scholarly journals Mildly Increased Renin Expression in the Absence of Kidney Injury in the Murine Transverse Aortic Constriction Model

2021 ◽  
Vol 12 ◽  
Author(s):  
Marian Wesseling ◽  
Eva Mulder ◽  
Maike A. D. Brans ◽  
Daniek. M. C. Kapteijn ◽  
Marian Bulthuis ◽  
...  
Keyword(s):  
Heart Failure ◽  
Renal Function ◽  
Cardiac Function ◽  
Renal Dysfunction ◽  
Systemic Hypertension ◽  
Invasive Technique ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction ◽  
Plasma Urea ◽  
Progressive Heart Failure

Cardiorenal syndrome type 2 is characterized by kidney failure as a consequence of heart failure that affects >50% of heart failure patients. Murine transverse aortic constriction (TAC) is a heart failure model, where pressure overload is induced on the heart without any systemic hypertension or its consequences. Whether renal function is altered in this model is debated, and if so, at which time post-TAC renal dysfunction starts to contribute to worsening of cardiac function. We therefore studied the effects of progressive heart failure development on kidney function in the absence of chronically elevated systemic blood pressure and renal perfusion pressure. C57BL/6J mice (N = 129) were exposed to TAC using a minimally invasive technique and followed from 3 to 70 days post-TAC. Cardiac function was determined with 3D ultrasound and showed a gradual decrease in stroke volume over time. Renal renin expression and plasma renin concentration increased with progressive heart failure, suggesting hypoperfusion of the kidney. In addition, plasma urea concentration, a surrogate marker for renal dysfunction, was increased post-TAC. However, no structural abnormalities in the kidney, nor albuminuria were present at any time-point post-TAC. Progressive heart failure is associated with increased renin expression, but only mildly affected renal function without inducing structural injury. In combination, these data suggest that heart failure alone does not contribute to kidney dysfunction in mice.

scholarly journals Growth hormone-releasing hormone attenuates cardiac hypertrophy and improves heart function in pressure overload-induced heart failure

2017 ◽  
Vol 114 (45) ◽  
pp. 12033-12038 ◽  
Author(s):  
Iacopo Gesmundo ◽  
Michele Miragoli ◽  
Pierluigi Carullo ◽  
Letizia Trovato ◽  
Veronica Larcher ◽  
...  
Keyword(s):  
Heart Failure ◽  
Growth Hormone ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Therapeutic Potential ◽  
Growth Hormone Releasing Hormone ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction

It has been shown that growth hormone-releasing hormone (GHRH) reduces cardiomyocyte (CM) apoptosis, prevents ischemia/reperfusion injury, and improves cardiac function in ischemic rat hearts. However, it is still not known whether GHRH would be beneficial for life-threatening pathological conditions, like cardiac hypertrophy and heart failure (HF). Thus, we tested the myocardial therapeutic potential of GHRH stimulation in vitro and in vivo, using GHRH or its agonistic analog MR-409. We show that in vitro, GHRH(1-44)NH2 attenuates phenylephrine-induced hypertrophy in H9c2 cardiac cells, adult rat ventricular myocytes, and human induced pluripotent stem cell-derived CMs, decreasing expression of hypertrophic genes and regulating hypertrophic pathways. Underlying mechanisms included blockade of Gq signaling and its downstream components phospholipase Cβ, protein kinase Cε, calcineurin, and phospholamban. The receptor-dependent effects of GHRH also involved activation of Gαs and cAMP/PKA, and inhibition of increase in exchange protein directly activated by cAMP1 (Epac1). In vivo, MR-409 mitigated cardiac hypertrophy in mice subjected to transverse aortic constriction and improved cardiac function. Moreover, CMs isolated from transverse aortic constriction mice treated with MR-409 showed improved contractility and reversal of sarcolemmal structure. Overall, these results identify GHRH as an antihypertrophic regulator, underlying its therapeutic potential for HF, and suggest possible beneficial use of its analogs for treatment of pathological cardiac hypertrophy.

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.

