A Sex-Specific Role of Endothelial Sirtuin 3 on Blood Pressure and Diastolic Dysfunction in Female Mice

Background: Heart failure with preserved ejection fraction (HFpEF) is characterized by a diastolic dysfunction and is highly prevalent in aged women. Our study showed that ablation of endothelial Sirtuin 3 (SIRT3) led to diastolic dysfunction in male mice. However, the sex-specific role of endothelial SIRT3 deficiency on blood pressure and diastolic function in female mice remains to be investigated. Methods and Results: In this study, we demonstrate that the ablation of endothelial SIRT3 in females elevated blood pressure as compared with control female mice. Diastolic function measurement also showed that the isovolumic relaxation time (IVRT) and myocardial performance index (MPI) were significantly increased, whereas the E’ velocity/A’ velocity (E’/A’) ratio was reduced in the endothelial-specific SIRT3 knockout (SIRT3 ECKO) female mice. To further investigate the regulatory role of endothelial SIRT3 on blood pressure and diastolic dysfunction in metabolic stress, SIRT3 ECKO female mice were fed a normal diet and high-fat diet (HFD) for 20 weeks. The knockout of endothelial SIRT3 resulted in an increased blood pressure in female mice fed with an HFD. Intriguingly, SIRT3 ECKO female mice + HFD exhibited impaired coronary flow reserve (CFR) and more severe diastolic dysfunction as evidenced by an elevated IVRT as compared with control female mice + HFD. In addition, female SIRT3 ECKO mice had higher blood pressure and diastolic dysfunction as compared to male SIRT3 ECKO mice. Moreover, female SIRT3 ECKO mice + HFD had an impaired CFR and diastolic dysfunction as compared to male SIRT3 ECKO mice + HFD. Conclusions: These results implicate a sex-specific role of endothelial SIRT3 in regulating blood pressure and diastolic function in mice. Deficiency of endothelial SIRT3 may be responsible for a diastolic dysfunction in aged female.

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Abstract 009: Regulatory Role of Endothelial Sirt3 on Blood Pressure and Diastolic Dysfunction in a Female Mice

Hypertension ◽

10.1161/hyp.72.suppl_1.009 ◽

2018 ◽

Vol 72 (Suppl_1) ◽

Author(s):

Heng Zeng ◽

Rebecca A Worsham ◽

Jian Xiong Chen

Keyword(s):

Blood Pressure ◽

Diastolic Dysfunction ◽

Regulatory Role ◽

Female Mice

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Features of heart failure with preserved ejection fraction (HFpEF) in diabetic patients with resistant hypertension

Diabetes Mellitus ◽

10.14341/dm12732 ◽

2021 ◽

Vol 24 (4) ◽

pp. 304-314

Author(s):

M. A. Manukyan ◽

A. Y. Falkovskaya ◽

V. F. Mordovin ◽

T. R. Ryabova ◽

I. V. Zyubanova ◽

...

Keyword(s):

