Jan 3, 2023
This week, please join author Judith Hochman, Editorialist Steven Bradley, and Guest Host Mercedes Carnethon as they discuss the article " Survival After Invasive or Conservative Management of Stable Coronary Disease" and editorial “If the Fates Allow: The Zero-Sum Game of ISCHEMIA-EXTEND.”
Dr. Greg Hundley:
Welcome everyone to our new year 2023, and we are here on this January 3rd edition of Circulation on the Run. I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr. Peder Myhre:
I am Dr. Peder Myhre, Social Media Editor and doctor at the Akershus University Hospital and University of Oslo.
Dr. Greg Hundley:
Very nice. Well, welcome listeners and this week's feature, ah, very interesting. You know many times patients with stable coronary artery disease, we're seeing a lot in the literature about an invasive strategy versus a conservative strategy. But what happens long term for these patients? What's their prognosis? Well, more to come in the feature discussion. But first, how about we grab a cup of coffee and we discuss some of the other issues in this session. Peder, would you like to go first?
Dr. Peder Myhre:
Yes, Greg I would love to and the first paper today is very interesting and relates to one of the most important challenges globally, namely climate changes and extreme temperatures. And in this paper, which comes to us from corresponding author, Barrak Alahmad from Harvard Chan School of Public Health in the United States, together with a large international group of authors, investigated the associations between extreme temperatures and cardiovascular cause-specific mortality in 567 cities in 27 countries from 1979 to 2019.
Dr. Greg Hundley:
Wow Peder, that is a really large comprehensive study. So, how did they perform this analysis? What did they find?
Dr. Peder Myhre:
So Greg, the investigators collected city-specific daily ambient temperatures from weather stations and analyzed cause-specific cardiovascular mortality and excess deaths in association with extreme hot and extreme cold temperatures. And in total, the analysis included more than 32 million deaths from any cardiovascular cause, which were subdivided into deaths from ischemic heart disease, stroke, heart failure and arrhythmia and at extreme temperature percentiles. And that is defined as heat above the 99th percentile and as cold below the first percentile were associated with a high risk of dying from any cardiovascular cause, ischemic heart disease, stroke and heart failure as compared to the minimum mortality temperature, which is the temperature associated with least mortality.
And Greg, across a range of extreme temperatures, hot days above the 97.5 percentile and cold days below the 2.5 percentile accounted for more than two and more than nine excess deaths for every thousand cardiovascular death respectively. And heart failure was associated with the highest excess death proportions from extreme hot and cold days. So Greg, it seems like extreme temperatures really impact the cardiovascular mortality across the globe.
Dr. Greg Hundley:
Yeah, beautiful description Peder. And I think what was really exciting about that particular article is you had results from 27 countries. Wow, so really quite a global study and very informative.
Dr. Peder Myhre:
Yes, indeed very impressive.
Dr. Greg Hundley:
Well, Peder my next study comes to us from the world of preclinical science. And Peder, these investigators led by Professor Jose Luis de la Pompa from CNIC, evaluated two structural cardiac diseases, left ventricular non-compaction and bicuspid aortic valve. And they wanted to determine if those two conditions were caused by a set of inherited heterozygous gene mutations affecting the notch ligand regulator, Mind bomb-1 and co-segregating genes.
Dr. Peder Myhre:
Okay Greg, so we are looking at mechanisms for non-compaction and bicuspid aortic valve. What did they find?
Dr. Greg Hundley:
Right Peder, so whole exome sequencing of the left ventricular non-compaction families identified heterozygous missense mutations in five genes co-segregating with E3 ubiquitin protein ligase-1 Mib-1 as well as left ventricular non-compaction. And corresponding mouse models showed that left ventricular non-compaction or bicuspid aortic valve in a notch-sensitized genetic background. Now, also gene profiling showed that increased cardiomyocyte proliferation and defective morphological and metabolic maturation in mouse hearts and human pluripotent stem cell cardiomyopathy. Biochemistry suggested a direct interaction between notch and some of the identified gene products.
And so, these data Peder support a shared genetic basis for left ventricular non-compaction and bicuspid aortic valve with Mib-1 notch playing a crucial role. And thus, identification of heterozygous mutations leading to left ventricular non-compaction or bicuspid aortic valve may allow us to expand the genetic testing panel repertoire for better diagnosis and or risk stratification of both of these conditions, left ventricular non-compaction and bicuspid aortic valve.
