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1.  Targeting Inflammation and Oxidative Stress in Atrial Fibrillation: Role of 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Inhibition with Statins 
Antioxidants & Redox Signaling  2014;20(8):1268-1285.
Significance: Atrial fibrillation (AF) is a burgeoning health-care problem, and the currently available therapeutic armamentarium is barely efficient. Experimental and clinical evidence implicates inflammation and myocardial oxidative stress in the pathogenesis of AF. Recent Advances: Local and systemic inflammation has been found to both precede and follow the new onset of AF, and NOX2-dependent generation of reactive oxygen species in human right atrial samples has been independently associated with the occurrence of AF in the postoperative period in patients undergoing cardiac surgery. Anti-inflammatory and antioxidant agents can prevent atrial electrical remodeling in animal models of atrial tachypacing and the new onset of AF after cardiac surgery, suggesting a causal relationship between inflammation/oxidative stress and the atrial substrate that supports AF. Critical Issues: Statin therapy, by redressing the myocardial nitroso-redox balance and reducing inflammation, has emerged as a potentially effective strategy for the prevention of AF. Evidence indicates that statins prevent AF-induced electrical remodeling in animal models of atrial tachypacing and may reduce the new onset of AF after cardiac surgery. However, whether statins have antiarrhythmic properties in humans has yet to be conclusively demonstrated, as data from randomized controlled trials specifically addressing the relevance of statin therapy for the primary and secondary prevention of AF remain scanty. Future Directions: A better understanding of the mechanisms underpinning the putative antiarrhythmic effects of statins may afford tailoring AF treatment to specific clinical settings and patient's subgroups. Large-scale randomized clinical trials are needed to support the indication of statin therapy solely on the basis of AF prevention. Antioxid. Redox Signal. 20, 1268–1285.
PMCID: PMC3934546  PMID: 23924190
2.  Advanced Electrophysiologic Mapping Systems 
Executive Summary
To assess the effectiveness, cost-effectiveness, and demand in Ontario for catheter ablation of complex arrhythmias guided by advanced nonfluoroscopy mapping systems. Particular attention was paid to ablation for atrial fibrillation (AF).
Clinical Need
Tachycardia refers to a diverse group of arrhythmias characterized by heart rates that are greater than 100 beats per minute. It results from abnormal firing of electrical impulses from heart tissues or abnormal electrical pathways in the heart because of scars. Tachycardia may be asymptomatic, or it may adversely affect quality of life owing to symptoms such as palpitations, headaches, shortness of breath, weakness, dizziness, and syncope. Atrial fibrillation, the most common sustained arrhythmia, affects about 99,000 people in Ontario. It is associated with higher morbidity and mortality because of increased risk of stroke, embolism, and congestive heart failure. In atrial fibrillation, most of the abnormal arrhythmogenic foci are located inside the pulmonary veins, although the atrium may also be responsible for triggering or perpetuating atrial fibrillation. Ventricular tachycardia, often found in patients with ischemic heart disease and a history of myocardial infarction, is often life-threatening; it accounts for about 50% of sudden deaths.
Treatment of Tachycardia
The first line of treatment for tachycardia is antiarrhythmic drugs; for atrial fibrillation, anticoagulation drugs are also used to prevent stroke. For patients refractory to or unable to tolerate antiarrhythmic drugs, ablation of the arrhythmogenic heart tissues is the only option. Surgical ablation such as the Cox-Maze procedure is more invasive. Catheter ablation, involving the delivery of energy (most commonly radiofrequency) via a percutaneous catheter system guided by X-ray fluoroscopy, has been used in place of surgical ablation for many patients. However, this conventional approach in catheter ablation has not been found to be effective for the treatment of complex arrhythmias such as chronic atrial fibrillation or ventricular tachycardia. Advanced nonfluoroscopic mapping systems have been developed for guiding the ablation of these complex arrhythmias.
The Technology
Four nonfluoroscopic advanced mapping systems have been licensed by Health Canada:
CARTO EP mapping System (manufactured by Biosense Webster, CA) uses weak magnetic fields and a special mapping/ablation catheter with a magnetic sensor to locate the catheter and reconstruct a 3-dimensional geometry of the heart superimposed with colour-coded electric potential maps to guide ablation.
EnSite System (manufactured by Endocardial Solutions Inc., MN) includes a multi-electrode non-contact catheter that conducts simultaneous mapping. A processing unit uses the electrical data to computes more than 3,000 isopotential electrograms that are displayed on a reconstructed 3-dimensional geometry of the heart chamber. The navigational system, EnSite NavX, can be used separately with most mapping catheters.
The LocaLisa Intracardiac System (manufactured by Medtronics Inc, MN) is a navigational system that uses an electrical field to locate the mapping catheter. It reconstructs the location of the electrodes on the mapping catheter in 3-dimensional virtual space, thereby enabling an ablation catheter to be directed to the electrode that identifies abnormal electric potential.
Polar Constellation Advanced Mapping Catheter System (manufactured by Boston Scientific, MA) is a multielectrode basket catheter with 64 electrodes on 8 splines. Once deployed, each electrode is automatically traced. The information enables a 3-dimensional model of the basket catheter to be computed. Colour-coded activation maps are reconstructed online and displayed on a monitor. By using this catheter, a precise electrical map of the atrium can be obtained in several heartbeats.
Review Strategy
A systematic search of Cochrane, MEDLINE and EMBASE was conducted to identify studies that compared ablation guided by any of the advanced systems to fluoroscopy-guided ablation of tachycardia. English-language studies with sample sizes greater than or equal to 20 that were published between 2000 and 2005 were included. Observational studies on safety of advanced mapping systems and fluoroscopy were also included. Outcomes of interest were acute success, defined as termination of arrhythmia immediately following ablation; long-term success, defined as being arrhythmia free at follow-up; total procedure time; fluoroscopy time; radiation dose; number of radiofrequency pulses; complications; cost; and the cost-effectiveness ratio.
Quality of the individual studies was assessed using established criteria. Quality of the overall evidence was determined by applying the GRADE evaluation system. (3) Qualitative synthesis of the data was performed. Quantitative analysis using Revman 4.2 was performed when appropriate.
Quality of the Studies
Thirty-four studies met the inclusion criteria. These comprised 18 studies on CARTO (4 randomized controlled trials [RCTs] and 14 non-RCTs), 3 RCTs on EnSite NavX, 4 studies on LocaLisa Navigational System (1 RCT and 3 non-RCTs), 2 studies on EnSite and CARTO, 1 on Polar Constellation basket catheter, and 7 studies on radiation safety.
The quality of the studies ranged from moderate to low. Most of the studies had small sample sizes with selection bias, and there was no blinding of patients or care providers in any of the studies. Duration of follow-up ranged from 6 weeks to 29 months, with most having at least 6 months of follow-up. There was heterogeneity with respect to the approach to ablation, definition of success, and drug management before and after the ablation procedure.
Summary of Findings
Evidence is based on a small number of small RCTS and non-RCTS with methodological flaws.
Advanced nonfluoroscopy mapping/navigation systems provided real time 3-dimensional images with integration of anatomic and electrical potential information that enable better visualization of areas of interest for ablation
Advanced nonfluoroscopy mapping/navigation systems appear to be safe; they consistently shortened the fluoroscopy duration and radiation exposure.
Evidence suggests that nonfluoroscopy mapping and navigation systems may be used as adjuncts to rather than replacements for fluoroscopy in guiding the ablation of complex arrhythmias.
Most studies showed a nonsignificant trend toward lower overall failure rate for advanced mapping-guided ablation compared with fluoroscopy-guided mapping.
Pooled analyses of small RCTs and non-RCTs that compared fluoroscopy- with nonfluoroscopy-guided ablation of atrial fibrillation and atrial flutter showed that advanced nonfluoroscopy mapping and navigational systems:
Yielded acute success rates of 69% to 100%, not significantly different from fluoroscopy ablation.
Had overall failure rates at 3 months to 19 months of 1% to 40% (median 25%).
Resulted in a 10% relative reduction in overall failure rate for advanced mapping guided-ablation compared to fluoroscopy guided ablation for the treatment of atrial fibrillation.
Yielded added benefit over fluoroscopy in guiding the ablation of complex arrhythmia. The advanced systems were shown to reduce the arrhythmia burden and the need for antiarrhythmic drugs in patients with complex arrhythmia who had failed fluoroscopy-guided ablation
Based on predominantly observational studies, circumferential PV ablation guided by a nonfluoroscopy system was shown to do the following:
Result in freedom from atrial fibrillation (with or without antiarrhythmic drug) in 75% to 95% of patients (median 79%). This effect was maintained up to 28 months.
Result in freedom from atrial fibrillation without antiarrhythmic drugs in 47% to 95% of patients (median 63%).
Improve patient survival at 28 months after the procedure as compared with drug therapy.
Require special skills; patient outcomes are operator dependent, and there is a significant learning curve effect.
Complication rates of pulmonary vein ablation guided by an advanced mapping/navigation system ranged from 0% to 10% with a median of 6% during a follow-up period of 6 months to 29 months.
The complication rate of the study with the longest follow-up was 8%.
The most common complications of advanced catheter-guided ablation were stroke, transient ischemic attack, cardiac tamponade, myocardial infarction, atrial flutter, congestive heart failure, and pulmonary vein stenosis. A small number of cases with fatal atrial-esophageal fistula had been reported and were attributed to the high radiofrequency energy used rather than to the advanced mapping systems.
Economic Analysis
An Ontario-based economic analysis suggests that the cumulative incremental upfront costs of catheter ablation of atrial fibrillation guided by advanced nonfluoroscopy mapping could be recouped in 4.7 years through cost avoidance arising from less need for antiarrhythmic drugs and fewer hospitalization for stroke and heart failure.
Expert Opinion
Expert consultants to the Medical Advisory Secretariat noted the following:
Nonfluoroscopy mapping is not necessary for simple ablation procedures (e.g., typical flutter). However, it is essential in the ablation of complex arrhythmias including these:
Symptomatic, drug-refractory atrial fibrillation
Arrhythmias in people who have had surgery for congenital heart disease (e.g., macro re-entrant tachycardia in people who have had surgery for congenital heart disease).
Ventricular tachycardia due to myocardial infarction
Atypical atrial flutter
Advanced mapping systems represent an enabling technology in the ablation of complex arrhythmias. The ablation of these complex cases would not have been feasible or advisable with fluoroscopy-guided ablation and, therefore, comparative studies would not be feasible or ethical in such cases.
