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Prednisone prevents atrial fibrillation promotion by atrial tachycardia remodeling in dogs.
Year : Volume : 55 Issue : 4 Page : How to cite this article: Cholongitas E. J Postgrad Med ; J Postgrad Med [serial online] [cited Nov 22]; Atrial fibrillation associated with systemic lupus erythematosus and use of methylprednisolone. Am J Ther ; Holter electrocardiograghic monitoring in nephritic syndrome patients during methylprednisolone therapy.
Am J Nephrol ; Atrial fibrillation following methylprednisolone therapy in an adult. Chest ; Anaphylaxis after intravenous methylprednisolone administration. JAMA ; Abbott AV. Diagnostic approach to palpitations. There is a problem with information submitted for this request.
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❿Prednisone tachycardia. Adverse Effects of Prednisone – What’s Going to Happen to Me?
You are being redirected to our trusted and authorized Nutranize product website. The Nutranize website is designed, constructed and endorsed by Dr. Megan Milne, the Prednisone Pharmacist. Please grant us just a few seconds to get you there. Automated page speed optimizations for fast site performance. What is an Adverse Effect? What are the Adverse Effects of Prednisone? Appetite Many people notice an increased appetite, with unprecedented cravings.
Bones Prednisone is the drug most likely to cause osteoporosis , or thinning of bones, which can lead to broken bones. Insomnia Prednisone is well-known for causing insomnia. Heart Prednisone can affect many aspects of heart health. Watch Dr. Megan explain in more detail: My Adverse Effects to Prednisone The rest of this article describes in more detail how I created the lists of Adverse Effects of Prednisone. First, I share my personal experience.
My Personal Experience on Prednisone Dr. Emotional Roller Coaster: I felt like an emotional roller coaster. And it felt like it was uncontrollable. Blurry Vision : I had blurry eyes. I was losing muscle. Prednisone was breaking down all the muscles and I was losing protein. Insatiable Appetite: I felt hungry all the time. I wanted the entire cake. That led to weight gain! And a lot of things led to fat redistribution to my belly.
So I had these skinny arms and legs and a big fat belly. Urine was there—like lots all at once. Not a lot for a couple of days. And then—bam!
It just looked like a bruise. Swelling Knees: My knees felt swollen. It was my knees. Impaired Wound Healing: it felt like if I got a cut or if I had to have a procedure or anything, I took forever to heal. Blood Changes on Prednisone. Felt Old on Prednisone Then I felt old. The Truth I wanted to know what I was going to experience while on prednisone. Watch this video to find out where to get the information online instead: What are the side effects of Prednisone?
Atrial fibrillation following methylprednisolone therapy in an adult. Chest ; Anaphylaxis after intravenous methylprednisolone administration. JAMA ; Abbott AV. Diagnostic approach to palpitations. Am Fam Physician ; Lin J. Tsai M. Lai L. Activation of the calcineurin-nuclear activated T-cell signal transduction pathway in atrial fibrillation Chest Yan H.
Chen J. Zhu J. Expression of connexin in atrium of patients with atrial fibrillation and its signal transduction pathway Zhonghua Yi Xue Za Zhi 84 Brundel B. Henning R. Tuinenburg A. Deelman L. Tieleman R. Gene expression of proteins influencing the calcium homeostasis in patients with persistent and paroxysmal atrial fibrillation Cardiovasc Res 42 Blain H. Boileau C. Lapicque F. Guillaume C.
Perico N. Ruggenenti P. Gotti E. Gaspari F. Cattaneo D. Valente U. Study Investigators. In renal transplantation blood cyclosporine levels soon after surgery act as a major determinant of rejection: insights from the MY. Ausma J. Dispersyn G. Duimel H. Thone F. VerDonck L. Changes in ultrastructural calcium distribution in goat atria during atrial fibrillation J Mol Cell Cardiol 32 Sun H. Chartier D. Leblanc N. Intracellular calcium changes and tachycardia-induced contractile dysfunction in canine atrial myocytes Cardiovasc Res 49 Yue L.
Feng J. Wang Z. Ionic remodeling underlying action potential changes in a canine model of atrial fibrillation Circ Res 81 Dobrev D. Ravens U. Remodeling of cardiomyocyte ion channels in human atrial fibrillation Basic Res Cardiol 98 Goette A. Lendeckel U. Klein H. Signal transduction systems and atrial fibrillation Cardiovasc Res 54 Kampinga H. VanGelder I.
