Dilated Cardiomyopathic Hearts Research Articles

Importance of Mitochondrial-Related Genes in Dilated Cardiomyopathy Based on Bioinformatics Analysis

We designed this study to identify potential key protein interaction networks, genes, and correlated pathways in dilated cardiomyopathy (DCM) via bioinformatics methods. We selected the GSE3586 microarray dataset, consisting of 15 dilated cardiomyopathic heart biopsy samples and 13 nonfailing heart biopsy samples. Initially, the GSE3586 dataset was downloaded and was analyzed with the limma package to identify differentially expressed genes (DEGs). A total of 172 DEGs consisting of 162 upregulated genes and ten downregulated genes in DCM were selected by the criterion of adjusted Pvalues less than 0.01 and the log2-fold change of 0.6 or greater. Gene Ontology functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed to view the biological processes, cellular components, molecular function, and KEGG pathways of the DEGs. Next, protein-protein interactions were constructed, and the hub protein modules were identified. Then we selected the key genes DLD, UQCRC2, DLAT, SUCLA2, ATP5A1, PRDX3, FH, SDHD, and NDUFV1, which are involved in a wide range of biological activities, such as the citrate cycle, oxidation-reduction processes and cellular respiration, and energy derivation by oxidation of organic compounds in mitochondria. Finally, we found that currently there are no related gene-targeting drugs after exploring the predicted interactions between key genes and drugs, and transcription factors. In conclusion, our study provides greater understanding of the pathogenesis and underlying molecular mechanisms in DCM. This contributes to the exploration of potential gene therapy targets.

Corrigendum to "Evaluating the Hemodynamical Response of a Cardiovascular System under Support of a Continuous Flow Left Ventricular Assist Device via Numerical Modeling and Simulations".

[This corrects the article DOI: 10.1155/2013/986430.].

Unc-51 like autophagy activating kinase 1 accelerates angiotensin II-induced cardiac hypertrophy through promoting oxidative stress regulated by Nrf-2/HO-1 pathway

Unc-51 like autophagy activating kinase 1 (ULK1) is a serine/threonine kinase and the mammalian functional homolog of yeast Atg1, and plays an essential role in regulating various cellular processes. However, whether ULK1 can influence cardiac hypertrophy is unclear. In the study, we investigated the role of ULK1 in the pathogenesis of pathological cardiac hypertrophy and the molecular mechanism. We showed that ULK1 levels were increased in human dilated cardiomyopathic hearts and in mouse hypertrophic hearts. ULK1 knockout conferred resistance to angiotensin II (Ang II) infusion through markedly repressing hypertrophic growth, cardiac function and the deposition of fibrosis. In ULK1 transgenic (TG) mice with ULK1 over-expression, accelerated hypertrophy, reduced cardiac function and promoted fibrosis deposition were observed compared with non-transgenic mice following AngII challenge. In addition, mice lacking ULK1 showed alleviated oxidative stress by improving nuclear erythroid factor 2-related factor 2 (Nrf-2) and heme oxygenase-1 (HO-1) expression, whereas mice with ULK1 over-expression developed an accelerated reactive oxygen species (ROS) production. In vitro, we found that ULK1 knockdown-attenuated oxidative stress, inflammation and fibrosis deposition in AngII-exposed cardiomyocytes were significantly blunted by the inhibition of Nrf-2/HO-1 signaling. However, ULK1 overexpression-accelerated oxidative stress, inflammatory response and fibrosis were markedly ameliorated by the inhibition of ROS production. Our results indicated that ULK1 was a potential therapeutic target in pathological cardiac hypertrophy.

Smad Nuclear Interacting Protein 1 Acts as a Protective Regulator of Pressure Overload-Induced Pathological Cardiac Hypertrophy.

