May 30 2025 This Week in Cardiology

0:00 [Music] You're listening to this week in cardiology from the heart.org Medscape Cardiology. This podcast is intended for health care professionals only. Any views expressed are the presenter's own and do not necessarily reflect the views of WebMD or Medscape. Hi everyone, this is John Mandola from the heart.org Medscape Cardiology and this is this week in cardiology for May 30th, 2025. This week, listener feedback, CRT versus CSP, clues on the ECG, beta blockers after MI, novel approaches to LDL cholesterol lowering, and ICD decisions in cardiac saridosis. First up is some listener feedback. Dr. Steve Dixon, a heartfire

0:47 cardiologist from Kansas City, writes via email to push back on my persistent skepticism about rapid titration of godlin directed medical therapy in hardfire. SD says, I am right about the strong hardfire trial which used cardiologists for the majority of follow-up visits. And while cardsled care may currently be the case in many clinics across the country, he writes, times are changing. hospitalists, PCPs, and advanced practice practitioners are becoming more comfortable with these life-saving medication classes. And the future of heart failure care isn't just the burden of cardiologists, but internal medicine where there are more reinforcements. Dr. Dixon says that in

1:33 his clinic, they use a four weeks, four meds program for patients with heff mainly through nurse practitioners that he guides and manage. He said, "It's quite an aggressive program, but I can assure you that my CEO of the hospital loves seeing his re readmissions rates drop." Now, my comment to this is that I fully support programs like four weeks for meds programs. It's a great idea, but of course, this takes administrative support. It takes champions, incentives, and I would add that this is a great use of advanced practice clinicians. I say congratulations and I hope more programs like this became a reality. Clearly, heart failure care would improve if it did. The obvious advantage of such a program is not only

2:20 getting more patients on maximal GDMT, but also avoiding harm from overzealous GDMT titration without adequate follow-up. All right, next topic. CRT versus CSP, the concise CRT trial. As many of you know, because I have said it so many times, the most exciting thing in EP right now is not catheter ablation, but pacing, specifically conduction system pacing. I saw a tweet or post or whatever you call it this week saying that ablation had become more anatomic and wrote and pacing is becoming more physiologic. And it used to be the opposite. In in ablation, we would map and study electrophysiology

3:05 and in pacing, we would simply flop a catheter in the RV and we would just screw it in wherever it fell into the RV. But now, now in ablation, we put in a PFA catheter and boom, eS are gone. I mean, PFA ablation is basically ruining EP. Now, during a pacemaker, we meticulously record and we pace in areas of the conduction system. Six or so years ago, we were doing it with the H bundle, but now it's the left bundle. And to do conduction system pacing now is to bathe yourself in beautiful physiology. But beautiful images of CSP pacing on an ECG, that's not evidence. What we need is evidence that it is superior to BV pacing for the treatment

3:50 of patients with heart failure and left bundle. The thing is in BV pacing we have strong evidence right from multiple trials that BV pacing reduces heart outcomes like mortality compared to standard RV ICDS or medical therapy. Now we think and the emphasis on think that because CSP captive system pacing narrows the QRS and because smaller studies have shown improved hemodynamics with CSP and we think that it is superior or at least similar to BV pacing but we need trials. Well, I'm happy to say that I'm a local PI here at my hospital for the US government funded left versus left trial

4:36 and we've randomized a number of patients already. Left versus left will have death and hospitalization for heart failure as a primary endpoint. Its planned enrollment is over 2,000 patients and its follow-up is 5 years. So, that's going to be a long time to wait. This month, Jackie P has published another attempt to compare conduction system pacing with BV pacing in CRT eligible patients. Spanish investigators have now published a conci concised CRT trial. This was an R RCT of just 134 patients. 134 patients of CSP versus BV pacing. The design was not inferiority of CSP.