Crijns H. Molecular mechanisms of remodeling in human atrial fibrillation Cardiovasc Res 54 Schotten U. Electrical, contractile and structural remodeling during atrial fibrillation Cardiovasc Res 54 Lee S. Cheng J. Hung C. Ding Y. Chang M. Effect of verapamil in long-term tachycardia-induced atrial electrical remodeling Circulation Fareh S. Differential efficacy of L- and T-type calcium channel blockers in preventing tachycardia-induced atrial remodeling in dogs Cardiovasc Res 49 Mitamura H.
Ogawa S. Benardeau A. Thibault B. Kumagai K. Nakashima H. Saku K. The HMG—CoA reductase inhibitor atorvastatin prevents atrial fibrillation by inhibiting inflammation in a canine sterile pericarditis model Cardiovasc Res 62 Caldarulo M. Buffon A. Fenici R. Melina D. Histologic evidence of occult myocardial diseases Chest Fijnheer R. Nierich A. Kalkman C. C-reactive protein is a risk indicator for atrial fibrillation after myocardial revascularization Ann Thorac Surg 79 Menkes C.
Effects of disease-modifying anti-rheumatic drugs, steroids and non-steroidal anti-inflammatory drugs on acute-phase proteins in rheumatoid arthritis Br J Rheumatol 32 Suppl. Amano Y. Allison A. Cato A. Wade E. Molecular mechanisms of anti-inflammatory action of glucocorticoids Bioessays 18 Ishii Y. Schuessler R.
Gaynor S. Yamada K. Boineau J. Inflammation of atrium after cardiac surgery is associated with inhomogeneity of atrial conduction and atrial fibrillation Circulation Kroncke K. Nitrosative stress and transcription Biol Chem Barouch L. Harrison R. Skaf M. Rosas G. Cappola T. Kobeissi Z. Drug information provided by: IBM Micromedex. Along with its needed effects, a medicine may cause some unwanted effects.
Although not all of these side effects may occur, if they do occur they may need medical attention. Some side effects may occur that usually do not need medical attention.
These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects.
Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:.
❾-50%}- Prednisone tachycardia
How to cite this article: Cholongitas E. J Postgrad Med ; J Postgrad Med [serial online] [cited Nov 22]; Atrial fibrillation associated with systemic lupus erythematosus and use of methylprednisolone.
Am J Ther ; Holter electrocardiograghic monitoring in nephritic syndrome patients during methylprednisolone therapy. Am J Nephrol ; Atrial fibrillation following methylprednisolone therapy in an adult. Chest ; A role for inflammation was first suggested based on observations in postoperative AF [2].
The time of peak AF occurrence second to third postoperative day coincides with peak concentrations of the inflammatory marker, C-reactive protein CRP [2].
CRP concentrations are also a predictor of future AF [5]. A small clinical trial indicated that methylprednisolone therapy can prevent AF recurrence, supporting a potential role for inflammation in AF [6].
AF remodels atrial electrophysiology in a way that favors AF maintenance and increases vulnerability to recurrence should AF terminate [7—10] , an effect attributable principally to atrial tachycardia [1,8,10].
There is evidence that this process is important in AF pathophysiology, and suppressing it may contribute to the clinical efficacy of amiodarone [11]. Simvastatin, which has anti-inflammatory properties, suppresses atrial-tachycardia remodeling [12].
We wondered whether anti-inflammatory agents, such as glucocorticoids, might also suppress atrial-tachycardia remodeling. We therefore designed this study to assess the effects of prednisone and the non-steroidal anti-inflammatory drug ibuprofen on the electrophysiological consequences of atrial tachycardia in dogs. In addition, evidence has been presented for calcineurin activation as a signal transduction pathway in porcine tachycardia-induced AF [13] and in tissue from AF patients [14].
We therefore added an additional group of dogs to determine the effect on atrial-tachycardia remodeling of inhibiting calcineurin-signaling with the calcineurin-antagonist agent cyclosporine-A.
Animal-handling procedures followed guidelines of the National Institutes of Health. Forty-two mongrel dogs 20—37 kg were anesthetized with ketamine 5. Unipolar pacing leads were inserted through jugular veins into the right ventricular RV apex and right atrial RA appendage under fluoroscopic guidance, and were connected to pacemakers Vitatron, USA in subcutaneous pockets in the neck.