BackgroundSmad nuclear interacting protein 1 (SNIP1) plays a critical role in cell proliferation, transformation of embryonic fibroblasts, and immune regulation. However, the role of SNIP1 in cardiac hypertrophy remains unclear.Methods and ResultsHere we examined the role of SNIP1 in pressure overload–induced cardiac hypertrophy and its mechanisms. Our results demonstrated that SNIP1 expression was downregulated in human dilated cardiomyopathic hearts, aortic banding‐induced mice hearts, and angiotensin II–treated cardiomyocytes. Accordingly, SNIP1 deficiency significantly exacerbated aortic banding–induced cardiac hypertrophy, fibrosis, and contractile dysfunction, whereas cardiac‐specific overexpression of SNIP1 markedly recovered pressure overload–induced cardiac hypertrophy and fibrosis. Besides that, SNIP1 protected neonatal rat cardiomyocytes against angiotensin II–induced hypertrophy in vitro. Moreover, we identified that SNIP1 suppressed nuclear factor‐κB signaling during pathological cardiac hypertrophy, and inhibition of nuclear factor‐κB signaling by a cardiac‐specific conditional inhibitor of κBS 32A/S36A transgene blocked these adverse effects of SNIP1 deficiency on hearts.ConclusionsTogether, our findings demonstrated that SNIP1 had protective effects in pressure overload–induced pathological cardiac hypertrophy via inhibition of nuclear factor‐κB signaling. Thus, SNIP1 may be a novel approach for the treatment of heart failure.

Growth Arrest-Specific 6 Exacerbates Pressure Overload-Induced Cardiac Hypertrophy.

Growth arrest-specific 6 (GAS6) is a member of the vitamin K-dependent protein family that is involved in the regulation of the cardiovascular system, including vascular remodeling, homeostasis, and atherosclerosis. However, there is still no study that systemically elucidates the role of GAS6 in cardiac hypertrophy. Here, we found that GAS6 was upregulated in human dilated cardiomyopathic hearts, hypertrophic murine hearts, and angiotensin II-treated cardiomyocytes. Next, we examined the influence of GAS6 expression in response to a cardiac stress by inducing chronic pressure overload with aortic banding in wild-type and GAS6-knockout mice or cardiac-specific GAS6 overexpressing mice. Under basal conditions, the GAS6-knockout mice had normal left ventricular structure and function but after aortic banding, the mice demonstrated less hypertrophy, fibrosis, and contractile dysfunction when compared with wild-type mice. Conversely, cardiac-specific overexpression of GAS6 exacerbated aortic banding-induced cardiac hypertrophy, fibrosis, and dysfunction. Furthermore, we demonstrated that GAS6 activated the mitogen-activated protein kinase kinase 1/2-extracellular signal-regulated kinase 1/2 pathway during pressure overload-induced cardiac hypertrophy, and the pharmacological mitogen-activated protein kinase kinase 1/2 inhibitor U0126 almost completely reversed GAS6 overexpression-induced cardiac hypertrophy and fibrosis, resulting in improved cardiac function. Collectively, our data support the notion that GAS6 impairs ventricular adaptation to chronic pressure overload by activating mitogen-activated protein kinase kinase 1/2-extracellular signal-regulated kinase 1/2 signaling. Our findings suggest that strategies to reduce GAS6 activity in cardiac tissue may be a novel approach to attenuate the development of congestive heart failure.

