scholarly journals Sacubitril/valsartan inhibits obesity-associated diastolic dysfunction through suppression of ventricular-vascular stiffness

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Annayya R. Aroor ◽  
Srinivas Mummidi ◽  
Juan Carlos Lopez-Alvarenga ◽  
Nitin Das ◽  
Javad Habibi ◽  
...  
Keyword(s):  
Arterial Stiffness ◽  
Diastolic Dysfunction ◽  
Left Ventricular ◽  
Vascular Stiffness ◽  
Saline Control ◽  
Preclinical Model ◽  
Cardiovascular Protection ◽  
Group 5 ◽  
Group 2 ◽  
Hypertensive Drug

Abstract Objective Cardiac diastolic dysfunction (DD) and arterial stiffness are early manifestations of obesity-associated prediabetes, and both serve as risk factors for the development of heart failure with preserved ejection fraction (HFpEF). Since the incidence of DD and arterial stiffness are increasing worldwide due to exponential growth in obesity, an effective treatment is urgently needed to blunt their development and progression. Here we investigated whether the combination of an inhibitor of neprilysin (sacubitril), a natriuretic peptide-degrading enzyme, and an angiotensin II type 1 receptor blocker (valsartan), suppresses DD and arterial stiffness in an animal model of prediabetes more effectively than valsartan monotherapy. Methods Sixteen-week-old male Zucker Obese rats (ZO; n = 64) were assigned randomly to 4 different groups: Group 1: saline control (ZOC); Group 2: sacubitril/valsartan (sac/val; 68 mg•kg−1•day−1; ZOSV); Group 3: valsartan (31 mg•kg−1•day−1; ZOV) and Group 4: hydralazine, an anti-hypertensive drug (30 mg•kg−1•day−1; ZOH). Six Zucker Lean (ZL) rats that received saline only (Group 5) served as lean controls (ZLC). Drugs were administered daily for 10 weeks by oral gavage. Results Sac/val improved echocardiographic parameters of impaired left ventricular (LV) stiffness in untreated ZO rats, without altering the amount of food consumed or body weight gained. In addition to improving DD, sac/val decreased aortic stiffness and reversed impairment in nitric oxide-induced vascular relaxation in ZO rats. However, sac/val had no impact on LV hypertrophy. Notably, sac/val was more effective than val in ameliorating DD. Although, hydralazine was as effective as sac/val in improving these parameters, it adversely affected LV mass index. Further, cytokine array revealed distinct effects of sac/val, including marked suppression of Notch-1 by both valsartan and sac/val, suggesting that cardiovascular protection afforded by both share some common mechanisms; however, sac/val, but not val, increased IL-4, which is increasingly recognized for its cardiovascular protection, possibly contributing, in part, to more favorable effects of sac/val over val alone in improving obesity-associated DD. Conclusions These studies suggest that sac/val is superior to val in reversing obesity-associated DD. It is an effective drug combination to blunt progression of asymptomatic DD and vascular stiffness to HFpEF development in a preclinical model of obesity-associated prediabetes.

scholarly journals Sacubitril/valsartan Inhibits Obesity-associated Diastolic Dysfunction through Suppression of Ventricular-vascular Stiffness

2021 ◽  
Author(s):  
Annayya R Aroor ◽  
Srinivas Mummidi ◽  
Juan Carlos Lopez-Alvarenga ◽  
Nitin Das ◽  
Javad Habibi ◽  
...  
Keyword(s):  
Arterial Stiffness ◽  
Diastolic Dysfunction ◽  
Left Ventricular ◽  
Vascular Stiffness ◽  
Saline Control ◽  
Preclinical Model ◽  
Cardiovascular Protection ◽  
Group 5 ◽  
Group 2 ◽  
Hypertensive Drug

