,33, withV Figure  and a diV Figure . SimilarLVFigure . Systolil Figure , systolid Figure . The actd Figure  and 9F, d Figure . The sepLV and restricting LV filling, while increasing systolic PRV due to no leftward movement, and providing no aid to RV ejection  can be used to track septal movement, where septal volume is defined as the volume offset from the neutral septal position  has been employed consistently in this modeling study. To better analyze septal contribution to tamponade, plots of septal volume  during expiration (solid line) and inspiration (dashed line) are overlaid for the two cases post-pericardiocentesis (control) and pre-pericardiocentesis (1000 ml effusion). We note from this data that the isovolumic relaxation phase remains unchanged throughout the respiratory cycle; hence we have aligned single cycles of PLV in inspiration and expiration relative to this phase and in particular with aortic valve (AOV) closure. In control, respiratory effects are minor as reported in [In severe tamponade, the abnormal prolongation of PEP in Ph canine  and clinh canine ,38. Figuh canine , where pLV with tamponade  and diastolic VSPT are apparent in Figure LV and septal rightward shift during expiration. Systolic respiratory variation is negligible. For the tamponade case, with inspiration, PEP is prolonged  as noted in . LVET isRespiratory variation occurs in RV ejection time (RVET) as well, but with an increase in RVET of 3% for control and 13% for tamponade on inspiration compared to expiration. RV end-diastolic volume (RVEDV) varies by 26% for control and 49% for tamponade. RV stroke volume (RVSV) also varies by 39% for control and 59% for tamponade with maximum RVSV at inspiration. As can be noted to occur with tamponade, ejection time is more varied in the LV than the RV , but endWith tamponade, septal motion reflects abnormal hemodynamics associated with the pericardial constraint, i.e., the asynchrony and shortening of RV and LV ejection times which is exacerbated with inspiration. It should be noted that the use of term asynchrony to describe different ejection intervals should not be confused with asynchrony of electrical conduction through ventricles, as ventricular activation functions in the model are synchronized in time.PL waveforms  percent concentration differences . The triangular venous return pulse technique described earlier in Experiment 1 was again employed under conditions of normal septal stiffness and breath-holding at mean PLA was controlled by a constant pressure source, thus eliminating the series effect, the phase difference increased further to 178°.In severe tamponade, ventricular end-diastolic volumes tend to be 180° out of phase over the respiratory cycle . Such a The involvement of ventricular interaction in pulsus paradoxus is examined by way of tracking the effect on both ventricles of a vena caval volume pulse equivalent to a single inspiratory venous return increase. Parallel and series type ventricular interactions are isolated to compare the contributions of each to respiratory variation in LVSV. Model results reveal equally significant contributions to variation in LVSV.We have used our large-scale model of the H-CRS to simulate the compressive effects of cardiac tamponade on atrial and ventricular hemodynamics under conditions of normal and elevated tidal breathing. At levels of breathing consistent with observed breathing waveforms in severe tamponade , our modIt should be noted that our composite model represents a patient whose heart has normal characteristics based on various data sources but is encased in an abnormal pericardium of the patient described by Reddy et al. . TherefoOur modeling study presents a unique view of tamponade ranging from the dynamics occurring in a single cardiac cycle and how they come to play over a cycle of respiration, including analysis of septal motion, valve flows, chamber volumes, and pressures. This is largely due to our characterization of the septum as a third contractile pump. This premise provides the platform for atrioventricular as well as right-left ventricular interactions. Our heart model thus yields accurate representations of ventricular pressures ,12,37, iRA and lack of the y-descent feature [PERI waveform and ventricular filling with the diastolic dip is further impacted by septal motion. Elevated PPERI steers chamber pressures to undergo similar variations, particularly in the relatively more compliant right heart. In systole, the pericardial systolic dip draws PRV down as well, causing a premature pulmonic valve closure and early tricuspid flow. Normally, septal rightward motion upon deactivation administers a final aid to RV stroke output; however, due to the premature cessation of RV systole and commencement of tricuspid flow, this septal rightward thrust does no more than briefly interrupt RV filling. Therefore, pericardial constraint introduces asynchrony of outlet and AV valves, altering the nature and stroke volume impact of septal motion, respectively. Our simulation studies also show that pericardial constraint alone produces abnormality in septal mechanics regardless of the level of respiration  diaphragmatic descent on inspiration causing an increase in pericardial pressure which impedes LV filling ; (b) faiIt is generally agreed that in tamponade with a normal breathing pattern, inspiration produces an increase in right heart venous return and subsequently the left heart phenomenon of LVSV reduction ,10,17. TIsolated Series and Parallel Ventricular Interactions shows that these two mechanisms for ventricular interaction cause a significant respiratory variation in LVSV with tamponade. By virtue of the matched stroke volumes in control cases for the isolated series and isolated parallel interaction experimental setups, the contribution of each mechanism to LVSV variation could be evaluated. This comparison shows that the contribution by the