#25: Preventing AF: The role of ACE inhibitors and ARBs

Feb 14, 2013 21:45 EST

Popular treatment options fail to recognize AF as a consequence of other problems and instead attempt to treat atrial fibrillation as if it were the problem itself. Dr Jim Seward joins Dr Chet Rihal to share his approach to preventing and treating AF. What role can ACE inhibitors and ARBs play?

	James Seward MD Professor of Medicine and Pediatrics Mayo Clinic Rochester, MN
	Charanjit (Chet) Rihal MD MBA Chair, Division of Cardiovascular Diseases Professor of Medicine Mayo Clinic Rochester, MN

Drs Rihal and Seward have no relevant financial disclosures.

Transcript:

DR CHARANJIT RIHAL: This is Dr Chet Rihal from the Mayo Clinic and I'm here today with another episode of Mayo Clinic Talks. Today my special guest is Dr Jim Seward, who's professor emeritus of internal medicine here at Mayo Clinic and prior director of our echocardiography laboratory. I'm sure he's well known to you for his seminal contributions in the areas of cardiac imaging, atrial fibrillation, and many other things. Jim, good morning. 

DR JAMES SEWARD: Good morning, Chet.

CR: It's great to have you here with us today.

JS: It's great to be here. 

CR: So we're going to be talking about a very interesting and pertinent topic, which is the prevention of atrial fibrillation, specifically as it relates to the role of ACE inhibitors and ARBs, an association that many of us don't naturally make, Jim. Can you tell us about atrial fibrillation? Review for us how you got interested in AF and why ACE inhibitors or angiotensin receptor blockers may be useful in the management of atrial fibrillation.

JS: These are all good questions in the sense that atrial fibrillation is a known epidemic. Epidemic means that—in fact, from Mayo's publications, in the last 20 to 30 years, the incidence of atrial fibrillation has not changed at all. It continues to rise unabated. Most of the focus of treatment and management has been on the prevention of recurrent or existing atrial fibrillation. 

Like most epidemics, there are two essential features that you need to understand. One is cause and effect, meaning what causes atrial fibrillation and then results and effects. And the other is you need to have a logical classification. Those two features are well published but, interestingly, very little understood by the medical community. 

CR: Why is that, Jim? 

JS: Most of the time people treat atrial fibrillation as though it's a disease. It isn't. It's a consequence. It's caused by something. For example, historically—there are a couple forms of atrial fibrillation such as lone atrial fibrillation, one not attached to a disease. You can have lone AF for 30 years, no stroke, no heart failure, no increased mortality. The first point to be made: atrial fibrillation
does not cause stroke.

Number two, problematic atrial fibrillation occurs usually at an older age. We have found and it's well published that people with atrial fibrillation get complications when the atrial pressure goes up. This usually occurs because of some sort of filling abnormality, usually beginning in the left ventricle. Atrial pressures go up. The atrial myocyte stretches and is killed by the angiotensin system. The most vulnerable part of atria is the thin myocardium in the pulmonary veins, so often the common origin of atrial fibrillation with adverse effects occurs in the pulmonary veins. 

If you know that the atrial pressure, increased atrial pressure is the cause of atrial fibrillation directly related to its consequence, you might imagine that drugs that reduce atrial pressure or left ventricle filling pressure will have a profound effect on the presence or progression of atrial fibrillation. This is where ACE and angiotensin II receptor blockers come in—they are commonly used for hypertension, for heart failure, etc. And all the studies that have been performed on ARBs and ACE are retrospective—that is, they weren't designed to look at that drug. But what they find is that if blood pressure is controlled, heart failure is controlled, the incidence of atrial fibrillation goes down markedly.

If you look at the side effects or the adverse effects of atrial fibrillation, stroke being one, only three classes of drugs have a profound effect on stroke that are not anticoagulants: ARBs, calcium-channel blockers, and thiazide diuretics. Notice that I didn't mention ACE inhibitors. I didn't mention beta-blockers. I didn't mention statins. Those three drugs increase angiotensin levels.
Interesting, increase angiotensin levels and you get reduced stroke? Yes. 

