Abstract 813: Tnf-α Alters Superoxide And Nitric Oxide In The Brain Stem And Hypothalamus Contributes To Sympathoexcitation In Heart Failure Mice

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Anuradha Guggilam ◽  
Li Yu ◽  
Philip J Ebenezer ◽  
Irving H Zucker ◽  
Joseph Francis
Keyword(s):  
Nitric Oxide ◽  
Heart Failure ◽  
Cardiovascular Disease ◽  
Brain Stem ◽  
Mrna Expression ◽  
Natriuretic Peptide ◽  
Left Ventricular ◽  
List Type ◽  
Tnf Α ◽  
The Brain

Tumor necrosis factor-alpha (TNF-α) is a multifunctional cytokine that plays an important role in the pathophysiology of cardiovascular disease. Recent evidence suggests that TNF-αinduced oxidative stress contributes to the development of cardiovascular disease. The present study examined the effect of TNF-αon the imbalance between nitric oxide (NO) and superoxide (O 2 . − ) production in the brain stem and hypothalamus and its contribution to enhanced sympathetic drive in mice with heart failure. Methods and Results: Myocardial infarction (MI) was induced by ligation of the left coronary artery in wild type (WT) and TNF knockout (TNF KO) mice. After 5 weeks, WT + MI mice exhibited left ventricular (LV) dilatation and a decrease in fractional shortening (%FS). Real time RT-PCR exhibited an increase in the mRNA expression for atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in the LV of WT + MI mice. The mRNA expression for nNOS was significantly reduced in the brain stem, while that of iNOS and Nox2 were elevated in the brain stem as well as hypothalamus of WT + MI mice. Plasma norepinephrine (NE) levels in WT + MI mice were greater in WT + MI mice than that in sham, or TNF KO + MI mice indicating that sympathetic drive was enhanced by TNF-αin this model. Conclusions: The present study shows that TNF-α contributes to left ventricular hypertrophy leading to ventricular dysfunction. TNF-αinduces the production of O 2 . − and modulates the production of nitric oxide in the brain stem of HF mice. TNF-αcontributes to sympatho-excitation in HF.

Abstract 814: Atorvastatin Attenuates Oxidative Stress And Improves Neuronal Nitric Oxide Synthase In The Brain Stem Of Heart Failure Mice

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Joseph Francis ◽  
Li Yu ◽  
Anuradha Guggilam ◽  
Srinivas Sriramula ◽  
Irving H Zucker
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Myocardial Infarction ◽  
Heart Failure ◽  
Brain Stem ◽  
Mrna Expression ◽  
Natriuretic Peptide ◽  
Left Ventricular ◽  
Neuronal Nos ◽  
The Brain

3-Hydroxyl-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been shown to reduce the incidence of myocardial infarction independent of their lipid-lowering effects. Nitric oxide (NO) in the central nervous system contributes to cardiovascular regulatory mechanisms. Imbalance between nitric oxide (NO) and superoxide anion (O 2 . − ) in the brain may contribute to enhanced sympathetic drive in heart failure (HF). This study was done to determine whether treatment with atorvastatin (ATS) ameliorates the imbalance between NO and O 2 . − production in the brain stem and contributes to improvement of left ventricular (LV) function. Methods and Results: Myocardial infarction (MI) was induced by ligation of the left coronary artery or sham surgery. Subsequently, mice were treated with ATS (10 μg/kg) (MI + ATS), or vehicle (MI + V). After 5 weeks, echocardiography revealed left ventricular dilatation in MI mice. Realtime RT-PCR indicated an increase in the mRNA expression of the LV hypertrophy markers, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Neuronal NOS (nNOS) and endothelial NOS (eNOS) mRNA expression were significantly reduced, while that of NAD(P)H oxidase subunit (gp91phox) expression was elevated in the brain stem of MI mice. Compared with sham-operated mice, ATS-treated mice showed reduced cardiac dilatation, decreased ANP and BNP in the LV. ATS also reduced gp91phox expression and increased nNOS mRNA expression in the brain stem, while no changes in eNOS and iNOS were observed. Conclusion: These findings suggest that ATS reduces oxidative stress and increases neuronal NOS in the brain stem, and improves left ventricular function in heart failure.