5:22 The primary endpoint was a composite of many bad things, right? Death, transplant, heart failure, hospitalization, or a failure of the left trigger ejection fraction to improve more than 5%. Now, I hope you're seeing the problems already, and I'm going to go over the issues in the comments. The first finding of this trial was that 18 of the 67 patients crossed over from CSP to BV pacing. That's a lot. Second finding, 23.9% in the CSP group had a primary outcome event versus 29.8 of the BV pacing. That's an absolute risk difference of minus5.9%. However, the conference interval went from minus

6:07 21%. Which is far better with CSP to 9.2% worse for CSP. Now the accepted non-inferiority margin was 10% worse and so 9% which is the upper bound is less than 10% and this allowed investigators to claim non-inferiority with a p value of 0.02. Now the secondary endpoints also favored CSP things like QRS narrowing was better in the CSP arm. The echo response was better as was New York Heart Association functional class improvement. The combined endpoint of death, transplant, and heart failure hospitalization also showed non-inferiority, though I could not find any conference intervals on the difference. The authors concluded that CSP was non-inferior to BV pacing in

6:54 achieving clinical and echo cardiographic response, suggesting that CSP could be an alternative to BV pacing. Okay, my comments. Look, I lo trials on clinicians who attempt them. It's it's great. The CSP versus BV pacing is an important question, but if you're going to experiment on people, you need to have a chance of telling a difference. There is no way this trial had a chance with only 134 patients and one in three crossed over. There was no way to detect signal from noise with this small number of patients and high degree of crossover. For instance, there were 16 versus 20 primary outcome events respectively. There were one versus three-0 versus one transplant and 8

7:41 versus 10 heart failure hospitalizations. The most common outcome was failing to improve EF, which is far from a hard clinical outcome. It's just a tiny number of events. Not only was the composite endpoint problematic, but followup for a year is totally inadequate. The left versus left trial is asking the same question, enrolling 2,000 or more patients and uh following patients for 5 years. Now I think these small trials would be fine to compare hemodymodynamics, right? So that's a continuous outcome. You can measure that, but we already have oodles of those sorts of studies and it really shows similar effects on the ejection fraction with CSP or BV pacing. And in fact, some of the studies show that CSP pacing is maybe a little bit better for

8:27 hemodynamics. I mean no malice to the Spanish team. to be sure I was part of the his sync trial which was another woefully underpowered trial between his bundle pacing and 5V pacing. But this type of effort tells us too little about the long-term effects of the two strategies and I think underpowered trials should be avoided. All right, next topic is the important QRS complex. Since the beauty of the ECG is what interested me in cardiology to begin with, I am always on the lookout for studies on the ECG. A U. UCSF group reports a research letter in circulation EP journal on the association between a fragmented QRS and myioardial fibrosis

9:14 burden and autopsy defined arhythmic causes of presumed sudden cardiac death. Now my friends QRS complexes should be sharp and narrow. There should be no notches or fragments. This is a report from the ongoing project called the post SCD or postmortem systematic investigation of sudden cardiac death study. The idea of the study is to use autopsy and clinical data to adjudicate arhythmic versus non-arithmic death. Why is that important? Because arhythmic death is potentially treatable with an ICD and non-arithmic death such as overdose, PE, stroke, etc. is not. So far the post SEDD team has had

10:00 943 presumed sudden cardiac death of which 402 had ECGs before death and 98 or about one in four of these had available hisytological data. A fragmented QRS was defined as greater than one notch for the QRS if it's less than 120 milliseconds and greater than two notches if the QRS was greater than 120 milliseconds. and fragmented QRS's had to be in two leads. The findings of this research letter were that presumed sudden cardiac death with a fractionated QRS on more than one lead were more likely to have arhythmic causes compared with presumed sudden deaths without fractionated QRS's was like 76% versus 55%. So the odds ratio

10:49 is 2.6 which was statistically significant. The team found no other ECG marker associated with her higher odds of arrhythmic death. Coronary disease was the most common cause of a fragmented QRS. Right? That's what we used to call Perry infarction block. presumed sudden cardiac death with fractionated QRS greater than one lead had a higher mean total and higher replacement fibrosis as well as more interstitial fibrosis than presumed sudden cardiac death without fractionated QRS's. Now I cover this imperfect study because the value of the ECG is under recognized. I say it's imperfect because only half the presumed sudden cardiac death events had ECGs

11:36 before death and only a fraction of those had hisystological samples. What's more, the difference in associations were statistically significant, but the positive and negative predictive value of the fractionated fragmented QRS is surely low. I cover this study and discuss this as sort of a public service announcement to my colleagues in cardiology. Please when you are sorting out whether a patient say with syncopy or near syncopy has a worrisome structural heart condition study the QRS. When someone is telling me the story of a patient with syncopy my first question after the story is what does the QRS look like. Fragmented QRS is an electrical manifestation of disordered ventricular conduction which is often due to scar