Abstract 214: Septin4 Deletion Prevents Hypertrophy to Heart Failure Transition After Transverse Aortic Constriction

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Dogacan Yucel ◽  
Jop H Van Berlo ◽  
Preethy Parthiban
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Cardiac Function ◽  
Ventricular Remodeling ◽  
Pressure Overload ◽  
Small Gtpase ◽  
Calcium Handling ◽  
Future Research ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction

In response to cardiac injury or increased workload, the mammalian heart undergoes ventricular remodeling to maintain cardiac function. Initally, these changes are compensatory, although ultimately, they can lead to death of cardiomyocytes, ventricular dilation, and progression to heart failure. It is critical to understand the underlying mechanisms that regulate this transition, since it could identify new therapeutic targets. The role of the small GTPase Septin4 in the heart, and in regulating cardiac stress response is unknown. Previous research has implicated Septin 4 in regulation of Store Operated Calcium entry, as well as cell death regulation through a splice isoform (ARTS). We performed cardiac pressure overload in wild type controls and Septin 4 knockout (-/-) mice. Importantly, we did not detect differences in cardiac hypertrophy or function at baseline (57% ejection fraction in both groups). Four weeks following transverse aortic constriction (TAC), Septin4-/- mice showed improved cardiac function with higher ejection fraction (51%) compared to controls (40%), while the level of hypertrophy was similar. Furthermore, we detected reduced cleaved caspase-3 staining after TAC in Septin4-/- mice, due to inhibition of cardiomyocyte apoptosis in Septin4 -/- mice. Mechanistically, we detected increases in protein expression of both total and phosphorylated phospholamban and CaMKII in Septin4-/- mice, suggesting alterations in Calcium handling, and indicating compensatory signaling pathways were still active in Septin4-/- mice, while control mice were transitioning to heart failure. In conclusion, genetic deletion of Septin4 prevented cardiomyocyte death and protected mice from heart failure following cardiac pressure overload. Future research will focus on regulation of calcium handling in Septin4-/- mice to determine the exact mechanisms through which Septin4 plays a detrimental role in cardiac remodeling.

Abstract 5700: Worsening Renal Function and Arrhythmic Event in Implantable Cardioverter Defibrillator Patients with Nonischemic Heart Failure

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Atsushi Takahashi ◽  
Tsuyoshi Shiga ◽  
Daigo Yagishita ◽  
Keisuke Futagawa ◽  
Naoki Serizawa ◽  
...  
Keyword(s):  
Heart Failure ◽  
Renal Function ◽  
Renal Dysfunction ◽  
Implantable Cardioverter Defibrillator ◽  
Shock Therapy ◽  
Electrical Storm ◽  
Icd Implantation ◽  
Cardioverter Defibrillator ◽  
Arrhythmic Event ◽  
Icd Shock

Purpose: Implantable Cardioverter Defibrillator (ICD) prevents sudden cardiac death in high risk patients with heart failure (HF). Worsening renal function (WRF) is associated with mortality in patients with myocardial infarction or HF, but its effect on lethal arrhythmia is unknown. We evaluated the influence of WRF on the occurrence of arrhythmic events in patients with nonischemic HF and ICD. Methods: A total of 286 nonischemic HF patients who underwent ICD implantation between 1990 and 2007 were studied. Estimated Glomerular Filtration Rate (eGFR) was calculated using the Modification of Diet in Renal Disease. Renal dysfunction was defined as eGFR <60mL/min/1.73m 2 and WRF was defined as 15mL/min/1.73m 2 per year. Differences in arrhythmia recurrences according to the eGFR and WRF were compared by Kaplan-Meier survival curves. Results: During a mean follow-up time of 2.2+/−1.0 years, 94 (33%) of 286 patients (mean age; 57+/−15 years, 72% male) experienced appropriate ICD shock therapy. There was a significantly higher cumulative rate of appropriate ICD shock therapy (p<0.05) and electrical storm (p<0.05) in patients with renal dysfunction than others. The patients with renal dysfunction at baseline experience WRF more frequently than other patients (53% vs. 23%, respectively, p<0.01). After correcting for age, sex, left ventricular ejection fraction (LVEF), indication for ICD implantation, and use of beta-blockers in a Cox regression model, WRF was still an independent predictor of the time to first appropriate shock (HR 2.21, 95% CI 1.32–3.69, p<0.05) and electrical storm (HR 2.22, 95% CI 1.19 – 4.13, p<0.05). The result of subgroup analysis of 147 patients with low LVEF (LVEF<35%) indicated that the patients with WRF experienced electrical storms more frequently (p<0.05). Conclusion: WRF is associated with increased rate of arrhythmic event in nonischemic HF patients. Especially, those patients with low LVEF and WRF experience more frequent ICD shocks.

scholarly journals Impact of Cardiac Function Improvement on Cardiac Surgery Associated Acute Kidney Injury for Patients with Preoperative Renal Dysfunction

2020 ◽  
Author(s):  
Jiarui Xu ◽  
Xin Chen ◽  
Jing Lin ◽  
Yang Li ◽  
Bo Shen ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Renal Function ◽  
Cardiac Surgery ◽  
Cardiac Function ◽  
Renal Dysfunction ◽  
Significant Risk ◽  
Kidney Injury ◽  
Normal Function ◽  
Function Group ◽  
Postoperative Aki