A bipolar electrode was inserted into the RA for stimulation and recording during serial closed-chest electrophysiological studies EPSs. Atrioventricular block was created by radiofrequency-catheter ablation to avoid excessively rapid ventricular responses during atrial tachypacing ATP.
The RV demand-pacemaker was programmed to 80 bpm. After h post-operative recovery, a baseline closed-chest EPS was performed and then 7-day ATP at bpm was instituted.
All drugs were given orally in 2 divided doses, started 3 days prior to ATP onset and continued until the morning of the final open-chest EPS. We used a larger number of non-paced and ATP dogs than in the drug-intervention groups because we performed concomitant controls for each intervention series.
For closed-chest EPS, dogs were anesthetized with ketamine 5. The atrial tachypacemaker was deactivated and effective refractory period ERP of the RA appendage was measured at basic cycle lengths BCLs of , , , , and ms with 10 basic stimuli S1 followed by premature extrastimuli S2s with 5-ms decrements. All stimuli were twice-threshold, 2-ms pulses. A min rest period was then allowed before continuing measurements.
If prolonged AF was induced twice, no further AF induction was performed. A median sternotomy was performed, and bipolar electrodes were hooked into the RA and left atrial LA appendages for recording and stimulation. Silicon sheets containing bipolar electrodes were attached to the atria as previously described [10—12].
AF vulnerability was determined as the percentage of atrial sites at which AF was induced by single extrastimuli. Serum ibuprofen concentration was analyzed by high-performance liquid chromatography with an LCDB column and ultraviolet detection nm, Mayo Medical Laboratories. Tissue samples were homogenized in Radio-immuno-precipitation assay buffer as previously described [15]. Horseradish peroxidase-conjugated anti-mouse IgG Santa Cruz Biotechnology was the secondary antibody.
Protein was loaded in the linear immunoreactive-signal range and target-band intensities expressed relative to GAPDH intensity from the same sample. AF duration and CRP data were analyzed after normalization by logarithmic transformation. Bonferroni-corrected t -tests were applied to evaluate individual mean differences when ANOVA revealed significant group effects. There were no significant differences in ERPs among groups at baseline day 0.
ERP decreased slightly in prednisone-treated dogs, but the changes were much smaller than in ATP-only dogs. Although lower-dose prednisone produced slightly smaller effects than higher-dose, both resulted in ERPs significantly greater than AT-only.
The loss of ERP rate-adaptation in ibuprofen- Fig. Time course of atrial tachypacing-induced changes in ERP rate-adaptation during serial closed-chest electrophysiological studies. ERP rate-adaptation was better preserved during the study period despite atrial tachypacing in prednisone-treated dogs B.
Group abbreviations are as in Fig. ATP during treatment with ibuprofen Fig. No significant increase in DAF was observed in prednisone-treated dogs. There were no significant differences among groups in body weight or hemodynamic variables at final open-chest study, although systolic pressures tended to be higher in the high-dose prednisone group Table 1.
The mean day-7 trough ibuprofen serum concentration was No significant differences were observed between ATP-only dogs and ibuprofen-treated or cyclosporine-A-treated dogs. For reference, results are shown in each panel for non-paced dogs NP and from atrial tachypaced dogs that did not receive drug therapy ATP. However, ERP rate-adaptation was preserved in prednisone-treated dogs. ERP rate-adaptation was significantly decreased in dogs subjected to atrial tachypacing without drug therapy ATP.
ERP rate-adaptation was relatively preserved not significantly different from non-paced NP dogs in both atria of prednisone-treated dogs. Bottom: Indices of AF promotion at the final open-chest study. D: AF vulnerability percentage of atrial sites at which AF could be induced by single extrastimuli. Abbreviations as in Fig. In non-paced control dogs, AF was generally short-lasting and always terminated spontaneously within 5 min.
No prolonged AF requiring cardioversion occurred in prednisone-treated dogs. ATP dogs treated with ibuprofen or cyclosporine-A demonstrated increased AF duration relative to non-paced controls, to the range of — s, not significantly different from ATP-only dogs. ATP-induced increases in AF duration were significantly attenuated in prednisone-treated dogs.
There were no significant CRP differences among groups on day 0 Fig. CRP values in various experimental groups on day 0 P0 , immediately prior to tachypacing onset A , and on day 7 P7 of tachypacing B. CRP was not significantly different among study groups on day 0. Neither ibuprofen nor cyclosporine-A significantly altered the ATP effect. ATP-only dogs. Western-blot data are available only for high-dose prednisone experiments PDN.