Abstract 3295: De-induction of the Maladaptive Fetal Gene Program During Chronic Monotherapy with Metoprolol Succinate is Retained Following Withdrawal of Therapy in Dogs with Chronic Heart Failure

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Rasha Bazari ◽  
Sharad Rastogi ◽  
Valerio Zaca ◽  
Sidney Goldstein ◽  
Hani N Sabbah
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Mrna Expression ◽  
Natriuretic Peptide ◽  
Left Ventricular ◽  
Lv Function ◽  
Metoprolol Succinate ◽  
Myosin Heavy Chain Isoform ◽  
Chronic Therapy ◽  
Lv Remodeling

Background: Chronic therapy with extended release metoprolol succinate (MET), a selective β1 adrenergic receptor blocker, improves left ventricular (LV) function and attenuates global LV remodeling in dogs with chronic heart failure (HF). We previously showed that chronic therapy with β-blockade results in de-induction of the fetal gene program (FGP) in LV myocardium of dogs with HF. In this study, we tested the hypothesis that in dogs with HF withdrawal of chronic MET does not lead to re-induction of FGP. Methods: Studies were performed in 17 intracoronary microembolization-induced HF dogs randomized to 3 months oral therapy with MET (100 mg, once daily, n=11) or no therapy at all (Controls, n=6). In dogs randomized to MET, 6 were sacrificed after 3 months of therapy and in the remaining 5, MET was withdrawn after 3 months of therapy and dogs were observed for 6 weeks after withdrawal of MET (MET-W) and then sacrificed. LV tissue was also obtained from 6 normal (NL) dogs for comparison. mRNA expression of the FGP genes namely, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), sarcoplasmic reticulum calcium ATPase (CAA), cardiac β-1 adren-ergic receptor (AR) and α-myosin heavy chain isoform (α-MHC) was measured using reverse transcriptase polymerase chain reaction (RT-PCR) and bands were quantified in densitometric units (du). Results: In Controls, mRNA expression of ANP and BNP increased and expression of CAA, β 1-AR and α-MHC decreased. Treatment with MET decreased expression of ANP and BNP and increased expression of CAA, β 1-AR and α-MHC. Except for α-MHC, the improvement in FGP seen during MET treatment was preserved in MET-W dogs. Conclusions: Withdrawal of MET is associated with sustained de-induction of the FGP in LV myocardium of dogs with HF. This observation supports the concept that chronic β-blockade therapy in HF confers lasting reversal of LV remodeling and molecular recovery of the failing myocardium.

scholarly journals Neurotransmission to parasympathetic cardiac vagal neurons in the brain stem is altered with left ventricular hypertrophy-induced heart failure

2015 ◽  
Vol 309 (8) ◽  
pp. H1281-H1287 ◽  
Author(s):  
Edmund Cauley ◽  
Xin Wang ◽  
Jhansi Dyavanapalli ◽  
Ke Sun ◽  
Kara Garrott ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiovascular Diseases ◽  
Left Ventricular Hypertrophy ◽  
Cardiac Hypertrophy ◽  
Brain Stem ◽  
Ventricular Hypertrophy ◽  
Cardiac Activity ◽  
Left Ventricular ◽  
Parasympathetic Activity ◽  
The Brain

