ID: 137: GRK2 INHIBITION REDUCES POST-MYOCARDIAL INFARCTION CARDIAC FIBROBLAST MEDIATED ADVERSE REMODELING

2016 ◽  
Vol 64 (4) ◽  
pp. 912.1-912
Author(s):  
M Razzaque ◽  
JL Philip ◽  
X Xu ◽  
M Han ◽  
J Li ◽  
...  
Keyword(s):  
Collagen Synthesis ◽  
Left Ventricular ◽  
Male Rats ◽  
Lv Function ◽  
Intracellular Camp ◽  
Adrenergic Signaling ◽  
Adenoviral Delivery ◽  
Collagen Iii ◽  
Adverse Remodeling ◽  
Fractional Shortening

ObjectivesRemote (non-infarct) territory fibrosis is a significant cause of post-infarction heart failure (HF). We have previously shown that increased G protein-coupled receptor kinase-2 (GRK2) activity in adult human cardiac fibroblasts (CF) isolated from failing hearts is an important mechanism of cardiac fibrosis through uncoupling β-adrenergic receptor (β-AR) signaling. This study investigates the potential therapeutic role of GRK2 inhibition on CF biology in vivo.MethodsAdult male rats underwent LAD ligation to induce post-MI HF. Left ventricular (LV) function was assessed by echocardiography. Myocardial fibrosis was quantitated by histologic staining. LV CF were isolated and cultured. GRK2 was inhibited by intra-coronary adenoviral-mediated delivery of a GRK2 inhibitor (Ad-GRK2ct) immediately following LAD ligation (n=11). Control rats received a null adenovirus (n=10). Animals were studied prior to and 12 weeks post-MI and adenoviral delivery.ResultsThere was a significant decline in LV function at 12 weeks post-MI which [Fractional shortening: 0.35±0.01 vs. 0.52±0.01, p<0.01]. There was significant increase in remote territory (non-infarct area) fibrosis at 12 weeks post-MI compared to control [12±1% vs. 2±1% fibrosis, p<0.05], consistent with adverse remodeling. Additionally, collagen synthesis was significantly upregulated in isolated CF 12 weeks post-MI compared to control CF [3559±760 vs. 1029±45 cmp/mg protein, p<0.02]. At 12 weeks post-MI, GRK2 activity was increased 1.4-fold [p<0.01]. There was a 42% decrease in intracellular cAMP [p<0.05] and loss of b-agonist (isoproterenol)-stimulated inhibition of collagen synthesis characteristic of normal CF, indicating uncoupling of β-AR signaling post-MI. Adenoviral mediated overexpression of GRK2ct, GRK2 inhibitor, in vitro in the cultured CF post-MI led to a 50% decrease in aSMA expression (p<0.01) as well as a significant decreased collagen expression and synthesis compared to null adenovirus (Ad-Null) control [1928±126 vs. 2611±213 cmp/mg protein, p<0.05], restoring the control CF phenotype. Intra-coronary delivery of Ad-GRK2ct following MI significantly reduced post-MI LV dysfunction vs. Ad-Null as measured by improved fractional shortening [0.42±0.01 vs. 0.30±0.02, p<0.01] and ejection fraction [72±1% vs. 57±2%, p<0.03]. Ad-GRK2ct also decreased peri-infarct and remote territory fibrosis by 60% [p<0.03]. Consistent with these findings, Ad-GRK2ct resulted in an over 25% decreased in α-SMA, collagen I, and collagen III expression in CF isolated 12 weeks post-MI vs. Ad-Null [p<0.04] providing evidence of decreased post-MI CF activation and myofibroblast transformation with Ad-GRK2ct.ConclusionsUncoupling of β-adrenergic signaling in CF via increased GRK2 appears to be a key mechanism of post-MI fibrosis. Targeted inhibition of GRK2 and restoration of b-adrenergic signaling/cAMP production in CF may represent a novel therapeutic approach to prevent pathological fibrosis and maladaptive remodeling.