Abstract Background: We aim to investigate whether the postoperative cardiac function improve or not would affect the risk of cardiac surgery associated acute kidney injury (AKI) for patients with preoperative renal dysfunction. Method: Data from patients underwent cardiac surgery from April 2012 to February 2016 were collected. Renal dysfunction was defined as preoperative SCr >1.2 mg/dL (females) or >1.5 mg/dL (males). Patients were grouped as normal renal function group, renal dysfunction with chronic kidney disease (CKD group), and non CKD group. △LVEF=postoperative LVEF - preoperative LVEF. Cardiac function improved was defined as △LVEF ≥10. Patients were further divided into non CKD & cardiac function improved (non CKD+), non CKD & cardiac function not improved (non CKD-), CKD & cardiac function improved (CKD+) and CKD & cardiac function not improved (CKD-) subgroups.Results: A total of 8,661 patients were allocated as normal renal function (n=7,903), non CKD(n = 662) and CKD (n = 136) groups. Both non CKD and CKD groups had higher AKI incidence than normal function group (39.5% vs 30.0%, P < 0.001; 61.8% vs 30.0%, P<0.001), and non CKD+ group had the similar AKI incidence with normal function group (30.9% vs 30.0%, P=0.729). Multivariate logistic regression analysis revealed that non CKD-, CKD+ and CKD- were significant risk factors, whereas non CKD+ was not a significant risk factor for postoperative AKI. The SCr at discharge in non CKD+ subgroup was significantly lower than its preoperative SCr (1.4 ± 0.8 vs 1.7 ± 0.9 mg/dL, P = 0.020).Conclusions: For renal dysfunction patients with no CKD, the risk of postoperative AKI did not exist if the cardiac function improved after surgery. For CKD patients, the risk of postoperative AKI increase regardless whether the cardiac function improved or not.

scholarly journals Aerobic Exercise Attenuates Pressure Overload-Induced Cardiac Dysfunction through Promoting Skeletal Muscle Microcirculation and Increasing Muscle Mass

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Ling-Yan Yuan ◽  
Pei-Zhao Du ◽  
Min-Min Wei ◽  
Qi Zhang ◽  
Le Lu ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Cardiac Function ◽  
Aerobic Exercise ◽  
Muscle Mass ◽  
Cardiac Dysfunction ◽  
Pressure Overload ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction ◽  
Protein Levels ◽  
Skeletal Muscle Microcirculation

Background. Aerobic exercise has been proven to have a positive effect on cardiac function after hypertension; however, the mechanism is not entirely clarified. Skeletal muscle mass and microcirculation are closely associated with blood pressure and cardiac function. Objective. This study was designed to investigate the effects of aerobic exercise on the skeletal muscle capillary and muscle mass, to explore the possible mechanisms involved in exercise-induced mitigation of cardiac dysfunction in pressure overload mice. Methods. In this study, 60 BALB/C mice aged 8 weeks were randomly divided into 3 groups: control (CON), TAC, and TAC plus exercise (TAE) group and utilized transverse aortic constriction (TAC) to establish hypertensive model; meanwhile, treadmill training is used for aerobic exercise. After 5 days of recovery, mice in the TAE group were subjected to 10-week aerobic exercise. Carotid pressure and cardiac function were examined before mice were executed by Millar catheter and ultrasound, respectively. Muscle mass of gastrocnemius was weighed; cross-sectional area and the number of capillaries of gastrocnemius were detected by HE and immunohistochemistry, respectively. The mRNA and protein levels of VEGF in skeletal muscle were determined by RT-PCR and western blot, respectively. Results. We found that ① 10-week aerobic exercise counteracted hypertension and attenuated cardiac dysfunction in TAC-induced hypertensive mice; ② TAC decreased muscle mass of gastrocnemius and resulted in muscle atrophy, while 10-week aerobic exercise could reserve transverse aortic constriction-induced the decline of muscle mass and muscle atrophy; and ③ TAC reduced the number of capillaries and the protein level of VEGF in gastrocnemius, whereas 10-week aerobic exercise augmented the number of capillaries, the mRNA and protein levels of VEGF in mice were subjected to TAC surgery. Conclusions. This study indicates that 10-week aerobic exercise might fulfill its blood pressure-lowering effect via improving skeletal muscle microcirculation and increasing muscle mass.

scholarly journals Disruption of adenylyl cyclase type V does not rescue the phenotype of cardiac-specific overexpression of Gαq protein-induced cardiomyopathy

2010 ◽  
Vol 299 (5) ◽  
pp. H1459-H1467 ◽  
Author(s):  
Valeriy Timofeyev ◽  
Cliff A. Porter ◽  
Dipika Tuteja ◽  
Hong Qiu ◽  
Ning Li ◽  
...  
Keyword(s):  
Heart Failure ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Mouse Model ◽  
Transgenic Mice ◽  
Cardiac Function ◽  
Adenylyl Cyclase ◽  
Electrical Remodeling ◽  
Kinase C ◽  
Progressive Heart Failure

