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In This Week’s Podcast
For the week ending February 3, 2023, John Mandrola, MD comments on the following news and features stories.
A Huge Finding for HFpEF
JAMA-Cardiology has published a fascinating randomized controlled trial (RCT) this week. The myPACE trial leads me to believe that I and perhaps the entire cardiology community have been wrong about a core concept in cardiology, for decades. Pause there. Yes, turn down the pace of the treadmill or back off on the watts if you’re on your bike.
Seriously, my friends, this could be big. It’s a story about heart failure with preserved ejection fraction (HFpEF) and special pacemakers. First some background facts, then the study, then the results, then the potentially massive implications.
The study involved patients who had HFpEF but who also had pacers that were capable of pacing the heart without creating right ventricle (RV)- left ventricle (LV) dyssynchrony. This later point cannot be understated. These were not standard RV leads.
This was an RCT of patients who had HFpEF and a previously implanted pacemaker.
One arm got standard pacing at a lower rate of 60 beats/minute. Like it is out of the box.
The other group got a higher rate, based on age, height, and EF. Of course, higher rates could mean more RV pacing, so that is why the study included only patients who had pacers such as cardiac resynchronization therapy (CRT) or conduction system pacing (CSP) or atrial-based pacing.
Since this was a single-center trial at University of Vermont Medical Center, which has been a leader in his-bundle pacing, CRT, and left-bundle pacing, I suspect most of their pacer patients have pacers that could be increased without causing more RV dyssynchrony.
Some background facts.
Patients with HFpEF far outnumber those with HF with reduced EF (HFrEF). Almost everything studied in this space doesn’t work — at least if you look at real endpoints, not that silly HF hospitalizations endpoint, which is only a fraction of total hospitalizations. In other words, HFpEF is a major health issue.
The typical patient with HFpEF I have in mind is an older woman with a small, very stiff ventricle. The problem is not systole, it’s diastole. I’ve always thought that such a stiff ventricle needs slower rates — more time to fill. Others must think so too because nearly all the HFpEF trials enroll patients taking beta bockers. I looked at three of these studies, and all had more than 80% of patients on beta blockers.
When I looked into the supporting data for the myPACE trial, I found a not small number of studies that show higher rates actually shift the pulmonary vascular resistance (PVR) to the left a bit. That means that a higher rate reduces LV volumes and pressures. This reduces exposure to the exponential rise in myocardial stiffness and promotes early diastolic filling by suction. And, of course, these benefits are transmitted to the left atrium (LA) which then has lower LA pressure. And...since cardiac output (CO) is heart rate (HR) x stroke volume (SV), a higher pacing rate actually increases CO.
Sitting alone, uncommented on in the Journal of the American College of Cardiology (JACC) last year is a trial from Spanish authors, first author, Patricia Palau, which found that beta blocker withdrawal in patients with HFpEF improved maximal functional capacity in patients with HFpEF and chronotropic incompetence.
Remember the RACE-II trial of strict vs lenient control of atrial fibrillation (AF). This trial, which included many patients with hypertension (HTN) and likely diastolic dysfunction, demonstrated that a more lenient HR control strategy of up to 110 beats per minute was noninferior to a HR of less than 80 beats per minute with a numerical signal towards better outcomes at higher HRs. This isn’t exactly the same situation, but maybe there is something about higher rates that benefits patients with stiffer ventricles.
Most patients with HFpEF have no Class 1 indication for beta blocker use. Beta blockers remain strongly indicated when there is LV dysfunction; okay, maybe in patients with EF around 40% to 50%. But other conditions that occur with HFpEF, such as coronary artery disease (CAD), HTN, and AF do not compel us to use beta blockers.
This may be the most compelling piece of data: Sergio Pinski, the John Roberts of electrophysiology (EP), messaged me that he has been taking patients with HFpEF off beta blockers for years because he’s noted no evidence supporting the drug’s use, and patients often feel better.
Now to the trial:
They screened 1500 patients with HFpEF and randomly assigned 107. Yes, that’s a select group, but you had to have a pacemaker that allowed increasing the rate without causing more RV dyssynchrony.