Interplay of Mitochondrial Biogenesis and Oxidative Stress in Heart Failure

The dawn of mitochondrially powered cells began 1 to 2 billion years ago when an amitochondriate host subsumed α-proteobacterium, a hydrogen-producing symbiont.1 Equipped to oxidize nutrients, eukaryotic cells acquired a boost to cellular energy, enabling the emergence of multicellular mammals, sustained by a nearly inexhaustible muscular pump: the heart. Article see p 1957 In this issue of Circulation , Ahuja et al2 examine the interplay of mitochondria biogenesis and oxidative stress in human cardiomyopathy. They reveal that disparate changes in mitochondrial biogenesis and mitochondrial oxidative stress distinguish between ICM and DCM. Using a complement of ultrastructural, biochemical, and genetic analyses, Ahuja et al convincingly show that mitochondrial content is increased in dilated cardiomyopathic (DCM) hearts (n=8) but not ischemic cardiomyopathic (ICM) hearts (n=8). Regardless of the type of heart failure, oxidative phosphorylation (OXPHOS) was severely impaired, a finding universally reported by others. Given that mitochondrial content was increased ≈2-fold in DCM hearts, these data may imply better maintenance of total cellular OXPHOS in DCM hearts compared with ICM hearts. Because mitochondrial mass is influenced by proliferation (mitochondrial biogenesis) and clearance (mitophagy), the authors investigated the mechanistic basis for increased mitochondrial content in DCM hearts. Notably, PGC-1α (PPARGC1α ), a potent regulator of mitochondrial biogenesis,3 and several target genes of PGC-1α were induced at the level of mRNA and protein in DCM hearts but not in ICM hearts. These genetic data replicate a previously reported study.4 Even so, this topic is not immune to controversy or the Proteus phenomenon; findings by others oppugn the conclusions of Ahuja et al. Using a mixed cohort, 1 study showed that PGC-1α, which promotes mitochondrial biogenesis, was reduced in both ICM and DCM hearts.5 Induction of adenine nucleotide translocator ( SLC25A4 ), a gene with an induction that signifies mitochondrial biogenesis, was reported …

Divergent Mitochondrial Biogenesis Responses in Human Cardiomyopathy

Mitochondria are key players in the development and progression of heart failure (HF). Mitochondrial (mt) dysfunction leads to diminished energy production and increased cell death contributing to the progression of left ventricular failure. The fundamental mechanisms that underlie mt dysfunction in HF have not been fully elucidated. To characterize mt morphology, biogenesis, and genomic integrity in human HF, we investigated left ventricular tissue from nonfailing hearts and end-stage ischemic (ICM) or dilated (DCM) cardiomyopathic hearts. Although mt dysfunction was present in both types of cardiomyopathy, mt were smaller and increased in number in DCM compared with ICM or nonfailing hearts. mt volume density and mtDNA copy number was increased by ≈2-fold (P<0.001) in DCM hearts in comparison with ICM hearts. These changes were accompanied by an increase in the expression of mtDNA-encoded genes in DCM versus no change in ICM. mtDNA repair and antioxidant genes were reduced in failing hearts, suggestive of a defective repair and protection system, which may account for the 4.1-fold increase in mtDNA deletion mutations in DCM (P<0.05 versus nonfailing hearts, P<0.05 versus ICM). In DCM, mt dysfunction is associated with mtDNA damage and deletions, which could be a consequence of mutating stress coupled with a peroxisome proliferator-activated receptor γ coactivator 1α-dependent stimulus for mt biogenesis. However, this maladaptive compensatory response contributes to additional oxidative damage. Thus, our findings support further investigations into novel mechanisms and therapeutic strategies for mt dysfunction in DCM.

Evaluating the Hemodynamical Response of a Cardiovascular System under Support of a Continuous Flow Left Ventricular Assist Device via Numerical Modeling and Simulations

Dilated cardiomyopathy is the most common type of the heart failure which can be characterized by impaired ventricular contractility. Mechanical circulatory support devices were introduced into practice for the heart failure patients to bridge the time between the decision to transplant and the actual transplantation which is not sufficient due to the state of donor organ supply. In this study, the hemodynamic response of a cardiovascular system that includes a dilated cardiomyopathic heart under support of a newly developed continuous flow left ventricular assist device—Heart Turcica Axial—was evaluated employing computer simulations. For the evaluation, a numerical model which describes the pressure-flow rate relations of Heart Turcica Axial, a cardiovascular system model describing the healthy and pathological hemodynamics, and a baroreflex model regulating the heart rate were used. Heart Turcica Axial was operated between 8000 rpm and 11000 rpm speeds with 1000 rpm increments for assessing the pump performance and response of the cardiovascular system. The results also give an insight about the range of the possible operating speeds of Heart Turcica Axial in a clinical application. Based on the findings, operating speed of Heart Turcica Axial should be between 10000 rpm and 11000 rpm.

