Ablation of brainstem C1 neurons improves cardiac function in volume overload heart failure

2019 ◽  
Vol 133 (3) ◽  
pp. 393-405 ◽  
Author(s):  
David C. Andrade ◽  
Camilo Toledo ◽  
Hugo S. Díaz ◽  
Claudia Lucero ◽  
Alexis Arce-Álvarez ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Volume Overload ◽  
Conclusive Evidence ◽  
Ventrolateral Medulla ◽  
Sprague Dawley ◽  
Autonomic Tone ◽  
Autonomic Imbalance ◽  
Tone Function

Abstract Activation of the sympathetic nervous system is a hallmark of heart failure (HF) and is positively correlated with disease progression. Catecholaminergic (C1) neurons located in the rostral ventrolateral medulla (RVLM) are known to modulate sympathetic outflow and are hyperactivated in volume overload HF. However, there is no conclusive evidence showing a contribution of RVLM-C1 neurons to the development of cardiac dysfunction in the setting of HF. Therefore, the aim of this study was to determine the role of RVLM-C1 neurons in cardiac autonomic control and deterioration of cardiac function in HF rats. A surgical arteriovenous shunt was created in adult male Sprague-Dawley rats to induce HF. RVLM-C1 neurons were selectively ablated using cell-specific immunotoxin (dopamine-β hydroxylase saporin [DβH-SAP]) and measures of cardiac autonomic tone, function, and arrhythmia incidence were evaluated. Cardiac autonomic imbalance, arrhythmogenesis and cardiac dysfunction were present in HF rats and improved after DβH-SAP toxin treatment. Most importantly, the progressive decline in fractional shortening observed in HF rats was reduced by DβH-SAP toxin. Our results unveil a pivotal role played by RVLM-C1 neurons in cardiac autonomic imbalance, arrhythmogenesis and cardiac dysfunction in volume overload-induced HF.

scholarly journals Inhibitor of lysyl oxidase improves cardiac function and the collagen/MMP profile in response to volume overload

2018 ◽  
Vol 315 (3) ◽  
pp. H463-H473 ◽  
Author(s):  
Elia C. El Hajj ◽  
Milad C. El Hajj ◽  
Van K. Ninh ◽  
Jason D. Gardner
Keyword(s):  
Heart Failure ◽  
Extracellular Matrix ◽  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Lysyl Oxidase ◽  
Volume Overload ◽  
Left Ventricular ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Primary Role ◽  
Collagen Deposition

The cardiac extracellular matrix is a complex architectural network that serves many functions, including providing structural and biochemical support to surrounding cells and regulating intercellular signaling pathways. Cardiac function is directly affected by extracellular matrix (ECM) composition, and alterations of the ECM contribute to the progression of heart failure. Initially, collagen deposition is an adaptive response that aims to preserve tissue integrity and maintain normal ventricular function. However, the synergistic effects of proinflammatory and profibrotic responses induce a vicious cycle, which causes excess activation of myofibroblasts, significantly increasing collagen deposition and accumulation in the matrix. Furthermore, excess synthesis and activation of the enzyme lysyl oxidase (LOX) during disease increases collagen cross-linking, which significantly increases collagen resistance to degradation by matrix metalloproteinases (MMPs). In the present study, the aortocaval fistula model of volume overload (VO) was used to determine whether LOX inhibition could prevent adverse changes in the ECM and subsequent cardiac dysfunction. The major findings from this study were that LOX inhibition 1) prevented VO-induced increases in left ventricular wall stress; 2) partially attenuated VO-induced ventricular hypertrophy; 3) completely blocked the increases in fibrotic proteins, including collagens, MMPs, and their tissue inhibitors; and 4) prevented the VO-induced decline in cardiac function. It remains unclear whether a direct interaction between LOX and MMPs exists; however, our experiments suggest a potential link between the two because LOX inhibition completely attenuated VO-induced increases in MMPs. Overall, our study demonstrated key cardioprotective effects of LOX inhibition against adverse cardiac remodeling due to chronic VO. NEW & NOTEWORTHY Although the primary role of lysyl oxidase (LOX) is to cross-link collagens, we found that elevated LOX during cardiac disease plays a key role in the progression of heart failure. Here, we show that inhibition of LOX in volume-overloaded rats prevented the development of cardiac dysfunction and improved ventricular collagen and matrix metalloproteinase/tissue inhibitor of metalloproteinase profiles.

