Canagliflozin Suppresses Atrial Remodeling in a Canine Atrial Fibrillation Model.

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.

Untargeted metabolomics and lipidomics uncovering the cardioprotective effects of Huanglian Jiedu Decoction on pathological cardiac hypertrophy and remodeling.

ETHNOPHARMACOLOGICAL RELEVANCE: As a classic herbal prescription, Huanglian Jiedu Decoction (HLJDD) exhibits positive effects against cardiac dysfunction. However, its cardioprotective effects and potential mechanism(s) of action still need to be systematically investigated. AIM OF THE STUDY: This study aimed to reveal the underlying therapeutic mechanism of HLJDD on transverse aortic constriction (TAC)-induced pathological cardiac hypertrophy and remodeling. MATERIALS AND METHODS: TAC-induced cardiac hypertrophy and remodeling mice model was established to evaluate the therapeutic effects of HLJDD. Serum untargeted metabolomics and lipidomic profiling were performed using ultra-performance liquid chromatography quadrupole-time-of-flight mass spectrometry coupled with multivariate statistical analyses. RESULTS: Oral administration of HLJDD (2.5 g/kg/day, 5.0 g/kg/day) significantly improved the heart morphology, enhanced the heart function, and alleviated the accumulation of fibrosis in the interstitial space and the infiltration of inflammatory cells in TAC-stimulated mice. Serum untargeted metabolomics analysis showed that significant alterations were observed in metabolic signatures between the TAC-model and sham group. Principal component analysis and orthogonal partial least-squares discriminant analysis screened 59 differential metabolic features and 13 metabolites were identified. The disturbed metabolic pathways in TAC group mainly related to lipid metabolism. Further serum lipidomic profiling showed that most lipids including cholesterol esters, ceramides, glycerides, fatty acids and phospholipids were decreased in TAC group and these alterations were reversed after HLJDD intervention. CONCLUSION: HLJDD alleviates TAC-induced pathological cardiac hypertrophy and remodeling, and its potential therapeutic mechanism involves the regulation of lipid metabolism.

Cardioprotective Effects of the Novel Compound Vastiras in a Preclinical Model of End-Organ Damage.

Cardiac hypertrophy and renal damage associated with hypertension are independent predictors of morbidity and mortality. In a model of hypertensive heart disease and renal damage, we tested the actions of continuous administration of Vastiras, a novel compound derived from the linear fragment of ANP (atrial natriuretic peptide), namely pro-ANP31-67, on blood pressure and associated renal and cardiac function and remodeling. Of note, this peptide, unlike the ring structured forms, does not bind to the classic natriuretic peptide receptors. Dahl/Salt-Sensitive rats fed a 4% NaCl diet for 6 weeks developed hypertension, cardiac hypertrophy, and renal damage. Four weeks of treatment with 50 to 100 ng/kg per day of Vastiras exhibited positive effects on renal function, independent of blood pressure regulation. Treated rats had increased urine excretion, natriuresis, and enhanced glomerular filtration rate. Importantly, these favorable renal effects were accompanied by improved cardiac structure and function, including attenuated cardiac hypertrophy, as indicated by decreased heart weight to body weight ratio, relative wall thickness, and left atrial diameter, as well as reduced fibrosis and normalized ratio of the diastolic mitral inflow E wave to A wave. A renal subtherapeutic dose of Vastiras (25 ng/kg per day) induced similar protective effects on the heart. At the cellular level, cardiomyocyte size and t-tubule density were preserved in Vastiras-treated compared with untreated animals. In conclusion, these data demonstrate the cardiorenal protective actions of chronic supplementation of a first-in-class compound, Vastiras, in a preclinical model of maladaptive cardiac hypertrophy and renal damage induced by hypertension.

Wenxin Keli Regulates Mitochondrial Oxidative Stress and Homeostasis and Improves Atrial Remodeling in Diabetic Rats.