Many of the studies included patients with relatively simple arrhythmias (e.g., typical atrial flutter and atrial ventricular nodal re-entrant tachycardia), for which the success rates using the fluoroscopy approach were extremely high and unlikely to be improved upon using nonfluoroscopic mapping.
By age 50, almost 100% of people who have had surgery for congenital heart disease will develop arrhythmia.
Some centres are under greater pressure because of expertise in complex ablation procedures for subsets of patients.
The use of advanced mapping systems requires the support of additional electrophysiologic laboratory time and nursing time.
For patients suffering from symptomatic, drug-refractory atrial fibrillation and are otherwise healthy, catheter ablation offers a treatment option that is less invasive than is open surgical ablation.
Small RCTs that may have been limited by type 2 errors showed significant reductions in fluoroscopy exposure in nonfluoroscopy-guided ablation and a trend toward lower overall failure rate that did not reach statistical significance.
Pooled analysis suggests that advanced mapping systems may reduce the overall failure rate in the ablation of atrial fibrillation.
Observational studies suggest that ablation guided by complex mapping/navigation systems is a promising treatment for complex arrhythmias such as highly symptomatic, drug-refractory atrial fibrillation for which rate control is not an option
In people with atrial fibrillation, ablation guided by advanced nonfluoroscopy mapping resulted in arrhythmia free rates of 80% or higher, reduced mortality, and better quality of life at experienced centres.
Although generally safe, serious complications such as stroke, atrial-esophageal, and pulmonary vein stenosis had been reported following ablation procedures.
Experts advised that advanced mapping systems are also required for catheter ablation of:
Hemodynamically unstable ventricular tachycardia from ischemic heart disease
Macro re-entrant atrial tachycardia after surgical correction of congenital heart disease
Atypical atrial flutter
Catheter ablation of atrial fibrillation is still evolving, and it appears that different ablative techniques may be appropriate depending on the characteristics of the patient and the atrial fibrillation.
Data from centres that perform electrophysiological mapping suggest that patients with drug-refractory atrial fibrillation may be the largest group with unmet need for advanced mapping-guided catheter ablation in Ontario.
Nonfluoroscopy mapping-guided pulmonary vein ablation for the treatment of atrial fibrillation has a significant learning effect; therefore, it is advisable for the province to establish centres of excellence to ensure a critical volume, to gain efficiency and to minimize the need for antiarrhythmic drugs after ablation and the need for future repeat ablation procedures.
PMCID: PMC3379531  PMID: 23074499
3.  Pleiotropic effects of statins in atrial fibrillation patients: the evidence 
Atrial fibrillation (AF) is the most common sustained arrhythmia in clinical practice. The understanding of the pathophysiology of AF has changed during the last several decades, and a significant role of inflammation and of the renin–angiotensin–aldosterone system has been postulated both experimentally and clinically. There is emerging evidence of an association between inflammation and AF, and mounting evidence links increased C-reactive protein levels not only to already existing AF but also to the risk of developing future AF. The beneficial effects of statins on AF have been reported in several studies. Several randomized clinical and large observational studies have shown similar result that show the beneficial effect of statins in AF. In clinical studies, statins were considered effective in preventing AF after electrical cardioversion, post-ablation, and after permanent pacemaker and implantable cardioverter defibrillator insertion. The antiarrhythmic mechanisms of statins regarding AF prevention in patients with heart failure are still not clear. Perioperative statin use has been associated with favorable postoperative outcome in both cardiovascular and noncardiovascular conditions. Despite a growing body of evidence that drugs with anti-inflammatory properties such as statins may prevent AF, the observed positive effects of statins on the burden of AF appeared to be independent of their cholesterol-reducing properties. However, further data from large-scale randomized trials are clearly needed.
PMCID: PMC2704895  PMID: 19590588
statins; pleiotropic effects; atrial fibrillation
4.  Ablation for Atrial Fibrillation 
Executive Summary
To review the effectiveness, safety, and costing of ablation methods to manage atrial fibrillation (AF). The ablation methods reviewed were catheter ablation and surgical ablation.
Clinical Need
Atrial fibrillation is characterized by an irregular, usually rapid, heart rate that limits the ability of the atria to pump blood effectively to the ventricles.
Atrial fibrillation can be a primary diagnosis or it may be associated with other diseases, such as high blood pressure, abnormal heart muscle function, chronic lung diseases, and coronary heart disease. The most common symptom of AF is palpitations. Symptoms caused by decreased blood flow include dizziness, fatigue, and shortness of breath. Some patients with AF do not experience any symptoms.
According to United States data, the incidence of AF increases with age, with a prevalence of 1 per 200 people aged between 50 and 60 years, and 1 per 10 people aged over 80 years. In 2004, the Institute for Clinical Evaluative Sciences (ICES) estimated that the rate of hospitalization for AF in Canada was 582.7 per 100,000 population. They also reported that of the patients discharged alive, 2.7% were readmitted within 1 year for stroke.
One United States prevalence study of AF indicated that the overall prevalence of AF was 0.95%. When the results of this study were extrapolated to the population of Ontario, the prevalence of AF in Ontario is 98,758 for residents aged over 20 years.
Currently, the first-line therapy for AF is medical therapy with antiarrhythmic drugs (AADs). There are several AADs available, because there is no one AAD that is effective for all patients. The AADs have critical adverse effects that can aggravate existing arrhythmias. The drug selection process frequently involves trial and error until the patient’s symptoms subside.
The Technology
Ablation has been frequently described as a “cure” for AF, compared with drug therapy, which controls AF but does not cure it. Ablation involves directing an energy source at cardiac tissue. For instance, radiofrequency energy uses heat to burn tissue near the source of the arrhythmia. The purpose is to create a series of scar tissue, so that the aberrant electrical pathways can no longer exist.
Because the pulmonary veins are the predominant source of AF initiation, the primary goal of ablation is to isolate the pulmonary veins from the left atria through the creation of a conduction block.
There are 2 methods of ablation: catheter ablation and surgical (operative) ablation. Radiofrequency energy is most commonly used for ablation. Catheter ablation involves inserting a catheter through the femoral vein to access the heart and burn abnormal foci of electrical activity by direct contact or by isolating them from the rest of the atrium. The surgical ablation is performed minimally invasively via direct visualization or with the assistance of a special scope for patients with lone AF.
Review Strategy
In March 2006, the following databases were searched: Cochrane Library International Agency for Health Technology Assessment (first quarter 2006), Cochrane Database of Systematic Reviews (first quarter 2006), Cochrane Central Register of Controlled Trials (first quarter 2006), MEDLINE (1966 to February 2006), MEDLINE In-Process and Other Non-indexed Citations (1966 to March 1, 2006), and EMBASE (1980 to 2006 week 9). The Medical Advisory Secretariat also searched Medscape on the Internet for recent reports on trials that were unpublished but that were presented at international conferences. In addition, the Web site Current Controlled Trials ( was searched for ongoing trials investigating ablation for atrial fibrillation. Search terms included: radiofrequency ablation, catheter ablation and atrial fibrillation.
Summary of Findings
Sixteen RCTs were identified that compared ablation methods in patients with AF. Two studies were identified that investigated first-line therapy for AF or atrial flutter. Seven other studies examined patients with drug-refractory, lone AF; and the remaining 7 RCTs compared ablation plus heart surgery to heart surgery alone in patients with drug-refractory AF and concomitant heart conditions.
First-line Catheter Ablation for Atrial Fibrillation or Atrial Flutter
Both studies concluded that catheter ablation was associated with significantly improved long-term freedom from arrhythmias and quality of life compared with medical therapy. These studies included different patient populations (those with AF in one pilot study, and those with atrial flutter in the other). Catheter ablation as first-line treatment is considered experimental at this time.
Catheter Ablation Versus Medical Therapy in Patients With Drug-Refractory, Lone Atrial Fibrillation
In this review, catheter ablation had success rates (freedom from arrhythmia) that ranged from 42% to 90% (median, 74%) in patients with drug-refractory, lone AF. All 3 of the RCTs comparing catheter ablation to medical therapy in patients with drug-refractory, lone AF found a significant improvement in terms of freedom from arrhythmia over a minimum of 12 months follow-up (P<.05).
Ablation Plus Heart Surgery Versus Heart Surgery Alone in Patients With Atrial Fibrillation
It is clear that patients with drug-refractory AF who are undergoing concomitant heart surgery (usually mitral valve repair or replacement) benefit significantly from surgical ablation, in terms of long-term freedom from AF, without substantial additional risk compared to open heart surgery alone. This group of patients represents about 1% of the patients with atrial fibrillation, thus the majority of the burden of AF lies within the patients with lone AF (i.e. those not requiring additional heart surgery).
Catheter ablation appears to be an effective treatment for patients with drug-refractory AF whose treatment alternatives are limited. Ablation technology is continually evolving with increasing success rates associated with the ablation procedure.
PMCID: PMC3379526  PMID: 23074498
5.  C-Reactive Protein Levels and Atrial Fibrillation after Cardiac Surgery in Women 
The Annals of thoracic surgery  2006;82(1):97-102.
The aim of this study was to evaluate whether risk for postoperative atrial fibrillation in women is related to pre-existing inflammation as detected by plasma C-reactive protein (CRP) concentrations. We further sought to assess for the importance of atrial fibrillation for outcome after cardiac surgery in women.
CRP was measured before coronary artery bypass grafting and/or valvular surgery using cardiopulmonary bypass in 141 women. Univariate and multivariate analysis were used to evaluate for differences in CRP levels between women with and without atrial fibrillation, and to assess for the importance of the arrhythmia and postoperative outcomes.
Atrial fibrillation developed in 46 (33%) women. Neither CRP concentrations (median±SE, 13.3±2.5 mg/L vs 11.7±1.4 mg/L, p=0.847), nor the frequency of elevated levels (defined as > upper 95% CI or > 19.2 mg/L) (19% vs 21%, p=0.807) differed between women with or without atrial fibrillation. Patient age and previous stroke, but not CRP levels, were independently associated with atrial fibrillation. Women with atrial fibrillation were more likely to have low cardiac output syndrome (p= 0.018), stroke (p=0.031), longer duration of hospitalization in the intensive care unit (p=0.012) and on the postoperative (p=0.0008) ward, and they were more likely to require an extended care facility after surgery (p=0.046).
