Showing papers on "Ventricle published in 2016"

Contemporary management of acute right ventricular failure: a statement from the Heart Failure Association and the Working Group on Pulmonary Circulation and Right Ventricular Function of the European Society of Cardiology

Abstract: Acute right ventricular (RV) failure is a complex clinical syndrome that results from many causes. Research efforts have disproportionately focused on the failing left ventricle, but recently the need has been recognized to achieve a more comprehensive understanding of RV anatomy, physiology, and pathophysiology, and of management approaches. Right ventricular mechanics and function are altered in the setting of either pressure overload or volume overload. Failure may also result from a primary reduction of myocardial contractility owing to ischaemia, cardiomyopathy, or arrhythmia. Dysfunction leads to impaired RV filling and increased right atrial pressures. As dysfunction progresses to overt RV failure, the RV chamber becomes more spherical and tricuspid regurgitation is aggravated, a cascade leading to increasing venous congestion. Ventricular interdependence results in impaired left ventricular filling, a decrease in left ventricular stroke volume, and ultimately low cardiac output and cardiogenic shock. Identification and treatment of the underlying cause of RV failure, such as acute pulmonary embolism, acute respiratory distress syndrome, acute decompensation of chronic pulmonary hypertension, RV infarction, or arrhythmia, is the primary management strategy. Judicious fluid management, use of inotropes and vasopressors, assist devices, and a strategy focusing on RV protection for mechanical ventilation if required all play a role in the clinical care of these patients. Future research should aim to address the remaining areas of uncertainty which result from the complexity of RV haemodynamics and lack of conclusive evidence regarding RV-specific treatment approaches.

Nonischemic Left Ventricular Scar as a Substrate of Life-Threatening Ventricular Arrhythmias and Sudden Cardiac Death in Competitive Athletes

Abstract: Background— The clinical profile and arrhythmic outcome of competitive athletes with isolated nonischemic left ventricular (LV) scar as evidenced by contrast-enhanced cardiac magnetic resonance remain to be elucidated. Methods and Results— We compared 35 athletes (80% men, age: 14–48 years) with ventricular arrhythmias and isolated LV subepicardial/midmyocardial late gadolinium enhancement (LGE) on contrast-enhanced cardiac magnetic resonance (group A) with 38 athletes with ventricular arrhythmias and no LGE (group B) and 40 healthy control athletes (group C). A stria LGE pattern with subepicardial/midmyocardial distribution, mostly involving the lateral LV wall, was found in 27 (77%) of group A versus 0 controls (group C; P <0.001), whereas a spotty pattern of LGE localized at the junction of the right ventricle to the septum was respectively observed in 11 (31%) versus 10 (25%; P =0.52). All athletes with stria pattern showed ventricular arrhythmias with a predominant right bundle branch block morphology, 13 of 27 (48%) showed ECG repolarization abnormalities, and 5 of 27 (19%) showed echocardiographic hypokinesis of the lateral LV wall. The majority of athletes with no or spotty LGE pattern had ventricular arrhythmias with a predominant left bundle branch block morphology and no ECG or echocardiographic abnormalities. During a follow-up of 38±25 months, 6 of 27 (22%) athletes with stria pattern experienced malignant arrhythmic events such as appropriate implantable cardiac defibrillator shock (n=4), sustained ventricular tachycardia (n=1), or sudden death (n=1), compared with none of athletes with no or LGE spotty pattern and controls. Conclusions— Isolated nonischemic LV LGE with a stria pattern may be associated with life-threatening arrhythmias and sudden death in the athlete. Because of its subepicardial/midmyocardial location, LV scar is often not detected by echocardiography.

Multidisciplinary Pulmonary Embolism Response Teams.