Dr. Peder Myhre:
All right, that is really great and novel linking left ventricular non-compaction to bicuspid aortic valve, really great. And now Greg, we're going to go back to clinical science and we're going to talk about lipoprotein(a) or Lp(a). And as you know, elevated Lp(a) is a common risk factor for cardiovascular disease outcomes with unknown mechanisms. And the authors of this next paper coming to us from corresponding author Olli Raitakari from University of Turku in Finland, examined Lp(a)'s potential role in identifying youths who are at increased risk of developing adult atherosclerotic cardiovascular disease, ASCVD. And they did this by measuring Lp(a) in youths nine to 24 years old and linking that to a diagnosis of ASCVD as adults and also linking it to carotid intermediate thickness in the Young Finns Study. And in addition, these results were validated in the Bogalusa Heart Study.
Dr. Greg Hundley:
Oh, very nice Peder. So, what did they find?
Dr. Peder Myhre:
So Greg, those who have been exposed to high Lp(a) levels in youth and that was defined as greater than or equal to 30 milligrams per deciliter, had about two times greater risk of developing adult ASCVD compared to non-exposed individuals. In fact, all the following youth risk factors were independently associated with a higher risk. Lp(a), LD, cholesterol, body mass index and smoking all independently associated with ASCVD. And similar findings were made in the validation cohort who were participants with a high Lp(a) had 2.5 times greater risk of developing adult ASCVD compared to non-exposed individuals. And this also persisted in adjusted models. Now, what about the carotid intermediate thickness? In that analysis, there were no associations detected to youth Lp(a) levels in either of the cohorts.
Dr. Greg Hundley:
Very nice, Peder. So, great description of the utility of lipoprotein(a) measurements in the youth and for predicting future major cardiovascular events. Well, the next paper goes back to the world of preclinical science. And Peder, cardiac hypertrophy increases demands on protein folding, which causes an accumulation of misfolded proteins in the endoplasmic reticulum. Now, these misfolded proteins can be removed via the adaptive retro-translocation, poly-ubiquitylation and a proteasome mediated degradation process. The endoplasmic reticulum-associated degradation, ERAD, which altogether as a biological process and rate has not been studied in vivo.
So, these investigators led by Dr. Christopher Glembotski from University of Arizona College of Medicine, investigated the role of ERAD in a pathophysiological model and they examined the function of the functional initiator of ERAD, VCP-interacting membrane protein and positing that the VCP-interacting membrane protein would be adaptive in pathological cardiac hypertrophy in mice.
Dr. Peder Myhre:
Thanks Greg. So, we're talking about degradation of the endoplasmatic reticulum and the association to hypertrophy. So, what did these investigators find, Greg?
Dr. Greg Hundley:
Right, Peder. So, this was really the first study to demonstrate that endoplasmic reticulum-associated protein degradation or ERAD is responsible for degrading and thus, regulating the levels of a cytosolic non-endoplasmic reticular protein. The results reported here describe a new mechanism mediating the pathological growth of the heart, such that in the healthy heart SGK-1 levels are low due to ERAD-mediated degradation. While in the setting of pathology, ERAD-mediated degradation of SGK-1 is disrupted, allowing the pro-growth kinase to accumulate and contribute to pathological cardiac hypertrophy.
And so Peder, the clinical relevance of these findings is that the investigators found that a variety of proteins that constitute the ERAD machinery were decreased in both mouse and human heart failure samples while SGK-1 was increased, supporting the possibility that SGK-1 is a contributor to the disease phenotype. And this is notable and that these studies could lead to the development of new therapeutic approaches for managing pathological cardiac hypertrophy and heart failure that target the ERAD to restore efficient SGK-1 degradation.
Dr. Peder Myhre:
That was an excellent explanation of a very difficult topic. Thank you, Greg.
Dr. Greg Hundley:
Well, Peder how about we take a look and see what else is in the issue? And now I'll go first. Well, first there's an In Depth by Professor Ntsekhe entitled, "Cardiovascular Disease Among Persons Living with HIV: New Insights into Pathogenesis and Clinical Manifestations within the Global Context." And then, there's a Research Letter by Professor Verma entitled, "Empagliflozin in Black Patients Versus White Patients With Heart Failure: Analysis of EMPEROR results-Pooled."
Dr. Peder Myhre:
Great Greg and there is an On My Mind by Gabriel Steg entitled, "Do We Need Ischemia Testing to Monitor Asymptomatic Patients With Chronic Coronary Syndromes?" Very timely and interesting. And finally, there is an AHA Update from Michelle Albert, the President of the AHA entitled, "Tackling Adversity and Cardiovascular Health: It is About Time."
Dr. Greg Hundley:
All right. Well Peder, how about we get onto that feature discussion looking at survival after invasive or conservative management in stable coronary heart disease?
Dr. Mercedes Carnethon:
Thank you so much for joining us for this episode of Circulation on the Run. I'm Mercedes Carnethon, Professor and Vice Chair of Preventive Medicine at the Northwestern University, Feinberg School of Medicine. And I'm very excited today to have as a guest, Dr. Judith Hochman, who is going to be discussing the long-awaited findings from the ISCHEMIA-EXTEND trial that are looking at survival after invasive or conservative management of stable coronary disease. Really pleased to have you with us today, Judy to hear about these findings.