Exercise cardiac MRI unmasks cardiac dysfunction in childhood and adolescent cancer survivors with reduced cardiopulmonary fitness

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S Foulkes ◽  
B Costello ◽  
E.J Howden ◽  
K Janssens ◽  
H Dillon ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Cancer Survivors ◽  
Pediatric Cancer ◽  
Cardiac Dysfunction ◽  
Cardiopulmonary Fitness ◽  
Cardiac Reserve ◽  
Pediatric Cancer Survivors ◽  
Increased Risk

Abstract Background Young cancer survivors are at increased risk of impaired cardiopulmonary fitness (VO2peak) and heart failure. Assessment of exercise cardiac reserve may reveal sub-clinical abnormalities that better explain impairments in fitness and long term heart failure risk. Purpose To investigate the presence of impaired VO2peak in pediatric cancer survivors with increased risk of heart failure, and to assess its relationship with resting cardiac function and cardiac reserve Methods Twenty pediatric cancer survivors (aged 8–24 years) treated with anthracycline chemotherapy underwent cardiopulmonary exercise testing to quantify VO2peak, with a value <85% of predicted defined as impaired VO2peak. Resting cardiac function was assessed using 3-dimensional echocardiography, with cardiac reserve quantified from resting and peak exercise heart rate (HR), stroke volume index (SVi) and cardiac index (CI) using exercise cardiac magnetic resonance imaging. Results 12 of 20 survivors (60%) had impaired VO2peak (97±14% vs. 70±16% of age and gender predicted). There were no differences in echocardiographic or CMR measurements of resting cardiac function between survivors with normal or impaired VO2peak. However, those with reduced VO2peak had diminished cardiac reserve, with a lesser increase in CI (Fig. 1A) and SVi (Fig. 1B) during exercise (Interaction P=0.001 for both), whilst the HR response was similar (Fig. 1C; P=0.71). Conclusions Resting measures of cardiac function are insensitive to significant cardiac dysfunction amongst pediatric cancer survivors with reduced VO2peak. Measures of cardiopulmonary fitness and cardiac reserve may aid in early identification of survivors with heightened risk of long-term heart failure. Figure 1 Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): National Heart Foundation

Abstract 1213: Cardiac Overexpression of Epac1 in Transgenic Mice Protects Heart from Lipopolysaccharide-induced Cardiac Dysfunction and Inhibits JAK-STAT Pathway

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Satoshi Okumura ◽  
Yunzhe Bai ◽  
Meihua Jin ◽  
Sayaka Suzuki ◽  
Akiko Kuwae ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cyclic Amp ◽  
Transgenic Mice ◽  
Cardiac Function ◽  
Proinflammatory Cytokines ◽  
Cardiac Dysfunction ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Stat Pathway

The sympathetic nervous system and proinflammatory cytokines are believed to play independent roles in the pathophysiology of heart failure. However, the recent identification of Epac (exchange protein activated by cyclic AMP), a new cyclic AMP-binding protein that directly activates Rap1, have implicated that there may be a potential cross talk between the sympathetic and cytokine signals. In order to examine the role of Epac in cytokine signal to regulate cardiac function, we have generated transgenic mice expressing the human Epac1 gene under the control of alpha-cardiac myosin heavy chain promoter (Epac1-TG), and examined their response in lipopolysaccharide (LPS)-induced cardiac dysfunction, a well established model for sepsis-induced cardiac dysfunction. Sepsis-induced cardiac dysfunction results from the production of proinflammatory cytokines. At baseline, left ventricular ejection fraction (LVEF) was similar (TG vs. NTG, 67±1.7 vs. 69±2.1%, n =7–9). The degree of cardiac hypertrophy (LV(mg)/tibia(mm)) was also similar at 3 months old (TG vs. NTG 4.0±0.1 vs. 4.2±0.1, n =5–6), but it became slightly but significantly greater in Epac1-TG at 5 month old (TG vs. NTG 4.9±0.1 vs. 4.4±0.1, p< 0.05, n =5–7). LPS (5mg/kg) elicited a significant and robust reduction of LVEF in both Epac1-TG and NTG, but the magnitude of this decrease was much less in Epac1-TG at 6 hr after injection (TG vs. NTG 48±2.4 vs. 57±1.8%, p< 0.01, n =6–9). At 24 hr after injection, cardiac function was restored to the baseline in both Epac1-TG and NTG. We also examined the activation of JAK-STAT pathway at 24 hr after injection. The tyrosine phosphorylation of STAT1 (Tyr701) and STAT3 (Tyr705) in LV, which is an indicator of STAT activation, was reduced to a greater degree in Epac1-TG by 31±8.8% ( p< 0.05, n =4) and 29±5.9% ( p< 0.05, n =7), respectively, relative to that in NTG. Taken together, Epac1 protects the heart from the cytokine-induced cardiac dysfunction, at least in part, through the inhibition of the JAK-STAT pathway, suggesting the beneficial role played by sympathetic signal to antagonize proinflammatory cytokine signal in heart failure.

