Pioglitazone attenuates atrial remodeling and vulnerability to atrial fibrillation in alloxan‐induced diabetic rabbits

Liu, Changle; Liu, Ruimeng; Fu, Hai-Xia; Li, Jian; Wang, Xinghua; Cheng, Lijun; Korantzopoulos, Panagiotis; Tse, Gary; Li, Guangping; Liu, Tong

doi:10.1111/1755-5922.12284

Cited by 33 publications

(18 citation statements)

References 52 publications

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“…The alloxan-induced diabetes model using rabbits has been previously used by our group [15, 16]. Briefly, it involves intravenous injection of 5% alloxan (alloxan monohydrate, Sigma Aldrich Chemical; 120 mg/kg) dissolved in sterile normal saline into the marginal ear vein.…”

Section: Methodsmentioning

confidence: 99%

Alogliptin prevents diastolic dysfunction and preserves left ventricular mitochondrial function in diabetic rabbits

Zhang

Yang

et al. 2018

Cardiovasc Diabetol

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Background: There are increasing evidence that left ventricle diastolic dysfunction is the initial functional alteration in the diabetic myocardium. In this study, we hypothesized that alogliptin prevents diastolic dysfunction and preserves left ventricular mitochondrial function and structure in diabetic rabbits. Methods: A total of 30 rabbits were randomized into control group (CON, n = 10), alloxan-induced diabetic group (DM, n = 10) and alogliptin-treated (12.5 mg/kd/day for 12 weeks) diabetic group (DM-A, n = 10). Echocardiographic and hemodynamic studies were performed in vivo. Mitochondrial morphology, respiratory function, membrane potential and reactive oxygen species (ROS) generation rate of left ventricular tissue were assessed. The serum concentrations of glucagon-like peptide-1, insulin, inflammatory and oxidative stress markers were measured. Protein expression of TGF-β1, NF-κB p65 and mitochondrial biogenesis related proteins were determined by Western blotting. Results: DM rabbits exhibited left ventricular hypertrophy, left atrial dilation, increased E/e′ ratio and normal left ventricular ejection fraction. Elevated left ventricular end diastolic pressure combined with decreased maximal decreasing rate of left intraventricular pressure (− dp/dtmax) were observed. Alogliptin alleviated ventricular hypertrophy, interstitial fibrosis and diastolic dysfunction in diabetic rabbits. These changes were associated with decreased mitochondrial ROS production rate, prevented mitochondrial membrane depolarization and improved mitochondrial swelling. It also improved mitochondrial biogenesis by PGC-1α/NRF1/Tfam signaling pathway. Conclusions: The DPP-4 inhibitor alogliptin prevents cardiac diastolic dysfunction by inhibiting ventricular remodeling, explicable by improved mitochondrial function and increased mitochondrial biogenesis.

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Section: Methodsmentioning

confidence: 99%

Alogliptin prevents diastolic dysfunction and preserves left ventricular mitochondrial function in diabetic rabbits

Zhang

Yang

et al. 2018

Cardiovasc Diabetol

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“…Fibrotic change within the atria in diabetes has been demonstrated in animals and humans, while electrical remodelling also appears to be an important mechanism for the association. In particular, changes in the sodium current have been demonstrated within atrial myocytes of diabetic rabbits 26. In addition, expression of connexin 40 has also been demonstrated to be downregulated in a rat model of diabetes, resulting in slowed conduction velocities and heterogeneous conduction patterns 27.…”

Section: Diabetesmentioning

confidence: 99%

Lifestyle modifications for treatment of atrial fibrillation

Middeldorp

Ariyaratnam

Lau

et al. 2019

Heart

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The management of atrial fibrillation (AF) has focused on anticoagulation, rhythm control and ventricular rate control. Recently, a fourth pillar of AF management has been incorporated recognising the importance of risk factor management (RFM). There are several risk factors that contribute to the development and progression of AF, these include traditional risk factors such as age, hypertension, heart failure, diabetes and valvular heart disease. However, increasingly it is recognised that obesity, sleep apnoea, hyperlipidaemia, smoking, alcohol, physical inactivity, genetics, aortic stiffness are associated with the development of AF. Importantly, several of these risk factors are modifiable. We have seen the evolution of RFM programmes which have demonstrated promising results. Indeed, the evidence is now so compelling that major clinical guidelines strongly advocate that aggressive treatment of these risk factors as a key component of AF management. Patients with AF who comprehensively managed their risk factors demonstrate greater reduction in symptoms, AF burden, more successful ablations and improved outcomes with greater AF freedom. In this article, we will review the evidence for the association between cardiac risk factors and AF and assess the burgeoning evidence for improved AF outcomes associated with aggressive cardiac RFM.