parallel mechanism (28.9% variation) is roughly the same as that of the series mechanism (25.3% variation) (Table Experiment 2 (Results section) on Other mechanisms for production of pulsus paradoxus are quoted in various studies. Golinko, et al.  and RuskAnother theory is that inspiration during tamponade creates an increased pressure afterload ,48,50. SLarge-scale integrated models of the human cardiovascular and respiratory systems can provide a means of analyzing complicated problems associated with critical care medicine. Cardiac tamponade with pulsus paradoxus is only one example. Our H-CRS model has allowed us to dissect the problem into two aspects: 1) pericardial constraint modifying ventricular and septal mechanics, hence, lowering stroke volume, and 2) ventricular interaction relating to how respiration varies RV and LV stroke volume.RV. These effects prolong LPEP, reduce RV and LV ejection times, and thereby reduce stroke volume. Thus, with the aid of the model, we have been able to break down pericardial constraint into diastolic and systolic components. The diastolic effects are well known in literature, but our simulations suggest that the systolic effects come about because of AV interaction determining LV preload.Our model offers two explanations for lowered stroke volume seen in cardiac tamponade. They are independent effects of pericardial constraint, one occurring in diastole and the other occurring in systole. In diastole, pericardial constraint causes overall filling volume constraint, due to both ventricular constriction and AV interaction, which reduces the overall volume available from the atria. The reduction of filling volume contributes to a reduction in stroke volume. In systole, pericardial constraint causes reduced LV preload, resulting in abnormal septal movement in early systole and premature reduction in PRespiratory variation in stroke volume manifests itself as pulsus paradoxus, and we have identified parallel and series ventricular interactions as mechanistic explanations. Specifically, parallel interaction occurs with respiratory fluctuation of right heart inflow because of filling volume constraint (imposed by the septum and pericardium) and abnormal septal movement. These are both a direct result of AV interaction stemming from pericardial constraint. Likewise, respiration controls septal movement, favoring one heart over the other in systolic ejection. Series interaction exists due to the nature of the series blood pathway, but the magnitude of filling volume variation is exaggerated in tamponade due to lower stroke volumes. The end result of these multifaceted parallel and series interactions is a 180° phasic relationship between the ventricular end diastolic volumes. Importantly, we show both these interactions have an equal and significant contribution to LVSV respiratory variation, and hence to pulsus paradoxus.Our H-CRS model has the following impacts to the field of tamponade study:(a) It fully describes the clinical hemodynamic spectrum of tamponade including right heart signs, pulsus paradoxus, transvalvular flow variation at the cardiac inlets and outlets, and cardiac output compromise;(b) It introduces the concept that fluid pericardial pressure in tamponade directly modulates cardiac chamber dynamics in both diastole and systole;(c) It quantitatively dissects the exaggerated right-left ventricular interaction, atrioventricular interaction, and the pleural (respiratory) pressure-mediated hemodynamic changes that is characteristic of pulsus paradoxus in tamponade;(d) It introduces the concept that septal motion and septal characteristics directly affect ventricular interaction  It produces a full hemodynamic and respiratory analysis of tamponade which may serve as a roadmap for future study of pericardial diseases.R: reversal wave; AV: atrioventricular; PEP: pre-ejection period; SV: stroke volume; CO: cardiac output; HR: heart rate; MAP: mean arterial pressure; EDV: end-diastolic volume; RPEP: right ventricular pre-ejection period; LPEP: left ventricular pre-ejection period; RVSV: right ventricular stroke volume; LVSV: left ventricular stroke volume; RVET: right ventricular ejection time; LVET: left ventricular ejection time; λ: pericardial stiffness parameter; PRA: right atrial pressure; PLA: left atrial pressure; PRV: right ventricular pressure; PLV: left ventricular pressure; PPERI: pericardial pressure; PTPERI: transmural pericardial pressure; PPL: pleural pressure; PPA: pulmonary arterial pressure; PAO: aortic pressure; P0: pericardial pressure parameter; VRA: right atrial volume; VLA: left atrial volume; VRV: right ventricular volume; VLV: left ventricular volume; VPERI: pericardial volume; VH: total heart volume; V0: pericardial volume offset; VSPT: septal volume; QVC: vena cava flow; QPV: pulmonary venous flow; QTC: tricuspid flow; QM: mitral flow; QPA: pulmonary arterial flow; QAO: aortic flow; PO2: O2 partial pressure; PCO2: CO2 partial pressure; SO2: Percent O2 saturation; A-V: arterio-venous.H-CRS: human cardiovascular-respiratory system; P-V: pressure-volume; RA: right atrium; LA: left atrium; RV: right ventricle; LV: left ventricle; SPT: septum; PERI: pericardium; TCV: tricuspid valve; PAV: pulmonic  valve; MV: mitral valve; AOV: aortic valve; PO: pulmonic valve opening; PC: pulmonic valve closure; AO: aortic valve opening; AC: aortic valve closure; S: systole; D: diastole; AThe authors declare that they have no competing interests.DR carried out the tamponade modeling studies and drafted the manuscript. CL significantly contributed to the development of the human cardiopulmonary model and was involved in the analysis of data. TSM made substantial intellectual contributions to the study and in drafting of the manuscript. JWC made key contributions to the conception and design, analysis and interpretation of data, and drafting of the manuscript. All authors read and approved the final manuscript.