Mitochondrial dysfunction and oxidative stress play an important role in the pathogenesis of both atrial fibrillation (AF) and diabetes mellitus (DM). Wenxin Keli (WXKL), an antiarrhythmic traditional Chinese medicine, has been shown to prevent cardiac arrhythmias through modulation of cardiac ion channels. This study tested the hypothesis that WXKL can improve atrial remodeling in diabetic rats by restoring mitochondrial function. Primary atrial fibroblasts of neonatal SD rats were divided into four groups: control, hydrogen peroxide (H2O2), H2O2+WXKL 1 g/L, and H2O2+WXKL 3 g/L groups. Intracellular mitochondrial membrane potential (MMP), reactive oxygen species (ROS), and mitochondrial oxygen consumption were measured. SD male rats were randomly divided into three groups: control, DM, and DM+WXKL groups. Rats in the DM+WXKL group were treated with daily gavage of WXKL at 3 g/kg. After eight weeks, echocardiography, hemodynamic examination, histology, electrophysiology study, mitochondrial respiratory function, and western blots were assessed. H2O2 treatment led to increased ROS and decreased intracellular MMP and mitochondrial oxygen consumption in primary atrial fibroblasts. WXKL improved the above changes. DM rats showed increased atrial fibrosis, greater left atrial diameter, lower atrial conduction velocity, higher conduction heterogeneity, higher AF inducibility, and lower mitochondrial protein expression, and all these abnormal changes except for left atrial diameter were improved in the DM+WXKL group. WXKL improves atrial remodeling by regulating mitochondrial function and homeostasis and reducing mitochondrial ROS in diabetic rats.

Arnebiae Radix prevents atrial fibrillation in rats by ameliorating atrial remodeling and cardiac function.

ETHNOPHARMACOLOGICAL RELEVANCE: Arnebiae Radix, a common herbal medicine in China, is often utilized to treat blood-heat syndrome and has been reported to exert an effect on the heart. AIM OF THE STUDY: The combination of acetylcholine (Ach) and CaCl2 has been widely used to induce atrial fibrillation (AF) in animals. However, whether Arnebiae Radix displays any preventive action on Ach-CaCl2 induced AF in rats remains uncertain. In our study, we attempted to investigate the protective effects of Arnebiae Radix on Ach-CaCl2 induced AF compared to amiodarone, which was employed as the positive control. MATERIALS AND METHODS: To establish the AF model, SD rats were treated with a mixture of 0.1 mL/100 g Ach-CaCl2 (60 µg/mL Ach and 10 mg/mL CaCl2) by tail vein injection for 7 days. Rats were also given a gavage of Arnebiae Radix (0.18 g/mL) one week before or concurrently with the establishment of the AF model. At the end of the experimental period, the induction, duration and timing of AF were monitored using electrocardiogram recordings. Left atrial tissues were stained to observe the level of fibrosis. Electrophysiological measurements were used to examine atrial size and function. RESULTS: In Ach-CaCl2-induced AF rats, Arnebiae Radix decreased AF induction, duration and susceptibility to AF. In addition, Arnebiae Radix significantly reduced atrial fibrosis and inhibited atrial enlargement induced by Ach-CaCl2. Moreover, there was an apparent improvement in cardiac function in the Arnebiae Radix-treated group. CONCLUSIONS: Our findings indicate that Arnebiae Radix treatment can attenuate Ach-CaCl2-induced atrial injury and serve as an effective therapeutic strategy for the treatment of AF in the future.

Linagliptin Suppresses Electrical and Structural Remodeling in the Isoproterenol Induced Myocardial Injury Model.

