AIM2-driven inflammasome activation in chronic heart failure

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M Ruppert ◽  
Z.S Onodi ◽  
P Leszek ◽  
V.E Toth ◽  
G Koncsos ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Animal Models ◽  
Left Ventricular ◽  
Inflammasome Activation ◽  
Coronary Artery Ligation ◽  
Funding Source ◽  
Human Cardiomyocytes ◽  
Pannexin 1 ◽  
End Stage

Abstract Background Inflammation and cytokine release have been implicated in the pathogenesis of chronic heart failure (CHF). Of particular interest, Canakinumab, a monoclonal antibody against interleukin-1b (IL-1β), had provided benefit against cardiovascular events, suggesting that blockade of IL-1β secretion and signaling might be a promising new therapeutic target. Although, recent studies have provided evidence that inflammasome activation is the main contributor to IL-1β maturation, the role of inflammasome activation in CHF remains unknown. Objective Therefore, we aimed to assess inflammasome activation in myocardial samples from end-stage failing hearts. Methods Inflammasome activation was assessed by immunoblotting in left ventricular myocardial specimens harvested from patients with end-stage CHF. Furthermore, immunoblot measurements were also performed on translational animal models of CHF (e.g. rat models of permanent coronary artery ligation and transverse aortic constriction). Left ventricular monocyte and macrophage infiltration was detected by immunohistochemistry. To investigate the molecular background of inflammasome activation, a series of cell culture experiments were performed on AC16 human cardiomyocytes and THP-1 human monocytic cell lines. Results Out of the 4 major inflammasome sensors tested, expression of the inflammasome protein absent in melanoma 2 (AIM2) and NLR family CARD domain-containing protein 4 (NLRC4) increased in human CHF while the NLRP1 and NLRP3 (NLR family, pyrin domain containing 1 and 3) inflammasome showed no change. A similar expression pattern in AIM2 and NLRC4 was also noted in CHF animal models. Furthermore, robust infiltration of Iba1+ monocytes/macrophages was observed in human failing hearts as well as in different animal models of CHF. In vitro AIM2 inflammasome activation, as induced by transfection with double-stranded DNA [poly(deoxyadenylic-deoxythymidylic)] was reduced significantly by the pharmacological blockade of pannexin-1 channels. Conclusions AIM2 and NLRC4 inflammasome activation might contribute to chronic inflammation in CHF. Our findings suggest that pannexin-1 channels might be a promising novel target to reduce inflammasome activation. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): NVKP_16-1-2016-0017

Atrial natriuretic peptide transcription, storage, and release in rats with myocardial infarction

1987 ◽  
Vol 253 (6) ◽  
pp. H1449-H1455 ◽  
Author(s):  
R. E. Mendez ◽  
J. M. Pfeffer ◽  
F. V. Ortola ◽  
K. D. Bloch ◽  
S. Anderson ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Chronic Heart Failure ◽  
Atrial Natriuretic Peptide ◽  
Infarct Size ◽  
Natriuretic Peptide ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Mrna Levels ◽  
Atrial Natriuretic

To study the role of atrial natriuretic peptide (ANP) in chronic heart failure, ANP synthesis, storage, and release were examined by measuring atrial ANP messenger ribonucleic acid (mRNA) levels and atrial and plasma ANP concentrations in rats with myocardial infarction produced by coronary artery ligation. Three groups were defined as the following: 1) controls, sham-operated, or operated, but noninfarcted; 2) moderate infarcts, involving 5-30% of the left ventricular circumference; and 3) large infarcts (greater than or equal to 30%). In addition, to determine a possible modulation by dietary Na intake on ANP levels in heart failure, plasma immunoreactive ANP (iANP) levels were measured in rats with and without infarcts given low, regular, or high Na intake for 2 wk, by which time all groups were in neutral balance. Plasma iANP levels varied directly with increasing infarct and atrial sizes, irrespective of Na intake. In contrast, atrial ANP concentration varied inversely with increasing infarct size. The ANP mRNA content index, a measure of total atrial ANP mRNA, was significantly increased in rats with large infarcts compared with control rats. These results indicate that in rats with myocardial infarction, the severity of left ventricular dysfunction, as inferred from infarct size, but not chronic Na intake, is the primary determinant of the extent of activation of the ANP system. Elevated circulating ANP levels are maintained through enhanced atrial synthesis and release. ANP may thus play an important role in the hemodynamic and renal adaptations to chronic heart failure.

