More on the "lying"or at best really stupid electronic medical record

My medical record at a well known medical center -which shall remain nameless-has labelled me as having atrial fibrillation and it seems to be written in indelible electronic ink refractory to my attempts to erase it.

It came about because of two computers conspiring  together. The first was the computer inside of my pace maker.Its algorithm to detect atrial fibrillation detected signals which were interpreted at "AT/AF", meaning atrial tachycardia/ atrial fibrillation. It was a false positive  , tricked by a Pacemaker phenomenon called far field sensing. This occur when the sensing lead in one cardiac chamber senses activity in the other chamber and miscounts it. Ultimately the Medtronic tech recognized it and adjusted the atrial lead sensitivity so that the double counting would not occur. Problem fixed but..

The second computer, my electronic medical record (EMR) latched on to the "diagnosis of atrial fibrillation and will not let go. I have written my "patient portal" with a full explanation indicating that my EP cardiologist concurred.

Recently, I met with my new primary care internist who is attached to the same computer system and we discussed my blood pressure, my pacemaker and no mention was made of AF.He never said the words atrial fibrillation.I gave him two of my old EKGs which did not show atrial fibrillation . Yet when he gave me a copy of my patient visit summary my current health issues were said to be 1.pacemaker 2.atrial fibrillation.

Did the computer write the second diagnosis on its own. Did the doc see it, did he even read what was printed out? I cannot believe he even saw it. I cannot believe a board certified internist of over 25 years experience would not have asked why was I not taking an anticoagulant as my CHADS2-VASc score of 3 would warrant anticoagulation according to all guidelines.In the days of the paper medical record can one imagine an internist handing a patient a report that said he had atrial fibrillation when he was aware of no evidence that he in fact had AF?

Of perhaps less significance, my printout also listed a physician who I had never seen, never heard of before and apparently is a pediatrician not even affiliated with the hospital.

The computer systems with which physicians try to make "meaningful use" were  designed to assist coding and quality reporting,have little to do with  improving patient care and often have the opposite effect and not infrequently are harmful and at least sometimes seem invulnerable to correction by the patient.

How do patients with atrial fibrillation do when not treated with anticoagulants?

Clinical guidelines and conventional medical wisdom all recommend oral anticoagulation (OAC) for patients with atrial fibrillation who are determined to have an increased risk of stroke according to widely used risk indicator tools. Usually the CHA2DS2-VASc risk assessment tool is used and for   patients with a risk score of greater  than  or equal 2 ,OAC is generally recommended.European and Canadian and U.S.  guidelines differ  in regard to recommendations for risk score of 1. For risk categories 0 and 1 there are no randomized clinical trials demonstrating the net clinical benefit of OAC . Those recommendations are driven simply observational trials and  expert option seems to vary geographically.


 According to a 2016 article by Overvad et al :. "current guidelines discrepancies also reflect the fact that the level of stroke risk among men with a score of 1 and women with a score of 2 is on the borderline of where the impact of anticoagulation treatment shifts from beneficial to harmful."( ref 2)
In simple terms-it is a close call. 

 The clinical issue is the trade off between OAC reduction in ischemic stroke risk and the risk of serious bleeding complications the worse of which is intracranial hemorrhage. Importantly and perhaps ironically the higher the CHA2DS2 score , the higher the risk of major hemorrhage. Analysis (ref 1)  of over 44 thousand in the Military Health System patients with non-valvular atrial fibrillation over a 2.5 year period treated with rivaroxaban demonstrated a strong relationship between the risk score and the risk of major bleeding.So the patients at the highest risk of stroke are  the same people who have the highest risk of major hemorrhage.,especially those with the high vascular disease components of the risk score score.The data indicated that while the risk of hemorrhage increases with the risk score the stroke risk increases more so it is generally believed that there is net clinical benefit even at the highest hemorrhage risk levels.

Hess et al published a study focused on data from a outcomes registry for patients with atrial fibrillation in part to determine if patients with afib were being treated according to  accepted guidelines.(American Journal of Medicine 2016 , Nov 22).See here for link to abstract.

There were 9555 patients with afib and 1846 of those were not being treated with OAC even though they had a CHA2DS2-Vasc score greater than 2.

Interestingly the stroke risk in those not treated compared with those who were treated was not statistically significantly elevated.. The adjusted HR was 1.18 with a 95% Confidence interval of 0.91--1.54.

It is often stated that risk of stroke in afib patients is increased by a factor of 3- 5 (based on Framingham data) and that OAC may decrease that risk by 60% or more.Yet in this large data base OAC did not seem to bring about that degree of benefit. However, absence of OAC was associated with a statistically significant increase in risk of death. ( HR 1..22 (1.05--1.41).

So how do patients do  with atrial fibrillation  not treated  with OAC ? Based on this observational data- better than you might expect. On the other hand if we look at older data from a randomized clinical trial published in 1991 ( SPAF trial) the stroke risk per year for the placebo arm was 6.3% versus the warfarin  arm which was 2.3% and surprisingly the aspirin  arm was 3.6%.Later studies never confirmed the value of aspirin  in stroke prevention in afib but the SPAF numbers conform with the broad brush comments that the risk of stroke is about  three to five times and the risk reduction from OAC may be in the 40-60% range. The BAFTA study not only failed to show the value of aspirin in stroke reduction in afib patients but demonstrated that in older patient s ( over 75 years of age) aspirin caused a similar risk of intracranial bleeding as warfarin.


So the question remains why did the patients without treatment do so well in Hess's data or maybe the real life treatment of afib with OAC is much less impressive than it  is in randomized clinical trials or maybe there are so many potential biases in observational big data exercises  that solid "take home" messages are difficult to find and/or rely upon..

And things get even murkier or perhaps more clear when Dr. H. Kamel  discusses challenges to the notion that the risk of stroke in afib is in fact  solely due to   thrombi in the left atrium and proposes  that things are much more complicated including the notion that at least sometimes a stroke can cause an atrial thrombus. It is well known that stroke can precede the onset of afib.He and coauthors discuss a new model for stroke and afib in which both afib and emboli are downstream  effect of abnormal atria substrate (an atrial myopathy).This model might explain why stroke  risk is not eliminated by rhythm control strategies and why stroke can predate afib and generally the poor temporal relationship that exist between afib onset and stroke and why some reports do not show a dose response relationship between afib duration and stroke(.However, other reports such as the TRENDS data do show  dose response relationship .)

Drs Akar and Marieb make similar comments and say in part "...AF may simply be a marker of underlying conditions that causes stroke as opposed to an active participant in the stroke  pathogenesis"

 In short, they are saying  there   is reason to believe there is much  more to it than simply that afib cause thrombi in the left atrium and the clot embolizes  to the brain. although no one is saying that does not happen (" Atrial Fibrillation and Thrombogenesis:Innocent bystander or guilty accomplice", JACEEP 2015, 2015;1(13) p 218.

Another article  (ref 3) tends to support the notion that there is more to afib and stroke than the century old model that the former simply  leads to the later.Boriani published a study evaluating the risk of stroke in men and women with pacemakers and found that atrial fibrillation of at least five minutes occurred in 44% of 2398 patients and that a higher atrial fibrillation burden was not associated with a higher stroke risk. Confirming other studies this analysis found the stroke and TIA risk in women was twice that on men.

 references

1.Peacock,WF et al CHA2DS2-VASc Scores and Major Bleeding in Patients with Nonvalvular Atrial Fibrillation Who are Receiving Rivaroxaban.Annals of Emergency Medicine, published online, accessed  12/4/16

2. Overvad TF et al. "Treatment thresholds for stroke prevention in atrial fibrillation :observations on the CHA2DS2-VASC Score" Euro Heart Journal-Cardiovascular pharmacology Published on line August 2016

3. Boriani, G et al " The increased risk of stroke/transient ischemic attack in women with a cardiac implantable electronic device is not associated with a higher atrial fibrillation burden. Europace: 2016, dec 28.