Hypertension, cardiac hypertrophy, and heart failure (HF) are widespread and debilitating cardiovascular diseases that affect nearly 23 million people worldwide. A distinctive hallmark of these cardiovascular diseases is autonomic imbalance, with increased sympathetic activity and decreased parasympathetic vagal tone. Recent device-based approaches, such as implantable vagal stimulators that stimulate a multitude of visceral sensory and motor fibers in the vagus nerve, are being evaluated as new therapeutic approaches for these and other diseases. However, little is known about how parasympathetic activity to the heart is altered with these diseases, and this lack of knowledge is an obstacle in the goal of devising selective interventions that can target and selectively restore parasympathetic activity to the heart. To identify the changes that occur within the brain stem to diminish the parasympathetic cardiac activity, left ventricular hypertrophy was elicited in rats by aortic pressure overload using a transaortic constriction approach. Cardiac vagal neurons (CVNs) in the brain stem that generate parasympathetic activity to the heart were identified with a retrograde tracer and studied using patch-clamp electrophysiological recordings in vitro. Animals with left cardiac hypertrophy had diminished excitation of CVNs, which was mediated both by an augmented frequency of spontaneous inhibitory GABAergic neurotransmission (with no alteration of inhibitory glycinergic activity) as well as a diminished amplitude and frequency of excitatory neurotransmission to CVNs. Opportunities to alter these network pathways and neurotransmitter receptors provide future targets of intervention in the goal to restore parasympathetic activity and autonomic balance to the heart in cardiac hypertrophy and other cardiovascular diseases.

scholarly journals Quantitative Myocardial Cytokine Expression and Activation of the Apoptotic Pathway in Patients Who Require Left Ventricular Assist Devices

Circulation ◽  
2001 ◽  
Vol 104 (suppl_1) ◽  
Author(s):  
Emma J. Birks ◽  
Najma Latif ◽  
Virginia Owen ◽  
Christopher Bowles ◽  
Leanne E. Felkin ◽  
...  
Keyword(s):  
Heart Failure ◽  
Heart Transplantation ◽  
Mrna Expression ◽  
Left Ventricular ◽  
Ventricular Assist Devices ◽  
Inos Mrna ◽  
Left Ventricular Assist Devices ◽  
Apoptotic Pathway ◽  
Tnf Α ◽  
Lvad Support

Background Molecular mechanisms underlying the deterioration of patients undergoing LV assist device (LVAD) implantation remain poorly understood. We studied the cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-1β and IL-6 and the terminal stage of the apoptotic pathway in patients with decompensating heart failure who required LVAD support and compared them with patients with less severe heart failure undergoing elective heart transplantation. Methods and Results Myocardial and serum samples from 23 patients undergoing LVAD implantation were compared with those from 36 patients undergoing elective heart transplantation. Myocardial TNF-α mRNA (1.71-fold; P <0.05) and protein (3.43±0.19 versus 2.95±0.10 pg/mg protein; P <0.05) were elevated in the LVAD patients. Immunocytochemistry demonstrated TNF expression in the myocytes. Serum TNF-α was also elevated (12.5±1.9 versus 4.0±0.4 pg/mL; P <0.0001) in the LVAD patients. IL-6 mRNA (2.57-fold higher; P <0.005) and protein (27.83±9.35 versus 4.26±1.24 pg/mg protein; P <0.001) were higher in the LVAD candidates, as was serum IL-6 (79.3±23.6 versus 7.1±1.6 pg/mL; P <0.0001). Interleukin-1β mRNA expression was 9.78-fold higher in the LVAD patients ( P <0.001). iNOS mRNA expression was similar to that in advanced heart failure patients and was not further elevated in the LVAD patients. Levels of procaspase-9 (8.02±0.91 versus 6.16±0.43 oligodeoxynucleotide [OD] units; P <0.01), cleaved caspase-9 (10.02±1.0 versus 7.34±0.40 OD units; P <0.05), intact and spliced DFF-45 (4.58±0.75 versus 2.84±0.23 OD units; P <0.05) were raised in LVAD patients, but caspase-3 and human nuclease CPAN were not. Conclusions Elevated TNF-α, IL-1β, and IL-6 and alterations in the apoptotic pathway were found in the myocardium and elevated TNF-α and IL-6 in serum of deteriorating patients who required LVAD support. These occurrences may have therapeutic implications and influence the timing of LVAD insertion.