264 Is ventricular fibrillation different in ischemic compared to non-ischemic dilated cardiomyopathic human hearts?

It is unknown if VF dynamics are dependent on the etiology of the cardiomyopthay. In this study we compared transmural dominant frequency gradient, during ventricular fibrillation (VF), in ischemic and non-ischemic dilated cardiomyopathic human hearts. The study was conducted in human langendorff model. These were ischemic (ICM, n = 5) and dilated (DCM, n = 5) cardiomyopathic human hearts explanted from patients undergoing cardiac transplant. Data was collected using an epicardial sock and an endocardial balloon each having 112 unipolar electrodes, arranged in 14 columns and 8 rows. Ischemia was induced by halting the perfusion to the heart and VF was initiated by brief application of 9V batter to epicardium. VF was recorded at onset, 90 seconds and 180 seconds for 20 seconds each. Dominant frequency (DF) was computed using Welch periodogram method as described in our previous studies. Repeated measure ANOVA was employed using mixed model in SAS. The mean DF in LV-endocardium and LV-epicardium is reported in table 1. At the onset of VF, no difference was observed between LV epicardium and endocardium in dilated cardiomyopathic hearts (P = 0.6) while the difference was statistically significant in ischemic cardiomyopathic hearts (P < 0.05). After 180 seconds of VF, there was a significant transmural DF gradient in both ischemic and dilated cardiomyopathic hearts (P < 0.05).Tabled 1 There is a LV transmural DF gradient during VF in both DCM and ICM after 3 minutes of ischemia. This gradient is established early in ischemia in ICM but not in DCM. These finding may relate to differential transmural ion channel remodelling that is dependent of the etiology of cardiomyopathic process.

Perspectives in Microvascular Fluid Handling: Does the Distribution of Coagulation Factors in Human Myocardium Comply with Plasma Extravasation in Venular Coronary Segments?

Background: Heterogeneity of vascular permeability has been suggested for the coronary system. Whereas arteriolar and capillary segments are tight, plasma proteins pass readily into the interstitial space at venular sites. Fittingly, lymphatic fluid is able to coagulate. However, heart tissue contains high concentrations of tissue factor, presumably enabling bleeding to be stopped immediately in this vital organ. The distribution of pro- and anti-coagulatively active factors in human heart tissue has now been determined in relation to the types of microvessels. Methods and Results: Samples of healthy explanted hearts and dilated cardiomyopathic hearts were immunohistochemically stained. Albumin was found throughout the interstitial space. Tissue factor was packed tightly around arterioles and capillaries, whereas the tissue surrounding venules and small veins was practically free of this starter of coagulation. Thrombomodulin was present at the luminal surface of all vessel segments and especially at venular endothelial cell junctions. Its product, the anticoagulant protein C, appeared only at discrete extravascular sites, mainly next to capillaries. These distribution patterns were basically identical in the healthy and diseased hearts, suggesting a general principle. Conclusions: Venular extravasation of plasma proteins probably would not bring prothrombin into intimate contact with tissue factor, avoiding interstitial coagulation in the absence of injury. Generation of activated protein C via thrombomodulin is favored in the vicinity of venular gaps, should thrombin occur inside coronary vessels. This regionalization of distribution supports the proposed physiological heterogeneity of the vascular barrier and complies with the passage of plasma proteins into the lymphatic system of the heart.