Diabetes Mellitus ◽

Heart Failure ◽

Blood Pressure ◽

Blood Flow ◽

Ejection Fraction ◽

Diastolic Dysfunction ◽

Diastolic Function ◽

Resistant Hypertension ◽

Diabetic Patients ◽

Preserved Ejection Fraction

BACKGROUND: It is expected that a steady increase in the incidence of diabetes and resistant hypertension (RHTN), along with an increase in life expectancy, will lead to a noticeable increase in the proportion of patients with heart failure with preserved ejection fraction (HFpEF). At the same time, data on the frequency of HFpEF in a selective group of patients with RHTN in combination with diabetes are still lacking, and the pathophysiological and molecular mechanisms of its formation have not been yet studied sufficiently.AIM: To assess the features of the development HFpEF in diabetic and non-diabetic patients with RHTN, as well as to determine the factors associated with HFpEF.MATERIALS AND METHODS: In the study were included 36 patients with RHTN and type 2 diabetes mellitus (DM) (mean age 61.4 ± 6.4 years, 14 men) and 33 patients with RHTN without diabetes, matched by sex, age and level of systolic blood pressure (BP). All patients underwent baseline office and 24-hour BP measurement, echocardiography with assess diastolic function, lab tests (basal glycemia, HbA1c, creatinine, aldosterone, TNF-alpha, hsCRP, brain naturetic peptide, metalloproteinases of types 2, 9 (MMP-2, MMP-9) and tissue inhibitor of MMP type 1 (TIMP-1)). HFpEF was diagnosed according to the 2019 AHA/ESC guidelines.RESULTS: The frequency of HFpEF was significantly higher in patients with RHTN with DM than those without DM (89% and 70%, respectively, p=0.045). This difference was due to a higher frequency of such major functional criterion of HFpEF as E/e’≥15 (p=0.042), as well as a tendency towards a higher frequency of an increase in left atrial volumes (p=0.081) and an increase in BNP (p=0.110). Despite the comparable frequency of diastolic dysfunction in patients with and without diabetes (100% and 97%, respectively), disturbance of the transmitral blood flow in patients with DM were more pronounced than in those without diabetes. Deterioration of transmitral blood flow and pseudo-normalization of diastolic function in diabetic patients with RHTN have relationship not only with signs of carbohydrate metabolism disturbance, but also with level of pulse blood pressure, TNF-alfa, TIMP-1 and TIMP-1 / MMP-2 ratio, which, along with the incidence of atherosclerosis, were higher in patients with DM than in those without diabetes.CONCLUSIONS: Thus, HFpEF occurs in the majority of diabetic patients with RHTN. The frequency of HFpEF in patients with DN is significantly higher than in patients without it, which is associated with more pronounced impairments of diastolic function. The progressive development of diastolic dysfunction in patients with diabetes mellitus is associated not only with metabolic disorders, but also with increased activity of chronic subclinical inflammation, profibrotic state and high severity of vascular changes.

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Abstract 14648: Interleukin-18 Blockade Prevents Diastolic Dysfunction in a Mouse Model of Heart Failure With Preserved Ejection Fraction

Circulation ◽

10.1161/circ.132.suppl_3.14648 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Jessica A Regan ◽

Adolofo G Mauro ◽

Salvatore Carbone ◽

Carlo Marchetti ◽

Eleonora Mezzaroma ◽

...

Keyword(s):

Heart Failure ◽

Blood Pressure ◽

Ejection Fraction ◽

Mouse Model ◽

Diastolic Dysfunction ◽

Diastolic Function ◽

Low Dose ◽

Preserved Ejection Fraction ◽

Interleukin 18 ◽

Lv Diastolic Function

Background: Heart failure with preserved ejection fraction (HFpEF) is characterized by elevated left ventricular (LV) filling pressures due to impaired LV diastolic function. Low-dose infusion of angiotensin 2 (AT2) in the mouse induces a HFpEF phenotype without increasing blood pressure. AT2 infusion induces expression of Interleukin-18 (IL-18) in the heart. We therefore tested whether IL-18 mediated AT2-induced LV diastolic dysfunction in this model. Methods: We infused subcutaneously AT2 (0.2 mg/Kg/day) or a matching volume of vehicle via osmotic pumps surgically implanted in the interscapular space in adult wild-type (WT) male mice and IL-18 knock-out mice (IL-18KO). We also treated WT mice with daily intraperitoneal injections of recombinant murine IL-18 binding protein (IL-18bp, a naturally occurring IL-18 blocker) at 3 different doses (0.1, 0.3 and 1.0 mg/kg) or vehicle for 25 days starting on day 3. We performed a Doppler-echocardiography study before implantation and at 28 days to measure LV dimensions, mass, and systolic and diastolic function in all mice. LV catheterization was performed prior to sacrifice to measure LV end-diastolic pressure (LVEDP) using a Millar catheter. Results: AT2 induces a significant increase in isovolumetric relaxation time (IRT) and myocardial performance index (MPI) at Doppler echocardiography and elevation of LVEDP at catheterization, indicative of impaired LV diastolic function, in absence of any measurable effects on systolic blood pressure nor LV dimensions, mass, or systolic function. Mice with genetic deletion of IL-18 (IL-18 KO) or WT mice treated with IL-18bp had no significant increase in IRT, MPI or LVEDP with AT2 infusion. Conclusion: Genetic or pharmacologic IL-18 blockade prevent diastolic dysfunction in a mouse model of HFpEF induced by low dose AT2 infusion, suggesting a critical role of IL-18 in the pathophysiology of HFpEF.