The effect of DPP-4 inhibitor on the electrical and structural remodeling in myocardial injury has not been evaluated. We hypothesized that linagliptin, DPP-4 inhibitor, suppresses myocardial remodeling in the isoproterenol (ISP)-induced myocardial injury model.Sprague-Dawley rats were assigned to 3 groups: 1) sham group, 2) ISP group (subcutaneous ISP injection of 70 mg/kg), and 3) ISP + linagliptin (ISP + Lin) (5 mg/kg/day, p.o.) group. Serum was sampled on day 1 (acute phase) and day 7 (sub-acute phase) to evaluate derivatives of reactive oxidative metabolites (d-ROMs). The electrophysiological study was performed in sub-acute phase for the evaluation of the ventricular effective refractory period (VERP) and monophasic action potential duration (MAPD). The VERP and MAPD were markedly prolonged in the ISP group in comparison with the sham (MAPD20: 14 ± 6 versus 11 ± 3 ms, MAPD90: 57 ± 8 versus 44 ± 7 ms, VERP: 74 ± 22 versus 38 ± 10 ms, P < 0.05). In contrast in the ISP + Lin group, such prolongations were suppressed, and the parameters were shorter than the ISP group (MAPD20: 9 ± 2 ms, MAPD90: 35 ± 6 ms, VERP: 52 ± 13 ms, P < 0.05). ISP treatment induced myocardial injury. The injured area was reduced in the ISP + Lin group in comparison with the ISP group (P < 0.05). Serum d-ROMs level in acute phase was higher in ISP group than the other 2 groups (sham: 214 ± 55 versus ISP: 404 ± 45 versus ISP + Lin: 337 ± 20 U.CARR, P < 0.05).Linagliptin suppressed structural and electrical changes, possibly through the antioxidative effect, in this myocardial injury model.

Qiliqiangxin attenuates atrial structural remodeling in prolonged pacing-induced atrial fibrillation in rabbits.

Qiliqiangxin (QL) can attenuate myocardial remodeling and improve cardiac function in some cardiac diseases, including heart failure and hypertension. This study was to explore the effects and mechanism of QL on atrial structural remodeling in atrial fibrillation (AF). Twenty-one rabbits were randomly divided into a sham-operation group, pacing group (pacing with 600 beats per minute for 4 weeks), and treatment group (2.5 g/kg/day). Before pacing, the rabbits received QL-administered p.o. for 1 week. We measured atrial electrophysiological parameters in all groups to evaluate AF inducibility and the atrial effective refractory period (AERP). Echocardiography evaluated cardiac function and structure. TUNEL detection, hematoxylin and eosin (HE) staining, and Masson's trichrome staining were performed. Immunohistochemistry and western blotting (WB) were used to detect alterations in calcium channel L-type dihydropyridine receptor α2 subunit (DHPR) and fibrosis-related regulatory factors. AF inducibility was markedly decreased after QL treatment. Furthermore, we found that AERP and DHPR were reduced significantly in pacing rabbits compared with sham rabbits; treatment with QL increased DHPR and AERP compared to the pacing group. The QL group showed significantly decreased mast cell density and improved atrial ejection fraction values compared with the pacing group. Moreover, QL decreased interventricular septum thickness (IVSd) and left ventricular end-diastolic diameter (LVEDD). Compared with the sham group, the levels of TGFß1 and P-smad2/3 were significantly upregulated in the pacing group. QL reduced TGF-ß1 and P-smad2/3 levels and downstream fibrosis-related factors. Our study demonstrated that QL treatment attenuates atrial structural remodeling potentially by inhibiting TGF-ß1/P-smad2/3 signaling pathway.

Moderate alcohol consumption is associated with atrial electrical and structural changes: Insights from high-density left atrial electroanatomic mapping.