We present an unusual transient pro-arrhythmic effect of ajmaline in a patient with resuscitated cardiac arrest and a left ventricular apical aneurysm. We discuss the clinical presentation and the possible physio-pathological explanation for this new pro-arrhythmic effect linked to administration of intravenous ajmaline. Brugada syndrome (BrS) is a well-recognized arrhythmogenic disease associated with an increased risk of sudden death related to ventricular tachyarrhythmias or ventricular fibrillation . Sodium A potential pro-arrhythmic effect of class I drugs has been reported . AjmalinWe present the case of a 29 year-old man admitted to our hospital after a resuscitated cardiac arrest. His family history was negative for sudden cardiac death and channelopathies. His past medical history was unremarkable: the patient was completely asymptomatic and never complained of syncope or palpitations. Moreover, on clinical examination he didn't show any apparent abnormality. Electrocardiographic findings were completely normal. An exercise testing was clinically and electrically negative but rare isolated ventricular ectopic beats were documented during the test and in the recovery phase. For this reason the patient was planned for a 24 hour Holter ECG registration. In the afternoon following the exercise testing, during a small effort, the patient experienced cardiac arrest. In the emergency room, he was found to be in ventricular fibrillation. Four DC shocks and iv adrenaline and cardio-pulmonary reanimation maneuvers obtained restoration of vital signs and sinus rhythm. The ECG after resuscitation showed non-specific abnormalities of the repolarization in the infero-lateral leads . The patAt the end of the hospitalization, an ajmaline test was performed to exclude BrS. The ajmaline test (1mg/kg of body weight) was negative for BrS, but, after 0.7 mg/kg injection (49 mg complexively), we documented an accelerated idioventricular rhythm (AIVR) with a heart rate of 95 bpm . DiagnosTo the best of our knowledge, our case report is the first to describe an AIVR during ajmaline test in a patient with a resuscitated cardiac arrest and with a left ventricular apical aneurysm.AIVR is defined as 3 or more successive wide QRS beats at a rate close to the baseline rhythm, with a maximal difference of 10-15% and with a heart rate between 100 and 120 bpm. AIVR is found to be the most common reperfusion arrhythmia in pre-thrombolytic and thrombolytic era: it is usually well tolerated -8 and noto channels. Both therapeutic, toxic and proarrhythmic effects of all sodium channel blockers are manifested on the ECG by a different degree of PR and QRS prolongation [Ajmaline test is a well-recognized diagnostic tool used to unmask the electrocardiographic pattern of BrS in patients with resuscitated cardiac arrest or syncopes and in genetic carriers belonging to families affected by this pathology . Among tongation . One larongation  revealedOur case substantially differs from the latter for different reasons: 1) our patient had a negative ajmaline test; 2) echocardiography showed left apical ventricular aneurysm and 3) the arrhythmia related to the intravenous administration of ajmaline was an AIVR and not a VT. Triggered activity could be addressed as potential electrophysiological mechanism leading to the cited arrhythmia, seen the capability of ajmaline of inducing early afterdepolarizations in the Purkinje fibers . AnotherAjmaline-related AIVR has never been reported. In this case report AIVR was probably favored by the presence of a left ventricular apical aneurysm. Our case report postulates that ajmaline induced AIVR increasing triggered activity of Purkinje fibers or decreasing the conduction on the two fascicles of the left bundle branch, determining a slow macro-reentry in the left bundle branch. Further investigation is needed to define the mechanism underlying this finding.


Congestive heart failure as a consequence of ischemic heart disease is an increasing medical problem. Notwithstanding the huge advances in the medical and conventional surgical management of heart failure, eventual outcomes remain suboptimal. This 2 part article outlines the magnitude of the problem, the limitations of conventional therapies as they exist, and the use of newer procedures that directly address the restoration of ventricular pump function.The first part of the article deals with the pathology of different facets of the remodeling process, and the unique anatomy, geometry and flow dynamics as they pertain to ventricular function in the normal as well as the failing heart. It then details the limitations of conventional therapy, thereby laying the basis for the need and evolution of newer surgical procedures and ends with the selection of patients for ventricular restoration procedures and the pitfalls in the choice of patients for such newer techniques. Emergen2A.The geometric adaptations following acute MI constitute LV remodeling and are characterized by increases in LV end-diastolic and systolic volumes, wall thinning, increased sphericity and progressive worsening of cardiac function resulting in CHF ,5. VentrDilatation increases wall tension by Laplace's law. LV wall stress/tension is proportional to the radius and pressure within the LV chamber and inversely proportional to LV wall thickness. Increasing LV volume translates to increasing myocyte stress, which impedes effective contraction. The augmented wall stress results in increased oxygen consumption, decreased subendocardial blood flow and reduced systolic shortening. LV function may deteriorate toward cardiogenic shock in the early phase or may eventually lead to severe HF. Increased sphericity leads to MR. LV dilatation and MR are linked in a vicious cycle whereby MR causes dilation that in turn changes ventricular shape, thereby promoting MR. The sphere becomes a unifying geometric concept that arises from ischemia, valve