One group gets personalized accelerated pacing, which was based on height and EF. Senior author Markus Meyer did modeling studies to determine the exact algorithm, which I need to better understand. But suffice to say, there were higher median heart rates in the active arm than the control arm which was left at 60 beats/min. This resulted in a median pacer-recorded HR of 75 beats/min vs 65 beats/min.
Patients were 75 years old, half female, and had a body mass index BMI of 30. Most had mild to moderate NY Heart Association HF symptoms. Mean EF was 60%.
Follow-up was 1 year.
Primary outcome: Quality of life as measured by the Minnesota Living with Heart Failure Questionnaire (MLHFQ) score.
Four secondary outcomes: Changes in N-terminal pro–brain natriuretic peptide (NT-proBNP) levels, pacemaker-detected physical activity, atrial fibrillation from baseline, and adverse clinical events.
There were substantial improvements in the MLHFQ scores in the active arm. These easily met statistical significance. However, there was an issue here with looking at the change from baseline rather than the change in the two groups. In other words, both groups improved, a lot, and the absolute difference between groups was less than the change from baseline.
NT-proBNP levels dropped significantly in the active arm whereas it increased in the control arm.
Patient activity measured by the pacemaker increased more in the higher rate arm.
There was less AF noted in the higher pacing rate arm.
Comments. Wow. Wow. Double wow. As always, good studies raise specific implications and larger conceptual issues. This small study suggests that a slightly higher pacing rate may improve patients with HFpEF. It comports with the JACC paper from Spain showing that withdrawal of beta blockers improves function in patients with HFpEF.
But the larger epistemic implications are huge. The entire dogma, held by nearly everyone, that patients with HFpEF and diastolic dysfunction, or stiff hearts, benefit from lower rates to allow more filling may be utterly wrong. And if this is true, we have been wrong for years and years. I want to emphasize may be, because this is a small study from one center that needs to be repeated.
But if this is correct, and some of the supporting data suggests it is, this could be another hormone replacement therapy, or antiarrhythmic drug after myocardial infarction (MI) reversal.
In the excellent report from Steve Stiles, Dr. Michael Zile says the current study “...basically rewrites what we know about the pathophysiology of this form of clinical heart failure....”
HF trialist Javed Butler called this fascinating data and wondered whether SGLT2 inhibitors or ARNI drugs may have been more beneficial without beta blockers.
The reduction of AF with higher heart rates is also a huge finding. And it’s consistent with the wall stress argument made by the authors. Reducing AF in patients with HFpEF would be a major advance because AF hurts people with stiff hearts.
The next steps clearly need to be placebo-controlled trials of beta blocker withdrawal in patients with HFpEF. Hopefully these are being planned this weekend.
And before implanting pacers in HFpEF patients, we should surely have placebo (sham) controlled trials. Some of my colleagues are worried about yet another wild west of over-eager EP docs.
And please don’t willy-nilly increase pacer rates; these were special pacers that did not increase RV apical dyssynchronous pacing.
This trial has only been out for days. I have much to learn. A column is in the works. But I have a sense that this is a biggie.
MRI and ICD Function
The Annals of Internal Medicine has published yet another cohort study suggesting the safety of patients with non-MRI-conditional implantable cardioverter-defibrillators (ICDs) who underwent MRI scans. The short story — again — is that nothing bad happens.
This was a series of about 536 patients from Johns Hopkins who had non-labeled ICD and MRI between the years 2003 and 2015. Johns Hopkins has been doing non-conditional MRIs for nearly 2 decades. We struggle to do this now.
Important is that patients with abandoned leads, epicardial leads, and subcutaneous devices were excluded.
Of these nearly 600 patients who had MRI, in follow-up, many had ventricular tachycardia (VT), ventricular fibrillation (VF), and supraventricular tachycardia (SVT).
They received therapy, both appropriate for VT and VF and inappropriate for SVT and the authors observed not one shred of ICD malfunction.
The authors found no direct relationship of deaths attributable to prior MRI exposure.
This paper adds to the literature on the safety of MRIs and cardiac inplantable electronic devices (CIEDs) by adding long term data on device function.
