The Pathophysiology of Atrial Fibrillation (AF) and the Importance of Sinus Rhythm
Remodeling of the atria caused by atrial fibrillation makes it more difficult to return to sinus rhythm, more difficult to respond to treatment, and increases vulnerability to relapse.1
Classification
- The American College of Cardiology (ACC), the American Heart Association Task Force (AHA), and the European Society of Cardiology Committee (ESC), in collaboration with the Heart Rhythm Society have established guidelines for the classification of AF2
- First-detected episode of AF – may or may not be symptomatic; the actual duration of the episode and previous undetected episodes may be uncertain2
- Recurrent AF - 2 or more episodes2
- Permanent AF – refractory to cardioversion or has persisted for a long period of time2
- Lone AF – occurring in a patient younger than 60 years who has no clinical or echocardiographic evidence of cardiopulmonary disease, including hypertension2
- Valvular and nonvalvular AF – occurs in a patient who has evidence or history of rheumatic mitral valve disease, who has a prosthetic heart valve, or who has valve repair; all other forms of AF are classified as nonvalvular AF2
- The American College of Cardiology (ACC), the American Heart Association Task Force (AHA), and the European Society of Cardiology Committee (ESC), in collaboration with the Heart Rhythm Society have established guidelines for the classification of AF2
- First-detected episode of AF – may or may not be symptomatic; the actual duration of the episode and previous undetected episodes may be uncertain2
- Recurrent AF - 2 or more episodes2
- Permanent AF – refractory to cardioversion or has persisted for a long period of time2
- Lone AF – occurring in a patient younger than 60 years who has no clinical or echocardiographic evidence of cardiopulmonary disease, including hypertension2
- Valvular and nonvalvular AF – occurs in a patient who has evidence or history of rheumatic mitral valve disease, who has a prosthetic heart valve, or who has valve repair; all other forms of AF are classified as nonvalvular AF2
Atrial Fibrillation Begets Atrial Fibrillation
- One of the main challenges of atrial fibrillation is the tendency of the disease to become chronic over time, during which a combination of molecular and structural changes make it difficult to achieve and maintain sinus rhythm3
- One of the main challenges of atrial fibrillation is the tendency of the disease to become chronic over time, during which a combination of molecular and structural changes make it difficult to achieve and maintain sinus rhythm3
Electrical Remodeling
- The concept that AF is self-perpetuating has been studied extensively in a goat model using an automatic atrial fibrillator that detected spontaneous termination of AF and reinduced AF by electrical stimulation. At first, the electrically induced AF terminated spontaneously. However, with repeated inductions, AF episodes became progressively more sustained until AF persisted and at a more rapid rate. The increasing propensity to AF was associated with progressive shortening of the effective refractory period as well as with increasing episode duration2 (See Figure)
- Electrophysiological remodeling has led to the phrase “atrial fibrillation begets atrial fibrillation,” originally coined by Wijffels and colleagues2,3
- In addition to remodeling and changes in electrical refractoriness, prolonged AF disturbs atrial contractile function. After a period of persistent AF, recovery of atrial contraction can be delayed for days or weeks following the restoration of sinus rhythm2
Figure. Posterior view of principal electrophysiological mechanisms of atrial fibrillation. A. Focal activation. The initiating focus (indicated by the star) often lies within the region of the pulmonary veins. The resulting wavelets represent fibrillatory conduction, as in multiple-wavelet reentry. B. Multiple wavelet reentry. Wavelets (indicated by arrows) randomly reenter tissue previously activated by the same or another wavelet. The routes the wavelets travel vary. LA indicates left atrium; PV, pulmonary vein; ICV, inferior vena cava; SCV, superior vena cava; and RA, right atrium. Adapted from Konings.2,4
- Electrophysiological remodeling occurs on 2 time scales: rapid (seconds or minutes) and slower (days or weeks)3
- Rapid electrophysiological remodeling involves translational modulation of Ica and ITO ionic currents by altered pH, intracellular Ca2+, phosphorylation and oxidation state, and metabolic regulation of pore forming alpha and beta subunits3
- Slower changes are due to changes in the rate of translation, synthesis, and degradation of ion channel subunits in the myocyte membrane3