insufficiency or myocyte disease.LV dilatation in ischemic cardiomyopathy falls into three categories:Dyskinetic aneurysms from extensive scar in the absence of reperfusion - The commonest cause of an LV aneurysm is acute occlusion of the LAD, with aneurysm formation in the anterior wall and septum. Development of a LVA leads to heart failure, VT and thromboembolic events.Akinetic extensively scarred regions following early reperfusion with epicardial salvage andAkinetic areas occurring late due to remote muscle dilation after early aneurysm formation - These patients have significantly dilated poorly contracting left ventricles but without massive scars.2B.Medical therapy acting against neurohumoral activation slows progression but fails to arrest remodeling. When LV volume has increased beyond a certain extent and the geometry is markedly abnormal, HF progresses independently of neurohumoral activation, according to the biomechanical model of HF expressed by Mann and Bristow .At some point in the natural history of the disease, a transition occurs that takes the disease beyond the limits of conventional medical or surgical therapy. The concept of a biomechanical model of HF introduces the need for procedures such as SVR that reduce LV volumes and restore geometry.2C.Ischemic cardiomyopathy [ICMPY] is characterized by inter and intraventricular conduction delay. Interventricular conduction delay produces RV-LV dyssynchrony. Electrical resynchronization improves LV performance by avoiding right ventricular septal displacement and limiting presystolic MR -12.LV dyssynchrony may involve different components of the LV mass to produce intraventricular dyssynchrony  Ischemic2D.Systolic lengthening occurs during the isovolumic phase and is caused by stretching of the ischemic/scarred segments by the adjacent normally contracting segments. Energy is expended as normal segments contract to produce pressure. The ischemic/scarred segment is unable to generate sufficient tension and thus passively bulges. The consequence is dissipation and wasting of energy produced by normal segments, which stretch the ischemic/scarred tissue and therefore does not contribute to ejection .Pressure volume loops show abnormalities in morphology, size and orientation. The most common abnormalities are early shortening and early relaxation, with markedly reduced effective work. Early shortening occurs because of the unloading effect of dyskinetic myocardium, which acts as an elastic slack element during isovolumic contraction . Within 2E.Remodeling involves concomitant neurohumoral activation, which is characterized by increased plasma norepinephrine [NE], renin (PRA) , angiote3.2. The hallmark insight into the importance of using ventricular volume rather than EF to prognosticate post MI survival comes from White’s . This approach to HF has been considered the ‘triple V’ since the operation corrects the abnormal vascular, valvular and ventricular components of the heart failure process.12.In the recent update of the European Society of Cardiology Guidelines for the diagnosis and treatment of chronic heart failure, LV aneurysmectomy is indicated in patients with large, discrete LV aneurysms who develop heart failure.SVR as described by Dor and associates, was developed as a more physiologic repair of LV aneurysm, compared with simple linear repair, but was later applied to ischemic cardiomyopathy without the classic signs of the true aneurysm.Dor demonstrated that equivalent results could be achieved with SVR even in patients without discrete ventricular aneurysms.Dor  recogniz13.Indications for SVR include:Refractory heart failure in NYHA class III or IVA left ventricle diastolic dimension > 75 mm.2LVESVI>60ml/m2LVEDVI>100ml/mPrevious anterior MI.LV dysfunction with regional asynergy (either akinetic or dyskinetic) greater than 35% of the ventricular perimeter.Ventricular arrhythmias and/or angina.For patients who are asymptomatic despite post-infarction LV dysfunction, serial echocardiographic studies could be performed to detect the first signs of deterioration .14. The following are contraindications:Severe right ventricular dysfunction (absolute)Severe pulmonary hypertension not associated with MR (relative).Severe regional asynergy without LV dilatation (absolute).Restrictive diastolic pattern associated with high functional class and MR (absolute).An entirely akinetic LV with no increase in systolic wall thicknessReduced EF is not a contraindication, but an increased use of IABP should be anticipated. With severe and diffuse cardiac dysfunction, a stress dobutamine stress echo could be performed. SVR is offered if contractility improves.15.Studies have shown that SVR can benefit patients with severe left ventricular dysfunction (EF <20%), multiterritory MI, and pulmonary hypertension [PHTN], which were previously considered to be contraindications to SVR  - 53. ThSVR has also been offered to patients with multiterritory MI. A critical amount of viable myocardium is considered necessary for a successful outcome regardless of the location of infarction. For instance, patients with < 50% involvement of the lateral wall showed similar improvements in cardiac function and survival when compared with those without lateral wall MI’s. When lateral wall involvement exceeded 50%, there were differences in clinical outcomes .PHTN has been shown to be a predictor of death in patients with ischemic cardiomyopathy. However, improved LV function after SVR reduces the load on the pulmonary vasculature, and lowers pulmonary resistance and pressures.A consideration of the real world application of ventricular restoration procedures reveals that the overall results do not match those seen in large volume centres of expertise, and consequently the premature expansion of such indications outwith such centres of expertise could be potentially detrimental and may not yield equivalent outcomes in borderline patients.