Abstract: A 67-year-old man with no previous medical history presented to the emergency department with 5 days of insidious, progressive dyspnea and chest congestion. On physical examination, he was found to be tachycardic to 126 beats/min, borderline hypotensive with blood pressure of 95/50 mm Hg, and hypoxemic to 87% on 4 L of oxygen by nasal cannula. He underwent contrast-enhanced chest computed tomogram that demonstrated a bilateral pulmonary embolism (PE) (Figure 1). Urgent bedside echocardiography demonstrated a severely dilated and hypokinetic right ventricle, interventricular septal flattening, and a serpiginous mobile mass (clot-in-transit) in the right atrium, prolapsing across the tricuspid valve with each cardiac cycle (Figure 2 and online-only Data Supplement Movie). The emergency department team discussed administering systemic fibrinolytic therapy, but also considered consulting Cardiothoracic Surgery for possible surgical pulmonary embolectomy and Interventional Cardiology for catheter-directed therapy. The emergency department attending physician decided to activate the hospital’s newly instituted multidisciplinary PE response team through the page operator. Within 30 minutes, a team consisting of representatives from Vascular Medicine, Interventional Cardiology, Cardiothoracic Surgery, Pulmonology, Echocardiography, and Radiology convened to evaluate the patient’s case and review the imaging studies. Figure 1. Axial image from a contrast-enhanced chest computed tomogram showing significant right and left main pulmonary artery filling defects (arrows). Figure 2. The transthoracic echocardiogram, apical 4-chamber view, at end diastole shows dilatation of the right ventricle and a serpiginous intracardiac mass (arrow) in the right atrium, prolapsing across the tricuspid valve into the right ventricle. Please also see the online-only Data Supplement Movie. PE is a prevalent and potentially life-threatening cardiovascular condition that may be difficult to diagnose. It has protean and often nonspecific manifestations. It is the third most common cardiovascular cause of death in the United States, and yet, in comparison with ischemic heart disease, does not enjoy a similar robust clinical trial …

Intercellular Adhesion Molecule 1 Regulates Left Ventricular Leukocyte Infiltration, Cardiac Remodeling, and Function in Pressure Overload–Induced Heart Failure

Abstract: Background Left ventricular dysfunction and heart failure are strongly associated in humans with increased circulating levels of proinflammatory cytokines, T cells, and soluble intercellular cell adhesion molecule 1 (ICAM1). In mice, infiltration of T cells into the left ventricle contributes to pathological cardiac remodeling, but the mechanisms regulating their recruitment to the heart are unclear. We hypothesized that ICAM1 regulates cardiac inflammation and pathological cardiac remodeling by mediating left ventricular T‐cell recruitment and thus contributing to cardiac dysfunction and heart failure. Methods and Results In a mouse model of pressure overload–induced heart failure, intramyocardial endothelial ICAM1 increased within 48 hours in response to thoracic aortic constriction and remained upregulated as heart failure progressed. ICAM1‐deficient mice had decreased T‐cell and proinflammatory monocyte infiltration in the left ventricle in response to thoracic aortic constriction, despite having numbers of circulating T cells and activated T cells in the heart‐draining lymph nodes that were similar to those of wild‐type mice. ICAM1‐deficient mice did not develop cardiac fibrosis or systolic and diastolic dysfunction in response to thoracic aortic constriction. Exploration of the mechanisms regulating ICAM1 expression revealed that endothelial ICAM1 upregulation and T‐cell infiltration were not mediated by endothelial mineralocorticoid receptor signaling, as demonstrated in thoracic aortic constriction studies in mice with endothelial mineralocorticoid receptor deficiency, but rather were induced by the cardiac cytokines interleukin 1β and 6. Conclusions ICAM1 regulates pathological cardiac remodeling by mediating proinflammatory leukocyte infiltration in the left ventricle and cardiac fibrosis and dysfunction and thus represents a novel target for treatment of heart failure.

Myocardial oedema in acute myocarditis detected by echocardiographic 2D myocardial deformation analysis

Abstract: Aims The clinical diagnosis of acute myocarditis is based on symptoms, electrocardiography, elevated myocardial necrosis biomarkers, and echocardiography. Often, conventional echocardiography reveals no obvious changes in global cardiac function and therefore has limited diagnostic value. Myocardial deformation imaging by echocardiography is an evolving method used to characterize quantitatively longitudinal systolic function, which may be affected in acute myocarditis. The aim of our study was to assess the utility of echocardiographic deformation imaging of the left ventricle in patients with diagnosed acute myocarditis in whom cardiovascular magnetic resonance (CMR) evaluation was performed. Methods and results We included 28 consecutive patients (mean age 32 ± 13 years) with CMR-verified diagnosis of acute myocarditis according to the Lake Louise criteria. Cardiac function was evaluated by a comprehensive assessment of left ventricular (LV) function, including 2D speckle-tracking echocardiography. We found no significant correlation between the peak values of cardiac enzymes and the amount of myocardial oedema assessed by CMR (troponin: r = 0.3; P = 0.05 and CK-MB: r = 0.1; P = 0.3). We found a larger amount of myocardial oedema in the basal part of the left ventricle [American Heart Association (AHA) segments 1–6] in inferolateral and inferior segments, compared with the anterior, anterolateral, anteroseptal, and inferoseptal segments. In the mid LV segments (AHA segments 7–12), this was more pronounced in the anterior, anterolateral, and inferolateral segments. Among conventional echocardiographic parameters, LV function was not found to correlate with the amount of myocardial oedema of the left ventricle. In contrast, we found the wall motion score index to be significantly correlated with the amount of myocardial oedema, but this correlation was only present in patients with an extensive amount of oedema (>11% of the total left ventricle). Global longitudinal systolic myocardial strain correlated significantly with the amount of oedema ( r = 0.65; P < 0.001). We found that both the epicardial longitudinal and the endocardial longitudinal systolic strains were significantly correlated with oedema ( r = 0.55; P = 0.003 and r = 0.54; P < 0.001). Conclusion In patients with acute myocarditis, 2D speckle-tracking echocardiography was a useful tool in the diagnostic process of acute myocarditis. Global longitudinal strain adds important information that can support clinical and conventional echocardiographic evaluation, especially in patients with preserved LV ejection fraction in relation to the diagnosis and degree of myocardial dysfunction.