Concurrent upregulation of endogenous proapoptotic and antiapoptotic factors in failing human hearts

Despite widespread activation of proapoptotic stimuli and mediators, the degree of apoptosis in failing hearts is not very high. Endogenous antiapoptotic mechanisms are thought to be triggered by the heart-failure process. We investigated whether activation of endogenous apoptosis inhibitors plays a part when death receptor and mitochondrial apoptotic pathways have been triggered. We evaluated various proapoptotic and antiapoptotic factors in myocardial tissue specimens obtained from normal and explanted end-stage ischemic and dilated cardiomyopathic hearts. Caspases (CASPs) 3, 8 and 9, total and activated Bcl-2 homology domain 3-interacting domain death agonist, the X-linked inhibitor of apoptosis (XIAP), and DNA fragmentation factor (DFF) proteins were analyzed by western blotting. Expression of messenger RNA was measured by reverse-transcription polymerase chain reaction for the XIAP, DIABLO, CFLAR and DFF genes. We also assessed CASP3, CASP8 and CASP9 and DFF activity. Cytochrome c1 localization in myocytes was analyzed by immunohistochemistry and immunoelectron microscopy. We collected myocardial tissue from eight cardiomyopathic hearts and five normal hearts. Cytochrome c1 was released from mitochondria into the cytosol in the cardiomyopathic hearts but CASP9 was not activated. CASP8 activity was increased compared with that in normal myocardium. Although CASP3 was cleaved, activity was not greatly increased because of an increase in XIAP and decrease in DIABLO expression. DFF proteins were conspicuously absent. Concurrent upregulation of endogenous antiapoptotic mechanisms can interrupt the apoptotic cascade and prevents cell loss despite the presence of multiple proapoptotic factors. This period might offer a therapeutic window for restoration of myocardial function in heart failure.

Role of Copper and Homocysteine in Pressure Overload Heart Failure

Elevated levels of homocysteine (Hcy) (known as hyperhomocysteinemia HHcy) are involved in dilated cardiomyopathy. Hcy chelates copper and impairs copper-dependent enzymes. Copper deficiency has been linked to cardiovascular disease. We tested the hypothesis that copper supplement regresses left ventricular hypertrophy (LVH), fibrosis and endothelial dysfunction in pressure overload DCM mice hearts. The mice were grouped as sham, sham + Cu, aortic constriction (AC), and AC + Cu. Aortic constriction was performed by transverse aortic constriction. The mice were treated with or without 20 mg/kg copper supplement in the diet for 12 weeks. The cardiac function was assessed by echocardiography and electrocardiography. The matrix remodeling was assessed by measuring matrix metalloproteinase (MMP), tissue inhibitor of metalloproteinases (TIMPs), and lysyl oxidase (LOX) by Western blot analyses. The results suggest that in AC mice, cardiac function was improved with copper supplement. TIMP-1 levels decreased in AC and were normalized in AC + Cu. Although MMP-9, TIMP-3, and LOX activity increased in AC and returned to baseline value in AC + Cu, copper supplement showed no significant effect on TIMP-4 activity after pressure overload. In conclusion, our data suggest that copper supplement helps improve cardiac function in a pressure overload dilated cardiomyopathic heart.

Aetiology‐specific patterns in end‐stage heart failure patients identified by functional annotation and classification of microarray data

The objective of the present study was to use gene expression profiling, functional annotations and classification to identify aetiology-specific biological processes and potential molecular markers for different aetiologies of end-stage heart failure. Individual left ventricular myocardial samples from eleven coronary artery disease and nine dilated cardiomyopathy transplant patients were co-hybridized with pooled RNA from four non-failing hearts on custom-made arrays of 7000 human genes. Significance analysis identified differential expression of 153 and 147 genes, respectively, in coronary artery disease or dilated cardiomyopathy versus non-failing hearts. Analysis of Gene Ontology biological process annotations indicated aetiology-specific patterns, primarily related to genes involved in catabolism and in regulation of protein kinase activity. Gene expression classifiers were obtained and used for class prediction of random samples of coronary artery diseased and dilated cardiomyopathic hearts. Best classifiers frequently included matrix metalloproteinase 3, fibulin 1, ATP-binding cassette, sub-family B member 1 and iroquois homeobox protein 5. Combining functional annotation from microarray data and classification analysis constitutes a potent strategy to identify disease-specific biological processes and gene expression markers in e.g. end-stage coronary artery disease and dilated cardiomyopathy.