Abstract 13917: Inhibition of GRK2 Prevents Cardiac Fibroblast-Mediated Maladaptive Ventricular Remodeling

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Jennifer L Philip ◽  
Xianyao Xu ◽  
Mei Han ◽  
Jinju Li ◽  
Abdur Razzaque ◽  
...  
Keyword(s):  
Collagen Synthesis ◽  
Cardiac Fibrosis ◽  
Ventricular Remodeling ◽  
Cardiac Fibroblasts ◽  
Male Rats ◽  
Lv Function ◽  
Intracellular Camp ◽  
Adenoviral Delivery ◽  
Fractional Shortening

Remote (non-infarct) territory fibrosis is a significant cause of post-myocardial infarction (MI) heart failure (HF). We have previously shown that increased activity of G protein-coupled receptor kinase-2 (GRK2) in adult human cardiac fibroblasts (CF) isolated from failing hearts is an important mechanism of cardiac fibrosis. This study investigates the potential therapeutic role of GRK2 inhibition on CF biology in vivo. Adult male rats underwent LAD ligation to induce post-MI HF. GRK2 was inhibited by intra-coronary adenoviral-mediated delivery of a GRK2 inhibitor (Ad-GRK2ct) immediately following LAD ligation (n=11). Control rats received a null adenovirus (n=10). Animals were studied prior to and up to 12 weeks (wks) post-MI and adenoviral delivery. There was a significant decline in LV function at 2 wks post-MI which was present through 12 wks [Fractional shortening: 0.35±0.01 vs. 0.52±0.01, p<0.01] in Ad-null rats vs. pre-MI. Remote territory (non-infarct area) fibrosis increased by 2 wks post-MI [6±1% vs. 2±1% fibrosis, p<0.01] progressing by 12 wks to 12% fibrosis [p<0.01], consistent with adverse remodeling. Collagen synthesis was upregulated 2.9-fold in CF isolated 12 wks post-MI [p<0.03] and GRK2 activity was increased 1.4-fold [p=0.002]. There was a 42% decrease in intracellular cAMP [p<0.05] and loss of β-agonist-stimulated inhibition of collagen synthesis characteristic of normal CF [3969±1058 vs. 708±95 cmp/mg protein, p<0.01]. Intra-coronary delivery of Ad-GRK2ct following LAD ligation significantly inhibited post-MI LV dysfunction vs. Ad-Null as measured by improved fractional shortening [0.42±0.01 vs. 0.30±0.02, p<0.01] and ejection fraction [72±1% vs. 57±2%, p<0.01]. Ad-GRK2ct also decreased peri-infarct and remote territory fibrosis by 60% [p<0.001]. Consistent with these findings, Ad-GRK2ct resulted in decreased a-SMA, collagen I, and collegen III expression in CF isolated 12 wks post-MI vs. Ad-Null providing evidence of decreased post-MI CF activation and myofibroblast transformation with Ad-GRK2ct. Targeted inhibition of GRK2 and restoration of β-adrenergic signaling/cAMP production in CF may represent a novel therapeutic approach to prevent pathological fibrosis and maladaptive remodeling post-MI.

Abstract 15989: Intracoronary Infusion of Multicellular Cardiospheres Can Be Safely Used to Prevent Adverse Remodeling in a Pig Model of Myocardial Infarction

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Romain Gallet ◽  
Eleni Tseliou ◽  
James Dawkins ◽  
Ryan Middleton ◽  
Jackelyn Valle ◽  
...  
Keyword(s):  
Troponin I ◽  
Diastolic Pressure ◽  
Left Ventricular ◽  
Lv Function ◽  
Self Assembling ◽  
Timi Flow ◽  
Intracoronary Infusion ◽  
Post Infusion ◽  
Adverse Remodeling ◽  
Hemodynamic Improvement