Right Ventricular Contractile Reserve and Pulmonary Circulation Uncoupling During Exercise Challenge in Heart Failure: Pathophysiology and Clinical Phenotypes

Abstract: Objectives Right ventricular (RV) exercise contractile reserve (RVECR), its phenotypes, and its functional correlates are among the unresolved issues with regard to the role of the right ventricle in heart failure (HF) syndrome, and understanding these issues constitutes the objective of this study Background Although the role of the right ventricle in HF syndrome might be fundamental, the pathophysiology of the failing right ventricle has not been extensively investigated Methods Ninety-seven patients with HF (mean age 64 years, 70% men, mean left ventricular ejection fraction 33 ± 10%) underwent maximal exercise stress echocardiographic and cardiopulmonary exercise testing RVECR and RV–to–pulmonary circulation (PC) coupling were assessed using the length-force relationship (tricuspid annular plane systolic excursion [TAPSE] vs pulmonary artery systolic pressure) and the slope of mean pulmonary artery pressure versus cardiac output On the basis of TAPSE, patients were categorized into 3 groups: those with TAPSE at rest ≥16 mm (group A, n = 60) and those with TAPSE at rest Results Although they had similar left ventricular ejection fractions and rest RV impairment, compared with patients in group C, those in group B showed some degree of RVECR (upward shift of the length-force relationship), better RV-to-PC coupling (lower mean pulmonary artery pressure vs cardiac output slope), and greater ventilatory efficiency (lower slope of minute ventilation to carbon dioxide output) Rest mitral regurgitation and net changes in pulmonary artery systolic pressure were the variables retained in the best regression model as correlates of RVECR Conclusions In patients with HF, RVECR unmasks different phenotypes Impaired RV function at rest might not invariably lead to unfavorable RVECR and exercise RV-to-PC coupling Testing these variables appears useful even in more advanced stages of HF to define various clinical conditions and, most likely, to define different levels of risk

Left ventricular global systolic function assessment by echocardiography.

Abstract: The left ventricle, with its thickened myocardial walls, unlike the right ventricle has no measurable geometric shape. It has a conical apex and its function quantification, needs intensive, 2D, 3D and M mode transesophageal echocardiography, which is described in this review.

Computed tomography for planning transcatheter tricuspid valve therapy

Abstract: Aims Percutaneous transcatheter tricuspid valve therapy is an evolving treatment option for patients with significant tricuspid regurgitation (TR) deemed too fragile for open heart surgery. The present study proposes comprehensive anatomical evaluation of the tricuspid valve, right ventricle (RV), and vena cavae and its spatial relationships with the right coronary artery (RCA) using computed tomography (CT) and investigates the implications for suitability for current technologies. Methods and results A total of 250 patients (mean age 80 ± 7.2 years, 52.4% men) undergoing CT were divided according to the presence of moderate or severe TR (≥3+, n = 40) and less than moderate TR (<3+, n = 210). Tricuspid valve annulus, RV, and vena cavae dimensions and the course of the RCA relative to the tricuspid annulus were evaluated. Patients with TR ≥ 3+ showed significantly larger dimensions of the tricuspid annulus, RV and vena cavae. In 64.8% of patients, the RCA coursed along the tricuspid valve annulus. Patients with TR <3+ showed more frequently a course of the RCA superior to the tricuspid annulus at the levels of the anterior and the posterior tricuspid leaflet compared with their counterparts (12.4% vs. 0%, P = 0.019). A less favourable course of the RCA (≤2.0 mm distance to the annulus) for current annuloplasty techniques was observed at the level of the anterior tricuspid and posterior leaflets in respective 12.5 and 27.5% of patients with TR ≥3+. Conclusion The present study proposes a first systematic approach based on CT to define the patient suitability for current transcatheter tricuspid valve devices.