Early induction of matrix metalloproteinase-9 transduces signaling in human heart end stage failure.

Extracellular matrix (ECM) turnover is regulated by matrix metalloproteinases (MMPs) and plays an important role in cardiac remodeling. Previous studies from our lab demonstrated an increase in gelatinolytic-MMP-2 and -9 activities in endocardial tissue from ischemic cardiomyopathic (ICM) and idiopathic dilated cardiomyopathic (DCM) hearts. The signaling mechanism responsible for the left ventricular (LV) remodeling, however, is unclear. Administration of cardiac specific inhibitor of metalloproteinase (CIMP) prevented the activation of MMP-2 and -9 in ailing to failing myocardium. Activation of MMP-2 and -9 leads to induction of proteinase activated receptor-1 (PAR-1). We hypothesize that the early induction of MMP-9 is a key regulator for modulating intracellular signaling through activation of PAR and various downstream events which are implicated in development of cardiac fibrosis in an extracellular receptor mediated kinase-1 (ERK-1) and focal adhesion kinase (FAK) dependent manner. To test this hypothesis, explanted human heart tissues from ICM and DCM patients were obtained at the time of orthotopic cardiac transplants. Quantitative analysis of MMP-2 and -9 gelatinolytic activities was made by real-time quantitative zymography. Gel phosphorylation staining for PAR-1 showed a significant increase in ICM hearts. Western blot and RT-PCR analysis and in-situ labeling, showed significant increased expression of PAR-1, ERK-1and FAK in ICM and DCM. These observations suggest that the enhanced expression and potentially increased activity of LV myocardial MMP-9 triggers the signal cascade instigating cardiac remodeling. This early mechanism for the initiation of LV remodeling appears to have a role in end-stage human heart failure.

Increased Nitration of Sarcoplasmic Reticulum Ca 2+ -ATPase in Human Heart Failure

Reduced sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA2a isoform) activity is a major determinant of reduced contractility in heart failure. Ca2+-ATPase inactivation can occur through SERCA2a nitration. We therefore investigated the role of SERCA2a nitration in heart failure. We measured SERCA2a levels and nitrotyrosine levels in tissue from normal and failing human hearts using Western blots. We found that nitrotyrosine levels in idiopathic dilated cardiomyopathic (DCM) hearts were almost double those of control hearts in age-matched groups. Nitrotyrosine was dominantly present in a single protein with the molecular weight of SERCA2a, and immunoprecipitation confirmed that the protein recognized by the nitrotyrosine antibody was SERCA2a. There was a positive correlation between the time to half relaxation and the nitrotyrosine/SERCA2a content (P<0.01) in myocytes isolated from control and DCM hearts. In experiments with isolated SR vesicles from porcine hearts, we also showed that the Ca pump is inactivated by peroxynitrite exposure, and inactivation was prevented by protein kinase A pretreatment. We conclude that SERCA2a inactivation by nitration may contribute to Ca pump failure and hence heart failure in DCM.

Differential functional expression of human myocardial G protein receptor kinases in left ventricular cardiac diseases

