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Remodeling of cardiac venous system in heart failure
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ABSTRACTS / Journal of Molecular and Cellular Cardiology 42 (2007) S145–S161
phosphatase. Using the Pro-Q diamond phosphoprotein gel stain to detect phosphorylated proteins we found that the crude phosphatase specifically dephosphorylated troponin I and not troponin T. When measured with PKA-phosphorylated recombinant troponin I as the substrate, heart muscle myofibrils contained substantial phosphatase activity (up to 40,000 pmol/ mg myofibril/min). Phosphatase activity was 94% inhibited by 2 nM okadaic acid, 30% inhibited by 0.2 μM inhibitor-2 and Ca2+-activated phosphatase activity was less than 5%. All this indicates that protein phosphatase 2a is the predominant phosphatase type present in human heart myofibrils. The specific activity of the troponin I phosphatase was increased by about 19.3 ± 7.4% in failing heart muscle myofibrils compared with non-failing heart muscle myofibrils. Therefore, enhanced phosphatase activity may be responsible for the low levels of phosphorylation observed in failing heart muscle. Keywords: Heart failure; Phosphorylation; Proteins doi:10.1016/j.yjmcc.2007.03.498
MicroRNAs in the human heart: A clue to fetal gene reprogramming in heart failure T. Thum1, P. Galuppo1, S. Kneitz1, J. Fiedler1, L. Van Laake2, C. Mummery2, G. Ertl1, J. Bauersachs1. 1Universities of Würzburg, Germany. 2Utrecht, Netherlands Chronic heart failure is characterized by left ventricular remodeling and reactivation of a fetal gene program; the underlying mechanisms are only partly understood. Here we provide evidence that cardiac microRNAs, recently discovered key regulators of gene expression, critically determine the transcriptional changes observed in heart failure. Cardiac transcriptome analyses revealed striking similarities between fetal and failing human heart tissue. Using microRNA arrays, we discovered profound alterations of microRNA expression in failing hearts. These changes closely mimicked the microRNA expression pattern observed in fetal cardiac tissue. Bioinformatic analysis demonstrated a striking concordance between deregulated messenger RNA expression in heart failure and the presence of microRNA binding sites in the respective 3′ untranslated regions. Messenger RNAs upregulated in the failing heart contained preferentially binding sites for downregulated microRNAs and vice versa. Mechanistically, transfection of cardiomyocytes with a set of fetal microRNAs induced cellular hypertrophy and disarray as well as changes in gene expression comparable to the failing heart. Our data support a novel mode of regulation for the transcriptional changes in cardiac failure. Reactivation of a fetal microRNA program substantially contributes to alterations of gene expression in the failing human heart. Keywords: Heart failure; Hypertrophy; MicroRNAs doi:10.1016/j.yjmcc.2007.03.499
Transient enhancement of oxidant stress and collagen turnover in patients with acute decompensated congestive heart failure Yoshiyuki Kijima, Megumi Kunishige, Taku Sakai, Osamu Akutagawa, Akiko Matsuo, Akira Nishibe, Yusuke Nakagawa, Takeshi Hata. Department of Cardiology, Higashi-Osaka City General Hospital, Osaka, Japan Myocardial remodeling is a crucial step for progression of heart failure. Free radical generation from failing myocardium has been proposed to be linked to myocardial remodeling. The aim of this study was to evaluate urinary excretion of 8-isoprostaglandin F2α (8-iso-PGF2α), a reliable marker for oxidant stress in vivo, and collagen turnover in patients with acute worsening of congestive heart failure (CHF). Enrolled were 43 patients with acute worsening of CHF due to various etiologies. At their admission (acute phase) and after approximately 2week conventional treatment (chronic phase), we measured (1) immunoreactive urinary 8-iso-PGF2α, (2) serum total antioxidant status (TAS); and (3) serum levels of procollagen type I carboxyterminal peptide (PIP) and carboxyterminal collagen type I telopeptide (CITP), biochemical markers for collagen synthesis and degradation, respectively. From acute phase to chronic phase these parameters were monitored: 335.1 ± 245.4 to 205.3 ± 107.4 pg/mg creatinine for urinary 8-iso-PGF2α (P < 0.0001); 0.92 ± 0.16 to 0.98 ± 0.13 mM for TAS (P < 0.01); 171.4 ± 72.5 to 93.7 ± 33.9 ng/ml for PIP (P < 0.0001); and 7.2 ± 3.6 to 12.6 ± 8.4 ng/ml for CITP (P < 0.0001). In conclusion, acute worsening of CHF promotes free radical generation and collagen synthesis.