Effect of trabeculae and papillary muscles on the hemodynamics of the left ventricle

Abstract: The impact of surface trabeculae and papillary muscles on the hemodynamics of the left ventricle (LV) is investigated using numerical simulations. Simulations of ventricular flow are conducted for two different models of the LV derived from high-resolution cardiac computed tomography (CT) scans using an immersed boundary method-based flow solver. One model comprises a trabeculated left ventricle (TLV) that includes both trabeculae and papillary muscles, while the second model has a smooth left ventricle that is devoid of any of these surface features. Results indicate that the trabeculae and papillary muscles significantly disrupt the vortices that develop during early filling in the TLV model. Large recirculation zones are found to form in the wake of the papillary muscles; these zones enhance the blockage provided by the papillary muscles and create a path for the mitral jet to penetrate deeper into the ventricular apex during diastole. During systole, the trabeculae enhance the apical washout by ‘squeezing’ the flow from the apical region. Finally, the trabeculae enhance viscous dissipation rate of the ventricular flow, but this effect is not significant in the overall power budget.

Bone Morphogenetic Protein Receptor Type 2 Mutation in Pulmonary Arterial Hypertension: A View on the Right Ventricle.

Abstract: Background—The effect of a mutation in the bone morphogenetic protein receptor 2 (BMPR2) gene on right ventricular (RV) pressure overload in patients with pulmonary arterial hypertension is unknown. Therefore, we investigated RV function in patients who have pulmonary arterial hypertension with and without the BMPR2 mutation by combining in vivo measurements with molecular and histological analysis of human RV and left ventricular tissue. Methods and Results—In total, 95 patients with idiopathic or familial pulmonary arterial hypertension were genetically screened for the presence of a BMPR2 mutation: 28 patients had a BMPR2 mutation, and 67 patients did not have a BMPR2 mutation. In vivo measurements were assessed using right heart catheterization and cardiac MRI. Despite a similar mean pulmonary artery pressure (noncarriers 54±15 versus mutation carriers 55±9 mm Hg) and pulmonary vascular resistance (755 [483–1043] versus 931 [624–1311] dynes·s−1·cm−5), mutation carriers presented with a more severely c...

Results of Cryoenergy and Radiofrequency-Based Catheter Ablation for Treating Ventricular Arrhythmias Arising From the Papillary Muscles of the Left Ventricle, Guided by Intracardiac Echocardiography and Image Integration.

Abstract: Background— Catheter radiofrequency ablation of ventricular arrhythmias (VAs) arising from the left ventricle’s papillary muscles has been associated with inconsistent results. The use of cryoenergy versus radiofrequency has not been compared yet. This study compares outcomes and complications of catheter ablation of VA from the papillary muscles of the left ventricle with either cryoenergy or radiofrequency. Methods and Results— Twenty-one patients (40±12 years old; 47% males; median ejection fraction 59±7.3%) with drug refractory premature ventricular contractions or ventricular tachycardia underwent catheter cryoablation or radiofrequency ablation. VAs were localized using 3-dimensional mapping, multidetector computed tomography, and intracardiac echocardiography, with arrhythmia foci being mapped at either the anterolateral papillary muscle or posteromedial papillary muscles of the left ventricle. Focal ablation was performed using an 8-mm cryoablation catheter or a 4-mm open-irrigated radiofrequency catheter, via transmitral approach. Acute success rate was 100% for cryoenergy (n=12) and 78% for radiofrequency (n=9; P =0.08). Catheter stability was achieved in all patients (100%) treated with cryoenergy, and only in 2 (25%) patients treated with radiofrequency ( P =0.001). Incidence of multiple VA morphologies was observed in 7 patients treated with radiofrequency (77.7%), whereas none was observed in those treated with cryoenergy ( P =0.001). VA recurrence at 6 months follow-up was 0% for cryoablation and 44% for radiofrequency ( P =0.03). Conclusions— Cryoablation was associated with higher success rates and lower recurrence rates than radiofrequency catheter ablation, better catheter stability, and lesser incidence of polymorphic arrhythmias.

Quantification of Right Ventricular Volume and Function Using Single-Beat Three-Dimensional Echocardiography: A Validation Study with Cardiac Magnetic Resonance

Abstract: Background Because of the unique geometry of the right ventricle, assessment of right ventricular (RV) volume and function is clinically challenging. The aim of this study was to investigate the feasibility of single-beat three-dimensional echocardiography (sb3DE) for RV volume and functional assessment in patients with dilated right ventricles. Methods Fifty-two patients with severe tricuspid regurgitation or atrial septal defects were enrolled. Fifty patients underwent sb3DE and cardiac magnetic resonance (CMR) within 24 hours under a euvolemic state, and the results of sb3DE were compared with those of CMR, the reference method. Fifteen normal subjects were also recruited for a broader validation of sb3DE. Results Of the 67 individuals, data from 59 study participants (44 patients and 15 normal subjects) with adequate image quality were analyzed (mean age, 46.9 ± 19.3 years; 58% women). The correlation was excellent between sb3DE and CMR for measuring RV volumes and RV ejection fraction (RVEF) ( r = 0.96, r = 0.93, and r = 0.93 [ P P = .041). Conclusions In patients with dilated right ventricles and in normal subjects, assessment of RV volume and systolic function by sb3DE is feasible in terms of accuracy and reproducibility. RV analysis using sb3DE can be performed in patients with atrial fibrillation, with the possibility of RVEF underestimation.