scholarly journals Effects of canagliflozin in patients with type 2 diabetes and chronic heart failure: a randomized trial (CANDLE)

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A Tanaka ◽  
I Hisauchi ◽  
I Taguchi ◽  
A Sezai ◽  
S Toyoda ◽  
...  
Keyword(s):  
Heart Failure ◽  
Type 2 Diabetes ◽  
Chronic Heart Failure ◽  
Primary Endpoint ◽  
Nyha Class ◽  
Left Ventricular ◽  
Percentage Change ◽  
Left Ventricular Ejection ◽  
Funding Source

Abstract Background Little is known about the impacts of sodium glucose co-transporter 2 inhibitors on cardiac functional parameters, such as natriuretic peptides, in type 2 diabetes (T2D) patients with concomitant chronic heart failure (CHF). Purpose To compare the effect of canagliflozin with glimepiride, based on changes in N-terminal pro-brain natriuretic peptide (NT-proBNP), in that patient population. Methods This trial was an investigator-initiated, multicenter, prospective, randomized, open-label, blinded-endpoint trial at 34 centers in Japan. Patients with T2D and clinically stable CHF excluding NYHA class IV, randomized to receive canagliflozin 100 mg or glimepiride (starting dose: 0.5 mg), were examined using the primary endpoint of non-inferiority of canagliflozin versus glimepiride, defined as a margin of 1.1 in the upper-limit of the 2-sided 95% confidence interval (95% CI) for the group ratio of percentage change in NT-proBNP at 24 weeks. Results Data analysis of 233 patients (mean age 68.6±10.1 yrs; 75% male) showed mean left ventricular ejection fraction (LVEF) at randomization was 57.6±14.6%, with 71% of patients having a preserved LVEF (≥50%). The ratio of NT-proBNP percentage change was 0.48 (95% CI, −0.13 to 1.59, P=0.226), and therefore did not meet the prespecified non-inferiority margin. However, data stratified according to baseline NT-proBNP levels showed a trend that canagliflozin treatment reduced NT-proBNP levels to a greater extent than in subgroups with elevated levels of NT-proBNP (Figure A). Furthermore, NT-proBNP levels in the canagliflozin group did show a nonsignificant trend lower in the subgroup with preserved LVEF (Figure B), but not in the subgroup with reduced LVEF (Figure C). Additionally, the changes in the NYHA class were comparable between groups (P=0.061) in the overall cohort, whereas in the subgroup with a preserved LVEF canagliflozin caused a significant improvement in NYHA classes compared to that found for glimepiride treatment (P=0.027). Conclusions This trial did not meet the predefined primary endpoint of changes in NT-proBNP levels, with 24 weeks of treatment with canagliflozin relative to glimepiride which together with other recent studies would question the value of continuing to monitor NT-proBNP levels after the initial diagnosis of heart failure. Nevertheless, in a subgroup with preserved LVEF, there was a non-significant trend for canagliflozin treatment to reduce NT-proBNP levels and improve symptoms even in stable HF patients. Further research is therefore warranted to determine whether patients with preserved LVEF, regardless of diabetes status, could potentially benefit from treatment with SGLT2 inhibitors. Changes in NT-proBNP Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Mitsubishi Tanabe Pharma Corporation

Increasing Apoptosis-Related Gene Expression in Human Myocardium with Congestive Heart Failure

2000 ◽  
Vol 6 (S2) ◽  
pp. 628-629
Author(s):  
D. Xie ◽  
C. Wei
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Normal Subjects ◽  
Left Ventricular ◽  
Cardiac Tissues ◽  
Human Cardiomyocytes ◽  
Cycle Arrest ◽  
Induced Apoptosis ◽  
End Stage ◽  
Apoptosis Related Gene