12:22 and disordered conduction aka anosotropy sets the stage for re-entry. Recall one of the fundamentals of cardiology is that re-entry requires three things two pathways delayed conduction and unidirectional block. Scar sets a stage for this because they have all three are possible and two pathways can be functional pathways. In the same way that atrial structural disease increases the odds that a PAC fibrillates the atria, ventricular structural disease makes it more likely that the PVC fibrillates the ventricle. No, I am not saying that every notched fragmented QRS is malignant, but it's a clue. It's one piece of data. Don't overreact but don't

13:08 ignore the QRS. Okay. Next topic is the Abyss trial of beta blocker interruption after MI and it continues to be misinterpreted. European heart journal has a substy trial of beta blocker interruption versus continuation after MI. The sub study purported to show spikes in heart rate and blood pressure after beta blocker discontinuation and that this explains why the abyss trial failed to show that stopping beta blocker therapy could be safely done in stable patients who were postmi. None of this is correct. None. And I want to correct the record about abyss again. In my mind, the Abyss trial is entirely

13:54 consistent with the reduced AMI trial of not using beta blocker in the postMI patient with normal EF. Reduce AMI found that not giving long-term beta blocker resulted in similar MACE outcomes compared with standard beta blocker therapy in postMI patients who had preserved lepentric ejection fraction. The main abyss trial published in New England Journal of Medicine in August of 2024 compared interruption of beta blocker or continuation of beta blocker in patients who had had a previous MI and an EF greater than 40%. An MI at least 6 months before randomization and the median time from MI to randomization in Abyss was about 3 years. Abyss enrolled a lot of patients, 3,700

14:39 patients, and it had a non-inferiority design with a four-point composite endpoint of MI, stroke, death, or hospitalization for cardiac reasons. The non-inferiority margin was a difference of three percentage points for the upper bound of the 95% conference interval. And the results of the main abyss trial was that interruption was not only not not inferior to continuation but actually inferior to continuation. Here were the numbers. There was 23.8% primary outcome events in the interruption group versus 21.1% primary outcome events in the continuation group. So more that's an absolute risk increase of 2.8% 8% with a 95% confidence interval that went from

15:27 0.1 to 5.5. And since 5.5% was greater than the non-inferior margin of 3%, non-inferiority was not met. And when you looked at the conference intervals, the entire 95% conference interval was above zero for the interruption group. So it was actually inferior. But but the entire composite was driven by hospitalization for cardiac reasons was 349 versus 307. There were no differences in death, MI or stroke. The major MACE outcomes were nearly identical. The only reason that the Abyss trial was found to be against interruption of beta blocker was a surrogate outcome. CV hospitalization that requires adjudication. The less biased

16:13 outcomes of death, stroke, and MI were identical. Now, let me go to the European Heart Journal sub study. This looked at changes in blood pressure and heart rate from baseline to postrandomization in two groups. The authors also assessed the changes in heart rate and blood pressure impact on the primary endpoint for the pre-specified subgroups of patients with or without a history of hypertension. And the main findings were with little to no surprise beta blocker interruption group sustained an increase in heart rate on average about 10 beats per minute and an increase in systolic blood pressure on average about 3.7 millm of mercury and these deltas remain stable after discontinuation over

16:59 months. Now with regard to the hypertension and no hypertension subgroup which was almost about 50/50 split there were largely similar effects that was an increase in heart rate and systolic blood pressure. Also not surprising was that the primary outcome occurred more often in patients with hypertension than in those without hypertension. And this basically shows that hypertension patients are higher risk. But I'm not sure we needed that analysis because we've known for about 30 years that hypertension is a known risk factor. Now the observed harm harm a higher rate of the primary outcome was numerically higher in the hypertension group for interruption. The difference was not statistically significant. However, in other words, this

17:47 substy treatment effect for hypertension and no hypertension. But remember harm in quotes as described by the primary outcome in Abyss is flawed because it was driven only by CV hospitalizations. In table two of the European heart journal paper, the authors show the results of the components of the primary outcome in the beta blocker interruption and continuation arm based on the subgroup of hypertension. And in MI, stroke and death, the P for interactions were close to one, as in absolutely no difference. The authors in the European Heart Journal concluded that interruption of beta blocker treatment after an uncomplicated MI led to a sustained increase in blood pressure and heart rate with potentially dilotarious