In contrast to findings from studies that have included mostly men, preoperative CRP concentrations are not associated with risk for atrial fibrillation after cardiac surgery for women. Postoperative atrial fibrillation in women is associated with increased risk for stroke, longer hospitalization, and extended care facility admission.
PMCID: PMC1780029  PMID: 16798197
Arrhythmia; Atrial Fibrillation; Gender; Inflammation; On-pump
6.  Myeloperoxidase acts as a profibrotic mediator of atrial fibrillation 
Nature medicine  2010;16(4):470-474.
Observational clinical and ex vivo studies have established a strong association between atrial fibrillation and inflammation1. However, whether inflammation is the cause or the consequence of atrial fibrillation and which specific inflammatory mediators may increase the atria's susceptibility to fibrillation remain elusive. Here we provide experimental and clinical evidence for the mechanistic involvement of myeloperoxidase (MPO), a heme enzyme abundantly expressed by neutrophils, in the pathophysiology of atrial fibrillation. MPO-deficient mice pretreated with angiotensin II (AngII) to provoke leukocyte activation showed lower atrial tissue abundance of the MPO product 3-chlorotyrosine, reduced activity of matrix metalloproteinases and blunted atrial fibrosis as compared to wild-type mice. Upon right atrial electrophysiological stimulation, MPO-deficient mice were protected from atrial fibrillation, which was reversed when MPO was restored. Humans with atrial fibrillation had higher plasma concentrations of MPO and a larger MPO burden in right atrial tissue as compared to individuals devoid of atrial fibrillation. In the atria, MPO colocalized with markedly increased formation of 3-chlorotyrosine. Our data demonstrate that MPO is a crucial prerequisite for structural remodeling of the myocardium, leading to an increased vulnerability to atrial fibrillation.
PMCID: PMC2880896  PMID: 20305660
7.  Are Markers of Inflammation More Strongly Associated with Risk for Fatal Than for Nonfatal Vascular Events? 
PLoS Medicine  2009;6(6):e1000099.
In a secondary analysis of a randomized trial comparing pravastatin versus placebo for the prevention of coronary and cerebral events in an elderly at-risk population, Naveed Sattar and colleagues find that inflammatory markers may be more strongly associated with risk of fatal vascular events than nonfatal vascular events.
Circulating inflammatory markers may more strongly relate to risk of fatal versus nonfatal cardiovascular disease (CVD) events, but robust prospective evidence is lacking. We tested whether interleukin (IL)-6, C-reactive protein (CRP), and fibrinogen more strongly associate with fatal compared to nonfatal myocardial infarction (MI) and stroke.
Methods and Findings
In the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), baseline inflammatory markers in up to 5,680 men and women aged 70–82 y were related to risk for endpoints; nonfatal CVD (i.e., nonfatal MI and nonfatal stroke [n = 672]), fatal CVD (n = 190), death from other CV causes (n = 38), and non-CVD mortality (n = 300), over 3.2-y follow-up. Elevations in baseline IL-6 levels were significantly (p = 0.0009; competing risks model analysis) more strongly associated with fatal CVD (hazard ratio [HR] for 1 log unit increase in IL-6 1.75, 95% confidence interval [CI] 1.44–2.12) than with risk of nonfatal CVD (1.17, 95% CI 1.04–1.31), in analyses adjusted for treatment allocation. The findings were consistent in a fully adjusted model. These broad trends were similar for CRP and, to a lesser extent, for fibrinogen. The results were also similar in placebo and statin recipients (i.e., no interaction). The C-statistic for fatal CVD using traditional risk factors was significantly (+0.017; p<0.0001) improved by inclusion of IL-6 but not so for nonfatal CVD events (p = 0.20).
In PROSPER, inflammatory markers, in particular IL-6 and CRP, are more strongly associated with risk of fatal vascular events than nonfatal vascular events. These novel observations may have important implications for better understanding aetiology of CVD mortality, and have potential clinical relevance.
Please see later in the article for Editors' Summary
Editors' Summary
Cardiovascular disease (CVD)—disease that affects the heart and/or the blood vessels—is a common cause of death in developed countries. In the USA, for example, the leading cause of death is coronary heart disease (CHD), a CVD in which narrowing of the heart's blood vessels by “atherosclerotic plaques” (fatty deposits that build up with age) slows the blood supply to the heart and may eventually cause a heart attack (myocardial infarction). Other types of CVD include stroke (in which atherosclerotic plaques interrupt the brain's blood supply) and heart failure (a condition in which the heart cannot pump enough blood to the rest of the body). Smoking, high blood pressure, high blood levels of cholesterol (a type of fat), having diabetes, and being overweight all increase a person's risk of developing CVD. Tools such as the “Framingham risk calculator” take these and other risk factors into account to assess an individual's overall risk of CVD, which can be reduced by taking drugs to reduce blood pressure or cholesterol levels (for example, pravastatin) and by making lifestyle changes.
Why Was This Study Done?
Inflammation (an immune response to injury) in the walls of blood vessels is thought to play a role in the development of atherosclerotic plaques. Consistent with this idea, several epidemiological studies (investigations of the causes and distribution of disease in populations) have shown that people with high circulating levels of markers of inflammation such as interleukin-6 (IL-6), C-reactive protein (CRP), and fibrinogen are more likely to have a stroke or a heart attack (a CVD event) than people with low levels of these markers. Although these studies have generally lumped together fatal and nonfatal CVD events, some evidence suggests that circulating inflammatory markers may be more strongly associated with fatal than with nonfatal CVD events. If this is the case, the mechanisms that lead to fatal and nonfatal CVD events may be subtly different and knowing about these differences could improve both the prevention and treatment of CVD. In this study, the researchers investigate this possibility using data collected in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER; a trial that examined pravastatin's effect on CVD development among 70–82 year olds with pre-existing CVD or an increased risk of CVD because of smoking, high blood pressure, or diabetes).
What Did the Researchers Do and Find?
The researchers used several statistical models to examine the association between baseline levels of IL-6, CRP, and fibrinogen in the trial participants and nonfatal CVD events (nonfatal heart attacks and nonfatal strokes), fatal CVD events, death from other types of CVD, and deaths from other causes during 3.2 years of follow-up. Increased levels of all three inflammatory markers were more strongly associated with fatal CVD than with nonfatal CVD after adjustment for treatment allocation and for other established CVD risk factors but this pattern was strongest for IL-6. Thus, a unit increase in the log of IL-6 levels increased the risk of fatal CVD by half but increased the risk of nonfatal CVD by significantly less. The researchers also investigated whether including these inflammatory markers in tools designed to predict an individual's CVD risk could improve the tool's ability to distinguish between individuals with a high and low risk. The addition of IL-6 to established risk factors, they report, increased this discriminatory ability for fatal CVD but not for nonfatal CVD.
What Do These Findings Mean?
These findings indicate that, at least for the elderly at-risk patients who were included in PROSPER, inflammatory markers are more strongly associated with the risk of a fatal heart attack or stroke than with nonfatal CVD events. These findings need to be confirmed in younger populations and larger studies also need to be done to discover whether the same association holds when fatal heart attacks and fatal strokes are considered separately. Nevertheless, the present findings suggest that inflammation may specifically help to promote the development of serious, potentially fatal CVD and should stimulate improved research into the use of inflammation markers to predict risk of deaths from CVD.
Additional Information
Please access these Web sites via the online version of this summary at
The MedlinePlus Encyclopedia has pages on coronary heart disease, stroke, and atherosclerosis (in English and Spanish)
MedlinePlus provides links to many other sources of information on heart diseases, vascular diseases, and stroke (in English and Spanish)
Information for patients and caregivers is provided by the American Heart Association on all aspects of cardiovascular disease, including information on inflammation and heart disease
Information is available from the British Heart Foundation on heart disease and keeping the heart healthy
More information about PROSPER is available on the Web site of the Vascular Biochemistry Department of the University of Glasgow
PMCID: PMC2694359  PMID: 19554082
8.  Trends in Atrial Fibrillation in Patients Hospitalized with an Acute Coronary Syndrome 
The American journal of medicine  2012;125(11):1076-1084.
Atrial fibrillation is common among patients with cardiovascular disease and is a frequent complication of the acute coronary syndrome. Data are needed on recent trends in the magnitude, clinical features, treatment, and prognostic impact of pre-existing and new-onset atrial fibrillation in patients hospitalized with an acute coronary syndrome.
The study population consisted of 59,032 patients hospitalized with an acute coronary syndrome at 113 sites in the Global Registry of Acute Coronary Events Study between 2000 and 2007.
4,494 participants (7.6%) with acute coronary syndrome reported a history of atrial fibrillation and 3,112 (5.3%) developed new-onset atrial fibrillation during their hospitalization. Rates of new-onset atrial fibrillation (5.5% to 4.5%) and pre-existing atrial fibrillation (7.4% to 6.7%) declined during the study. Pre-existing atrial fibrillation was associated with older age and greater cardiovascular disease burden, whereas new-onset atrial fibrillation was closely related to the severity of the index acute coronary syndrome. Patients with atrial fibrillation were less likely than patients without atrial fibrillation to receive evidence-based therapies and were more likely to develop in-hospital complications, including heart failure. Overall hospital death rates in patients with new-onset and pre-existing atrial fibrillation were 14.5% and 8.9%, respectively, compared to 1.2% in those without atrial fibrillation. Short-term death rates in atrial fibrillation patients declined over the study period.
Despite a reduction in the rates of, and mortality from, atrial fibrillation, this arrhythmia exerts a significant adverse effect on survival among patients hospitalized with an acute coronary syndrome. Opportunities exist to improve the identification and treatment of acute coronary syndrome patients with, or at risk for, atrial fibrillation to reduce the incidence and resultant complications of this dysrhythmia.
PMCID: PMC3524515  PMID: 23098864
atrial fibrillation; acute coronary syndrome; mortality
9.  Intra and Extracardiac Markers of Inflammation During Atrial Fibrillation 
A decrease in inflammation after cure of atrial arrhythmias suggests that such arrhythmias are pro-inflammatory, and lower inflammatory marker levels in the coronary sinus suggest that atrial arrhythmias result in the intracardiac appropriation of inflammatory cytokines.
To investigate the effect of atrial fibrillation on inflammatory markers drawn from intra and extracardiac chambers.
We performed a case control study of 167 AF patients and 207 controls. Blood from intra and extracardiac sites was obtained from a subset of patients undergoing curative AF ablation (n=46).