The right ventricle and pulmonary hypertension.

Abstract: In patients with pulmonary hypertension (PH), the primary cause of death is right ventricular (RV) failure. Improvement in RV function is therefore one of the most important treatment goals. In order to be able to reverse RV dysfunction and also prevent RV failure, a detailed understanding of the pathobiology of RV failure and the underlying mechanisms concerning the transition from a pressure-overloaded adapted right ventricle to a dilated and failing right ventricle is required. Here, we propose that insufficient RV contractility, myocardial fibrosis, capillary rarefaction, and a disturbed metabolism are important features of a failing right ventricle. Furthermore, an overview is provided about the potential direct RV effects of PH-targeted therapies and the effects of RV-directed medical treatments.

Prognostic Benefit of Cardiac Magnetic Resonance Over Transthoracic Echocardiography for the Assessment of Ischemic and Nonischemic Dilated Cardiomyopathy Patients Referred for the Evaluation of Primary Prevention Implantable Cardioverter–Defibrillator Therapy

Abstract: Background— The aim of this study was to determine the prognostic benefit of cardiac magnetic resonance (CMR) over transthoracic echocardiography (TTE) in ischemic cardiomyopathy and nonischemic dilated cardiomyopathy patients evaluated for primary prevention implantable cardioverter–defibrillator therapy. Methods and Results— We enrolled 409 consecutive ischemic and dilated cardiomyopathy patients (mean age: 64±12 years; 331 men). All patients underwent TTE and CMR, and left ventricle end-diastolic volume, left ventricle end-systolic volume, and left ventricle ejection fraction (LVEF) were evaluated. In addition, late gadolinium enhancement was also assessed. All patients were followed up for major adverse cardiac events (MACE) defined as a composite end point of long runs of nonsustained ventricular tachycardia, sustained ventricular tachycardia, aborted sudden cardiac death, or sudden cardiac death. The median follow-up was 545 days. CMR showed higher left ventricle end-diastolic volume (mean difference: 43±22.5 mL), higher left ventricle end-systolic volume (mean difference: 34±20.5 mL), and lower LVEF (mean difference: −4.9±10%) as compared to TTE ( P <0.01). MACE occurred in 103 (25%) patients. Patients experiencing MACE showed higher left ventricle end-diastolic volume, higher left ventricle end-systolic volume, and lower LVEF with both imaging modalities and higher late gadolinium enhancement per-patient prevalence as compared to patients without MACE. At multivariable analysis, CMR-LVEF ≤35% (hazard ratio=2.18 [1.3–3.8]) and the presence of late gadolinium enhancement (hazard ratio=2.2 [1.4–3.6]) were independently associated with MACE ( P <0.01). A model based on CMR-LVEF ≤35% or CMR-LVEF ≤35% plus late gadolinium enhancement detection showed a higher performance in the prediction of MACE as compared to TTE-LVEF resulting in net reclassification improvement of 0.468 (95% confidence interval, 0.283–0.654; P <0.001) and 0.413 (95% confidence interval, 0.23–0.63; P <0.001), respectively. Conclusions— CMR provides additional prognostic stratification as compared to TTE, which may have direct impact on the indication of implantable cardioverter–defibrillator implantation.

Real-time 3D visualization of cellular rearrangements during cardiac valve formation

Abstract: During cardiac valve development, the single-layered endocardial sheet at the atrioventricular canal (AVC) is remodeled into multilayered immature valve leaflets. Most of our knowledge about this process comes from examining fixed samples that do not allow a real-time appreciation of the intricacies of valve formation. Here, we exploit non-invasive in vivo imaging techniques to identify the dynamic cell behaviors that lead to the formation of the immature valve leaflets. We find that in zebrafish, the valve leaflets consist of two sets of endocardial cells at the luminal and abluminal side, which we refer to as luminal cells (LCs) and abluminal cells (ALCs), respectively. By analyzing cellular rearrangements during valve formation, we observed that the LCs and ALCs originate from the atrium and ventricle, respectively. Furthermore, we utilized Wnt/β-catenin and Notch signaling reporter lines to distinguish between the LCs and ALCs, and also found that cardiac contractility and/or blood flow is necessary for the endocardial expression of these signaling reporters. Thus, our 3D analyses of cardiac valve formation in zebrafish provide fundamental insights into the cellular rearrangements underlying this process.

