Electrical and structural remodeling contribute to atrial fibrillation in type 2 diabetic db/db mice

Bohne, Loryn J.; Jansen, Hailey J.; Daniel, Irene M.; Dorey, Tristan W.; Moghtadaei, Motahareh; Belke, Darrell D.; Ezeani, Martin; Rose, Robert A.

doi:10.1016/j.hrthm.2020.08.019

Cited by 25 publications

(41 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The present study also shows that baseline HR and spontaneous AP firing in SAN myocytes are reduced in db/db mice. This is consistent with previous studies showing lower HR and impaired SAN function in animal models of T1DM and T2DM 12 , 38 – 42 . In the present study, baseline I f density tended to be lower in db/db SAN myocytes; however, there were no differences in baseline V 1/2(act) or in the gene and protein expression of HCN1, HCN2 or HCN4 in db/db mice suggesting I f does not play a major role in baseline HR differences.…”

Section: Discussionsupporting

confidence: 94%

“…The db/db mice contain a mutation in the leptin receptor ( Lepr ) gene leading to hyperphagia 11 . These db/db mice exhibit the expected features of T2DM including obesity and hyperglycemia, as we 12 and others 13 , 14 have shown. All experimental procedures were approved by the University of Calgary Animal Care and Use Committee or the Dalhousie University Committee for Laboratory Animals and were in accordance with the guidelines of the Canadian Council on Animal Care and the ARRIVE guidelines.…”

Section: Methodssupporting

confidence: 73%

See 1 more Smart Citation

Impaired regulation of heart rate and sinoatrial node function by the parasympathetic nervous system in type 2 diabetic mice

Liu

Jansen

Krishnaswamy

et al. 2021

Sci Rep

Self Cite

View full text Add to dashboard Cite

Heart rate (HR) and sinoatrial node (SAN) function are modulated by the autonomic nervous system. HR regulation by the parasympathetic nervous system (PNS) is impaired in diabetes mellitus (DM), which is denoted cardiovascular autonomic neuropathy. Whether blunted PNS effects on HR in type 2 DM are related to impaired responsiveness of the SAN to PNS agonists is unknown. This was investigated in type 2 diabetic db/db mice in vivo and in isolated SAN myocytes. The PNS agonist carbachol (CCh) had a smaller inhibitory effect on HR, while HR recovery time after CCh removal was accelerated in db/db mice. In isolated SAN myocytes CCh reduced spontaneous action potential firing frequency but this effect was reduced in db/db mice due to blunted effects on diastolic depolarization slope and maximum diastolic potential. Impaired effects of CCh occurred due to enhanced desensitization of the acetylcholine-activated K+ current (IKACh) and faster IKACh deactivation. IKACh alterations were reversed by inhibition of regulator of G-protein signaling 4 (RGS4) and by the phospholipid PIP3. SAN expression of RGS4 was increased in db/db mice. Impaired PNS regulation of HR in db/db mice occurs due to reduced responsiveness of SAN myocytes to PNS agonists in association with enhanced RGS4 activity.

show abstract

Section: Discussionsupporting

confidence: 94%

Section: Methodssupporting

confidence: 73%

Impaired regulation of heart rate and sinoatrial node function by the parasympathetic nervous system in type 2 diabetic mice

Liu

Jansen

Krishnaswamy

et al. 2021

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…The pathophysiology of AF development in DM has not been elaborately investigated. In a diabetic mice model, increased AF susceptibility was associated with reduced atrial conduction velocity, action potential duration prolongation, increased heterogeneity in repolarization, and increased interstitial atrial fibrosis [ 23 ]. In addition to blood sugar level, increased magnitude of GV may generate more reactive oxygen species than hyperglycemia alone.…”

Section: Discussionmentioning

confidence: 99%

Higher long-term visit-to-visit glycemic variability predicts new-onset atrial fibrillation in patients with diabetes mellitus