Keywords: Heart failure; Free radicals; Cardiac remodeling doi:10.1016/j.yjmcc.2007.03.500
Remodeling of cardiac venous system in heart failure Antonio Sorgente, Cristina Conca, Angelo Auricchio, Francesco Fulvio Faletra, Elena Pasotti, Giovanbattista Pedrazzini, Tiziano Moccetti. Relational changes in patients with heart failure (HF) among coronary sinus (CS), left atrial and ventricular volumes and coronary arteries have been neglected so far. The aim of this work was to study the spatial relationship among these structures through 64 multi-slice computed tomography (64 MSCT). The 64 MSCT data of individuals (age 65.1 ± 11.5 years, 58.7% men) were evaluated. Subjects were divided in 3 groups: 28 controls, 18 patients with coronary artery disease but with a preserved left ventricular ejection fraction (LVEF) and 34 patients with symptomatic HF of any etiology. The following parameters were measured: CS length (CS-L), CS ostium area (CS-Oa), axial angle (AA) measured as the angle between CS and mitral annulus (MA) assessed in axial section, mitral annulus area (MAA), left atrium volume (LAV)
ABSTRACTS / Journal of Molecular and Cellular Cardiology 42 (2007) S145–S161
and LCX (left circumflex artery)–CS relationship referring to MA. Results: Patients with depressed LVEF had significantly longer (p = 0.000) and larger (p = 0.002) CS; there was a strong correlation between the CS-L and LAV (r = 0.60, p = 0.000) and between CS-L and MAA (r = 0.63, p = 0.000). Patients with HF showed a more acute angle between CS and MA (p = 0.000), with a good correlation between AA and MAA (r = − 0.604, p = 0.001). Finally, in the 77% of the patients, regardless to the LVEF, LCX was located between CS and MA. Conclusions: Our observations are consistent with a remodeling process of the CS in HF as shown by the increase of CSL and CS-Oa. There was a shift of the CS from the posterior wall of left atrium to the atrio-ventricular groove due to increase of LAV and MAA. In the vast majority of patients LCX was located between CS and MV. These findings may have implications for applicability of percutaneous mitral annuloplasty. Keywords: Percutaneous mitral annuloplasty; Heart failure; Coronary venous system doi:10.1016/j.yjmcc.2007.03.501
Skeletal muscle myofibrillar protein oxidation in patients with heart failure Luciano Dalla Libera, Barbara Ravara, Giorgio Vescovo. CNR Institute of Neurosciences, Padova; Internal Medicine, City Hospital, Vicenza, Italy Heart failure is a clinical syndrome characterized by decreased exercise capacity with early appearance of dyspnea and fatigue. It has been shown that the inflammatory status produces a skeletal muscle myopathy with muscle atrophy and transition from slow to fast fibers. Free radicals also contribute to target organ damage in this syndrome. With Oxyblot technique, we have already demonstrated that myofibrillar proteins are greatly oxidized in an animal model of heart failure, the monocrotalinetreated rat. We have analyzed by means of Oxyblot assay skeletal muscle, to monitor the presence of oxidized proteins. We had the possibility to obtain from patients with heart failure microbiopsies taken with the Menghini needle. We demonstrate that muscle biopsy performed with this technique displays fairly low invasivity and thus higher patient compliance compared to surgical muscle biopsy. The amount of tissue obtained was indeed sufficient to perform the analysis. The data obtained clearly demonstrate that skeletal muscle proteins are more oxidized in patients than that in a control muscle. Furthermore the oxidation pattern observed is very similar to that obtained from the experimental CHF rat. Keywords: Heart failure; Skeletal muscle; Oxidative stress doi:10.1016/j.yjmcc.2007.03.502