Effect of metformin therapy on cardiac function and survival in a volume-overload model of heart failure in rats

2011 ◽  
Vol 121 (1) ◽  
pp. 29-41 ◽  
Author(s):  
Jan Benes ◽  
Ludmila Kazdova ◽  
Zdenek Drahota ◽  
Josef Houstek ◽  
Dasa Medrikova ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Glycogen Synthesis ◽  
Volume Overload ◽  
Left Ventricular ◽  
Atp Depletion ◽  
Term Survival ◽  
Palmitate Oxidation ◽  
Substrate Metabolism ◽  
Mitochondrial Functions

Advanced HF (heart failure) is associated with altered substrate metabolism. Whether modification of substrate use improves the course of HF remains unknown. The antihyperglycaemic drug MET (metformin) affects substrate metabolism, and its use might be associated with improved outcome in diabetic HF. The aim of the present study was to examine whether MET would improve cardiac function and survival also in non-diabetic HF. Volume-overload HF was induced in male Wistar rats by creating ACF (aortocaval fistula). Animals were randomized to placebo/MET (300 mg·kg−1 of body weight·day−1, 0.5% in food) groups and underwent assessment of metabolism, cardiovascular and mitochondrial functions (n=6–12/group) in advanced HF stage (week 21). A separate cohort served for survival analysis (n=10–90/group). The ACF group had marked cardiac hypertrophy, increased LVEDP (left ventricular end-diastolic pressure) and lung weight confirming decompensated HF, increased circulating NEFAs (non-esterified ‘free’ fatty acids), intra-abdominal fat depletion, lower glycogen synthesis in the skeletal muscle (diaphragm), lower myocardial triacylglycerol (triglyceride) content and attenuated myocardial 14C-glucose and 14C-palmitate oxidation, but preserved mitochondrial respiratory function, glucose tolerance and insulin sensitivity. MET therapy normalized serum NEFAs, decreased myocardial glucose oxidation, increased myocardial palmitate oxidation, but it had no effect on myocardial gene expression, AMPK (AMP-activated protein kinase) signalling, ATP level, mitochondrial respiration, cardiac morphology, function and long-term survival, despite reaching therapeutic serum levels (2.2±0.7 μg/ml). In conclusion, MET-induced enhancement of myocardial fatty acid oxidation had a neutral effect on cardiac function and survival. Recently reported cardioprotective effects of MET may not be universal to all forms of HF and may require AMPK activation or ATP depletion. No increase in mortality on MET supports its safe use in diabetic HF.

Abstract P045: Sex And Age Specific Circulating Aldosterone Changes In Transgenic Hypertensive (mRen2)27 Rats And Hannover Sprague Dawley (SD) Rats And Its Association With Blood Pressure And Cardiac Function

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Fatima Ryalat ◽  
N Cruz-Diaz ◽  
W Graham ◽  
T Gwathmey-Williams ◽  
P E Gallagher ◽  
...  
Keyword(s):  
Heart Failure ◽  
Blood Pressure ◽  
Cardiac Function ◽  
Target Organ Damage ◽  
Aging Effect ◽  
Female Rats ◽  
Male Rats ◽  
Sprague Dawley ◽  
Aldosterone Antagonists ◽  
Sd Rats