BACKGROUND: Regular alcohol intake is an important modifiable risk factor associated with atrial fibrillation (AF) and left atrial (LA) dilation. OBJECTIVE: The purpose of this study was to determine the impact of different degrees of alcohol consumption on atrial remodeling using high-density electroanatomic mapping. METHODS: We enrolled 75 patients before AF ablation to undergo high-density LA mapping (CARTO, Biosense Webster) using a multipolar catheter. The Confidense algorithm was used to create maps during distal coronary sinus pacing at 600 ms. Bipolar voltage and complex atrial activity were assessed, and isochronal activation maps were created to determine global conduction velocity (CV). Patients were classified as lifelong nondrinkers, mild drinkers (2-7 drinks/week), or moderate drinkers (8-21 drinks/week). RESULTS: High-density electroanatomic mapping (mean 1016 ± 445 points per patient) was performed on 25 lifelong nondrinkers, 25 mild drinkers (4.4 ± 2.3 drinks/week), and 25 moderate drinkers (14.0 ± 4.2 drinks/week). Moderate drinkers had significantly lower mean global bipolar voltages (1.53 ± 0.62 mV vs 1.89 ± 0.45 mV; P = .02), slower CV (33.5 ± 14.4 cm/s vs 41.7 ± 12.1 cm/s; P = .04), and a higher proportion of complex atrial potentials (7.8% ± 4.7% vs 4.5% ± 2.7%; P = .004) compared to nondrinkers. Global voltage and CV did not differ significantly in mild drinkers, but there was a significant increase in global complex potentials (6.6% ± 4.6%; P = .04) and regional low-voltage zones (<0.5 mV) in the septum and lateral wall (P <.05) compared with nondrinkers. CONCLUSION: Regular moderate alcohol consumption, but not mild consumption, is an important modifiable risk factor for AF associated with lower atrial voltage and conduction slowing. These electrical and structural changes may explain the propensity to AF in regular drinkers.

Recovery of Cardiac Remodeling and Dysmetabolism by Pancreatic Islet Injury Improvement in Diabetic Rats after Yacon Leaf Extract Treatment.

Yacon (Smallanthus sonchifolius) is a native Andean plant rich in phenolic compounds, and its effects on dysmetabolism and cardiomyopathy in diabetic rats was evaluated. The rats (10/group) were allocated as follows: C, controls; C + Y, controls treated with Yacon leaf extract (YLE); DM, diabetic controls; and DM + Y, diabetic rats treated with YLE. Type 1 diabetes (T1DM) was induced by the administration of streptozotocin (STZ; 40 mg-1/kg body weight, single dose, i.p.), and treated groups received 100 mg/kg body weight YLE daily via gavage for 30 d. The YLE group shows an improvement in dysmetabolism and cardiomyopathy in the diabetic condition (DM versus DM + Y) promoting a significant reduction of glycemia by 63.39%, an increase in insulin concentration by 49.30%, and a decrease in serum triacylglycerol and fatty acid contents by 0.39- and 0.43-fold, respectively, by ameliorating the pancreatic islet injury, as well as increasing the activity of the antioxidant enzymes (catalase, superoxide dismutase, and glutathione peroxidase) and decreasing the fibrosis and cellular disorganization in cardiac tissue. The apparent benefits of YLE seem to be mediated by ameliorating dysmetabolism and oxidative stress in pancreatic and cardiac tissues.

Cilostazol Prevents Atrial Structural Remodeling through the MEK/ERK Pathway in a Canine Model of Atrial Tachycardia.

OBJECTIVES: Atrial fibrillation (AF) is the most common sustained arrhythmia in clinical practice. Atrial structural remodeling (ASR), particularly atrial fibrosis, is an important contributor to the AF substrate. This study aimed to investigate the preventive effects of the phosphodiesterase 3 inhibitor cilostazol on ASR and its potential molecular mechanisms in a canine model of rapid atrial pacing (RAP). METHODS: Thirty dogs were assigned to sham (Sham), paced/ no treatment (Paced) and paced + cilostazol 5 mg/kg/day (Paced + cilo) groups, with 10 dogs in each group. RAP at 500 beats/min was maintained for 2 weeks, while the Sham group was instrumented without pacing. Cilostazol was provided orally during pacing. Western blotting, RT-PCR and pathology were used to assess ASR. RESULTS: Cilostazol attenuated atrial interstitial fibrosis and structural remodeling in canines with RAP. MEK/ERK transduction pathway gene expression was upregulated in the Paced group compared with the Sham group. Cilostazol markedly alleviated these changes in the MEK/ERK pathway. Transforming growth factor-ß1 protein expression in the Paced group was significantly higher than in the Sham group (p < 0.01), and was significantly reduced by cilostazol (p < 0.01). CONCLUSIONS: Our findings suggest that cilostazol is beneficial for prevention and treatment in atrial tachycardia-induced ASR in a canine model of RAP.