True emergencies due to unstable arrhythmias in children are rare, as most rhythm disturbances in this age group are well-tolerated. However, presentation to an emergency department with symptoms of palpitations, fatigue and/or syncope is much more common. Sinus tachycardia is by far the most commonly reported arrhythmia, followed by supraventricular tachycardia. Emergency physicians should be prepared for diagnosis and to acutely manage various types of arrhythmias seen in children, to assess the need for further diagnostic testing, and to determine whether cardiology evaluation and follow-up are needed. This article is intended to provide diagnostic and management guidelines of the most common types of arrhythmias seen in children with structurally normal hearts as well as those associated with congenital heart disease and cardiomyopathies. True emergencies due to unstable arrhythmias in children are rare, as most rhythm disturbances in this age group are well-tolerated. However, presentation to an emergency department with symptoms of palpitations, fatigue and/or syncope is much more common. Pediatric arrhythmias account for approximately 55.1 per 100,000 patients evaluated in pediatric emergency departments. Sinus tachycardia is by far the most commonly reported arrhythmia, followed by supraventricular tachycardia (SVT) which represents about 13%, and bradycardia accounting for about 6% of all cases. and manaNarrow complex tachycardia refers to any arrhythmia that originates above or at the bundle of His. These are by far the most common tachycardias seen in children, with an estimated incidence of 0.1–0.4%. Three meantidromic tachycardia reverses the direction of conduction, with transmission down the accessory pathway and up the AV node, creating a widened QRS complex, which will be discussed under wide complex tachycardias. Once normal sinus rhythm is re-established, 50% of patients manifest ventricular pre-excitation in the form of a delta wave on electrocardiogram, consistent with Wolf-Parkinson-White syndrome (WPW); the remainder of patients have a “concealed” pathway that is not evident during sinus rhythm. The only difference between the two forms is the presence of manifest antegrade conduction to the ventricle in WPW. Because conduction through the pathway can occur before the AV node is activated, a shortened PR interval slurred QRS upstroke and widensed QRS result [This is also known as accessory-pathway mediated tachycardia or orthodromic reciprocating tachycardia, and is by far the most common type of SVT seen in children, representing 82% of arrhythmias occurring during infancy. AVRT invS result . This alThis is also is due to a re-entry circuit but with pathways that involve the AV node. In this tachycardia, there are also two discrete conduction limbs, a “slow” pathway which usually conducts antegrade, and a so-called “fast” pathway which usually conducts retrograde. This accounts for ~15% of SVT in the pediatric age group, increases with age, and is rarely seen in infants. These twHistory of poor feeding, lethargy, irritability, pallor in infants;Historyof palpitation, dizziness, chest pain, syncope and shortness of breath in older children and adolescents;Signs and symptoms of congestive heart failure in some infants andHistory of abrupt onset and termination.These are presented in HeartRates >220 in infants and >180 in children;Narrow QRS complex andAV ratio 1:1In AVNRT, terminal QRS notching ± visible.In AVRT, inverted P waves ± visible.Attempt vagal maneuver ;if unsuccessful, give adenosine 100 mcg/kg rapid bolus, increase the dose and repeat as needed;Synchronized DC cardioversion if adenosine is unsuccessful, starting at 0.5J/kg andIntravenous amiodarone alternative in experienced hands.Once normal sinus rhythm is established, repeat electrocardiogram to rule out pre-excitation and underlying cardiac disease.Laboratory work-up: serum electrolytes, thyroid function tests and complete blood count.All patients under 1 year of age and those with hemodynamically unstable SVT should be admitted for observation. Patients with first time episode and normal hearts should be observed overnight, without treatment. In patients with known structural heart disease, therapy is recommended on an individualized basis. If patient is discharged, provide instruction on vagal maneuvers to treat recurrence, as well as a list of indications to seek medical attention.Initiation of maintenance therapy would depend on patient age and severity of symptoms and recurrence, and should be discussed with cardiologist.Cardiology follow-up is recommended for all new patients. Provide a copy of EKGs to the parents, to be brought during their visit.Infants with suspected prolonged episodes should have echocardiography to rule out thrombus and ventricular dysfunction. Otherwise, echocardiogram may be obtained during cardiology evaluation to rule out underlying heart disease.Of note, patients found to have asymptomatic pre-excitation on EKG should also be referred for cardiology evaluation.The probability of complete resolution of SVT is dependent on age of onset. In the majority of infants diagnosed at 1 year of age or less, SVT is likely to resolve, compared to only 33% of patients diagnosed after 1 year of age. MaintenaIn children, atrial flutter usually occurs in fetal life or shortly following birth. It is rarely seen beyond the newborn period except in the setting of underlying congenital heart disease and cardiac surgery, where it is most common in children who have undergone Fontan procedures, atrial septal closure and tetralogy of Fallot (TOF) repair. Congenital heart disease and post-operative patients represent about 80% of older children presenting with atrial flutter. It accouin-utero during fetal ultrasound evaluation;Diagnosed Fetal hydrops common if prolonged;Most newborns are asymptomatic unless tachycardic>48hours;Infants with prolonged tachycardia may present with history of poor feeding, irritability, lethargy, diaphoresis and pallor andOlder children may complain of palpitations, chest pain and/or dizziness.The findings are presented in Regular atrial rates of 240–360 bpm;AV ratio >1:1, variable but generally regular, ventricular rate 120–240;Typical sawtooth appearance may be seen in lead II, III and aVF andNormal appearing QRS complex.Vagal maneuvers or adenosine do not convert this rhythm but may increase the degree of