Measurement of left and right atrial volume in patients undergoing ablation for atrial arrhythmias: comparison of a manual versus semiautomatic algorithm of real time 3D echocardiography.

AIMS: Real time full-volume 3D echocardiography (3DE) allows rapid and noninvasive measurement of left (LA) and right atrial (RA) volume without geometric assumptions. Different algorithms from different commercial providers are available. Older software requires manual tracing of endocardial contours. Recently, software with semiautomatic endocardial contour-finding algorithms has become available, which considerably speeds up the procedure. Our aim was to compare, in the same dataset, both LA and RA volumes determined by an algorithm involving manual tracing to the corresponding volumes obtained by an algorithm with semiautomatic contour detection. METHODS: Maximal atrial volumes were measured in 88 patients using a multiplane interpolation method algorithm based on manual planimetry of 8 slices. These volumes were compared with volumes determined by the QLAB 8.1 software using semiautomatic border detection. RESULTS: Linear regression showed excellent correlation between volumes determined by manual and by semiautomatic software for both LA and RA (r(2) = 0.90 and 0.89, respectively, P < 0.001). Bland-Altman analysis of manual versus semiautomatic volume determination showed narrow 95% limits of agreement (-15.9 to +12.0 mL for LA volume and -13.9 to +12.2 mL for RA volume) with a minimal bias of -1.9 ± 7.0 mL and -0.8 ± 6.5 mL, respectively, by the semiautomatic method. CONCLUSION: The semiautomatic border detection method shows excellent correlation for maximal LA and RA volume determination compared to the more time-consuming, multiplane interpolation method, with only slight underestimation. The results indicate that values of LA and RA volumes obtained by either algorithm can be compared, for example, during follow-up examinations.

Regulation and dysregulation of glucose transport in cardiomyocytes.

The ability of the heart muscle to derive energy from a wide variety of substrates provides the myocardium with remarkable capacity to adapt to the ever-changing metabolic environment depending on factors including nutritional state and physical activity. There is increasing evidence that loss of metabolic flexibility of the myocardium contributes to cardiac dysfunction in disease conditions such as diabetes, ischemic heart disease and heart failure. At the level of glucose metabolism reduced metabolic adaptation in most cases is characterized by impaired stimulation of transarcolemmal glucose transport in the cardiomyocytes in response to insulin, referred to as insulin resistance, or to other stimuli such as energy deficiency. This review discusses cellular mechanisms involved in the regulation of glucose uptake in cardiomyocytes and their potential implication in impairment of stimulation of glucose transport under disease conditions. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Cardiac Pathways of Differentiation, Metabolism and Contraction.

Inhibition of nicotinamide phosphoribosyltransferase reduces neutrophil-mediated injury in myocardial infarction.

AIMS: Nicotinamide phosphoribosyltransferase (Nampt) is a key enzyme for nicotinamide adenine dinucleotide (NAD(+)) biosynthesis, and recent evidence indicates its role in inflammatory processes. Here, we investigated the potential effects of pharmacological Nampt inhibition with FK866 in a mouse myocardial ischemia/reperfusion model. In vivo and ex vivo mouse myocardial ischemia/reperfusion procedures were performed. RESULTS: Treatment with FK866 reduced myocardial infarct size, neutrophil infiltration, and reactive oxygen species (ROS) generation within infarcted hearts in vivo in a mouse model of ischemia and reperfusion. The benefit of FK866 was not shown in the Langendorff model (ex vivo model of working heart without circulating leukocytes), suggesting a direct involvement of these cells in cardiac injury. Sera from FK866-treated mice showed reduced circulating levels of the neutrophil chemoattractant CXCL2 and impaired capacity to prime migration of these cells in vitro. The release of CXCL8 (human homolog of murine chemokine CXCL2) by human peripheral blood mononuclear cells (PBMCs) and Jurkat cells was also reduced by FK866, as well as by sirtuin (SIRT) inhibitors and SIRT6 silencing, implying a pivotal role for this NAD(+)-dependent deacetylase in the production of this chemokine. INNOVATION: The pharmacological inhibition of Nampt might represent an effective approach to reduce neutrophilic inflammation- and oxidative stress-mediated tissue damage in early phases of reperfusion after a myocardial infarction. CONCLUSIONS: Nampt inhibition appears as a new strategy to dampen CXCL2-induced neutrophil recruitment and thereby reduce neutrophil-mediated tissue injury in mice.