- The concept that AF is self-perpetuating has been studied extensively in a goat model using an automatic atrial fibrillator that detected spontaneous termination of AF and reinduced AF by electrical stimulation. At first, the electrically induced AF terminated spontaneously. However, with repeated inductions, AF episodes became progressively more sustained until AF persisted and at a more rapid rate. The increasing propensity to AF was associated with progressive shortening of the effective refractory period as well as with increasing episode duration2 (See Figure)
- Electrophysiological remodeling has led to the phrase “atrial fibrillation begets atrial fibrillation,” originally coined by Wijffels and colleagues2,3
- In addition to remodeling and changes in electrical refractoriness, prolonged AF disturbs atrial contractile function. After a period of persistent AF, recovery of atrial contraction can be delayed for days or weeks following the restoration of sinus rhythm2
Figure. Posterior view of principal electrophysiological mechanisms of atrial fibrillation. A. Focal activation. The initiating focus (indicated by the star) often lies within the region of the pulmonary veins. The resulting wavelets represent fibrillatory conduction, as in multiple-wavelet reentry. B. Multiple wavelet reentry. Wavelets (indicated by arrows) randomly reenter tissue previously activated by the same or another wavelet. The routes the wavelets travel vary. LA indicates left atrium; PV, pulmonary vein; ICV, inferior vena cava; SCV, superior vena cava; and RA, right atrium. Adapted from Konings.2,4
- Electrophysiological remodeling occurs on 2 time scales: rapid (seconds or minutes) and slower (days or weeks)3
- Rapid electrophysiological remodeling involves translational modulation of Ica and ITO ionic currents by altered pH, intracellular Ca2+, phosphorylation and oxidation state, and metabolic regulation of pore forming alpha and beta subunits3
- Slower changes are due to changes in the rate of translation, synthesis, and degradation of ion channel subunits in the myocyte membrane3
Structural Remodeling
- The most frequent structural changes in AF are atrial fibrosis and loss of atrial muscle mass2
- Atrial fibrosis may precede the onset of AF. Nonhomogeneity of conduction may result from the juxtaposition of patchy fibrosis with normal atrial fibers2
- Interstitial fibrosis may be triggered by atrial dilation in any type of heart disease associated with AF. Also, interstitial fibrosis may result from apoptosis leading to replacement of atrial myocytes, loss of myofibrils, disruption of cell coupling gap junctions and organelle aggregates, or accumulation of glycogen granules2
- Apoptosis, or programmed cell death, provides temporal and spatial control of a cell and determines the cell’s lifetime. Apoptosis may occur inappropriately under pathophysiological conditions. When this happens in the heart, myocytes die and contractile capacity as well as electrical activity is permanently lost. The pathways of electrical activation may be altered due to replacement fibrosis. The presence of apoptotic myocytes in the atrial tissues of patients with chronic AF was documented by Aime-Sempe and colleagues3
- Structural changes in AF occur at a slow rate, significantly slower than electrophysiological remodeling, and probably most structural changes are irreversible3
- The most frequent structural changes in AF are atrial fibrosis and loss of atrial muscle mass2
- Atrial fibrosis may precede the onset of AF. Nonhomogeneity of conduction may result from the juxtaposition of patchy fibrosis with normal atrial fibers2
- Interstitial fibrosis may be triggered by atrial dilation in any type of heart disease associated with AF. Also, interstitial fibrosis may result from apoptosis leading to replacement of atrial myocytes, loss of myofibrils, disruption of cell coupling gap junctions and organelle aggregates, or accumulation of glycogen granules2
- Apoptosis, or programmed cell death, provides temporal and spatial control of a cell and determines the cell’s lifetime. Apoptosis may occur inappropriately under pathophysiological conditions. When this happens in the heart, myocytes die and contractile capacity as well as electrical activity is permanently lost. The pathways of electrical activation may be altered due to replacement fibrosis. The presence of apoptotic myocytes in the atrial tissues of patients with chronic AF was documented by Aime-Sempe and colleagues3
- Structural changes in AF occur at a slow rate, significantly slower than electrophysiological remodeling, and probably most structural changes are irreversible3
Molecular Changes in AF
- In atrial tissue specimens from a total of 53 explanted hearts of transplantation recipients with dilated cardiomyopathy, 18 had persistent, 19 had permanent, and 16 had no documented AF. Extracellular matrix remodeling including selective upregulation of matrix metalloproteinase 2 (MMP-2), type 1 collagen volume fraction (CVF-1) and downregulation of insulin-like growth factor II mRNA-binding protein 2 (IMP-2) were associated with sustained AF2