"Truth is much too complicated to allow anything but approximations" John Von Neumann 


Addendum: 12/22/2016. Unfortunately I became aware of the 2016 Circulation article by GR Quinn et al after the above commentary was published.  That very important article  provides good reason to question the dogma that the CHA2DS2-VASc score translate to fixed stoke rate. It is generally accepted that if a person's stroke rate is estimated to be 1-2% per year then treatment with an OAC offers a a net clinical benefit and that the risk score clearly relates to a quantitative stroke risk, e.g. a CHA2DS2-VASC score of 1 means the person has a risk of about 1 % per year and a score of 2 indicates a risk of 2%. 
 However, analysis of 34 studies of patients not treated with anticoagulants demonstrated that the stroke rate varies widely in various cohorts. For example, with a risk score  of 2, 27% of the cohorts reported a stroke risk of less than 1% and 33% reported stroke risk greater than 2% per year. So the correlation between risk score and stroke risk varies with the cohort studied.The numbers from the Northern European studies formed the basis of the alleged relationship between the CHA2DS2-VASc score and annual stroke risk and the North American Cohort analyses indicate significantly lower ( about 1/3 of the European rate) stroke rates for untreated AF.
 Quoting from the authors conclusions: " The majority of cohorts did not observe stroke rate that would indicate a clear expected net clinical benefit for anticoagulating AF patients with a CHA2DS2-VASc score of 1 or 2."
  

The old and the new paroxysmal atrial fibrillation- new questions raised by new technology

Paroxysmal atrial fibrillation (PAF) has typically been diagnosed in a patient with cardiac symptoms seeking care for   episodic symptoms  which ultimately- by either  office EKG or some monitoring device shown to have atrial fibrillation ( AF).

The medical literature is conflicted in regard to the risk of PAF versus permanent or persistent AF. It is not surprising that expert opinion in that regard is conflicted as well, While opinions may differ current US guidelines recommend oral anticoagulation( OAC) for PAF patients based on their risk assessment score. Usually the CHA2DS2-VASc score is used and a value of 2  or more would lead to recommendation of OAC.In other words. the same recommendation for persistent or permanent AF applies to PAF.Note this refers to what I will call "clinical PAF"  subclinical PAF (SCAF) has become an  clinical management  issue as huge amounts of data has become available from the rate and rhythm recordings of pace maker patients.

A 2014 report by Vanassche which analyzed data from 6563 AF patients not treated with oral anticoagulants (OAC) determined that stroke risk in permanent AF was roughly twice that of PAF.
They reported that  AF pattern ( PAF versus non PAF )  was the second strongest predictor of stroke second only to previous history of stroke. If their data are  conclusive in this regard that does not necessarily mean that OAC  not be used . Even though the risk of stroke is lower, still the stroke risk may overwhelm the risk of  serious bleeding  from OAC leading  to a positive clinical benefit or trade-off and a reasonable recommendation for OAC.

A new and expanding data base has emerged from the experience of pacemaker (PM) patients. The ability of PMs to store and analyze large amounts of rate and rhythm data has lead to the realization that typically asymptomatic bursts or runs of subclinical atrial fibrillation  are very common in PM patients, values from several studies reporting  an incidence of 30-55%.

The questions arises-is the risk of  these SCAFs equivalent to that of the classically diagnosed PAF. Further, is there value to quantitative the SCAF perhaps in terms of duration or frequency . The literature has adopted the concept of atrial fibrillation burden ( AFB) and several studies have attempted to determine if there is a correlation between PAF ( as in minutes per day) and stroke risk). More importantly  is it possible to find an AFB threshold associated with a clinically important risk of stroke or how much SCAF is necessary to warrant OAC.

In general ,reports  of these attempts  indicate  there is a correlation between PM detected  AFB and stroke risk , however the reports differ in regards to  finding  burden levels that demonstrate an increase hazard ratio- usually in the range of 2 or under (and  sometimes statistically significant and sometimes not). The small number of events of interest-stroke and peripheral emboli- in various duration based subgroups lead to wide confidence intervals and HR values that fluctuate as burden levels increase-sometime being statistically significant at lower levels but  surprisingly not at higher which was the case, for example in the SOS-AF project.

Some of the of  AF burden levels at which a increased hazard ratio (HR) for stroke or other embolic events) have been reported from various studies are shown here: ( note with one exception runs of SCAF less than five or six minutes-depending of the particular study-are not analyzed.) So to date with one recent  exception there is essentially no data on the risk of SCAF events of less than 5 minutes

ASSERT six minutes
TRENDS -5.5 hours
SOS AF - one hour
CARELINK/VA 5.5 hours

These studies were reviewed by Chen-Scarabelli et al in 2015 and also by Camm et al in 2016 and they reached opposing conclusions. Camm's review concluded that data were insufficient to recommend OAC in SCAF while Chen-Scarabelli  and Kenneth  Ellenbogen said that OAC should be initiated on the basis of stroke  risk assessment using the CHA2DS2-VASc score regardless of the mechanism of detection of the atrial fibrillation.

 In the observational TRENDS project, data from 3035 PM patients were analyzed. Those characterized as a "low" AF burden (AFB) ( low is  defined as less than or equal to 5.5 hours on an single day) gave a risk estimate similar to having zero  AF.  An AF burden of greater than 5.5 hours doubled the thromboembolism risk.

Also a sub-study of the TRENDS project showed that 29 of the 40 patients who had a embolic event had no AF detected in the 30 day period  preceding the event suggesting that the relationship between AF and stroke may not be a simple as the former invariably causing the latter.  


As Glotzer and his co-authors in the TRENDS project emphasized, the available data-even combining data from several studies as  was done in the SOS AF project- do not necessarily make it possible define a "safe "AFB that confers no risk greater than observed with no AFB. The event rates ( i.e stroke and other embolism events) are low in all of these studies, lower than predicted based on a widely accepted 4% per year rate in atrial fibrillation patients) and this  limits statistical precision and produces wide confidence limits as well as limits the number of threshold ranges that can be analyzed with the expectation of statistical significance.

 Small numbers in each  duration subgroup lead to results that sometimes seem counter intuitive- for example : In the SOS AF a statistically increased HR was found for the five minutes cutoff and the one hour cutoff but not the six hours or 12 hour or 23 hour. A long duration would have been thought to impair a higher HR.

The RATE RHYTHM study was designed to determine if there is a definable burden of AFIB that will be predictive of thromboembolic events. At this writing I have only access to an abstract of the findings. I believe that the investigators found there were no risk for bursts of atrial fibrillation less than 20 seconds. . 


The data indicate  that the risk of PM detected SCAF is lower than the clinically detected classical PAF but there is a  correlation between SCAF and stroke risk and SCAF is an independent risk factor for or  predictor of stroke. ( An independent risk factor is not necessarily causal- see here) .  Of course  the question is with the variable  coarse- grain risk values derived from any of  these studies is anticoagulation for these SCAF warranted and in that regard there is not unanimity of expert opinion.

Guidelines ,with the exception of the Canadian Cardiovascular Society guidelines, do not recommend  specifically to give OAC for device-detected AF. The Canadians suggested that OAC could be given to patients 64 and older with a CHADS score one or more who have SCAF episodes lasting a day or more  or for those with a shorter interval if they have recently had a cryptogenic stroke. ( ref 1)

A number of researchers have argued that randomized trials are needed to determine the clinical  benefit for OAC in PM detected   PAF. Two such trials are now in progress The ARTESIA project aims to enroll 4000 patients and randomize patients with at least one episode equal to or greater than 6 minutes of AF  to either apixaban or aspirin. 2019 is the projected end date.  Note even after this trial is complete there will still not be any RCT level evidence about what to do with patients  with AF burdens of less than 6 minutes per day.  The NOAH project will compare edoxaban or aspirin/placebo in patients over 65 years of age with one additional CHA2DS2VASc risk factor.