AV block, unmasking underlying flutter waves.If patient has rapid ventricular response with reduced cardiac output, or for elective cardioversion, use DC cardioversion starting at 0.5J/kg, increasing to 1–2J/kg if needed.If stable, pharmacotherapy can be aimed at rhythm control with IV amiodarone or ibutilide, or at rate control with beta-blockers or calcium-channel blockers.In patients with pacemaker, pace termination can be attempted by the cardiologist.Laboratory work-up: serum electrolytes and thyroid function tests;Cardiology consultation and echocardiogram to rule underlying structural heart disease, tachycardia-mediated cardiomyopathy and thrombus;Admit for observation andAnticoagulation therapy for episodes >48 hours and in all Fontan patients.In the presence of a structurally normal heart, the risk of recurrence of neonatal atrial flutter is low and no long-term therapy is needed. In cases of structurally abnormal heart and/or recurrent atrial flutter, long-term therapy may be required. Management is directed at either rhythm control with agents such as amiodarone and flecainide, or control of ventricular response with digoxin, calcium channel blockers or beta-blockers in selected patients. Catheter ablation can be highly successful in the older child.Ectopic atrial tachycardia is uncommon, accounting for about 10% of SVT in children. It is duIs predominantly observed in infants and children with structurally normal hearts.Patients present with symptoms of chest pain, palpitations, pre-syncopal or syncopal events. Older children may present with exercise intolerance or be asymptomatic.Infants may present with feeding difficulties, diaphoresis with feeds or in respiratory distress secondary to chronic tachycardia.These are shown in Atrial rate that is inappropriately rapid for age. Sometimes difficult to distinguish from sinus tachycardia;Abnormal P wave morphology and axis;Atrial rate variable, ranging from 120 to 300 bpm;May exhibit a “warm up” period at initiation with progressive P-P interval shortening and a “cooling down” period prior to termination and>1:1 AV conduction can be seen in patients at rest or while asleep without termination of the tachycardia.Responds poorly to adenosine and DC cardioversion.First line treatment for symptomatic patients includes IV amiodarone. Load with 5mg/kg bolus over 20–60 minutes.Can be followed by amiodarone maintenance drip at 10–15mg/kg/day.Minimally symptomatic patients do not require acute treatment.Laboratory work-up: serum electrolytes, complete blood count, toxicology screen. If cardiac function is poor, additional laboratory evaluation should include viral panel, blood culture and cardiac enzymes to help differentiate infection versus tachycardia-induced cardiomyopathy.Cardiology consultation and echocardiographic evaluation is recommended.Obtain 24-hour cardiac monitor to determine duration of tachycardia and ventricular rates.Treatment is dependent on patient age, symptoms, clinical status, tachycardia rate and duration, and ventricular function.Asymptomatic patients can be treated conservatively.Children younger than 1 year and symptomatic patients should be admitted for management of arrhythmia and congestive heart failure. In the setting of normal cardiac function, beta-blockers can be useful by slowing AV node conduction, lowering the ventricular rate and improving symptoms.More aggressive treatment consists of flecainide, amiodarone or sotalol which have moderate success rates. Patients who fail medical therapy can undergo catheter ablation.Spontaneous resolution may be observed in 30–50% of affected children. ChildrenAtrial fibrillation is mostly seen in children with underlying structural heart disease and in those who have undergone cardiac surgery. In infants and children with structurally normal hearts, atrial fibrillation is often associated with an AV accessory connection such as WPW. These patients can be at increased risk of sudden death if there is rapid conduction to the ventricle via a manifest accessory pathway. Atrial fibrillation can also be associated with cardiomyopathies, myocarditis, pericarditis and hyperthyroidism, and in rare instances has a genetic predisposition. The mechanism involves multiple reentry circuits predominantly within the left atrium. Patients are usually symptomatic at presentation and in the setting of rapid ventricular rates, hypotension and syncope may ensue. As in adults, the possibility of atrial thrombus with the risk of embolic stroke is of great concern.Children and adolescents present with complaints of palpitations. Weakness and signs of congestive heart failure may be seen.In patients presenting with syncope, WPW should be highly suspected.Chaotic/irregular atrial waves best seen in lead V1;Atrial rates of 350–600 bpm;No discrete, uniform P waves;AV ratio >1:1;Variable, changing ventricular response rate (irregularly irregular), ranging from 110 to 200 bpm andNormal appearing QRS complex, except in WPW.If the patient has rapid ventricular response with reduced cardiac output, DC cardioversion starting at 2J/kg is used.For stable patients, pharmacotherapy aimed at ventricular rhythm or rate control can be used. IV rhythm control agents include amiodarone and ibutilide. Less effective are sotalol, digoxin and procainimide.Cardioversion in stable patients with unknown or prolonged (>48 hours) duration of tachycardia should be delayed until assessment for atrial thrombus is made with echocardiography.Once in normal sinus rhythm, repeat EKG.Laboratory work-up: serum electrolytes, thyroid function, complete blood count, toxicology screen. If cardiomyopathy is suspected, additional laboratory evaluation should include viral panel, blood culture and cardiac enzymes.Echocardiography is indicated in all cases.Admit for observation and treatment.Initiate anticoagulation therapy in most cases.Despite medical therapy, atrial fibrillation has a high recurrence rate and often requires catheter or surgical intervention. Chronic anticoagulation therapy is indicated in patients with persistent or recurrent atrial fibrillation. Ablation of the AV node with implantation of a pacemaker may be necessary in some refractory cases.Although less common in children than in adults, wide complex tachycardia still occurs with some frequency. As outlined in VT is a potentially life-threatening arrhythmia recognized as a cause of sudden death in both