Feb 28, 2022
This week, join author Makoto Hibino and editorialist Christoph Nienaber as they discuss the article "Blood Pressure, Hypertension, and the Risk of Aortic Dissection Incidence and Mortality: Results From the J-SCH Study, the UK Biobank Study, and a Meta-Analysis of Cohort Studies" and accompanying editorial "Taming Hypertension to Prevent Aortic Dissection: Universal Recognition of a "New Normal" Blood Pressure?"
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, associate editor, director of the Poly Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn this week's feature discussion. Oh, very interesting. We are going to delve into results from the Japan specific health checkup study, as well as the UK Bio bank study and also a meta-analysis of several cohorts and investigate the relationship between hypertension and the future risk of aortic dissection. Well, Carolyn, but first, how about we grab a cup of coffee and delve into some of the other articles in this issue, and I'll go first?
Dr. Carolyn Lam:
Please do.
Dr. Greg Hundley:
I'm going to discuss with you the AVATAR trial.
Dr. Carolyn Lam:
Hold on, Greg, remind us, the AVATAR trial?
Dr. Greg Hundley:
Right, Carolyn. So the aortic valve replacement versus conservative treatment in asymptomatic, severe aortic stenosis or the AVATAR trial is an investigator initiated international prospective randomized control trial that evaluated the safety and efficacy of early SAVR or surgical aortic valve replacement in the treatment of asymptomatic patients with severe aortic stenosis, according to common criteria.
Dr. Greg Hundley:
So for example, the valve area is less than one centimeter squared with an aortic jet velocity of greater than four meters per second, or a mean trans aortic gradient of greater than 40 millimeters of mercury. They also, all of the patients had normal LV function and negative exercise testing was mandatory for inclusion.
Dr. Greg Hundley:
And so these authors, led by professor Marco Banovic from the University Clinical Center of Serbia, tested the primary hypothesis that early SAVR would reduce the primary composite endpoint of all cause death, acute myocardial infarction, stroke, or unplanned hospitalization for heart failure as compared to a conservative strategy, according to guidelines. And the trial was designed as event driven to reach a minimum of 35 pre-specified events. The study was performed across nine centers in seven European countries.
Dr. Carolyn Lam:
Wow. A big important study. What did they find?
Dr. Greg Hundley:
Right, Carolyn? So they had 157 patients and they age average, 67 years and 57% were men and they were randomly allocated to early surgery, so 78 were in that group, or conservative treatment, and 79 were in that group. The follow-up was completed in May of 2021 and the overall medium follow was 32 months, 28 months in the early surgery group and 35 months in the conservative treatment group.
Dr. Greg Hundley:
There was a total of 39 events, 13 in early surgery and 26 in the conservative treatment arm. So Carolyn, in asymptomatic patients with severe aortic stenosis, early surgery reduced the primary composite all cause death, acute myocardial infarction, stroke, or unplanned hospitalization for heart failure compared to the conservative treatment. And so, Carolyn, this randomized trial provides preliminary support for early SAVR once aortic stenosis becomes severe, regardless of symptoms.
Dr. Carolyn Lam:
Wow. Interesting. Well, this next paper that I'm looking at describes a novel therapeutic target that, listen up, can lower plasma cholesterol and prevent thrombosis simultaneously.
Dr. Greg Hundley:
What? Are you sure about this? All right, Carolyn. All right. Describe this for us.
Dr. Carolyn Lam:
Well, I'll tell you what that target is. It is the coagulation factor prekallikrein, which I'm going to call PK, prekallikrein. Okay. Now, as a reminder, coagulation cascades are activated by tissue factor initiated extrinsic pathway and the contact system initiated intrinsic pathway. Both of which converge into the common pathway. Plasma kallikrein is a serine protease playing a crucial regulatory role in the intrinsic pathway and is generated from the liver expressed prekallikrein, a pro enzyme encoded by the KLKB one gene.