Transthoracic echocardiography in the evaluation of pediatric pulmonary hypertension and ventricular dysfunction

Abstract: Transthoracic echocardiography (TTE) is the most accessible noninvasive diagnostic procedure for the initial assessment of pediatric pulmonary hypertension (PH). This review focuses on principles and use of TTE to determine morphologic and functional parameters that are also useful for follow-up investigations in pediatric PH patients. A basic echocardiographic study of a patient with PH commonly includes the hemodynamic calculation of the systolic pulmonary artery pressure (PAP), the mean and diastolic PAP, the pulmonary artery acceleration time, and the presence of a pericardial effusion. A more detailed TTE investigation of the right ventricle (RV) includes assessment of its size and function. RV function can be evaluated by RV longitudinal systolic performance (e.g., tricuspid annular plane systolic excursion), the tricuspid regurgitation velocity/right ventricular outflow tract velocity time integral ratio, the fractional area change, tissue Doppler imaging-derived parameters, strain measurements, the systolic-to-diastolic duration ratio, the myocardial performance (Tei) index, the RV/left ventricle (LV) diameter ratio, the LV eccentricity index, determination of an enlarged right atrium and RV size, and RV volume determination by 3-dimensional echocardiography. Here, we discuss the potential use and limitations of TTE techniques in children with PH and/or ventricular dysfunction. We suggest a protocol for TTE assessment of PH and myocardial function that helps to identify PH patients and their response to pharmacotherapy. The outlined protocol focuses on the detailed assessment of the hypertensive RV; RV-LV crosstalk must be analyzed separately in the evaluation of different pathologies that account for pediatric PH.

The effect of milrinone on right and left ventricular function when used as a rescue therapy for term infants with pulmonary hypertension

Abstract: Introduction Milrinone may be an appropriate adjuvant therapy for infants with persistent pulmonary hypertension of the newborn. We aimed to describe the effect of milrinone administration on right and left ventricular function in infants with persistent pulmonary hypertension not responding to inhaled nitric oxide after 4 hours of administration. Materials and methods This is a retrospective review of infants born after or at 34 weeks of gestation with persistent pulmonary hypertension who received milrinone treatment. The primary endpoint was the effect of milrinone on myocardial performance and haemodynamics, including right and left ventricular outputs, tissue Doppler velocities, right ventricle and septal strain, and strain rate. Secondary endpoints examined included duration of inhaled nitric oxide and oxygen support. Results A total of 17 infants with a mean (standard deviation) gestation and birth weight of 39.8 (2.0) weeks and 3.45 (0.39) kilograms, respectively, were included in the study. The first echocardiogram was performed 15 hours after the commencement of nitric oxide inhalation. Milrinone treatment was started at a median time of 1 hour after the echocardiogram and was associated with an increase in left ventricular output (p=0.04), right ventricular output (p=0.004), right ventricle strain (p=0.01) and strain rate (p=0.002), and left ventricle s` (p<0.001) and a` (p=0.02) waves. There was a reduction in nitric oxide dose and oxygen requirement over the subsequent 72 hours (all p<0.05). Conclusion The use of milrinone as an adjunct to nitric oxide is worth further exploration, with preliminary evidence suggesting an improvement in both oxygenation and myocardial performance in this group of infants.

Genetic defects in a His-Purkinje system transcription factor, IRX3, cause lethal cardiac arrhythmias.

Abstract: Aim Ventricular fibrillation (VF), the main cause of sudden cardiac death (SCD), occurs most frequently in the acute phase of myocardial infarction: a certain fraction of VF, however, develops in an apparently healthy heart, referred as idiopathic VF. The contribution of perturbation in the fast conduction system in the ventricle, the His-Purkinje system, for idiopathic VF has been implicated, but the underlying mechanism remains unknown. Irx3/IRX3 encodes a transcription factor specifically expressed in the His-Purkinje system in the heart. Genetic deletion of Irx3 provides a mouse model of ventricular fast conduction disturbance without anatomical or contraction abnormalities. The aim of this study was to examine the link between perturbed His-Purkinje system and idiopathic VF in Irx3 -null mice, and to search for IRX3 genetic defects in idiopathic VF patients in human. Methods and results Telemetry electrocardiogram recording showed that Irx3 -deleted mice developed frequent ventricular tachyarrhythmias mostly at night. Ventricular tachyarrhythmias were enhanced by exercise and sympathetic nerve activation. In human, the sequence analysis of IRX3 exons in 130 probands of idiopathic VF without SCN5A mutations revealed two novel IRX3 mutations, 1262G>C (R421P) and 1453C>A (P485T). Ventricular fibrillation associated with physical activities in both probands with IRX3 mutations. In HL-1 cells and neonatal mouse ventricular myocytes, IRX3 transfection up-regulated SCN5A and connexin-40 mRNA, which was attenuated by IRX3 mutations. Conclusion IRX3 genetic defects and resultant functional perturbation in the His-Purkinje system are novel genetic risk factors of idiopathic VF, and would improve risk stratification and preventive therapy for SCD in otherwise healthy hearts.