adults and pediatrics. It is rare in children and accounts for about 6% of patients followed for tachycardias. Defined Variable, may present with symptoms ranging from dizziness and palpitations to syncope and cardiac arrest.Hallmarks are prolonged QRS duration for age and VA dissociation with ventricular rates exceeding atrial rates (AV ratio < 1:1).Rates range from ~110 to >200 bpm.When VA conduction is 1:1, VT cannot be excluded. Features consistent with the diagnosis of VT rather than SVT with a wide QRS include variation in RR interval and presence of fusion complexes.Complexes may appear uniform or vary from beat to beat as in polymorphic VT.If unstable, synchronized cardioversionis started at 2J/kg and repeated, increasing the dose if needed.If stable, may attempt amiodarone at 5mg/kg IV over 30–60 minutes or procainimide at 15mg/kg IV over 30–60 minutes.History should focus on prior symptoms, symptoms suggestive of myocarditis or long-standing cardiomyopathy, and the possibility of drug toxicity, as well as a thorough family history for known arrhythmias or history of sudden death.Once in normal sinus rhythm, repeat EKG to rule out underlying abnormalities including long QT, Brugada, arrhythmogenic right ventricular cardiomyopathy, structural heart disease, electrolyte abnormalities and ischemia.Laboratory work-up should include toxicology screen, serum electrolytes, complete blood count, viral panel, blood culture and cardiac enzymes.Cardiac consultation and echocardiographic evaluation are done to rule underlying structural heart disease, cardiomyopathy, cardiac tumors.Admit for observation.After cardioversion, return to sinus rhythm may be transient and continual infusion of amiodarone may be required.In the setting of a structurally normal heart and stable, well-tolerated monomorphic VT, many minimally symptomatic patients can be followed closely without therapy. Such patients may benefit from B-blockers to reduce ectopy. Chronic treatment otherwise depends on rate, duration, symptoms, type of VT and the presence of genetic channelopathy such as long QT. Aggressive antiarrhythmic therapy usually in addition to implantable cardioverterdefribrillator (ICD) placement is required for life-threatening VT.The congenital long QT syndrome is a genetic disorder of prolonged cardiac repolarization that may cause cardiac arrest and sudden death. Abnormalities in cardiac ion channels predispose patients to a characteristic polymorphic VT called “torsades de pointes”. Events are often precipitated by adrenergic stimuli. Acquired long QT may also occur and can be caused by drugs, underlying medical conditions or electrolyte imbalances.Patients may present with presyncope, syncope, seizures, or cardiac arrest.Precipitating factors may include exercise, especially swimming, emotional stress, exposure to loud noises or even sleep.Although rare, infants can present with poor feeding, or with episodes of lethargy, cyanosis or poor perfusion.Sinus rhythm ECG, QTc of >460 in post-pubertal females and 450 in others, best obtained from lead II .Borderline QTc>440 ms in the setting of clinical symptoms and/or family history should be investigated.Abnormal T wave morphology including notching and low amplitude.Torsade de pointes seen during events.torsades de pointes, perform emergent defibrillation followed by administration of magnesium sulfate and possibly lidocaine.For Correct underlying problem if acquired long QT.Intravenous beta-blockade may calm an adrenergic storm.Obtain thorough family history of rhythm abnormalities, sudden death, deafness.Ascertain all medications.Review history of event that may have triggered arrhythmia.Obtain electrolytes and treat underlying abnormalities.If presented with symptoms or documented VT, admit for observation, cardiology consultation and treatment.For patients presenting with non-cardiac issues and noted to have abnormal QTc interval, out-patient cardiology follow-up may be arranged.Restrict all strenuous activity pending cardiology follow-up.Provide list to the patients of medications known to prolong QT that should be avoided.Immediate family members should also be screened with 12-lead EKGs.Prognosis is poor in untreated symptomatic patients, with an annual mortality of 20%. B-blockers are the mainstream therapy and reduce risk of sudden death to about 6% annually but do not eliminate it completely. High risPatients with congenital heart disease are at lifelong risk for the development of arrhythmias. Types of arrhythmias depend on the underlying cardiac anomaly and more importantly on the surgical repair, and can range from atrial flutter to ventricular fibrillation. See  ED managVentricular septal defects (VSD), by far the most common congenital heart defect, are not generally associated with rhythm abnormalities. In the present era, clinically significant VSDs are repaired in early childhood, decreasing the incidence of arrhythmias. By avoiding right ventriculotomies, newer surgical approaches have significantly altered the incidence of ventricular arrhythmias. Operated patients, however, remain at an increased risk for developing heart block, even late after repair. The presence of a small, hemodynamically insignificant VSD does not increase the risk of arrhythmia.Atrial septal defect (ASD) occurs in 5–10% of all congenital heart defects and is found in 30–50% of children with other types of congenital heart disease as well. In largeet al. found an incidence of 2–6% of arrest or sudden late death in patients repaired during infancy.