There were no significant differences in C-Reactive Protein (CRP) or interleukin-6 (IL-6) between those with and without a history of AF. Both were significantly higher when blood was drawn during AF compared to in sinus rhythm: median CRP 3.1 mg/dL (interquartile range [IQR] 1.0–6.0) versus 1.7 mg/dL (IQR 0.7 – 3.9, p=0.0005); median IL-6 2.3 ng/ml (IQR 1.5–3.9) versus 1.5 ng/ml (IQR 0.7–2.5; p=0.007). This finding persisted after adjusting for potential confounders. AF ablation patients in AF exhibited a positive median left atrial minus coronary sinus (LA-CS gradient) CRP (0.3 mg/dL , IQR −0.03–1.1), whereas those in sinus rhythm had a negative median LA-CS gradient CRP (−0.2, IQR −0.8-[−0.02], p=0.01); femoral artery minus femoral vein gradients in AF versus sinus rhythm failed to show any differences.
AF at the time of the blood draw, rather than a history of AF, was independently associated with inflammation. Differences in trans-cardiac gradients suggest that AF results in sequestration of inflammatory cytokines in the heart.
PMCID: PMC2900773  PMID: 20022819
Atrial fibrillation; CRP; C-Reactive Protein; IL-6; inflammation; coronary sinus; left atrium
10.  High-sensitivity C-reactive protein, statin therapy, and risks of atrial fibrillation: an exploratory analysis of the JUPITER trial 
European Heart Journal  2011;33(4):531-537.
Increasing evidence supports a role for inflammation in promoting atrial fibrillation (AF) and statins have anti-inflammatory effects that may be relevant for the prevention of AF. However, studies of statin therapy and incident AF have yielded mixed results and not focused on individuals with an underlying pro-inflammatory response. We studied whether high-sensitivity C-reactive protein is associated with incident AF and whether treatment with rosuvastatin is associated with a lower incidence of AF compared with placebo.
Methods and results
We randomized men and women with LDL cholesterol <130 mg/dL and high-sensitivity C-reactive protein ≥2 mg/L to receive either rosuvastatin 20 mg daily or placebo. Atrial fibrillation was determined from treatment-blind adverse event reports. Among 17 120 participants without prior history of arrhythmia, each increasing tertile of baseline high-sensitivity C-reactive protein was associated with a 36% increase in the risk of developing AF (95% CI: 1.16–1.60; P-trend < 0.01). Allocation to rosuvastatin when compared with placebo was associated with a 27% reduction in the relative risk of developing AF during the trial period; specifically, AF was reported among 138 participants in the placebo group and 100 in the rosuvastatin group (incidence rate 0.78 vs. 0.56/100 person-years, HR: 0.73, 95% CI: 0.56–0.94, P = 0.01). The exclusion of participants who developed a major cardiovascular event prior to the report of AF yielded similar results.
Within the JUPITER trial cohort of individuals selected for underlying inflammation, increasing levels of high-sensitivity C-reactive protein were associated with an increased risk of incident AF and random allocation to rosuvastatin significantly reduced that risk.
PMCID: PMC3279315  PMID: 22187510
C-reactive protein; Atrial fibrillation; Statins
11.  A Genetic Association Study of Serum Acute-Phase C-Reactive Protein Levels in Rheumatoid Arthritis: Implications for Clinical Interpretation 
PLoS Medicine  2010;7(9):e1000341.
A genetic association study by Timothy Vyse and colleagues suggests that there is a significant association between CRP variants and acute-phase serum CRP concentrations in patients with rheumatoid arthritis, including those with chronic inflammation.
The acute-phase increase in serum C-reactive protein (CRP) is used to diagnose and monitor infectious and inflammatory diseases. Little is known about the influence of genetics on acute-phase CRP, particularly in patients with chronic inflammation.
Methods and Findings
We studied two independent sets of patients with chronic inflammation due to rheumatoid arthritis (total 695 patients). A tagSNP approach captured common variation at the CRP locus and the relationship between genotype and serum CRP was explored by linear modelling. Erythrocyte sedimentation rate (ESR) was incorporated as an independent marker of inflammation to adjust for the varying levels of inflammatory disease activity between patients. Common genetic variants at the CRP locus were associated with acute-phase serum CRP (for the most associated haplotype: p = 0.002, p<0.0005, p<0.0005 in patient sets 1, 2, and the combined sets, respectively), translating into an approximately 3.5-fold change in expected serum CRP concentrations between carriers of two common CRP haplotypes. For example, when ESR = 50 mm/h the expected geometric mean CRP (95% confidence interval) concentration was 43.1 mg/l (32.1–50.0) for haplotype 1 and 14.2 mg/l (9.5–23.2) for haplotype 4.
Our findings raise questions about the interpretation of acute-phase serum CRP. In particular, failure to take into account the potential for genetic effects may result in the inappropriate reassurance or suboptimal treatment of patients simply because they carry low-CRP–associated genetic variants. CRP is increasingly being incorporated into clinical algorithms to compare disease activity between patients and to predict future clinical events: our findings impact on the use of these algorithms. For example, where access to effective, but expensive, biological therapies in rheumatoid arthritis is rationed on the basis of a DAS28-CRP clinical activity score, then two patients with identical underlying disease severity could be given, or denied, treatment on the basis of CRP genotype alone. The accuracy and utility of these algorithms might be improved by using a genetically adjusted CRP measurement.
Please see later in the article for the Editors' Summary
Editors' Summary
C-reactive protein (CRP) is a serum marker for inflammation or infection and acts by binding to a chemical (phosphocholine) found on the surface of dead or dying cells (and some types of bacteria) in order to activate the immune system (via the complement system). Fat cells release factors that stimulate the liver to produce CRP, and serum levels greater than 10 mg/l are generally considered indicative of an infectious or inflammatory process. After an inflammatory stimulus, serum CRP levels may exceed 500 times baseline, so CRP is used in all medical specialities to help diagnose inflammation and infection. Although patients with chronic inflammatory diseases, such as rheumatoid arthritis, have raised levels of CRP, levels of CRP are still highly variable. Some studies have suggested that there may be genetic variations of CRP (CRP variants) that determine the magnitude of the acute-phase CRP response, a finding that has important clinical implications: CRP thresholds are used as a diagnostic component of formal clinical algorithms and play an important role in a clinician's decision-making process when diagnosing inflammatory disease and choosing treatment options. Therefore, it is possible that false reassurance could be given to a patient with disease, or optimal treatment withheld, because some patients are genetically predisposed to have only a modest increase in acute-phase CRP.
Why Was This Study Done?
Although some studies have looked at the CRP gene variant response, few, if any, studies have examined the CRP gene variant response in the context of chronic inflammation, such as in rheumatoid arthritis. Therefore, this study aimed to determine whether CRP gene variants could also influence CRP serum levels in rheumatoid arthritis.
What Did the Researchers Do and Find?
The authors studied two independent sets of patients with chronic inflammation due to rheumatoid arthritis (total 695 patients): one patient set used a cohort of 281 patients in the UK, and the other patient set (used for replication) consisted of 414 patients from New Zealand and Australia. A genetic technique (a tagSNP approach) was used to capture common variations at the CRP locus (haplotype association analysis) at both the population and the individual level. The relationship between genotype and serum CRP was explored by linear modeling. The researchers found that common genetic variants at the CRP locus were associated with acute-phase serum CRP in both patient sets translating into an approximate 3.5-fold change in expected serum CRP between carriers of two common CRP variants. For example, when ESR = 50 mm/h the expected CRP serum level for one common CRP variant was 43.1 mg/l and for another CRP variant was 14.2 mg/l.
What Do These Findings Mean?
The findings of this study raise questions about the interpretation of acute-phase serum CRP, as they suggest that there is a significant association between CRP variants and acute-phase serum CRP concentrations in a group of patients with rheumatoid arthritis, including those with chronic active inflammation. The size of the genetic effect may be large enough to have a clinically relevant impact on the assessment of inflammatory disease activity, which in turn may influence therapeutic decision making. Failure to take into account the potential for genetic effects may result in the inappropriate reassurance or undertreatment of patients simply because they carry low-CRP–associated genetic variants. CRP is increasingly being incorporated into clinical algorithms to compare disease activity between patients and to predict future clinical events, so these findings impact on the use of such algorithms. The accuracy and utility of these algorithms might be improved by using a genetically adjusted CRP measurement.
Additional Information
Please access these Web sites via the online version of this summary at
Lab Test Online provides information on CRP
The Wellcome Trust provides a glossary of genetic terms
Learn.Genetics provides access to the Genetic Science Learning Center, which is part of the human genome project
PMCID: PMC2943443  PMID: 20877716
12.  Clinical Features and Serum Biomarkers in HIV Immune Reconstitution Inflammatory Syndrome after Cryptococcal Meningitis: A Prospective Cohort Study 
PLoS Medicine  2010;7(12):e1000384.
David Boulware and colleagues investigate clinical features in a prospective cohort with AIDS and recent cryptococcal meningitis after initiation of antiretroviral therapy to identify biomarkers for prediction and diagnosis of CM-IRIS (cryptococcal meninigitis-related immune reconstitution inflammatory syndrome).
Although antiretroviral therapy (ART) improves survival in persons with cryptococcal meningitis (CM) and AIDS, ART frequently elicits HIV immune reconstitution inflammatory syndrome (IRIS), an exaggerated and frequently deadly inflammatory reaction that complicates recovery from immunodeficiency. The pathogenesis of IRIS is poorly understood and prediction of IRIS is not possible.