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Abstract 2280: Urine Albumin/creatinine Ratio, Cardiac Structure And Diastolic Function In Patients With Hypertension And Diastolic Dysfunction: The Validd Study

Circulation ◽

10.1161/circ.116.suppl_16.ii_497-c ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Anil Verma ◽

Rajesh Janardhanan ◽

William L Daley ◽

Susan Ritter ◽

William A Kaye ◽

...

Keyword(s):

Blood Pressure ◽

Diastolic Dysfunction ◽

Diastolic Function ◽

Organ Damage ◽

Left Ventricular ◽

Creatinine Ratio ◽

Albumin Creatinine Ratio ◽

End Organ Damage ◽

Urine Albumin ◽

Urine Albumin Creatinine Ratio

Background: Increasing urine albumin/creatinine ratio (ACR) is associated with systemic microvascular damage and increased cardiovascular morbidity and mortality. However, the relationship between albuminuria and left ventricular (LV) diastolic function, an early measure of myocardial end-organ damage in hypertension, has not been well defined. Methods: Urine ACR and echocardiographic measures of LV structure and function were assessed in 384 patients enrolled in the VALsartan In Diastolic Dysfunction (VALIDD) trial with mild hypertension and no heart failure and evidence of diastolic dysfunction based on Doppler assessment of myocardial relaxation velocities. Results: Urine ACR was undetected in 151 (39.3%) subjects, between 1 to 30 mg/g in 194 (50.5%), and > 30mg/g in 39 (10.2%). The mean blood pressure in the cohort was 143.8 ± 16.1/86.2 ± 10.3 mmHg and LV hypertrophy was present in < 4% of enrolled patients. Higher urine ACR was associated with lower annular relaxation velocity (E′), higher E/E′ (Figure ), higher prevalence of concentric LV remodeling and higher NT-ProBNP even after adjusting for age, diabetes, systolic BP, eGFR and LV mass index (LVMi) (p < 0.02 for all associations). Conclusion: Albuminuria is associated with worsening diastolic function in patients with hypertension, and both measures may represent important and modifiable markers of early end-organ damage even in patients with mild blood pressure elevation. E′ stratified by urine albumin creatinine ratio E/E′ stratified by urine albumin creatinine ratio

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Abstract 7: Angiotensin II Type 2 Receptor Deficiency Increases Renal ACE/ACE2 Ratio-Ang II-AT1R Expression In Male but not in Female Mice

Hypertension ◽

10.1161/hyp.60.suppl_1.a7 ◽

2012 ◽

Vol 60 (suppl_1) ◽

Author(s):

Quaisar Ali ◽

Yonnie Wu ◽

Tadashi Inagami ◽

Tahir Hussain

Keyword(s):