Aldosterone plays a significant role in hypertension and target organ damage. Aldosterone antagonists are used in the management of heart failure. However, neither the influence of age nor sex on aldosterone pathophysiology is well understood. We investigated the changes in circulating aldosterone with age and its association with cardiovascular function, using male and female hypertensive renin transgenic (mRen2)27 rats and SD rats at 20 and 50 weeks of age. Both male (22 ± 3 vs. 12 ± 2 ng/dL, n = 9 - 12, p < 0.05) and female (59 ± 10 vs. 23 ± 8 ng/dL, n = 6 - 10, p < 0.05) hypertensive rats had higher serum aldosterone compared with SD rats at 20 weeks of age. At 50 weeks of age, the difference persisted in the hypertensive female rats (63 ± 8 vs. SD: 33 ± 7 ng/dL, n = 6 - 7, p < 0.05), but not in the males. SD male rats have higher systolic blood pressure (SBP) as they age, and consequently develop cardiac diastolic dysfunction associated with higher aldosterone at 50 weeks compared to 20 weeks (28 ± 3 vs. 12 ± 2 ng/dL, n = 7 - 9, p < 0.05). This aging effect on aldosterone was not significant in the other groups. We showed previously that SD males treated with polyphenol rich muscadine grape extract (MGE) have lower aldosterone, less aortic stiffness and better cardiac diastolic function (E/e’) than controls at the older age; the MGE effect was not seen in (mRen2)27 males. Sex differences in aldosterone were not significant in the SD rats at either time point. However, (mRen2)27 female rats had higher aldosterone than (mRen2)27 males at both 20 weeks (59 ± 10 vs. 22 ± 3 ng/dL, n = 10 - 12, p < 0.05) and 50 weeks (63 ± 8 vs. 31 ± 7 ng/dL, n = 6 - 7, p < 0.05), despite the lack of significant differences in SBP. (mRen2)27 female rats preserve cardiac function better than males throughout their life span, while males develop indices of heart failure. Our data suggest that lower aldosterone levels in hypertensive males compared with females do not protect against the higher lifetime burden of elevated SBP and also may reflect different mechanisms controlling circulating aldosterone between sexes. In addition, data suggest a potential therapeutic effect of MGE in the management of age-associated moderate hypertension.

scholarly journals ZEB2 regulates a transcriptional network of calcium-handling genes in the injured heart

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M Gladka ◽  
A De Leeuw ◽  
A Kohela ◽  
B Molenaar ◽  
D Versteeg ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transcription Factor ◽  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Calcium Handling ◽  
Funding Source ◽  
Post Injury ◽  
Mesenchymal Transition

Abstract   Intracellular calcium (Ca2+) overload is known to play a critical role in the development of cardiac dysfunction. Despite the remarkable progress in managing the progression of the disease, the development of effective therapies for heart failure (HF) remains challenging. Therefore, it is of great importance to understand the molecular mechanisms that maintain calcium level and contractility in homeostatic conditions. Here we identified a transcription factor ZEB2 that regulates the expression of numerous contractile and calcium-related genes. Zinc finger E-box-binding homeobox2 (ZEB2) is a transcription factor that plays a role during early fetal development and epithelial-to-mesenchymal transition (EMT); however, its function in the heart remains to be determined. Recently, we found that ZEB2 is upregulated in murine cardiomyocytes shortly after an ischemic event, but returns to baseline levels as the disease progresses. Gain- and loss-of-function genetic mouse models revealed the necessity and sufficiency of ZEB2 to maintain proper cardiac function after ischemic injury. We show that cardiomyocyte-specific ZEB2 overexpression (Zeb2 cTG) protected from ischemia-induced diastolic dysfunction and attenuated the structural remodeling of the heart. Moreover, RNA-sequencing of Zeb2 cTG hearts post-injury implicated ZEB2 in the regulation of numerous calcium-handling and contractile-related genes when compared to wildtype mice. Mechanistically, ZEB2 overexpression increased the phosphorylation of phospholamban (PLN) at both serine-16 and threonine-17, implying enhanced activity of the sarcoplasmic reticulum Ca2+-ATPase (SERCA2A), thereby augmenting contractility. Improved cardiac function in ZEB2-overexpressing hearts correlated with higher expression of several sarcomeric proteins like myosin-binding protein C3 (MYBPC3), desmin (DES) and myosin regulatory light chain 2 (MYL2) further contributing to the observed protective phenotype. Furthermore, we observed a decrease in the activity of Ca2+-depended calcineurin/NFAT signaling, which is the main driver of pathological cardiac remodeling. Conversely to Zeb2 cTg mice, loss of ZEB2 from cardiomyocytes perturbed the expression of calcium- and contractile-related proteins and increased the activity of calcineurin/NFAT pathway, exacerbating cardiac dysfunction. Together, we show that ZEB2 is a central regulator of contractile and calcium-handling components, consequently mediating contractility in the mammalian heart. Further mechanistic understanding of the role of ZEB2 in the regulation of calcium homeostasis in cardiomyocytes is a critical step towards the development of improved therapies for various forms of heart failure. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): DR. E. Dekker from Dutch Heart Foundation

scholarly journals Effects of a myofilament calcium sensitizer on left ventricular systolic and diastolic function in rats with volume overload heart failure