Differential regulation of cardiac ANP and BNP mRNA in different stages of experimental heart failure

2000 ◽  
Vol 278 (5) ◽  
pp. H1500-H1506 ◽  
Author(s):  
Thomas Langenickel ◽  
Ines Pagel ◽  
Klaus Höhnel ◽  
Rainer Dietz ◽  
Roland Willenbrock
Keyword(s):  
Heart Failure ◽  
Mrna Expression ◽  
Natriuretic Peptide ◽  
Diastolic Pressure ◽  
Venous Pressure ◽  
Plasma Concentrations ◽  
Left Ventricular ◽  
Differential Regulation ◽  
Failure Group ◽  
Failure Models

Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are cardiac hormones that are involved in water and electrolyte homeostasis in heart failure. Although both hormones exert almost identical biological actions, the differential regulation of cardiac ANP and BNP mRNA in compensated and overt heart failure is not known. To study the hypothesis that cardiac BNP is more specifically induced in overt heart failure, a large aortocaval shunt of 30 days duration was produced in rats and compared with compensated heart failure. Compensated heart failure was induced either by a small shunt of 30 days duration or by a large shunt of 3 days duration. Both heart failure models were characterized by increased cardiac weight, which was significantly higher in the large-shunt model, and central venous pressure. Left ventricular end-diastolic pressure was elevated only in the overt heart failure group (control: 5.7 ± 0.7; small shunt: 8.6 ± 0.9; large shunt 3 days: 8.5 ± 1.7; large shunt 30 days: 15.9 ± 2.6 mmHg; P < 0.01). ANP and BNP plasma concentrations were elevated in both heart failure models. In compensated heart failure, ANP mRNA expression was induced in both ventricles. In contrast, ventricular BNP mRNA expression was not upregulated in any of the compensated heart failure models, whereas it increased in overt heart failure (left ventricle: 359 ± 104% of control, P < 0.001; right ventricle: 237 ± 33%, P < 0.01). A similar pattern of mRNA regulation was observed in the atria. These data indicate that, in contrast to ANP, cardiac BNP mRNA expression might be induced specifically in overt heart failure, pointing toward the possible role of BNP as a marker of the transition from compensated to overt heart failure.

scholarly journals Variants of SNPs – the Brain Natriuretic Peptide Gene Polymorphism and Appropriate Structural and Functional Parameters of the Myocardial State in Men with Essential Hypertension and Chronic Heart Failure Living in Podillia Region

2016 ◽  
Vol 23 (3) ◽  
Author(s):  
Іuliia P Pashkova
Keyword(s):  
Heart Failure ◽  
Essential Hypertension ◽  
Chronic Heart Failure ◽  
Left Ventricle ◽  
Brain Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Left Ventricular ◽  
Left Ventricular Myocardium ◽  
Peptide Gene ◽  
The Brain

In the development of essential hypertension cardiac remodeling is determined by both hemodynamic and neurohumoral factors. The influence of hemodynamic factors is sufficiently studied, while the role of stimulating and inhibiting humoral agents in the development of cardiac remodeling is completely unknown. Therefore, the study of structural and functional indicators of the myocardial state in patients with essential hypertension and heart failure being carriers of different BNP genotypes is promising in terms of the possible role of the BNP gene polymorphisms in the development and progression of cardiac disease manifestations.The objective of the research was to examine structural and functional indicators of the myocardial state in men with essential hypertension and co-existent chronic heart failure Class IIА being carriers of different variants of the brain natriuretic peptide gene at the age of 40-60 years living in Podillia region.Materials and methods. Genotyping of the brain natriuretic peptide gene was performed using the polymerase chain reaction. Structural and functional indicators of the myocardial state were assessed by cardiac ultrasound with ultrasound device ULTIMA RA (Radmir, Ukraine).Results. The results revealed that among men with stage II essential hypertension the frequency of the T381T genotype of the brain natriuretic peptide gene was 35.48% and 64.52% of patients were carriers of C allele (р<0.001); among patients with essential hypertension and co-existent chronic heart failure Class IIА the frequency of the T381T genotype was 42.00% and 58.00% of patients were carriers of C allele (р≤0.05). In patients with chronic heart failure Class IIА being carriers of the T381T genotype the size and volume of the left ventricle at the end of systole and diastole were significantly larger, the indicators of the left ventricular myocardium mass index and left ventricular wall thickness were higher than in carriers of C allele (р<0.05). The indicators of the size and volume of the left ventricle, posterior left ventricular wall thickness and systemic hemodynamics regardless of the brain natriuretic peptide genotype were significantly higher in men with essential hypertension and co-existent chronic heart failure Class IIА compared to patients with stage II essential hypertension (p<0.05).Conclusion. In patients with symptoms of chronic heart failure Class IIA being carriers of the Т381Т genotype the size and volume of the left ventricle at the end of systole and diastole were significantly larger, the indicators of the left ventricular myocardium mass index and left ventricular wall thickness were higher than in carriers of C allele of the brain natriuretic peptide gene (р<0.05). In patients with essential hypertension and co-existent chronic heart failure Class IIА EF<45% being carriers of the Т381Т genotype, the highest indicators of the size of the left ventricle, end-systolic volume index, end-diastolic volume index, left ventricular myocardium mass index were observed. The inheritance of the T381T genotype by patients with symptoms of chronic heart failure Class IIA was found to be associated with higher levels of systolic blood pressure and diastolic blood pressure irrespective of the state of left ventricular systolic function.

