P2867Vildagliptin reduces inducibility of atrial fibrillation in hypertensive rats complicated with diabetes mellitus

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
T Soeki ◽  
K Matsumoto ◽  
D Fukuda ◽  
E Uematsu ◽  
T Matsuura ◽  
...  

Abstract Background Atrial fibrillation (AF) is the most common arrhythmia in clinical practice, increasing the incidence of ischemic stroke. Diabetes mellitus (DM) is a predictor of stroke and thromboembolism, and it was reported to be an independent risk factor for AF. A recent study has shown that, in obese mice with diabetes, dipeptidyl peptidase-4 (DPP-4) inhibitor prevents myocardial fibrosis, active oxygen stress, weight loss and improves myocardial hypertrophy. However, the effects of DPP-4 inhibitors on atrial remodeling associated with diabetes and atrial fibrillation have not yet been clarified. Purpose This study was performed to assess whether a DPP-4 inhibitor (vildagliptin) ameliorates atrial remodeling in spontaneously hypertensive rats (SHR) with streptozotocin-induced diabetes. Methods Rats were divided into 3 groups: SHR without DM, SHR with DM treated with vehicle and SHR-DM treated with vildagliptin (3mg/kg/day; intragastric gavage). For each group, blood pressure, blood glucose level and body weight were measured serially. Cardiac function was also evaluated by echocardiography. Then, we examined AF inducibility by intracardiac electrophysiological study and the inflammation-induced atrial remodeling by biochemical analysis after 4 weeks of treatment. Results There was no significant difference in blood pressure and blood gucose level between vehicle and vildagliptin groups. Administration of vildagliptin significantly reduced AF inducibility compared with rats with vehicle. In DM rats treated with vehicle, rapid atrial pacing promoted the gene expression of inflammatory and fibrosis-related biomarkers (TNF-α, MCP-1, collagen-1) in atrium. Vildagliptin reduced these gene expression levels. In addition, administration of vildagliptin significantly reduced the interstitial fibrosis in atrium. Conclusions DPP-4 inhibitor, vildagliptin. could prevent atrial inflammation and reduce the AF inducibility in SHR complicated with DM.

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
T Soeki ◽  
K Matsumoto ◽  
D Fukuda ◽  
E Uematsu ◽  
T Matsuura ◽  
...  

Abstract Background Atrial fibrillation (AF) is the most common type of arrhythmia seen in clinical practice. Recent studies suggest that inflammation contributes to the pathogenesis of AF. On the other hand, several evidence suggests that toll-like receptor (TLR) 9 recognizes bacterial DNA, activating innate immunity, whereas it also provokes inflammation in response to fragmented DNA released from mammalian cells. Recently, we have reported that TLR 9 plays a pivotal role in the development of vascular inflammation and atherogenesis through proinflammatory activation of macrophages. Purpose This study aimed to assess whether TLR9 contributes to the AF arrhythmogenesis. Methods TLR9 deficient (TLR9−/−) and wild-type mice were infused with angiotensin II (Ang II) or vehicle via an osmotic minipump for 4 weeks. Blood pressure and body weight were measured serially. Then, we examined AF inducibility by intracardiac electrophysiological study and the inflammation-induced atrial remodeling by biochemical analysis after 4 weeks of Ang II infusion. Results There was no significant difference in blood pressure and pulse rate between TLR9−/− and wild-type mice both before and after Ang II infusion. Ang II-treated TLR9−/− mice showed lower incidence of AF compared with wild-type mice treated with Ang II. Genetic deletion of TLR9 significantly reduced the interstitial fibrosis in atrium of Ang II-treated mice. TLR9−/− mice also showed less mRNA expressions of inflammatory and fibrosis-related biomarkers (TNF-α, interleukin-6, TGF-β, collagen-1, collagen-3) in atrium compared with wild-type mice. Conclusions TLR9 might contribute to the AF arrhythmogenesis associated with atrial inflammation. TLR9 might serve as a potential therapeutic target for AF. Funding Acknowledgement Type of funding source: None


Author(s):  
Ryo Nishinarita ◽  
Shinichi Niwano ◽  
Hiroe Niwano ◽  
Hironori Nakamura ◽  
Daiki Saito ◽  
...  

