Mar 20, 2023
This week, please join author Mikael Dellborg and Associate Editor Gerald Greil as they discuss the article "Adults With Congenital Heart Disease: Trends in Event-Free Survival Past Middle Age."
Dr. Greg Hundley:
Welcome listeners to this March 21st issue. And I am one of your co-hosts, Dr. Greg Hundley, Associate Editor Director of the Pauley Heart Center at VSU Health in Richmond, Virginia.
Dr. Peder Myhre:
And I am the other co-host, Dr. Peder Myhre, from Akershus University Hospital and University of Oslo in Norway.
Dr. Greg Hundley:
Well, Peder, we have a very interesting feature discussion this week. It focuses on adults with congenital heart disease. And as you are aware, over the last 25 to 30 years the survival rate of individuals with congenital heart disease has really improved. And this group, led by Professor Dellborg, will discuss with us more on results from a Swedish registry examining patients after the age of 18 with adult congenital heart disease. But before we get to that, how about we grab a cup of coffee and jump into some of the other articles in the issue? Would you like to go first?
Dr. Peder Myhre:
I would love it to, Greg, thank you. So Greg, the first paper is about aortic stenosis and the genome-wide association study looking at aortic stenosis in patients from the Million Veteran Program. And as you know, Greg, calcific aortic stenosis is the most common valve of heart disease in older adults and has no effective preventive therapies. Genome-wide Association studies, GWAS, can identify genes influencing disease and may help prioritize therapeutic targets for aortic stenosis. And in this study, which comes to us from co-corresponding authors, O'Donnell from VA Boston Health System and Dr. Natarajan from Massachusetts General Hospital, both in Boston Massachusetts, performed genetic analysis in 14,451 cases with aortic stenosis and almost 400,000 controls in the Multiancestry Million Veteran Program. And replication for these results was performed in five other cohorts.
Dr. Greg Hundley:
Wow, Peder, so a very large gene-wide association study. So what did they find?
Dr. Peder Myhre:
So Greg, the authors found 23 lead variants representing 17 unique genomic regions. And of the 23 lead variants, 14 were significant in replication, representing 11 unique genomic regions. And five replicated genomic regions were previously known risk loci for aortic stenosis, while six were novel. And of the 14 replicated lead variants, only two of these were also significant in atherosclerotic cardiovascular disease GWAS. And in Mendelian randomization, lipoprotein a and LDL cholesterol were both associated with aortic stenosis, but the association between LDL cholesterol and aortic stenosis was attenuated when adjusting for LP a. So Greg, in conclusion this study identified six novel genomic regions for aortic stenosis, and secondary analysis highlighted roles of lipid metabolism, inflammation, cellular senescence and adiposity in the pathobiology of or stenosis, and also clarified the shared and differential genetic architectures of aortic stenosis with atherosclerotic cardiovascular disease.
Dr. Greg Hundley:
Wow, Peder, what a beautiful description. Very comprehensive study. Well, my study comes to us from the world of preclinical science and, Peder, it involves embryonic heart development. So Peder, placental and embryonic heart development occur in parallel, and these organs have been proposed to exert reciprocal regulation during gestation. Poor presentation has been associated with congenital heart disease, an important cause of infant mortality. However, the mechanisms by which altered placental development can lead to congenital heart disease remain really unresolved. So in this study, led by Dr. Suchita Nadkarni from Queen Mary University of London and colleagues, the team used an in vivo neutrophil-driven placental inflammation model via antibody depletion of maternal circulating neutrophils at key stages during time-mated murine pregnancy, embryonic day 4.5, 7.5, and then the animals were culled at embryonic day 14.5 to assess placental and embryonic heart development.
Dr. Peder Myhre:
Oh, wow. Very interesting design. And, Greg, I'm curious to know what did they find?
Dr. Greg Hundley:
Right, Peder. So they found that neutrophil-driven placental inflammation leads to inadequate placental development and loss of barrier function. And consequently, placental inflammatory monocytes of maternal origin become capable of then migrating to the embryonic heart and alter the normal composition of resonant cardiac macrophages and cardiac tissue structure. This cardiac impairment continues into postnatal life, hindering normal tissue architecture and function. Also, they found that tempering placental inflammation can prevent this fetal cardiac defect and is sufficient to promote normal cardiac function in postnatal life.
So in conclusion, Peder, these observations provide a mechanistic paradigm whereby neutrophil-driven inflammation in pregnancy can preclude normal embryonic heart development as a direct consequence of poor placental development. And this in turn certainly has major implications on cardiac function into the adult life of these animals. And this really warrants further study in larger animal models and perhaps human subjects.
Dr. Peder Myhre:
Very interesting, Greg. Thank you for summarizing that. And we also have some other articles in the mail bag today. Do you mind going first?