[et al, assessing risk factors for VT and sudden death in TOF patients found that QRS duration of >180ms, an increasing QRS duration, older age of repair, and/or presence of right ventricular patch were associated with increased risk of arrhythmia.Tetralogy of Fallot (TOF) is the most common cyanotic heart disease, representing 3.5–9% of patients with CHD. Arrhythm infancy. Although infancy. Sinus no infancy. A large The so-called “congenitally corrected” or L-transposition of the great arteries is rare, estimated to occur in 1% of all patients with congenital heart disease, but risk of arrhythmia is high. In this condition, the right atrium is attached to the left ventricle which empties to the pulmonary artery, and the left atrium enters the right ventricle and thus into the aorta. The incidence of spontaneous complete heart block has been reported to be as high as 22% owing to intrinsic abnormalities of the His bundle.D-transposition of the great arteries (right ventricular connection to aorta and left ventricular connection to pulmonary artery) is much more common, and was a uniformly lethal disease prior to corrective surgery. With current surgical techniques, arrhythmia risk is relatively low. During outpatient follow-up, Rhodes and colleagues found an incidence of 4.4% of some form of AV block. SVT was seen in 5%, whereas almost half of the patients showed evidence of ventricular arrhythmias, mostly isolated premature beats, 6–12 months following repair.Ebstein’s anomaly is a very rare condition in which the tricuspid valve leaflets have an abnormal attachment causing displacement of the valve into the right ventricle, so called “atrialized” ventricle. Patients are at increased risk for the development of SVT, with an incidence as high as 42%. In the sCardiomyopathies are a group of disorders of intrinsic muscle disease. These patients are at increased risk for atrial and VTs. Treatment can be challenging and ICD implant is being used increasingly in these populations.Patients with hypertrophic cardiomyopathy (HCM) are at increased risk of malignant VT and sudden death. Multiple risk factors have been implicated, including family history of sudden death, history of syncope, dramatic septal thickness, non-sustained VT and inappropriate blood pressure response to exercise. Death is often sudden and usually occurs in the setting of vigorous exertion with an annual incidence of 3–5% in children and adolescents with HCM. Current Dilated cardiomyopathy (DCM) is the most common severe cardiomyopathy, accounting for more than 50% of pediatric cases. EtiologyMyocarditis, a common precursor to DCM, may present with sudden death. Although the exact incidence of arrhythmias associated with myocarditis is unknown, VTs and high-degree AV block are not uncommon .Arrythmogenic right ventricular dysplasia (ARVD) is a genetic myopathy involving fibrofatty degeneration of the right ventricle and is commonly associated with VT and sudden death. Inheritance is mainly autosomal dominant but sporadic cases have been described. Peak age of presentation is late teenage years to the 20s, and a common presenting symptom is syncope with exercise. Electrocardiographic findings include right ventricular conduction delay, inverted T waves in the right precordial leads inappropriate for age and PVCs of right ventricular morphology. Treatment usually involves ICD implantation.Bradycardias are a group of disorders that include sinus node dysfunction and abnormal conduction through the AV node. AV conduction abnormalities include first-, second- or third-degree heart block. First-degree heart block, prolongation of PR interval without loss of conduction, does not cause bradycardia or hemodynamic instability and is primarily of interest as a marker for an underlying cause. Causes of first-degree block are numerous and include enhanced vagal tone, previous cardiac surgeries, myopathies, and infections including Lyme disease, myocarditis, endocarditis and hypothyroidism.Sinus bradycardia can result from multiple disease states, most of which are not primary cardiac. The exception is sinus node dysfunction, an abnormality of impulse generation and propagation of the sinus node usually caused in pediatrics by direct injury or disruption of blood supply to the node from previous cardiac surgery. Associated atrial reentry tachycardias are common and when they occur, the term “brady-tachy syndrome” is applied. Etiology of sinus bradycardia other than congenital heart disease is diverse and includes increased intracranial pressure, electrolyte abnormalities, respiratory compromise, hypothyroidism and certain medications. The need for acute treatment for sinus bradycardia itself is rare. The presence of sinus bradycardia in an otherwise healthy appearing child is generally of no concern, although anorexia nervosa should be considered. In the moribund patient with sinus bradycardia, urgent determination of the underlying cause is of paramount importance. Atropine and epinephrine increases sinus rates in most patients. Symptomatic patients with true sinus node dysfunction and/or those with coexistent tachycardias are likely to require elective pacemaker implantation.Second-degree heart block refers to intermittent failure of conduction through the AV node. It is further subdivided into Mobitz type I (Wenkebach), a gradual PR interval prolongation followed by a nonconducted beat, and Mobitz type II, an abrupt loss of conduction without previous change in PR interval duration. Mobitz type I is generally more benign and may be a normal finding in adolescents during sleep. Other causes are similar to those described for first-degree heart block. Treatment is aimed at underlying reversible causes. Progression to higher degree block has been reported and symptomatic patients may benefit from treatment with atropine or isoproterenol. Mobitz type II is thought to be more likely to progress to complete heart block. Elective pacemaker implantation has been advised for symptomatic patients in this group.Third degree AV block is the absence of conduction from the atria to the ventricle, manifested by AV dissociation. QRS duration of the escape rhythm may be normal or prolonged. Third-degree block can be congenital, mainly associated with maternal collagen vascular disease or congenital heart disease, or acquired, due to AV node injury from cardiac surgery, viral myocarditis, Lyme disease, or metabolic or neuromuscular disorders. Many children are asymptomatic when diagnosed. In infancy, symptomatic patients may appear severely ill at presentation. Older children and adolescents may present with symptoms of exercise intolerance, fatigue, dizziness, syncope or signs of congestive heart failure. Sudden death may occur. Most patients eventually require pacemaker implantation, unless the cause is reversible such as in Lyme disease, where temporary pacing may suffice.Proper diagnosis and management of the diverse rhythm disturbances in children is challenging. Emergency healthcare providers must be comfortable in performing a systematic evaluation and interpretation of ECG findings. An understanding of the variety of diseases that can predispose children with normal hearts or with structural heart disease to arrhythmias is essential for appropriate treatment.