scholarly journals Association of Lipoprotein (a) variants with risk of cardiovascular disease: a Mendelian randomization study

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Juan Xia ◽  
Chunyue Guo ◽  
Kuo Liu ◽  
Yunyi Xie ◽  
Han Cao ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Cardiovascular Disease ◽  
Chinese Population ◽  
Left Ventricular Mass Index ◽  
Mendelian Randomization ◽  
Left Ventricular ◽  
Han Chinese ◽  
Han Chinese Population ◽  
Internal Dimension

Abstract Background There is a well-documented empirical relationship between lipoprotein (a) [Lp(a)] and cardiovascular disease (CVD); however, causal evidence, especially from the Chinese population, is lacking. Therefore, this study aims to estimate the causal association between variants in genes affecting Lp(a) concentrations and CVD in people of Han Chinese ethnicity. Methods Two-sample Mendelian randomization analysis was used to assess the causal effect of Lp(a) concentrations on the risk of CVD. Summary statistics for Lp(a) variants were obtained from 1256 individuals in the Cohort Study on Chronic Disease of Communities Natural Population in Beijing, Tianjin and Hebei. Data on associations between single-nucleotide polymorphisms (SNPs) and CVD were obtained from recently published genome-wide association studies. Results Thirteen SNPs associated with Lp(a) levels in the Han Chinese population were used as instrumental variables. Genetically elevated Lp(a) was inversely associated with the risk of atrial fibrillation [odds ratio (OR), 0.94; 95% confidence interval (95%CI), 0.901–0.987; P = 0.012)], the risk of arrhythmia (OR, 0.96; 95%CI, 0.941–0.990; P = 0.005), the left ventricular mass index (OR, 0.97; 95%CI, 0.949–1.000; P = 0.048), and the left ventricular internal dimension in diastole (OR, 0.97; 95%CI, 0.950–0.997; P = 0.028) according to the inverse-variance weighted method. No significant association was observed for congestive heart failure (OR, 0.99; 95% CI, 0.950–1.038; P = 0.766), ischemic stroke (OR, 1.01; 95%CI, 0.981–1.046; P = 0.422), and left ventricular internal dimension in systole (OR, 0.98; 95%CI, 0.960–1.009; P = 0.214). Conclusions This study provided evidence that genetically elevated Lp(a) was inversely associated with atrial fibrillation, arrhythmia, the left ventricular mass index and the left ventricular internal dimension in diastole, but not with congestive heart failure, ischemic stroke, and the left ventricular internal dimension in systole in the Han Chinese population. Further research is needed to identify the mechanism underlying these results and determine whether genetically elevated Lp(a) increases the risk of coronary heart disease or other CVD subtypes.

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