Rhodiola Inhibits Atrial Arrhythmogenesis in a Heart Failure Model.

INTRODUCTION: Rhodiola, a popular plant in Tibet, has been proven to decrease arrhythmia. The aim of this study was to elucidate the molecular mechanism and electrophysiological properties of rhodiola in the suppression of atrial fibrillation. METHODS: This study consisted of 3 groups as follows: Group 1: normal control rabbits (n = 5); Group 2: rabbits with heart failure (HF) created by coronary ligation and who received 2 weeks of water orally as a placebo (n = 5); and Group 3: rabbits with HF who received 2 weeks of a rhodiola 270 mg/kg/day treatment orally (n = 5). The monophasic action potential, histology, and real-time polymerase chain reaction (RT-PCR) analysis of ionic channels and PI3K/AKT/eNOS were examined. RESULTS: Compared with the HF group, attenuated atrial fibrosis (35.4 ± 17.4% vs. 16.9 ± 8.4%, P = 0.05) and improved left ventricular (LV) ejection fraction (51.6 ± 3.4% vs. 68.0 ± 0.5%, P = 0.001) were observed in the rhodiola group. The rhodiola group had a shorter ERP (85.3 ± 6.8 vs. 94.3 ± 1.2, P = 0.002), APD90 (89.3 ± 1.5 vs. 112.7 ± 0.7, P < 0.001) in the left atrium (LA), and decreased AF inducibility (0.90 ± 0.04 vs. 0.42 ± 0.04, P < 0.001) compared with the HF group. The mRNA expressions of Kv1.4, Kv1.5, Kv4.3, KvLQT1, Cav1.2, and SERCA2a in the HF LA were up-regulated after rhodiola treatment. The rhodiola-treated HF LA demonstrated higher mRNA expression of PI3K-AKT compared with the HF group. CONCLUSIONS: Rhodiola reversed LA electrical remodeling, attenuated atrial fibrosis and suppressed AF in rabbits with HF. The beneficial electrophysiological effect of rhodiola may be related to upregulation of Kv1.4, Kv1.5, Kv4.3, KvLQT1, Cav1.2, SERCA2a, and activation of PI3K/AKT signaling.

Effects of magnesium supplementation on electrophysiological remodeling of cardiac myocytes in L-NAME induced hypertensive rats.

Hypertension is one of the major risk factors of cardiac hypertrophy and magnesium deficiency is suggested to be a contributing factor in the progression of this complication. In this study, we aimed to investigate the relationship between intracellular free Mg(2+) levels and electrophysiological changes developed in the myocardium of L-NAME induced hypertensive rats. Hypertension was induced by administration of 40 mg/kg of L-NAME for 6 weeks, while magnesium treated rats fed with a diet supplemented with 1 g/kg of MgO for the same period. L-NAME administration for 6 weeks elicited a significant increase in blood pressure which was corrected with MgO treatment; thereby cardiac hypertrophy developing secondary to hypertension was prevented. Cytosolic free magnesium levels of ventricular myocytes were significantly decreased with hypertension and magnesium administration restored these changes. Hypertension significantly decreased the fractional shortening with slowing of shortening kinetics in left ventricular myocytes whereas magnesium treatment was capable of restoring hypertension-induced contractile dysfunction. Long-term magnesium treatment significantly restored the hypertension-induced prolongation in action potentials of ventricular myocytes and suppressed Ito and Iss currents. In contrast, hypertension dependent decrement in intracellular Mg(2+) level did not cause a significant change in L-type Ca(2+) currents, SR Ca(2+) content and NCX activity. Nevertheless, hypertension mediated increase in superoxide anion, hydrogen peroxide and protein oxidation mitigated with magnesium treatment. In conclusion, magnesium administration improves mechanical abnormalities observed in hypertensive rat ventricular myocytes due to reduced oxidative stress. It is likely that, changes in intracellular magnesium balance may contribute to the pathophysiology of chronic heart diseases.