ACE inhibitors reduce angiotensin levels. It doesn't help stroke very much. Beta-blockers don't increase the angiotensin levels. It doesn't increase stroke. Statins, to some extent because of the antioxidant effect do, a little bit. 

So the premise behind the use of ARBs, particularly ARBs, is they affect the A-1 receptor, that is, the adverse effects of the angiotensin system, while increasing the angiotensin levels, angiotensin II being a positive effect on vascular physiology; angiotensin IV on the closure of the blood-brain barrier. 

And so one other takeaway is if you're going to treat atrial fibrillation, you must treat it, all of its problems, not just atrial fibrillation, and unfortunately the history of treatment of atrial fibrillation has concentrated on AF as though it were the problem.  It's not. It's a consequence. And it appears that the increase in atrial pressure is the primary cause of adverse-event–related atrial fib. 

Back to classification: There's a benign form of AF where the atrial pressures don't go up; we call that primary AF. There's an adverse form of atrial fibrillation: atrial pressures go up; that's called secondary atrial fib. The cause and effect appears to be a rise in atrial pressure. 

CR: You mentioned earlier that left atrial hypertension induces apoptosis in atrial myocytes. 

JS: It's not apoptosis. It's death. If you take a myocyte and stretch it, it will die. If you take a myocyte and reduce its stretch, it will hibernate. Apoptosis means sort of a programmed death. Well, stretching a myocyte is not a programmed death. It's death by stretching and pulling it apart, and the angiotensin system is directly related to causing that death of the myocyte. When the myocyte dies, there is replacement fibrosis, and with that you get electrical heterogeneity. The most vulnerable parts of the atria are the pulmonary vein and the interstices, the thin parts of the atria.  If you do an ablation procedure and isolate the pulmonary veins but don't treat the underlying cause, AF will come back one, two, three years later because of the other stretched myocytes in the atrium. 

CR: Is this entirely a hemodynamic effect? 

JS: It's hemodynamic, but it's also a structural effect in the sense both structure and physiology. The point being that today we have physiologic tools, mainly echo Dopplers; the most important test for the determination of heart failure is an echo-Doppler study. You can measure atrial pressures today and there is no other way. We have no other means of doing it except a catheter. 

If we can measure the presence of atrial pressure or elevated pressure, we can distinguish primary from secondary AF, which needs to be treated. Primary AF is best treated with ablation procedure, whereas secondary AF probably will benefit immensely from the use of something that will reduce filling pressure.

The question you might ask: What about ARBs vs ACE? I mentioned one reason.  What about stroke? ARBs have a tremedous effect on stroke. Forty-five percent reduction in stroke incidence with ARBs. What do you get with warfarin anticoagulation? Around 50%. What if you use the two drugs in concert, together? It's believed that you get a tremendous effect on stroke reduction. What if you can't use warfarin or [other] anticoagulant? What you'd like to do is normalize the clotting system.  

Why is AF associated with stroke? One of the largest concentrations of nitroso products in your body is in your left atrium. And if you kill the cells or kill the tissue, the nitric-oxide effect is markedly reduced, and this seems to be why the clotting system becomes more hypercoagatable in the presence of atrial fib. It's not caused by atrial fib. It's caused by this pressure elevation and cell death. 

CR: It's much more so than just stagnation. 

JS: It's not stagnation. Say, well, stagnation, yes, of course.  But it's not stagnation in the left atrium. 

CR: Jim, from a technical standpoint, what are the features on the echo-Doppler study that you're looking at? I know many of our listeners may already be aware of this, but just quickly review for us what you are looking for specifically. 

JS: First of all, in physiology, no single observation, structural or physiologic, will define a complex problem. But first, interesting with AF you only need two measures: atrial volume—with adverse or secondary AF the atrial volumes are always increased, virtually almost always. 