Dr. Carolyn Lam:
Now that was the background. In the current study, Drs. Song and Luo from Wuhan University in China and their colleagues identified that the plasma coagulation factor prekallikrein or PK interacts with the LDL receptor and induces its degradation in the lysosomes. In young Chinese Han adults serum PK concentrations positively correlate with LDL cholesterol levels. In hamsters genetic ablation of the KLKB one decreases plasma lipid levels through up-regulating LDL receptor in a manner additively to the PCSK nine inhibitor cyclocumarol.
Dr. Carolyn Lam:
Injections of the anti PK neutralizing antibody in mice and knock down of the KLKB one gene in rats also increased hepatic LDL receptor levels and reduced plasma cholesterol levels. Furthermore, in mice with ample E deficient background PK absence arrested the progression of atherosclerotic lesions. So in totality, these results suggest that PK, remember that's prekallikrein, regulates both LDL and thrombosis, and that PK inhibition can be an attractive therapeutic strategy to lower plasma cholesterol and prevent thrombosis simultaneously.
Dr. Greg Hundley:
Very nice, Carolyn. Well, before we get to our feature discussion on aortic dissection, I've got a paper that pertains to preclinical science and involves the study of aortic dissection. And it comes to us from Professor Aijun Sun from the Shanghai Institute of Cardiovascular Diseases at the Song Hang Hospital in Futon University, the Institute of Biomedical Science in Futon University.
Dr. Greg Hundley:
So Carolyn, the development of thoracic aortic dissection is closely related to the extracellular matrix degradation and the vascular smooth muscle cell transformation from contractile to synthetic type and legumin degrades the extracellular matrix components directly, or by activating downstream signals. However, the role of legumin in the vascular smooth muscle cell differentiation and the occurrence of thoracic aortic dissection, that remains elusive or unsolved.
Dr. Carolyn Lam:
Oh, so what did this study show?
Dr. Greg Hundley:
Right, Carolyn. So these authors found that the elevation of legumin is observed in thoracic aortic dissection tissues of both human subjects and in mice and deletion or pharmacologic inhibition of legumin rescues BAPN induced thoracic aortic dissection development in mice by alleviating extracellular matrix degradation and the vascular smooth muscle cell transformation. Carolyn, legumin depletion may represent a novel therapeutic strategy for thoracic aortic dissection and further studies are required to explore the diagnostic value of serum legumin as a novel biomarker for thoracic aortic dissection.
Dr. Carolyn Lam:
Wow. That's cool. Thanks, Greg. Well, there are other really cool papers in today's issue. There's a Cardiovascular Case Series by Dr. Bockus on a “Heart of Gold: A Scintillating Leading Pericardial Effusion. And I'll give you a hint, it's a case of cholesterol pericarditis. There are letters by Drs. Lucas and Taegtmeyer regarding the article “One Year Committed Exercise Training Reverses Abnormal Left Ventricular Myocardial Stiffness in Patients with Stage B HFpEF” with a response by Dr. Levine. There are highlights from the Circulation Family of Journals by Sara O'Brien.
Dr. Greg Hundley:
Well, Carolyn, I have some other papers to discuss in this issue as well. First, there's an On My Mind piece from Professor Lawler entitled, “What Are Adaptive Platform Clinical Trials, and What Role May They Have in Cardiovascular Medicine?” Next, there's an In Depth piece from Professor Damman entitled Evidence Based Medical Therapy in Heart Failure Patients With Reduced Dejection Fraction and Chronic Kidney Disease. And then finally, Professor Yoshida has a Research Letter entitled The Efficacy and Safety of Edoxoban 15 Milligrams According to Renal Function in Very Elderly Patients With Atrial Fibrillation, a Sub-Analysis of the Elder Care AF Trial. Wow, Carolyn, how about now we get onto that feature discussion.
Dr. Carolyn Lam:
Oh, let's go Greg.
Dr. Carolyn Lam:
For our feature discussion today, we are talking about aortic dissection and the association with hypertension or elevated blood pressure. Now at first sight, you may think, well, we all know that hypertension and elevated blood pressure is an important risk factor for aortic dissection, but I'd like you to question, do we really know?