The relationship between myocardial G protein receptor kinase (GRK) expression and β-adrenoceptor signalling in human left heart diseases has not been fully elucidated yet. In this study, we characterized and compared the GRK2–7 expression in patients with left ventricular volume overload disorders and dilated cardiomyopathic hearts, and evaluated the relationship of this expression with alterations in myocardial β-adrenoceptor signalling in volume overload, in order to test the notion that GRK functional expression is influenced in a disease-specific and selective fashion. We established that GRK2, GRK3, and GRK5 are well expressed, while GRK4, GRK6, and GRK7 are only scarcely detectable in the healthy human heart. Compared to control hearts ( n=8), GRK2 mRNA expression was elevated by 71% ( P<0.005) in the left ventricle, 110% ( P<0.05) in the right ventricle, 130% ( P<0.05) in the left atrium, and 1300% ( P<0.005) in the right atrium (RA) of the dilated cardiomyopathy hearts ( n=6). In the volume overload group ( n=10), it was increased by approximately 40% ( P<0.05) in the left ventricle, 38% in the right ventricle, 81% ( P<0.05) in the left atrium, and 850% ( P<0.005) in the right atrium. On the other hand, GRK5 was significantly elevated only in the left ventricle by 68% ( P<0.05) in the dilated cardiomyopathy hearts and by 48% ( P<0.01) in volume overload patients, while in contrast, GRK3 remained unchanged in dilated cardiomyopathy, but was slightly elevated by 36% ( P=0.05) in the right ventricle of the volume overload patients. The alterations in GRK expression were accompanied with a decrease in myocardial β 1-adrenoceptor mRNA in all four chambers, and these trends in gene expression were paralleled with those of their immunodetectable protein levels. Furthermore, these changes were in association with a decrease in downstream receptor-stimulated, adenylyl cyclase-mediated functional expression and an increase in ventricular protein kinase A activity. The results point to differences in which myocardial GRKs are regulated in cardiac disease, whereby changes in GRK2 expression may be related to the global effects of the disease on myocardial adrenoceptor function and those in GRK5 may be localized to the ventricles, depending on the nature of the myocardial load.

Alterations in apoptotic signaling in human idiopathic cardiomyopathic hearts in failure.

Dilated cardiomyopathy, a disease of unknown etiology and pathogenesis, is associated with heart failure and compensatory hypertrophy. Although cell and animal models suggest a role for altered gene expression in the transition to heart failure, there is a paucity of data derived from the study of human heart tissue. In this study, we used DNA microarray profiling to investigate changes in the expression of genes involved in apoptosis that occur in human idiopathic dilated cardiomyopathic hearts that had progressed to heart failure. We observed altered gene expression consistent with a proapoptotic shift in the TNF-alpha signaling pathway. Specifically, we found decreased expression of TNF-alpha- and NF-kappaB-induced antiapoptotic genes such as growth arrest and DNA damage-inducible (GADD)45beta, Flice inhibitory protein (FLIP), and TNF-induced protein 3 (A20). Consistent with a role for apoptosis in heart failure, we also observed a significant decrease in phosphorylation of BAD at Ser-112. This study identifies several pathways that are altered in human heart failure and provides new targets for therapy.

Effects of cardioselective KATP channel antagonism on basal, stimulated, and ischaemic myocardial function in in vivo failing canine heart.

Inhibition of cardiomyocyte-specific ATP-sensitive potassium (K(ATP)) channels prolongs the action potential during intense ischaemia with attendant antiarrhythmic effects. However, this is accompanied by contractile depression in some models. These changes may be particularly troublesome in dilated cardiomyopathic hearts that display basal systolic dysfunction, limited energy reserve, and prolonged repolarization favouring arrhythmia. Mechanical effects of selective myocyte K(ATP) channel blockade on basal, beta-adrenergic stimulated, and ischemic responses were therefore tested in dogs with cardiac failure induced by tachypacing. Cardiovascular function was assessed by pressure - dimension relationships in 10 conscious, chronically instrumented dogs (sonomicrometry/micromanometry), with or without cardiac failure. Cardiomyocyte K(ATP) channels were inhibited by HMR 1098, and data obtained under basal conditions, during epinephrine infusion to raise metabolic demand, during regional ischaemia, and with combined ischaemia+epinephrine. HMR 1098 had no effect on baseline cardiac function nor did it induce arrhythmia in normal or failing hearts. Epinephrine raised cardiac work 65% and oxygen consumption 55%, yet HMR 1098 had no functional effect in either heart condition. Regional ischaemia with or without epinephrine co-stimulation depressed regional and global function, yet both were also unaffected by HMR 1098. There was minimal arrhythmia without HMR 1098, and drug infusion did not alter this. Thus, myocyte-K(ATP) channels play a negligible role modulating intact in vivo cardiac contraction or arrhythmia in normal and failing heart with and without increased metabolic demand and/or regional ischaemia. This supports the feasibility of administering such agents to depressed hearts, despite underlying contractile and electrophysiologic abnormalities.