Background: Pre-clinical studies in rodents and pigs indicate that the self-assembling microtissues known as cardiospheres (CSp), when administered intramyocardially, may be more effective than dispersed CSp-derived cells (CDCs). However, the more desirable intracoronary (IC) route has been assumed to be unsafe for CSp delivery: CSp are large (>35 μm), raising concerns about likely microembolization. Objective: We sought to evaluate the safety and efficacy of IC delivery of allogeneic CSp in a porcine model of convalescent MI. Methods: Dosage was optimized by infusing CSp (3.25x10 5 particles [n=2], 6.5 x10 5 [n=3] and 1.3x10 6 [n=2], size=44±23, 29%>50μm) in the LAD of naïve pigs, looking for acute adverse effects (troponin I [TnI] leak, low TIMI flow, stunning). We next tested the efficacy of IC allogeneic Csp (1.3x10 6 ; n=7) or vehicle (n=8) in a minipig model of chronic MI. Animals underwent MRI before infusion and 1 month later. Left ventricular (LV) ejection fraction (EF), scar mass and viable mass were evaluated at both time points. Results: In the dosing study, we observed no impairment of TIMI flow or LVEF after CSp infusion. TnI at 24 hours was 0.7±0.5ng/mL and did not differ among groups (P=0.11). In the post-MI study, EF was identical in the two groups at baseline. One month post-infusion, LV function was preserved in the CSp group but not in controls (ΔEF=+0.5±1.6% vs. -4.5±1.8%, p<0.001). CSp reduced scar mass (P<0.001) and increased viable mass (+17±8% vs. +6±6% from baseline, P=0.04) compared to controls. IC CSp also decreased LV end diastolic pressure (-7±4mmHg vs. -1±4 mmHg in control, P<0.01)) and increased cardiac output (+0.5±0.4 mL/min vs. -0.1±0.3mL/min, P<0.01. Conclusions: IC delivery of allogeneic CSp is safe and preserves LV function after MI. In addition, global hemodynamic improvement is observed, which may have significant clinical implications. The decision to use CDCs or CSp is not forced, therefore, by an inability to infuse CSp safely via the IC route.

Abstract 16121: Recombinant Human Placental Growth Factor 2 is a Safe and Effective Therapy for Ischemic Cardiomyopathy in Atherosclerotic Mice

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Ming Wu ◽  
Melissa Swinnen ◽  
Ellen Caluwe ◽  
Hilde Gillijns ◽  
Nina Vanden Driessche ◽  
...  
Keyword(s):  
Growth Factor ◽  
Atherosclerotic Plaque ◽  
Ischemic Cardiomyopathy ◽  
Contractile Function ◽  
Left Ventricular ◽  
Placental Growth Factor ◽  
Plaque Burden ◽  
Lv Function ◽  
Plaque Vulnerability ◽  
Adverse Remodeling

Aim: Angiogenic growth factor therapy carries a risk of stimulating atherosclerotic plaque growth. We evaluated whether systemic infusion of recombinant human placental growth factor (rhPlGF) 2 improves myocardial neovascularization, left ventricular (LV) function and adverse remodeling in a murine model of advanced atherosclerosis and chronic myocardial infarction (MI) without increasing atherosclerotic plaque size and plaque vulnerability. Methods: ApoE -/- mice were fed a high cholesterol diet and MI was induced 4 weeks (w) later using 60 min LAD occlusion followed by reperfusion. After 8 w, we assessed LV function using echocardiography and randomized mice to receive rhPlGF2 (450μg/kg/day, n=20) or PBS (n=20) via osmotic minipumps for 28 days. Echocardiography and histological analyses were performed at 12 and 20 w. Results: Infusion of rhPlGF2 increased PlGF plasma levels for 3 w up to ~1600-fold without adverse side effects, or changes in total cholesterol and high sensitive CRP levels. In rhPlGF2-treated mice, capillary and arteriolar density was significantly higher in ischemic myocardium (2813±212 capillaries/mm 2 at 12 w vs 2144±478 in PBS, P <0.05; 125±18 arterioles/mm 2 at 20 w vs 77±13 in PBS, P =0.001). RhPlGF2 significantly improved ejection fraction (EF), reduced LV end-systolic and end-diastolic volume indices at 12 w and prevented further LV dilation and EF deterioration at 20 w (Figure). RhPlGF2 did not increase plaque area in the aortic arch, or the degree of fibrosis, calcification, capillary or arteriolar density and MAC3-positive cell areas in plaques at 12 and 20 w. Conclusion: Systemic rhPlGF2 infusion significantly improves neovascularization and contractile function, and prevents LV adverse remodeling in chronic ischemic cardiomyopathy without increasing atherosclerotic plaque burden or plaque vulnerability. RhPlGF2 may represent a promising and safe therapeutic strategy in chronic ischemic cardiomyopathy.

