Circulation on the Run

Each monthly episode will discuss recent publications in the fields of genomics and precision medicine of cardiovascular disease.
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Now displaying: April, 2019
Apr 29, 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, associate editor as well, at Circulation, and director of the Pauley Heart Center in Richmond, Virginia at VCU Health. Carolyn, this issue, we've got a super-exciting interaction to follow related to SGL2 inhibitors on 24-hour ambulatory blood pressure in African-Americans, something used to treat diabetes, and maybe a positive effect on blood pressure, but more to come on that. Now, Carolyn, you're also planning to discuss some results from another SGL2 study.

Dr Carolyn Lam:                                You bet. This time, I'm taking you to Japan for the results of the SACRA study which stands for SGLT2 Inhibitor and Angiotensin Receptor Blocker Combination Therapy in Patients with Diabetes and Uncontrolled Nocturnal Hypertension and this is from Dr Kario and colleagues from Tochigi in Japan. It's a multi-centered, double-blind parallel study of 132 non-obese older adults with type 2 diabetes and uncontrolled nocturnal hypertension, receiving stable antihypertensive therapy, including angiotensin receptor blockers, who were then randomized to 12 weeks' treatment with empagliflozin 10 milligrams once daily or placebo. Clinic blood pressure was performed at baseline in weeks four, eight and 12. Twenty-four hour ambulatory blood pressure monitoring was performed at baseline and week 12 and morning home blood pressure was determined for five days before each visit. The primary efficacy endpoint was changed from baseline in nighttime blood pressure.

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

Dr Carolyn Lam:                                Well, empagliflozin significantly reduced nighttime systolic blood pressure versus the baseline. The reductions in daytime 24-hour morning, home, and clinic systolic blood pressure at 12 weeks with empagliflozin was also greater than placebo. Between group differences in body weight and glycosylated hemoglobin reductions were significant, but small and the changes in antihypertensive medication during the study also did not differ significantly between the groups.

Dr Greg Hundley:                             Very good. Well, I'm going to switch gears and talk also on the same theme of sugar and diabetes and evaluate the long-term consumption of sugar-sweetened and artificially-sweetened beverages and the risk of mortality in U.S. adults. This is a study by Vasanti Malik from the Harvard School of Public Health. Now, as you know, in epidemiologic studies, intake of sugar-sweetened beverages has been associated with weight gain, a higher risk of type 2 diabetes, coronary heart disease and stroke, but to date, few studies have examined the association between sugar-sweetened beverages and intake and mortality. All right, Carolyn, I'm going to give you a quiz now. Here's the first question.

Dr Carolyn Lam:                                What?

Dr Greg Hundley                               That's right, sugar-sweetened beverages are the single largest source of added sugar in the U.S. diet, true or false?

Dr Carolyn Lam:                                I'm going to guess true.

Dr Greg Hundley:                             Okay, so all those consumption of sugar-sweetened beverages in the United States has decreased in the past decade. National survey data show a slight rebound in consumption in recent years among adults in many age groups. With the average equivalent being, multiple choice, 2%, 6.5% or 10% of our total energy requirements?

Dr Carolyn Lam:                                Oh, my goodness. One of the higher ones. I'm just going to go in the middle, 6.5.

Dr Greg Hundley:                             Excellent, good choice, you're a good multiple-choice taker, 6.5%. So, among younger adults, sugar-sweetened beverages contributed. They're a little bit higher, 9.3% of the daily calories in men and 8.2% in women in the United States. Now, how about other parts of the world, particularly developing countries? The intake of sugar-sweetened beverages, is it dropping, is it flat or is it rising dramatically?

Dr Carolyn Lam:                                Sorry, Greg, but that one's too easy. It's definitely rising.

Dr Greg Hundley:                             Yup, you got that right.

Dr Carolyn Lam:                                I live in those other developing countries, so I've seen so.