miR-223–IGF-IR signalling in hypoxia- and load-induced right-ventricular failure: a novel therapeutic approach

Abstract: Aims Pulmonary hypertension is a progressive disease with poor prognosis, characterized by pathological inward remodelling and loss of patency of the lung vasculature. The right ventricle is co-affected by pulmonary hypertension, which triggers events such as hypoxia and/or increased mechanical load. Initially the right ventricle responds with ‘adaptive’ hypertrophy, which is often rapidly followed by ‘maladaptive’ changes leading to right heart decompensation and failure, which is the ultimate cause of death. Methods and results We report here that miR-223 is expressed in the murine lung and right ventricle at higher levels than in the left ventricle. Moreover, lung and right-ventricular miR-223 levels were markedly down-regulated by hypoxia. Correspondingly, increasing right-ventricular load by pulmonary artery banding, induced right-ventricular ischaemia, and the down-regulation of miR-223. Lung and right ventricle miR-223 down-regulation were linked with increased expression of the miR-223 target; insulin-like growth factor-I receptor (IGF-IR) and IGF-I downstream signalling. Similarly, miR-223 was decreased and IGF-IR increased in human pulmonary hypertension. Notably in young mice, miR-223 overexpression, the genetic inactivation or pharmacological inhibition of IGF-IR, all attenuated right-ventricular hypertrophy and improved right heart function under conditions of hypoxia or increased afterload. Conclusion These findings highlight the early role of pulmonary and right-ventricular miR-223 and the IGF-IR in the right heart failure programme initiated by pulmonary hypoxia and increased mechanical load and may lead to the development of novel therapeutic strategies that target the development of PH and right heart failure.

Contractile properties of developing human fetal cardiac muscle

Abstract: The contractile properties of human fetal cardiac muscle have not yet been described and functional information has been primarily obtained via studies in vivo with echocardiography. Most of what is known about the contractile properties of developing mammalian cardiac muscle comes from experiments in animal models. However, these studies are limited in their applicability to human cardiac development because of differences in the temporal pattern and the composition of contractile protein isoform expression. As the human fetal heart ages, the longitudinal shortening (ratio of atrioventricular plane displacement to left ventricular length) decreases (Elmstedt et al. 2012) and the left ventricle end diastolic volume increases (Luewan et al. 2014; Brooks et al. 2014). Heart rate decreases as the fetus grows, while diastolic filling and atrial contraction durations, and the peak velocities of the septum, atrial contraction and ventricle ejection all increase (Elmstedt et al. 2013). However, conclusions from these studies are limited by a lack of ex vivo quantitative muscle contractile studies, and thus cannot decouple the effects of Ca2+ handling and whole cell maturation from the function of the myofilament proteins. It is unknown if the changes in gross contraction of the heart are a result of protein isoform expression pattern changes, structural development or changes to the Ca2+ handling apparatus. Ex vivo studies on human fetal heart tissue report significant changes in morphology, ultrastructure and protein composition as the fetus develops. The gross morphology of the heart undergoes considerable change through the first 112 days of development, including septation (separating the left and right halves between 35 and 53 days of gestation), formation of the valve components between 49 and 56 days, and delamination of the leaflets into the tricuspid valve between 56 and 112 days (Lamers et al. 1995). At 119 days, there are few myofibrils in the heart and they are scattered, very short, with thick z‐bands and are loosely packed (Kim et al. 1992); however, there is no information on the ultrastructure of cardiomyocytes before this time point. Previous studies have shown that several key contractile protein isoforms change in expression levels between 49 days and full‐term gestation. The human fetal heart ventricle shows a marked decrease in the small amount of α‐myosin heavy chain (α‐MHC) between 47 and 110 days of gestation (Reiser et al. 2001). Moreover, slow skeletal troponin I (ssTnI) is the predominant TnI isoform expressed in the heart from as early as 63 days of gestation to 12 weeks after birth (Sasse et al. 1993). The continued expression of ssTnI may lead to slower overall ATPase activity (Anderson et al. 1991; Purcell et al. 1999). The contractile properties of the developing human fetal heart probably change over time due to this complex combination of protein isoform expression changes and the structural maturation of sarcomeres. An in‐depth study of the function of the developing myocardium is needed to better understand the developmental process of the heart and create better informed hypotheses regarding the dysfunction that occurs in disease development from structural abnormalities or genetic mutations within the heart. Knowledge of the contractile properties of human fetal cardiac muscle could also help to identify potential avenues for early intervention into cardiac muscle diseases that develop in utero. Here we provide an initial report of the mechanical and structural properties of human fetal left ventricle myofibrils (the contractile organelles of striated muscle cells) and isolated myosin, using isolated myofibril preparations and purified actin and myosin (heavy meromyosin; HMM) in an in vitro motility assay. In agreement with reports by others (Sasse et al. 1993; Reiser et al. 2001), throughout the age range studied (52 to 134 days of gestation), the fetal cardiac muscle predominantly expresses the β‐myosin heavy chain (β‐MHC), and there is a progressive increase in the relative proportion of cardiac TnI (cTnI) to the total amount of TnI present throughout gestation. We report that human fetal myofibrils produce more force and have faster activation and relaxation kinetics as they develop, and this is correlated with maturation of sarcomere structure and myofibril alignment. Unregulated F‐actin filament sliding velocity (V f) on human fetal cardiac myosin decreased with age, in agreement with a decrease in cross‐bridge detachment rate estimated from the early, slow phase of relaxation in myofibrils. The V f of fetal cardiac myosin at 134 days is close to the speed of human adult left ventricle myosin (Moussavi‐Harami et al. 2015). Our study is an important step towards improved understanding of the development of the human fetal heart contractile properties and we conclude that the fetal left ventricle increases in force production magnitude and speed as it ages from 52 to 134 days of gestation. A preliminary report of this work were presented in abstract form (Racca et al. 2014).