Abstract Objective: Both cardiac diastolic dysfunction (DD) and arterial stiffness are early manifestations of obesity-associated prediabetes and serve as risk factors for the development of heart failure with preserved ejection fraction (HFpEF). Since the incidence of DD and arterial stiffness are increasing worldwide due to exponential growth in obesity, an effective treatment is urgently needed to blunt their development and progression. Here we investigated whether the combination of an inhibitor of neprilysin (sacubitril), a natriuretic peptide-degrading enzyme, and an angiotensin II type 1 receptor blocker (valsartan), suppresses DD and arterial stiffness in an animal model of prediabetes more effectively than valsartan monotherapy.Methods: Sixteen week-old male Zucker Obese rats (ZO; n=64) were assigned randomly to 4 different groups: Group 1: saline control (ZOC); Group 2: sacubitril/valsartan (sac/val; 68 mg•kg-1•day-1; ZOSV); Group 3: valsartan (31 mg•kg-1•day-1; ZOV) and Group 4: hydralazine, an anti-hypertensive drug (30 mg•kg-1•day-1; ZOH). Six Zucker Lean (ZL) rats that received saline only (Group 5) served as lean controls (ZLC). Drugs were administered daily for 10 weeks by oral gavage.Results: Sac/val improved echocardiographic parameters of impaired left ventricular (LV) stiffness in untreated ZO rats, without altering the amount of food consumed or body weight gained. In addition to improving DD, sac/val also decreased aortic stiffness and reversed impairment of nitric oxide-induced vascular relaxation seen in ZO rats. However, sac/val had no impact on LV hypertrophy. Notably, sac/val was more effective at ameliorating DD compared to val. Although, hydralazine was as effective as sac/val in improving these parameters, it adversely affected LV mass index. Further, proteomics revealed distinct effects of sac/val, including marked suppression of Notch-1 by both valsartan and sac/val suggesting that cardiovascular protection afforded by both share some common mechanisms; however, sac/val increased IL-4 which is increasingly been recognized for its cardiovascular protection, possibly contributing, in part, to more favorable effects of sac/val over val alone in improving obesity associated DD.Conclusions: These studies suggest that sac/val is superior to val in reversing obesity-associated DD. It is an effective drug combination to blunt progression of asymptomatic DD and vascular stiffness to HFpEF development in a preclinical model of obesity-associated prediabetes.

Abstract 18141: Is There Systolic Myocardial Mechanical Dysfunction in Patients With Different Degrees of Diastolic Dysfunction and Normal Ejection Fraction?

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Sergio Barros-Gomes ◽  
Patricia A Pellikka ◽  
Angela Dispenzieri ◽  
Hector R Villarraga
Keyword(s):  
Ejection Fraction ◽  
Diastolic Dysfunction ◽  
Systolic Dysfunction ◽  
Left Ventricular ◽  
Al Amyloidosis ◽  
Normal Ejection Fraction ◽  
Group 4 ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

Introduction: Diastolic dysfunction has been characterized in relation to the relaxation and compliance properties of the left ventricle; limited information exists regarding its relationship to systolic function as assessed by deformation imaging. Objectives: To determine if there is left ventricular systolic dysfunction detected by global longitudinal strain (GLS) measured by two dimensional speckle tracking echocardiography in patients with immunoglobulin light chain (AL) amyloidosis with different degrees of diastolic dysfunction and normal ejection fraction (EF). Methods: Consecutive biopsy-proven AL patients with preserved EF (≥ 55%) who had a comprehensive echocardiogram performed and strain analysis were included. Cohort was divided into 5 groups according to the different grades of diastolic dysfunction: Group 0: normal filling pressures; Group 1: abnormal relaxation; Group 2: pseudo-normal pattern; Group 3: reversible restrictive; Group 4: fixed restrictive. Images were acquired and performed on a Vivid 9 from the 3 apical views, and analyzed on vendor-specific software (Echo-PAC, GE). GLS was averaged from the 16 segments, and their means compared by ANOVA and each pair with Student’s t test. Results: A total of 858 patients were included, mean age was 63.7 years ± 10.1, and 61.5% were male. From those, 205 (24%) were in group 0; 299 (35%) in group 1; 255 (30%) in group 2; 65 (7%) in group 3; and 34 in group 4 (4%). GLS means measurements were -18.95 ± 2.4, -16.86 ± 3.4, -15.60 ± 3.9, -12.31 ± 3.0, and -10.48 ± 3.3, respectively (P<0.0001). All individual GLS values were significantly different statistically when compared between each group (P<0.01 for all pairs; figure). Conclusions: Longitudinal systolic mechanical function is progressively impaired in AL amyloid patients as diastolic dysfunction progresses, despite normal EF. This systolic dysfunction provides insights into the intrinsic relationship between the components of the cardiac cycle.

scholarly journals The risk of developing chronic heart failure in patients with hypertension depending on the actual arterial stiffness

2020 ◽  
Vol 35 (2) ◽  
pp. 98-105
Author(s):  
A. I. Chernyavina ◽  
N. A. Koziolova
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Arterial Stiffness ◽  
Left Ventricular ◽  
Myocardial Mass ◽  
Developing Heart ◽  
Group 2 ◽  
Lv Volume ◽  
Lv Diastolic Function ◽  
Group 1