RCTs do seem to be needed, I believe we have learned all we can from the type the observational trials mentioned above and expert opinion differs regarding the management of SCAAF detected by PM recordings. An optimistic view is that these 2 RCTS may allow recommendations regarding OAC and device detected to move past battling expert opinion and trying to tease clinical truth from conflicting observational data.


1.Verma A et al 2014 Focused update of the Canadian Cardiovascular  Society Guidelines for the Management of Atrial fibrillation. Can J Cardiol. 2014 30 114-1130

update 12/16/16 A paragraph inadvertently omitted was added. 
addendum 1/18/17 and 2/4/17  several minor changes made in syntax and typos corrected.

More on subclinical atrial fibrillation (SCAF) and what to do when we find it

A 2014 study-Crystal AF- examined patients with cryptogenic stroke using a implantable cardiac monitor and reported that over a three year period 30% had episodes of atrial fibrillation(AF) lasting 30 seconds on longer. This study likely energized the effort to implant cardiac monitoring devices and to anticoagulate those patients found to have atrial fibrillation (AF).A more recent study might serve to cast some doubt on that practice.

The study,Reveal AF,studied 394 patients using an implantable cardiac monitor with no history of AF but who  were considered high risk for stroke  based on the CHADS2 score.At the end of 18 months 29.3 % of the patients had episodes of AF of six minutes or more and at 30 months 40% had AF. Further, 12% had AF durations of 6 hours or more.

 So we know that  AF is common in 1) patients with history of stroke and no obvious  cause  2) patients classified as high risk using the CHADS2 scoring system and 3) patients with pacemakers.

Should all patients with cryptogenic stroke shown to have AF by a implantable  device receive oral anticoagulation? That seems to be common clinical practice but I am aware of no clinical trials showing the efficacy and safety of that approach. Should all patients with a CHAD2 score similar to that used in the Reveal AF study receive anticoagulation? ( in the trial 56% of the patients were actually prescribed OAC by their private physicians). Should all patients with pacemakers (PMs )with SCAF ( above some level of AF burden) receive OAC?

There are at least 2 randomized clinical trials underway which are designed to determine the effects of OAC on patients  with subclinical AF (SCAF) as determined by data collected on patients with pace makers.

In addition a recent study ( see here) and analysis casts more than a little doubt on the validity of the various CHADS risk determination systems.

The prolific EP cardiologist author and blogger John Mandrola  puts it this way in his discussion of the Reveal AF  " ..if the average high risk older person has the same amount of short-duration AF as a person who just had a stroke how does this ( long term monitoring) help decide on therapy?"  Point well taken. Actually at the end of 30 months in Reveal AF trial 40% had SCAF versus 30% with SCAF and 36 months.Taken at face value could nt  one claim that AF is protective? I think not but still that just amplifies Mandrola's point.

Dr. H Kamel and associates have published an excellent commentary and review (3) of the mechanisms of stroke and atrial fibrillation which along with the Reveal AF trial results might slow down enthusiasm  for implanting devices in all patients with cryptogenic stroke and the increasing call for more screening for the detection of afib.

1)Sanna, T Cryptogenic stroke and Underlying atrial fibrillation NEJM 2014: 370, 2478


2) Reiffel, JA presented at Heart rhythm Society Meeting, May 10-13, 2017.

3)Kamel, H et al Atrial fibrillation and mechanisms of stroke.Time for a new model.Stroke 2016 47 895-900.


Additions made Aug 2,2017 .

Still more data linking endurance exercise and atrial fibrillation

A number of  studies have shown a relationship between long time endurance exercise and increased  risk of atrial arrhythmias. and there is a growing consensus that this is a causal relationship. As a long time marathoner I don't welcome the news but I cannot no longer ignore it and have to worry about it. 

One of Bradford Hill's classic  criteria for assessing if a relationship between variables is causal is the dose response principle also referred to as biological gradient. This simply means that a larger dose or exposure should lead to a greater incidence of the effects.Myrstar and co authors  have published a study demonstrating a dose response relationship between years of endurance type activity and risk of atrial fibrillation and atrial flutter. In this article Myrstad and co-authors reported an odds ratio of development of atrial fibrillation of 1.16 per ten years of endurance exercise. (confidence interval 1.06--1.29).

 In another study from Norway the same lead author reported in regard to  a cohort study  of 2626 long time cross-country skiers and 2326 people from the general population. He found a prevalence of 12.3%  of self reported atrial fibrillation (AF) in the skiers versus 5% in the non-skiers. Of those, 64% continued to engage in regular endurance exercise after the onset of AF.Interestingly some 1/3 of AF patients did not use oral anticoagulants even though they had a CHA2DS-VASc scored of greater than or equal to 2,a score that current conventional medical wisdom believes anti coagulation is needed to decrease stroke risk.

 To get some approximation of context consider the ATRIA study (Go,A, et al, JAMA 2001:285:2370) which reported a prevalence of 0.1% in those younger than 60 years,3.8 % age 60 and older, and 9 % age 90 and older More extensive data can be found here in the discussion of a pooled analysis of five randomized clinical trials in which the relative risk of a fib increased 1.4 by decade ( C.I. 1.1 to 1.8). Some older runners would like to take those factoids to suggest that getting old is even more risky than running.

 An enlarged left atrium  has thought to be the  likely link between atrial fibrillation and hypertension.Some long term endurance athletes have been demonstrated to have larger left atria and while it can be considered a "physiological" adaption to increased exercise and periods of increased cardiac output the increased surface per se  may predispose to atrial rhythm mischief.Is the enlarged athletes' left atrium less pathological than that of the long term hypertensive patient?


Most of this is a "dog bites man" or duhh story but I continue to be impressed with how easily one can effortlessly find medical articles even in Journals that are not that widely read. The second article mentioned above was first published  in the official journal of the German Cardiac Society, one that I do not typically read. The ease with which you can follow current journal articles on a number of topics of your choosing on the free app QxMD is amazing particularly for someone who grew up wrestling the unwieldy Index Medicus tomes and wandering the medical library book stacks to find the volume of interest missing.You can easily learn more in an hour with that app and your tablet than you could in all day at the medical library.


addendum:10/1/15 some editorial flourishes made.

addendum: 12/2/2016 Another article presented some  data on dose response relationship.Anderson and co workers from Sweden compered the risk of atrial fib and brady rhythm problems in a large cohort of cross-country skiers. Those who took part in five or more events were compared with those who only completed on one  90km race and found a hazard ratio of 1.3 (1.08--1.58) for those who raced more. Though a increased risk of atrial fibrillation gets most of the attention , this study  showed a greater risk of bradyarrhythmias with a HR.of 1.85 , though not statistically  significant with a CI of 0.97--3.54.The quantification of the "dose" is crude as well but data are suggestive.
(Anderson, K et al., Risk of arrhythmias in 52 775 long-distance cross country Skiers: a cohort study.
European Heart Journal 2013 34: 3264 )

Why a non-cardiologist thinks generally ablation is bettter than medication for rhythm control

Of course the teaser tittle is misleading.You should ask "better for what".Remember the old auto ad that claimed Fords (or some brand) are better,again better than what and for what.

A  better,more focused claim is that ablation is better than drugs to convert atrial fibrillation to normal sinus rhythm.That issue arises only after the decision of rate versus rhythm control has been made.There is convincing evidence to that point that ablation works better. There is also general agreement that patients feel better with a sinus rhythm than when their atria are fibrillating.Atrial fibrillation is a bad method of running a cardiac pump.

What has not been proven with randomized clinical trials is that ablation results in longer lives and fewer strokes.

The recently presented CABANA trial (https://www.acc.org/latest-in-cardiology/clinical-trials/2018/05/10/15/57/cabana) was long awaited and was hoped to answer that question

This was a large (n=2204),multicenter trial  with five year followup comparing standard AF ablation procedure with either rhythm or rate control medication.When the data were analyzed by the venerable,preferred, orthodox method of analysis ( intention-to-treat or ITT) there was no difference in the combined end points of death,disabling stroke,or cardiac arrest nor was there for each component of the combined end point.

