scholarly journals Chronic exogenous ketone supplementation blunts the decline of cardiac function in the failing heart

2021 ◽  
Author(s):  
Shingo Takahara ◽  
Shubham Soni ◽  
Kiran Phaterpekar ◽  
Ty T. Kim ◽  
Zaid H. Maayah ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Failing Heart

Abstract 14309: A Novel Fibroblast Activation Inhibitor, NM922, Attenuates Maladaptive Fibrotic Remodeling to Preserve Cardiac Function Following the Onset of Heart Failure

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Jessica M Bradley ◽  
Craig M Ziblich ◽  
Kazi N Islam ◽  
Amanda M Rushing ◽  
David J Polhemus ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Structural Changes ◽  
Volume Fraction ◽  
Left Ventricular ◽  
Normal Fibroblast ◽  
Wall Thickening ◽  
Cellular Mechanisms ◽  
Collagen Formation ◽  
Failing Heart

Background: Cardiac fibroblasts are critical mediators of fibrotic remodeling in the failing heart. These maladaptive structural changes can worsen cardiac function accelerating the progression to decompensated heart failure (HF). We investigated the effects of a novel inhibitor of the conversion of normal fibroblast to the myofibroblast phenotype in the setting of pressure overload induced HF. Methods: Male C57BL/6J mice (10 wks) were subjected to transverse aortic constriction (TAC; 27 g needle) and NM922 (NovoMedix, LLC50 mg/kg/d i.p.) or VEH (DMSO + HS-15) was administered daily starting at 6 wks post TAC. Echocardiography was assessed at baseline and for 16 wks post TAC. At the 16 wk endpoint, mice were sacrificed and hearts were collected for biochemical and molecular assessment. Results: NM922 significantly attenuated TAC-induced left ventricular (LV) dilation at 16 wks post TAC (LVEDD: 3.5 ± 0.1 vs. 4.5 ± 0.2 mm, p < 0.01; LVESD: 2.5 ± 0.2 vs. 3.8 ± 0.3 mm, p < 0.01) compared to VEH. NM922 treated mice displayed reduced wall thickening (LVPWd: 1.0 ± 0.03 vs. 1.2 ± 0.05 mm; p < 0.05) at 10 wks post TAC compared to VEH. LV ejection fraction (LVEF) was preserved in NM922 treated mice at 8-16 wks post TAC compared to VEH (*p < 0.05; **p < 0.001) compared to VEH. Treatment with NM922 resulted in reductions in heart (8.5 ± 0.5 vs. 12.0 ± 0.9 mg/mm; p < 0.01) and lung (8.2 ± 0.3 vs. 11.5 ± 0.6 mg/mm; p < 0.0001) weights compared to VEH. Picrosirius Red staining revealed that NM922 reduced cardiac interstitial collagen volume fraction by 50% (p < 0.05 vs. VEH). Circulating BNP levels trended toward lower (p = 0.08) in the NM922 mice when compared to VEH. Conclusion: Chronic treatment with NM922 following the onset of cardiac hypertrophy and HF resulted in attenuated myocardial collagen formation and adverse remodeling with preservation of LVEF. Future studies are aimed at further elucidation of the molecular and cellular mechanisms by which this novel agent protects the failing heart.

REGENERATION THERAPY TO IMPROVE CARDIAC FUNCTION OF FAILING HEART SUPPORTED WITH LVAD

ASAIO Journal ◽  
2005 ◽  
Vol 51 (2) ◽  
pp. 47A
Author(s):  
Yoshiaki Takewa ◽  
Yoshiyuki Taenaka ◽  
Eisuke Tatsumi ◽  
Ray Kansaku ◽  
Noritoshi Nagaya ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Failing Heart

Cardiac function and functional capacity: Implications for the failing heart

1993 ◽  
Vol 18 (12) ◽  
pp. 710-758 ◽  
Author(s):  
Louis J. Dell'Italia ◽  
Gregory L. Freeman ◽  
William H. Gaasch
Keyword(s):  
Cardiac Function ◽  
Functional Capacity ◽  
Failing Heart

scholarly journals A novel fibroblast activation inhibitor attenuates left ventricular remodeling and preserves cardiac function in heart failure