- The concentration of membrane-bound glycoproteins that regulate cell-cell and cell-matrix interactions (disintegrin and metalloproteinases) in human atrial myocardium has been reported to double during AF, potentially contributing to atrial dilation. Dilation of the atria activates several molecular pathways including the renin-angiotensin-aldosterone system (RAAS). Angiotensin II is upregulated in response to stretch, and atrial tissue from patients with persistent AF demonstrates increased expression in angiotensin-converting enzyme (ACE). Angiotensin inhibition and angiotensin II receptor blockage may prevent AF by reducing fibrosis2
- A genetic defect, such as mutations in lamin AC gene, has been associated with AF. Other triggers of fibrosis include inflammation as seen in cardiac sarcoidosis and autoimmune disorder2
- In atrial tissue specimens from a total of 53 explanted hearts of transplantation recipients with dilated cardiomyopathy, 18 had persistent, 19 had permanent, and 16 had no documented AF. Extracellular matrix remodeling including selective upregulation of matrix metalloproteinase 2 (MMP-2), type 1 collagen volume fraction (CVF-1) and downregulation of insulin-like growth factor II mRNA-binding protein 2 (IMP-2) were associated with sustained AF2
- The concentration of membrane-bound glycoproteins that regulate cell-cell and cell-matrix interactions (disintegrin and metalloproteinases) in human atrial myocardium has been reported to double during AF, potentially contributing to atrial dilation. Dilation of the atria activates several molecular pathways including the renin-angiotensin-aldosterone system (RAAS). Angiotensin II is upregulated in response to stretch, and atrial tissue from patients with persistent AF demonstrates increased expression in angiotensin-converting enzyme (ACE). Angiotensin inhibition and angiotensin II receptor blockage may prevent AF by reducing fibrosis2
- A genetic defect, such as mutations in lamin AC gene, has been associated with AF. Other triggers of fibrosis include inflammation as seen in cardiac sarcoidosis and autoimmune disorder2
Long-term Impact of AF
- A retrospective analysis demonstrated that 20% of patients with intermittent AF were in permanent AF after 4 years5
- 77% of patients with paroxysmal AF were in permanent AF after a mean of 14 years.5 Independent risk factors for early progression to permanent AF included age, dilated left atrium, MI, and valvular disease5
- The longer one waits to initiate a rhythm treatment strategy, the harder it is to regain sinus rhythm. Patients who converted to sinus rhythm within 3 months of onset of AF were more likely to remain in sinus rhythm at 6 months than patients who converted more than 12 months after onset of AF (67% versus 27%)6
- By shortening the atrial refractory period, reducing conduction velocity and provoking contractile and structural remodeling, AF sets the stage for self-perturbation
- A retrospective analysis demonstrated that 20% of patients with intermittent AF were in permanent AF after 4 years5
- 77% of patients with paroxysmal AF were in permanent AF after a mean of 14 years.5 Independent risk factors for early progression to permanent AF included age, dilated left atrium, MI, and valvular disease5
- The longer one waits to initiate a rhythm treatment strategy, the harder it is to regain sinus rhythm. Patients who converted to sinus rhythm within 3 months of onset of AF were more likely to remain in sinus rhythm at 6 months than patients who converted more than 12 months after onset of AF (67% versus 27%)6
- By shortening the atrial refractory period, reducing conduction velocity and provoking contractile and structural remodeling, AF sets the stage for self-perturbation
The Importance of Sinus Rhythm
The Impact of Atrial Fibrillation on the Heart
Can You Stop Disease Progression?
The Management of Atrial Fibrilliation and the Value of Sinus Rhythm
EXPERT INTERVIEW With Eric Prystowsky, MD
Medscape recently had the opportunity to discuss the management of atrial fibrillation (AF) and the value of sinus rhythm with Eric Prystowsky, MD — Consulting Professor of Medicine, Duke University Medical Center, Durham, NC and Director of the Electrophysiology Laboratory, St. Vincent's Hospital, Indianapolis, IN.
Question: What factors affect the overall management strategy for atrial fibrillation?
Dr Prystowsky: I approach this from several viewpoints. As one of the writers of the first international guidelines for the management of patients with AF and also the updated guidelines, and sprinkling into this the personal experience of several decades of managing patients with AF, it is important to have a game plan about the present and future management of that individual.
For example, is this paroxysmal or persistent AF? Are there concomitant medical illnesses that may affect your long-term and even short-term game plan? Is this postop management of atrial fibrillation versus somebody who has been in AF for years? These issues affect whether you're going to do rate or rhythm control, drugs, ablation and so forth.