Inhibition of aldosterone synthase (CYP11B2) by torasemide prevents atrial fibrosis and atrial fibrillation in mice.

Loop diuretics are used for fluid control in patients with heart failure. Furosemide and torasemide may exert differential effects on myocardial fibrosis. Here, we studied the effects of torasemide and furosemide on atrial fibrosis and remodeling during atrial fibrillation. In primary neonatal cardiac fibroblasts, torasemide (50µM, 24h) but not furosemide (50µM, 24h) reduced the expression of connective tissue growth factor (CTGF; 65±6%) and the pro-fibrotic miR-21 (44±23%), as well as the expression of lysyl oxidase (LOX; 57±8%), a regulator of collagen crosslinking. Mineralocorticoid receptor (MR) expression and activity were not altered. Torasemide but not furosemide inhibited human aldosterone synthase (CYP11B2) activity in transfected lung fibroblasts (V79MZ cells) by 75±1.8%. The selective CYP11B2 inhibitor SL242 mimicked the torasemide effects. Mice with cardiac overexpression of Rac1 GTPase (RacET), which develop atrial fibrosis and spontaneous AF with aging, were treated long-term (8months) with torasemide (10mg/kg/day), furosemide (40mg/kg/day) or vehicle. Treatment with torasemide but not furosemide prevented atrial fibrosis in RacET as well as the up-regulation of CTGF, LOX, and miR-2, whereas MR expression and activity remained unaffected. These effects correlated with a reduced prevalence of atrial fibrillation (33% RacET+Tora vs. 80% RacET). Torasemide but not furosemide inhibits CYP11B2 activity and reduces the expression of CTGF, LOX, and miR-21. These effects are associated with prevention of atrial fibrosis and a reduced prevalence of atrial fibrillation in mice.

Rosuvastatin attenuates atrial structural remodelling in rats with myocardial infarction through the inhibition of the p38 MAPK signalling pathway.

OBJECTIVE: The purpose of this study was to verify the hypothesis that rosuvastatin attenuates atrial structural remodelling in rats with myocardial infarction (MI) through the regulation of the p38 mitogen-activated protein kinase (MAPK) signalling pathway. METHODS: A total of 66 rats were used in this study to establish a model of MI. The 56 rats that survived the first 24h after surgery were randomly divided into four groups: the control group (C group), the rosuvastatin group (R group), the low-dose torasemide group (T1 group), and the high-dose torasemide group (T2 group). The four groups of rats received daily intragastric administration of normal saline, rosuvastatin, or torasemide (T1: 1mg/kg body weight; T2: 2mg/kg body weight) for a total of four weeks. The rats in the sham-operated group (n=14) also received daily intragastric administration of normal saline for four weeks. After four weeks of intervention, the left ventricular end-diastolic pressure (LVEDP) was measured in all groups of rats by haemodynamic methods. The rats were then sacrificed, and the left atrial tissues were collected. The collagen volume fractions (CVFs) in the left atrial tissues were determined using Masson's trichrome staining. The expression of phosphorylated p38 (P-p38) MAPK in the left atrial tissues was examined by immunohistochemistry and western blot analysis. RESULTS: The results showed that LVEDP, CVF, and P-p38 MAPK expression were drastically elevated in the four MI groups in comparison to the sham-operated group (p<0.001). Rosuvastatin elevated the left ventricular fractional shortening (LVFS) and left ventricular ejection fraction (LVEF). Both rosuvastatin and torasemide improved the haemodynamic parameters. No significant difference was detected in LVEDP between the R group and the T1 group (p=0.37). In contrast, LVEDP was significantly higher in the R group than in the T2 group (p <0.05). CVF (%) was markedly decreased in the R group compared to the C, T1, and T2 groups (decreased by 47.4%, 28%, and 20.1%, respectively). Immunohistochemical analysis showed that the indices of P-p38 MAPK positive cells were significantly decreased in the R group in comparison with the C, T1, and T2 groups (decreased by 44.6%, 36.6%, and 21.4%, respectively). Western blot analysis demonstrated that P-p38 MAPK expression was markedly reduced in the R group compared with the C and T1 groups (reduced by 67% and 40.5%, respectively). The level of P-p38 MAPK in the R group was slightly higher than in the T2 group. However, the difference was not statistically significant (p>0.05). CONCLUSION: Rosuvastatin attenuates atrial structural remodelling in rats with MI. The mechanism underlying this phenomenon may be associated with the downregulation of P-p38 MAPK by rosuvastatin.