Dr. Judith Hochman:
It's a pleasure to be here.
Dr. Mercedes Carnethon:
Thank you. So, just to start off, can you tell us about this study? What motivated this long-term follow-up of this particular trial?
Dr. Judith Hochman:
Yeah, so as I think the viewers or the listeners will recall, we built on a wealth of data from COURAGE and BARI 2D, some of the landmark trials that looked at revascularization versus optimal medical therapy or guideline-directed medical therapy alone. We tested an invasive strategy versus a conservative strategy dating back already to 2012 is when we started. And we had a five component primary outcome, which included cardiovascular death, myocardial infarction or hospitalization for unstable angina, heart failure or resuscitated cardiac arrest. And at the end of 3.2 median years of follow-up, we saw no difference in the primary outcome in that the curves crossed with some excess risk upfront due to periprocedural MI and decreased risk of spontaneous MI long-term. But the net overall timeframe spent free of event was similar between the groups.
So, we did observe improved quality of life for the invasive strategy, but in terms of clinical outcomes there was no difference. So, cardiovascular death at the end of that time period was no different between the groups, all-cause mortality was no different, non-cardiovascular death, there was actually an increase in the invasive group, which was somewhat of a mystery. We can get into that a little bit later because I think that becomes important. But 3.2 years meeting and follow-up is relatively short. So, everyone was very interested in what would the long-term outcomes be. So, we had another grant from the National Heart, Lung and Blood Institute to follow these patients long-term. And this is an interim report with seven years of follow-up, a median of 5.7 years.
And the bottom line is that all-cause mortality was the same at seven years but for the first time, an invasive strategy resulted in lower cardiovascular mortality, which was very interesting and very exciting except that it was offset, exactly offset by the continued excess that we had previously observed in non-cardiovascular mortality. And that's basically the upshot of what we just reported and why we continue to follow patients and why we're going to continue to follow patients and have a final report in 2026.
Dr. Mercedes Carnethon:
This is really fantastic work. As you point out, the initial follow-up was fairly short and the findings were so critically important demonstrating that there were subtle differences between the two approaches but that overall, things appeared relatively similar. Did it surprise you? Oh, please correct me.
Dr. Judith Hochman:
I should point out that because there were less spontaneous MIs during follow-up and spontaneous MIs are associated with a heightened risk of subsequent death more so than the periprocedural MIs, we did hypothesize and we're very interested in longer term cardiovascular and all-cause mortality thinking that those reduced spontaneous MIs in the invasive group would be associated with reduced cardiovascular death and perhaps reduced mortality. As I did indicate, cardiovascular death mortality was reduced but all-cause mortality was the same with a hazard ratio of 1.0.
Dr. Mercedes Carnethon:
Well, nothing seems more clear than a hazard ratio of 1.0 with those very tight confidence limits so thank you so much. I'm really pleased that our editorialist, Dr. Steve Bradley was also able to join us today because to hear his thoughts about where this fits in the context of what we know can be really insightful. So, I'd really love to turn to you, Dr. Bradley. In your opinion, why was this study question so important and tell us a little bit about how you think the clinical field should use these findings.
Dr. Steven Bradley:
Absolutely and thanks for having me. I think there were some indication that perhaps the farther we follow the patients out from the original ISCHEMIA trial that we might start to see some evidence of benefit for revascularization. I think Dr. Hochman spoke about the evidence of more of these spontaneous myocardial infarctions that were happening in the non-revascularization arm of the study and an association with worse cardiovascular outcomes in patients that experience spontaneous events. And so, the thoughts might be that over time we would see the benefit of that. And certainly if you parse out cardiovascular versus non- cardiovascular outcomes, we do, we see lower rates of cardiovascular death in the patients who undergo revascularization but it's balanced out by non-cardiovascular death. And so, it becomes a zero sum game for a patient. They want to be alive, it doesn't matter by what mechanism.
So, if we have a therapy that doesn't actually prolong their life but it leads to different mechanisms by which they have an outcome, that's important for us to understand. This adds to an already robust evidence-based that ISCHEMIA really did inform and it gives us that long-term trajectory to help us understand for patients what the implications are. I will note that and we've commented in the editorial and this is something that was shown in the original ISCHEMIA trial, that it's not just about mortality for patients, it's important that we help them live better as well. And certainly we know that revascularization is associated with quality of life improvement so that's an important part of the conversation with patients. But again, continuing to refine our understanding of what the implications of revascularization are for mortality is where this study leads us now.
Dr. Mercedes Carnethon:
Thank you so much. One of the things that I find so impressive about clinical trials of this scale are that you incorporate such a broad audience. I note that 36 countries contributed data to this particular trial. I wonder whether, did you have an opportunity to investigate whether these findings were similar in low and middle income countries as compared with higher income countries? And how would you expect clinicians in low and middle income countries to use this information?