Predominant inner-half wall thickening of left ventricle is attenuated in dilated cardiomyopathy: an application of tissue doppler tracking technique

The importance of the inner half (IH) of the left ventricular (LV) wall has been reported in hearts that contract normally. However, it is difficult to verify this fact in an in vivo human heart with clinical echocardiography. By using a recently developed tissue Doppler tracking technique, we could assess the systolic wall thickening of the IH and outer half (OH) of the LV wall in 11 normal and 7 dilated cardiomyopathic hearts. Percent wall thickening and the fractional contribution of the IH and OH to the transmural wall thickening were calculated. In healthy subjects, percent wall thickening of the IH, OH, and transmural wall of the left ventricle were 75.8% ± 24.1%, 39.4% ± 14.4% (P <.001 versus IH), and 57.6% ± 17.6%, respectively. In patients with dilated cardiomyopathy, those values were 31.3% ± 17.1%, 31.2% ± 20.1% (not significant versus IH), and 31.2% ± 16.5%, respectively. On the other hand, the fractional contributions of the IH and OH were 66.2% ± 7.7% and 33.8% ± 7.7% (P <.01 versus IH) in healthy subjects and 50.5% ± 11.8% and 49.5% ± 11.8% (not significant versus IH) in patients with dilated cardiomyopathy. Specifically, the IH contributed to the transmural wall thickening nearly twice as much as the OH did in healthy subjects, however, the predominance of IH contribution was attenuated in dilated cardiomyopathy. The tissue Doppler tracking technique is useful in assessing the IH and OH LV wall thickening separately in the clinical situation. (J Am Soc Echocardiogr 2001;14:97-103.)

Autologous smooth muscle cell transplantation improved heart function in dilated cardiomyopathy

Background. Transplantation of myocytes into scarred myocardium has been shown to inhibit ventricular remodeling and maintain myocardial contractility. However, the effect of cell transplantation on hearts with global rather than regional dysfunction is unknown. Therefore, we evaluated the effect of transplantation of autologous smooth muscle cells on the morphometry and function of dilated cardiomyopathic hearts. Methods. Smooth muscle cells were isolated from the ductus deferens of 13-week-old BIO 53.58 hamsters with dilated cardiomyopathy, and cultured for 4 weeks before transplantation. Smooth muscle cells (4 × 10 6 cells) or culture medium were injected into 17-week-old animals in the transplantation and control groups (n = 12 each), respectively. Prelabeling of the smooth muscle cells with 5-bromo-2′-deoxyuridine was performed before transplantation in a group of transplanted hamsters. Another group (sham, n = 12) underwent the operation but did not receive an injection either of smooth muscle cells or of culture medium. Four weeks after transplantation, heart function was evaluated in a Langendorff preparation. Results. Musclelike tissue, labeled with 5-bromo-2′-deoxyuridine, was found at the site of transplantation in the cell-transplanted animals. The cell-transplanted hearts were smaller ( p < 0.001), and had greater developed pressures and maximum rate of increase of left ventricular pressure (both p < 0.001) than control and sham hearts. Control hamsters injected with culture medium did not differ from sham-operated animals. Conclusions. Transplantation of autologous smooth muscle cells prevented cardiac dilatation and improved ventricular function in hamsters with dilated cardiomyopathy.