Levosimendan as rescue therapy in severe cardiogenic shock after ST-elevation myocardial infarction.

Data on the use of levosimendan in patients with myocardial infarction related cardiogenic shock already under combined catecholamine treatment and intra-aortic balloon counterpulsation (IABP) are scarce. Seven consecutive patients with refractory cardiogenic shock after ST-elevation myocardial infarction, multi-organ dysfunction syndrome and under maximal intensive care (combined catecholamine treatment, IABP) were treated with levosimendan (bolus 12 microg/kg i.v., thereafter 0.1 microg/kg over 24 h). Hemodynamic effects were registered invasively and monitored over 72h post infusion. Therapy with levosimendan significantly reduced required epinephrine dose after 48h (P=0.02 versus baseline). Norepinephrine dose had to be increased during the first 12 h of levosimendan (+25%; P=ns), but was significantly reduced at 72 h compared to baseline (median 0.14 versus 0.06 microg/kg/min after 72 h; P<0.05). Cardiac power output increased (baseline 0.6 versus 1.1 > or = 48 h after infusion; P<0.01) and systemic vascular resistance decreased (median 1294 dyn*s*cm-5 at baseline versus 858 dyn*s*cm-5 at 24 h; P<0.05) after levosimendan infusion. IABP therapy could be weaned in all patients during 5 days after infusion and all patients survived the cardiogenic shock (ICU mortality 29%). Levosimendan as an adjunctive, rescue therapy in patients with severe cardiogenic shock may be safe with beneficial effects on hemodynamics over 72 h.

Genomic analysis reveals poor separation of human cardiomyopathies of ischemic and nonischemic etiologies.

Clinically, the differentiation between ischemic (ICM) and nonischemic (NICM) human cardiomyopathies is highly relevant, because ICM and NICM differ with respect to prognosis and certain aspects of pharmacological therapy, despite a common final phenotype characterized by ventricular dilatation and reduced contractility. So far, it is unclear whether microarray-based signatures can be used to infer the etiology of heart failure. Using three different classification algorithms, we independently analyzed one cDNA and two publicly available high-density oligonucleotide microarray studies comprising a total of 279 end-stage human heart failure samples. When classifiers identified in a single study were applied to the remaining studies, misclassification rates >25% for ICM and NICM specimens were noted, indicating poor separation of both etiologies. However, data mining of 458 classifier genes that were concordantly identified in at least two of the three data sets points to different biological processes in ICM vs. NICM. Consistent with the underlying ischemia, cytokine signaling pathways and immediate-early response genes were overrepresented in ICM samples, whereas NICM samples displayed a deregulation of cytoskeletal transcripts, genes encoding for the major histocompatibility complex, and antigen processing and presentation pathways, potentially pointing to immunologic processes in NICM. Overall, our results suggest that ICM and NICM exhibit substantial heterogeneity at the transcriptomic level. Prospective studies are required to test whether etiology-specific gene expression patterns are present at earlier disease stages or in subsets of both etiologies.

Identification of a common gene expression signature in dilated cardiomyopathy across independent microarray studies.

OBJECTIVES: This study was designed to identify a common gene expression signature in dilated cardiomyopathy (DCM) across different microarray studies. BACKGROUND: Dilated cardiomyopathy is a common cause of heart failure in Western countries. Although gene expression arrays have emerged as a powerful tool for delineating complex disease patterns, differences in platform technology, tissue heterogeneity, and small sample sizes obscure the underlying pathophysiologic events and hamper a comprehensive interpretation of different microarray studies in heart failure. METHODS: We accounted for tissue heterogeneity and technical aspects by performing 2 genome-wide expression studies based on cDNA and short-oligonucleotide microarray platforms which comprised independent septal and left ventricular tissue samples from nonfailing (NF) (n = 20) and DCM (n = 20) hearts. RESULTS: Concordant results emerged for major gene ontology classes between cDNA and oligonucleotide microarrays. Notably, immune response processes displayed the most pronounced down-regulation on both microarray types, linking this functional gene class to the pathogenesis of end-stage DCM. Furthermore, a robust set of 27 genes was identified that classified DCM and NF samples with >90% accuracy in a total of 108 myocardial samples from our cDNA and oligonucleotide microarray studies as well as 2 publicly available datasets. CONCLUSIONS: For the first time, independent microarray datasets pointed to significant involvement of immune response processes in end-stage DCM. Moreover, based on 4 independent microarray datasets, we present a robust gene expression signature of DCM, encouraging future prospective studies for the implementation of disease biomarkers in the management of patients with heart failure.

Functional profiling of human atrial and ventricular gene expression.

The purpose of our investigation was to identify the transcriptional basis for ultrastructural and functional specialization of human atria and ventricles. Using exploratory microarray analysis (Affymetrix U133A+B), we detected 11,740 transcripts expressed in human heart, representing the most comprehensive report of the human myocardial transcriptome to date. Variation in gene expression between atria and ventricles accounted for the largest differences in this data set, as 3.300 and 2.974 transcripts showed higher expression in atria and ventricles, respectively. Functional classification based on Gene Ontology identified chamber-specific patterns of gene expression and provided molecular insights into the regional specialization of cardiomyocytes, correlating important functional pathways to transcriptional activity: Ventricular myocytes preferentially express genes satisfying contractile and energetic requirements, while atrial myocytes exhibit specific transcriptional activities related to neurohumoral function. In addition, several pro-fibrotic and apoptotic pathways were concentrated in atrial myocardium, substantiating the higher susceptibility of atria to programmed cell death and extracellular matrix remodelling observed in human and experimental animal models of heart failure. Differences in transcriptional profiles of atrial and ventricular myocardium thus provide molecular insights into myocardial cell diversity and distinct region-specific adaptations to physiological and pathophysiological conditions. Moreover, as major functional classes of atrial- and ventricular-specific transcripts were common to human and murine myocardium, an evolutionarily conserved chamber-specific expression pattern in mammalian myocardium is suggested.