The next set of issues relate to rate control, rhythm control and the risk of stroke.
The first thing you have to make sure about right away is the risk of stroke and need for risk reduction.
Then, you have to be sure you can control their heart rate. Regardless if you select a rate or rhythm treatment strategy, you have to at least be sure that when they do have episodes of AF that they are not going so fast as to get themselves into trouble.
The third thing is the rate versus rhythm question. Is this a person who will do better in sinus rhythm or is this a person who will do very well just staying in good rate control?
Once you've considered the issues and answered all those questions, you can then lay out a reasonable treatment goal for that individual.
Question: What are the short- and long-term goals you set for your patients?
Dr Prystowsky: The short-term goal is to ensure you've covered stroke risk, whether or not sinus rhythm is your long-term goal. Managing stroke risk to cover the period of time around the cardioversion is important, because patients who have been in persistent AF for 48 hours or more develop atrial myopathy. They're known to be at risk for developing thrombi that can embolize and cause strokes and other problems, and require three weeks of stroke risk management before and at least four weeks after cardioversion.
Short-term, you must be sure that you also take care of rate control. By short-term, I mean during the first few days of treatment to be sure that the patient will not develop a tachycardia-mediated cardiomyopathy.
Long-term goals are very different. If my long-term goal for a patient is to maintain sinus rhythm, then I know I am going to try to cardiovert the patient. My immediate concern is risk of stroke, but I don't want to postpone cardioversion for too long since it may be more difficult to achieve sinus rhythm.
On the other hand, if it's a 75-year-old with newly discovered AF who is truly totally asymptomatic and you feel he or she is an excellent candidate for rate control, once you've covered the stroke risk, you need to be sure this patient has a long-term goal of good, adequate rate control.
The short-term goal is to stabilize the patient, make sure he or she is not in a risk situation, and then you can determine where the fork in the road is, that is rhythm or rate control long-term.
Question: Which patients are best suited for a rhythm control strategy?
Dr Prystowsky: It is clear that some people can do well with either a rate or rhythm control strategy. There have been a series of randomized, prospective trials published in the last few years that have addressed this issue. The one that is most often quoted—and clearly the biggest trial—was the AFFIRM study.
The AFFIRM study asked the question, "Do people have a better or worse chance or no difference in survival if they have rate control versus rhythm control?" Patients did equally well whether they were rate or rhythm controlled. That conclusion has been misrepresented, or at the very least misunderstood as physicians have extended the trial results to other groups of patients.
The entry point in this trial was patients who were suitable for either rhythm or rate control and who were at high risk for events such as stroke. It turned out to be a patient population averaging about 70 years old.
The issue is, can you apply the AFFIRM data to a 30-year-old, a 40-year-old and a 50-year-old? I say you certainly cannot.
That kind of data migration, or conclusion migration, is really not appropriate. You have to stick to the question asked and the population in whom it was asked.
The other major issue is that there was a substantial number of patients who were potential candidates but not enrolled because either the treating physician or the trialist did not think they were adequate candidates for rate control. In other words, they needed sinus rhythm, or they weren't going to tolerate just being out of sinus rhythm.
That's a large group of excluded patients even in the elderly patient population. In an AFFIRM type of patient population, I think they have clearly shown rate and rhythm are equivalent treatment strategies, as long as rate control gets the patient to a point of feeling good.
There are three types of patients that I would initially target for sinus rhythm.
In patients who have not been studied, my own bias is that sinus rhythm is best, until someone shows me that rate control in a person in the younger age group is better. Until we know more, I think that sinus rhythm is the preferred initial approach.
Sinus rhythm is also clearly the approach for a second group of patients, in whom you've tried rate control and there are still substantial symptoms. You get them back into sinus rhythm and suddenly they feel much better.
The third group of patients are individuals in whom AF, if not now, but in the future, could be a problem for them. These typically are people who have diastolic compliance problems in their left ventricle.
If a person has ventricular hypertrophy and is on the borderline of diastolic dysfunction or has, even mild to moderate dysfunction that's going to worsen over time, I think leaving them in AF may be an unwise thing to do. At a point in time when there is a problem, it may be too late to restore sinus rhythm.
Question: Do you believe that being in sinus rhythm has an impact on disease progression?
Dr Prystowsky: First of all, let's look at the heart itself. Will keeping somebody in sinus rhythm make a difference as to whether or not that person's heart stays the same? It's well known if you stay in AF, you will have progressive changes in the atrial tissue that can become permanent. These changes are both anatomic, for example atrial dilatation, as well as electrophysiologic, such as shortening of action potentials in the atrium, and can promote the continuation of AF and make it difficult, even several years later, to maintain and restore sinus rhythm. Persistence of AF can change the atria.