Inclusion into a heart failure critical pathway reduces the risk of death or readmission after hospital discharge.

BACKGROUND: Evidence-based therapies can lower the risk of death or hospital admission in heart failure (HF) patients, but are underprescribed. Critical pathways are one means of supporting systematic use of evidence-based recommendations. METHODS: Patients admitted for HF in one hospital in 2009 and included in a critical pathway were compared with a control group of patients admitted in 2007. The primary endpoint was the risk of death or readmission within 90 days after discharge. The hazard ratio of death or readmission was evaluated in a multivariate Cox proportional hazard model adjusting for age, sex, co-morbidities, and length of stay. RESULTS: Three hundred and sixty-three patients were evaluated (151 in the critical pathway and 212 in the control group). Adjusted hazard ratio for death or readmission at 90 days was 0.72 (95 CI 0.51-1.00, p=0.049). Adhesion to guidelines was significantly better for patients included in the critical pathway (p=0.004), with more frequent prescription of beta-blockers (70.9% (95% CI 62.9-78.0) vs. 56.6% (95% CI 49.6-63.4), p=0.006), and evaluation of left ventricular ejection fraction (LVEF, 73.5% (95% CI 65.7-80.3) vs. 57.5% (95% CI 50.6-64.3), p=0.002). Patients with reduced LVEF seem to have benefited the most from the inclusion in the critical pathway. CONCLUSIONS: Implementation of a critical pathway for patients hospitalized for HF was associated with a 28% reduction of the relative risk of death or readmission and improved adhesion to guidelines.

Differential effects of high-fat diet on myocardial lipid metabolism in failing and nonfailing hearts with angiotensin II-mediated cardiac remodeling in mice.

Normal myocardium adapts to increase of nutritional fatty acid supply by upregulation of regulatory proteins of the fatty acid oxidation pathway. Because advanced heart failure is associated with reduction of regulatory proteins of fatty acid oxidation, we hypothesized that failing myocardium may not be able to adapt to increased fatty acid intake and therefore undergo lipid accumulation, potentially aggravating myocardial dysfunction. We determined the effect of high-fat diet in transgenic mice with overexpression of angiotensinogen in the myocardium (TG1306/R1). TG1306/R1 mice develop ANG II-mediated left ventricular hypertrophy, and at one year of age approximately half of the mice present heart failure associated with reduced expression of regulatory proteins of fatty acid oxidation and reduced palmitate oxidation during ex vivo working heart perfusion. Hypertrophied hearts from TG1306/R1 mice without heart failure adapted to high-fat feeding, similarly to hearts from wild-type mice, with upregulation of regulatory proteins of fatty acid oxidation and enhancement of palmitate oxidation. There was no myocardial lipid accumulation or contractile dysfunction. In contrast, hearts from TG1306/R1 mice presenting heart failure were unable to respond to high-fat feeding by upregulation of fatty acid oxidation proteins and enhancement of palmitate oxidation. This resulted in accumulation of triglycerides and ceramide in the myocardium, and aggravation of contractile dysfunction. In conclusion, hearts with ANG II-induced contractile failure have lost the ability to enhance fatty acid oxidation in response to increased fatty acid supply. The ensuing accumulation of lipid compounds may play a role in the observed aggravation of contractile dysfunction.

Differential regulation of stimulated glucose transport by free fatty acids and PPARα or -δ agonists in cardiac myocytes.