Background Recent clinical trials have demonstrated the possible pleiotropic effects of SGLT2 (sodium–glucose cotransporter 2) inhibitors in clinical cardiovascular diseases. Atrial electrical and structural remodeling is important as an atrial fibrillation (AF) substrate. Methods and Results The present study assessed the effect of canagliflozin (CAN), an SGLT2 inhibitor, on atrial remodeling in a canine AF model. The study included 12 beagle dogs, with 10 receiving continuous rapid atrial pacing and 2 acting as the nonpacing group. The 10 dogs that received continuous rapid atrial pacing for 3 weeks were subdivided as follows: pacing control group (n=5) and pacing+CAN (3 mg/kg per day) group (n=5). The atrial effective refractory period, conduction velocity, and AF inducibility were evaluated weekly through atrial epicardial wires. After the protocol, atrial tissues were sampled for histological examination. The degree of reactive oxygen species expression was evaluated by dihydroethidium staining. The atrial effective refractory period reduction was smaller ( P =0.06) and the degree of conduction velocity decrease was smaller in the pacing+CAN group compared with the pacing control group ( P =0.009). The AF inducibility gradually increased in the pacing control group, but such an increase was suppressed in the pacing+CAN group ( P =0.011). The pacing control group exhibited interstitial fibrosis and enhanced oxidative stress, which were suppressed in the pacing+CAN group. Conclusions CAN and possibly other SGLT2 inhibitors might be useful for preventing AF and suppressing the promotion of atrial remodeling as an AF substrate.


Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Ayuna Yamaoka ◽  
Yukiko Segawa ◽  
Saki Maruyama ◽  
Natsumi Saito ◽  
Hiroko Hashimoto ◽  
...  

Objective: Hesperidin (HES) is a flavonoid which is contained in citrus fruit peel. It has physiological effects on blood vessels such as strengthening capillary vessels. Thus, it is known to be one of the effective ingredients of herbal medicine. Some studies have shown that the intake of HES decreases blood pressure (BP) in spontaneously hypertensive rats. The antihypertensive effect of HES is suggested to be due to vasodilation by nitric oxide (NO). However, its mechanism has not been clarified in detail. In this study, we observed whether HES intake decreases BP in 2-kidney, 1-clip renovasucular hypertensive rats (2K1C) and evaluated endothelial NO synthase (eNOS) mRNA to investigate its role in the mechanism. Methods: Male Sprague-Dawley rats (6 weeks old) were treated with sham operation (SHAM) or clipping the left renal artery (2K1C). After surgery, the rats started receiving continuously a control diet (C) or a diet containing 0.1% (w/w) HES for 6 weeks. The systolic BP (SBP) was measured by a tail-cuff method every week. At the end of the protocol, mean arterial blood pressure (MAP) was measured in each rat under anesthesia. Then, the aortas were removed for extracting mRNA. eNOS mRNA expression was evaluated using real-time RT-PCR. Results: At the end of the protocol, SBP in 2K1C-C was significantly higher than in SHAM-C (170±6 vs 117±6 mmHg, p <0.001). On the other hand, 2K1C-HES was lower in SBP (141±4 mmHg) than 2K1C-C ( p <0.01). There were no significant differences between SHAM-HES (122±7 mmHg) and SHAM-C. MAP at the end of the protocol were similar to in SBP. ANOVA revealed mRNA expression of eNOS was significantly higher in 2K1C than in SHAM ( p <0.05), and showed no significant difference between C and HES, nor a significant interaction. Conclusion: Continuous intake of HES may suppress BP increase in 2K1C. The role of eNOS mRNA expression may not be involved in the mechanism.


2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Tomomi Nagayama ◽  
Yoshitaka Hirooka ◽  
Akiko Chishaki ◽  
Masao Takemoto ◽  
Yasushi Mukai ◽  
...  

Objective.Many previous clinical studies have suggested that atrial fibrillation (AF) is closely associated with hypertension. However, the benefits of antihypertensive therapy on AF are still inconsistent, and it is necessary to explore the factors augmenting AF in hypertensive rats. The aim of the present study was to investigate the correlation between arterial pressure or voltage stimulus and to the duration of electrically induced AF in normotensive or hypertensive rats.Methods.AF was reproducibly induced by transesophageal atrial burst pacing in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). We did the burst pacing at high (20 V) or low (5 V) voltage.Results.Duration of AF did not correlate with systolic blood pressure (SBP) and stimulus voltage in WKY. However, only in SHR, duration of AF with high stimulus voltage significantly correlated with SBP and was significantly longer in high than in low voltage stimulus.Discussion and Conclusion.Duration of AF is augmented by high voltage stimulus with higher blood pressure in SHR.