2014 ◽  
Vol 307 (11) ◽  
pp. H1605-H1617 ◽  
Author(s):  
Kristin Wilson ◽  
Anuradha Guggilam ◽  
T. Aaron West ◽  
Xiaojin Zhang ◽  
Aaron J. Trask ◽  
...  
Keyword(s):  
Heart Failure ◽  
Troponin I ◽  
Regulatory Protein ◽  
Volume Overload ◽  
Left Ventricular ◽  
Lv Function ◽  
Stroke Work ◽  
Sprague Dawley ◽  
Diastolic Relaxation ◽  
Systolic And Diastolic Function

Aortocaval fistula (ACF)-induced volume overload (VO) heart failure (HF) results in progressive left ventricular (LV) dysfunction. Hemodynamic load reversal during pre-HF (4 wk post-ACF; REV) results in rapid structural but delayed functional recovery. This study investigated myocyte and myofilament function in ACF and REV and tested the hypothesis that a myofilament Ca2+ sensitizer would improve VO-induced myofilament dysfunction in ACF and REV. Following the initial sham or ACF surgery in male Sprague-Dawley rats (200–240 g) at week 0, REV surgery and experiments were performed at weeks 4 and 8, respectively. In ACF, decreased LV function is accompanied by impaired sarcomeric shortening and force generation and decreased Ca2+ sensitivity, whereas, in REV, impaired LV function is accompanied by decreased Ca2+ sensitivity. Intravenous levosimendan (Levo) elicited the best inotropic and lusitropic responses and was selected for chronic oral studies. Subsets of ACF and REV rats were given vehicle (water) or Levo (1 mg/kg) in drinking water from weeks 4–8. Levo improved systolic (% fractional shortening, end-systolic elastance, and preload-recruitable stroke work) and diastolic (τ, dP/d tmin) function in ACF and REV. Levo improved Ca2+ sensitivity without altering the amplitude and kinetics of the intracellular Ca2+ transient. In ACF-Levo, increased cMyBP-C Ser-273 and Ser-302 and cardiac troponin I Ser-23/24 phosphorylation correlated with improved diastolic relaxation, whereas, in REV-Levo, increased cMyBP-C Ser-273 phosphorylation and increased α-to-β-myosin heavy chain correlated with improved diastolic relaxation. We concluded that Levo improves LV function, and myofilament composition and regulatory protein phosphorylation likely play a key role in improving function.

scholarly journals Temporal changes in integrin-mediated cardiomyocyte adhesion secondary to chronic cardiac volume overload in rats

2014 ◽  
Vol 306 (1) ◽  
pp. H101-H108 ◽  
Author(s):  
James A. Stewart ◽  
Jason D. Gardner ◽  
Gregory L. Brower ◽  
Joseph S. Janicki
Keyword(s):  
Heart Failure ◽  
Vascular Resistance ◽  
Isolated Heart ◽  
Volume Overload ◽  
Neutralizing Antibody ◽  
Ventricular Dilatation ◽  
Integrin Subunit ◽  
Coronary Vascular Resistance ◽  
Sprague Dawley ◽  
Cardiac Volume

Previous studies have established integrins as cell surface receptors that mediate cardiomyocyte-extracellular matrix (ECM) attachments. This study sought to determine the contributions of the myocardial β1- and β3-integrin subunits to ventricular dilatation and coronary flow regulation using a blood-perfused isolated heart preparation. Furthermore, cardiomyocyte adhesion to collagen types I and IV, fibronectin, and laminin with and without a β1-integrin subunit neutralizing antibody was assessed during the course of remodeling secondary to a sustained cardiac volume overload, including the onset of heart failure. Isolated cardiomyocytes were obtained during the initial, compensated, and decompensated phases of remodeling resulting from an aortocaval fistula created in 8-wk-old male Sprague-Dawley rats. Blocking the β1-integrin subunit in isolated normal hearts produced ventricular dilatation, whereas this was not the case when the β3-subunit was blocked. Substantial reductions in cardiomyocyte adhesion coincided with the previously documented development of ventricular dilatation and decreased contractility postfistula, with the β1-integrin contribution to adhesion ranging from 28% to 73% over the course of remodeling being essentially substrate independent. In contrast, both integrin subunits were found to be involved in regulating coronary vascular resistance. It is concluded that marked reductions in integrin-mediated cardiomyocyte adhesion to the ECM play a significant role in the progression of adverse myocardial remodeling that leads to heart failure. Furthermore, although both the β1- and β3-integrin subunits were involved in regulating coronary vascular resistance, only inhibition of β1-integrin-mediated adhesion resulted in ventricular dilatation of the normal heart.