Stimulation of glucose transport in response to insulin or metabolic stress is an important determinant of cardiac myocyte function and survival, particularly during ischemia-reperfusion episodes. The impact of dyslipidemia and its consequence PPAR activation on stimulated glucose transport in cardiac myocytes remains unknown. Isolated adult rat cardiac myocytes were chronically exposed to free fatty acids (FFA) or PPAR agonists. Insulin- (ISGT) and oligomycin-stimulated glucose transport (OSGT) and related cell signaling were analyzed. Exposure of cardiac myocytes to FFA reduced both ISGT and OSGT. Exposure to either PPARα or PPARδ agonists, but not to a PPARγ agonist, reduced ISGT but not OSGT and increased fatty acid oxidation (FAO). The reduction in ISGT was associated with impaired insulin signaling and, in the case of PPAR stimulation, overexpression of SOCS-3, a protein known to hinder proximal insulin signaling. In contrast, the reduction of OSGT could not be explained by a reduced activity of the cellular energy-sensing system, as assessed from the maintained phosphorylation state of AMPK. Inhibition of FAO at the level of mitochondrial acylcarnitine uptake restored OSGT but not ISGT. Seemingly paradoxically, further stimulation of FAO with PPARα or PPARδ agonists also restored OSGT but not ISGT. Together, these results suggest that inhibition of OSGT occurs downstream of energy gauging and is caused by some intermediate(s) of fatty acid oxidation, which does not appear to be acylcarnitines. The results indicate that the mechanisms underlying FFA-mediated inhibition of ISGT and OSGT differ remarkably.

High time-resolved cardiac functional imaging using temporal regularization for small animal on a clinical 3T scanner.

Accurate assessment of mice cardiac function with magnetic resonance imaging is essential for longitudinal studies and for drug development related to cardiovascular diseases. Whereas dedicated small animal MR scanners are not readily available, it would be a great advantage to be able to perform cardiac assessment on clinical systems, in particular, in the context of translational research. However, mouse imaging remains challenging since it requires both high spatial and temporal resolutions, while gradient performances of clinical scanners often limit the reachable parameters. In this study, we propose a new cine sequence, named "interleaved cine," which combines two repetitions of a standard cine sequence shifted in time in order to reach resolution parameters compatible with mice imaging. More precisely, this sequence allows temporal resolution to be reduced to 6.8 ms instead of 13.5 ms initially imposed by the system's hardware. We also propose a two-step denoising algorithm to suppress some artifacts inherent to the new interleaved cine thus allowing an efficient enhancement of the image quality. In particular, we model and suppress the periodic intensity pattern and further denoise the sequence by soft thresholding of the temporal Fourier coefficients. This sequence was successfully validated with mass and function measurements on relevant mice models of cardiovascular diseases.

Role of ERK1/2 activation in microtubule stabilization and glucose transport in cardiomyocytes.

We previously demonstrated that microtubule disruption impairs stimulation of glucose uptake in cardiomyocytes and that 9-cis retinoic acid (9cRA) treatment preserved both microtubule integrity and stimulated glucose transport. Herein we investigated whether 1) activation of the extracellular signal-regulated kinases (ERK1/2) is responsible for microtubule destabilization and 2) ERK1/2 inactivation may explain the positive effects of 9cRA on glucose uptake and microtubule stabilization. Adult rat cardiomyocytes in primary culture showed increased basal ERK1/2 phosphorylation. Cardiomyocytes exposed to inhibitors of the ERK1/2 kinase mitogen/extracellular signal-regulated kinase (MEK) 1/2 had preserved microtubular scaffold, including microtubule-organizing centers (MTOC), together with increased insulin and metabolic stress-stimulated glucose transport as well as signaling, thus replicating the effects of 9cRA treatment. Although 9cRA treatment did not significantly reduce global ERK1/2 activation, it markedly reduced perinuclear-activated ERK1/2 at the location of MTOC. 9cRA also triggered relocation of the ERK1/2 phosphatase mitogen-activated protein kinase phosphatase-3 from the cytosol to the nucleus. These results indicate that, in cardiomyocytes, microtubule destabilization, leading to impaired stimulation of glucose transport, is mediated by ERK1/2 activation, impacting on the MTOC. 9cRA acid restores stimulated glucose transport indirectly through compartmentalized inactivation of ERK1/2.

Cardiac raptor ablation impairs adaptive hypertrophy, alters metabolic gene expression, and causes heart failure in mice.

