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.

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.

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.

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.

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.

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.

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.

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.

Forkhead transcription factors coordinate expression of myocardial KATP channel subunits and energy metabolism.

Coordinate adaptation of myocyte metabolism and function is fundamental to survival of the stressed heart, but the mechanisms for this coordination remain unclear. Bioinformatics led us to discover that Foxs are key transcription factors involved. We performed experiments on the mouse atrial cell line HL-1, neonate rat heart myocytes, and an adult rat model of myocardial infarction. In electrophoretic mobility-shift assays, FoxO1 binds to the FoxO concensus site of the KATP channel subunit KIR6.1 promoter. In primary atrial culture, targeting FoxO1 and FoxO3 with siRNA specifically reduces mRNA expression of FoxO1 and -O3 and KIR6.1. Western blots, confocal immunofluorescence, and quantitative RT-PCR was applied for measuring expression of 10 Fox, 6 KATP channel subunits, and 12 metabolic genes. FoxF2, -O1, and -O3 strongly associate with expression of KATP channel subunits (in particular, KIR6.1, SUR1A and SUR2B) in different heart tissues and in the periinfarct zone of the left ventricle. Patch-clamp recordings demonstrate that molecular plasticity of these channels is matched by pharmacological plasticity and increased sensitivity to a metabolic challenge mimicked by the protonophore CCCP. A balance of FoxF2 and FoxO also regulates expression of at least 9 metabolic genes involved in setting the balance of glycolysis and beta-oxidation. Bioinformatics shows that the transcriptional mechanisms are highly conserved among chicken, mouse, rat, and human, and Fox are intimately linked to other metabolic sensors. Thus, FoxF2 and -O are key transcription factors coordinating expression of KATP channels and energy metabolism.

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.

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.

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).

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.

A DNA resequencing array for pathogenic mutation detection in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a heterogeneous autosomal dominant cardiac disorder with a prevalence of 1 in 500. Over 450 different pathogenic mutations in at least 16 genes have been identified so far. The large allelic and genetic heterogeneity of HCM requires high-throughput, rapid, and affordable mutation detection technologies to efficiently integrate molecular screening into clinical practice. We developed a custom DNA resequencing array that contains both strands of all coding exons (160), splice-site junctions, and 5'UTR regions of 12 genes that have been clearly implicated in HCM (MYH7, MYBPC3, TNNT2, TPM1, TNNI3, MYL3, MYL2, CSRP3, PLN, ACTC, TNNC1, and PRKAG2). We analyzed a first series of 38 unrelated patients with HCM (17 familial, 21 sporadic). A total of 953,306 bp across the 38 patients were sequenced with a mean nucleotide call rate of 96.92% (range: 93-99.9%). Pathogenic mutations (single nucleotide substitutions) in MYH7, MYBPC3, TNNI3, and MYL3 (six known and six novel) were identified in 60% (10/17) of familial HCM and 10% of sporadic cases (2/21). The high-throughput HCM resequencing array is the most rapid and cost-effective tool for molecular testing of HCM to date; it thus has considerable potential in diagnostic and predictive testing, and prognostic stratification.

Nuclear receptor agonists improve insulin responsiveness in cultured cardiomyocytes through enhanced signaling and preserved cytoskeletal architecture.

Insulin resistance is the failure of insulin to stimulate the transport of glucose into its target cells. A highly regulatable supply of glucose is important for cardiomyocytes to cope with situations of metabolic stress. We recently observed that isolated adult rat cardiomyocytes become insulin resistant in vitro. Insulin resistance is combated at the whole body level with agonists of the nuclear receptor complex peroxisome proliferator-activated receptor gamma (PPARgamma)/retinoid X receptor (RXR). We investigated the effects of PPARgamma/RXR agonists on the insulin-stimulated glucose transport and on insulin signaling in insulin-resistant adult rat cardiomyocytes. Treatment of cardiomyocytes with ciglitazone, a PPARgamma agonist, or 9-cis retinoic acid (RA), a RXR agonist, increased insulin- and metabolic stress-stimulated glucose transport, whereas agonists of PPARalpha or PPARbeta/delta had no effect. Stimulation of glucose transport in response to insulin requires the phosphorylation of the signaling intermediate Akt on the residues Thr308 and Ser473 and, downstream of Akt, AS160 on several Thr and Ser residues. Phosphorylation of Akt and AS160 in response to insulin was lower in insulin-resistant cardiomyocytes. However, treatment with 9-cis RA markedly increased phosphorylation of both proteins. Treatment with 9-cis RA also led to better preservation of microtubules in cultured cardiomyocytes. Disruption of microtubules in insulin-responsive cardiomyocytes abolished insulin-stimulated glucose transport and reduced phosphorylation of AS160 but not Akt. Metabolic stress-stimulated glucose transport also involved AS160 phosphorylation in a microtubule-dependent manner. Thus, the stimulation of glucose uptake in response to insulin or metabolic stress is dependent in cardiomyocytes on the presence of intact microtubules.