ITT is also referred to as "once randomized always analyzed". If 1,000 were assigned to medication and another 1000 assigned to ablation, all of the Medication group would be analyzed according to the group to which they  were assigned even if they switched over to the ablation group. This method is ,according to standard epidemiologic-statistical dogma, is the only analytic approach which will preserved the "integrity of the randomization process." Randomization is done in the first place to control for the effect of known and unknown variables so that the two groups are balanced in regard to prognostic variables. ITT has been called the de facto standard and it is "conservative", i.e it minimizes Type I error,  it is less likely to show a difference when there is no difference. In criticism of ITT one could say it is too conservative and more susceptible to Type II .

Per protocol analysis (PPA) compares treatment groups that include only those who completed the treatment as originally allocated.Whereas ITT makes the two treatments look similar PPA is more able to how differences.

When PPA was applied to the CABANA data there was demonstrated a decrease in mortality in the ablation group.So there are dueling conclusions based on the method of analysis.(1)

My argument is that regardless of there being no difference in mortality (or maybe there is a difference favoring ablation depending of what analysis you prefer) ablation works better to decrease atrial fibrillation and people feel better without AF and the procedure is safe. It is safe according to either way  you analyze CABANA and we already knew it was safe. The extensive data from Cleveland Clinic  (2) makes that clear. So you do not have to believe that ablation save lives or decreases strokes to favor ablation over rhythm control medication, but of course ablation is not for everyone.

After the data were presented the predictable flurry of spin emerged touting the results  of the PPA and of the "as treated "data.But the EP folks did not really need an alternative analysis to continue with business as usual as ablation is safe,it works better and when successful in decreasing or eliminating the atrial fibrillation "burden" there is better quality of life.

This is certainty not a recommendation to treat everyone with af with ablation but rather an argument in favor of ablation over medication for rhythm control.For  many patients for various clinical reasons, rate control may be the better choice and  a trial of rhythm control meds before ablation is a reasonable and common approach.

1) "...a man hears what he wants to hear and disregards the rest".The Boxer, Simon  and Garfunkel.1982

2)Rehman,KA Life-threatening complications of atrial fibrillation ablation. 16 year experience in a large tertiary care cohort. JACC,March2019, vol 5 no. 3, p 284
(fifteen year period,10,278 patients, no deaths, 100 life threatening complications (mainly pericardial effusions and stroke),no aorto-esophageal fistulas,

Addendum: 10/30/19 This article from the Nov.2019, Journal of American College of Cardiology by Cheng et al presents data suggesting that the Cleveland Clinic experience may not be universal.
http://www.onlinejacc.org/content/74/18/2254?download=true

Mayo study: higher cardiorespiratory fitness associated with lower risk of atrial fibrillation

Data and analysis continues to address the issue of exercise level and risk of atrial fibrillation (AF)-sometimes referred to as the U-shaped curve controversy.

Hussain et al (1) published a follow-up study on 14,094 selected subjects who had been referred to Mayo Clinic for exercise stress testing. These were from a much larger group from whom those with a history of heart failure, atrial fibrillation or flutter or stroke were excluded.The average follow-up was 14 years and the outcomes of interest were incident atrial fibrillation ,stroke and death.
They divided the subjects into 4 groups based on functional cardiorespiratory capacity as estimated by their performance on the Bruce protocol stress test.

Those subjects in the highest exercise performance category showed no increase in the risk for AF.

The authors concluded:

"...better cardiorespiratory fitness is associated with lower risk of incident AF, stroke and mortality. Similarly risk of stroke and mortality in patients with AF is also inversely associated with cardiorespiratory fitness."

They also commented that the reduction in these risks with increasing exercise capacity  "may be a direct physiological effect of exercise and physical activity or a consequence of a lower burden of cardiovascular risk factors" I would add "or both".

This is  another coarse grain study which will not settle the U shaped curve argument.I think often these "controversies " just dwindle away rather than get settled. The etiology of AF and stroke with AF involves a complex array of numerous possible  and possibly interacting input variables and here we look at the effect of  only one such variable ( exercise capacity-as a surrogate for exercise level) on the outcome (s) but at least  long time endurance exercisers may find some solace here. Critics can justifiably point out that a number of potentially confounding variables were not available  for analysis including, smoking history,alcohol use,and actual exercise habits.

Again quoting  Simon (2) ".. a man hears what he wants to hear and disregards the rest"





1) Hussain,N Impact of cardiorespiratory fitness on frequency of atrial fibrillation , stroke,and all cause mortality. AJC Jan 1, 2018. vol 121 issue 1, p 41-49

2) Simon, P .Lyrics from the song ,The Boxer, 1969


H/T "notes from DR RW"

Exercise level ,cardiovascular risk reduction and risk of atrial fibrillation

 Six years ago  after I had recovered from my pacemaker implantation and the subsequent complications  (pulmonary emboli and pocket hematoma)  I mentioned to my EP cardiologist that I believed that I could run a half marathon. I had abandoned thoughts of completing a full marathon  because for  the proceeding two years I had barely finished in under six hour which was the cut off time to be officially counted as a finisher. for the full marathon.

The EP doc said that is not a good idea and when asked why he mentioned the risk of atrial fibrillation. I thought he was wrong but let the mater drop. I did not doubt that there is a relationship between running and AF but felt sure that the level of exercise sufficient to train for a half marathon was not in the range where there would be worry about AF.

The irony of recently seeing the EP doc's picture posted by him on a social medium site showing him with the half marathon medal along with his finishing time  did not go unnoticed. 

This is a good time to review the current recommendation for exercise to reduce cardiovascular risk,at what level of exercise  does it becomes too much or a good thing,and at what level does there appear to be an increased risk of atrial fibrillation. 

Currently the widely accepted view  and the WHO recommendation is that as a minimum one should exercise at a  level of 8 met hours per week.This is equivalent to 1/2 hr of moderate exercise for five days a week. Moderate is defined at a 3-6 Met level.8 met hours per week can also be achieved by vigorous exercise ( defined at greater then 7 mets) for 1.25 hours per day for five days  per week.

8 met hours per week is good but it is widely believed that at least a bit more is better, for example exercise at twice the minimum level would be better in term of cardiovascular risk reduction.This would be exercising at a moderate intensity for one hour a day for five days a week. 

So it seems in terms of cardiovascular risk reduction more is better but there must be limits to that.Is there a level of exercise beyond which there is no further improvement in risk reduction?

Eisvogel's data analysis suggest that that level is around 41 met hours per week. That is five times the minimum or 2.5 hours of moderate exercise per day five times a week . Interestingly the risk reduction exercise volume curve flattens out at a much lower level for vigorous  exercise, at 11 Met hrs per week according to Eisjvogels analysis data from Wen and from Aren.    

At what level of exercise can we expect an increased risk of atrial fibrillation?

Data from Ricci 2018 suggests that level may be about 55 met hours per week or 7 times the minimum recommended dose which would be 3.5 hr moderate exercise per day five times a week 

The level of exercise sufficient to train for a half marathon is definitely less than the estimated threshold for increased risk of atrial fibrillation. Check out any of the numerous half marathon training program and you will see the volume suggested is much less than 7 times the minimal WHO recommended exercise level.

 

What is the evidence that prolonged endurance execise damages the conduction system of the heart.

In 1985, RJ Northcutt studied 20 males endurance athletes that were recruited from a Scottish Harrier's club. All were  older than 45 years and ran for 25 miles per week  or more. Stress testing and 48 hour Holter type monitoring were done.. He found that 9 had heart  rates less than 35 beats per minutes,6 had a prolonged PR interval, 4 had Mobitz type ii heart block and three with complete heart block one of whom had a pacemaker implanted. With exercise all of the various blocks disappeared.