2018 ◽  
Vol 315 (3) ◽  
pp. H563-H570 ◽  
Author(s):  
Jessica M. Bradley ◽  
Pablo Spaletra ◽  
Zhen Li ◽  
Thomas E. Sharp ◽  
Traci T. Goodchild ◽  
...  
Keyword(s):  
Heart Failure ◽  
Left Ventricular Ejection Fraction ◽  
Ejection Fraction ◽  
Cardiac Function ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction ◽  
Ventricular Ejection Fraction ◽  
Failing Heart

Cardiac fibroblasts are critical mediators of fibrotic remodeling in the failing heart and transform into myofibroblasts in the presence of profibrotic factors such as transforming growth factor-β. Myocardial fibrosis worsens cardiac function, accelerating the progression to decompensated heart failure (HF). We investigated the effects of a novel inhibitor (NM922; NovoMedix, San Diego, CA) of the conversion of normal fibroblasts to the myofibroblast phenotype in the setting of pressure overload-induced HF. NM922 inhibited fibroblast-to-myofibroblast transformation in vitro via a reduction of activation of the focal adhesion kinase-Akt-p70S6 kinase and STAT3/4E-binding protein 1 pathways as well as via induction of cyclooxygenase-2. NM922 preserved left ventricular ejection fraction ( P < 0.05 vs. vehicle) and significantly attenuated transverse aortic constriction-induced LV dilation and hypertrophy ( P < 0.05 compared with vehicle). NM922 significantly ( P < 0.05) inhibited fibroblast activation, as evidenced by reduced myofibroblast counts per square millimeter of tissue area. Picrosirius red staining demonstrated that NM922 reduced ( P < 0.05) interstitial fibrosis compared with mice that received vehicle. Similarly, NM922 hearts had lower mRNA levels ( P < 0.05) of collagen types I and III, lysyl oxidase, and TNF-α at 16 wk after transverse aortic constriction. Treatment with NM922 after the onset of cardiac hypertrophy and HF resulted in attenuated myocardial collagen formation and adverse remodeling with preservation of left ventricular ejection fraction. Future studies are aimed at further elucidation of the molecular and cellular mechanisms by which this novel antifibrotic agent protects the failing heart. NEW & NOTEWORTHY Our data demonstrated that a novel antifibrotic agent, NM922, blocks the activation of fibroblasts, reduces the formation of cardiac fibrosis, and preserves cardiac function in a murine model of heart failure with reduced ejection fraction.

scholarly journals Both gain and loss of Nampt function promote pressure overload-induced heart failure

2019 ◽  
Vol 317 (4) ◽  
pp. H711-H725 ◽  
Author(s):  
Jaemin Byun ◽  
Shin-ichi Oka ◽  
Nobushige Imai ◽  
Chun-Yang Huang ◽  
Guersom Ralda ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Pressure Overload ◽  
Protein Acetylation ◽  
Atp Production ◽  
Failing Heart ◽  
Metabolic Genes ◽  
Nicotinamide Phosphoribosyl Transferase ◽  
Rate Limiting ◽  
Cultured Cardiomyocytes