BACKGROUND: Cardiac hypertrophy involves growth responses to a variety of stimuli triggered by increased workload. It is an independent risk factor for heart failure and sudden death. Mammalian target of rapamycin (mTOR) plays a key role in cellular growth responses by integrating growth factor and energy status signals. It is found in 2 structurally and functionally distinct multiprotein complexes called mTOR complex (mTORC) 1 and mTORC2. The role of each of these branches of mTOR signaling in the adult heart is currently unknown. METHODS AND RESULTS: We generated mice with deficient myocardial mTORC1 activity by targeted ablation of raptor, which encodes an essential component of mTORC1, during adulthood. At 3 weeks after the deletion, atrial and brain natriuretic peptides and ß-myosin heavy chain were strongly induced, multiple genes involved in the regulation of energy metabolism were altered, but cardiac function was normal. Function deteriorated rapidly afterward, resulting in dilated cardiomyopathy and high mortality within 6 weeks. Aortic banding-induced pathological overload resulted in severe dilated cardiomyopathy already at 1 week without a prior phase of adaptive hypertrophy. The mechanism involved a lack of adaptive cardiomyocyte growth via blunted protein synthesis capacity, as supported by reduced phosphorylation of ribosomal S6 kinase 1 and 4E-binding protein 1. In addition, reduced mitochondrial content, a shift in metabolic substrate use, and increased apoptosis and autophagy were observed. CONCLUSIONS: Our results demonstrate an essential function for mTORC1 in the heart under physiological and pathological conditions and are relevant for the understanding of disease states in which the insulin/insulin-like growth factor signaling axis is affected such as diabetes mellitus and heart failure or after cancer therapy.

Late tamponade secondary to aortic root perforation by BioSTAR septal closure device.

We report a patient who presented with pericardial tamponade 9 months after percutaneous closure of a patent foramen ovale using a BioSTAR septal closure device (NMT Medical, Boston, MA). During the operation, bleeding was observed on the posterior aortic root caused by a nonendothelialized strut. The device was explanted, followed by pericardial patch aortoplasty and patch closure of the patent foramen ovale. This report presents a case of late tamponade related to the new-generation bioabsorbable BioSTAR device. Although late complications related with BioSTAR are rare, the presentation may be dramatic. A high index of suspicion and quick intervention is often lifesaving.

Rapid detection of genetic variants in hypertrophic cardiomyopathy by custom DNA resequencing array in clinical practice.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease (1/500) and the most common cause of sudden cardiac death in young people. Pathogenic mutation detection of HCM is having a growing impact on the medical management of patients and their families. However, the remarkable genetic and allelic heterogeneity makes molecular analysis by conventional methods very time-consuming, expensive and difficult to realise in a routine diagnostic molecular laboratory. METHOD AND RESULTS: The authors used their custom DNA resequencing array which interrogates all possible single-nucleotide variants on both strands of all exons (n=160), splice sites and 5'-untranslated region of 12 HCM genes (27 000 nucleotides). The results for 122 unrelated patients with HCM are presented. Thirty-three known or novel potentially pathogenic heterozygous single-nucleotide variants were identified in 38 patients (31%) in genes MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL3 and ACTC1. CONCLUSIONS: Although next-generation sequencing will replace all large-scale sequencing platforms for inherited cardiac disorders in the near future, this HCM resequencing array is currently the most rapid, cost-effective and reasonably efficient technology for first-tier mutation screening of HCM in clinical practice. Because of its design, the array is also an appropriate tool for initial screening of other inherited forms of cardiomyopathy.

Isolated cleft mitral valve with posterior and anterior clefts: a rare cause of congenital valve regurgitation.

We report a case of isolated cleft mitral valve with two clefts in the posterior and one in the anterior leaflet. Our case adds to the few reports of posterior and multiple mitral valve clefts and to our knowledge is the first using real-time transoesophageal three-dimensional echocardiography (3DE) for assessment of isolated cleft mitral valve. (Echocardiography 2010;27:E50-E52).

Single administration of the CXC chemokine-binding protein Evasin-3 during ischemia prevents myocardial reperfusion injury in mice.

