Antioxidant changes in hypertrophied and failing guinea pig hearts

1994 ◽  
Vol 266 (4) ◽  
pp. H1280-H1285 ◽  
Author(s):  
A. K. Dhalla ◽  
P. K. Singal
Keyword(s):  
Heart Failure ◽  
Lipid Peroxidation ◽  
Clinical Signs ◽  
Left Ventricular ◽  
Heart Weight ◽  
Sod Activity ◽  
Failure Group ◽  
Malondialdehyde Content ◽  
Ventricular Wall Thickness ◽  
Gshpx Activity

Hypertrophy and heart failure were induced by placing a mildly constrictive band around the ascending aorta in young guinea pigs. Based on heart weight, left ventricular wall thickness, hemodynamic data, and other clinical signs, these animals were found to have physiological hypertrophy at 10 wk and congestive heart failure (CHF) at 20 wk. Hearts from these two groups of animals were examined for superoxide dismutase (SOD), glutathione peroxidase (GSHPx), and catalase activities as well as lipid peroxidation and glutathione [reduced glutathione (GSH)/oxidized glutathione (GSSG)] levels. There was an age-dependent increase in SOD activity and GSH content in sham controls. SOD activity was 28% higher in the 10-wk-hypertrophy group and 46% lower in the CHF group than in respective sham controls. GSHPx activity increased significantly in the hypertrophied hearts, whereas in the failing hearts, the activity was not different from the 20-wk controls but was significantly lower than in the hypertrophied hearts. Catalase activity did not change at either stage. GSH content in the hypertrophied hearts was significantly higher compared with sham controls. In the CHF group, GSH content was significantly lower and GSSG content was significantly higher than in sham controls. Lipid peroxidation, as indicated by malondialdehyde content, was significantly decreased in the hypertrophy group but increased toward control levels in the failure group. It is proposed that a relative deficit in myocardial antioxidant capacity as well as in the redox state may play a role in the pathogenesis of cardiac failure.

Inhibition and reversal of myocardial infarction-induced hypertrophy and heart failure by NHE-1 inhibition

2004 ◽  
Vol 286 (1) ◽  
pp. H381-H387 ◽  
Author(s):  
Ling Chen ◽  
Chang Xun Chen ◽  
Xiaohong Tracey Gan ◽  
Norbert Beier ◽  
Wolfgang Scholz ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Infarct Size ◽  
Treatment Delay ◽  
Left Ventricular ◽  
Heart Weight ◽  
Coronary Artery Ligation ◽  
Treatment Protocols ◽  
Beneficial Effects ◽  
All Treatment

Sodium/hydrogen exchange (NHE) inhibitors show promise as potential therapeutic agents for the treatment of heart failure, but it is not known whether they can reverse the maladaptive remodeling that results in heart failure. We sought to determine the effect of the NHE-1-specific inhibitor EMD-87580 (EMD) on heart failure produced by myocardial infarction in the rat and to assess whether up to 4 wk of treatment delay results in beneficial effects. Male Sprague-Dawley rats were subjected to coronary artery ligation (or a sham procedure) and followed for up to 3 mo, at which time hypertrophy and hemodynamics were determined. EMD was provided in the diet, and treatment commenced immediately or 2–4 wk after ligation. EMD significantly reduced hemodynamic abnormalities, including the elevation in left ventricular end-diastolic pressure, and diminished the loss of systolic function with all treatment protocols. Left ventricular dilatation and hypertrophy, as assessed by heart weight, cell size, and atrial natriuretic peptide (ANP) expression, were similarly reversed to sham or near-sham levels. In addition, the increased plasma ANP and pro-ANP values were reversed to levels not significantly different from sham. Surprisingly, virtually all beneficial effects were identical with all treatment protocols. These effects were observed in the absence of infarct size reduction or blood pressure-lowering effects. Our results suggest that NHE-1 inhibition attenuates and reverses postinfarction remodeling and heart failure with a treatment delay of up to 4 wk after infarction. The effect is independent of infarct size or afterload reduction, indicating a direct effect on the myocardium.