Protective effects of epigallocatechin-3 gallate on atrial electrical and structural remodeling in a rabbit rapid atrial pacing model.

Epigallocatechin-3 gallate (EGCG) is the major catechin in green tea. The aim of this study is to investigate the effects of EGCG on atrial electrical and structural remodeling in a rabbit rapid atrial pacing (RAP) model. New Zealand white rabbits were subjected to RAP with or without EGCG treatment. The atrial electrophysiology was studied. ELISA, Western blots, and RT-PCR were performed to determine the level of the inflammation markers, oxidative stress, and fibrogenic agents. Atrial tissue was stained with Masson's trichrome stain for fibrosis detection. RAP rabbits showed a significantly shorter atrial effective refractory period than control rabbits. Higher AF inducibility and longer AF duration were seen in the RAP group. AERP of rabbits received high dose EGCG were prolonged compared to RAP rabbits, and AF inducibility and duration of rabbits received high dose EGCG were lower. RAP rabbits have higher inflammation markers, higher oxidative stress, and more significant fibrosis within atrium, while high dose intervention of EGCG can lower the inflammation, oxidative stress, and fibrosis induced by RAP. Results showed that EGCG have protective effects on atrial electrical and structural remodeling in a rabbit RAP model in terms of attenuating of inflammation and oxidative stress.

Impact of short-term treatment with telmisartan on cerebral arterial remodeling in SHR.

BACKGROUND AND PURPOSE: Chronic hypertension decreases internal diameter of cerebral arteries and arterioles. We recently showed that short-term treatment with the angiotensin II receptor blocker telmisartan restored baseline internal diameter of small cerebral arterioles in spontaneously hypertensive rats (SHR), via reversal of structural remodeling and inhibition of the angiotensin II vasoconstrictor response. As larger arteries also participate in the regulation of cerebral circulation, we evaluated whether similar short-term treatment affects middle cerebral arteries of SHR. METHODS: Baseline internal diameters of pressurised middle cerebral arteries from SHR and their respective controls, Wistar Kyoto rats (WKY) and responses to angiotensin II were studied in a small vessel arteriograph. Pressure myogenic curves and passive internal diameters were measured following EDTA deactivation, and elastic modulus from stress-strain relationships. RESULTS: Active baseline internal diameter was 23% lower in SHR compared to WKY, passive internal diameter (EDTA) 28% lower and elastic modulus unchanged. Pressure myogenic curves were shifted to higher pressure values in SHR. Telmisartan lowered blood pressure but had no effect on baseline internal diameter nor on structural remodeling (passive internal diameter and elastic modulus remained unchanged compared to SHR). Telmisartan shifted the pressure myogenic curve to lower pressure values than SHR. CONCLUSION: In the middle cerebral arteries of SHR, short-term treatment with telmisartan had no effect on structural remodeling and did not restore baseline internal diameter, but allowed myogenic tone to adapt towards lower pressure values.