18:33 effects on outcomes, especially in patients with a history of hypertension. Of course, my comments, my friends, the Abyss trial is a perfectly nice trial. It addressed an important question. The problem was just a simple one, the choice of an end point. When you look at MI, stroke and death beta blocker interruption was totally fine. This substing why Abyss found harm is flawed because the main trial chose a flawed endpoint to begin with. Further, finding that heart rate and blood pressure go up slightly when a beta blocker is stopped is like finding out you get wet when walking in the rain. Of course, that happens. Blood beta blockers reduce heart rate and blood pressure. And when you stop them, heart rate and blood pressure will go up a bit. Since the

19:20 main abyss trial found no increase in mace, we can say that the small rise in heart rate and blood pressure don't have dilotarious effects. The most we can take from this sub study is that that there's that there does not seem to be a heterogeneous treatment effect for the presence of hypertension. So I think we can stop beta blockers in patients with a history of MI if they have a normal EF and no other reason to take beta blocker. Now the one caveat some of you may push back. The one caveat to my argument that death, MI, and stroke were not different is that it's a little underpowered, right? For the composite of death, MI, and stroke, when you go back to the main Abyss paper in New England, the hazard ratio was 0.96. So no difference in the

20:06 interruption versus continuation arm, but the conference intervals went from 0.74 to 1.24. So that could be 26% better or 24% worse. But again, a little underpowered and perhaps this is why the authors decided to add CV hospitalizations because they knew that if you just had stroke, MI and death in a postMI group with a normal EF, those event rates are going to be pretty low. Yet overall I think if you combine you take the totality of the data from reduced AMI and observational data from Denmark the abyss finding of no increase in mace after interruption of beta blocker

20:52 supports supports the idea that interruption of beta blocker after MI is reasonable and safe and of course less medicine is always better. All right, next topic is about oral PCSK9 inhibitors in the pursuit trial. Jack has published a phase 2 dose ranging study with another oral PCSK9 inhibitor. This drug is called funnally a ZD0780. In other words, it doesn't have a name yet. The drug has a novel mechanism which I won't delve into at this point, but it did achieve a dose dependent drop in LDL cholesterol. The maximum dose of 30 milligram tablet achieved a 50% placebo adjust reduction

21:38 of LDL cholesterol and all of these patients were on statins and all had LDL cholesterol greater than 70 mg per deciliter. Now there were no adverse effects noted but the study was quite short at only 12 weeks. The accompanying editorial was quite good. I learned a lot from it. First, I learned that there are multiple PCSK9 inhibitors in development. And I think this is a good thing because pills are better than shots. And I say that because shots increase the work of being a patient. There's just more inertia. There's insurance restrictions and there's just more effort to take a shot, however infrequent it is to swallow a tablet. The editorialist also discussed the pricing dilemma and the role that pharmacy benefit managers will have. Now

22:25 PBMs are rebate based pricing models and they often dictate drug availability in the US and to be honest I don't quite understand PBMs anywhere near well enough to explain them but can but I can also say that I don't get the feeling that PBMs contribute much to the health of US citizens. Now there is also a potential and I emphasize the potential part for permanent inhibition of the PCSK9 complex via crisper mediated gene editing. Dr. Seatheration's company Verve is working on that and it has progressed to early stage human trials. This is a oneanddone approach to LDL cholesterol management. It's obviously a a highreward high-risisk strategy and

23:12 there will be need there need to be rigorous safety data before this could become a reality. I mean two safety issues have already arisen. One patient developed a very high hypatic enzymes and in another trial two patients had serious cardio cardiac events. These were not felt to be due to the intervention. So we shall see. I mean, there would have to be a heck of a lot more data on safety before I signed up to permanently change my genes, especially when you can accomplish the same thing with a tiny daily pill. And I know that I sound old saying this, but if you stop and think, it's quite shocking that such an approach could be close to becoming a possibility, right? Editing genes so as to reduce LDL cholesterol for life. That

24:00 is remarkable. All right, the final topic today is on cardiac sarcidosis and the risk of VTVF. One of the toughest calls in EP is deciding an on ICD treatment of patients with suspected cardiac sarcoid. I mean, it's hard for many reasons, not least because the diagnosis of cardiac sarcoid and its risk stratification is super difficult. The European Heart Journal has published a nice study from a Dutch and two American centers. They had about 1,500 patients with biopsy proven sarcoid now mostly non-cardiac biopsy proven and these patients had not had VT and therefore were being considered only for a primary prevention ICD. There's not much controversy on aborted sudden