Northcott with co-author Stuart Hood (1,2) studied 19 of the 20 subjects  twelve years later.Two of the group had pacemaker implantation in the interval, one for complete heart block with atrial fibrillation and the other for asystolic intervals up to 15 seconds. None of the others had any "bradycardic problems". 7 of the 20 in 1985 has systolic pauses greater than 2 seconds and 5 of those had none on follow-up. The other two had decreased the intensity of their running. ( not clear from the article if those 2 had pauses or not) Quoting the authors: "Our finding nonetheless suggest that clinically significant bradycardia symptoms are a real but rare potential complication of lifetime endurance exercise."

Baldesberger et al  (3) studied 62 former professional cyclists who had long since (over thirty years) retired from active competition.Two had pacemaker implantation. None had complete RBBB or LBBB and two had EKG pattern of left anterior hemiblock.None had second degree heart block. Six had "sinus node disease which the authors defined as heart rate less than 40 beats per minute.

Andersen's 2013 article (4) is often quoted in support of the argument that there is an increased risk of atrial fibrillation in endurance athletes but it also has data on the risk of  "bradyarrhythmias".The authors studied the records of over 52 thousand participants in a 90 km cross country race in Sweden  (the Vasaloppet). They then compared those who raced more (five or more races) with those who only did one race and compared the faster skiers with the slower. The  Hazard ratio (HR) for atrial fibrillation was 1.2 (0.93-155) while the HR for bradyarrhythmias was 1.85 (0.97--3.54). When comparing those who did more races with those who did only  one they reported a HR for AF of 1.29 (1.04-1.61 and a HR for bradyarrhythmias 2.10 (1.28-3.47).The bradyarrrythmis were mainly type ii heart block but the ICD s codes used did not enable the investigators to separate type 1 and 2 second degree block, an important distinction as Wenckeback is usually considered much less  serious that type 2 second degree block. No mention was made on any one requiring a pacemaker. The rhythm outcome endpoints were obtained from hospital records those race finishers hospitalized with rhythm disturbances.

Comment.This is a very "coarse grain" study.All that was known about the subjects was the race numbers and times ,ICD codes of those hospitalized with arrhythmias, and their age, education and occupational status. How much they exercised outside of this race and other pertinent health factors that could influence the outcome ( BP,diabetes,obesity,height,smoking history,alcohol use) were not known and the various hazard ratios were not all statistically significant. Incidentally,  the HR for atrial fibrillation were much lower than the five times increased risk often quoted for AF in several case control studies.



1.Northcote R. et al. Electrocardiographic findings in male veteran endurance athletes. Br Heart J. 1989, 61: 155-160

2.Hood S and Northcote,R Cardiac Assessment of veteran endurance athletes;a 12 year follow up study. Br J Sport Med, 1999, 33: 239-243

3.Baldesberger S,  et al Sinus Node disease and arrhythmias in the long term followup of former professional cyclists. Eur Hear J. 200829.71-78

4.Andersen K. Risk of arrhythmias in 52,755 long-distance cross country skiers: A cohort study.
Eur Heart J 2013 Dec 34(47) 3624-3631

Is the key to prevention of post ablation atrial fibrillation risk factor modification?

Dr. Rajeen Pathar (1) and co researchers from Adelaide Australia seem to think so.

Hypertension,diabetes,obesity, sleep apnea and smoking are recognized risk factors for the development of atrial fibrillation (AF).The authors reasoned that the same risk factors might predispose to  recurrence of AF after a successful atrial fibrillation ablation and that aggressive risk factor reduction just might decrease the recurrence rate. Their published data (1) tends to support that hypothesis.

A excellent discussion of risk factor importance in AF  by Dr. John Mandrola on Medscape can be found here.



1) Pathak,RK Aggressive risk factor reduction study for atrial fibrillation and implications for the outcome of ablation.The Arrest-AF study. JACC2014 Dec 2;64 (2) 2222

High Intensity interval training and atrial fibrillation

Does high intensity interval training increase the risk of atrial fibrillation (AF) or does it mitigate the AF burden in patients with non permanent AF or both?

An article from Brazil with a 3 year followup suggest that HIIT increases the risk of AF and increases atrial size when compared with moderate exercise in hypertensive patients with chronic renal failure (1). But what about normotensive folks with no renal disease?

A short term trial (2) from Norway comparing HIIT with no exercise in patients with non permanent AF demonstrated less AF burden in the HIIT group.



1)Kiuchi,MG The effects of different activities on atrial fibrillation in patients with hypertension and renal failure. Kidney Research and Clnical Practice. 2017, spet 36 (3) 264

2)Malmo,  Aerobic interval training reduces the burden of atrial fibrillation in the short term  Circ 2016,133 466-473

Is there a U shaped curve relating exercise volume and risk of atrial fibrillation?

 RS Mishima (1) et al reviewed fifteen studies with a total of 1,464,539 individuals from databases of prospective cohort studies to determine the risk of atrial fibrillation (AF) at various exercise levels compared with those individuals who did not meet guideline recommended activity levels.

The current exercise recommendation are at a minimum 450-500 met minutes per week.However, both the US panel and more recently WHO have also said that higher levels, i.e. 2 or 3 times that amount will likely results in greater health benefits. The health benefits are apparent in large epidemiology studies which have demonstrated a curvilinear relationship between exercise volume  and reduction in cardiovascular and all cause mortality.

500 met-minutes per week is equivalent to 2 1/2 hours of moderate (less than 7 METs) exercise or 1 1/4 hours of vigorous exercise. 

While studies of long time athletes have generally shown longer longevity there have also been reports of an apparent increased risk of atrial fibrillation (AF) in endurance athletes particularly those who exercise at levels many times the minimal recommended level .

Mishima found that at exercise levels up to the 2000 met minutes per week level  ( four times the minimal recommended level )there was a decreased risk of AF but "past that point the benefit is less clear".At levels less than 2000 there was a 6 -11% lower risk of AF. At least in this study the upward arm of the U was not found.

 

(1) Mishima,RS  et al Self reported physical activity and atrial fibrillation risk: A systematic Review and Meta-analysis, Heart Rhythm 2020 Dec. 18 

Exercise intensity and risk of atrial fibrillation-a possible gender specific effect

Dr, S. Moharty  et al have presented a meta-analysis on the relationship between exercise level and risk of atrial fibrillation (AF). In what is the largest data analysis to date on this topic they found that  women's risk of AF is reduced at all levels of exercise while in men low and moderate levels of exercise seem protective risk of AF increases at the highest levels.

The term coined by Jim Manzi,( ref 5)  "high causal density", seems appropriate in regard to the etiology of AF. Both inactivity and allegedly " too much exercise" both increase the risk of AF as do aging,obesity, alcohol , hypertension ,  perhaps pericardial fat deposition. and apparently being too tall as well as a number of other putative risk factors.The trick is to figure out what is "too much". Moharty's paper suggests there may be  no "too much" for women ,at least they did not demonstrate a threshold, a claim  which I believe has not been made before.

Reviewing 22 studies (665,750 subjects) they found:

1) In men moderate exercise was protective ,OR .72 , while vigorous exercise increased AF risk with an OR of 3.30 (1.97--4.63). When the authors excluded some small case control studies that had very wide confidence intervals the estimated  risk level was reduced but not eliminated to OR of 2.45 ( 1.1-3.8)


2 )In women moderate exercise was protective with an OR of 0.91 while vigorous exercise seemed even better with an OR of  0.72. So for them more was better without discernable  limit?

Previous studies were conflicting with some showing in men the so called J or U shaped curve while others claimed greater physical activity was associated with a lower risk of AF. i.e. a continuing downsloping risk curve as exercise levels increase. Moharty's study indicates that in women the curve is continuously down sloping and supported the existence of a  U-shaped curve in men.

 Intensity levels of exercise in most (all?) of the studies is at best a "coarse grain" indication. Some  of the exercise levels were based on the subjects' declaration of  their exercise level. In Anderson's study of cross country skier exercise  level was defined as finishing one race versus those who finished 5 or more. In some trials AF was self reported, in others AF was  physician confirmed. Often exercise level reflects duration of exercise per week with no consideration of level of intensity of exercise and  some times quantified by number of endurance events completed usually without consideration of intensity, i.e completion times.