Blood Pressure ◽

Renal Function ◽

Angiotensin Ii ◽

Renin Activity ◽

Ang Ii ◽

Male And Female ◽

Female Mice ◽

Gender Specific

Angiotensin II acting via Angiotensin II type 2 receptors (AT2Rs) is believed to be protective against blood pressure increase and affects renal function under pathophysiological condition. Recently we have observed that stimulation of AT2Rs in male obese Zucker rats has shifted the two opposing arms of renin angiotensin system (RAS) i.e. ACE-Ang II-AT1 vs ACE2/Ang-(1-7)-Mas. Evidence suggests that estrogen regulates RAS, including AT2R in female mice. We hypothesized that AT2R has a gender specific regulation of RAS. In the present study, we investigated the role of AT2Rs in regulating RAS components in male and female mice. Kidney cortex from AT2R knockout (AT2RKO) male and female mice and wild type (WT) with similar background (C57BL/6) of 20 weeks of age were used in the study. The cortical ACE expression (ng ACE/μg tissue) was significantly increased in AT2RKO mice (3±0.02) compared to WT males (1.9±0.02). LC/MS analysis of cortical tissue revealed that Ang II was also significantly increased in AT2RKO mice (WT: 31±3, AT2RKO: 47±3 fmoles/mg tissue). Deletion of AT2R significantly increased AT1R (204%, 204 of 100) expression and had no effect on renin activity compared to WT males. The cortical expression of ACE2 activity (WT: 113±8, AT2RKO: 40±11, RFU/min), Ang-(1-7) levels (WT: 7.3±1.4, AT2RKO: 3±0.8 fmoles/mg tissue) and Mas receptor (AT2RKO: 54±15, % of WT) was significantly decreased in AT2RKO males compared to WT. The cortical expression of the AT2R and MasR was 2-fold greater in WT females compared to WT male. The renin activity (WT: 32±2, AT2RKO: 21±0.3, RFU/min) and MasR expression (WT: 187.5±55, AT2KO: 47±9) was significantly decreased in AT2RKO females compared to the female WT. Interestingly, Ang-(1-7) level (WT: 5.7±0.7, AT2RKO 2.6±0.7 fmoles/mg tissue) was decreased but no changes in ACE or ACE2 activity was observed in AT2KO females compared to their WT, suggesting a role of non-ACE2 pathway. This study suggests that AT2R regulates ACE/ACE2 ratio-Ang II-AT1R expression negatively only in males, whereas in females, it regulates Ang-(1-7) potentially via non-ACE2 pathway. Such changes indicate a gender specific mechanisms potentially associated with AT2R-mediated regulation of renal function and blood pressure control.

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Abstract 47: Circulating Human Sprr Increased Blood Pressure In Female Mice Fed A Low-fat Diet

Hypertension ◽

10.1161/hyp.78.suppl_1.47 ◽

2021 ◽

Vol 78 (Suppl_1) ◽

Author(s):

Audrey Poupeau ◽

Gertrude Arthur ◽

Kellea Nichols ◽

Frederique B Yiannikouris

Keyword(s):

Blood Pressure ◽

Nervous System ◽

Humanized Mouse ◽

Low Fat ◽

Humanized Mouse Model ◽

Control Female ◽

Female Mice ◽

Low Fat Diet ◽

Sympathetic Nervous ◽

And Control

Elevated plasma soluble prorenin receptor (sPRR) is associated with essential hypertension and obesity-hypertension in men. Additionally, our laboratory previously found that the infusion of mouse sPRR elevates systolic blood pressure (SBP) in high-fat (HF) fed male mice through activation of the sympathetic nervous system but did not elevate SBP in HF-fed female mice. Interestingly, mouse sPRR infusion increased renal and hepatic angiotensinogen (AGT) and plasma renin concentration in female mice fed a low-fat diet. However, whether sPRR-activates the renin angiotensin system (RAS) and increases blood pressure in low-fat fed female mice remains to be investigated. Additionally, little is known concerning the influence of human sPRR on blood pressure in women. Therefore, we developed a humanized mouse model with high circulating human sPRR. Human sPRR-Myc-tag transgenic mice were bred with mice expressing Alb/Cre recombinase to induce human sPRR release in the circulation. Control and Alb-HsPRR female mice were fed a LF-diet for 8 months (n=11/groups). Body weight and body composition were examined and blood pressure assessed by radiotelemetry. Human sPRR-Myc-tag was detected in the liver of Alb-HsPRR female mice and plasma sPRR levels increased by 50-fold (CTL: 3.6±0.5 ng/ml, HsPRR:190.5±24.4 ng/ml; P<0.05), which validated the humanized mouse model. Elevated circulating human sPRR did not change body weight (CTL: 22.2±0.37, HsPRR: 23.0±0.32 g) or fat mass (CTL: 2.5±0.2, HsPRR: 3.1±0.2 g). Liver-derived human sPRR significantly elevated SBP in Alb-HsPRR compared to control female mice (Night SBP: CTL: 130.5±1.2 mmHg; Alb-HsPRR: 135.9±2 mmHg; P<0.05) and acute injection of AngII exacerbated SBP elevation. Interestingly, the decrease in blood pressure mediated by losartan was not different between Alb-HsPRR and control female mice (Night ΔSBP: CTL: -13.11±2.2 mmHg; Alb-HsPRR: -14.8±2.7 mmHg; P>0.05). Plasma AGT and renin activity were similar between Alb-HsPRR and control female mice. Therefore, whether the local RAS or the sympathetic nervous system are involved in human sPRR-mediated increase of SBP remains to be examined. Altogether, our results suggest an important role of circulating human sPRR in blood pressure control in women.