Objective. To determine the risk of developing chronic heart failure (CHF) in patients with hypertension (HTN) depending on the actual arterial stiffness.Material and Methods. The study included 175 patients with HTN without a verified diagnosis of heart failure. The average age was 48.5 ± 6.8 years. Patients underwent general clinical examination, volume sphygmoplethysmography assessments of cardio-ankle vascular index (CAVI), echocardiography study (left ventricular (LV) ejection fraction, LV diastolic function, LV myocardial mass index, indexed LV volume by echocardiography), and tests for serum N-terminal pro-B-type natriuretic peptide (NT-proBNP). Patients were divided into two groups depending on CAVI. Group 1 included 141 (80.6%) patients with CAVI < 9; group 2 included 34 (19.4%) patients with CAVI > 9.Results. In patients of group 1, the level of NT-proBNP was 0.008 [0.006; 5.770], which was significantly lower than the corresponding value in group 2, where the level of NT-proBNP was 13.08 [0.01; 350.65] ng/mL (p = 0.041). Indicators of odds ratio (OR) and relative risk (RR) were also significant. The chance of developing CHF with CAVI > 9 increased by almost 7 times (OR = 6.9; 95% CI = 2.8–16.8), and OR of CHF onset was 4.1 (95% CI = 2.2–7.6). Sensitivity and specificity rates were 55.9% and 84.4%, respectively. Correlation analysis revealed a medium degree of dependence and direct relationships between NT-proBNP level and CAVI values (r = 0.35; p <0.05).Conclusion. Serum level of NT-proBNP depended on the actual arterial stiffness. Patients with CAVI > 9 indicative of an increase in true arterial stiffness had a greater risk of developing heart failure assessed based on the level of NT-proBNP in the blood. Further studies are required to assess the effects of arterial stiffness, registered within the intermediate values of CAVI index, on the risk of heart failure onset. 

scholarly journals Contribution of Global and Regional Longitudinal Strain for Clinical Assessment of HFpEF in Coronary and Hypertensive Patients

Medicina ◽  
2021 ◽  
Vol 57 (12) ◽  
pp. 1372
Author(s):  
Gheorghe Stoichescu-Hogea ◽  
Florina Nicoleta Buleu ◽  
Ruxandra Christodorescu ◽  
Raluca Sosdean ◽  
Anca Tudor ◽  
...  
Keyword(s):  
Diastolic Dysfunction ◽  
Clinical Assessment ◽  
Longitudinal Strain ◽  
Systolic Dysfunction ◽  
Global Longitudinal Strain ◽  
Left Ventricular ◽  
Control Group ◽  
Hypertensive Patients ◽  
Group 2 ◽  
Artery Disease

Background: Contribution of global and regional longitudinal strain (GLS) for clinical assessment of patients with heart failure with preserved ejection fraction (HFpEF) is not well established. We sought to evaluate subclinical left ventricular dysfunction secondary to coronary artery disease (CAD) in HFpEF patients compared with hypertensive patients and age-matched healthy subjects. Material and methods: This was a retrospective study that included 148 patients (group 1 = 62 patients with HFpEF, group 2 = 46 hypertensive patients, and group 3 = 40 age-matched control subjects). Peak systolic segmental, regional (basal, mid, and apical), and global longitudinal strain were assessed for each study group using two-dimensional speckle-tracking echocardiography (2D-STE). Results: GLS values presented statistically significant differences between the three groups (p < 0.001); markedly increased values (more negative) were observed in the control group (−20.2 ± 1.4%) compared with HTN group values (−18.4 ± 3.0%, p = 0.031) and with HFpEF group values (−17.6 ± 2.3%, p < 0.001). The correlation between GLS values and HTN stages was significant, direct, and average (Spearman coefficient rho = 0.423, p < 0.001). GLS had the greatest ability to detect patients with HFpEF when HFpEF + CAD + HTN diastolic dysfunction (n = 30) + CON diastolic dysfunction (n = 2) from HFpEF + CAD + HTN + CON was analyzed. (optimal GLS limit of −19.35%, area under curve = 0.833, p < 0.001). Conclusions: Global longitudinal strain can be used for clinical assessment in differentiating coronary and hypertensive patients at higher risk for development of systolic dysfunction.

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