Dr. Carolyn Lam:
Surprisingly few prospective studies have been published. We know that aortic dissection is an extremely important and serious complication, but it's low incidence means we need huge numbers to be able to answer questions such as, what blood pressure does the start taking off at? For example, is it systolic or diastolic blood pressure and so on? Well, guess what? We finally, I think, have some of the best evidence on this topic published in today's issue of Circulation.
Dr. Carolyn Lam:
And I'm so proud to have the first and corresponding author with us, Dr. Makoto Hibino from the University of Toronto to discuss his fantastic paper. As well as an editorialist, Dr. Christoph Nienaber from Imperial College, London, who will discuss the significance of this paper. Well, let's start with you, Dr. Habino or Makoto, if you don't mind, could you please tell us what you did and what you found?
Dr. Makoto Hibino:
Thank you, Carolyn. So it's my honor to be here to present my case in this podcast. So first, some of the recent data shows that the number of aortic dissection operation and this increasing trend, depending on countries and given the critical nature of aortic dissection preventive strategy against aortic dissection is expected. On the other hand, hypertension is still global issue and is responsible for constant number of deaths from cardiovascular diseases, including aortic dissection, but due to the relatively rare instance of dissection and acute critical nature of the disease, the available epidemiological evidence has been limited. So this time we wanted to investigate how the relationship of hypertension and blood pressure with the instance of the aortic dissection is, in terms of strengths association and the shape of the association.
Dr. Makoto Hibino:
We also hypothesized that association may not be leading a relationship. And what we did is our study is consist of three parts. The first two parts are original cohort studies using a Japanese specific health checkup study and UK Bio bank study in both of which we prospectively followed about half a million general population and analyzed the hazard risk of other aortic dissection instance for hypertension and systolic and diastolic blood pressure using Cox proportional analysis. And the last part is meta-analysis including eight cohort studies and examine the robustness and shape of the association between hypertension and systolic and diastolic blood pressure and the risk of aortic dissection.
Dr. Carolyn Lam:
Wow. So a huge study across diverse cohorts. What did you find?
Dr. Makoto Hibino:
Yes. So in both of our cohort studies, there was significant risk of aortic dissection for hypertension and systolic and diastolic blood pressure as a continuous variable. Also, there was increasing trend in hazard ratios for categorical systolic and diastolic blood pressure with two to five, for higher risk in the highest systolic blood pressure category and four to 12 for higher risk in the highest diastolic blood pressure category in the meta-analysis. The summary relative risk shows that those with hypertension has threefold risk of aortic dissection and the robustness of the result confirmed with the sensitivity and subgroup analysis. Lastly, in the non-linear dose response, meta-analysis, there was very strong dose response relationship between systolic blood pressure and aortic dissection with evidence of non-linearity. And similar, but still, those response relationship was found between diastolic blood pressure and aortic dissection. This analysis showed that the risk of aortic dissection was significant at systolic blood pressure more than 132 millimeter mercury, and diastolic blood pressure more than 75 millimeter mercury suggesting a risk of aortic dissection, even in non-hypertensive population.
Dr. Carolyn Lam:
Wow. That last part really grabbed me. And I think I should repeat that the risk was significant at the systolic blood pressure of only 132 and a diastolic blood pressure of 75. That's really striking. Chris toff, would you agree with me when I said, I think this is like the best data that we have now, sort of correlating blood pressure and hypertension with aortic dissection. I loved your editorial by the way.
Dr. Christoph Nienaber:
Thank you very much. I'm pleased to have the chance to write this editorial. Because, when I reviewed the article, I was thrilled of the data and the fact that somebody some consortium had managed to pool data from two different, let's say population studies in two different gene pools in Japan and in the UK together. And finding in a very granular way, that even within the normal spectrum of blood pressures, up to let's say 140 systolic, we find an increasing risk of dissection with a high normal blood pressure as compared to a low normal blood pressure. This has been very convincingly shown by Makoto's analysis. The entire group has to be congratulated for that fantastic idea. Collaboration from two different ends of the world, and then coming up with a similar conclusion in both populations, tells us that this is a general principle at work, that works in both gene pools in both Asian, as well as European populations, and tells us how important it is to keep an eye on blood pressure and even manage blood pressure within the normal range to a low normal in the future.