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Skeletal muscle protein oxidation in heart failure: The effect of carvedilol Giorgio Vescovo, Barbara Ravara, Daniela Danieli, Annalisa Angelini, Luciano Dalla Libera. CNR Inst. of Neurosciences, Padova; City Hospital, Vicenza, Italy Heart Failure is characterized by a skeletal muscle myopathy with atrophy and shift toward fast fibres. An inflammatory status with elevated pro-inflammatory cytokines and exaggerated free radicals production can worsen muscle damage. In a well-established model of heart failure, the monocrotalinetreated rat, we show that CHF is accompanied by oxidation of the skeletal muscle actin, tropomyosin and myosin, which further depresses muscle function and exercise capacity. We have also tested the efficacy of Carvedilol, a non-selective beta1-beta2-blocker, which has been widely used in clinical trials to improve exercise tolerance and reduce mortality in moderate and severe CHF, in preventing contractile protein oxidation in CHF rats. Carvedilol at the dose of 2 mg/kg/day was able to prevent the myofibrillar protein oxidation, as demonstrated by the oxyblot analysis and improved force production on isolated muscles. Inhibition of ROS production and of pro-inflammatory cytokines may also lead to decreased muscle wastage, another factor contributing to worsening of exercise tolerance. Keywords: Heart failure; Oxidative stress; Carvedilol doi:10.1016/j.yjmcc.2007.03.503
Prognostic significance of NT-PROBNP and inferior vena cava diameter in patients with severe acute heart failure R. Pudil, M. Tichy, V. Blaha, J. Vojacek. Charles University Prague, Medical Faculty Hradec Kralove, Czech Republic Background: Increased pressure in right atrium is associated with the diameter of inferior vena cava in patients with acute heart failure. We evaluated the relation between vena cava inferior diameter (IVCD) and short- and long-term mortality in patients with severe acute heart failure. Methods and results: Study population consisted of 96 patients (65 men, 62.3 ± 13.9 years) with severe acute heart failure. During 1-year follow-up, 32 patients died. IVCD was increased (22.2 ± 3.4 mm, vs.15.4 ± 1.9 mm, p < 0.01). In survivors, the IVCD was lower (20.5 ± 1.7 mm, vs.24.4 ± 2.1 mm, p < 0.05). In multiple logistic regression analysis, plasma IVCD was closely associated with plasma creatinine level, NT-proBNP levels (p < 0.01), and gender (p < 0.05). RR for 7-day mortality was 2.0, for 28 days mortality was 1.8, and for 1-year mortality 4.1. Conclusions: IVCD was independent on risk factors as age, history of coronary artery disease, presence of diabetes mellitus, smoking and hyperlipidemia.
ABSTRACTS / Journal of Molecular and Cellular Cardiology 42 (2007) S145–S161
phosphatase. Using the Pro-Q diamond phosphoprotein gel stain to detect phosphorylated proteins we found that the crude phosphatase specifically dephosphorylated troponin I and not troponin T. When measured with PKA-phosphorylated recombinant troponin I as the substrate, heart muscle myofibrils contained substantial phosphatase activity (up to 40,000 pmol/ mg myofibril/min). Phosphatase activity was 94% inhibited by 2 nM okadaic acid, 30% inhibited by 0.2 μM inhibitor-2 and Ca2+-activated phosphatase activity was less than 5%. All this indicates that protein phosphatase 2a is the predominant phosphatase type present in human heart myofibrils. The specific activity of the troponin I phosphatase was increased by about 19.3 ± 7.4% in failing heart muscle myofibrils compared with non-failing heart muscle myofibrils. Therefore, enhanced phosphatase activity may be responsible for the low levels of phosphorylation observed in failing heart muscle. Keywords: Heart failure; Phosphorylation; Proteins doi:10.1016/j.yjmcc.2007.03.498
MicroRNAs in the human heart: A clue to fetal gene reprogramming in heart failure T. Thum1, P. Galuppo1, S. Kneitz1, J. Fiedler1, L. Van Laake2, C. Mummery2, G. Ertl1, J. Bauersachs1. 1Universities of Würzburg, Germany. 2Utrecht, Netherlands Chronic heart failure is characterized by left ventricular remodeling and reactivation of a fetal gene program; the underlying mechanisms are only partly understood. Here we provide evidence that cardiac microRNAs, recently discovered key regulators of gene expression, critically determine the transcriptional changes observed in heart failure. Cardiac transcriptome analyses revealed striking similarities between fetal and failing human heart tissue. Using microRNA arrays, we discovered profound alterations of microRNA expression in failing hearts. These changes closely mimicked the microRNA expression pattern observed in fetal cardiac tissue. Bioinformatic analysis demonstrated a striking concordance between deregulated messenger RNA expression in heart failure and the presence of microRNA binding sites in the respective 3′ untranslated regions. Messenger RNAs upregulated in the failing heart contained preferentially binding sites for downregulated microRNAs and vice versa. Mechanistically, transfection of cardiomyocytes with a set of fetal microRNAs induced cellular hypertrophy and disarray as well as changes in gene expression comparable to the failing heart. Our data support a novel mode of regulation for the transcriptional changes in cardiac failure. Reactivation of a fetal microRNA program substantially contributes to alterations of gene expression in the failing human heart. Keywords: Heart failure; Hypertrophy; MicroRNAs doi:10.1016/j.yjmcc.2007.03.499