Regulation of apoptosis involves a number of genes that can be classified into broad categories. These include genes that act as effectors of apoptosis, such as p53, c-myc, bax, p21- WAF, and genes that primarily suppress apoptosis, such as Bcl-2 gene family. These genes have been reported to be responsible for the modulation of certain stress induced apoptosis and cell cycle arrest.It has also been reported that apoptosis involved in cardiovascular diseases such as myocardial infarction, reperfusion injury, left ventricular hypertrophy, and hypertension. However, the expression of apoptosis-related genes in human cardiomyocytes in normal subjects and in patients with congestive heart failure (CHF) remains unclear. Therefore, the present study was designed to determine the expression and localization of apoptosis-related genes in human heart.Five normal subjects and five end-stage CHF human ventricular cardiac tissues were obtained from cardiac transplantation. The expression of p53, p21-WAF and Bcl-2 were determined by immunohistochemical staining (IHCS).

Atrial fibrillation is not associated with altered left atrial microRNA expression profile in ischemic end-stage human heart failure

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M Ruppert ◽  
B Agg ◽  
A.A Sayour ◽  
S.Z Kugler ◽  
P Perge ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Mrna Expression ◽  
Mirna Expression ◽  
Left Atrial ◽  
Interstitial Fibrosis ◽  
Left Ventricular ◽  
Funding Source ◽  
Human Heart Failure ◽  
End Stage

Abstract Introduction In patients with chronic heart failure (CHF) left ventricular dysfunction results in elevated left atrial (LA) pressure, triggering pathological atrial remodelling and atrial fibrillation (AF). Nevertheless, it has been reported that some patients with CHF remain in sinus rhythm (SR) despite of the pathological structural alterations (e.g. dilation and fibrosis) of the LA. Of particular interest, data is scarce regarding the molecular explanation for the observed variability in AF development among CHF patients. Recent studies have indicated that alterations in microRNA (miRNA) expression might contribute to the pathogenesis of AF. However, the majority of previous studies focusing on miRNA expression compared healthy LA with SR to pathologically remodelled, dilated LA with AF. Consequently, whether dysregulation of miRNA expression directly contribute to AF and not only to pathological LA remodelling has not been tested before. Purpose The present study aimed to investigate miRNA expression in comparably remodelled LA from end-stage CHF patients with permanent AF (CHF-AF) or SR (CHF-SR). Methods LA samples were collected from male, non-diabetic, ischemic end-stage CHF patients undergoing heart transplantation (n=24). Patients were carefully selected to avoid any differences in age (55±2 vs. 54±2 years, CHF-AF vs. CHF-SR, n.s.), ejection fraction ([EF]: 22.5±1.8 vs. 23.3±2.5%, CHF-AF vs. CHF-SR, n.s.) LA diameters (longitudinal LA diameter: 56±4 vs. 48±5mm.; CHF-AF vs. CHF-SR, n.s.; horizontal LA diameter: 61±2 vs. 54±3, CHF-AF vs. CHF-SR, n.s.) and NYHA stage. As a molecular marker of atrial load, the mRNA expression of atrial natriuretic peptide (ANP) was measured with qRT-PCR. The extent of left atrial fibrosis was assessed on picrosirius red stained histological sections. Global LA miRNA expression profiling (including the measurement of 800 human miRNA) was carried out using a commercially available kit. Results LA mRNA expression of ANP was comparable between the AF-CHF and the SR-CHF groups, suggesting that atrial load occurred to the same level in the two experimental groups. Furthermore, no differences could be observed in the extent of atrial collagen content between the AF-CHF and the SR-CHF groups (collagen area: 20.3±1.3% vs. 23.9±3.1%, n.s.), providing evidence that fibrotic remodelling had occurred to a similar magnitude. The high-throughput miRNA measurement revealed no differences in atrial miRNA expression between the two study groups. Conclusion The present study provides evidence for the first time that AF is not associated with different LA miRNA expression in end-stage CHF patients with comparable level of LA dilatation, ANP expression (atrial load) and interstitial fibrosis. Based on these findings, the potential of miRNA-based therapeutic interventions might be limited in AF patients with ischemic end-stage CHF. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): NVKP_16-1-2016-0017

scholarly journals Chronic heart failure in younger patients: temporal trends in clinical characteristics, treatment and outcomes over two decades in a nationwide cardiology registry