The effect of men's age on risk of AF at various exercise levels is also a consideration. At least it seemed to be in Aizer's paper. This was an analysis of AF in men in a post hoc analysis of the randomized aspirin study as part of the Physicians health study. (Ref 1) The only increased AF  risk was shown in men less than age fifty at the highest self reported exercise level.Suggested non-causal explanations for this include survivor effect and the increased risk of so called lone-AF in otherwise healthy runners  typically occuring in a younger or middle aged man 

Another study presented data that suggested increased risk of AF in younger but not older men. This study  by Nikola Drca from Sweden  was a long term followup of 44,000 men with retrospective estimates of their exercise levels. Those 30 year olds who exercised more than 5 hours per week has an increased RR (1.19) but that was not the case for fifty year olds.  Again, could this be a survivor effect or a high number of so-called "lone parasympathetic AF" in the younger runners? Here we have the relative risk of less than 2, a topic I have ranted about before. An age differential effect was not mentioned in Moharty's paper.

Being the pattern seeking story telling creatures that people are ( ref 4) there are bound to be speculations as to why/how this purported  gender difference could occur. Here is one such such speculation found in a 2011 article by Wilhelm ( ref 3). The authors compared male and female non elite runners and found that the men has subtle changes in diastolic function, slightly large left atria ,changes in heart rate variability and higher BP during exercise, a constellation of findings arguably making male runners, holding training levels constant, more at risk for AF and in fact 4 of the 70 men  studied did have episodes of paroxysmal AF.

How to determine where moderate ( and allegedly therefore benefit) ends and excessive ( and allegedly therefore harm) begins either with group data or for an individual is the problem, one that I suspect is not solvable.



ref
1. Aizer,a et al. Atrial fibrillation is association with different levels of exercise at different ages in men. Heart 2014;100, 1037-1042.

2.Drca, N Atrial fibrillation is associated with different levels of physical activity at different ages in men. Heart, 2014 ,100 (13), p 1037

3. Wilhelm, M et al.Gender Differences of atrial and ventricular remodeling and autonomic tone in non elite athletes.American Coll cardio nov15,2011, vol 108, pg 1489


4."Humans are pattern seeking story telling creatures and are quite adept at telling stories about patterns whether they are true or not.: Usually attributed to  Michael Sherma.The phrase became a theme for Ed Lemer, UCLA economist, in his Book "Macroeconomic Patterns and Stories.


5."Uncontrolled:The surprising payoff of trial-and-error" Jim Manzi ,2012 Basic Books

Thoughts about the epidemiology of exercise volume and health effects

Considerable data exist that  allow reasonable estimates of the volume of exercise required to : 1) decrease cardiovascular disease (CVD) risk 2) decrease the risk of heart failure.

There are considerable coarse grain epidemiologic data that support the notion that regular aerobic exercise will decrease heart attack risk, reduce heart failure risk and reduce all-cause mortality.

The 2018 Physical activity guidelines for Americans recommended at a minimum of  approximately 8 metabolic-equivalent hours per week ( 8 met-hours or 500 met minutes per week.)

The recommendations translate to 150 minutes of moderate exercise (less than 7 Mets) or 75 minutes of vigorous  exercise per week.

 Arem et al ( 1) pooled data from 6 studies (661,137 men and women) and  demonstrated a 20% reduction in mortality among those who exercised at the recommended level with an HR of 0.8 (CI 0.78-0.82) and a 37% lower risk for those who exercised at 2-3 times the minimum level and the maximal benefit at 3-5 times the minimum (  0.61, CI 0.59-0,62)

Further no excess risk was evident even at exercise levels of 10 times the minimum.Here more did seem to be better and no definitive upper limit was apparent.

Wen et al (2) published all cause mortality  data similar  to Arem and  also found that the maximum  CVD mortality risk reduction (45%) ( HR 0.55 CI 0.46-0.66)  at an exercise level of 523 minutes per week, a level roughly 3.5  times the minimum recommendation.


These 2 articles are part of the evidence  regarding the safety of exercise levels higher than the 2018 recommendation. Drs Carl Lavie and James O'keefe have spoken ( TED) and warned  in print about the purported hazards of long bouts of  or too many years of aerobic exercise. In 2015,  perhaps in part reaction to the Arem article and commentary by Dr. Ben Levine,  Lavie and O'Keefe toned down their emphasis on the risk of long distant running.See here for a Runner's World article concerning that issue.

The conclusion to the Arem publication is refreshingly non-ambiguous and prescriptive ,quoting
Arem:

"In regard to mortality health care professionals should encourage inactive adults to perform leisure time physical time activity and do not need to discourage adults who already participate in high-activity levels."


Coarse grain epidemiological evidence strongly support the generally accepted notion that people who exercise none or very little have the highest risk and those who exercise the most have the lowest risk.

In a nutshell-the large coarse grain epidemiologic studies demonstrated that relativity low levels of exercise are better than none and further these studies were not able to demonstrate a upper level of exercise that is more risky than no exercise  though some data indicted that risk reduction at the highest level studied may have reached a plateau.

It is possible that there could  be some harmful or potentially harmful cardiac effects in a small number of long time and/or high volume endurance athletes that would not be detected by large data analysis such as that of Arem and Wen.

 That appears to be the case.

There are  three  conditions that  appear to be more common in high level exercisers. These are 1) atrial fibrillation 2) myocardial fibrosis and 3)coronary calcification.

While the current consensus view is that the relationship between exercise level and all-cause and cardiovascular mortality is curvilinear and not U shaped, the same cannot be said in regard to atrial fibrillation (AF) .

In a  2018 review (4) of the "extreme exercise hypothesis", which states that there is some level of exercise   that results in a harmful effects. Three conditions have been considered in that regard: 1) atrial fibrillation (AF), 2) myocardial fibrosis (detected by MR gadolenium scaning) and 3) acceleration of coronary artery calcification (CAC).


Eijsvogels,Thompson and Franklin (4) concluded in regard to AF :

 "that the relationship between physical activity and incident AF is best summarized by a reverse J shaped curve.Light to moderate  amounts of exercise decrease but large volumes of exercise potentially increasing the risk of AF."

Two of the studies mentioned are their review are  the Henry Ford study and Anderson's cross country ski study .

Even though a study from the Henry Ford Exercise testing project (5) demonstrated that higher cardiorespiratory fitness was associated with a graded reduction in AF (the higher the fitness level the lower the risk of AF),a large cohort study of cross-country skiers showed that those who finished more races and those who raced faster had higher risk of AF than those who did only one race and those who raced at a slower pace. In that study by Anderson  (6) of  52,755 long distance skiers those who finished five or more races versus those who finished only one race had a Hazard ratio for AF  of 1.29 95% CI 1.04-1.61.

The Henry Ford study looked at the relationship between fitness and incident AF and the Anderson study looked at volume of exercise and intensity of exercise and while  fitness and exercise level are correlated they are not the same. After the entry into the study when fitness level was determined there are no data on  the exercise history of the participants at Henry Ford.The Anderson study used number of races and speed of racing to give some broad measure of amount exercise which relates to the questions of exercise volume versus AF risk which is not directly addressed by the Henry Ford study.


The large mega data studies,such as those by Arem and by Wen , lack the statistical power to detect any mortality effect that might occur from AF,CAC and myocardial fibrosis in endurance athletes whose exercise volumes fall at the  extreme right end of the volume axis since there are relatively few subjects exercising at mega volumes.

Even though the relationship between exercise volume and/or intensity and CVD and all cause mortality is not U shaped, the relationship between exercise volume and AF is. 