2015 ◽  
Vol 7 (1) ◽  
pp. 1-6
Author(s):  
Kyuzi Kamoi

Previous longitudinal studies have demonstrated that blood pressure measurements at home (HBP) in the wakening- up display stronger predictive power for death, and vascular complications in patients with type 2 diabetes mellitus (T2DM) than clinic blood pressure measurements (CBP). The leading cause of death was cancer. Patients with T2DM have associated with cancer, and high CBP is a risk factor for cancer. Therefore, this study investigated whether HBP or CBP is related to cancer event in patients with T2DM for 10 years. At baseline, 400 Japanese patients with T2DM were classified as hypertensive (HT) or normotensive (NT) based on HBP and CBP. Mean (± SD) duration was 95 ± 35 months. Primary and secondary endpoints were death and cancer, respectively. Differences in outcome between HT and NT were analyzed using survival curves from Kaplan-Meier analysis and log-rank testing. Associated risk factors were assessed using Cox proportional hazards. On basis of HBP, death and event of cancer were significantly higher in HT than in NT. The leading cause of death was cancer. On basis of CBP, there was no significant difference in the incidence of death and event of cancer between patients with HT and NT at baseline. Associated risk factor for cancer was T2DM. Home morning HT may be reflected more keenly state of cancer than clinic HT, which may be superior to clinic NT. When we meet with such patients, it is important that cancer may be one of many causes for morning HT in Japanese patients with T2DM.


2019 ◽  
Vol 23 (1) ◽  
pp. 83
Author(s):  
L. D. Hidirova ◽  
D. A. Yakhontov ◽  
S. A. Zenin ◽  
V. N. Maximov

<p><strong>Letter to the editor:</strong></p><p>The world medical community has categorised atrial fibrillation (AF) as one of the three cardiovascular ‘epidemics of the 21st century’, along with chronic heart failure and diabetes mellitus [1]. In recent years, the prevalence of AF has increasing steadily. However, the exact cause for the increase in the incidence of AF<br />cannot be explained only by the increase in life expectancy, prevalence of cardiac valve disease or prevalence of myocardial infarction [2].</p><p>Although AF occurs in individuals with various manifestations of coronary heart disease, it is increasingly being diagnosed in patients with arterial hypertension without coronary heart disease [3]. AF causes serious cardiovascular complications; thus, a deep understanding of its pathogenetic aspects and a comprehensive study that considers comorbid pathologies for identifying the predictors of the development and progression of AF are required [4].</p><p>Hereditary factors can play a significant role in the development of AF and hypertension; consequently, the worldwide practice of scientific research in basic medicine pays significant attention to the molecular genetics methods of analysis.</p><p>This study aimed to evaluate the genetic determinants in patients with hypertension with AF progression accompanied by various extra-cardiac comorbid pathologies.</p><p>This prospective cohort study included 167 patients with a paroxysmal and persistent form of AF and stage III hypertonic disease without coronary heart disease. The average age of the patients was 53.3 ± 7.1 years. DNA isolation from blood leucocytes was performed using phenol–chloroform extraction. The rs1378942 polymorphism of the CSK gene, the rs220073 polymorphism and the -174G/C polymorphism (rs1800795) of the IL6 gene were assessed using polymerase chain reaction-restriction fragment length polymorphism. The statistical hypotheses were considered significant at a critical level of p = 0.05, i.e.<br />the difference was considered statistically significant at p &lt; 0.05. The lower limit of evidentiary power was equal to 80%.</p><p>This study reported associations between the rs1378942 polymorphism of the CSK gene, the rs1800795 polymorphism of the IL6 gene and the rs220073 polymorphism and the progression of AF in combination with the following associated diseases: hypertension, chronic obstructive pulmonary disease, hypothyroidism, type 2 diabetes mellitus and abdominal obesity. The relative risk of the progression of AF in carriers of the allele C was 1.94 times higher than that in carriers of the allele A [95% confidence interval (CI), 1.21–3.09]. Carriage of the AA genotype was conditionally protective against the progression of AF (relative risk, 0.41; 95% CI, 0.21–0.80; p = 0.010).</p><p>Associations of the rs1378942 and rs1800795 polymorphisms with the risk of recurrence of AF in combination with certain diseases were also found. In addition, associations were identified between rs1378942 and glomerular filtration rate, systolic and diastolic blood pressure, left atrial wall thickness and glucose, high-density lipoprotein (HDL) cholesterol, triglyceride and creatinine levels; between rs220073 and levels of triglycerides, atherogenic index, creatinine, fibrinogen and the number of months before the development of relapse and between rs1800795 and HDL cholesterol, creatinine and galectin-3 levels and diastolic blood pressure.</p><p>The secondary form of AF as a multi-factorial disease develops under the influence of many factors of both the external environment and hereditary nature. The complexity of the etio-pathogenesis of the disease makes it extremely difficult for researchers to identify the factors that play a leading role in the development of the pathological process. Currently, associative studies of AF with polymorphisms of &gt;260 genes have been conducted, and genome-wide associative studies have been performed as well. The reproducibility of the results depends on several factors: age, sex, comorbidities, ethnicity, penetrance, expressiveness, pleiotropy, various epigenetic influences and many more.</p><p>Despite the limitations of the sample, our study adds to the data material already available that can serve in the prognostic assessment of the development and progression of AF. Further studies will allow the development of a personalised algorithm for predicting the progression of AF in hypertension combined<br />with extra-cardiac diseases. In this regard, further larger studies are necessary that involve other institutions and a larger sample of patients, which will make it possible to predict the progression of AF with the definition of additional molecular criteria for evaluating the effectiveness of pathogenetic therapy and the possibilities of targeted treatment.<br /><strong></strong></p><p><strong>Funding:</strong> The study did not have sponsorship.<br /><strong></strong></p><p><strong>Conflict of interest:</strong> Authors declare no conflict of interest.</p>