In this study, we evaluated the effects of prednisone, ibuprofen, and cyclosporine-A on atrial remodeling due to 1 week of atrial tachycardia. We found that prednisone suppresses both the electrophysiological consequences of atrial tachycardia remodeling and the associated AF promotion, whereas ibuprofen and cyclosporine-A are without effect. Prednisone's anti-remodeling properties were associated with significant CRP reduction and attenuation of tachycardia-induced eNOS activation.
Atrial tachyarrhythmias alter atrial electrophysiology, shortening ERP, reducing ERP rate-adaptation and promoting AF occurrence and maintenance [7—10]. Because of clinical evidence for the importance of atrial tachycardia remodeling in the pathophysiology of AF, there have been considerable efforts to define its pathophysiology with an eye to developing pharmacological approaches to its prevention [1].
Calcium overload in cardiomyocytes is considered to play an important role in initiating the process of atrial remodeling [18,19] , subsequently leading to atrial ionic, molecular, contractile and ultrastructural changes [20—24]. A number of studies have been performed to pursue pharmacologic approaches to prevent atrial remodeling.
Simvastatin prevents atrial tachycardia-induced remodeling in dogs, an effect that could be related to an anti-inflammatory action [12]. In addition, atorvastatin prevents AF induced in the presence of sterile pericarditis in dogs, while decreasing CRP concentrations [29]. The present study is the first of which we are aware showing that glucocorticoids prevent tachycardia-induced remodeling in association with reduced CRP concentrations, and providing one possible mechanism for the results of studies indicating AF suppression by oral glucocorticoid therapy [6,30].
There is evidence for a role of inflammation in several forms of AF. Postoperative AF is associated with CRP increases and complement activation [2] , and baseline CRP concentrations are a predictor of postoperative AF for both on-pump and off-pump surgery [31].
CRP concentrations are higher in patients with AF than in sinus rhythm patients [4] , and there is an epidemiological association between CRP concentrations and AF prevalence at baseline as well as with AF risk on follow-up [5]. The present study supports a role for inflammatory changes in AF pathophysiology, by indicating that the potent anti-inflammatory compound prednisone suppresses atrial tachycardia remodeling in association with decreased CRP concentrations.
The anti-inflammatory action of NSAIDs is due only to cyclooxygenase inhibition, whereas glucocorticoids act via a variety of mechanisms including redirection of leukocytes and suppression of inflammatory cytokines and leukocyte adhesion molecules [33,34].
Our results are consistent with previous clinical observations of steroid efficacy in AF prevention [6,30] , as well as with a recent study showing beneficial effects of glucocorticoids in a model of post-cardiac surgical AF [35]. However, although the present findings are consistent with a role for inflammation in atrial tachycardia remodeling, they do not constitute proof of the notion.
Calcineurin enzyme activity is activated and expression of the downstream signal nuclear factor of activated thymocytes NFAT is augmented in pigs subjected to 6 weeks of atrial tachypacing [13]. Based on this information, we speculated that the calcineurin inhibitor cyclosporine-A would inhibit atrial tachycardia remodeling.
However, we were unable to demonstrate any protective effect of cyclosporine-A against atrial tachycardia-induced changes. Enhanced nitric oxide production can alter transcriptional mechanisms and contribute to inflammatory processes [36].
Barouch et al. This study is to our knowledge the first to assess the effects of glucocorticoids, NSAIDs or calcineurin inhibitors in an animal model of AF promotion by atrial tachycardia. Our results show that prednisone, but not ibuprofen or cyclosporine-A, suppresses atrial tachycardia-induced electrical remodeling and AF promotion.
The suppression by prednisone of CRP and eNOS levels may provide potential insights into mechanisms underlying prednisone's actions. This information is relevant to the pharmacological suppression of atrial remodeling and the development of new approaches to AF prevention, and suggests one potential candidate mechanism for previous observations of glucocorticoid efficacy in AF management [6,30].
In contrast to our results, Cai et al. However, Carnes et al. Mihm et al. Kim et al. However, glucocorticoids do not suppress iNOS in some inflammatory states [44]. The dosage of cyclosporine-A was selected based on previous studies of cyclosporine-A use in a dog model [45]. The mean cyclosporine-A trough concentration in our dogs was well into the therapeutic range in man and higher doses caused severe toxicity in pilot studies.