Dr. Greg Hundley:
Sure, Peder. So what I've got is a very nice exchange of letters from Doctors Deng, Schmidt, and Tabák regarding a prior paper entitled, "Risk of Macrovascular and Microvascular Disease in Diabetes Diagnosed Using Oral Glucose Tolerance Test With and Without Confirmation by Hemoglobin A1c: The Whitehall II Cohort Study."
Dr. Peder Myhre:
And Greg, we also have a Research Letter from Dr. Niklas Bergh entitled, "Risk of Heart Failure in Congenital Heart Disease: A Nationwide Register-based Cohort Study." And then there is an article summarizing Highlights from the Circulation Family written by Molly Robbins [and Dr. Parag Joshi] where she summarizes, first the characteristics of pleomorphic ventricular tachycardia described in Circulation: A and E, then racial inequities in assessing advanced heart failure therapies reported in Circulation: Heart Failure. Outpatient clinic-based vascular procedure outcomes are compared with those done in a hospital setting in Circulation: Cardiovascular Quality and Outcomes. Then there's a paper about immune cell imaging using nuclear methods from Circulation: Cardiovascular Imaging. And finally, temporal trends in left main PCI from the UK described in Circulation: Cardiovascular Interventions.
And then Greg, we have one final very interesting paper, which is a joint opinion from the European Society of Cardiology, American Heart Association, and American College of Cardiology, in addition to the World Heart Federation and it's entitled, "Randomized Trials Fit for the 21st Century."
And I'm going to read you a quote from the beginning of this article, Greg. It is, "Randomized controlled trials are the cornerstones for reliably validating therapeutic strategies. However, during the past 25 years, the rules and regulations governing randomized trials and their interpretation have become increasingly burdensome, and the cost and complexity of trials has become prohibitive. The present model is unsustainable, and the development of potentially effective treatments is often stopped prematurely on financial grounds, while existing drug treatments or non-drug interventions, such as screening strategies or management tools, may not be assessed reliably." What do you think about that?
Dr. Greg Hundley:
Oh, wow, Peder. Very provocative. So it'd be interesting for our listeners to take a gander at that particular paper. Well, what a great issue and how about we get on to that feature discussion?
Dr. Peder Myhre:
Let's go.
Dr. Mercedes Carnethon:
Thank you for joining us on this episode of Circulation on the Run Podcast. My name is Mercedes Carnethon. I'm an Associate Editor at the journal Circulation and Professor and Vice Chair of Preventive Medicine at the Northwestern University, Feinberg School of Medicine. I'm thrilled today to be able to host this podcast alongside my colleague at Circulation, Gerald Greil, and with our special guest today, Dr. Mikael Dellborg from the Sahlgrenska Academy at the University of Gothenburg and Sahlgrenska University Hospital. Welcome this morning, Mikael, to our podcast. We're really excited that you shared this important work to us about adults with congenital heart disease, particularly given the burden of the condition and how many more individuals are living to adulthood with congenital heart disease. So I'd love to really just open with asking you to tell us a little bit about your study and what you found.
Professor Mikael Dellborg:
Well, first thank you for inviting me to talk about these issues. I very much appreciate the opportunity and I appreciate having the paper published by Circulation, which of course is a great honor.
Our study included 37,278 patients with congenital heart disease born between 1950 and 1999, and alive at 18 years of age. Follow-up was started in 1968 and at 18 years of age, and went on until the end of 2017 or death. So the mean follow-up was 19.2 years. And for every patient with CHD, we had 10 randomly chosen controls from the general population registry, matched for year of birth and sex and, of course, without CHD, so 37,000 patients and 412,000 controls. During the follow-up, 1,937 patients with CHD died or 5.2%, as compared to 1.6% of controls, a mortality three to four times higher among patients with CHD.
Still, at 50 years of follow-up, i.e. at age 68, more than 75% of all patients with CHD were still alive, and I think that is the positive news of this paper. Mortality wise, this could be expected highest among those with the most severe defects, the conotruncal defects, i.e., the transposition of the great arteries, the tetrology patients, double out ventricles and so on. And there the hazard ratio for death was 10.1 times that of controls. But also, for non-com complex conditions such as that we consider very malignant such as atrial septal defect, the ASD, there was a slight but significant increase in risk with the hazard ratio 1.4 times that of controls. We also looked at how the increased risk of mortality changed over time. And when comparing birth year by birth year, we could see that things started to really change in the mid 1970s, where the hazard ratio began to decline.
So if you were born around 1950, '60 or '70, once you reached 18 years of age, your risk of dying had not really changed over the years. But once you were born '75, '80, '85 and on, your risk past 18 years of age declined and was lower as compared to those born before that, although still higher than the risk for controls. This decline was dramatic and significant for all patients with complex CHD. For patients with less complex conditions, it was smaller and not statistically significant. Although it trended in the same direction. The excess risk also declined with age. Typically, it declined from 20 to 100 times the risk of controls in the first years after turning 18, to seven to eight times after 30 years of follow-up. In other words, when you were in your fifties the difference between CHD and controls was much smaller, although still existed.
