scholarly journals Pressure Overload by Transverse Aortic Constriction Induces Maladaptive Hypertrophy in a Titin-Truncated Mouse Model

2015 ◽  
Vol 2015 ◽  
pp. 1-6 ◽  
Author(s):  
Qifeng Zhou ◽  
Scott Kesteven ◽  
Jianxin Wu ◽  
Parwez Aidery ◽  
Meinrad Gawaz ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mouse Model ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction ◽  
Ventricular Ejection Fraction ◽  
Human Phenotype ◽  
Large Pedigree

Mutations in the giant sarcomeric protein titin (TTN) are a major cause for inherited forms of dilated cardiomyopathy (DCM). We have previously developed a mouse model that imitates a TTN truncation mutation we found in a large pedigree with DCM. While heterozygousTtnknock-in mice do not display signs of heart failure under sedentary conditions, they recapitulate the human phenotype when exposed to the pharmacological stressor angiotensin II or isoproterenol. In this study we investigated the effects of pressure overload by transverse aortic constriction (TAC) in heterozygous (Het)Ttnknock-in mice. Two weeks after TAC, Het mice developed marked impairment of left ventricular ejection fraction(p<0.05), while wild-type (WT) TAC mice did not. Het mice also trended toward increased ventricular end diastolic pressure and volume compared to WT littermates. We found an increase in histologically diffuse cardiac fibrosis in Het compared to WT in TAC mice. This study shows that a pattern of DCM can be induced by TAC-mediated pressure overload in a TTN-truncated mouse model. This model enlarges our arsenal of cardiac disease models, adding a valuable tool to understand cardiac pathophysiological remodeling processes and to develop therapeutic approaches to combat heart failure.

scholarly journals Ketone Ester Treatment Improves Cardiac Function and Reduces Pathologic Remodeling in Preclinical Models of Heart Failure

2020 ◽  
Author(s):  
Salva R. Yurista ◽  
Timothy R. Matsuura ◽  
Herman H.W. Silljé ◽  
Kirsten T. Nijholt ◽  
Kendra S. McDaid ◽  
...  
Keyword(s):  
Heart Failure ◽  
Left Ventricular Ejection Fraction ◽  
Ventricular Dysfunction ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction ◽  
Ventricular Ejection Fraction ◽  
Failure Models ◽  
Ketone Ester

Background: Accumulating evidence suggests that the failing heart reprograms fuel metabolism toward increased utilization of ketone bodies and that increasing cardiac ketone delivery ameliorates cardiac dysfunction. As an initial step toward development of ketone therapies, we investigated the effect of chronic oral ketone ester (KE) supplementation as a prevention or treatment strategy in rodent heart failure models. Methods: Two independent rodent heart failure models were used for the studies: transverse aortic constriction/myocardial infarction (MI) in mice and post-MI remodeling in rats. Seventy-five mice underwent a prevention treatment strategy with a KE comprised of hexanoyl-hexyl-3-hydroxybutyrate KE (KE-1) diet, and 77 rats were treated in either a prevention or treatment regimen using a commercially available β-hydroxybutyrate-(R)-1,3-butanediol monoester (DeltaG; KE-2) diet. Results: The KE-1 diet in mice elevated β-hydroxybutyrate levels during nocturnal feeding, whereas the KE-2 diet in rats induced ketonemia throughout a 24-hour period. The KE-1 diet preventive strategy attenuated development of left ventricular dysfunction and remodeling post-transverse aortic constriction/MI (left ventricular ejection fraction±SD, 36±8 in vehicle versus 45±11 in KE-1; P =0.016). The KE-2 diet therapeutic approach also attenuated left ventricular dysfunction and remodeling post-MI (left ventricular ejection fraction, 41±11 in MI-vehicle versus 61±7 in MI-KE-2; P <0.001). In addition, ventricular weight, cardiomyocyte cross-sectional area, and the expression of ANP (atrial natriuretic peptide) were significantly attenuated in the KE-2–treated MI group. However, treatment with KE-2 did not influence cardiac fibrosis post-MI. The myocardial expression of the ketone transporter and 2 ketolytic enzymes was significantly increased in rats fed KE-2 diet along with normalization of myocardial ATP levels to sham values. Conclusions: Chronic oral supplementation with KE was effective in both prevention and treatment of heart failure in 2 preclinical animal models. In addition, our results indicate that treatment with KE reprogrammed the expression of genes involved in ketone body utilization and normalized myocardial ATP production following MI, consistent with provision of an auxiliary fuel. These findings provide rationale for the assessment of KEs as a treatment for patients with heart failure.