The issue of the relationship between exercise volume and coronary calcification is less straight foward. Defina's(7) study presents data that high levels of exercise  (3,000 Met min  per week which is about 6 times the minimal 2018 recommendation) are associated with prevalent coronary artery calcification but not  increase in cardiovascular mortality. This apparent paradox might be resolved if it turns out that the increased in runner's calcium scores represent density and not extent of calcium and that the increased density is related to heavy calcified plaques which are made less vulnerable to rupture. 

1)  Arem H   et al. Leisure time activity and mortality: a detailed pooled analysis of the dose-response relationship. JAMA Int Med 2015 Jun 175 (6) 959  (full text is on line)

2)Wen,CP Minimum amount of physical activity for reduced mortality and extended life expectancy .A prospective cohort study. Lancet 2011,378 , 144.

3)Franklin, BA Exercise related acute cardiovascular events and potentially deleterious adaptations
following long term exercise training. Placing the risks into perspective-An update A scientific statement from the American Heart Association. Circ 2020 Feb 26 PMID 32100573

4) Eijsvogels, TMH et al The "extreme exercise hypothesis":Recent findings and cardiovascular health implications." Curr Treat Options cardio med 2018 20  84 

5)Querishi,WT Cardiorespiratory fitness and risk of incident atrial fibrillation:results from the Henry Ford Exercise (FIT) project Circ 2015: 131 ;1827

6) Anderson K et al Risk of arrhythmias in 52,. 755 long distance cross country skiers: a cohort study
 Eur Heart J 2013 Dec 34 (47)36

7) Defina,LF Association of all-cause mortality and cardiovascular mortality with high levels of physical activity and concurrent coronary artery calcification . JAMA Cardiolog 2019, 42 (2) p 174

addendum 7/27/2020 Several changes made in the et to clarify meaning .8/14/20 and again minor changes to clarify meaning. also on 11/19/2020.3/21/21 Minor editing and typo corrections. 5/26/21 still more typos corrected.9/27/21 Comments regarding Defina's data added .

Can "too much" exercise increase risk of atrial fibrillation in men but not women?

Can "excessive " exercise increase the risk of atrial fibrillation in men but somehow spare women hyper-endurance exercisers from that risk? That seems to be what the data show in a 2016 Meta analysis by Mohanty et al published in the June issue of the Journal of Cardiovascular Electrophysiology . See here.

The really fun thing about meta analyses is the frequency with which one can cite conflicting results from various studies. In  another meta analysis Kwok et al found no association with increasing exercise and risk of AF in either sex.  In spite of these conflicting data sets a quasi consensus seems to be that at some level "too much"  exercise predisposes to atrial fibrillation.- determining the level of too much is another matter.  As in  many biological and medical issues it is easier to get a pretty good idea of the direction of the vector than is  ascertaining the magnitude but  sometimes the direction is in dispute as well. 

Inadequate warfarin dosing may be worse than no warfarin in regard to stroke severity

Sokomoto et al (1) investigated the relationship between adequacy of warfarin dosing and severity of stroke in patients with atrial fibrillation. Inadequate was defined as INR less than 2.0 ( less than 1.6 for patients older than 70 years.)

They studied 477 patients with atrial fibrillation (AF) and acute ischemic stroke,53 of whom were undertreated. Inadequate or insufficient dose of warfarin was present in 53 patients and the odds ratio for a severe stroke was 2.7. The numbers in the study were fairly small but  other research had demonstrated a similar pattern.

The authors suggested that underlying pathophysiology or pharmacologic explanation related to the vitamin K dependent anticoagulant protein,Protein C. Protein C levels decrease earlier and with lower doses of warfarin than do the other vitamin K dependent clotting proteins. So early on in warfarin therapy there may be a procoagulant effect. This was why  in the not-too-long ago-days physicians would treat thromboembolism with a few days of heparin along with the warfarin. Too little warfarin may be more of a pro than an anticoagulant medication.

So we have still another reason why the newer oral  direct acting anticoagulants are better than warfarin.




1) Sakamoto, Y et al, Insufficient warfarin therapy is associated with higher severity of stroke than non anticoagulation in patients with atrial fibrillation and acute anterior-circulation Stroke

Circulation Journal Official Journal of the Japanese Circulation society. 2017 December.

20 years from demonstration of AF origin in pulmonary veins to a clincal trial with controversial results

 In 1998, Haissaguerre et al (1) described atrial ectopy or premature atrial beats within the pulmonary veins as the trigger for atrial fibrillation.It seemed to be a particularly attractive theory for the origin of paroxysmal AF (PAF) and has also been proposed as a facilitator of continuation of AF to persistent AF.

This lead to the idea that electrical isolation of the pulmonary veins by burning atrial tissue would keep the ectopy from reaching the rest of the atrium .

And so Pulmonary vein isolation (PVI) really caught on being used for not only PAF but for persistent AF as well  and ever since  the electrophysiology world has awaited a randomized clinical trial answering the question does PVI decrease mortality in atrial fibrillation (AF). It is accepted dogma,backed by considerable experience that PVI is superior to medication treatment in suppressing AF and there is general agreement that restoration of sinus rhythm improves quality of life .A  unanswered question was does PVI decrease risk of death associated with AF.

The Long-awaited CABANA trial was supposed to  or at least hoped would  provide an "Answer" to that question.

When the results of this large (2204 subjects) multi-center,multi national (https://www.acc.org/latest-in-cardiology/clinical-trials/2018/05/10/15/57/cabana) were announced there was no widespread celebration in the EP community. When the data were analyzed according to the standard statistical method used in randomized superiority clinical trials ( namely the "intention to treat" (ITT)) method), there was no difference in the primary outcome which was the combined end points of death,disabling stroke,serious bleeding or cardiac arrest  between the ablation group and the treated with drugs group.Further using ITT analysis there was no significant difference between the two treatment arms for each of the components of the combined end point .

For ablation versus drug therapy :8% vrs. 9.2%  with a hazard ratio of 0.86 (0.65-1.15, ) p=0.3 in regard to the primary endpoint.

There was no difference in death nor in serious stroke between the two arms of the study.

However looking at secondary outcomes- In regard to the category of death or cardiovascular hospitalization  there was a significant difference.

 There is more than one way to analyze data and results of the "per protocol " analysis gave  consolation to the EP cardiologists.

The per protocol analysis showed: a significant decrease in the composite primary end point with ablation  -ablation 7% versus  drug10.9 %  ( HR 0.57 , 0.50 -0.89) and decrease in all cause mortality in the ablation group , 7.5 % for drugs versus 4.4 % for ablation.

So intention to treat analysis indicated that ablation was not superior while per protocol analysis indicated that ablation was superior.Something for everyone.

Though heralded by some as a "game changer", I see nothing in the results changing any game. EP cardiologists are not likely to change their practice in any meaningful way  Just look at the final sentence in the Conclusion slide presented at the American College of Cardiology meeting in August 2018:

"Ablation is an accepted treatment strategy for treating AF with low adverse event rates even in higher risk patients."
.

 Since the study confirms what other data have shown namely that ablation converts AF to sinus rhythm more often than drugs and since sinus rhythm is associated with a better "quality of life" and the results are more durable why would EP docs  change the way they are practicing ?



 1)Haissaguerre M, Jais P, Shah DC, Takahashi A, Hocini M, Quiniou G, Garrigue S, Mouroux AL, Metayer PL, Clementy J. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med.1998;339:659

Does the classsification of atrial fibrillation need to be revised?

I think so , here is why,

 Paroxsymal atrial fibrillation  (APF) is currently defined a a spontaneous remitting episode of atrial fibrillation (AFIB) lasting less than seven days and resolving without intervention. Current U.S. guidelines recommend oral anticoagulation therapy (OAC) for patients with all types of afib based on the stroke risk estimate using  CHA2DS2-Vasc score.

Modern pacemakers (PM) can now record tracings continuously and store them for long periods of time. Several studies have analyzed these tracings and we have learned that commonly PM patients have short runs of Afib,( or more accurately  atrial high rate episodesAHRE-some of which are in fact  not AF)  varying greatly in duration and frequency .