Abstract 18942: Inhibition of β-arrestin 1 Prevents post-MI Maladaptive Ventricular Remodeling

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Md Abdur Razzaque ◽  
Xianyao Xu ◽  
Abbasali Badami ◽  
Peter Klepacz ◽  
Mei Han ◽  
...  
Keyword(s):  
Cardiac Fibrosis ◽  
Ventricular Remodeling ◽  
Cardiac Fibroblasts ◽  
Male Rats ◽  
Lv Function ◽  
Adenoviral Delivery ◽  
Potential Therapeutic Role ◽  
Targeted Inhibition ◽  
Human Cardiac Fibroblasts

Remote (non-infarct) territory fibrosis is a significant cause of post-myocardial infarction (MI) heart failure (HF). We have previously shown that increased activity of β-arrestin 1 in adult human cardiac fibroblasts (CF) isolated from failing hearts is an important mechanism of cardiac fibrosis. This study investigates the potential therapeutic role of β-arrestin 1 inhibition on CF biology in vivo. Adult male rats underwent LAD ligation to induce post-MI HF. β-arrestin 1 was inhibited by intra-coronary adenoviral-mediated delivery of a β-arrestin 1 inhibitor (Ad-Barr1ct) immediately following LAD ligation (n=11). Ad-Barr1ct contains a rat β-arrestin 1 C-terminal fragment (aa. 369-418). Control rats received a null adenovirus (n=10). Animals were studied prior to and up to 8 weeks (wks) post-MI and adenoviral delivery. There was a significant decline in LV function at 8 wks post-MI in Ad-null rats vs. pre-MI. Remote territory (non-infarct area) fibrosis increased by 8 wks post-MI consistent with adverse remodeling. Intra-coronary delivery of Ad-Barr1ct following LAD ligation significantly inhibited post-MI LV dysfunction vs. Ad-Null as measured by improved fractional shortening and ejection fraction. Ad-Barr1ct also decreased peri-infarct and remote territory fibrosis. Consistent with these findings, Ad-arr1ct resulted in decreased α-SMA, collagen I, collegen III and fibronectin expression in CF isolated 8 wks post-MI vs. Ad-Null providing evidence of decreased post-MI CF activation and myofibroblast transformation with Ad-Barr1ct. Targeted inhibition of β-arrestin 1 in the heart may represent a novel therapeutic approach to prevent pathological fibrosis and maladaptive remodeling post-MI.

scholarly journals Valve Replacement for Aortic Stenosis in Patients With Poor Left Ventricular Function

Circulation ◽  
1999 ◽  
Vol 100 (suppl_2) ◽  
Author(s):  
Julian Collinson ◽  
Michael Henein ◽  
Marcus Flather ◽  
John R. Pepper ◽  
Derek G. Gibson
Keyword(s):  
Aortic Stenosis ◽  
Systolic Function ◽  
Left Ventricular ◽  
Lv Function ◽  
Valve Prosthesis ◽  
Transthoracic Doppler Echocardiography ◽  
Early Improvement ◽  
Lv Dysfunction ◽  
Lv Systolic Function ◽  
Fractional Shortening

Background —Long-standing aortic stenosis causes significant left ventricular (LV) dysfunction, which may progress irreversibly. In many cases, LV function can be salvaged by aortic valve surgery, although debate exists regarding the best valve prosthesis to use. Methods and Results —We studied 33 patients retrospectively who had significant aortic stenosis and impaired LV systolic function, as assessed by transthoracic Doppler echocardiography. Patients were assessed preoperatively and before discharge from the hospital. A total of 20 patients received a stentless (homograft or Toronto) valve, and 13, a stented valve. No patient had significant aortic regurgitation or other valvular disease. Preoperatively, fractional shortening was 18.8±5.5% in the stentless group and 18.6±3.8% in the stented group. Postoperatively, it was 25.6±6.9% ( P <0.001 compared with baseline) and 17.0±2.8%, respectively ( P <0.001 compared with stentless group). Fractional shortening improved because of a reduction in LV end-systolic and end-diastolic dimensions in the stentless group. Systolic long axis function at the LV free wall also recovered, with an increase in systolic excursion and both peak shortening and lengthening rates. No change was noted in mitral valve Doppler patterns. Conclusions —Patients who received a stentless valve demonstrated a significantly greater early improvement in LV systolic function compared with those who received a stented valve.