We chose the dosage of ibuprofen based on the maximal dosage for human use. The resulting ibuprofen trough concentrations were within the effective therapeutic range [16].
Larger doses were not tolerated because of gastrointestinal bleeding and systemic side-effects lassitude, failure to eat, etc. We based our higher dose of prednisone on doses used in prior clinical studies [30]. It would be interesting to do a full prednisone dose—response trial in a future study.
AF is often a progressive and slowly evolving condition in humans. This needs to be considered carefully in evaluating the results of relatively short-term studies like ours. Atrial tachycardia-induced electrophysiological remodeling and AF promotion are prevented by therapy with prednisone, but not by ibuprofen or cyclosporine-A. These results contribute potential new insights into the mechanisms and pharmacological prevention of atrial tachycardia-induced atrial arrhythmogenic remodeling.
Nattel S. Therapeutic implications of atrial fibrillation mechanisms: can mechanistic insights be used to improve AF management? Cardiovasc Res 54 Google Scholar. Bruins P. Yazdanbakhsh A. Jansen P. Activation of the complement system during and after cardiopulmonary bypass surgery: postsurgery activation involves C-reactive protein and is associated with postoperative arrhythmia Circulation 96 Frustaci A.
Chimenti C. Bellocci F. Morgante E. Russo M. Maseri A. Histological substrate of atrial biopsies in patients with lone atrial fibrillation Circulation 96 Chung M. Martin D. Sprecher D. Wazni O.
Kanderian A. Carnes C. C-reactive protein elevation in patients with atrial arrhythmias. Inflammatory mechanisms and persistence of atrial fibrillation Circulation Aviles R. Apperson-Hansen C. Houghtaling P. Rautaharju P. Heart palpitations, arrhythmias, or rhythm changes, can be harmless like a racing heart and trembling hands, or can be more dangerous and rare. The rest of this article describes in more detail how I created the lists of Adverse Effects of Prednisone.
This is me. Can you tell? Oh, those big strong muscles. Just kidding. This cartoon image is what I felt like while I was on prednisone. I was taking prednisone for a bleeding disorder. I had to get my blood checked every week, if not more often than that.
Those blood tests showed me that my blood sugar was high. My neutrophils, which are my white blood cells, were high. And if you want to hear more about the blood tests, and all the different ways that it was messing with my labs, I have a video you can check out below:. It was, it was weird.
Like all shaky, a weird jittery feeling from prednisone. I could feel my heart beating extra hard sometimes or in a weird rhythm, little heart palpitations. Moon Face : my round face. You can see my face right now after taking prednisone and and being off it for a year : I have a nice defined chin.
And my friend said that my face looked puffy. I thought. All right. I will do that. Then I felt old. Prednisone side effects make you feel old. You can see my beautiful red flushed cheeks there too. Insomnia: Finally, the prednisone adverse effect of insomnia.
Oh, insomnia. Just my mind was racing all the time. So that was my personal experience with prednisone adverse effects. When I first started taking prednisone, I wanted to know: what can I really expect?
Oh, and some weird stuff that we had to memorize that I was afraid that might happen to me. So I looked up a whole bunch of drug references. What are the side effects of prednisone? You can see this little funnel I made.
Those balls represent different online drug databases, Lexicomp, Clinical Pharmacology, and Micromedex.
And I looked up prednisone in each of those. I took all of the information on there and found there are over adverse effects of prednisone. There are over grouped different terms and you can see on the right terms like fat redistribution like the list below. This is how I grouped the term fat abnormalities :. So when you take all of these separate terms and then grouped them all, there are still 95 different things that are possible to expect. There are 95 , almost a hundred adverse effects that could happen to me while on prednisone!
I wanted to know:. I wanted to know what I was going to experience while on prednisone. So I was surprised to find when I did that, this pattern, you would think that all of those different drug references would have the exact same list! I thought if you took all of the drug side effects that are from Clinical Pharmacology and UpToDate and Micromedex that it would just be one circle and they would have the exact same list basically.
Clinical Pharmacology listed tons of prednisone adverse effects. It had 31 that nobody else even bothered to put on their list. The circle is instead a Venn Diagram! There were only 8 adverse effects that all four of these drug databases listed.
Click on image for details. Paroxysmal atrial tachycardia associated with prednisolone administration. Users online: Home Subscribe Feedback Login. Articles Current Issue Ahead of print. Year : Volume : 55 Issue : 4 Page : How to cite this article: Cholongitas E. J Postgrad Med ; J Postgrad Med [serial online] [cited Nov 22]; Atrial fibrillation associated with systemic lupus erythematosus and use of methylprednisolone.