Methods and Findings
We prospectively followed 101 ART-naïve Ugandans with AIDS and recent CM for one year after initiating ART, and used Luminex multiplex assays to compare serum cytokine levels in participants who did or did not develop IRIS. IRIS occurred in 45% of participants with recent CM on ART, including 30% with central nervous system (CNS) manifestations. The median time to CM-IRIS was 8.8 wk on ART. Overall mortality on ART was 36% with IRIS and 21% without IRIS. CM-IRIS was independently associated with death (HR = 2.3, 95% CI 1.1–5.1, p = 0.04). Patients experiencing subsequent CM-IRIS had 4-fold higher median serum cryptococcal antigen (CRAG) levels pre-ART (p = 0.006). Higher pre-ART levels of interleukin (IL)-4 and IL-17 as well as lower tumor necrosis factor (TNF)-α, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and vascular endothelial growth factor (VEGF) predicted future IRIS in multivariate analyses (area under the curve [AUC] = 0.82). An algorithm based on seven pre-ART serum biomarkers was a robust tool for stratifying high (83%), moderate (48%), and low risk (23%) for IRIS in the cohort. After ART was initiated, increasing levels of C-reactive protein (CRP), D-dimer, IL-6, IL-7, IL-13, G-CSF, or IL-1RA were associated with increasing hazard of IRIS by time-to-event analysis (each p≤0.001). At the time of IRIS onset, multiple proinflammatory cytokine responses were present, including CRP and IL-6. Mortality was predicted by pre-ART increasing IL-17, decreasing GM-CSF, and CRP level >32 mg/l (highest quartile). Pre-ART CRP level >32 mg/l alone was associated with future death (OR = 8.3, 95% CI 2.7–25.6, p<0.001).
Pre-ART increases in Th17 and Th2 responses (e.g., IL-17, IL-4) and lack of proinflammatory cytokine responses (e.g., TNF-α, G-CSF, GM-CSF, VEGF) predispose individuals to subsequent IRIS, perhaps as biomarkers of immune dysfunction and poor initial clearance of CRAG. Although requiring validation, these biomarkers might be an objective tool to stratify the risk of CM-IRIS and death, and could be used clinically to guide when to start ART or use prophylactic interventions.
Please see later in the article for the Editors' Summary
Editors' Summary
Since 1981, AIDS has killed more than 25 million people and about 33 million people are now infected with HIV, which causes AIDS. HIV, which is most often transmitted through unprotected sex with an HIV-infected partner, infects and kills immune system cells. Eventually, the immune system becomes so weak that unusual infections begin to occur. These “opportunistic” infections are infections that take advantage of the opportunity offered by a weakened immune system. One common and deadly opportunistic infection in people affected by AIDS is cryptococcal meningitis (CM), an infection around the brain that is caused by the fungus Cryptococcus neoformans. About one million cases of CM occur every year. CM can be treated with a drug called amphotericin but usually recurs unless another drug called fluconazole is taken daily thereafter. HIV therapy is lifesaving by suppressing the HIV virus and allowing immune system recovery. This immune recovery also helps to prevent the recurrence of CM.
Why Was This Study Done?
Unfortunately, HIV therapy can also elicit a serious condition called immune reconstitution inflammatory syndrome (IRIS) in people with CM and AIDS. IRIS is an exaggerated inflammatory immune response that kills up to one-third of affected people. Inflammation, which is characterized by swelling and redness, is the body's first defense against infection, but uncontrolled inflammation causes widespread tissue damage. Experts think that CM-IRIS may be the result of an unbalanced recovery of the immune system leading to an inappropriate immune response to persisting C. neoformans fragments and proteins that are slowly cleared from the body over months. Unfortunately, it is impossible to predict which individuals with CM and AIDS will develop IRIS when they are given HIV therapy. In this prospective study, the researchers investigated clinical features and cytokine profiles in a group of Ugandans with AIDS and recent CM for one year after starting HIV therapy to identify biomarkers that could be used to predict and diagnose CM-IRIS. Cytokines are proteins secreted by immune system cells that regulate the immune response; biomarkers are proteins found in the blood that indicate specific diseases.
What Did the Researchers Do and Find?
The researchers enrolled 101 Ugandans with AIDS and recent CM who had not previously received HIV therapy. They compared cytokine patterns in individuals who did and did not subsequently develop IRIS after starting HIV therapy. Overall, 45% of the patients developed IRIS. Deaths occurred in 36% of the patients who developed IRIS and in 21% of those who did not develop IRIS. Patients who developed CM-IRIS after starting HIV therapy had 4-fold higher baseline concentrations of cryptococcal antigen in their blood than patients who did not develop CM-IRIS. Prior to starting HIV therapy, higher levels of the cytokines IL-4 and IL-17 and lower levels of four cytokines—TNF-α, G-CSF, GM-CSF, and VEGF—predicted IRIS development, and an algorithm (formula) based on the baseline levels of seven serum biomarkers was able to group the patients into high, moderate, and low risk of IRIS. After starting HIV therapy, increasing levels of the inflammatory proteins C-reactive protein and D-dimer, and of several cytokines, were associated with an increased risk of IRIS. At the time of IRIS onset, the levels of many proinflammatory cytokine increased. Biomarkers also predicted death after starting HIV therapy with increasing levels of IL-17, decreasing levels of GM-CSF, and a C-reactive protein level of more than 32 mg/l (four times higher than normal) predicted death within one year.
What Do These Findings Mean?
These findings support the hypothesis that some AIDS patients who have a very damaged immune system have a very poor initial immune response and poor clearance of cryptococcus, which predisposes them to IRIS. The findings also identify three distinct phases of IRIS development. Before HIV therapy, a very damaged immune system with a lack of inflammatory responses to infection or inappropriate responses leads to ineffective clearance of the organism and its antigens. After HIV therapy is started, the presence of copious antigens promotes proinflammatory signaling to the immune system. As the immune system recovers proinflammatory immune cells are promoted. Finally, at the time of IRIS, a generalized “cytokine storm” occurs, which is potentially fatal when this inflammation occurs in the brain. The biomarkers identified here as indicators of a predisposition to IRIS need to be validated in more patients in more countries before they can be used as a clinical tool for predicting the risk of IRIS. If they are validated, they could help clinicians decide when to start HIV therapy in patients with AIDS and recent CM, and could guide the use of therapies that could help prevent the abnormal inflammatory responses.
Additional Information
Please access these websites via the online version of this summary at
The US National Institute of Allergy and Infectious Diseases provides information on HIV infection and AIDS
HIV InSite has information on all aspects of HIV/AIDS, including Knowledge Base Chapters on cryptococcosis and HIV and on the clinical implications of IRIS
Information is available from Avert, an international AIDS charity on all aspects of HIV/AIDS, including HIV-related opportunistic infections (in English and Spanish)
The MedlinePlus encyclopedia has a page on cryptococcal meningitis (in English and Spanish)
AIDS InfoNet provides fact sheets on many HIV/AIDS topics, including a fact sheet on cryptococcal meningitis (in several languages) and treatment guidelines for opportunistic infections
PMCID: PMC3014618  PMID: 21253011
13.  Inflammatory Markers and Poor Outcome after Stroke: A Prospective Cohort Study and Systematic Review of Interleukin-6 
PLoS Medicine  2009;6(9):e1000145.
In a prospective cohort study of patient outcomes following stroke, William Whiteley and colleagues find that markers of inflammatory response are associated with poor outcomes. However, addition of these markers to existing prognostic models does not improve outcome prediction.
The objective of this study was to determine whether: (a) markers of acute inflammation (white cell count, glucose, interleukin-6, C-reactive protein, and fibrinogen) are associated with poor outcome after stroke and (b) the addition of markers to previously validated prognostic models improves prediction of poor outcome.
Methods and Findings
We prospectively recruited patients between 2002 and 2005. Clinicians assessed patients and drew blood for inflammatory markers. Patients were followed up by postal questionnaire for poor outcome (a score of>2 on the modified Rankin Scale) and death through the General Register Office (Scotland) at 6 mo. We performed a systematic review of the literature and meta-analysis of the association between interleukin-6 and poor outcome after stroke to place our study in the context of previous research. We recruited 844 patients; mortality data were available in 844 (100%) and functional outcome in 750 (89%). After appropriate adjustment, the odds ratios for the association of markers and poor outcome (comparing the upper and the lower third) were interleukin-6, 3.1 (95% CI: 1.9–5.0); C-reactive protein, 1.9 (95% CI: 1.2–3.1); fibrinogen, 1.5 (95% CI: 1.0–2.36); white cell count, 2.1 (95% CI: 1.3–3.4); and glucose 1.3 (95% CI: 0.8–2.1). The results for interleukin-6 were similar to other studies. However, the addition of inflammatory marker levels to validated prognostic models did not materially improve model discrimination, calibration, or reclassification for prediction of poor outcome after stroke.
Raised levels of markers of the acute inflammatory response after stroke are associated with poor outcomes. However, the addition of these markers to a previously validated stroke prognostic model did not improve the prediction of poor outcome. Whether inflammatory markers are useful in prediction of recurrent stroke or other vascular events is a separate question, which requires further study.
Please see later in the article for the Editors' Summary
Editors' Summary
Every year, 15 million people have a stroke. In the US alone, someone has a stroke every 40 seconds and someone dies from a stroke every 3–4 minutes. Stroke occurs when the blood supply to the brain is suddenly interrupted by a blood clot blocking a blood vessel in the brain (ischemic stroke, the commonest type of stroke) or by a blood vessel in the brain bursting (hemorrhagic stroke). Deprived of the oxygen normally carried to them by the blood, the brain cells near the blockage die. The symptoms of stroke depend on which part of the brain is damaged but include sudden weakness or paralysis along one side of the body, vision loss in one or both eyes, and confusion or trouble speaking or understanding speech. Anyone experiencing these symptoms should seek medical assistance immediately because prompt treatment can limit the damage to the brain. Risk factors for stroke include age (three-quarters of strokes occur in people over 65 years old), high blood pressure, and heart disease.
Why Was This Study Done?
Many people are left with permanent disabilities after a stroke. An accurate way to predict the likely long-term outcome (prognosis) for individual patients would help clinicians manage their patients and help relatives and patients come to terms with their changed circumstances. Clinicians can get some idea of their patients' likely outcomes by assessing six simple clinical variables. These include the ability to lift both arms and awareness of the present situation. But could the inclusion of additional variables improve the predictive power of this simple prognostic model? There is some evidence that high levels in the blood of inflammatory markers (for example, interleukin-6 and C-reactive protein) are associated with poor outcomes after stroke—inflammation is the body's response to infection and to damage. In this prospective cohort study, the researchers investigate whether inflammatory markers are associated with poor outcome after stroke and whether the addition of these markers to the six-variable prognostic model improves its predictive power. Prospective cohort studies enroll a group of participants and follow their subsequent progress.
What Did the Researchers Do and Find?