scholarly journals Osteopontin RNA aptamer can prevent and reverse pressure overload-induced heart failure

2017 ◽  
Vol 113 (6) ◽  
pp. 633-643 ◽  
Author(s):  
Jihe Li ◽  
Keyvan Yousefi ◽  
Wen Ding ◽  
Jayanti Singh ◽  
Lina A. Shehadeh
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Cardiac Fibrosis ◽  
Cardiac Myocyte ◽  
Pressure Overload ◽  
Cardiomyocyte Hypertrophy ◽  
Therapeutic Effects ◽  
Rna Aptamer ◽  
Myocyte Hypertrophy

Aims Cardiac myocyte hypertrophy, the main compensatory response to chronic stress in the heart often progresses to a state of decompensation that can lead to heart failure. Osteopontin (OPN) is an effector for extracellular signalling that induces myocyte growth and fibrosis. Although increased OPN activity has been observed in stressed myocytes and fibroblasts, the detailed and long term effects of blocking OPN signalling on the heart remain poorly defined. Targeting cardiac OPN protein by an RNA aptamer may be beneficial for tuning down OPN pathologic signalling. We aimed to demonstrate the therapeutic effects of an OPN RNA aptamer on cardiac dysfunction. Methods and results In vivo, we show that in a mouse model of pressure overload, treating at the time of surgeries with an OPN aptamer prevented cardiomyocyte hypertrophy and cardiac fibrosis, blocked OPN downstream signalling (PI3K and Akt phosphorylation), reduced expression of extracellular matrix (Lum, Col3a1, Fn1) and hypertrophy (Nppa, Nppb) genes, and prevented cardiac dysfunction. Treating at two months post-surgeries with the OPN aptamer reversed cardiac dysfunction and fibrosis and myocyte hypertrophy. While genetic homozygous deletion of OPN reduced myocardial wall thickness, surprisingly cardiac function and myocardial fibrosis, specifically collagen deposition and myofibroblast infiltration, were worse compared with wild type mice at three months of pressure overload. Conclusion Taken together, these data demonstrate that tuning down cardiac OPN signalling by an OPN RNA aptamer is a novel and effective approach for preventing cardiac hypertrophy and fibrosis, improving cardiac function, and reversing pressure overload-induced heart failure.

scholarly journals Exercise intolerance in volume overload heart failure is associated with low carotid body mediated chemoreflex drive

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
David C. Andrade ◽  
Esteban Díaz-Jara ◽  
Camilo Toledo ◽  
Karla G. Schwarz ◽  
Katherin V. Pereyra ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Training Program ◽  
Carotid Body ◽  
Exercise Tolerance ◽  
Systolic Function ◽  
Volume Overload ◽  
Exercise Intolerance ◽  
Ventilatory Responses ◽  
Cardiac Systolic Function

AbstractMounting an appropriate ventilatory response to exercise is crucial to meeting metabolic demands, and abnormal ventilatory responses may contribute to exercise-intolerance (EX-inT) in heart failure (HF) patients. We sought to determine if abnormal ventilatory chemoreflex control contributes to EX-inT in volume-overload HF rats. Cardiac function, hypercapnic (HCVR) and hypoxic (HVR) ventilatory responses, and exercise tolerance were assessed at the end of a 6 week exercise training program. At the conclusion of the training program, exercise tolerant HF rats (HF + EX-T) exhibited improvements in cardiac systolic function and reductions in HCVR, sympathetic tone, and arrhythmias. In contrast, HF rats that were exercise intolerant (HF + EX-inT) exhibited worse diastolic dysfunction, and showed no improvements in cardiac systolic function, HCVR, sympathetic tone, or arrhythmias at the conclusion of the training program. In addition, HF + EX-inT rats had impaired HVR which was associated with increased arrhythmia susceptibility and mortality during hypoxic challenges (~ 60% survival). Finally, we observed that exercise tolerance in HF rats was related to carotid body (CB) function as CB ablation resulted in impaired exercise capacity in HF + EX-T rats. Our results indicate that: (i) exercise may have detrimental effects on cardiac function in HF-EX-inT, and (ii) loss of CB chemoreflex sensitivity contributes to EX-inT in HF.

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