Right Atrial Approach for Ablation of Ventricular Arrhythmias Arising From the Left Posterior–Superior Process of the Left Ventricle

Abstract: Background— The posterior–superior process of the left ventricle (PSP-LV) is the most inferior and posterior aspect of the basal LV that extends posteriorly to the plane of the tricuspid valve. The PSP-LV is anatomically adjacent to the inferior and medial aspect of the right atrium (RA). We report a series of patients with ventricular arrhythmias (VAs) arising from the PSP-LV and describe a mapping and ablation approach from the RA guided by intracardiac echocardiography. Methods and Results— Mapping and ablation of the PSP-LV with an RA approach under intracardiac echocardiography guidance were performed in 5 patients with VAs (aged 44±14 years, 2 males) who had failed ablation attempts from multiple endocardial and epicardial (1 patient) sites. Mapping of the PSP-LV from the adjacent inferomedial RA was performed at sites anatomically opposite to the earliest endocardial site of activation under direct intracardiac echocardiography visualization. From the RA side of the PSP-LV, a small atrial signal and a larger ventricular signal were recorded in each case, with an activation time of 32±7 ms pre-QRS (versus 16±5 ms pre-QRS in the LV endocardium; P =0.068). We were able to capture the LV from these sites. Cryoablation was performed in 2 patients, and radiofrequency was used in the remaining 3 cases. In all patients, ablation from the RA eliminated the arrhythmia. All patients remained free of recurrent VAs after a mean follow-up of 12 (7–16) months. There were no immediate or long-term complications. Conclusions— The PSP-LV can be a site of origin of VAs, which can be successfully eliminated from the adjacent RA under direct intracardiac echocardiographic visualization.

Differences in Left Versus Right Ventricular Electrophysiological Properties in Cardiac Dysfunction and Arrhythmogenesis.

Abstract: A wide range of ion channels, transporters, signaling pathways and tissue structure at a microscopic and macroscopic scale regulate the electrophysiological activity of the heart. Each region of the heart has optimised these properties based on its specific role during the cardiac cycle, leading to well-established differences in electrophysiology, Ca(2+) handling and tissue structure between atria and ventricles and between different layers of the ventricular wall. Similarly, the right ventricle (RV) and left ventricle (LV) have different embryological, structural, metabolic and electrophysiological features, but whether interventricular differences promote differential remodeling leading to arrhythmias is not well understood. In this article, we will summarise the available data on intrinsic differences between LV and RV electrophysiology and indicate how these differences affect cardiac function. Furthermore, we will discuss the differential remodeling of both chambers in pathological conditions and its potential impact on arrhythmogenesis.