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P2595The role of epicardial fat thickness and other parameters of visceral adiposity in right ventricular diastolic function in patients with metabolic syndrome

European Heart Journal ◽

10.1093/eurheartj/ehz748.0920 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

E Sedaia ◽

V Revenco

Keyword(s):

Metabolic Syndrome ◽

Diastolic Dysfunction ◽

Diastolic Function ◽

Tricuspid Valve ◽

Tissue Doppler ◽

Visceral Adiposity ◽

Epicardial Fat ◽

Epicardial Fat Thickness ◽

Fat Thickness

Abstract Background Abdominal obesity is associated with an increased risk of cardiovascular disease and all-cause mortality especially in patients with metabolic syndrome (MetS). Despite the undeniable importance of right ventricle (RV) function, little is known about RV diastolic function implication in obesity and MetS. Purpose The objective of our study was to evaluate the role of epicardial fat thickness (EFT) and other parameters of visceral obesity in diastolic function of RV in patients with MetS. Methods The study included 70 subjects with MetS (mean age 52.6±9.4 years) and 70 controls without MetS (mean age 53.8±7.5 years). MetS was defined by ≥3 criteria of International Diabetes Federation and American Heart Association/National Heart, Lung, and Blood Institute. We assessed RV diastolic function by pulsed wave and tissue Doppler echocardiography and determined the ratio of early (TV E) and late (TV A) trans-tricuspid valve inflow velocities (TV E/A), early tricuspid valve (TV) annular tissue Doppler velocity (TV e'), the TV E/e' ratio and TV deceleration time (DT). Anthropometric and sonographic parameters of visceral adiposity included: waist circumference (WC), waist-to-hip ratio (WHR), visceral adiposity index (VAI), intraabdominal fat thickness (IFT), abdominal wall fat index (AWFI) and epicardial fat thickness (EFT). Results Mean values of WC (p=0.030), WHR (p=0.008), VAI (p=0.001), IFT (p=0.035), AWFI (p=0.013) and EFT (p=0.012) were significantly higher in the group with MetS vs. controls. RV diastolic function parameters were also significantly changed in the group with MetS vs controls (tab.1). TV E/e' was positively correlated with WC (r=0.297, p<0.01), WHR (r=0.238, p<0.05), VAI (r=0.271, p<0.05), IFT (r=0.556, p<0.01), AWFI (r=0.604, p<0.01) and EFT (r=0.795, p<0.01). Using multivariate regression analysis EFT, WC and plasma glucose level were the most important predictors for RV diastolic dysfunction in subjects with MetS (p<0.05 for all parameters). Table 1. RV diastolic function Variables MetS (n=70) Controls (n=70) p TV E, cm/s 48±11.1 52.1±14 0.025 TV A, cm/s 56.54±11 52.3±11.7 0.034 TV E/A 0.92±0.4 1.07±0.44 0.029 TV e', cm/s 10.6±2.7 10.7±3.5 0.001 TV E/e' 5.84±1.04 4.59±0.82 0.001 DT, ms 227.9±12.4 217±17.8 0.009 Conclusion Our findings support that EFT and WC play an important role in RV diastolic dysfunction in patients with MetS.

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