The next question is, "Will that change affect the cardiovascular state of that person?" That question is difficult to predict. In some patients who have heart failure, it's been shown even with good rate control they just simply don't do as well because of the AF. When you restore sinus rhythm, they literally feel better and do better.
The same holds true for people who have substantial left ventricular diastolic compliance problems. Again, will they actually get worse if you leave them in AF? I don't think we have data to support that.
I think there are people in whom maintaining sinus rhythm will prevent further deterioration of left ventricular function, and I believe there are some data to suggest that's true. I don't think there are any data to suggest that's true for hypertrophy.
Question: Do you think AF is an under-recognized cardiovascular risk factor?
Dr Prystowsky: Atrial fibrillation, I believe, is felt by many people to be more of a nuisance than a real problem.
There are a number of patients with AF who will call you for even four seconds of AF. Their chart is on your desk the next morning: Mrs. Smith had a brief run of AF yesterday.
No matter what you do, you're never going to make that person happy, so doctors don't necessarily want to deal with AF. They don't want to find out if a patient has it. They'd rather it just simply go away.
AF can cause strokes. It can cause heart failure. It can cause deterioration in health. In study after study it's been associated with increased mortality. It is a problem, regardless of being a nuisance.
I think it is totally unrecognized in a large part of the medical community how serious AF can be. What makes it worse is that AF can disguise itself because it is frequently asymptomatic. A patient has a stroke or a TIA, and his or her doctor doesn't do the appropriate workup, which is long-term monitoring to see if, indeed, the person in that age group might have unrecognized AF, and if so needs to be aggressively managed to prevent future strokes. This goes on all the time.
It's a nuisance and therefore avoided, but it's also grossly unrecognized because of its very frequent asymptomatic presentation.
Atrial fibrillation has a very important effect on the health of our citizens. If you look at the major expenditure for hospitalizations in arrhythmias, it's usually AF. People get admitted to the hospital when it can be totally outpatient managed.
Our job to educate on AF is dramatically important, not only for the individual health of the patient, but for the health of the entire medical healthcare system.
Question: Please just comment on the public health challenge of atrial fibrillation.
Dr Prystowsky: From a global perspective there is a need to identify the causes of AF and find ways to minimize its occurrence.
Let's look at risk factors. Probably the most important risk factor, certainly in western civilization, is hypertension. Hypertension is associated with at least 40%-50% of the patients who have AF. Patients with hypertension tend to get left ventricular diastolic dysfunction, which often translates to increased pressure in the left atrium.
Data published in the Journal of Cardiovascular Electrophysiology have shown pulmonary veins are largest in a subgroup of patients who have both hypertension and AF versus hypertension alone, and versus patients without hypertension.
Most patients with AF have their triggers in the pulmonary veins, and one could hypothesize that there are stretch receptors that cause increased automaticity that are more actively engaged in patients who have significant hypertension, pressure changes, and so forth.
Also general cardiovascular care, such as minimizing heart failure and coronary disease, will again minimize the risk of AF. Conditions such as sleep apnea can increase the risk of AF. Attention to patients with these problems will minimize the occurrence of AF.
We're never going to totally eradicate it based on just those risk factors, but we could hopefully have a substantial reduction in the numbers of AF patients.
The second thing is how can we best manage AF in a cost effective way. First of all, most people with AF do not have to be hospitalized. Clearly, there are exceptions, such as for patients starting drugs that might be somewhat risky for proarrhythmia, which you feel more comfortable starting in a hospital under observation.
There are some people whose AF has caused worsening of heart failure. But for the most part, AF does not require a person to be hospitalized, including cardioversion. In most people, you can perform cardioverversion as an outpatient and send the patient home the same day. An exception is a patient who has started on treatment that prolongs the QT interval, and in that case you would want to monitor the QT interval in sinus rhythm for at least 24 hours.
If we can learn to tailor outpatient therapy and only admit people who really need hospitalization, it's good for the patient and it's good for the general health bill for the country.
I think if we pay attention to both these areas, preventing the episodes as best we can by paying more attention to preventive medicine, and once the patient has been diagnosed with AF, really thinking it through carefully on how to minimize occurrences and avoid admittance to the hospital, I think will make a large step forward in the management of AF for the patient and society.