Am J Ther ; Holter electrocardiograghic monitoring in nephritic syndrome patients during methylprednisolone therapy. Am J Nephrol ; Atrial fibrillation following methylprednisolone therapy in an adult.
Chest ; Anaphylaxis after intravenous methylprednisolone administration. JAMA ; Abbott AV. Diagnostic approach to palpitations. Am Fam Physician ; A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther ; This article has been cited by. Inhaled bronchodilators and the risk of tachyarrhythmias.
Previous article. Next article. Online since 12 th February ' Published by Wolters Kluwer - Medknow.
Prednisone is a steroid drug used to treat inflammatory conditions and autoimmune diseases. While effective, the drug can cause bradycardia . fast, slow, pounding, or irregular heartbeat or pulse. Prednisone can affect many aspects of heart health. High blood pressure, or hypertension, is a common side effect of prednisone that can lead to other heart. Due to the close temporal association between prednisolone administration and the arrhythmia, atrial tachycardia was thought to be causally. Prednisone is a corticosteroid medicine that is often referred to as a steroid. Every day our bodies naturally make cortisone, which is a steroid that is. Search ADS. In renal transplantation blood cyclosporine levels soon after surgery act as a major determinant of rejection: insights from the MY. Risk and protective factors for atrial fibrillation after cardiac surgery and valvular interventions: an umbrella review of meta-analyses. Megan explain in more detail: My Adverse Effects to Prednisone The rest of this article describes in more detail how I created the lists of Adverse Effects of Prednisone. There is evidence for a role of inflammation in several forms of AF. Wijffels M. Pharmacology textbooks and medical references will refer to the harms caused by a drug as an Adverse Effector an Adverse Drug Eventwhich is often abbreviated as ADE.Akiko Shiroshita-Takeshita, Bianca J. This study evaluated the efficacy of anti-inflammatory and calcineurin-inhibitory drugs on promotion of atrial fibrillation by atrial tachycardia-induced remodeling in dogs. Serial closed-chest electrophysiological studies were performed in each dog at baseline and 2, 4, and 7 days after tachypacing onset. A final open-chest study was performed on day 8.
In addition, prednisone but not ibuprofen or cyclosporine significantly decreased C-reactive protein concentrations and attenuated the increase in endothelial nitric oxide synthase expression caused by atrial tachypacing. Conclusions: Prednisone prevents the electrophysiological and atrial fibrillation-promoting effects of atrial tachycardia-remodeling, possibly by an anti-inflammatory action, whereas the less potent anti-inflammatory ibuprofen and the calcineurin inhibitor cyclosporine-A are without effect.
Atrial fibrillation AF is the most common arrhythmia in clinical practice. Drug therapy for AF is presently suboptimal and there is interest in developing novel approaches that target specific mechanistic determinants [1]. A role for inflammation was first suggested based on observations in postoperative AF [2]. The time of peak AF occurrence second to third postoperative day coincides with peak concentrations of the inflammatory marker, C-reactive protein CRP [2].
CRP concentrations are also a predictor of future AF [5]. A small clinical trial indicated that methylprednisolone therapy can prevent AF recurrence, supporting a potential role for inflammation in AF [6]. AF remodels atrial electrophysiology in a way that favors AF maintenance and increases vulnerability to recurrence should AF terminate [7—10] , an effect attributable principally to atrial tachycardia [1,8,10].
There is evidence that this process is important in AF pathophysiology, and suppressing it may contribute to the clinical efficacy of amiodarone [11]. Simvastatin, which has anti-inflammatory properties, suppresses atrial-tachycardia remodeling [12]. We wondered whether anti-inflammatory agents, such as glucocorticoids, might also suppress atrial-tachycardia remodeling.
We therefore designed this study to assess the effects of prednisone and the non-steroidal anti-inflammatory drug ibuprofen on the electrophysiological consequences of atrial tachycardia in dogs. In addition, evidence has been presented for calcineurin activation as a signal transduction pathway in porcine tachycardia-induced AF [13] and in tissue from AF patients [14].