2012 ◽  
Vol 56 (5) ◽  
pp. 285-290 ◽  
Author(s):  
Serdal Korkmaz ◽  
Abdulkerim Yilmaz ◽  
Gürsel Yildiz ◽  
Fatih Kiliçli ◽  
Serhat Içağasioğlu

OBJECTIVE: The rate of reduction of nocturnal blood pressure (NBP) is lesser than normal in patients with type 2 diabetes mellitus (type 2 DM). Hyperhomocysteinemia (HHC) disrupts vascular structure and function, no matter the underlying causes. The risk of development of vascular disease is greater in diabetic patients with hyperhomocysteinemia than in patients with normal homocystein levels. The aim of the study was to investigate whether there are differences of homocystein levels in dipper and non-dippers patients with type 2 DM. SUBJECTS AND METHODS: We compared 50 patients (33 females, 17 males) with type 2 DM and 35 healthy individuals (18 females, 17 males ) in a control group. Ambulatory blood pressure monitoring (ABPM) was performed and homocysteine levels were measured in all patients. RESULTS: We found that the percentage of non-dipper pattern was 72% in patients with type 2 DM and 57% in control group. In diabetic and control individuals, homocystein levels were higher in non-dipper (respectively 13.4 ± 8.1 µmol/L and 11.8 ± 5 µmol/L) than in dipper subjects (respectively, 11.8 ± 5.8 µmol/L and 10.1 ± 4.2 µmol/L), but there was no significant difference between the two groups (respectively, p = 0.545, p = 0.294). CONCLUSION: In both groups, homocystein levels were higher in non-dipper than in dipper participants, but there was no significant difference between the groups. High homocystein levels and the non-dipper pattern increases cardiovascular risk. Therefore, the relationship between nocturnal blood pressure changes and homocystein levels should be investigated in a larger study.


Heart Rhythm ◽  
2016 ◽  
Vol 13 (12) ◽  
pp. 2368-2376 ◽  
Author(s):  
Takanori Yaegashi ◽  
Takeshi Kato ◽  
Soichiro Usui ◽  
Naomi Kanamori ◽  
Hiroshi Furusho ◽  
...  

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