scholarly journals Drug-Induced Heart Failure (Part 2: Mechanisms of Development, Clinical Signs, Differential Diagnosis, Risk Factors, Treatment and Prevention)

2020 ◽  
Vol 8 (2) ◽  
pp. 57-65
Author(s):  
O. D. Ostroumova ◽  
I. V. Goloborodova
Keyword(s):  
Heart Failure ◽  
Beta Blockers ◽  
Clinical Signs ◽  
Clinical Manifestations ◽  
Left Ventricular ◽  
Clinical Syndrome ◽  
Channel Blockers ◽  
Drug Induced ◽  
Treatment And Prevention ◽  
Developing Heart

Heart failure is a complex clinical syndrome caused by an impaired pumping function of the heart muscle, etiologically associated with cardiovascular disease and, in the vast majority of cases, requiring complex therapeutic regimens and simultaneous prescription of several drugs. To date, we know several classes of drugs (including those used for heart failure) which can induce development/progression of heart failure in both patients with left ventricular dysfunction, and in patients who do not have cardiovascular diseases. The aim of the study was to analyse and systematize data on development mechanisms, as well as methods of prevention and treatment of drug-induced heart failure when using diff erent groups of drugs. It has been established that drug-induced heart failure is most often associated with the use of calcium channel blockers (verapamil, diltiazem, nifedipine), beta-blockers, antiarrhythmic drugs (disopyramide, fl ecainide, propafenone, amiodarone, ibutilide, dofetilide, dronedarone), anthracyclines (doxorubicin) and other antitumor drugs (trastuzumab, bevacizumab, infl iximab), hypoglycemic drugs (thiazolidinediones, saxagliptin, alogliptin), and nonsteroidal anti-infl ammatory drugs, including selective cyclooxygenase-2 inhibitors. The study revealed various mechanisms of heart failure development following drug treatment. In some patients, heart failure development is associated with the cardiotoxic eff ect of a particular drug, in others with adverse eff ects on hemodynamics. Much depends on risks of developing heart failure, including specifi c risks attributable to groups of drugs and individual drugs. The identifi cation of drugs that can contribute to the development/ progression of heart failure, and possible clinical manifestations of drug-induced heart failure, as well as provision of timely information to physicians, and engagement of clinical pharmacologists with the aim of optimizing treatment of patients can facilitate timely diagnosis, treatment and prevention of drug-induced heart failure. 

Role of Diastole in Left Ventricular Function, II: Diagnosis and Treatment

2004 ◽  
Vol 13 (6) ◽  
pp. 453-466 ◽  
Author(s):  
Shannan K. Hamlin ◽  
Penelope S. Villars ◽  
Joseph T. Kanusky ◽  
Andrew D. Shaw
Keyword(s):  
Heart Failure ◽  
Diastolic Dysfunction ◽  
Left Atrial ◽  
Diastolic Heart Failure ◽  
Systolic Heart Failure ◽  
Clinical Signs ◽  
Left Ventricular ◽  
Exercise Intolerance ◽  
Radiographic Findings ◽  
Ventricular Compliance

Left ventricular diastolic dysfunction plays an important role in congestive heart failure. Although once thought to be lower, the mortality of diastolic heart failure may be as high as that of systolic heart failure. Diastolic heart failure is a clinical syndrome characterized by signs and symptoms of heart failure with preserved ejection fraction (0.50) and abnormal diastolic function. One of the earliest indications of diastolic heart failure is exercise intolerance followed by fatigue and, possibly, chest pain. Other clinical signs may include distended neck veins, atrial arrhythmias, and the presence of third and fourth heart sounds. Diastolic dysfunction is difficult to differentiate from systolic dysfunction on the basis of history, physical examination, and electrocardiographic and chest radiographic findings. Therefore, objective diagnostic testing with cardiac catheterization, Doppler echocardiography, and possibly measurement of serum levels of B-type natriuretic peptide is often required. Three stages of diastolic dysfunction are recognized. Stage I is characterized by reduced left ventricular filling in early diastole with normal left ventricular and left atrial pressures and normal compliance. Stage II or pseudonormalization is characterized by a normal Doppler echocardiographic transmitral flow pattern because of an opposing increase in left atrial pressures. This normalization pattern is a concern because marked diastolic dysfunction can easily be missed. Stage III, the final, most severe stage, is characterized by severe restrictive diastolic filling with a marked decrease in left ventricular compliance. Pharmacological therapy is tailored to the cause and type of diastolic dysfunction.

