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Circulation on the Run

Jul 8, 2019

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley:             And I'm Greg Hundley, also Associate Editor from the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr Carolyn Lam:                I'm so excited about our feature discussion today, Greg, because it is about a familiar but very important problem of hypertension, and we will be looking at trial results of a new drug, a first in its class type of drug. And tackling a problem that is particularly important perhaps in black patients with hypertension. Well, more very soon. First, let's discuss some papers, shall we? Do you have one?

Dr Greg Hundley:             My paper is from Joseph Burgoyne from King's College in London and pertains to resveratrol. Now, resveratrol is a non-flavonoid polyphenolic compound that has been found in the skin of several fruits, with the most notable being grapes. The compound exhibits beneficial effects, including the prevention of cardiovascular neurologic diseases, cancer, metabolic syndrome, as well as it promotes bone and eye health. And in this study, the investigative team explains how resveratrol may mediate its numerous beneficial effects including lowering of blood pressure by direct thiol oxidation. Also, they demonstrate that resveratrol can counter-intuitively induce direct protein oxidation, a process that is enhanced under pro-oxidative conditions associated with disease. The oxidation of cyclic GMP dependent protein kinase 1 alpha, or PKG1 alpha, by resveratrol lowers blood pressure in hypertensive mice.

Dr Carolyn Lam:                Okay. But what does that mean for us clinically, Greg?

Dr Greg Hundley:             Well, the results demonstrate how blood pressure can be lowered by using resveratrol, and targeting cysteine 42, or PKG1 alpha, may provide a new class of anti-hypertensive agents. In addition, identifying additional proteins modified by resveratrol may provide new targets for therapy to treat cardiovascular disease. Carolyn, how about your first paper?

Dr Carolyn Lam:                We are going to look at the further results of the ODYSSEY OUTCOMES trial. And as a reminder, ODYSSEY OUTCOMES was a double-blind randomized comparison of the PCSK9 antibody Alirocumab with placebo in almost 19,000 patients who had an acute coronary syndrome 1-12 months previously and elevated at the atherogenic lipoproteins despite intensive statin therapy.

                                                And that trial found that Alirocumab reduced the risk of the primary composite outcome of coronary heart disease, death, ischemic stroke, myocardial infarction, or unstable angina requiring hospital admissions. The current paper looked further at the effects of Alirocumab on death.

Dr Greg Hundley:             So Carolyn, what did they find?

Dr Carolyn Lam:                Well, there are quite a number of findings here. The first, there were fewer deaths in total that occurred with the PCSK9 inhibitor Alirocumab versus placebo, and this resulted from a non-significantly cardiovascular and non-cardiovascular deaths with Alirocumab. The second finding was that in a pre-specified analysis of more than 8,200 patients eligible for 3 or more years of follow-up, Alirocumab reduced death.

                                                And then, the third finding was that patients with non-fatal cardiovascular events were at increased risk for both cardiovascular and non-cardiovascular deaths, and a post-Hoc analysis found that compared to patients with a lower LDL, those with a baseline LDL above 100 had a greater absolute risk of death, and a larger mortality benefit with Alirocumab. In the Alirocumab group, all cause death declined with a lower achieved LDL achieved at 4 months of treatment to a level of approximately 30.

                                                So in summary, Alirocumab added to intensive statin therapy, has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for 3 or more years, and if baseline LDL is 100 or more, or if achieved LDL is low.

Dr Greg Hundley:             That's great, Carolyn. My next paper is going to talk a little bit about endothelial cells. And what I think we're going to learn is that not all endothelial cells are alike. This comes from Dr Rajat Gupta from Brigham and Women's Hospital, and I really thought this was an interesting article that used single-cell RNA sequencing to make it possible to identify and characterize cellular sub-populations.

Dr Greg Hundley:             The investigative team performed enzymatic dissociation of 4 whole mouse aortas, followed by single-cell sequencing of over 10,000 cells.

Dr Carolyn Lam:                Wow. What did they find?

Dr Greg Hundley:             Well using cluster analysis of gene expression from the aortic cells, they identified 10 populations of cells representing each of the main arterial cell types. There were fibroblasts, vascular smooth muscle cells, endothelial cells, immune cells, including monocytes, macrophages, and lymphocytes. And importantly, there were 3 distinct endothelial cell sub-populations with differences in them driven by major functional gene programs including adhesion and lipid handling.