Hsu

Yang

Chuang

et al. 2021

Cardiovasc Diabetol

View full text Add to dashboard Cite

Background Atrial fibrillation (AF) is prevalent in patients with type 2 diabetes mellitus (T2DM). Glycemic variability (GV) is associated with risk of micro- and macrovascular diseases. However, whether the GV can increase the risk of AF remains unknown. Methods The cohort study used a database from National Taiwan University Hospital, a tertiary medical center in Taiwan. Between 2014 and 2019, a total of 27,246 adult patients with T2DM were enrolled for analysis. Each individual was assessed to determine the coefficients of variability of fasting glucose (FGCV) and HbA1c variability score (HVS). The GV parameters were categorized into quartiles. Multivariate Cox regression models were employed to estimate the relationship between the GV parameters and the risk of AF, transient ischemic accident (TIA)/ischemic stroke and mortality in patients with T2DM. Results The incidence rates of AF and TIA/ischemic stroke were 21.31 and 13.71 per 1000 person-year respectively. The medium follow-up period was 70.7 months. In Cox regression model with full adjustment, the highest quartile of FGCV was not associated with increased risk of AF [Hazard ratio (HR): 1.12, 95% confidence interval (CI) 0.96–1.29, p = 0.148] or TIA/ischemic stroke (HR: 1.04, 95% CI 0.83–1.31, p = 0.736), but was associated with increased risk of total mortality (HR: 1.33, 95% CI 1.12–1.58, p < 0.001) and non-cardiac mortality (HR: 1.41, 95% CI 1.15–1.71, p < 0.001). The highest HVS was significantly associated with increased risk of AF (HR: 1.29, 95% CI 1.12–1.50, p < 0.001), total mortality (HR: 2.43, 95% CI 2.03–2.90, p < 0.001), cardiac mortality (HR: 1.50, 95% CI 1.06–2.14, p = 0.024) and non-cardiac mortality (HR: 2.80, 95% CI 2.28–3.44, p < 0.001) but was not associated with TIA/ischemic stroke (HR: 0.98, 95% CI 0.78–1.23, p = 0.846). The Kaplan–Meier analysis showed significantly higher risk of AF, cardiac and non-cardiac mortality according to the magnitude of GV (log-rank test, p < 0.001). Conclusions Our data demonstrate that high GV is independently associated with the development of new-onset AF in patients with T2DM. The benefit of maintaining stable glycemic levels to improve clinical outcomes warrants further studies.

show abstract

“…In contrast to Akita (T1DM) mice, 107 atrial I Na was not reduced in db/db atrial myocytes. 125 The only alteration observed in atrial I Na in db/db mice was a shift in steady-state inactivation that resulted in a larger I Na window current, which could contribute to the prolongation of APD. This observation identifies potentially important differences in electrical remodelling between T1DM and T2DM that may have important implications for AF therapy in these related, but distinct conditions.…”

Section: Af In Diabetes Mellitusmentioning

confidence: 96%

“…AF in T2DM was recently investigated in db/db mice, which carry a mutation in the leptin receptor leading to obesity, insulin resistance, and hyperglycaemia. 125 The db/db mice have increased susceptibility to burst-pacing induced AF, associated with increased P-wave duration and AERP, reduced RA and LA conduction velocity, and prolonged heterogeneous APD. These changes were accompanied by a decrease in I to (associated with reduced expression of Kcnd2 mRNA and K v 4.2 protein) and suppressed I Kur, occurring in the presence of unchanged K V 1.5 expression.…”

Section: Af In Diabetes Mellitusmentioning

confidence: 99%

New aspects of endocrine control of atrial fibrillation and possibilities for clinical translation

Aguilar

Rose

Takawale

et al. 2021

Cardiovascular Research

View full text Add to dashboard Cite

Hormones are potent endo-, para- and autocrine endogenous regulators of the function of multiple organs, including the heart. Endocrine dysfunction promotes a number of cardiovascular diseases, including atrial fibrillation (AF). While the heart is a target for endocrine regulation, it is also an active endocrine organ itself, secreting a number of important bioactive hormones that convey significant endocrine effects, but also through para-/autocrine actions, actively participate in cardiac self-regulation. The hormones regulating heart-function work in concert to support myocardial performance. AF is a serious clinical problem associated with increased morbidity and mortality, mainly due to stroke and heart failure. Current therapies for AF remain inadequate. AF is characterized by altered atrial function and structure, including electrical and profibrotic remodeling in the atria and ventricles, which facilitates AF progression and hampers its treatment. Although features of this remodeling are well-established and its mechanisms are partly understood, important pathways pertinent to AF arrhythmogenesis are still unidentified. The discovery of these missing pathways has the potential to lead to therapeutic breakthroughs. Endocrine dysfunction is well-recognized to lead to AF. In this review, we discuss endocrine and cardiocrine signaling systems that directly, or as a consequence of an underlying cardiac pathology, contribute to AF pathogenesis. More specifically, we consider the roles of products from the hypothalamic-pituitary axis, the adrenal glands, adipose tissue, the renin-angiotensin system, atrial cardiomyocytes and the thyroid gland in controlling atrial electrical and structural properties. The influence of endocrine/paracrine dysfunction on AF risk and mechanisms is evaluated and discussed. We focus on the most recent findings and reflect on the potential of translating them into clinical application.

show abstract

Electrical and structural remodeling contribute to atrial fibrillation in type 2 diabetic db/db mice

Cited by 25 publications

References 33 publications

Impaired regulation of heart rate and sinoatrial node function by the parasympathetic nervous system in type 2 diabetic mice

Impaired regulation of heart rate and sinoatrial node function by the parasympathetic nervous system in type 2 diabetic mice

Higher long-term visit-to-visit glycemic variability predicts new-onset atrial fibrillation in patients with diabetes mellitus

New aspects of endocrine control of atrial fibrillation and possibilities for clinical translation

Contact Info

Product

Resources

About