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 O-ring-induced transverse aortic constriction (OTAC) is a new simple method to develop cardiac hypertrophy and heart failure in mice

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Yasuhisa Nakao ◽  
Jun Aono ◽  
Mika Hamaguchi ◽  
Kayo Takahashi ◽  
Tomohisa Sakaue ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Pressure Overload ◽  
Experimental Models ◽  
Left Ventricular ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction ◽  
Lung Weight ◽  
Simple Method ◽  
Fractional Shortening

AbstractSuture-based transverse aortic constriction (TAC) in mice is one of the most frequently used experimental models for cardiac pressure overload-induced heart failure. However, the incidence of heart failure in the conventional TAC depends on the operator’s skill. To optimize and simplify this method, we proposed O-ring-induced transverse aortic constriction (OTAC) in mice. C57BL/6J mice were subjected to OTAC, in which an o-ring was applied to the transverse aorta (between the brachiocephalic artery and the left common carotid artery) and tied with a triple knot. We used different inner diameters of o-rings were 0.50 and 0.45 mm. Pressure overload by OTAC promoted left ventricular (LV) hypertrophy. OTAC also increased lung weight, indicating severe pulmonary congestion. Echocardiographic findings revealed that both OTAC groups developed LV hypertrophy within one week after the procedure and gradually reduced LV fractional shortening. In addition, significant elevations in gene expression related to heart failure, LV hypertrophy, and LV fibrosis were observed in the LV of OTAC mice. We demonstrated the OTAC method, which is a simple and effective cardiac pressure overload method in mice. This method will efficiently help us understand heart failure (HF) mechanisms with reduced LV ejection fraction (HFrEF) and cardiac hypertrophy.

scholarly journals CX3CR1 is a prerequisite for the development of cardiac hypertrophy and left ventricular dysfunction in mice upon transverse aortic constriction

PLoS ONE ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. e0243788
Author(s):  
Christina Katharina Weisheit ◽  
Jan Lukas Kleiner ◽  
Maria Belen Rodrigo ◽  
Sven Thomas Niepmann ◽  
Sebastian Zimmer ◽  
...  
Keyword(s):  
Heart Failure ◽  
Immune Response ◽  
Cardiac Hypertrophy ◽  
Left Ventricular Dysfunction ◽  
Ventricular Dysfunction ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction ◽  
Deficient Mice

The CX3CL1/CX3CR1 axis mediates recruitment and extravasation of CX3CR1-expressing subsets of leukocytes and plays a pivotal role in the inflammation-driven pathology of cardiovascular disease. The cardiac immune response differs depending on the underlying causes. This suggests that for the development of successful immunomodulatory therapy in heart failure due to chronic pressure overload induced left ventricular (LV) hypertrophy, the underlying immune patterns must be examined. Here, the authors demonstrate that Fraktalkine-receptor CX3CR1 is a prerequisite for the development of cardiac hypertrophy and left ventricular dysfunction in a mouse model of transverse aortic constriction (TAC). The comparison of C57BL/6 mice with CX3CR1 deficient mice displayed reduced LV hypertrophy and preserved cardiac function in response to pressure overload in mice lacking CX3CR1. Moreover, the normal immune response following TAC induced pressure overload which is dominated by Ly6Clow macrophages changed to an early pro-inflammatory immune response driven by neutrophils, Ly6Chigh macrophages and altered cytokine expression pattern in CX3CR1 deficient mice. In this early inflammatory phase of LV hypertrophy Ly6Chigh monocytes infiltrated the heart in response to a C-C chemokine ligand 2 burst. CX3CR1 expression impacts the immune response in the development of LV hypertrophy and its absence has clear cardioprotective effects. Hence, suppression of CX3CR1 may be an important immunomodulatory therapeutic target to ameliorate pressure-overload induced heart failure.