The researchers recruited 844 patients who had had a stroke (mainly mild ischemic strokes) in Edinburgh. Each patient was assessed soon after the stroke by a clinician and blood was taken for the measurement of inflammatory markers. Six months after the stroke, the patient or their relatives completed a postal questionnaire that assessed their progress. Information about patient deaths was obtained from the General Register Office for Scotland. Dependency on others for the activities of daily life or dying was recorded as a poor outcome. In their statistical analysis of these data, the researchers found that raised levels of several inflammatory markers increased the likelihood of a poor outcome. For example, after allowing for age and other factors, individuals with interleukin-6 levels in the upper third of the measured range were three times as likely to have a poor outcome as patients with interleukin-6 levels in the bottom third of the range. A systematic search of the literature revealed that previous studies that had looked at the potential association between interleukin-6 levels and outcome after stroke had found similar results. Finally, the researchers found that the addition of inflammatory marker levels to the six-variable prognostic model did not substantially improve its ability to predict outcome after stroke for this cohort of patients.
What Do These Findings Mean?
These findings provide additional support for the idea that increased levels of inflammatory markers are associated with a poor outcome after stroke. However, because patients with infections were not excluded from the study, infection may be responsible for part of the observed association. Importantly, these findings also show that although the inclusion of inflammatory markers in the six variable prognostic model slightly improves its ability to predict outcome, the magnitude of this improvement is too small to warrant the use of these markers in routine practice. Whether the measurement of inflammatory markers might be useful in the prediction of recurrent stroke—at least a quarter of people who survive a stroke will have another one within 5 years—requires further study.
Additional Information
Please access these Web sites via the online version of this summary at
This study is further discussed in a PLoS Medicine Perspective by Len Kritharides
The US National Institute of Neurological Disorders and Stroke provides information about all aspects of stroke (in English and Spanish); the Know Stroke site provides educational materials about stroke prevention, treatment, and rehabilitation (in English and Spanish)
The Internet Stroke Center provides detailed information about stroke for patients, families and health professionals (in English and Spanish)
The UK National Health Service also provides information for patients and their families about stroke (in several languages)
MedlinePlus provides links to further resources and advice about stroke (in English and Spanish)
The six simple variable model for prediction of death or disability after stroke is available here:
PMCID: PMC2730573  PMID: 19901973
14.  Microbial Translocation Is Associated with Extensive Immune Activation in Dengue Virus Infected Patients with Severe Disease 
Severe dengue virus (DENV) disease is associated with extensive immune activation, characterized by a cytokine storm. Previously, elevated lipopolysaccharide (LPS) levels in dengue were found to correlate with clinical disease severity. In the present cross-sectional study we identified markers of microbial translocation and immune activation, which are associated with severe manifestations of DENV infection.
Serum samples from DENV-infected patients were collected during the outbreak in 2010 in the State of São Paulo, Brazil. Levels of LPS, lipopolysaccharide binding protein (LBP), soluble CD14 (sCD14) and IgM and IgG endotoxin core antibodies were determined by ELISA. Thirty cytokines were quantified using a multiplex luminex system. Patients were classified according to the 2009 WHO classification and the occurrence of plasma leakage/shock and hemorrhage. Moreover, a (non-supervised) cluster analysis based on the expression of the quantified cytokines was applied to identify groups of patients with similar cytokine profiles. Markers of microbial translocation were linked to groups with similar clinical disease severity and clusters with similar cytokine profiles.
Cluster analysis indicated that LPS levels were significantly increased in patients with a profound pro-inflammatory cytokine profile. LBP and sCD14 showed significantly increased levels in patients with severe disease in the clinical classification and in patients with severe inflammation in the cluster analysis. With both the clinical classification and the cluster analysis, levels of IL-6, IL-8, sIL-2R, MCP-1, RANTES, HGF, G-CSF and EGF were associated with severe disease.
The present study provides evidence that both microbial translocation and extensive immune activation occur during severe DENV infection and may play an important role in the pathogenesis.
Author Summary
The pathogenesis of severe dengue virus (DENV) infection is still not fully understood. It is hypothesized that it is caused by a cytokine storm as is described in severe sepsis. In the sepsis field, the potent immunostimulator lipopolysaccharide (LPS) is proposed to play an important role in the development of a cytokine storm. In a previous study we have found elevated levels of LPS in children with severe DENV infection. In this study we have investigated if we could confirm that microbial translocation occurs in DENV-infected patients. Moreover, we have determined the levels of thirty cytokines to get more insight in the cytokine storm during DENV infections and we have investigated whether microbial translocation is associated with immune activation. The patients in this cohort were classified according to their clinical presentation. Furthermore, a cluster analysis based on the expression of the determined cytokines was applied to identify patients with similar cytokine profiles. With these two techniques, we identified cytokines that may contribute significantly to the cytokine storm, and we could relate elevated levels of LPS to patients with a pro-inflammatory cytokine profile.
PMCID: PMC3662706  PMID: 23717702
15.  Effect of high-dose intravenous vitamin C on inflammation in cancer patients 
An inflammatory component is present in the microenvironment of most neoplastic tissues. Inflammation and elevated C-reactive protein (CRP) are associated with poor prognosis and decreased survival in many types of cancer.
Vitamin C has been suggested as having both a preventative and therapeutic role in a number of pathologies when administered at much higher-than-recommended dietary allowance levels.
Since in vitro studies demonstrated inhibition of pro-inflammatory pathways by millimolar concentrations of vitamin C, we decided to analyze the effects of high dose IVC therapy in suppression of inflammation in cancer patients.
45 patients with prostate cancer, breast cancer, bladder cancer, pancreatic cancer, lung cancer, thyroid cancer, skin cancer and B-cell lymphoma were treated at the Riordan Clinic by high doses of vitamin C (7.5 g -50 g) after standard treatments by conventional methods.
CRP and tumor markers were measured in serum or heparin-plasma as a routine analysis. In addition, serum samples were collected before and after the IVCs for the cytokine kit tests.
According to our data positive response to treatment, which was demonstrated by measurements of C- reactive protein, was found in 75% of patients and progression of the inflammation in 25% of patients. IVC treatments on all aggressive stage cancer patients showed the poor response of treatment.
There was correlation between tumor markers (PSA, CEA, CA27.29 and CA15-3) and changes in the levels of C-reactive protein.
Our test of the effect of IVC on pro-inflammatory cytokines demonstrated that inflammation cytokines IL-1α, IL-2, IL-8, TNF-α, chemokine eotaxin and CRP were reduced significantly after treatments.
The high dose intravenous ascorbic acid therapy affects C-reactive protein levels and pro-inflammation cytokines in cancer patients. In our study, we found that modulation of inflammation by IVC correlated with decreases in tumor marker levels.
In summary, our data support the hypothesis that high dose intravenous ascorbate treatments may reduce inflammation in cancer patients. Our results suggest that further investigations into the use of IVC to reduce inflammation in diseases where inflammation is relevant are warranted.
PMCID: PMC3480897  PMID: 22963460
16.  Evaluating the Quality of Research into a Single Prognostic Biomarker: A Systematic Review and Meta-analysis of 83 Studies of C-Reactive Protein in Stable Coronary Artery Disease 
PLoS Medicine  2010;7(6):e1000286.
In a systematic review and meta-analysis of 83 prognostic studies of C-reactive protein in coronary disease, Hemingway and colleagues find substantial biases, preventing them from drawing clear conclusions relating to the use of this marker in clinical practice.
Systematic evaluations of the quality of research on a single prognostic biomarker are rare. We sought to evaluate the quality of prognostic research evidence for the association of C-reactive protein (CRP) with fatal and nonfatal events among patients with stable coronary disease.
Methods and Findings
We searched MEDLINE (1966 to 2009) and EMBASE (1980 to 2009) and selected prospective studies of patients with stable coronary disease, reporting a relative risk for the association of CRP with death and nonfatal cardiovascular events. We included 83 studies, reporting 61,684 patients and 6,485 outcome events. No study reported a prespecified statistical analysis protocol; only two studies reported the time elapsed (in months or years) between initial presentation of symptomatic coronary disease and inclusion in the study. Studies reported a median of seven items (of 17) from the REMARK reporting guidelines, with no evidence of change over time.
The pooled relative risk for the top versus bottom third of CRP distribution was 1.97 (95% confidence interval [CI] 1.78–2.17), with substantial heterogeneity (I2 = 79.5). Only 13 studies adjusted for conventional risk factors (age, sex, smoking, obesity, diabetes, and low-density lipoprotein [LDL] cholesterol) and these had a relative risk of 1.65 (95% CI 1.39–1.96), I2 = 33.7. Studies reported ten different ways of comparing CRP values, with weaker relative risks for those based on continuous measures. Adjusting for publication bias (for which there was strong evidence, Egger's p<0.001) using a validated method reduced the relative risk to 1.19 (95% CI 1.13–1.25). Only two studies reported a measure of discrimination (c-statistic). In 20 studies the detection rate for subsequent events could be calculated and was 31% for a 10% false positive rate, and the calculated pooled c-statistic was 0.61 (0.57–0.66).
Multiple types of reporting bias, and publication bias, make the magnitude of any independent association between CRP and prognosis among patients with stable coronary disease sufficiently uncertain that no clinical practice recommendations can be made. Publication of prespecified statistical analytic protocols and prospective registration of studies, among other measures, might help improve the quality of prognostic biomarker research.
Please see later in the article for the Editors' Summary
Editors' Summary
Coronary artery disease is the leading cause of death among adults in developed countries. With age, fatty deposits called atherosclerotic plaques coat the walls of the arteries, the vessels that carry blood to the body's organs. Because they narrow the arteries, atherosclerotic plaques restrict blood flow. If plaques form in the arteries that feed the heart, the result is coronary artery disease, the symptoms of which include shortness of breath and chest pains (angina). If these symptoms only occur during exertion, the condition is called stable coronary artery disease. Coronary artery disease can cause potentially fatal heart attacks (myocardial infarctions). A heart attack occurs when a plaque ruptures and a blood clot completely blocks the artery, thereby killing part of the heart. Smoking, high blood pressure, high blood levels of cholesterol (a type of fat), diabetes, and being overweight are risk factors for coronary artery disease. Treatments for the condition include lifestyle changes and medications that lower blood pressure and blood cholesterol. Narrowed arteries can also be widened using a device called a stent or surgically bypassed.
Why Was This Study Done?