24:46 cardiac death or VT. Those patients get an ICD and we don't worry too much about that decision. The authors then compared outcomes based on multiple ways to risk stratify these patients. I, for instance, did not know that there were multiple professional societal recommendations for an ICD. For instance, there's a 2014 HRS statement. There's a 2017 AHA ACC guideline, and there's a 2022 ESC guideline. And they're all a little different. The purpose of this study is that the Dutch and American authors propose a different way. They propose CMR phenotyping, and that it's better. Now, CMR phenotyping sounds tricky, but they actually made it

25:31 pretty easy. In this study, you are either CMR high or low risk. It's based on injection fraction and quote pathology frequent LG, late gatalinium enhancement. They had four CMR phenotypes. No LG in normal EF, no LG in abnormal LVF, pathology frequent LG and pathology rare LG. Pathology frequent LG included at least one of the four features. It had to be subpocardial, multif focal, septal, and right ventricular free wall involvement. The authors then dichotomized CMR phenotypes into simply high risk which was pathology frequent LG and low risk

26:18 which were the other three groups. The no LG and normally FF, the no LG and abnormal LVF and the pathology rare LG phenotypes. Their next step was to follow the 1500 or so patients over 5 to 10 years for VT events. Of note, most of these patients were young, 54 years old. Now let me stop there and say that when you have a 50s something year old patient with heart block before putting in a pacemaker stop and think about sarcoy get your CMR and see if they have cardiac sarcoid. Now the first finding was that when an ICD was indicated based on either the society or CMR phenotype the likelihood of an eventricular arhythmia event at 10 years was pretty high and it ranged from 20% to 35% for the

27:05 high-risisk CMR group. When an ICD was felt not indicated by either the society guidelines or the CMR low-risk phenotype, the rates of ventricular arrhythmia were low. They ranged from 5% for like the HRS statement to 2.6% for the CMR lowrisisk group. Now the key finding of this study was in figure three that the CMR dichotomized method used by these authors had the best area under the curve. At five years, it was about 0.86 for VT events, which is pretty darn good. And it was statistically better than each of the professional society criteria for choosing an ICD. The problem of course is that the ICD need is imperfect. Right? A subgroup

27:51 of the 1500, about 8% of these patients or 119 patients received a loop recorder. And about a third of these loop recorder patients had a high-risisk CMR and 2/3 had a low-risisk CMR. Four of the 38 patients or 4% per year had VT in the CMR high-risisk group. And only one of 81 patients in the CMR low-risk group had a ventricular arhythmia. And that calculates to 0.4% per year risk. And herein is the problem of prediction. Most high-risk patients do not have a VT event and not every low-risk patient remains totally free of VT and this is the same as it is for es schemic

28:37 cardiammyopathy and non-eskeemic heart failure patients but I do like the CMR approach though and this study is quite nice as there were more than a thousand patients all of them had biopsy proven sarcoid there was good followup and the CMRs were centrally adjudicated and blinded and there are of course limit the patients, right? ICD therapy as a VT event is not always a surrogate for sudden cardiac death. Some of these events were ICD therapies and that doesn't mean the patient would have died. Just because a person has VT on an ICD and gets a shock or ATP, that does not mean it was aborted sudden cardiac death. The second limitation is that patients without ICDs in a study may have had VT and it went undetected. To me though, if we had some

29:22 replication or confirmation of such a CMR high or lower strategy, it would seem like the best strategy. Realizing of course the imperfect nature of prediction of ventricular arhythmia events. The things to keep in mind with ICD therapy always, this is general rule of thumb is that a ICDS are never an insurance policy. Insurance policies confer no risk to the policy holder and ICDs surely confer risk. Second general concept, you always want to deploy an ICD in a patient with a high risk of the primary outcome, the ventricular arhythmia and a low risk of competing risks such as severe heartfire or dementia or CKD or a host of diseases that are seen in the elderly. Therefore, the 54 year old patient with

30:10 heart block and LG and reduced EF from cardiac saroids seems like an ideal patient for an ICD. All right, that's it for this week in cardiology. As always, I'm grateful that you listened. Thank you. And remember, if you like this podcast, please take the time to give us a rating, write us a review, and of course, if you don't agree with something, write me an email. I always learn from these feedbacks. Until next week, this is John Mandola from theart.org Medscape Cardiology. You're listening to this week in cardiology from the heart.org or Medscape Cardiology. This podcast is intended for health care professionals only. Any views expressed are the presenter's own and do not necessarily reflect the views of WebMD or Medscape.