SCN10A-knock-out improves survival and proarrhythmia in a transgenic heart failure mouse model

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
P.R.F Bengel ◽  
C Krekeler ◽  
S Ahmad ◽  
N Hartmann ◽  
P Tirilomis ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mouse Model ◽  
Sodium Channel ◽  
Structural Parameters ◽  
Left Ventricular ◽  
Heart Weight ◽  
Na Channel ◽  
Funding Source ◽  
Patch Clamp Technique ◽  
Knock Out

Abstract Background In heart failure (HF) both Ca2+/Calmodulin-dependent protein-kinase II (CaMKII) and late sodium current (INaL) are known to contribute to arrhythmogenesis as they contribute to action-potential (AP) prolongation and the occurrence of early- (EADs) and delayed afterdepolarizations (DADs). Further, augmented CaMKII and INaL maintain a vicious cycle as they both can activate each other. We recently found that the sodium channel isoform NaV1.8 is upregulated in HF and hypertrophy and that it is involved in INaL-generation. In the current study we investigated the effects of NaV1.8-knock-out (KO) on HF-progression and arrhythmogenesis in a CaMKII-overexpressing HF mouse model. Methods/Results CaMKII overexpressing mice (CaMKII+/T) were crossbred with NaV1.8-KO mice (SCN10A−/−). To our surprise knock-out of NaV1.8 in CaMKII+/T mice (SCN10A−/−/CaMKII+/T) significantly improved survival (median survival 103 days vs 74.5 CaMKII+/T, p<0.01). CaMKII+/T mice exhibited a strong HF phenotype compared to WT with increased heart-weight to tibia length ratio as well as reduced ejection fraction and left-ventricular end-diastolic diameter obtained by echocardiography. However, these structural parameters did not differ between SCN10A−/−/CaMKII+/T and CaMKII+/T. Therefore, cellular electrophysiology experiments were performed in isolated cardiomyocytes for a better understanding of the observed improvement in survival. INaL, measured by patch-clamp technique, was significantly augmented in CaMKII+/T vs WT and SCN10A−/−, while SCN10A−/−/CaMKII+/T showed significantly less INaL than CaMKII+/T alone. Further, AP-duration (APD) was significantly reduced in SCN10A−/−/CaMKII+/T vs CaMKII+/T while AP-amplitude, resting membrane-potential and upstroke velocity (dv/dtmax) remained unchanged. In addition, the occurrence of afterdepolarizations was significantly lower in SCN10A−/−/ CaMKII+/T vs CaMKII+/T. Confocal microscopy using the dye Fluo-4AM was performed and significantly less diastolic Ca2+-waves occurred in SCN10A−/−/CaMKII+/T compared to CaMKII+/T. In order to analyze an organ-specific SCN10A-KO, we generated homozygous SCN10A-KO lines of induced pluripotent stem cells by using CRISPR/Cas9 technology. 2-month old iPSC-cardiomyocytes lacking NaV1.8 were treated with low dose isoprenaline and showed significantly less INaL, thereby serving as a final proof of the relevant role of this Na+-channel on INaL-generation in the cardiomyocyte. Conclusion We found a survival benefit by selective knock-out of the neuronal sodium channel isoform NaV1.8 in a proarrhythmic HF mouse model with augmented CaMKII expression. However, in our model NaV1.8-knock-out showed no effects on HF progression, while cellular proarrhythmic triggers were attenuated. Taken together with our findings in IPS-cardiomyocytes treated with the CRSIPR/Cas9 technology NaV1.8 plays a significant role for the generation of INaL and cellular arrhythmogenic triggers in the cardiomyocyte. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Deutsche Stiftung für Herzforschung

scholarly journals Ginsenoside Re Improves Isoproterenol-Induced Myocardial Fibrosis and Heart Failure in Rats