Tachycardia-induced cardiomyopathy: effects on blood flow and capillary structure

1991 ◽  
Vol 261 (1) ◽  
pp. H140-H148 ◽  
Author(s):  
F. G. Spinale ◽  
J. L. Zellner ◽  
M. Tomita ◽  
G. E. Tempel ◽  
F. A. Crawford ◽  
...  
Keyword(s):  
Blood Flow ◽  
Capillary Density ◽  
Left Ventricular ◽  
Lv Function ◽  
Atrial Pacing ◽  
Capillary Structure ◽  
Potential Factor ◽  
Rapid Pacing ◽  
Tachycardia Induced Cardiomyopathy ◽  
Fractional Shortening

Chronic supraventricular tachycardia (SVT) causes a dilated cardiomyopathy. A potential factor contributing to the development of SVT-induced cardiomyopathy is abnormal myocardial blood flow (MBF). The purpose of this study was to relate changes in left ventricular (LV) function, MBF, and capillary structure with the development of SVT-induced cardiomyopathy. LV function and MBF were measured in two groups of conscious pigs: sham control (CON; n = 8) and after 3 wk of atrial pacing (SVT; 240 beats/min; n = 8) using echocardiography-catheterization and microspheres. Measurements were made under three states: 1) at rest with a basal heart rate, 2) during rapid atrial pacing (240 beats/min), and 3) during adenosine infusion (1.5 microM.kg-1.min-1) without pacing. LV capillary density, diameter, wall thickness, and capillary-myocyte distance were measured in four additional pigs from each group. LV fractional shortening was lower, and left atrial pressure was significantly higher in the SVT group compared with CON at rest, during pacing, and with adenosine (P less than 0.05). In the CON group, average LV-MBF at rest was 2.0 +/- 0.2 ml.min-1.g-1, increased with pacing to 3.0 +/- 0.2 ml.min-1.g-1 (P less than 0.05), and increased further with adenosine to 4.1 +/- 0.3 ml.min-1.g-1 (P less than 0.05). In all states, SVT LV-MBF was significantly reduced vs. CON (P less than 0.05); SVT LV-MBF was 0.8 +/- 0.2 ml.min-1.g-1 at rest, increased to 1.3 +/- 0.3 ml.min-1.g-1 with rapid pacing (P less than 0.05), and remained unchanged during adenosine (1.3 +/- 0.4 ml.min-1.g-1).(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Fructose plus High-Salt Diet in Early Life Results in Salt-Sensitive Cardiovascular Changes in Mature Male Sprague Dawley Rats

Nutrients ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 3129
Author(s):  
Peter E. Levanovich ◽  
Charles S. Chung ◽  
Dragana Komnenov ◽  
Noreen F. Rossi
Keyword(s):  
Phase I ◽  
Left Ventricular ◽  
High Salt ◽  
Male Rats ◽  
Phase Iii ◽  
Lv Function ◽  
Sprague Dawley ◽  
High Salt Diet ◽  
Salt Diet ◽  
Sprague Dawley Rats

