Related Experiment Video
Updated: Feb 6, 2026
Lumped-Parameter and Finite Element Modeling of Heart Failure with Preserved Ejection Fraction
Published on: February 13, 2021
Cilostazol ameliorates heart failure with preserved ejection fraction and diastolic dysfunction in obese and
Sukka Santosh Reddy1, Heena Agarwal2, Manoj Kumar Barthwal2
1Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific & Innovative Research (AcSIR), New Delhi 110025, India.
Insights
Cilostazol (Ciloz) effectively treats obesity-related heart dysfunction by improving cardiac function and reducing inflammation and fibrosis. This phosphodiesterase inhibitor offers a potential therapeutic strategy for preventing heart failure.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Metabolic Disease
Background:
- Obesity and insulin resistance are linked to left ventricular diastolic dysfunction and heart failure with preserved ejection fraction (HFpEF).
- Cilostazol (Ciloz), a phosphodiesterase type III inhibitor, shows anti-inflammatory and anti-insulin resistance effects.
- The impact of Ciloz on obesity-associated diastolic dysfunction remains unexplored.
Purpose of the Study:
- To investigate the therapeutic potential of Ciloz in mitigating cardiac remodeling and diastolic dysfunction in obese, insulin-resistant mice subjected to Angiotensin II (AngII) infusion.
- To elucidate the molecular mechanisms underlying Ciloz's protective effects against AngII and high-fat diet (HFD)-induced cardiac pathology.
Main Methods:
- Male C57BL/6J mice were fed a chow or HFD for 19 weeks, followed by 1 week of AngII infusion or saline, with or without Ciloz administration.
- Echocardiography was used to assess left ventricular function, including ejection fraction and fractional shortening.
- Cardiac histology, gene expression analysis (including inflammatory markers, fibrosis, hypertrophic markers, and glycolytic pathway components), and Western blotting were performed to evaluate cardiac remodeling and molecular signaling.
Main Results:
- AngII infusion in both non-obese and obese mice induced significant diastolic dysfunction and HFpEF features.
- Ciloz treatment in HFD-fed mice significantly improved left ventricular function, reduced cardiomyocyte size, interstitial/perivascular fibrosis, and collagen deposition.
- Ciloz suppressed cardiac inflammation (reduced F4/80+, CD68+ cells, IL-1β, IL-6), normalized hypertrophic/fibrotic markers, inhibited TGF-β1/SMAD3 and Akt/mTOR signaling, and diminished AngII/HFD-induced glycolytic flux.
Conclusions:
- Cilostazol demonstrates significant therapeutic benefits against Angiotensin II and obesity-associated left ventricular diastolic dysfunction.
- Ciloz mitigates cardiac remodeling, inflammation, fibrosis, and metabolic dysregulation, offering a promising strategy for preventing heart failure.
- The findings suggest Ciloz could be a valuable therapeutic agent for patients with obesity-related cardiovascular complications.
Abstract:
Cilostazol (Ciloz) a potent Type III phosphodiesterase inhibitor is effective against inflammation, insulin resistance and cardiomyopathy. However, the effect of Ciloz on obesity-associated left ventricular diastolic dysfunction has not been explored yet. Hence, we examined the effect of Ciloz on cardiac remodelling and dysfunction in non-obese and obese-insulin resistant mice infused with AngiotensinII (AngII). Male C57BL/6 J mice were initially subjected to 19 weeks of chow or high fat diet (HFD) regimen and thereafter animals were randomised for AngII (1500 ng/kg/min, s.c) infusion or saline and Ciloz (50 mg/kg, p.o) for another 1 week. Obese and non-obese mice infused with AngII exhibited significant diastolic dysfunction and features of heart failure with preserved ejection fraction (HFpEF) since a decrease in fractional shortening and no change in ejection fraction were observed when compared with respective controls. Administration of AngII and Ciloz in HFD fed mice significantly improved the left ventricular function compared with AngII infused HFD mice as evinced from the echocardiographic data. Further, Ciloz treatment significantly reduced cardiomyocyte area, interstitial and perivascular fibrosis; and collagen deposition. Moreover, Ciloz reduced the inflammatory milieu in the heart as evinced by decreased F4/80+ and CD68+ cells; IL-1β and IL-6 gene transcripts. Quantitative assessment of the expression levels revealed substantial upregulation of MMP-9 (pro- and mature-forms) and α-SMA in the left ventricle of AngII infused HFD-fed mice, which was considerably suppressed by Ciloz regimen. The beneficial effect of Ciloz was associated with the normalization in gene expression of hypertrophic and fibrotic markers. Likewise, Ciloz administration markedly reduced the AngII and HFD induced TGF-β1/SMAD3 and Akt/mTOR signalling. Additionally, AngII administered and HFD-fed mice showed increased glycolytic flux, which was considerably diminished by Ciloz treatment as indicated from suppressed PKM2, HK-2, PDK-2, HIF-1α mRNA and GLUT-1 protein expression. Taken together, Ciloz might be therapeutically exploited against AngII and obesity-associated diastolic dysfunction thereby preventing overt heart failure.
Related Concept Videos
01:24Obesity
01:21Drug Dosing: Obese Patients
01:25Pharmacokinetics in Obese Patients: Drug Absorption and Distribution
01:20Pharmacokinetics in Obese Patients: Drug Metabolism and Excretion
01:29Heart Failure II: Pathophysiology
01:17Pathophysiology of Heart Failure