Adenylyl cyclase (AC) is the principal effector molecule in the β-adrenergic receptor pathway. ACV and ACVI are the two predominant isoforms in mammalian cardiac myocytes. The disparate roles among AC isoforms in cardiac hypertrophy and progression to heart failure have been under intense investigation. Specifically, the salutary effects resulting from the disruption of ACV have been established in multiple models of cardiomyopathy. It has been proposed that a continual activation of ACV through elevated levels of protein kinase C could play an integral role in mediating a hypertrophic response leading to progressive heart failure. Elevated protein kinase C is a common finding in heart failure and was demonstrated in murine cardiomyopathy from cardiac-specific overexpression of Gαq protein. Here we assessed whether the disruption of ACV expression can improve cardiac function, limit electrophysiological remodeling, or improve survival in the Gαq mouse model of heart failure. We directly tested the effects of gene-targeted disruption of ACV in transgenic mice with cardiac-specific overexpression of Gαq protein using multiple techniques to assess the survival, cardiac function, as well as structural and electrical remodeling. Surprisingly, in contrast to other models of cardiomyopathy, ACV disruption did not improve survival or cardiac function, limit cardiac chamber dilation, halt hypertrophy, or prevent electrical remodeling in Gαq transgenic mice. In conclusion, unlike other established models of cardiomyopathy, disrupting ACV expression in the Gαq mouse model is insufficient to overcome several parallel pathophysiological processes leading to progressive heart failure.

scholarly journals Bone Morphogenetic Protein 9 Reduces Cardiac Fibrosis and Improves Cardiac Function in Heart Failure

Circulation ◽  
2018 ◽  
Vol 138 (5) ◽  
pp. 513-526 ◽  
Author(s):  
Kevin J. Morine ◽  
Xiaoying Qiao ◽  
Sam York ◽  
Peter S. Natov ◽  
Vikram Paruchuri ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Human Subjects ◽  
Lv Function ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction ◽  
Bone Morphogenetic Protein 9 ◽  
Human Cardiac Fibroblasts ◽  
Tgf Β1

Background: Heart failure is a growing cause of morbidity and mortality worldwide. Transforming growth factor beta (TGF-β1) promotes cardiac fibrosis, but also activates counterregulatory pathways that serve to regulate TGF-β1 activity in heart failure. Bone morphogenetic protein 9 (BMP9) is a member of the TGFβ family of cytokines and signals via the downstream effector protein Smad1. Endoglin is a TGFβ coreceptor that promotes TGF-β1 signaling via Smad3 and binds BMP9 with high affinity. We hypothesized that BMP9 limits cardiac fibrosis by activating Smad1 and attenuating Smad3, and, furthermore, that neutralizing endoglin activity promotes BMP9 activity. Methods: We examined BMP9 expression and signaling in human cardiac fibroblasts and human subjects with heart failure. We used the transverse aortic constriction–induced model of heart failure to evaluate the functional effect of BMP9 signaling on cardiac remodeling. Results: BMP9 expression is increased in the circulation and left ventricle (LV) of human subjects with heart failure and is expressed by cardiac fibroblasts. Next, we observed that BMP9 attenuates type I collagen synthesis in human cardiac fibroblasts using recombinant human BMP9 and a small interfering RNA approach. In BMP9 –/– mice subjected to transverse aortic constriction, loss of BMP9 activity promotes cardiac fibrosis, impairs LV function, and increases LV levels of phosphorylated Smad3 (pSmad3), not pSmad1. In contrast, treatment of wild-type mice subjected to transverse aortic constriction with recombinant BMP9 limits progression of cardiac fibrosis, improves LV function, enhances myocardial capillary density, and increases LV levels of pSmad1, not pSmad3 in comparison with vehicle-treated controls. Because endoglin binds BMP9 with high affinity, we explored the effect of reduced endoglin activity on BMP9 activity. Neutralizing endoglin activity in human cardiac fibroblasts or in wild-type mice subjected to transverse aortic constriction–induced heart failure limits collagen production, increases BMP9 protein levels, and increases levels of pSmad1, not pSmad3. Conclusions: Our results identify a novel functional role for BMP9 as an endogenous inhibitor of cardiac fibrosis attributable to LV pressure overload and further show that treatment with either recombinant BMP9 or disruption of endoglin activity promotes BMP9 activity and limits cardiac fibrosis in heart failure, thereby providing potentially novel therapeutic approaches for patients with heart failure.

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