In benign atrial fibrillation, they can be normal-sized or big. So in itself, atrial volume can't tell you the primary from secondary. But then if you also measure the atrial filling pressure or the atrial pressure, that's usually done with tissue Doppler, and you can look at the mitral inflow, E/A ratio, deceleration time. You can look tissue Doppler, the E' velocity, which looks at myocardial relaxation, etc.

But if you look at any one of those numbers—the common one is the E/E' ratio, which is filling pressure—it can be normal and you can have terrible congestive heart failure.  It can be abnormal and be normal. So the sense even looking at a number that equates with, say, filling pressure, you can make a mistake unless you look at two things or more at the same time, and this often confounds heart doctors—how can someone die of congestive heart failure with a normal ejection fraction? Well, the vast majority of people over the age of 70 die with a normal ejection fraction and congestive heart failure. So you've got to look at more than one number. 

CR: Jim, this has been a fascinating conversation. Could you give us your approach when confronted with a patient with atrial fibrillation? Let's say it's a new patient who's referred to you with atrial fibrillation. How would you go about evaluating and then subsequently managing that patient? What's your step-by-step approach? 

JS: You need to know the patient, that is, what's their physiologic milieu? If we are ever to prevent the first onset of AF you must find those features before they are there. So diastolic dysfunction by echo Doppler defines the likelihood of developing AF, and if you treat that functional abnormality, you will reduce the incidence of atrial fib. Prevent. True primary prevention.  

Secondary prevention, first of all, you need to know the patient. What type of AF do they have? Primary or secondary? Secondary has the elevation of filling pressures or atrial pressures and large atrium. Primary has normal atrial pressures, normal or maybe abnormal. 

If ARBs are the drug of choice, what you do—let's say the person is not on a medication at this point—you would increase the ARB up to tolerance. That means candesartan at 32 mg a day, which is the maximum dose; valsartan at 320 mg a day, and look at how you manage it. How do you know how to get up there?  You can't do an echo every other day or so on. Eighty percent of people with AF have an elevated blood pressure. Have the patient measure their blood pressure at home. Of course, before you send them out, get an electrolyte profile, make sure of their renal function, and so on. But starting on an ARB, first of all, has an adverse-effect ratio that's similar to a sugar pill. There are very few, if any, side effects. Get it up to maximum dose. What's the second drug? Calcium-channel blocker, which you add to that. 

Now, in treating the patient, you want to get their systolic blood pressure optimized.  That means around 120 mm Hg. If you add diuretics, be very careful. Start monitoring their renal function because prerenal azotemia is very common with a combination of a diuretic and an ARB or an ACE. 

Why do I keep avoiding ACE? Because it doesn't have the pleiotropic effects of ARB, and in the aging population, ARBs do not have side effects that you see with ACE. So staying on the drug and having pleiotropic effects; reduction of stroke, reduction of fibrosis, reduction of cell death, and reduction of AF are markedly related to this—big problem. 

You should ask: Has it been proven? There are no clinical trials at this point that are of substantial volume to prove this to be true. Why? Because we treat AF as though it's a disease. It's a consequence. Until the cardiovascular community begins to treat with end points that are physiologic, such as atrial pressure, filling pressure, you will never answer this question methodicallyand appropriately. You will continue to lag along. Let's do ablation. Let's do this. Let's do that. It doesn't work. 

CR: This has been a fascinating conversation, Jim. Thank you so much. I certainly learned a lot listening to you, and I think it will be an impetus for many of us to go back and rereview the literature related to these pharmacologic classes and the prevention of atrial fibrillation. 

My guest today has been Dr Jim Seward, profession emeritus at Mayo Clinic, prior director of the echocardiography laboratory, and we reviewed the role of blood-pressure management and the primary and secondary prevention of atrial fibrillation, specifically the role of ARBs, ACE inhibitors, and other classes. Jim, thank you very much. It's been fascinating.