Protective effects of aliskiren on atrial ionic remodeling in a canine model of rapid atrial pacing.

PURPOSE: Aliskiren inhibits the activation of the renin-angiotensin system. Here, we investigated the effects of aliskiren on chronic atrial iron remodeling in the experimental canine model of rapid atrial pacing. METHODS: Twenty-eight dogs were assigned to sham (S), control paced (C), paced + aliskiren (10 mg Kg(-1) d(-1), A1), and paced + aliskiren (20 mg Kg(-1) d(-1), A2) groups. Rapid atrial pacing at 500 bpm was maintained for 2 weeks, while group S was not paced. Levels of serum angiotensin-converting enzyme and angiotensin II after pacing were determined by ELISA. Whole-cell patch-clamp technique, western blot, and RT-PCR were applied to assess atrial ionic remodeling. RESULTS: The density of I CaL and I Na currents (pA/pF) was significantly lower in group C compared with group S (I CaL: -4.09 ± 1.46 vs. -6.12 ± 0.58,P < 0.05; I Na: 30.48 ± 6.08 vs. 46.31 ± 4.73, P < 0.05). However, the high dose of aliskiren elevated the density of I CaL and I Na currents compared with group C (I CaL: -6.23 ± 1.35 vs. -4.09 ± 1.46, P < 0.05; I Na: 58.62 ± 16.17 vs. 30.48 ± 6.08, P < 0.01). The relative mRNA and protein expression levels of Cav1.2 and Nav1.5α were downregulated in group C respectively (Cav1.2: 0.46 ± 0.08; Nav1.5α: 0.52 ± 0.08, P < 0.01; Cav1.2: 0.31 ± 0.03; Nav1.5α: 0.41 ± 0.04, P < 0.01;), but were upregulated by aliskiren. CONCLUSIONS: Aliskiren has protective effects on atrial tachycardia-induced atrial ionic remodeling.

Inefficacy of a highly selective T-type calcium channel blocker in preventing atrial fibrillation related remodeling.

BACKGROUND: The T-type Ca(2+) channel (I(CaT)) blocker mibefradil prevents AF-promoting remodeling occurring with atrial tachycardia, an action that has been attributed to I(CaT) inhibition. However, mibefradil has other effects, including ability to inhibit L-type Ca(2+) channels, Na(+) channels and cytochromes. Thus, the relationship between I(CaT) inhibition and remodeling protection in AF is still unknown. OBJECTIVE: To assess the effects of a novel highly selective Cav3 (I(CaT)) blocker, AZ9112, on atrial remodeling induced by 1-week atrial tachypacing (AT-P) in dogs. METHODS: Mongrel dogs were subjected to AT-P at 400 bpm for 7 days, with atrioventricular-node ablation and right-ventricular demand pacing (80 bpm) to control ventricular rate. Four groups of dogs were studied in investigator-blinded fashion: (1) a sham group, instrumented but without tachypacing or drug therapy (n = 5); (2) a placebo group, tachypaced but receiving placebo (n = 6); (3) a positive control tachypacing group receiving mibefradil (n = 6); and (4) a test drug group, subjected to tachypacing during oral treatment with AZ9112 (n = 8). RESULTS: One-week AT-P decreased atrial effective refractory period (ERP) at 6 of 8 sites and diminished rate-dependent atrial ERP abbreviation. Mibefradil eliminated AT-P-induced ERP-abbreviation at 4 of these 6 sites, while AZ9112 failed to affect ERP at any. Neither drug significantly affected AF vulnerability or AF duration. CONCLUSIONS: I(CaT) blockade with the highly selective compound AZ9112 failed to prevent rate-related atrial remodeling. Thus, prevention of atrial electrophysiological remodeling by mibefradil cannot be attributed exclusively to I(CaT) blockade. These results indicate that I(CaT) inhibition is not likely to be a useful approach for AF therapy.