Transient enhancement of oxidant stress and collagen turnover in patients with acute decompensated congestive heart failure Yoshiyuki Kijima, Megumi Kunishige, Taku Sakai, Osamu Akutagawa, Akiko Matsuo, Akira Nishibe, Yusuke Nakagawa, Takeshi Hata. Department of Cardiology, Higashi-Osaka City General Hospital, Osaka, Japan Myocardial remodeling is a crucial step for progression of heart failure. Free radical generation from failing myocardium has been proposed to be linked to myocardial remodeling. The aim of this study was to evaluate urinary excretion of 8-isoprostaglandin F2α (8-iso-PGF2α), a reliable marker for oxidant stress in vivo, and collagen turnover in patients with acute worsening of congestive heart failure (CHF). Enrolled were 43 patients with acute worsening of CHF due to various etiologies. At their admission (acute phase) and after approximately 2week conventional treatment (chronic phase), we measured (1) immunoreactive urinary 8-iso-PGF2α, (2) serum total antioxidant status (TAS); and (3) serum levels of procollagen type I carboxyterminal peptide (PIP) and carboxyterminal collagen type I telopeptide (CITP), biochemical markers for collagen synthesis and degradation, respectively. From acute phase to chronic phase these parameters were monitored: 335.1 ± 245.4 to 205.3 ± 107.4 pg/mg creatinine for urinary 8-iso-PGF2α (P < 0.0001); 0.92 ± 0.16 to 0.98 ± 0.13 mM for TAS (P < 0.01); 171.4 ± 72.5 to 93.7 ± 33.9 ng/ml for PIP (P < 0.0001); and 7.2 ± 3.6 to 12.6 ± 8.4 ng/ml for CITP (P < 0.0001). In conclusion, acute worsening of CHF promotes free radical generation and collagen synthesis.
Keywords: Heart failure; Free radicals; Cardiac remodeling doi:10.1016/j.yjmcc.2007.03.500
Remodeling of cardiac venous system in heart failure Antonio Sorgente, Cristina Conca, Angelo Auricchio, Francesco Fulvio Faletra, Elena Pasotti, Giovanbattista Pedrazzini, Tiziano Moccetti. Relational changes in patients with heart failure (HF) among coronary sinus (CS), left atrial and ventricular volumes and coronary arteries have been neglected so far. The aim of this work was to study the spatial relationship among these structures through 64 multi-slice computed tomography (64 MSCT). The 64 MSCT data of individuals (age 65.1 ± 11.5 years, 58.7% men) were evaluated. Subjects were divided in 3 groups: 28 controls, 18 patients with coronary artery disease but with a preserved left ventricular ejection fraction (LVEF) and 34 patients with symptomatic HF of any etiology. The following parameters were measured: CS length (CS-L), CS ostium area (CS-Oa), axial angle (AA) measured as the angle between CS and mitral annulus (MA) assessed in axial section, mitral annulus area (MAA), left atrium volume (LAV)
ABSTRACTS / Journal of Molecular and Cellular Cardiology 42 (2007) S145–S161
and LCX (left circumflex artery)–CS relationship referring to MA. Results: Patients with depressed LVEF had significantly longer (p = 0.000) and larger (p = 0.002) CS; there was a strong correlation between the CS-L and LAV (r = 0.60, p = 0.000) and between CS-L and MAA (r = 0.63, p = 0.000). Patients with HF showed a more acute angle between CS and MA (p = 0.000), with a good correlation between AA and MAA (r = − 0.604, p = 0.001). Finally, in the 77% of the patients, regardless to the LVEF, LCX was located between CS and MA. Conclusions: Our observations are consistent with a remodeling process of the CS in HF as shown by the increase of CSL and CS-Oa. There was a shift of the CS from the posterior wall of left atrium to the atrio-ventricular groove due to increase of LAV and MAA. In the vast majority of patients LCX was located between CS and MV. These findings may have implications for applicability of percutaneous mitral annuloplasty. Keywords: Percutaneous mitral annuloplasty; Heart failure; Coronary venous system doi:10.1016/j.yjmcc.2007.03.501