Abstract 364: Pathological Effects of Trimethylamine N-oxide (TMAO) on Pressure Overload-induced Heart Failure

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Chelsea L Organ ◽  
Hiroyuki Otsuka ◽  
Jessica Bradley ◽  
Shashi Bhushan ◽  
Rishi Trivedi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Control Diet ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Control Group ◽  
Ventricular Ejection Fraction ◽  
Increased Risk ◽  
Failure Severity ◽  
Heart Failure Severity

Rationale: Trimethylamine N-oxide (TMAO), a metabolite formed in the metabolism of dietary phosphatidylcholine, is elevated in the circulation of patients at increased risk for heart attack and adverse prognosis during heart failure. Objective: We investigated the effects of dietary choline and TMAO on the severity of heart failure following transverse aortic constriction (TAC). Methods and Results: Male C57Blk/6J mice were fed either control diet, a diet containing choline (1.2%) or a diet containing TMAO (0.12%) at 3 weeks prior to surgical TAC and were studied for 12 weeks. Left ventricular (LV) structure and function were monitored at 3 week intervals and myocardial tissue was collected at 12 weeks. Plasma TMAO levels were significantly (p < 0.01) increased in the choline (28.64 ± 2.30 μM) and TMAO (28.18 ± 4.27 μM) compared to the control group (1.87 ± 0.26 μM). Left ventricular ejection fraction (LVEF) was significantly (p < 0.05) worse in mice fed TMAO compared to control diet. LV end-diastolic and end-systolic diameters were significantly (p < 0.05) increased in the TMAO group compared to control diet. Myocardial fibrosis as measured with Picrosirius Red staining was also significantly greater (p < 0.01) in the TMAO and choline groups. Circulating BNP levels were significantly (p < 0.05) increased in the TMAO and choline groups. Conclusions: These data demonstrate that heart failure severity is significantly enhanced in mice fed diets containing either TMAO or choline. Our results suggest that consumption of food high in dietary nutrients that increase TMAO levels such as phosphatidylcholine may increase heart failure severity.

scholarly journals Considerable scatter in the relationship between left atrial volume and pressure in heart failure with preserved left ventricular ejection fraction

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Shiro Hoshida ◽  
◽  
Tetsuya Watanabe ◽  
Yukinori Shinoda ◽  
Tomoko Minamisaka ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Left Atrial ◽  
Pressure Overload ◽  
Left Atrial Volume ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Arterial Elastance ◽  
Ventricular Ejection Fraction ◽  
The Relationship

AbstractThe index for a target that can lead to improved prognoses and more reliable therapy in each heterogeneous patient with heart failure with preserved ejection fraction (HFpEF) remains to be defined. We examined the heterogeneity in the cardiac performance of patients with HFpEF by clarifying the relationship between the indices of left atrial (LA) volume (LAV) overload and pressure overload with echocardiography. We enrolled patients with HFpEF (N = 105) who underwent transthoracic echocardiography during stable sinus rhythm. Relative LAV overload was evaluated using the LAV index or stroke volume (SV)/LAV ratio. Relative LA pressure overload was estimated using E/e’ or the afterload-integrated index of left ventricular (LV) diastolic function: diastolic elastance (Ed)/arterial elastance (Ea) ratio = (E/e’)/(0.9 × systolic blood pressure). The logarithmic value of the N-terminal pro-brain natriuretic peptide was associated with SV/LAV (r = −0.214, p = 0.033). The pulmonary capillary wedge pressure was positively correlated to Ed/Ea (r = 0.403, p = 0.005). SV/LAV was negatively correlated to Ed/Ea (r = −0.292, p = 0.002), with no observed between-sex differences. The correlations between the LAV index and E/e’ and Ed/Ea and between SV/LAV and E/e’ were less prominent than the abovementioned relationships. SV/LAV and Ed/Ea, showing relative LAV and LA pressure respectively, were significantly but modestly correlated in patients with HFpEF. There may be considerable scatter in the relationships between these indices, which could possibly affect the selection of medications or efforts to improve the prognoses of patients with HFpEF.

scholarly journals CRD-733, a Novel PDE9 (Phosphodiesterase 9) Inhibitor, Reverses Pressure Overload–Induced Heart Failure