Dr. Mercedes Carnethon:
Oh, wow. So that really seems to shift over time and that gap got a little smaller with aging. What about these findings surprised you?
Professor Mikael Dellborg:
What surprised us was to see that there is a... For the CHD population as a group, we can see that the changes in operative techniques, the possibility to operate on much earlier time that became used in the '70s, mid-late '70s, early '80s, that has really changed life for so many patients. When we started the Adult Congenital Heart Unit at our hospital in 1996, there was a belief that either you were cured or you are a sad person to follow. You will only have trouble and you will die in your thirties or you'll get a transplant. That was the three conditions that we could see coming, but that's not true. I mean, again, once you turn 18, once you come to the adult cardiologist, you will most likely be 68, 70 years, 75 years of age.
Dr. Mercedes Carnethon:
Now, that is fantastic. I want to turn to you, Gerald, because you were obviously the handling editor of this piece and saw a lot of strengths. Can you tell us a little bit about why you wanted this piece for Circulation?
Dr. Gerald Greil:
Mikael, thank you so much for submitting to Circulation. The numbers of the patients you had for this study, including the controls, is impressive and we all think that it's one of the largest patients areas we looked at. Mikael, obviously this is all exceptional, but can you line out to us what are the strengths and limitations of your study? And how you think the results of your investigations are going to impact patient care in the future?
Professor Mikael Dellborg:
Thank you, Gerald. I think that the strengths are obviously, like you pointed out, there's 37,000 patients. There is 50 years of patients, there's 20 years of follow-up on average and that's clearly a strength. Also, that we have virtually no patients lost to follow-up. We have many controls and the registers we used are public, mandatory and have been fully operational for CHD care and CHD hospitals and including the death registry since 1968, which is when we really started the follow-up. So it's a broad and complete spectrum of patients with congenital heart disease, excluding none, and I think it's fair to say that our data reflect what you can expect from a population of eight to 10 million people, which is the Swedish population during these years.
The weaknesses are clearly, as with any data of this sort, i.e. Large public registers, you will always lack the granularity. The clinical data, the blood pressure, weight, ECG, the echocardiogram, the cath data, et cetera. And also the lifestyle information, smoking, exercise, diet.
It's also important to realize that Sweden was, particularly at this time before 2000, it was a fairly homogenous society in terms of ethnicity. One feature, which I'm not sure if it's a strength or a limitation, is that we group patients with CHD into one or sometimes two complex non-complex or at the most six groups. And since CHD consists of about 400 different diagnosis and entities, we paint a broader general picture. But if you want to know more about specific conditions such as say, hypoplastic left heart syndrome, you need to look for other and more specific papers.
We're currently working on several more analysis based on this material for more narrow patient groups where we can take into consideration also things such as type of surgery or intervention, timing of intervention, medication and so on. We have a lot of data on this, but it was simply not possible to put everything into one paper.
Dr. Gerald Greil:
Yeah, I mean speaking about getting more specific, we were fortunate enough having one of your colleagues publishing about patients with congenital heart disease. They looked at the time period from 1930 to 2017 using the same database. And they focused specifically on heart failure in this group of patient describing it in a research letter, actually in the same volume your paper's published. How does this study relate to your work? And how do you think are their results impacting the care of these patients?
Professor Mikael Dellborg:
I think they relate to our paper in a nice way, because one of the things we also could show was that the morbidities of patients with adult congenital heart disease are significant. The risk of heart failure, atrial fibrillation, stroke, nonfatal MI, diabetes, and so on, is much larger in that group. And the cumulative risk of having any such adverse event is about 75% at age 68 after 50 years of follow-up. The letter by Bergh et al. focuses on, as you say, heart failure. And during a follow-up or 25 years, there was an overall, like you said, 8.7 times higher risk for patients with CHD to develop heart failure. The most, I think, important factor from this is not only that the risk is increased, it has been described before and it's obvious and quite intuitive, but there was a dramatic difference in the age of onset of heart failure, which was about 40 years in patients with CHD compared to 66 years of age for the controls who developed heart failure.
And again, it was obvious that it was highest among the most complex CHD. The risk was 20 to 40 times higher. But also among non-complex CHD, the atrial receptor defects, the ventricular receptor defects, the risk was significantly higher, five to 10 times. One thing we saw there was that... That could be seen there was that the risk was particularly high in the youngest age group, the youngest patients, as compared to controls. And not so much, although still significant, it increased also in the higher age groups. We could also see that the risk of heart failure seemed to increase. It was higher among those born after 1970 as compared to those before 1930 to '69.