Clinicians can predict whether a patient with coronary artery disease is likely to have a heart attack by considering their risk factors. They then use this “prognosis” to help them manage the patient. To provide further help for clinicians, researchers are trying to identify prognostic biomarkers (molecules whose blood levels indicate how a disease might develop) for coronary artery disease. However, before a biomarker can be used clinically, it must be properly validated and there are concerns that there is insufficient high quality evidence to validate many biomarkers. In this systematic review and meta-analysis, the researchers ask whether the evidence for an association between blood levels of C-reactive protein (CRP, an inflammatory protein) and subsequent fatal and nonfatal events affecting the heart and circulation (cardiovascular events) among patients with stable coronary artery disease supports the routine measurement of CRP as recommended in clinical practice guidelines. A systematic review uses predefined criteria to identify all the research on a given topic; a meta-analysis is a statistical method for combining the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 83 studies that investigated the association between CRP levels measured in people with coronary artery disease and subsequent cardiovascular events. Their examination of these studies revealed numerous reporting and publication short-comings. For example, none of the studies reported a prespecified statistical analysis protocol, yet analyses should be prespecified to avoid the choice of analytical method biasing the study's results. Furthermore, on average, the studies only reported seven of the 17 recommended items in the REMARK reporting guidelines, which were designed to improve the reporting quality of tumor biomarker prognostic studies. The meta-analysis revealed that patients with a CRP level in the top third of the distribution were nearly twice as likely to have a cardiovascular event as patients with a CRP in the bottom third of the distribution (a relative risk of 1.97). However, the outcomes varied considerably between studies (heterogeneity) and there was strong evidence for publication bias—most published studies were small and smaller studies were more likely to report higher relative risks. Adjustment for publication bias reduced the relative risk associated with high CRP levels to 1.19. Finally, nearly all the studies failed to calculate whether CRP measurements discriminated between patients likely and unlikely to have a subsequent cardiovascular event.
What Do These Findings Mean?
These findings suggest that, because of multiple types of reporting and publication bias, the size of the association between CRP levels and prognosis among patients with stable coronary artery disease is extremely uncertain. They also suggest that CRP measurements are unlikely to add anything to the prognostic discrimination achieved by considering blood pressure and other standard clinical factors among this patient group. Thus, the researchers suggest, the recommendation that CRP measurements should be used in the management of patients with stable coronary artery disease ought to be removed from clinical practice guidelines. More generally, these findings increase concerns about the quality of research into prognostic biomarkers and highlight areas that need to be changed, the most fundamental of which is the need to preregister studies on prognostic biomarkers and their analytic protocols.
Additional Information
Please access these Web sites via the online version of this summary at
The MedlinePlus Encyclopedia has pages on coronary artery disease and C-reactive protein (in English and Spanish)
MedlinePlus provides links to other sources of information on heart disease
The American Heart Association provides information for patients and caregivers on all aspects of cardiovascular disease, including information on the role of C-reactive protein in heart disease
Information is available from the British Heart Foundation on heart disease and keeping the heart healthy
Wikipedia has pages on biomarkers and on C-reactive protein (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The EQUATOR network is a resource center for good reporting of health research studies
PMCID: PMC2879408  PMID: 20532236
17.  Biologic targeting in the treatment of inflammatory bowel diseases 
The etiology of inflammatory bowel disease (IBD) has not yet been clarified and immunosuppressive agents which nonspecifically reduce inflammation and immunity have been used in the conventional therapies for IBD. Evidence indicates that a dysregulation of mucosal immunity in the gut of IBD causes an overproduction of inflammatory cytokines and trafficking of effector leukocytes into the bowel, thus leading to an uncontrolled intestinal inflammation. Under normal situations, the intestinal mucosa is in a state of “controlled” inflammation regulated by a delicate balance of proinflammatory (tumor necrosis factor [TNF-α], interferon-gamma [IFN-γ], interleukin-1 [IL-1], IL-6, IL-12 and anti-inflammatory cytokines IL-4, IL-10, IL-11). The mucosal immune system is the central effector of intestinal inflammation and injury, with cytokines playing a central role in modulating inflammation. Cytokines may therefore be a logical target for inflammatory bowel disease therapy using specific cytokine inhibitors. Biotechnology agents targeted against TNF, leukocyte adhesion, Th1 polarization, T cell activation, nuclear factor-kappaB (NF-κB), and other miscellaneous therapies are being evaluated as potential therapies for the treatment of inflammatory bowel disease. In this context, infliximab and adalimumab are currently the only biologic agents approved in Europe for the treatment of inflammatory Crohn’s disease. Other anti-TNF biologic agents have emerged, including CDP571, certolizumab pegol, etanercept, onercept. However, ongoing research continues to generate new biologic agents targeted at specific pathogenic mechanism involved in the inflammatory process. Lymphocyte-endothelial interactions mediated by adhesion molecules are important in leukocyte migration and recruitment to sites of inflammation, and selective blockade of these adhesion molecules is a novel and promising strategy to treat Crohn’s disease. Therapeutics agents to inhibit leukocyte trafficking include natalizumab (approved for use in Crohn’s disease in USA), MLN-02, and ISIS 2302. Other agents being investigated for the treatment of Crohn’s disease include inhibitors of T cell activation, proinflammatory cytokine receptors, Th1 polarization, growth hormone, and growth factors. Agents being investigated for treatment of ulcerative colitis include many of those mentioned above. Controlled clinical trials are currently being conducted, exploring the safety and efficacy of old and new biologic agents, and the search certainly will open new and exciting perspective on the development of therapies for inflammatory bowel disease. A review is made of the main areas of research exploring the mechanisms associated with the pathogenesis of IBD, providing advances in the agents currently in use, and identifying a host of new therapeutic biologic targets.
PMCID: PMC2726060  PMID: 19707398
Crohn’s disease; ulcerative colitis; biological therapy
18.  Incidence and prognostic significance of atrial fibrillation in acute myocardial infarction: the GISSI-3 data 
Heart  2001;86(5):527-532.
BACKGROUND—Atrial fibrillation is the most common supraventricular arrhythmia in patients with acute myocardial infarction. Recent advances in pharmacological treatment of myocardial infarction may have changed the impact of this arrhythmia.
OBJECTIVE—To assess the incidence and prognosis of atrial fibrillation complicating myocardial infarction in a large population of patients receiving optimal treatment, including angiotensin converting enzyme (ACE) inhibitors.
METHODS—Data were derived from the GISSI-3 trial, which included 17 944 patients within the first 24 hours after acute myocardial infarction. Atrial fibrillation was recorded during the hospital stay, and follow up visits were planned at six weeks and six months. Survival of the patients at four years was assessed through census offices.
RESULTS—The incidence of in-hospital atrial fibrillation or flutter was 7.8%. Atrial fibrillation was associated with indicators of a worse prognosis (age > 70 years, female sex, higher Killip class, previous myocardial infarction, treated hypertension, high systolic blood pressure at entry, insulin dependent diabetes, signs or symptoms of heart failure) and with some adverse clinical events (reinfarction, sustained ventricular tachycardia, ventricular fibrillation). After adjustment for other prognostic factors, atrial fibrillation remained an independent predictor of increased in-hospital mortality: 12.6% v 5%, adjusted relative risk (RR) 1.98, 95% confidence interval (CI) 1.67 to 2.34. Data on long term mortality (four years after acute myocardial infarction) confirmed the persistent negative influence of atrial fibrillation (RR 1.78, 95% CI 1.60 to 1.99).
CONCLUSIONS—Atrial fibrillation is an indicator of worse prognosis after acute myocardial infarction, both in the short term and in the long term, even in an unselected population.

Keywords: atrial fibrillation; acute myocardial infarction; prognosis
PMCID: PMC1729969  PMID: 11602545
19.  Targeting ryanodine receptors for anti-arrhythmic therapy 
Acta Pharmacologica Sinica  2011;32(6):749-757.
Antiarrhythmic drugs are a group of pharmaceuticals that suppress or prevent abnormal heart rhythms, which are often associated with substantial morbidity and mortality. Current antiarrhythmic drugs that typically target plasma membrane ion channels have limited clinical success and in some cases have been described as being pro-arrhythmic. However, recent studies suggest that pathological release of calcium (Ca2+) from the sarcoplasmic reticulum via cardiac ryanodine receptors (RyR2) could represent a promising target for antiarrhythmic therapy. Diastolic SR Ca2+ release has been linked to arrhythmogenesis in both the inherited arrhythmia syndrome 'catecholaminergic polymorphic ventricular tachycardia' and acquired forms of heart disease (eg, atrial fibrillation, heart failure). Several classes of pharmaceuticals have been shown to reduce abnormal RyR2 activity and may confer protection against triggered arrhythmias through reduction of SR Ca2+ leak. In this review, we will evaluate the current pharmacological methods for stabilizing RyR2 and suggest treatment modalities based on current evidence of molecular mechanisms.
PMCID: PMC4009959  PMID: 21642946
arrhythmias; atrial fibrillation; calcium; heart failure; ryanodine receptor; sarcoplasmic reticulum
20.  Inflammation and C-Reactive Protein in Atrial Fibrillation: Cause or Effect? 
Texas Heart Institute Journal  2014;41(5):461-468.
Atrial fibrillation is associated with substantial morbidity and mortality rates. The incompletely understood pathogenesis of this cardiac dysrhythmia makes it difficult to improve approaches to primary and secondary prevention. Evidence has accumulated in regard to a relationship between inflammation and atrial fibrillation. Investigators have correlated the dysrhythmia with myocarditis, pericardiotomy, and C-reactive protein levels, suggesting that inflammation causes atrial fibrillation or participates in its onset and continuation. Conversely, other investigators suggest that atrial fibrillation induces an inflammatory response. In this review, we summarize and critically discuss the nature and clinical role of inflammation and C-reactive protein in atrial fibrillation.
PMCID: PMC4189345  PMID: 25425976
Atrial fibrillation/diagnosis/etiology/physiopathology/prevention & control; biological markers/blood; C-reactive protein/analysis/metabolism; disease management; heart conduction system/physiopathology; inflammation/complications/diagnosis/etiology; myocardial revascularization/adverse effects; polymorphism, genetic; primary prevention; risk factors
21.  A pilot study of circulating PPAR-γ receptor protein in elderly patients with atrial fibrillation 
The present study aimed to investigate the relationship between serum peroxisome proliferator-activated receptor-γ (PPAR-γ) protein concentration and inflammatory markers in elderly patients with atrial fibrillation (AF).
Material and methods
We enrolled a total of 73 elderly patients: 45 with AF as the test group and 28 in sinus rhythm as a control group. We assayed serum PPAR-γ receptor protein, high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), and tumour necrosis factor-α (TNF-α). The study protocol and written informed consent were approved by the Ethics Committee of Clinical Research, Peking University First Hospital.