OBJECTIVE: Evasins (chemokine-binding proteins) have been shown to selectively neutralize chemokine bioactivity. We investigated the potential benefits of Evasin-3 on mouse myocardial ischemia/reperfusion injury. METHODS AND RESULTS: In vivo and ex vivo (Langendorff model) left coronary artery ligature was performed in C57Bl/6 mice. Coronary occlusion was maintained for 30 minutes, followed by different times (up to 24 hours) of reperfusion. Five minutes after coronary occlusion, mice received 1 intraperitoneal injection of Evasin-3 or vehicle. Infarct size was assessed histologically and by serum cardiac troponin I ELISA. In vitro neutrophil chemotaxis, immunohistology, oxidative stress quantification, real-time RT-PCR analysis of leukocyte chemoattractants, and Western blots for cardioprotective intracellular pathway activation were performed. Evasin-3 reduced infarct size and cardiac troponin I levels compared with vehicle. This effect was associated with the reduction of neutrophil infiltration and reactive oxygen species production within the infarcted myocardium. Evasin-3 did not reduce infarct size in the absence of circulating neutrophils (Langendorff model). Evasin-3 did not influence the activation of intracellular cardioprotective pathways or the expression of leukocyte chemoattractants during early phases of reperfusion. CONCLUSIONS: Single administration of Evasin-3 during myocardial ischemia significantly reduced infarct size by preventing CXC chemokine-induced neutrophil recruitment and reactive oxygen species production in myocardial ischemia/reperfusion.

Isolated posterior mitral valve cleft: diagnosis by real-time three-dimensional transoesophageal echocardiography.

We report a case of an isolated cleft mitral valve with two clefts in the posterior leaflet. Our case adds to the few reports of posterior and multiple mitral valve clefts and, to our knowledge, is one of the first using real-time transoesophageal three-dimensional echocardiography for the assessment of isolated cleft mitral valve.

Measurement of left atrial volume in patients undergoing ablation for atrial fibrillation: comparison of angiography and electro-anatomic (CARTO) mapping with real-time three-dimensional echocardiography.

AIMS: Left atrial (LA) volume can be determined during radiofrequency catheter ablation (RFCA) of atrial fibrillation (AF) with angiography or electro-anatomic (CARTO) mapping. We compared these volumes with LA volume measured using transthoracic real-time three-dimensional echocardiography (3DE). METHODS AND RESULTS: One hundred and twenty-seven consecutive patients undergoing RFCA for AF were studied using biplane pulmonary vein angiography with opacification of the LA. LA volume was calculated from the diameter measurements with a formula using an ellipsoid model. A subset of 22 patients also underwent LA volume determination by CARTO mapping. These volumes were then correlated with LA volume determined non-invasively by real-time 3DE. Linear regression showed a significant correlation between LA volume determined by angiography and 3DE volume (r = 0.56, P < 0.0001). Bland-Altman analysis showed a bias of 38 +/- 22 ml by the angiographic method. LA volume measured using CARTO correlated better (r = 0.67, P < 0.001), but 3DE yielded smaller values (mean difference of -30 +/- 19 ml). CONCLUSION: LA volume determination by angiography and CARTO mapping correlate significantly with 3DE volume. However, both invasive techniques yield larger values for LA volume. The results indicate that LA volume obtained by angiography or CARTO should not be used as baseline value for non-invasive follow-up of LA remodelling by 3DE.

Measurement of left ventricular ejection fraction by real time 3D echocardiography in patients with severe systolic dysfunction: comparison with radionuclide angiography.

AIM: Measurement of left ventricular ejection fraction (LVEF) using real time 3D echocardiography (3DE) has been performed in subjects with preserved or modestly reduced systolic function. Our aim was to evaluate this technique in the subset of patients with severe systolic dysfunction. METHODS AND RESULTS: Consecutive patients with LVEF less than 0.35 at two-dimensional echocardiography were included. LVEF obtained by 3DE was compared to the value measured by radionuclide angiography (RNA). Real time full-volume 3DE was performed, with offline semiautomated measurement of LVEF using dedicated software (Cardioview RT, Tomtec) by a single observer blinded to the results of RNA. A total of 50 patients were evaluated, of whom 38 (76%, 27 males, age 69 +/- 13 years) had a 3DE of sufficient quality for analysis. LVEF for this group was 0.21 +/- 0.07 using 3DE and 0.27 +/- 0.08 using RNA. The agreement between the two techniques was rather poor (r = 0.49; P < 0.001; 95% limits of agreements of -0.20 to 0.09). Truncation of the apex was observed in 6 of 38 (16%) patients. CONCLUSION: In patients with severe systolic dysfunction, 3DE shows poor agreement for measurement of LVEF as compared to RNA. There may be underestimation of up to 20% in absolute terms by 3DE. Accordingly, the two methods are not interchangeable for the follow-up of LV function. A limitation of 3DE may, at least in part, be related to the incomplete incorporation of the apical region into the pyramidal image sector in patients with dilated hearts.