We therefore added an additional group of dogs to determine the effect on atrial-tachycardia remodeling of inhibiting calcineurin-signaling with the calcineurin-antagonist agent cyclosporine-A. Animal-handling procedures followed guidelines of the National Institutes of Health. Forty-two mongrel dogs 20—37 kg were anesthetized with ketamine 5. Unipolar pacing leads were inserted through jugular veins into the right ventricular RV apex and right atrial RA appendage under fluoroscopic guidance, and were connected to pacemakers Vitatron, USA in subcutaneous pockets in the neck.
A bipolar electrode was inserted into the RA for stimulation and recording during serial closed-chest electrophysiological studies EPSs. Atrioventricular block was created by radiofrequency-catheter ablation to avoid excessively rapid ventricular responses during atrial tachypacing ATP.
The RV demand-pacemaker was programmed to 80 bpm. After h post-operative recovery, a baseline closed-chest EPS was performed and then 7-day ATP at bpm was instituted. All drugs were given orally in 2 divided doses, started 3 days prior to ATP onset and continued until the morning of the final open-chest EPS. We used a larger number of non-paced and ATP dogs than in the drug-intervention groups because we performed concomitant controls for each intervention series.
For closed-chest EPS, dogs were anesthetized with ketamine 5. The atrial tachypacemaker was deactivated and effective refractory period ERP of the RA appendage was measured at basic cycle lengths BCLs of , , , , and ms with 10 basic stimuli S1 followed by premature extrastimuli S2s with 5-ms decrements. All stimuli were twice-threshold, 2-ms pulses. A min rest period was then allowed before continuing measurements.
If prolonged AF was induced twice, no further AF induction was performed. A median sternotomy was performed, and bipolar electrodes were hooked into the RA and left atrial LA appendages for recording and stimulation.
Silicon sheets containing bipolar electrodes were attached to the atria as previously described [10—12]. AF vulnerability was determined as the percentage of atrial sites at which AF was induced by single extrastimuli. Serum ibuprofen concentration was analyzed by high-performance liquid chromatography with an LCDB column and ultraviolet detection nm, Mayo Medical Laboratories.
Tissue samples were homogenized in Radio-immuno-precipitation assay buffer as previously described [15]. Horseradish peroxidase-conjugated anti-mouse IgG Santa Cruz Biotechnology was the secondary antibody.
Protein was loaded in the linear immunoreactive-signal range and target-band intensities expressed relative to GAPDH intensity from the same sample. AF duration and CRP data were analyzed after normalization by logarithmic transformation.
Bonferroni-corrected t -tests were applied to evaluate individual mean differences when ANOVA revealed significant group effects. There were no significant differences in ERPs among groups at baseline day 0. ERP decreased slightly in prednisone-treated dogs, but the changes were much smaller than in ATP-only dogs. Although lower-dose prednisone produced slightly smaller effects than higher-dose, both resulted in ERPs significantly greater than AT-only.
The loss of ERP rate-adaptation in ibuprofen- Fig. Time course of atrial tachypacing-induced changes in ERP rate-adaptation during serial closed-chest electrophysiological studies. ERP rate-adaptation was better preserved during the study period despite atrial tachypacing in prednisone-treated dogs B. Group abbreviations are as in Fig. ATP during treatment with ibuprofen Fig.
No significant increase in DAF was observed in prednisone-treated dogs. There were no significant differences among groups in body weight or hemodynamic variables at final open-chest study, although systolic pressures tended to be higher in the high-dose prednisone group Table 1. The mean day-7 trough ibuprofen serum concentration was No significant differences were observed between ATP-only dogs and ibuprofen-treated or cyclosporine-A-treated dogs.
For reference, results are shown in each panel for non-paced dogs NP and from atrial tachypaced dogs that did not receive drug therapy ATP. However, ERP rate-adaptation was preserved in prednisone-treated dogs. ERP rate-adaptation was significantly decreased in dogs subjected to atrial tachypacing without drug therapy ATP. ERP rate-adaptation was relatively preserved not significantly different from non-paced NP dogs in both atria of prednisone-treated dogs.
Bottom: Indices of AF promotion at the final open-chest study. D: AF vulnerability percentage of atrial sites at which AF could be induced by single extrastimuli. Abbreviations as in Fig. In non-paced control dogs, AF was generally short-lasting and always terminated spontaneously within 5 min. No prolonged AF requiring cardioversion occurred in prednisone-treated dogs.