                                                Comparison of aortic single-cell RNA sequence data sets from normal and Western diet-fed mice suggested that these sub-populations exist under both dietary conditions and have some unified responses to diet alteration. Also, immunofluorescence using single marker genes to identify endothelial cell sub-populations showed that the VCAM1 positive population was spatially located in regions of disturbed flow like the lesser curve of the aorta.

Dr Carolyn Lam:                Okay. So bring it home for us, Greg. What does this mean clinically?

Dr Greg Hundley:             Yeah exactly, Carolyn. So, characterizing functional sub-populations may serve as a novel method for understanding endothelial health in patients with vascular disease. And although aortic endothelial cell sub-populations demonstrate some unified responses to vascular disease relevant stimuli, like a Western diet, functionally different sub-populations may contribute differentially to vascular diseases, enabling sub-population targeted therapies to perhaps be implemented in the future.

Dr Carolyn Lam:                Cool. So Greg, cardiomyopathies have often been seen as genetic in origin, but what about potentially modifiable causes? So, this next paper that I picked looked at that, and it's from corresponding author Dr Rosengren from Sahlgrenska University in Gothenburg, Sweden, who with her colleagues, sought to investigate a potential link between obesity in adolescence and being diagnosed with cardiomyopathy in adulthood.

                                                So, this was a nation-wide register-based prospective cohort study of almost 1 million 690,000 adolescent men who were enlisted for compulsory military service from 1969 to 2005. Now at baseline, body mass index, blood pressure, and medical disorders were registered, along with test results for fitness and muscle strength. Cardiomyopathy diagnosis was then identified from the National Hospital Register and Cause of Death Register.

                                                So, they found that during a median follow-up of 27 years, 4,477 cases of cardiomyopathy were identified, of which 59% were dilated, 15% were hypertrophic, and 11% were alcohol or drug-induced. Increasing body mass index, or BMI, was strongly associated with elevated risk of cardiomyopathy, especially dilated cardiomyopathy, starting at levels considered normal, meaning a BMI of 22.5 to less than 25 kilograms per squared meters.

                                                And this was even after adjusting for age, years, center, and baseline comorbidities. There was a more than 8 fold increased risk of cardiomyopathy at a body mass index of 35 and above, compared with a BMI of between 18.5 and less than 20.

Dr Greg Hundley:             So, it sounds like BMI elevations and cardiomyopathies don't go together. So, what are the clinical implications?

Dr Carolyn Lam:                This really shows that even mildly elevated body weight in late adolescence may contribute to being diagnosed with cardiomyopathy in adulthood. So, the already marked importance of weight control in youth is really further strengthened by these findings, as well as the greater evidence for obesity as a potential important cause of adverse cardiac remodeling that is independent of clinically evident ischemic heart disease.

Dr Greg Hundley:             Outstanding. So, BMI, not good.

Dr Carolyn Lam:                Nope, Greg. High BMI, not good. That was fun, Greg. So, shall we move on to our feature discussion?

Dr Greg Hundley:             Absolutely.

Dr Carolyn Lam:                For our feature discussion today, we are talking about a familiar problem, but just so very important, and that is hypertension. And guess what? Our feature paper discusses a new first in class centrally-acting renin-angiotensin system blocker that has such remarkable initial results. I am so pleased to have with us the corresponding author for the paper, Dr Keith Ferdinand from Tulane University School of Medicine, as well as our Guest Editor, Dr David Calhoun from University of Alabama and Birmingham.

                                                Keith, could you start by telling us a little bit about the kinds of patients you see there in New Orleans that struggles with hypertension control perhaps? And then, please tell us about Firibastat.

Dr Keith Ferdinand:         I'm in New Orleans. In fact, I'm a native New Orleans. And as you know, most of the south and southeast and part of the United States has a high proportion of African American or US blacks. This population has higher rates of hypertension, increased prevalence, more severe hypertension, and more uncontrolled hypertension.

                                                We also note in the south that there tends to be an increase in obesity, which is a powerful risk factor for all patients with hypertension, regardless of race or ethnicity. And unfortunately, the rates of obesity appear to be increasing. So based on the fact that we have an increase in obesity, we have many patients whose blood pressures are not controlled, and some of the previous data have suggested less response to first step or monotherapy with ACE inhibitors and angiotensin receptor blockers, I initiated a trial with a first in its kind oral active brain aminopeptidase A inhibitor.

Dr Carolyn Lam:                Wow. Could you tell us a little bit more about brain aminopeptidase, and this new drug Firibastat?