Dr. Judith Hochman:
That's a great question and yes, the treatment effect was similar across regions, didn't really have any very low income regions but we did have India was in the study and a number of South American countries. And I think it's incredibly important for those countries where there are very limited resources to reassure them, the practitioners and their patients that just because they can't afford an expensive invasive procedure, stenting or bypass, does not mean it's going to cut their life shorter, it's not going to make them survive for a shorter amount of time. Therefore, they can limit the use of scarce resources to the most severely impaired in terms of quality of life, the patients with the most frequent angina. It also became extremely relevant during COVID.
Dr. Mercedes Carnethon:
Tell me more.
Dr. Judith Hochman:
Well, elective procedures were shut down during COVID and more publications that cited the ISCHEMIA trial to say that they felt comfortable not being able to do elective stenting in patients with stable ischemic heart disease that would've met the ISCHEMIA trial criteria, which by the way we should add was preserved ejection fraction, we excluded ejection fraction less than 35, patients had to be stable. They could not have had two coronary syndrome within the last few months. They could not have had angina refractory to medical therapy and they could not have had left main disease. So, those are key. There are other exclusion criteria but those are the key exclusion criteria.
Dr. Mercedes Carnethon:
Thank you for that. And I can really see a corollary and I appreciate the messaging around similar outcomes and preserving resources. And I think certainly even within our own country where we see vast differences in access to intensive medical therapies or tertiary care medical centers who do these procedures on a higher volume, at least we can feel reassured that outcomes may be quite similar as far as mortality. What do you-
Dr. Judith Hochman:
If they take their guideline-directed medical therapy.
Dr. Mercedes Carnethon:
Thank you for pointing that out.
Dr. Judith Hochman:
It's incredibly important. John Curtis' group looked at adherent patients by the modified Morisky score versus non-adherent patients. Non-adherent patients don't have as good a health status as adherent patients. So, just that also adds to a wealth of literature that you have much better outcomes if you actually take your medications.
Dr. Mercedes Carnethon:
No, I think that's a very good point. What are your thoughts, Steve on what the next steps might be?
Dr. Steven Bradley:
Well, I know that as was pointed out earlier, there's going to be the opportunity to see additional longer term follow-up beyond this interim analysis. So, it'll be interesting to see what that continues to show us in terms of understanding applications on mortality. I'll pose a question that we posed within our editorial around trying to identify non-fatal outcomes to see if there are any opportunity to capture those non-fatal outcomes to give us an understanding of potential mechanisms for why there is this cardiovascular versus non- cardiovascular mortality difference by treatment arm? Certainly, that may be helpful.
Dr. Judith Hochman:
Sorry. We're very, very interested in the excess in non-cardiovascular death. So, we are as a result of this interim analysis, revising our case report form, which was very lean, pragmatic because the funding is relatively limited to include especially collection of data around malignancy. Because as we reported before, the non-cardiovascular deaths were largely malignancy and to some extent infection. And what was driving the difference, the excess in non-cardiovascular death as we published in American Heart Journal in the invasive group was excess malignancy.
Dr. Mercedes Carnethon:
That's really interesting.
Dr. Judith Hochman:
To our deep surprise and shock, it appeared that the only variable associated with that excess risk was the number of tests or procedures you had that involve radiation. And of course, we're talking about medical doses of radiation. And this short timeframe, three and a half to seven years, which is when the curve started to diverge to three and a half, we filed to seven years is not thought to ... it's thought to be too short a timeframe for exposure to radiation to lead to excess malignancy.
So, we have partnered with some radiation experts, we are adding much more details to our case report form, not only in terms of death from malignancy but just the occurrence of malignancy. Did you get malignancy during the course of follow-up? And that's really critically important. We are not adding information about additional myocardial infarctions. We think that the key, if we're going to focus on site burden and how much they can actually collect, is to look at the mechanisms of death and the occurrence of malignancy, whether that leads to death or not, those are our top priorities at this point.
Dr. Mercedes Carnethon:
I could go on and on, I'm learning so much speaking with the two of you. And again, that really is the primary goal of our podcast to really have an opportunity to extend beyond what's written in the paper and really hear directly from the authors who led the study to hear your thoughts as well as those of the editorialists on where this is going. I really want to thank you both for the time you've spent today to share with our audience of the Circulation on the Run podcast.
Dr. Judith Hochman:
You're very welcome.
Dr. Steven Bradley:
My pleasure.
Dr. Mercedes Carnethon:
I just want to thank all of our listeners for joining us on this really stimulating discussion today on this episode of Circulation on the Run.
Please tune in next week where we will have more exciting discussions like this one. Thank you.
Dr. Greg Hundley:
This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.