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M Iacoviello ◽  
M Marini ◽  
M Gori ◽  
L Gonzini ◽  
M Benvenuto ◽  
...  
Keyword(s):  
Risk Factors ◽  
Heart Failure ◽  
Chronic Heart Failure ◽  
Clinical Characteristics ◽  
Temporal Trends ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Funding Source ◽  
All Cause Mortality ◽  
Over Time

Abstract Aim of the study We analyzed the temporal trends in characteristics, therapy and outcomes over two decades of younger chronic heart failure (CHF) patients enrolled in our nationwide registry. Methods Among the 14823 CHF patients enrolled in the registry since January 1999 through May 2018, 5465 (37%) were aged<65 years (78% men, 54+9 years, left ventricular ejection fraction (LVEF) 36+11%). Patients were divided into 3 cohorts according with the recruitment epoch: 1999–2005; 2006–2011; 2012–2018. We analyzed trends over time of clinical characteristics, therapy, one-year all-cause mortality, all-cause mortality and/or all-cause hospitalization, all-cause mortality and/or CV hospitalization, and all-cause mortality and/or HF hospitalization. Results From 1999 to 2018 the proportion of patients <65 years declined: 42% in first (2288/5404), 37% in second (1464/3971), 31% in third period (1713/5448). As shown in the Table, the proportion of women, diabetes, ischemic etiology and renin-angiotensin system inhibitor prescription did not change significantly among the three enrollment epochs, whereas preserved LVEF phenotype and prevalence of its driving risk factors increased. The proportion of guideline-recommended drug & device therapies significantly rose over time. All-cause mortality at 1-year follow-up decreased significantly across the 3 epochs studied (Figure). Conclusions During 20 years, the clinical characteristics, the implementation of recommended treatments and prognosis of patients <65 years enrolled in a nationwide cardiology registry have deeply changed. These modifications reflect the evolution of cardiovascular risk factors and improved management strategies of CV disease. Figure 1 Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Fondazione per il Tuo cuore – HCF onlus

scholarly journals The effects of dietary fish oil on exercising skeletal muscle vascular and metabolic control in chronic heart failure rats

2014 ◽  
Vol 39 (3) ◽  
pp. 299-307 ◽  
Author(s):  
Clark T. Holdsworth ◽  
Steven W. Copp ◽  
Daniel M. Hirai ◽  
Scott K. Ferguson ◽  
Gabrielle E. Sims ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Fish Oil ◽  
Blood Lactate ◽  
Diastolic Pressure ◽  
Muscle Blood Flow ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Pufa Supplementation

Impaired vasomotor control in chronic heart failure (CHF) is due partly to decrements in nitric oxide synthase (NOS) mediated vasodilation. Exercising muscle blood flow (BF) is augmented with polyunsaturated fatty acid (PUFA) supplementation via fish oil (FO) in healthy rats. We hypothesized that FO would augment exercising muscle BF in CHF rats via increased NO-bioavailability. Myocardial infarction (coronary artery ligation) induced CHF in Sprague–Dawley rats which were subsequently randomized to dietary FO (20% docosahexaenoic acid, 30% eicosapentaenoic acid, n = 15) or safflower oil (SO, 5%, n = 10) for 6–8 weeks. Mean arterial pressure (MAP), blood [lactate], and hindlimb muscles BF (radiolabeled microspheres) were determined at rest, during treadmill exercise (20 m·min−1, 5% incline) and exercise + NG-nitro-l-arginine-methyl-ester (l-NAME) (a nonspecific NOS inhibitor). FO did not change left ventricular end-diastolic pressure (SO: 14 ± 2; FO: 11 ± 1 mm Hg, p > 0.05). During exercise, MAP (SO: 128 ± 3; FO: 132 ± 3 mm Hg) and blood [lactate] (SO: 3.8 ± 0.4; FO: 4.6 ± 0.5 mmol·L−1) were not different (p > 0.05). Exercising hindlimb muscle BF was lower in FO than SO (SO: 120 ± 11; FO: 93 ± 4 mL·min−1·100 g−1, p < 0.05) but was not differentially affected by l-NAME. Specifically, 17 of 28 individual muscle BF’s were lower (p < 0.05) in FO demonstrating that PUFA supplementation with FO in CHF rats does not augment muscle BF during exercise but may lower metabolic cost.

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