The concentration of PPAR-γ receptor protein was lower in AF patients than that in the control group (p < 0.01), and the concentrations of hs-CRP, IL-6, and TNF-α were higher than those in the control group (all p < 0.01). The PPAR-γ level was negatively correlated with hs-CRP, IL-6, and left atrium diameter (LAD) level (all p < 0.05). On logistic regression analysis, PPAR-γ, hs-CRP, TNF-α and LAD level were associated with AF.
Elderly patients with AF show an inflammatory state and atrial remodeling. The PPAR-γ receptor protein concentration is inversely linked with inflammation in AF. As an important transcription factor regulating inflammatory gene expression, PPAR-γ may take part in the pathogenesis of AF.
PMCID: PMC3400903  PMID: 22852002
atrial fibrillation; peroxisome proliferator-activated receptor-γ; inflammation
22.  Protracted CRP Elevation After Atrial Fibrillation Ablation 
Atrial fibrillation (AF) has been linked to an inflammatory process detected through various biomarkers, including C-Reactive Protein (CRP). Early recurrence of AF within the first three months after curative AF ablation is not felt to reflect success or failure of the procedure. We hypothesized that this early recurrence is due to an inflammatory response to the ablation itself. We therefore sought to evaluate levels of CRP after AF ablation.
We prospectively enrolled subjects undergoing AF ablation. A control group of patients undergoing ablation for supraventricular tachycardia (SVT) was also enrolled. Each patient had CRP drawn on the day of the procedure (prior to ablation) and during their first follow-up (median 49 days, interquartile range [IQR] 37–93) and second follow-up (median 147 days, IQR 141–257) clinic visits. Patient interviews were performed and medical histories reviewed for evidence of recurrent AF prior to the first follow-up.
CRP levels significantly increased from baseline to first follow-up in the AF ablation group (p=0.0017). CRP did not significantly change after SVT ablation (p=0.92). Seventeen (45%) of the AF subjects exhibited recurrence of AF prior to first follow-up. After adjusting for multiple potential confounders, AF ablation patients with recurrent AF prior to their first follow-up had a statistically significant greater odds of having an increase in CRP (OR 21, 95% CI 1.1–417, p=0.045).
AF ablation generates an inflammatory response that persists for several weeks. This inflammation may explain early recurrence of AF after curative ablation.
PMCID: PMC2596767  PMID: 18834466
23.  Disrupted Calcium Release as a Mechanism for Atrial Alternans Associated with Human Atrial Fibrillation 
PLoS Computational Biology  2014;10(12):e1004011.
Atrial fibrillation (AF) is the most common cardiac arrhythmia, but our knowledge of the arrhythmogenic substrate is incomplete. Alternans, the beat-to-beat alternation in the shape of cardiac electrical signals, typically occurs at fast heart rates and leads to arrhythmia. However, atrial alternans have been observed at slower pacing rates in AF patients than in controls, suggesting that increased vulnerability to arrhythmia in AF patients may be due to the proarrythmic influence of alternans at these slower rates. As such, alternans may present a useful therapeutic target for the treatment and prevention of AF, but the mechanism underlying alternans occurrence in AF patients at heart rates near rest is unknown. The goal of this study was to determine how cellular changes that occur in human AF affect the appearance of alternans at heart rates near rest. To achieve this, we developed a computational model of human atrial tissue incorporating electrophysiological remodeling associated with chronic AF (cAF) and performed parameter sensitivity analysis of ionic model parameters to determine which cellular changes led to alternans. Of the 20 parameters tested, only decreasing the ryanodine receptor (RyR) inactivation rate constant (kiCa) produced action potential duration (APD) alternans seen clinically at slower pacing rates. Using single-cell clamps of voltage, fluxes, and state variables, we determined that alternans onset was Ca2+-driven rather than voltage-driven and occurred as a result of decreased RyR inactivation which led to increased steepness of the sarcoplasmic reticulum (SR) Ca2+ release slope. Iterated map analysis revealed that because SR Ca2+ uptake efficiency was much higher in control atrial cells than in cAF cells, drastic reductions in kiCa were required to produce alternans at comparable pacing rates in control atrial cells. These findings suggest that RyR kinetics may play a critical role in altered Ca2+ homeostasis which drives proarrhythmic APD alternans in patients with AF.
Author Summary
Atrial fibrillation is an irregular heart rhythm affecting millions of people worldwide. Effective treatment of this cardiac disorder relies upon our detailed knowledge and understanding of the mechanisms that lead to arrhythmia. Recent clinical observations have suggested that alternans, a phenomenon where the shape of the electrical signal in the heart alternates from beat to beat, may play an important role in this process, but the underlying mechanisms remain unknown. In this study, we use computational models to conduct a detailed examination of the causes and contributors to alternans associated with human atrial fibrillation. We find that in atria remodeled by atrial fibrillation, alternans appears near resting heart rates because several aspects of calcium cycling are disrupted in the atrial cells. In particular, the release and uptake of calcium from the cellular storage compartment, the sarcoplasmic reticulum, becomes imbalanced, leading to alternation in calcium signals from beat to beat. These findings provide important insights into the mechanisms of proarrhythmic alternans in human atrial fibrillation which may be used to develop novel therapeutic targets and treatment strategies in the future.
PMCID: PMC4263367  PMID: 25501557
24.  Class IC antiarrhythmic drug induced atrial flutter: electrocardiographic and electrophysiological findings and their importance for long term outcome after right atrial isthmus ablation 
Heart  2001;85(4):424-429.
OBJECTIVE—To describe the electrocardiographic and electrophysiological findings of new atrial flutter developing in patients taking class IC antiarrhythmic drugs for recurrent atrial fibrillation, and to report the long term results of right atrial isthmus ablation in relation to the ECG pattern of spontaneous atrial flutter.
DESIGN—Retrospective analysis.
SETTING—Tertiary care academic hospital.
PATIENTS—24 consecutive patients with atrial fibrillation (age 54 (12) years; 5 female, 19 male) developing atrial flutter while taking propafenone (n = 12) or flecainide (n = 12).
RESULTS—The ECG was classified as typical (n = 13; 54%) or atypical atrial flutter (n = 8) or coarse atrial fibrillation (n = 3). Counterclockwise atrial flutter was the predominant arrhythmia. Acute success after isthmus ablation was similar in patients with typical (12/13) and atypical (8/8) atrial flutter. After long term follow up (13 (6) months, range 6-26 months), continuation of antiarrhythmic drug treatment appeared to result in better control of recurrences of atrial fibrillation in patients with typical atrial flutter (11/13) than in those with atypical atrial flutter (4/8), but the difference was not significant. Ablation for coarse atrial fibrillation was unsuccessful.
CONCLUSIONS—New atrial flutter developing in patients taking class IC antiarrhythmic drugs for recurrent atrial fibrillation has either typical or atypical flutter wave morphology on ECG. The endocardial activation pattern and the acute results of ablation suggest that the flutter circuit was located in the right atrium and that the isthmus was involved in the re-entry mechanism. There appeared to be better long term control of recurrent atrial fibrillation in patients with typical (85%) as compared with atypical atrial flutter (50%). Patients developing coarse atrial fibrillation may not be candidates for this strategy.

Keywords: atrial flutter; antiarrhythmic agents; fibrillation; ablation
PMCID: PMC1729704  PMID: 11250970
25.  Atrial fibrillation (acute onset) 
Clinical Evidence  2011;2011:0210.
Acute atrial fibrillation is rapid, irregular, and chaotic atrial activity of less than 48 hours' duration. Risk factors for acute atrial fibrillation include increasing age, cardiovascular disease, alcohol, diabetes, and lung disease. Acute atrial fibrillation increases the risk of stroke and heart failure. The condition resolves spontaneously within 24 to 48 hours in over 50% of people; however, many people will require interventions to control heart rate or restore sinus rhythm.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions to prevent embolism, for conversion to sinus rhythm, and to control heart rate in people with recent-onset atrial fibrillation (within 7 days) who are haemodynamically stable? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
We found 30 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
In this systematic review we present information relating to the effectiveness and safety of the following interventions: amiodarone, antithrombotic treatment before cardioversion, digoxin, diltiazem, direct current cardioversion, flecainide, propafenone, quinidine, sotalol, timolol, and verapamil.
Key Points
Acute atrial fibrillation is rapid, irregular, and chaotic atrial activity of less than 48 hours' duration. It resolves spontaneously within 24 to 48 hours in over 50% of people. In this review we have included studies on patients with onset up to 7 days previously. Risk factors for acute atrial fibrillation include increasing age, CVD, alcohol abuse, diabetes, and lung disease.Acute atrial fibrillation increases the risk of stroke and heart failure.
The consensus is that people with haemodynamically unstable atrial fibrillation should have immediate direct current cardioversion. In people who are haemodynamically stable, we found no studies of adequate quality to show whether direct current cardioversion increases reversion to sinus rhythm. There is consensus that antithrombotic treatment with heparin should be given before cardioversion to reduce the risk of embolism in people who are haemodynamically stable, but we found no studies to show whether this is beneficial.
Oral or intravenous flecainide, propafenone, or amiodarone increase the likelihood of reversion to sinus rhythm compared with placebo in people with haemodynamically stable acute atrial fibrillation.
CAUTION: Flecainide and propafenone should not be used in people with ischaemic heart disease as they can cause (life-threatening) arrhythmias.
We don't know whether quinidine or sotalol increase reversion to sinus rhythm in people with haemodynamically stable atrial fibrillation, as few adequate trials have been conducted. Digoxin does not seem to increase reversion to sinus rhythm compared with placebo. We don't know whether verapamil increases reversion to sinus rhythm compared with placebo.
Treatment with digoxin may control heart rate in people with haemodynamically stable atrial fibrillation, despite its being unlikely to restore sinus rhythm. We don't know whether diltiazem, timolol, and verapamil are effective at controlling heart rate, but they are unlikely to restore sinus rhythm. No one drug has been shown to be more effective at controlling heart rate. However, intravenous bolus amiodarone is more effective than digoxin. Verapamil may cause hypotension. We don't know whether sotalol can control heart rate in people with acute atrial fibrillation who are haemodynamically stable, but it may cause arrhythmias at high doses.
PMCID: PMC3275309  PMID: 21718559

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