Dr. Carolyn Lam:
And I love the way you articulated that in that beautiful editorial, but could I now ask your thoughts, both of you, what are the clinical implications of this? I love Chris toff, that you discussed in your editorial, well, do we now lower the thresholds for treatment? Because aortic dissection is not the most common of incidences, right? So does lowering the blood pressure even more or targets come at a price? Or what should we be thinking of now, clinically?
Dr. Christoph Nienaber:
We are not treating dissection. We are trying to prevent dissection by gauging or gouging to a low normal blood pressure with various drugs and combinations of drugs in patients that are considered to be at risk with a slightly elevated blood pressure. So in the future, it's not enough to accept 140 systolic or 90 diastolic we should really pay attention to strictly lowering blood pressure in the idea of preventing vascular events.
Dr. Christoph Nienaber:
And that was considered to come at a price, but we have of course, reassuring data from Hope, from Sprint recently published that showed that even the low normal doesn't hurt. I mean, you have a lower risk of cardiovascular events, generally speaking, shown in Sprint with a low normal blood pressure. It comes a little bit at the expense of watching renal function, but that doesn't contribute to kind of prognostic sequelae. You just have to pay attention to it. You would not run any additional risk by lowering the blood pressure to a normal low blood pressure. And that's, I think, the convincing message, and even with a low incidence of the most important vascular accidents, such as dissection, you could prove that, or the group could prove that in almost 3000 patients that suffered from dissection, that whole pool of analyzed data. So again, I have to congratulate to this fantastic and convincing results.
Dr. Carolyn Lam:
Thank you. And Makoto, what do you think are the most important clinical take home messages from your study?
Dr. Makoto Hibino:
Yes. So let me, a little bit, step back to the summary of our findings. So our findings is so that this is a study is a fast summary of the evidence from the prospective stakeholder studies on the association of blood pressure and hypertension with the risk of aortic dissection. And this study improves the evidence base from being based on the case studies or single study to actual estimate of the relative risk. So also, with further study are needed, the current results suggests that the reducing blood pressure either through a healthier lifestyle or medication may reduce the instance of aortic dissection and furthermore the optimal target blood pressure may even lower than the current cut for hypertension. So from my perspective given the little rare instance of aortic dissection, intensive blood pressure management may be more effective or efficient in high risk population, such as those with bicuspid aortic valve or those with very ill medical follow for aortic aneurysm and those with genetic background. So further study in a specific subgroup, is warranted.
Dr. Carolyn Lam:
Thank you. And Chris toff, that's very interesting because I buy your argument too, that on the other hand, going lower, even in non-high risk, doesn't really come at a price as far as we can see. So what do you think Chris toff, what do you think are the further studies that are needed?
Dr. Christoph Nienaber:
Well, I was intrigued to see in their analysis that even the subgroups of patients, including patients with hereditary connective tissue disorders, survivors of previous dissection, patients with other conditions, including diabetes, et cetera, they're all across the board, benefited from low blood pressure adjust or adjustment to a low blood pressure. That gives me confidence to recommend to my colleagues, not only here, but in my further environment to follow those patients that are identified either as risk groups or with a slightly elevated blood pressure to definitely lower the blood pressure to lowest, lower to blood pressure with those side effects.
Dr. Carolyn Lam:
Nice. These are association studies just to take a step back rather than sort of treatment target studies, although we've discussed some of the treatment target studies, but I have to really agree that it's some of the strongest association data that I can frankly think of for blood pressure and aortic dissection. We're just so grateful that it has been published in Circulation. And thank you so much, Chris toff, for your elegant editorial, that really puts things in perspective with a very important final key take home message.
Dr. Carolyn Lam:
And with that, well listeners, you heard it right here on Circulation on the Run from Greg and I thank you for joining us this week. And, don't forget to tune in again next week.
Speaker 5:
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