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“…174,175 Presumably as a result of this action, pioglitazone attenuates atrial inflammation and fibrosis and alleviates the predilection for AF in experimental models of cardiac stress. [175][176][177][178][179] In observational studies, the use of pioglitazone in patients with diabetes is associated with a lower risk for new-onset or recurrent AF. 180,181 Furthermore, pioglitazone and rosiglitazone alleviate ventricular fibrosis and diastolic filling abnormalities and minimize the development of experimental HFpEF, even if weight increases because of increased adipogenesis; 182,183 accordingly, the use of thiazolidinediones has been associated with improvements in abnormal diastolic filling dynamics in patients with diabetes.…”

Section: Thiazolidinedionesmentioning

confidence: 99%

“…171,172 Dysmetabolism-mediated inflammation impairs PPARexpression, 173 but costimulation of PPAR-and adiponectin reverses the dysfunctional state of epicardial fat. 174,175 Presumably as a result of this action, pioglitazone attenuates atrial inflammation and fibrosis and alleviates the predilection for AF in experimental models of cardiac stress. [175][176][177][178][179] In observational studies, the use of pioglitazone in patients with diabetes is associated with a lower risk for new-onset or recurrent AF.…”

Section: Thiazolidinedionesmentioning

confidence: 99%

“…A key mechanism by which epicardial mesenchymal cells evolve into nutriutive adipocytes is PPAR‐γ signalling . Dysmetabolism‐mediated inflammation impairs PPAR‐γ expression, but costimulation of PPAR‐γ and adiponectin reverses the dysfunctional state of epicardial fat . Presumably as a result of this action, pioglitazone attenuates atrial inflammation and fibrosis and alleviates the predilection for AF in experimental models of cardiac stress .…”

Section: Therapeutic Challenges In Patients With a Metabolic Disordermentioning

confidence: 99%

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Do most patients with obesity or type 2 diabetes, and atrial fibrillation, also have undiagnosed heart failure? A critical conceptual framework for understanding mechanisms and improving diagnosis and treatment

Packer

2019

European J of Heart Fail

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Obesity and diabetes can lead to heart failure with preserved ejection fraction (HFpEF), potentially because they both cause expansion and inflammation of epicardial adipose tissue and thus lead to microvascular dysfunction and fibrosis of the underlying left ventricle. The same process also causes an atrial myopathy, which is clinically evident as atrial fibrillation (AF); thus, AF may be the first manifestation of HFpEF. Many patients with apparently isolated AF have latent HFpEF or subsequently develop HFpEF. Most patients with obesity or diabetes who have AF and exercise intolerance have increased left atrial pressures at rest or during exercise, even in the absence of diagnosed HFpEF. Among patients with AF, those who also have latent HFpEF have increased risk for systemic thromboembolism and death. The identification of HFpEF in patients with obesity or diabetes alters the risk‐to‐benefit relationship of commonly prescribed treatments. Bariatric surgery and statins can ameliorate AF and reduce the risk for HFpEF. Conversely, antihyperglycaemic drugs that promote adipogenesis or cause sodium retention (insulin and thiazolidinediones) may increase the risk for heart failure in patients with an underlying ventricular myopathy. Patients with obesity and diabetes who undergo catheter ablation for AF are at increased risk for AF recurrence and for post‐ablation increases in pulmonary venous pressures and worsening heart failure, especially if HFpEF coexists. Therefore, AF may be the earliest indicator of HFpEF in patients with obesity or type 2 diabetes, and recognition of HFpEF alters the management of these patients.

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Pioglitazone attenuates atrial remodeling and vulnerability to atrial fibrillation in alloxan‐induced diabetic rabbits

Abstract: Pioglitazone attenuates diabetes-induced structural and electrophysiological remodeling in the atria, thereby reducing the vulnerability to AF.

Cited by 33 publications

References 52 publications

Alogliptin prevents diastolic dysfunction and preserves left ventricular mitochondrial function in diabetic rabbits

Alogliptin prevents diastolic dysfunction and preserves left ventricular mitochondrial function in diabetic rabbits

Lifestyle modifications for treatment of atrial fibrillation

Do most patients with obesity or type 2 diabetes, and atrial fibrillation, also have undiagnosed heart failure? A critical conceptual framework for understanding mechanisms and improving diagnosis and treatment

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