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Quan-wei Wang ◽  
Xiao-feng Yu ◽  
Hua-li Xu ◽  
Xue-zhong Zhao ◽  
Da-yuan Sui
Keyword(s):  
Heart Failure ◽  
Myocardial Fibrosis ◽  
Group Treatment ◽  
Transforming Growth Factor ◽  
Diastolic Pressure ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Heart Weight ◽  
Hydroxyproline Content ◽  
Ginsenoside Re

Objective. Panax ginseng is used widely for treatment of cardiovascular disorders in China. Ginsenoside Re is the main chemical component of P. ginseng. We aimed to investigate the protective effect of ginsenoside Re on isoproterenol-induced myocardial fibrosis and heart failure in rats. Methods. A model of myocardial fibrosis and heart failure was established by once-daily subcutaneous injection of isoproterenol (5 mg/kg/day) to rats for 7 days. Simultaneously, rats were orally administrated ginsenoside Re (5 or 20 mg/kg) or vehicle daily for 4 weeks. Results. Isoproterenol enhanced the heart weight, myocardial fibrosis, and hydroxyproline content in rat hearts. Ginsenoside Re inhibited (at least in part) the isoproterenol-induced increase in heart weight, myocardial fibrosis, and hydroxyproline content. Compared with the isoproterenol group, treatment with ginsenoside Re ameliorated changes in left ventricular systolic pressure, left ventricular end diastolic pressure, and the positive and negative maximal values of the first derivative of left ventricular pressure. Ginsenoside Re administration also resulted in decreased expression of transforming growth factor (TGF)-β1 in serum and decreased expression of Smad3 and collagen I in heart tissue. Conclusion. Ginsenoside Re can improve isoproterenol-induced myocardial fibrosis and heart failure by regulation of the TGF-β1/Smad3 pathway.

scholarly journals Serial Assessment of Cardiac Function during and following Mitoxantrone Infusion in 30 Consecutive Patients with Multiple Sclerosis

2010 ◽  
Vol 2010 ◽  
pp. 1-4
Author(s):  
Damian Franzen ◽  
Angelika Haus ◽  
Martin Hellmich
Keyword(s):  
Multiple Sclerosis ◽  
Heart Failure ◽  
Cardiac Function ◽  
Low Dose ◽  
Therapeutic Option ◽  
Clinical Signs ◽  
Cardiac Effect ◽  
Left Ventricular ◽  
History Taking ◽  
Dose Dependent

Immunosuppressive therapy is an established therapeutic option in patients suffering from multiple sclerosis (MS). In an open nonrandomized study we serially assessed cardiac function in 30 consecutive patients with MS before, during, and after mitoxantrone therapy. Mitoxantrone (12 mg/m2) was administered intravenously at 3-month intervals. Before each infusion, cardiac function was assessed by history taking, resting electrocardiogram, and echocardiography. Whereas no patient experienced clinical signs of heart failure, left ventricular pump function decreased continuously during mitoxantrone therapy and did not recover after cessation. The presented data suggest a dose-dependent and long-lasting toxic cardiac effect of low-dose mitoxantrone therapy in MS.