Dr Keith Ferdinand:         Most people don't know anything about this molecule, because this is something that was discovered by some French physiologists. They approached me to design the clinical trial here in the United States. And what it does is, it blocks the conversion of angiotensin II to angiotensin III in the brain. Angiotensin III is actually the active component of the renin-angiotensin system centrally, and if you block angiotensin III production, it has a triple therapy effect.

                                                One is that it causes the diuresis. It decreases sympathetic tone, and it stimulates the carotid artery, such that you have, again, a decrease in sympathetic tone. Now, why choose it for patients who are obese, and why want to include a large proportion of non-Hispanic blacks here in the United States? Well, the reasons are that when you look at some of the bench research using rats, it appears to have a more beneficial effect in DOCA-salt rats, which is a model for salt-resistant hypertension.

                                                Salt-resistant hypertension is more common in blacks, more common in patients with obesity, and may indeed be one of the reasons why monotherapy or first-step with conventional renin-angiotensin system agents, specifically ACE inhibitors and ARBs, have not been as effective in the past.

Dr Carolyn Lam:                Gosh. That is so interesting, and it's really making me think about my patients too here in Asia, where we have a lot of salt-sensitive hypertension. Now, could you please tell us about the trial you did, and what you found?

Dr Keith Ferdinand:         We looked at a cohort of patients. All of the patients were overweight and obese. They were washed out for 2 weeks, and had a systolic blood pressure of 145-170, and a diastolic of less than 105. We wanted to get at least 50% self-identified blacks or Hispanics, and I suspect that any patient who meets this phenotype, and that would include Asians, or even Whites, may respond similarly.

                                                We then placed them in an open label format, and I can discuss why we used an open label, with monotherapy with Firibastat. After 2 weeks, we then titrated the dose level from 250 twice daily to 500 twice daily if needed, and we had a low dose thiazide and hydrochlorothiazide 25 mg addition, if needed, for escape, if patients had a blood pressure greater than 160/100.

                                                The other thing that was interesting and unique about this particular trial is that we used the automatic office blood pressure, where the blood pressure was taken 6 times. The first time was discarded, and then averaged, without a particular doctor or a nurse being there to do the blood pressure. We felt that this was a valid means of getting blood pressure loaded. It tends to mimic, to a large extent, what you see in 24 hour inventory daytime systolic blood pressure.

                                                So, this was a valid means of measuring blood pressure loads. This was a relatively high risk patients. And these were patients whom, previously, probably would not have responded as well to monotherapy with ACE inhibitors or ARBs.

Dr Carolyn Lam:                That's really clear, and clever design. I would love to hear a little bit more about why the open label, and of course, the results.

Dr Keith Ferdinand:         Well, that's one of the criticisms of this study, but actually, we presented to the FDA when we were discussing designing this trial, perhaps doing a placebo control trial. And we were told by the FDA that if you use a valid means of measuring blood pressure load, so that would be ambulatory blood pressure, or automated office blood pressure, that a placebo would not be necessary, because those means of checking blood pressure load would be considered a true valid means of finding a blood pressure effect.

                                                The other thing is, dealing with minority patients, and really dealing with patients in general, for blood pressure, if they have substantial hypertension, the message has been out there that this is a killer and cause of cardiovascular disease. It would probably have been very difficult to enroll the patients, you've got 254 patients in a national study. It would have been very difficult to enroll these patients, who would have known easily that they had substantial elevation of blood pressure, and we said, "You know, 50% chance you're going to get a sugar pill that has no effect."

Dr Carolyn Lam:                Right. Right. Very nice. The results?

Dr Keith Ferdinand:         Well, the results were a robust 9.7 mm reduction in systolic blood pressure. At day 56, the p-value was less than 0.0001. And when you do a sub-group analysis of patients who were in the study, it was effective for persons who are under 65, or over 65, male or female. All patients were overweight, and the patients who were obese, with a BMI of 30 or above, had a trend towards even a better blood pressure effect, which again, is not seen with first step with conventional ACE and ARBs.

                                                We also did an analysis based on black and non-black, and there was no difference, again with the trend towards the black patients actually doing fairly well. So, the take home from the particular study was this is the first in its kind, new approach to central Ras blockage with aminopeptidase A inhibitor, that was effective in a population which was overweight and obese, with over 50% minority, and showed substantial blood pressure reduction using a valid means of checking blood pressure, the automated blood pressure in the clinic.

Dr Carolyn Lam                  Keith, congratulations. A very important study. David, could I bring you in here? What were your thoughts as you were managing this paper, and what do you think are the future steps here?