And I have two explanations for that. One is that a lot of patients born in 1930 and so on were not captured by our registers, because they have died before that. But it also reflects that the most complex patients, the most likely to develop heart failure, they survive these days. They did not survive in their thirties, forties, fifties, sixties and early seventies and so on, so that's why. So things haven't been worse, but we do have a much sicker group of patients with congenital heart disease that are alive today.
Dr. Mercedes Carnethon:
That's very hopeful. When I hear that and I think about the impact that treatment and therapy has had on these improvements in survival, it's really exciting to hear. We were really enthusiastic because our colleagues, Dr. Rosenthal and Qureshi from London, submitted an editorial to discuss your piece as well as Dr. Bergh's piece. And they're discussing in it some of the complexity in providing this care and what it has taken to get us to this point where survival is better. Can you tell us a little bit based on the findings from your study and what you know of the field, how do you envision the future care of adults with congenital heart disease?
Professor Mikael Dellborg:
Yes, Mercedes, thank you. I think this is a very nice editorial. It summarizes very well where we are today, and I think they see the future very much along the same lines as I do and as we do. But the large number of patients with CHD living into their sixties, seventies, and eighties, they will not only live longer, they will also have more comorbidities. And I think that's what our data shown and what the editorial is discussing. This will require some changes to be made to the care of adults with congenital heart disease. We will clearly, as pointed out, need large, highly specialized, very competent ACHD centers located close to, or at least in close corporation with pediatric centers. There's no doubt about that building such centers need to continue and you need roughly one large complete such center with outpatient clinic, surgical interventions, structured transfer, specialized physicians, physiotherapists, nurses, education research, et cetera.
You need about one such center per 5 million people. But over time the need of ACHD patients will also change and this will have impact also on the large specialized centers. For instance, if you have an adult patient with say, tetrology of Fallot, fairly common disease in this setting, well operated on a early childhood, well-functioning, modest right ventricular dysfunction, modest pulmonary valve insufficiency, and it's followed by a large centralized ACHD unit. You will keep track of the right ventricle size waiting for the proper time to intervene and replace the right ventricular outflow tract by surgery or catheter. This waiting is probably 10, 15, maybe 20 years before anything needs to be done. But during that time the patient develops hypertension, type 2 diabetes, AFib, and the chances of this happening at some time are fairly substantial. So either the ACHD unit needs to take care of also these comorbidities and that's not always the case today.
And I think it's unrealistic to expect primary care GPs to do this. I mean, would you as primary... As a GP start the SGLT2 treatment? Is that okay for a patient with Fallot? Or the indications for anticoagulation the same as... And that's not easy patients to handle. So on the other hand, if the ACHD unit will take care also of all these comorbidities, they will, I think, have too much to do and I think they will find it difficult to completely cope with this. So as in increasing role for cardiologists who are knowledgeable on ACHD care, but who perhaps spend most of the time caring for the usual patients with heart failure and AFib, post-MI, type 2 diabetes and who are confident in using novel anti-diabetic medications, but at the same time they know about Fallot. They know enough to understand the do's and don'ts, and they can interact on a regular basis with the local ACHD units. So patients will see their general cardiologist twice a year perhaps, and the ACHD center every two years, something like that. I think there's a great need for that.
Dr. Mercedes Carnethon:
I really appreciate having your insights on that. Do you have anything, Gerald, that you'd like to follow up with? I think the feedback that you've shared with us, Mikael, about where you see the treatment field going for adults has been very comprehensive and it's fantastic to be able to have these conversations with you, because obviously these discussions go beyond what you can share in the original research article, which is why we really enjoy this opportunity with the podcast. So Gerald, I'd really like to turn it to you for a final wrap up, given your expertise in this area.
Dr. Gerald Greil:
Yeah, I mean, Mikael, thank you so much to you and your colleagues just giving us this great overview, and even more importantly giving us the perspective how this field is going. I think we are getting more and more aware that there are more patients with and adults with congenital heart disease we need to take care of. We need to find new strategies, as you correctly pointed out, to cope with the enormous burden of disease and providing these patients good quality of life and excellent outcome after sometimes a very difficult start in their lives. And we need to be aware of the pediatricians and adult cardiologists and other subspecialties are forming a team and working together and not working as separate entities. So thank you so much for giving us this perspective. And I would hand over to Mercedes to wrap up the whole discussion please.
Dr. Mercedes Carnethon:
Well, yes, I just really want to thank our listeners for tuning in with us today. It was such a delight to have you here with us, Dr. Dellborg, and thank you as well for sharing your insights.
Thank you for joining us again for this episode of Circulation on the Run Podcast. It's meant to whet your appetite and turn you towards the journal so that you can read more. So thank you very much.
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.