ATP dogs treated with ibuprofen or cyclosporine-A demonstrated increased AF duration relative to non-paced controls, to the range of — s, not significantly different from ATP-only dogs. ATP-induced increases in AF duration were significantly attenuated in prednisone-treated dogs. There were no significant CRP differences among groups on day 0 Fig. CRP values in various experimental groups on day 0 P0 , immediately prior to tachypacing onset A , and on day 7 P7 of tachypacing B.
CRP was not significantly different among study groups on day 0. Neither ibuprofen nor cyclosporine-A significantly altered the ATP effect. ATP-only dogs. Western-blot data are available only for high-dose prednisone experiments PDN.
In this study, we evaluated the effects of prednisone, ibuprofen, and cyclosporine-A on atrial remodeling due to 1 week of atrial tachycardia. We found that prednisone suppresses both the electrophysiological consequences of atrial tachycardia remodeling and the associated AF promotion, whereas ibuprofen and cyclosporine-A are without effect.
Prednisone's anti-remodeling properties were associated with significant CRP reduction and attenuation of tachycardia-induced eNOS activation. Atrial tachyarrhythmias alter atrial electrophysiology, shortening ERP, reducing ERP rate-adaptation and promoting AF occurrence and maintenance [7—10].
Because of clinical evidence for the importance of atrial tachycardia remodeling in the pathophysiology of AF, there have been considerable efforts to define its pathophysiology with an eye to developing pharmacological approaches to its prevention [1].
Calcium overload in cardiomyocytes is considered to play an important role in initiating the process of atrial remodeling [18,19] , subsequently leading to atrial ionic, molecular, contractile and ultrastructural changes [20—24]. A number of studies have been performed to pursue pharmacologic approaches to prevent atrial remodeling.
Simvastatin prevents atrial tachycardia-induced remodeling in dogs, an effect that could be related to an anti-inflammatory action [12]. In addition, atorvastatin prevents AF induced in the presence of sterile pericarditis in dogs, while decreasing CRP concentrations [29].
The present study is the first of which we are aware showing that glucocorticoids prevent tachycardia-induced remodeling in association with reduced CRP concentrations, and providing one possible mechanism for the results of studies indicating AF suppression by oral glucocorticoid therapy [6,30].
There is evidence for a role of inflammation in several forms of AF. Postoperative AF is associated with CRP increases and complement activation [2] , and baseline CRP concentrations are a predictor of postoperative AF for both on-pump and off-pump surgery [31]. CRP concentrations are higher in patients with AF than in sinus rhythm patients [4] , and there is an epidemiological association between CRP concentrations and AF prevalence at baseline as well as with AF risk on follow-up [5].
The present study supports a role for inflammatory changes in AF pathophysiology, by indicating that the potent anti-inflammatory compound prednisone suppresses atrial tachycardia remodeling in association with decreased CRP concentrations. The anti-inflammatory action of NSAIDs is due only to cyclooxygenase inhibition, whereas glucocorticoids act via a variety of mechanisms including redirection of leukocytes and suppression of inflammatory cytokines and leukocyte adhesion molecules [33,34].
Our results are consistent with previous clinical observations of steroid efficacy in AF prevention [6,30] , as well as with a recent study showing beneficial effects of glucocorticoids in a model of post-cardiac surgical AF [35].
However, although the present findings are consistent with a role for inflammation in atrial tachycardia remodeling, they do not constitute proof of the notion. Calcineurin enzyme activity is activated and expression of the downstream signal nuclear factor of activated thymocytes NFAT is augmented in pigs subjected to 6 weeks of atrial tachypacing [13]. Based on this information, we speculated that the calcineurin inhibitor cyclosporine-A would inhibit atrial tachycardia remodeling.
However, we were unable to demonstrate any protective effect of cyclosporine-A against atrial tachycardia-induced changes. Enhanced nitric oxide production can alter transcriptional mechanisms and contribute to inflammatory processes [36].
Barouch et al. This study is to our knowledge the first to assess the effects of glucocorticoids, NSAIDs or calcineurin inhibitors in an animal model of AF promotion by atrial tachycardia. Our results show that prednisone, but not ibuprofen or cyclosporine-A, suppresses atrial tachycardia-induced electrical remodeling and AF promotion. The suppression by prednisone of CRP and eNOS levels may provide potential insights into mechanisms underlying prednisone's actions.
This information is relevant to the pharmacological suppression of atrial remodeling and the development of new approaches to AF prevention, and suggests one potential candidate mechanism for previous observations of glucocorticoid efficacy in AF management [6,30]. In contrast to our results, Cai et al. However, Carnes et al.
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