Dr David Calhoun:            Looking at the submission, I was obviously excited about the results and the potential implications. I think, like Keith, in treating a lot of resistant or obesity-related hypertension, we're frustrated that control rates are not better, that the initial response to monotherapy is not better, and that's particularly true of Ras blockers. I think many of us are investigating the initial use of Ras blockers for a variety of reasons related to outcome benefit and reduction in incident and diabetes.

                                                So, I know I like to start with such an agent. I'm particularly excited that there may be, firstly, a new opportunity to block the Ras system, and potentially comparable or even better in the most difficult patients to treat. That is, the African American and the Hispanic patients, who often have very severe hypertension. So, my initial reading was I was very excited to see the potential, and that was brought out by the reviews as well. They shared my excitement. So, I'm looking forward to Keith advancing this compound.

Dr Carolyn Lam:                Indeed. Keith, I'm sure everyone's thinking now, wow, remarkable results. What's the drawbacks? How well-tolerated was this drug?

Dr Keith Ferdinand:         One of the drawbacks is that the structure of Firibastat included a sulfhydryl group. And we saw with early studies with captopril, which also has a sulfhydryl group, some skin rash, and we saw those similar changes with some of the patients in this particular study. At least 2 of them were suggested to potentially have erythema multiforme, although this was not proven. This was an investigator initiated adverse event.

                                                So, I don't know if we're going to be able to structure a similar type of aminopeptidase inhibitor without a sulfhydryl group. The other thing is that in its presence formulation, it's given twice daily. We know optimally you'd like to have a long-acting agent that can be given once daily. And I don't think we need a placebo control trial, but we may need to do a trial where patients are on 2 or more medications, and then, you add the Firibastat versus adding placebo. But, I don't think at this particular point, we need to get some of these more difficult to treat patients, and just place them on placebo, and watch and see what happens.

                                                We know what happens. The blood pressure goes up. Many of them may have acute heart failure, or progression of renal failure. And I just don't think it's necessary. And the FDA doesn't think it's necessary to prove that hypothesis.

Dr Carolyn Lam:                David, what do you think about that? Do we need a placebo control trial? And that use of ambulatory blood pressure, that's novel aspects of this trial too.

Dr David Calhoun:            I think use of placebo comparison has been for the traditional or conventional approach. I think most investigators, most clinicians, sort of anticipate seeing the placebo corrected effect. So, I think the results would have been, or will be potentially, more compelling if that's done. But, I can also appreciate Keith's contention, and it sounds like the FDA, that in this day and age, with use of automated office blood pressure measurements tend to minimize that white coat effect, and particularly true of ambulatory monitoring, that it may be that not using a placebo comparison maybe is compelling as well.

Dr Carolyn Lam:                Indeed. I really enjoy actually just digging deep into the study like this. Keith, if I could just ask for some final words from you, learning lessons, or even what have you got planned next.

Dr Keith Ferdinand:         The first lesson is, we need to continue to pay attention to hypertension. It's kind of been placed on the back burner with more interest now in diabetes and sugar, a lot of interest in lipids because of some of the new agents. But if you look across the globe, Asians, blacks, whites, regardless of race or ethnicity or geography, hypertension is the most potent cardiovascular risk factor, and I think we need to continue to address that.

                                                In terms of this particular agent, I believe that we will have to have some sort of placebo arm, but again, I think it's going to be built on a conventional medication, and then randomized with Firibastat versus placebo on top of conventional medications. In a more severe or a more difficult to treat hypertension, I'm just not really convinced that we need to do a purely placebo arm.

Dr Carolyn Lam:                Great, Keith. And David, how about yourself? Any take home messages?

Dr David Calhoun:            I think when there's a new in-class compound, I think that's always exciting, particularly when it has the initial results, preliminary results, that Keith is reporting. As many agents as there are out there to treat hypertension, we still are not doing as well as we should be. I think it can only help to have additional classes of agents as therapeutic options, and I think that's particularly true with minority patients, who are, as Keith has indicated, are at the biggest need in terms of controlling blood pressure. Keith, these initial results are very exciting, and I look forward to future studies.

Dr Carolyn Lam:                Completely sharing your enthusiasm here. Thank you so much, Keith, for publishing this remarkable paper with us at Circulation. Thank you, David, for helping us manage it.

                                                And thank you, audience, for joining us today. You've been listening to Circulation on the Run. Don't forget to tune in again next week.

                                                This program is copyright American Heart Association 2019.