Cardiotoxicity in Patients with Multiple Myeloma Treated with Tandem Autologous Hematopoetic Stem Cell Transplantation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4923-4923
Author(s):  
Samo Zver ◽  
Mirta Kozelj ◽  
Uros Mlakar
Keyword(s):  
Heart Failure ◽  
Multiple Myeloma ◽  
Stem Cell ◽  
Mitral Regurgitation ◽  
Stem Cell Transplantation ◽  
Treatment Modality ◽  
Clinical Signs ◽  
Tissue Doppler ◽  
Left Ventricular ◽  
High Doses

Abstract BACKGROUND. Tandem autologous hemopoetic stem cell transplantation (HSCT) was recognised as effective treatment modality in patients with multiple myeloma (MM). During the treatment period patients are treated with high doses of cyclophosphamide followed twice with high doses of melphalan. There are scant data, if any, regarding potential cardiotoxic side effects of this treatment modality. METHODS. We included 30 patients with newly diagnosed multiple myeloma. After they were treated with three cycles of chemotherapy, they received high doses of cyclophosphamide 4 mg/m2 (cycle CY), followed by two autologous tandem HSCT, where patients received melphalan 200 mg/m2 (cycle MEL I and cycle MEL II). During each fifteen-day treatment period blood was routinely controlled for biochemical parameters troponin I (TnI), brain natriiuretic peptide (BNP) and endothelin-1 (ET-1) at six time points. All patients underwent conventional and tissue Doppler echocardiographic examination before treatment with cyclophosphamide (Eho 0), before cycle MEL I (Eho 1), before cycle MEL II (Eho 2) and three months after completion of the therapy (Eho 3). RESULTS. None of the patients developed clinical signs of heart insufficiency. Highest TnI values in all three cycles of chemotherapy were observed on the eighth, eleventh and fifteenth day of treatment. But all TnI values in patients were lower than 0.04 μg/L. During all three cycles we noticed a significant increase in BNP values compared with the basal values and values on day one after treatment with cyclophosphamide and melphalan (CY: P = 0.0001, MEL I: P = 0.001, MEL II: P= 0.001). In cycle CY this was also the highest BNP value (0.517 ± 0.391 μg/L). The maximum BNP values in cycles MEL I and MEL II were noticed on day four after chemotherapy (MEL I 0.376 ± 0.418 μg/L; MEL II 0.363 ± 0.379 μg/L). The highest ET-1 values in all three cycles were noticed on day one after chemotherapy (CY 1.146 ± 1.313 ng/L; MEL I 1.054 ± 2.242 ng/L; MEL II 0.618 ± 0.539 ng/L). We observed a significant increase in ET-1 values compared with the basal values only in cycle MEL II (P = 0.003). Concerning the parameters of diastolic left ventricular function, the duration of wave a in Doppler pulmonary vein flow signal significantly increased compared with it’s basal value (Eho 0/Eho 1: P = 0.008, Eho 0/Eho 3; P = 0.026). The ratio A/a in flow velocities significantly decreased with cycles of chemotherapy (Eho 0/Eho 1: P = 0.002, Eho 0/Eho 3: P < 0.0001). Early diastolic tissue Doppler velocities (Em) decreased significantly within individual cycles of chemotherapy (P = 0.006). After the treatment a significant increase in mitral regurgitation was observed (Eho 0/Eho 3; P = 0.003). Pericardial effusion was observed in six patients (20.6%). CONCLUSIONS. Treatment of MM patients with autologous tandem HSCT is cardiotoxic. Patients did not develop clinical signs of overt heart failure and normal TnI values excluded myocardial necrosis. On the other hand, increased plasma BNP and ET-1 levels confirm transient neurohormonal activation of heart failure, likely in combination with toxic endothelial damage. Doppler echocardiography studies prove worsening of the left ventricular diastolic function and appearance of functional mitral regurgitation. The age of the patients has no influence on the clinical, laboratory and echocardiography parameters of cardiotoxicity.

scholarly journals Elevated Swelling-Activated Chloride Current Densities in Hypertrophied Ventricular Myocytes in a Rabbit Heart Failure Model

2019 ◽  
Vol 22 (2) ◽  
pp. E107-E111
Author(s):  
Hongwei Shi ◽  
Zhenming Jiang ◽  
Teng Wang ◽  
Yongting Chen ◽  
Feng Cao
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Protein Expression ◽  
Diastolic Pressure ◽  
Rabbit Model ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Control Group ◽  
Sham Operation ◽  
Failure Group