It does not make sense to assume we should have the same prognostic concerns  and therapeutic recommendations   to someone with a episode of afib lasting one minute as to  someone with afib lasting  five days without good data validating that position.

Several studies have attempted to correlate these runs of afib with stroke  rate. With one exception data  (see footnote 1) have not been analyzed if these episodes last less than 5 or 6 minutes.These studies have shown that there is a  coarse grain dose response relationship  between duration or  "burden" of afib and stroke risk. Attempts have been made to determine an afib burden level above which there is a significant increase in risk worth of initiating anticoagulation  and no consensus has been reached.

Various investigations have yielded different burden levels .

The ASSERT trial is widely quoted as showing a two fold increase in stroke risk for episodes of afib last over  6 minutes. See footnote 2 for a discussion of the surprisingly and diametrically  different ways these results were described in medical publications.

Yet another article discussing ASSERT  claims that a fib greater than 24 hours does have increased risk of stroke but for shorter episodes no statistically significant relationship was shown.





footnotes:

 1. The Rate Registry study reported no increase risk of stroke for afib duration episodes less than 10-20 seconds.But what about those episodes between 20 seconds and six minutes?

2. Chin-Scarabellit et al including senior author K. Ellenbogen  describe the ASSERT trial simply as showing  an increased hazard ratio (HR) even though it was not statistically significant while Conn  et al  say "surprisingly,no correlation was found in the ASSERT between AHRE (atrial high rate episodes) and a history of stroke" and speculated that this might have resulted from the fact that the sampling period was only the first 3 months after PM implantation. A third spin on the ARREST was offered by Dr B P Knight (EPLab Digest March 2012) who said that only the  highest quartile of duration ( more than 18 hours) was statistically significant.He did not discuss the problems involving in relying on subgroup analysis to reach a conclusion regarding outcome validity less alone  making therapeutic decisions on that basis. Data is often hard to obtain but sometimes  the real difficulty is in finding agreement as to what the data signify.

People who are more fit have less atrial fibrillation and less strokes if they develop AF

Individuals who are more fit ( have a higher functional aerobic capacity) are less likely to develop atrial fibrillation (AF) and if they do develop AF they are less likely to have a stroke or die.

These are the conclusions from a long , large study from Mayo Clinic.See https://www.ncbi.nlm.nih.gov/pubmed/29221502. ref 1

The final study cohort included 12,043 patients referred for a treadmill exercise test and were followed for a median time of 14 years (9-17).They were classified into four groups based on functional aerobic capacity (FAC) .Each 10% increase in FAC was associated with an decreased risk of incident AF ,stroke and mortality by 7 %.

Was the decreased risk observed in the more fit due to a direct physiological effect of exercise or a result of the reduction in the standard risk factors observed in the more fit individuals  or is that a distinction without a difference?

Folks who may be accused of exercising too much may find some satisfaction in the data revealing no level of fitness above which there was an increased risk of AF demonstrated in this study.In other words they found no "U-shaped curve" regarding level of exercise ( or more properly of fitness as this study did not measure exercise level) and AF risk.




1)Hussain, N, Impact of cardiorespiratory fitness on frequency of atrial fibrillation,stroke and all cause mortality. Am J Cardiol 2018, Jan 1, 121 41-49

Comments on the "Extreme Exercise Hypothesis"

Dr. THM Eijsvogels  from the Netherlands has written extensively about the relationship between endurance exercise levels and various cardiovascular outcomes and findings.

His  recent (1) review with an annotated references list  is available in full text on line.

Maybe the first question should be "what do you  mean "extreme'?

U.S. National and WHO guidelines  recommend 250 minutes of moderate exercise per week or 125 minutes of vigorous ( greater than 7 METS) per week based on in part a well established  reduction in cardiovascular mortality and morbidity as well as numerous other health benefits. However ,US guidelines also state that exercise above that levels is associated with added benefits. But how far "above" should one go. Can you go too far?

Is there a U-shaped curve when you plot health risk of the Y axis and exercise training volume on the x axis? If so, can the inflection point be defined?

Arem (2015) combined data from six prospective population based cohorts ( 661,137 individuals).Maximal all-cause mortality risk reduction was noted at exercise level of 3-5 times current recommendations and even  those exercising at 10 times current recommendation had a lower mortality risk  ( HR 0.69, 95% CI 0.59-0.78). But at the highest level the degree of risk reduction was  less than that achieved by lower exercise levels,

Ten times would be 25 hours ( one full day) of moderate exercise per week,I suggest very few exercise at that level while many preparing for a marathon would likely exercise  as much as 7 or 8 hours a week (3-5 the recommend levels). Olympic rowers might exercise as much as 17-18 hours a week .The relatively few exercisers at the highest volume make the confidence intervals for HR estimation at that exercise level so large as to not be reliable or useful.

Eijsvogels summarizes the quest for "what do mean by extreme" with this understatement:

" Based on limited current evidence and numerous potential confounders, it is difficult to delineate an upper limit for the for the benefits of physical activity at this time."

So there is no epidemiologic support for a U shaped relationship between exercise volume and health risk at least as measuring all-cause mortality. But what about certain medical conditions that have been reported to be increased in long time endurance athletes at levels said to be higher than those who exercise less.

The usual suspects include 1) atrial fibrillation 2)cardiac fibrosis 3)coronary artery calcifications.

I have commented on atrial fibrillation before ( see here) and will likely have more to say later and have blogged about the coronary  calcification paradox before( see here).

Cardiac or myocardial fibrosis (MF) is detected by cardiac MRI imaging with injection of gadolinium  and  is referred to as late gadolinium enhancement (LGE).There is a recognized pattern of LGE designating the  localized fibrosis following a heart attack. The  LGE pattern at issue in endurance athletes is something different-, i.e. a non-ischemic pattern. .

Van de Schoor et al did a systematic Pub Med search (2) and identified 65 athletes with MR imaging. A subgroup (30 subjects) were identified in an MRI study of 509 athletes.

The most frequent pattern was that located near the interventricular septum  and right ventricular insertion points. The significance of this type of myocardial fibrosis is unclear.

Levine (3) et al have suggested that LGE in endurance athletes may not represent irreversible fibrosis and note that a similar pattern of LGE at the insertion points is seen in hypertrophic cardiomyopathy and also pulmonary hypertension.

Chan et al (4) described the histopathology in patients with hypertrophic cardiomyopathy (HCM). In a multi institutional study of 1293 HCM 10% demonstrated small areas of LGE in the area of  ventricular insertion into the ventricular septum. Biopsies showed " greatly expanded extracellular space" with intestinal fibrosis and disorganized myocyte patterns." The authors emphasized the pattern was not that of myocyte death and replacement fibrosis.

Perhaps a similar histologic pattern would be found in the endurance athletes but to my knowledge that information is not available.

LGE has been reported in participants in various sports , the first case was a soccer player. Its significance and underlying mechanism  ( repetitive microtrauma, transient pulmonary artery pressure over load ??) are  not known.

 I have to agree with Eijsvogels' summary statement :  )"There is limited evidence that supports the "extreme exercise hypothesis",the most compelling relating to the increased risk of atrial fibrillation at high volume of exercise. 2) cardiac abnormalities may be present in a small proportion of the most active veteran athletes …"






1)Eijsvogels, TMH, er al The "Extreme Exercise Hypothesis:Recent findings and cardiovascular
health Implications. C"urr Teat Options Cardio Med 2018 20:84

2)Van de Schoor, F ,et all Myocardial Fibrosis in athletes . Mayo Clin Proc 2016,2016

3)Abdullah, Sm Lifelong Physical Activity regardless of does is not associated with myocardial
fibrosis. Circ Cardiovas Imaging. 2016 9,:e005511 (ful text)

4)Chan R, et al Significance of late gadolinium enhancement at right ventricular attachment to ventricular septum in patients with hypertrophic cardiomyopathy. Am J cardiol. 2015:116 436