Fructose and salt intake remain high, particularly in adolescents and young adults. The present studies were designed to evaluate the impact of high fructose and/or salt during pre- and early adolescence on salt sensitivity, blood pressure, arterial compliance, and left ventricular (LV) function in maturity. Male 5-week-old Sprague Dawley rats were studied over three 3-week phases (Phases I, II, and III). Two reference groups received either 20% glucose + 0.4% NaCl (GCS-GCS) or 20% fructose + 4% NaCl (FHS-FHS) throughout this study. The two test groups ingested fructose + 0.4% NaCl (FCS) or FHS during Phase I, then GCS in Phase II, and were then challenged with 20% glucose + 4% NaCl (GHS) in Phase III: FCS-GHS and FHS-GHS, respectively. Compared with GCS-GCS, systolic and mean pressures were significantly higher at the end of Phase III in all groups fed fructose during Phase I. Aortic pulse wave velocity (PWV) was elevated at the end of Phase I in FHS-GHS and FHS-FHS (vs. GCS-GCS). At the end of Phase III, PWV and renal resistive index were higher in FHS-GHS and FHS-FHS vs. GCS-GCS. Diastolic, but not systolic, LV function was impaired in the FHS-GHS and FHS-FHS but not FCS-FHS rats. Consumption of 20% fructose by male rats during adolescence results in salt-sensitive hypertension in maturity. When ingested with a high-salt diet during this early plastic phase, dietary fructose also predisposes to vascular stiffening and LV diastolic dysfunction in later life.

Abstract 36: Acute Inhibition Of O-GlcNAc Signaling Rescues Inotropic Responsiveness In Type 1 Diabetic Rat Hearts

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Chengxue Qin ◽  
Rochelle S S Sleaby ◽  
Lea M Delbridge ◽  
Amy J Davidoff ◽  
John C Chatham ◽  
...  
Keyword(s):  
Left Ventricular ◽  
Male Rats ◽  
Diabetic Heart ◽  
Diabetic Rat ◽  
Lv Function ◽  
Diabetic Patients ◽  
Cardiac Phenotype ◽  
Rat Hearts ◽  
The Impact

Metabolism of excess glucose is an important component of the aetiology of type 1 diabetes. The cardiac phenotype includes left ventricular (LV) remodelling and LV dysfunction. Increased hexosamine biosythesis (HBP) and downstream upregulation of protein O-GlcNAcylation has been linked to diabetic complications in many organs. Its impact on LV contractile responsiveness is however not well understood. This study aimed to test the hypothesis that acute inhibition of O-GlcNAc signaling protects inotropic responsiveness in type 1 diabetic heart. Hearts isolated from adult Sprague-Dawley male rats were Langendorff-perfused (constant flow, 10ml/min). Baseline and phenylephrine-stimulated (PE, 10μmol/L) LV function was determined in diabetic (8wks post-streptozotocin diabetes, 55mg/kg i.v.) versus non-diabetic sham rats in the presence of pharmacological inhibitors of HBP/O-GlcNAc including 6-diazo-5-oxo-L-norleucine (DON, 20μM) and alloxan (5mM). Diabetic rats exhibited a marked reduction in inotropic responsiveness to PE (Table, mean±SEM, one-way ANOVA, #P<0.05 vs non-diabetic vehicle rats, *P<0.05 vs diabetic vehicle, at 40 mins). Acute interruption of cardiac HBP/O-GlcNAc by DON and Alloxan significantly rescued LV responsiveness to PE in type 1 diabetic rat hearts. These results support further assessment of the impact of upregulated protein O-GlcNAcylation on LV function, particularly in the diabetic heart. Treatment strategies that target HBP may provide significant benefits alone or in combination with current standard treatments, to reduce progression of heart failure and death in type 1 diabetic patients.

scholarly journals Testosterone deprivation accelerates cardiac dysfunction in obese male rats

2016 ◽  
Vol 229 (3) ◽  
pp. 209-220 ◽  
Author(s):  
Wanpitak Pongkan ◽  
Hiranya Pintana ◽  
Sivaporn Sivasinprasasn ◽  
Thidarat Jaiwongkam ◽  
Siriporn C Chattipakorn ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Mitochondrial Function ◽  
Cardiac Dysfunction ◽  
Left Ventricular ◽  
Normal Diet ◽  
Metabolic Parameters ◽  
Male Rats ◽  
Lv Function ◽  
Insulin Resistant ◽  
Aging Men