Reprogramming of the human atrial transcriptome in permanent atrial fibrillation: expression of a ventricular-like genomic signature.

Atrial fibrillation is associated with increased expression of ventricular myosin isoforms in atrial myocardium, regarded as part of a dedifferentiation process. Whether reexpression of ventricular isoforms in atrial fibrillation is restricted to transcripts encoding for contractile proteins is unknown. Therefore, this study compares atrial mRNA expression in patients with permanent atrial fibrillation to atrial mRNA expression in patients with sinus rhythm and to ventricular gene expression using Affymetrix U133 arrays. In atrial myocardium, we identified 1434 genes deregulated in atrial fibrillation, the majority of which, including key elements of calcium-dependent signaling pathways, displayed downregulation. Functional classification based on Gene Ontology provided the specific gene sets of the interdependent processes of structural, contractile, and electrophysiological remodeling. In addition, we demonstrate for the first time a prominent upregulation of transcripts involved in metabolic activities, suggesting an adaptive response to increased metabolic demand in fibrillating atrial myocardium. Ventricular-predominant genes were 5 times more likely to be upregulated in atrial fibrillation (174 genes upregulated, 35 genes downregulated), whereas atrial-specific transcripts were predominantly downregulated (56 genes upregulated, 564 genes downregulated). Overall, in fibrillating atrial myocardium, functional classes of genes characteristic of ventricular myocardium were found to be upregulated (eg, metabolic processes), whereas functional classes predominantly expressed in atrial myocardium were downregulated (eg, signal transduction and cell communication). Therefore, dedifferentiation with adoption of a ventricular-like signature is a general feature of the fibrillating atrium.

Global gene expression in human myocardium-oligonucleotide microarray analysis of regional diversity and transcriptional regulation in heart failure.

To obtain region- and disease-specific transcription profiles of human myocardial tissue, we explored mRNA expression from all four chambers of eight explanted failing [idiopathic dilated cardiomyopathy (DCM), n=5; ischemic cardiomyopathy (ICM), n=3], and five non-failing hearts using high-density oligonucleotide arrays (Affymetrix U95Av2). We performed pair-wise comparisons of gene expression in the categories (1) atria versus ventricles, (2) disease-regulated genes in atria and (3) disease-regulated genes in ventricles. In the 51 heart samples examined, 549 genes showed divergent distribution between atria and ventricles (272 genes with higher expression in atria, 277 genes with higher expression in ventricles). Two hundred and eighty-eight genes were differentially expressed in failing myocardium compared to non-failing hearts (19 genes regulated in atria and ventricles, 172 regulated in atria only, 97 genes regulated in ventricles only). For disease-regulated genes, down-regulation was 4.5-times more common than up-regulation. Functional classification according to Gene Ontology identified specific biological patterns for differentially expressed genes. Eleven genes were validated by RT-PCR showing a good correlation with the microarray data. Our goal was to determine a gene expression fingerprint of the heart, accounting for region- and disease-specific aspects. Recognizing common gene expression patterns in heart failure will significantly contribute to the understanding of heart failure and may eventually lead to the development of pathway-specific therapies.

Selective block of sarcolemmal IKATP in human cardiomyocytes using HMR 1098.

PURPOSE: Activation of the myocardial, ATP-dependent potassium current (IK(ATP)) during ischemia causes shortening of the action potential duration thereby increasing dispersion of repolarization between ischemic and non-ischemic myocardium and predisposing to reentrant arrhythmias. The IK(ATP) inhibitor HMR1098 allows selective block of the sarcolemmal myocardial K(ATP)-channel in various animal species. Therefore, we studied the concentration and pH-dependence of HMR1098 in human ventricular myocytes. METHODS: Human ventricular cardiomyocytes were isolated enzymatically. IK(ATP) was measured with the patch-clamp technique in whole cell configuration at 35 degrees C. Action potentials were recorded using Amphotericine B in perforated patch conditions. In voltage clamp experiments, the K(ATP)-channel was activated by application of 1 microM rilmakalim, a K(ATP)-channel opener. In action potential recordings, 0.1 microM rilmakalim was used. RESULTS: At physiological pH (pH = 7.3) half-maximal block of the rilmakalim-induced current occurred at 0.42 +/- 0.008 microM HMR1098 (at 0 mV membrane potential); under acidic conditions as can be expected to be present under ischemic conditions (pH = 6.5), half-maximal block was achieved at markedly lower concentrations (IC(50) = 0.24 +/- 0.009 microM). In current clamp experiments, block of IK(ATP) by HMR1098 was capable of reversing the action potential shortening induced by rilmakalim, and restored the action potential plateau. CONCLUSIONS: HMR1098 appears to be useful to prevent IK(ATP)-induced shortening of the action potential in human ventricular myocardium. More acidic conditions, as observed in ischemia, increase the sensitivity to HMR1098, indicating a more potent effect in ischemic myocardium. Thus, HMR1098 may be a useful agent to prevent action potential shortening and dispersion of repolarization during ischemia, which may protect against ischemia induced ventricular arrhythmias.