The heart requires high-energy production, but metabolic ability declines in the failing heart. Nicotinamide phosphoribosyl-transferase (Nampt) is a rate-limiting enzyme in the salvage pathway of nicotinamide adenine dinucleotide (NAD) synthesis. NAD is directly involved in various metabolic processes and may indirectly regulate metabolic gene expression through sirtuin 1 (Sirt1), an NAD-dependent protein deacetylase. However, how Nampt regulates cardiac function and metabolism in the failing heart is poorly understood. Here we show that pressure-overload (PO)-induced heart failure is exacerbated in both systemic Nampt heterozygous knockout (Nampt+/−) mice and mice with cardiac-specific Nampt overexpression (Tg-Nampt). The NAD level declined in Nampt+/− mice under PO (wild: 377 pmol/mg tissue; Nampt+/−: 119 pmol/mg tissue; P = 0.028). In cultured cardiomyocytes, Nampt knockdown diminished mitochondrial NAD content and ATP production (relative ATP production: wild: 1; Nampt knockdown: 0.56; P = 0.0068), suggesting that downregulation of Nampt induces mitochondrial dysfunction. On the other hand, the NAD level was increased in Tg-Nampt mice at baseline but not during PO, possibly due to increased consumption of NAD by Sirt1. The expression of Sirt1 was increased in Tg-Nampt mice, in association with reduced overall protein acetylation. PO-induced downregulation of metabolic genes was exacerbated in Tg-Nampt mice. In cultured cardiomyocytes, Nampt and Sirt1 cooperatively suppressed mitochondrial proteins and ATP production, thereby promoting mitochondrial dysfunction. In addition, Nampt overexpression upregulated inflammatory cytokines, including TNF-α and monocyte chemoattractant protein-1. Thus endogenous Nampt maintains cardiac function and metabolism in the failing heart, whereas Nampt overexpression is detrimental during PO, possibly due to excessive activation of Sirt1, suppression of mitochondrial function, and upregulation of proinflammatory mechanisms. NEW & NOTEWORTHY Nicotinamide phosphoribosyl-transferase (Nampt) is a rate-limiting enzyme in the salvage pathway of nicotinamide adenine dinucleotide synthesis. We demonstrate that pressure overload-induced heart failure is exacerbated in both systemic Nampt heterozygous knockout mice and mice with cardiac-specific Nampt overexpression. Both loss- and gain-of-function models exhibited reduced protein acetylation, suppression of metabolic genes, and mitochondrial energetic dysfunction. Thus endogenous Nampt maintains cardiac function and metabolism in the failing heart, but cardiac-specific Nampt overexpression is detrimental rather than therapeutic.

Phosphoinositide 3-kinase activity is critical for maintaining cardiac function in the failing heart

2006 ◽  
Vol 41 (4) ◽  
pp. 741-741
Author(s):  
Julie R. McMullen ◽  
Russell D. Bouwman ◽  
Xiao-Ming Gao ◽  
Helen Kiriazis ◽  
Ziqiuo Ming ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Kinase Activity ◽  
Failing Heart ◽  
Phosphoinositide 3 Kinase

scholarly journals Experimentally observed phenomena on cardiac energetics in heart failure emerge from simulations of cardiac metabolism

2009 ◽  
Vol 106 (17) ◽  
pp. 7143-7148 ◽  
Author(s):  
Fan Wu ◽  
Jianyi Zhang ◽  
Daniel A. Beard
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Negative Impact ◽  
Adenine Nucleotide ◽  
Energy State ◽  
Left Ventricular ◽  
Emergent Properties ◽  
Resonance Spectroscopy ◽  
Failing Heart ◽  
Adenine Nucleotide Pool

The failing heart is hypothesized to suffer from energy supply inadequate for supporting normal cardiac function. We analyzed data from a canine left ventricular hypertrophy model to determine how the energy state evolves because of changes in key metabolic pools. Our findings—confirmed by in vivo 31P-magnetic resonance spectroscopy—indicate that the transition between the clinically observed early compensatory phase and heart failure and the critical point at which the transition occurs are emergent properties of cardiac energy metabolism. Specifically, analysis reveals a phenomenon in which low and moderate reductions in metabolite pools have no major negative impact on oxidative capacity, whereas reductions beyond a critical tipping point lead to a severely compromised energy state. The transition point corresponds to reductions in the total adenine nucleotide pool (TAN) of ≈30%, corresponding to the reduction observed in humans in heart failure [Ingwall JS, Weiss RG (2004) Is the failing heart energy starved? On using chemical energy to support cardiac function. Circ Res 95(2):135–145]. At given values of TAN and the total exchangeable phosphate pool during hypertrophic remodeling, the creatine pool attains a value that is associated with optimal ATP hydrolysis potential. Thus, both increases and decreases to the creatine pool are predicted to result in diminished energetic state unless accompanied by appropriate simultaneous changes in the other pools.

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