Comments. The MRI and CIED story is an utter tragedy. It’s safety-ism run amok. Bureaucracy run amok. I learned this while writing a section of the 2017 Heart Rhythm Society expert consensus document on MRI imaging in patients with CIED. First authors were Julia Indik and J Rod Gimbel. My section was the evidence review for non-conditional devices. I made the evidence tables; pages e109-111.
All the studies I found reported favorable reports for non-conditional devises.
This included studies of abandoned leads, epicardia leads and MRI scanners with > 1.5 tesla.
Sure, they are observational, and single -center case series. But my take-home was that as long as there was an institutional protocol and careful programming with informed people, MRIs can be done.
I’ve written about this in the past and it was like Sisyphus pushing the rock up hill. One company had a monopoly on MRI-labeled devices. And the societies were not budging. It had nothing to do with the fact that this company sponsored the societies.
Now all the companies have labeled devices but there are still mixed and matched leads and generators that aren’t technically labeled. Of course they could be done.
If this were a medical decision free of safety-ism and bureaucracy, it would not be an issue. But it persists, and journals will continue to publish more of the same sorts of studies. Radiologists and middle managers will still refuse to incorporate new evidence. And patients will suffer.
Few stories in modern cardiology expose the way in which safety-ism blocks a beneficial intervention. Yes. I am mad and frustrated about this story.
AF and Dementia
TheHeart.org | Medscape Cardiology has an excellent features piece wherein Dr. Jag Singh interviews Dr. Jared Bunch about Jared’s research looking into the relationship between AF and the different forms of dementia.
I highly recommend you point your browser to the sight and read or listen to the interview. The transcript features a trove of worthy references. It doesn’t hurt also that both doctors are some of the nicest people in our field. Beingnice can be over-rated, but these two are really really nice people.
The executive summary, which won’t do it justice:
AF and dementia studies are all associations at this point.
We all know that AF and dementia are associated with aging and cardiometabolic risk factors.
We also know that AF can cause strokes, so there is that association as well.
Bolstering the stroke-as-cause-of-dementia idea are studies showing that patients who are anticoagulated early and effectively have lower risks of dementia.
This sort of work is confounded by the fact that patients who take oral anticoagulants and do better with warfarin may have other characteristics that render them at lower risk for dementia.
But there are other interesting clues:
AF is associated with dementia without overt ischemic injury, such as Alzheimer’s type dementia, and the association is strongest in young people, before there is time to be confounded by age-related risk factors.
Why is this? I don’t know, but I’ve practiced long enough to see many a patients with AF develop dementia at a young age.
There is also some interesting work on overlap between the genetic markers that associate with both AF and dementia.
Bunch and Singh then offer some ideas on therapeutics. Apropos to the myPace study that I led with, Bunch mentioned that less aggressive rate control in patients with permanent AF may be important. Those pauses at night that we’ve always ignored because you have to if you want reasonable control during the day, may be more significant than not.
I do want to push back – ever so gently — on some of the observational data suggesting early rhythm control correlates with lower rates of dementia.
The three problems with this are:
Anytime you see a nonrandom comparison that purports to show that successful rhythm control associates with better central nervous system outcomes it’s going to be biased because healthier patients are more apt to have successful control of the rhythm.
The data supporting early rhythm control is much weaker than my colleagues think. The EAST AF trial found better outcomes with early rhythm control, but these results are surely the result of performance bias, not AF suppression. And the EARLY AF ablation trials simply show that ablation is better than drugs for reducing AF, and we already knew that.
Always remember that ablation causes “white spots” on MRI. This is classic euphemism, in that the white spots are areas of brain injury related to arterial debris from the procedure. Yes, they may improve over time, but I am not sure we have adequately sorted out the long-term effects of AF ablation on cognition.
The answer is the ever present ‘we need more studies.’ But I would be more specific, more RCTs. As the revelations in heart rate and HFpEF have revealed, the answer is randomization and long-term follow-up.
We are entering an era of cardiovascular medicine where it’s going to be hard for any new therapeutic to budge mortality, because patients live so long and when they become elderly, there are so many competing causes of mortality. To me, this makes cognitive outcomes a super-important endpoint for AF trials.
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Cite this: Feb 3, 2023 This Week in Cardiology Podcast - Medscape - Feb 03, 2023.