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Daniel A. Richards ◽  
Mark J. Aronovitz ◽  
Peiwen Liu ◽  
Gregory L. Martin ◽  
Kelly Tam ◽  
...  
Keyword(s):  
Heart Failure ◽  
Pulmonary Edema ◽  
Left Atrial ◽  
Phosphorylation Site ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Guanosine Monophosphate ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction ◽  
Cgmp Signaling

Background: Augmentation of NP (natriuretic peptide) receptor and cyclic guanosine monophosphate (cGMP) signaling has emerged as a therapeutic strategy in heart failure (HF). cGMP-specific PDE9 (phosphodiesterase 9) inhibition increases cGMP signaling and attenuates stress-induced hypertrophic heart disease in preclinical studies. A novel cGMP-specific PDE9 inhibitor, CRD-733, is currently being advanced in human clinical studies. Here, we explore the effects of chronic PDE9 inhibition with CRD-733 in the mouse transverse aortic constriction pressure overload HF model. Methods: Adult male C57BL/6J mice were subjected to transverse aortic constriction and developed significant left ventricular (LV) hypertrophy after 7 days ( P <0.001). Mice then received daily treatment with CRD-733 (600 mg/kg per day; n=10) or vehicle (n=17), alongside sham-operated controls (n=10). Results: CRD-733 treatment reversed existing LV hypertrophy compared with vehicle ( P <0.001), significantly improved LV ejection fraction ( P =0.009), and attenuated left atrial dilation ( P <0.001), as assessed by serial echocardiography. CRD-733 prevented elevations in LV end diastolic pressures ( P =0.037) compared with vehicle, while lung weights, a surrogate for pulmonary edema, were reduced to sham levels. Chronic CRD-733 treatment increased plasma cGMP levels compared with vehicle ( P <0.001), alongside increased phosphorylation of Ser 273 of cardiac myosin binding protein-C, a cGMP-dependent protein kinase I phosphorylation site. Conclusions: The PDE9 inhibitor, CRD-733, improves key hallmarks of HF including LV hypertrophy, LV dysfunction, left atrial dilation, and pulmonary edema after pressure overload in the mouse transverse aortic constriction HF model. Additionally, elevated plasma cGMP may be used as a biomarker of target engagement. These findings support future investigation into the therapeutic potential of CRD-733 in human HF.

Efficacy of Vitamin D on Chronic Heart Failure Among Adults

2020 ◽  
Vol 90 (1-2) ◽  
pp. 49-58 ◽  
Author(s):  
Wang Chunbin ◽  
Wang Han ◽  
Cai Lin
Keyword(s):  
Heart Failure ◽  
Vitamin D ◽  
Chronic Heart Failure ◽  
Left Ventricular Ejection Fraction ◽  
Confidence Interval ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Controlled Trials ◽  
Ventricular Ejection Fraction ◽  
Randomized Controlled

Abstract. Vitamin D deficiency commonly occurs in chronic heart failure. Whether additional vitamin D supplementation can be beneficial to adults with chronic heart failure remains unclear. We conducted a meta-analysis to derive a more precise estimation. PubMed, Embase, and Cochrane databases were searched on September 8, 2016. Seven randomized controlled trials that investigated the effects of vitamin D on cardiovascular outcomes in adults with chronic heart failure, and comprised 592 patients, were included in the analysis. Compared to placebo, vitamin D, at doses ranging from 2,000 IU/day to 50,000 IU/week, could not improve left ventricular ejection fraction (Weighted mean difference, WMD = 3.31, 95% confidence interval, CL = −0.93 to 7.55, P < 0.001, I2 = 92.1%); it also exerts no beneficial effects on the 6 minute walk distance (WMD = 18.84, 95% CL = −24.85 to 62.52, P = 0.276, I2 = 22.4%) and natriuretic peptide (Standardized mean difference, SMD = −0.39, 95% confidence interval CL = −0.48 to 0.69, P < 0.001, I2 = 92.4%). However, a dose-response analysis from two studies demonstrated an improved left ventricular ejection fraction with vitamin D at a dose of 4,000 IU/day (WMD = 6.58, 95% confidence interval CL = −4.04 to 9.13, P = 0.134, I2 = 55.4%). The results showed that high dose vitamin D treatment could potentially benefit adults with chronic heart failure, but more randomized controlled trials are required to confirm this result.

Sign in / Sign up

Export Citation Format

Share Document