Biatrial anatomical reverse remodelling after radiofrequency catheter ablation for atrial fibrillation: evidence from real-time three-dimensional echocardiography.

AIMS: Reports using two-dimensional echocardiography have indicated that radiofrequency catheter ablation (RFCA) for atrial fibrillation (AF) results in a reduction in the left atrial (LA) size. Furthermore, the effect of pulmonary vein isolation (PVI) on right atrial (RA) anatomical remodelling has not been studied. Three-dimensional echocardiography (3DE) allows us to more precisely quantify atrial volume. Our aim was to assess the effect of PVI on biatrial anatomical remodelling using real-time 3DE. METHODS AND RESULTS: We prospectively studied 91 patients (age 59 +/- 8 years, 79 males) referred for RFCA of paroxysmal (n = 79) or chronic (n = 19) AF. Left atrial and RA volumes were measured using real-time 3DE at baseline and after 6 months of follow-up. Data on AF recurrences were also collected. Left atrial volume was significantly reduced at follow-up when compared with baseline (51 +/- 16 vs. 60 +/- 21 mL, P < 0.001). The same occurred with RA volume (43 +/- 17 vs. 50 +/- 20 mL, P = 0.001). The reduction in the LA volume was more marked in patients with chronic than in those with paroxysmal AF (17 +/- 16 vs. 6 +/- 17 mL, P = 0.017). Patients with AF recurrence (23%) showed similar atrial volume reduction compared with those who were seemingly cured. CONCLUSION: Three-dimensional echocardiography shows evidence of biatrial anatomical reverse remodelling after RFCA for AF. A reduction in the atrial volume occurs despite recurrence of AF.

Poor agreement of echographic measures of ventricular dyssynchrony.

Echocardiography is playing an increasing role in patient selection for cardiac resychronization therapy (CRT). The most frequently used techniques for evaluating inter- and intraventricular dyssynchrony are standard echocardiography and tissue Doppler imaging (TDI). Whether these techniques give concordant results is unknown. We studied 44 patients with a left ventricular ejection fraction of 20 ms. Parameters using Sm(p) were highly variable with poor reproducibility, making them unsuitable for evaluating dyssynchrony. In conclusion, our study indicates that there is poor agreement between standard echocardiography and TDI for diagnosing dyssynchrony.

Evaluation of right atrial size in patients with atrial arrhythmias: comparison of 2D versus real time 3D echocardiography.

AIM: This study compares different parameters of right atrial size evaluated by two-dimensional (2D) echocardiography with right atrial volume measured using three-dimensional echocardiography (3DE). METHODS AND RESULTS: One hundred sixty-three consecutive patients with a history of atrial arrhythmias were studied by standard two-dimensional and by real time 3DE. Of these 142 (87%) recordings were of sufficient quality for interpretation of the right atrium by both imaging techniques. The following parameters of right atrial size were measured: apical four-chamber short-axis diameter (4CH short axis), apical four-chamber long axis diameter (4CH long axis), and apical four-chamber planimetry area. The 2D-derived right atrial volume was calculated by using the single plane area-length method (4CH area-length). The 2D parameters were then correlated with right atrial volume measured by real time 3DE. Linear regression analysis showed moderate correlation for four-chamber planimetry area (r = 0.72, P < 0.001) and 2D-derived volume calculation (r of 4CH single plane area-length RA volume = 0.70, P < 0.001). Diameters correlated clearly less well with 3DE volume (r of 4CH short axis = 0.61, 4CH long axis = 0.59, P < 0.001 respectively). CONCLUSION: Real time 3DE is highly feasible for right atrial volume determination. The results demonstrate that measurements of dimensions using 2D echocardiography may not accurately assess right atrial size. If 3DE is not available, apical 4CH planimetry area is a simple alternative that may be used for evaluating right atrial size in clinical practice. The 2D-derived right atrial volume by single plane area-length method was not better correlated with 3DE volume than four-chamber planimetry area.

[Diastolic heart failure: myth or fact?]. / Insuffisance cardiaque par dysfonction diastolique: mythe ou réalité?

Diastolic heart failure is a frequent diagnosis, but now it is more acurate to call this heart failure with preserved ejection fraction. The diagnosis can be made non invasively by the echocardiography and measuring BNP (brain natriuretic peptide). Consensus about treatment are less evidence-based than for heart failure with diminished ejection fraction. It is however certain that control of hypertension and heart rate are important. Fluid overload must also be treated with diuretics.

Echocardiography and patient selection for cardiac resynchronization therapy: a critical appraisal.

Echocardiography has been the focus of growing interest for improving patient selection for cardiac resynchronization therapy in order to reduce the number of nonresponders. Various techniques have been described for assessing dyssynchrony, using standard echocardiography (pulsed-wave Doppler and M-mode echocardiography), tissue Doppler imaging, and other imaging modes such as three-dimensional echocardiography. This article provides an overview of the technical and practical aspects of these different techniques and discusses the current evidence for optimizing patient selection by echocardiography.