Background: The status of the swelling-activated chloride channel (ICl, swell) during heart failure remains unclear. This study aimed to investigate whether the ICl, swell activity is altered during heart failure and to determine how the ICl, swell influences atrial arrhythmias of the failing heart. Methods: We established a heart failure rabbit model and analyzed the hemodynamic indicators 8 weeks after myocardial infarction, which include left ventricular systolic pressure (LVSP) and left ventricular end-diastolic pressure (LVDEP). Five untreated rabbits and 5 receiving a sham operation served as the control group. Left auricular appendage tissues were obtained and CLCN3 mRNA/CLCN3 protein expression levels were examined by using reverse transcription–polymerase chain reaction and Western blot, respectively. Results: Compared to the control group, the heart failure group showed a significantly decreased LVSP (14.2 ± 0.27 versus 16.9 ± 0.86 kPa, P <.05)and elevated LVDEP (2.49 ± 0.30 versus 0.15 ± 0.03 kPa, P <.05), indicating that myocardial infarction leads to progressive heart failure of rabbits in the heart failure group. CLCN3 mRNA and CLCN3 protein expression were both significantly elevated in the heart failure group compared to the control group (P <.05). Conclusion: In sum, we propose that the dynamic nature of ICl, swell upregulation may contribute to the elevated expression of CLCN3 mRNA and CLCN3 protein, resulting in myocardial cell remodeling induced by heart failure. However, further study is needed to investigate the potential functions of ICl, swell, especially the relation between ICl, swell augmentation and arrhythmia after heart failure.

Stress kinase phosphorylation is increased in pacing-induced heart failure in rabbits

2003 ◽  
Vol 285 (5) ◽  
pp. H2084-H2090 ◽  
Author(s):  
Rainer Schulz ◽  
Stephanie Aker ◽  
Sergej Belosjorow ◽  
Ina Konietzka ◽  
Ursula Rauen ◽  
...  
Keyword(s):  
Heart Failure ◽  
P38 Mapk ◽  
Ischemia Reperfusion ◽  
Systolic Dysfunction ◽  
Clinical Signs ◽  
Left Ventricular ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Cross Sectional ◽  
Mapk Phosphorylation ◽  
Mapk Activity

In hearts with chronic left ventricular (LV) systolic dysfunction secondary to hypertension or myocardial infarction, MAPK phosphorylation and/or activity are increased. Whether other settings of LV dysfunction not associated with ischemia-reperfusion are also characterized by increased MAPK phosphorylation or activity is unknown. After 3 wk of rapid LV pacing (400 beats/min), eight rabbits displayed clinical signs of heart failure (HF), and echocardiography revealed an increase in LV end-diastolic diameter from 15.6 ± 0.7 (means ± SE) to 18.8 ± 0.7 mm and a reduced shortening fraction from 31 ± 1to10 ± 2% (both P < 0.05). Morphological alterations in HF included increased numbers of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cardiomyocytes, extent of fibrosis, and cross-sectional cardiomyocyte area. Total p38 MAPK did not differ between failing and normal hearts ( n = 8). However, p38 MAPK phosphorylation [164,488 ± 29,323 vs. 43,565 ± 14,817 arbitrary units (AU), P < 0.05, densitometry] and the activities of p38 MAPK-α and -β were increased in failing compared with normal hearts (149,441 ± 38,381 and 170,430 ± 32,952 vs. 68,815 ± 28,984 and 81,788 ± 22,774 AU, respectively, both P < 0.05). In failing compared with normal hearts, total and phosphorylated JNK46 and JNK54 MAPK were increased, whereas total and phosphorylated ERK MAPK remained unchanged. In pacing-induced HF, p38 and JNK MAPK phosphorylation as well as p38 MAPK activity was increased. Further studies will have to define whether or not chronic specific blockade of MAPK activity can interfere with apoptosis/fibrosis and thereby attenuate the progression of HF.

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