Low testosterone level is associated with increased risks of cardiovascular diseases. As obese-insulin-resistant condition could impair cardiac function and that the incidence of obesity is increased in aging men, a condition of testosterone deprivation could aggravate the cardiac dysfunction in obese-insulin-resistant subjects. However, the mechanism underlying this adverse effect is unclear. This study investigated the effects of obesity on metabolic parameters, heart rate variability (HRV), left ventricular (LV) function, and cardiac mitochondrial function in testosterone-deprived rats. Orchiectomized or sham-operated male Wistar rats (n=36per group) were randomly divided into groups and were given either a normal diet (ND, 19.77% of energy fat) or a high-fat diet (HFD, 57.60% of energy fat) for 12weeks. Metabolic parameters, HRV, LV function, and cardiac mitochondrial function were determined at 4, 8, and 12weeks after starting each feeding program. We found that insulin resistance was observed after 8weeks of the consumption of a HFD in both sham (HFS) and orchiectomized (HFO) rats. Neither the ND sham (NDS) group nor ND orchiectomized (NDO) rats developed insulin resistance. The development of depressed HRV, LV contractile dysfunction, and increased cardiac mitochondrial reactive oxygen species production was observed earlier in orchiectomized (NDO and HFO) rats at week 4, whereas HFS rats exhibited these impairments later at week 8. These findings suggest that testosterone deprivation accelerates the impairment of cardiac autonomic regulation and LV function via increased oxidative stress and impaired cardiac mitochondrial function in obese-orchiectomized male rats.

scholarly journals Telmisartan ameliorates cardiac fibrosis and diastolic function in cardiorenal heart failure with preserved ejection fraction

2021 ◽  
pp. 153537022110350
Author(s):  
Di Chang ◽  
Ting-Ting Xu ◽  
Shi-Jun Zhang ◽  
Yu Cai ◽  
Shu-Dan Min ◽  
...  
Keyword(s):  
Heart Failure ◽  
Growth Factor ◽  
Ejection Fraction ◽  
Diastolic Function ◽  
Rat Model ◽  
Cardiac Fibrosis ◽  
Left Ventricular ◽  
Male Rats ◽  
Preserved Ejection Fraction ◽  
Collagen Iii

Chronic kidney disease (CKD) is a major contributor to the development of heart failure with preserved ejection fraction (HFpEF), whereas the underlying mechanism of cardiorenal HFpEF is still elusive. The aim of this study was to investigate the role of cardiac fibrosis in a rat model of cardiorenal HFpEF and explore whether treatment with Telmisartan, an inhibitor of renin-angiotensin-aldosterone system (RAAS), can ameliorate cardiac fibrosis and preserve diastolic function in cardiorenal HFpEF. Male rats were subjected to 5/6 subtotal nephrectomy (SNX) or sham operation (Sham), and rats were allowed four weeks to recover and form a stable condition of CKD. Telmisartan or vehicle was then administered p.o. (8 mg/kg/d) for 12 weeks. Blood pressure, brain natriuretic peptide (BNP), echocardiography, and cardiac magnetic resonance imaging were acquired to evaluate cardiac structural and functional alterations. Histopathological staining, real-time polymerase chain reaction (PCR) and western blot were performed to evaluate cardiac remodeling. SNX rats showed an HFpEF phenotype with increased BNP, decreased early to late diastolic transmitral flow velocity (E/A) ratio, increased left ventricular (LV) hypertrophy and preserved ejection fraction (EF). Pathology revealed increased cardiac fibrosis in cardiorenal HFpEF rats compared with the Sham group, while chronic treatment with Telmisartan significantly decreased cardiac fibrosis, accompanied by reduced markers of fibrosis (collagen I and collagen III) and profibrotic cytokines (α-smooth muscle actin, transforming growth factor-β1, and connective tissue growth factor). In addition, myocardial inflammation was decreased after Telmisartan treatment, which was in a linear correlation with cardiac fibrosis. Telmisartan also reversed LV hypertrophy and E/A ratio, indicating that Telmisartan can improve LV remodeling and diastolic function in cardiorenal HFpEF. In conclusion, cardiac fibrosis is central to the pathology of cardiorenal HFpEF, and RAAS modulation with Telmisartan is capable of alleviating cardiac fibrosis and preserving diastolic dysfunction in this rat model.

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