Skeletal muscle myofibrillar protein oxidation in patients with heart failure Luciano Dalla Libera, Barbara Ravara, Giorgio Vescovo. CNR Institute of Neurosciences, Padova; Internal Medicine, City Hospital, Vicenza, Italy Heart failure is a clinical syndrome characterized by decreased exercise capacity with early appearance of dyspnea and fatigue. It has been shown that the inflammatory status produces a skeletal muscle myopathy with muscle atrophy and transition from slow to fast fibers. Free radicals also contribute to target organ damage in this syndrome. With Oxyblot technique, we have already demonstrated that myofibrillar proteins are greatly oxidized in an animal model of heart failure, the monocrotalinetreated rat. We have analyzed by means of Oxyblot assay skeletal muscle, to monitor the presence of oxidized proteins. We had the possibility to obtain from patients with heart failure microbiopsies taken with the Menghini needle. We demonstrate that muscle biopsy performed with this technique displays fairly low invasivity and thus higher patient compliance compared to surgical muscle biopsy. The amount of tissue obtained was indeed sufficient to perform the analysis. The data obtained clearly demonstrate that skeletal muscle proteins are more oxidized in patients than that in a control muscle. Furthermore the oxidation pattern observed is very similar to that obtained from the experimental CHF rat. Keywords: Heart failure; Skeletal muscle; Oxidative stress doi:10.1016/j.yjmcc.2007.03.502
S155
Skeletal muscle protein oxidation in heart failure: The effect of carvedilol Giorgio Vescovo, Barbara Ravara, Daniela Danieli, Annalisa Angelini, Luciano Dalla Libera. CNR Inst. of Neurosciences, Padova; City Hospital, Vicenza, Italy Heart Failure is characterized by a skeletal muscle myopathy with atrophy and shift toward fast fibres. An inflammatory status with elevated pro-inflammatory cytokines and exaggerated free radicals production can worsen muscle damage. In a well-established model of heart failure, the monocrotalinetreated rat, we show that CHF is accompanied by oxidation of the skeletal muscle actin, tropomyosin and myosin, which further depresses muscle function and exercise capacity. We have also tested the efficacy of Carvedilol, a non-selective beta1-beta2-blocker, which has been widely used in clinical trials to improve exercise tolerance and reduce mortality in moderate and severe CHF, in preventing contractile protein oxidation in CHF rats. Carvedilol at the dose of 2 mg/kg/day was able to prevent the myofibrillar protein oxidation, as demonstrated by the oxyblot analysis and improved force production on isolated muscles. Inhibition of ROS production and of pro-inflammatory cytokines may also lead to decreased muscle wastage, another factor contributing to worsening of exercise tolerance. Keywords: Heart failure; Oxidative stress; Carvedilol doi:10.1016/j.yjmcc.2007.03.503
Prognostic significance of NT-PROBNP and inferior vena cava diameter in patients with severe acute heart failure R. Pudil, M. Tichy, V. Blaha, J. Vojacek. Charles University Prague, Medical Faculty Hradec Kralove, Czech Republic Background: Increased pressure in right atrium is associated with the diameter of inferior vena cava in patients with acute heart failure. We evaluated the relation between vena cava inferior diameter (IVCD) and short- and long-term mortality in patients with severe acute heart failure. Methods and results: Study population consisted of 96 patients (65 men, 62.3 ± 13.9 years) with severe acute heart failure. During 1-year follow-up, 32 patients died. IVCD was increased (22.2 ± 3.4 mm, vs.15.4 ± 1.9 mm, p < 0.01). In survivors, the IVCD was lower (20.5 ± 1.7 mm, vs.24.4 ± 2.1 mm, p < 0.05). In multiple logistic regression analysis, plasma IVCD was closely associated with plasma creatinine level, NT-proBNP levels (p < 0.01), and gender (p < 0.05). RR for 7-day mortality was 2.0, for 28 days mortality was 1.8, and for 1-year mortality 4.1. Conclusions: IVCD was independent on risk factors as age, history of coronary artery disease, presence of diabetes mellitus, smoking and hyperlipidemia.