Dr Greg Hundley:                             And it's really thought due to widespread urbanization and beverage marketing. So, now we've got an alternative, artificially-sweetened beverages. And they're often suggested as alternatives to sugar-sweetened beverages and intake levels have increased of these alternative sweeteners in the United States. So, next question. Are the artificially sweetened beverages a better alternative to sugar--sweetened beverages in regard to cardiovascular or all-cause mortality?

Dr Carolyn Lam:                                Yikes. Okay, so Greg I'm afraid to guess on this one because I have to admit I sometimes, with a sweet tooth, like to take these alternative beverages. I think you're going to be telling us.

Dr Greg Hundley:                             Well, we don't know. Most of the data in this area is from research and comes from associative analyses utilizing longitudinal cohorts and some studies suggest yes, some studies, no. For example, one in the elderly suggested artificially-sweetened beverages, but not sugar-sweetened beverages were associated with adverse events, but critiques indicated that finding may have related to reverse causation because the elderly patients were switching from sugar-sweetened to artificially-sweetened beverages. So, where are we now? Well this study, in our Journal, examined the associations between the consumption of sugar-sweetened beverages and artificially-sweetened beverages with the risk of total and cause-specific mortality among 37,716 men from the Health Professionals Follow-up Study between 1986 and 2014 and 80,647 women from the Nurse's Health Study from 1980 to 2014, who were free from chronic diseases.

Dr Carolyn Lam:                                Wow, that's a huge combined cohort. So, come on, what were the results?

Dr Greg Hundley:                             So, the researchers found after adjusting for major diet and lifestyle factors, consumption of sugar-sweetened beverages was associated with a higher risk of total mortality and cardiovascular mortality and cancer mortality and, thus, the results provide further support for the recommendations and policies to limit intake of sugar-sweetened beverages and to consume artificially-sweetened beverages in moderation did improve overall health. Now, what were the results from artificially-sweetened beverages? Well, they were associated with total and cardiovascular disease mortality in the highest intake category only. So, those consuming large amounts of those daily, but only in the cohort of women from the Nurse's Health Study, not from the men in the Health Professionals Follow-up Study. Artificially-sweetened beverages were not associated with cancer mortality in either cohort.

So, moving forward, the positive association between high intake of artificially-sweetened beverages and total and cardiovascular disease mortality observed among women requires more study and further confirmation and also, we might consider that even though artificially-sweetened beverages could be used to replace sugar-sweetened beverages among habitual sugar-sweetened beverage consumers, higher consumption of the artificially-sweetened beverages would probably be discouraged. Finally, policies and recommendations should continue to call for reductions and limits on sugar-sweetened beverages intake and also address alternative beverage offerings with an emphasis on our favorite, water.

Dr Carolyn Lam:                                Sweet, Greg! Or maybe not so sweet. Oh, goodness. All right, well my paper deals with related, but not related perhaps, but talking about ketone body, 3-hydroxybutyrate and the cardiovascular effects of treatment with this ketone body in chronic heart failure and this is from corresponding author, Dr Nielsen from Aarhus University Hospital in Denmark and his colleagues. Now, they performed a series of studies. In the first 16 chronic HFrEF patients were randomized in a crossover design to three hours' infusion of 3-hydroxybutyrate or placebo and monitored invasively with a Swan-Ganz catheter and studied with echocardiography and they found that infusion of 3-hydroxybutyrate increased cardiac output by two liters per minute or 40% with an absolute improvement in left ventricular ejection fraction of 8%, and the observed defects were accompanied by vasodilation with a resultant stable systemic and pulmonary blood pressure.

Now, in the second part of the study, they studied eight HFrEF patients examined at increasing infusion rates of 3-hydroxybutyrate and they found a dose response relationship with a significant increase in cardiac output. And, finally, they studied 10 HFrEF patients and 10 age-matched volunteers, randomized in a crossover design to a three hour infusion of 3-hydroxybutyrate or placebo and they looked this time at myocardial external energy efficiency and oxygen consumption using 11-carbon acetate PET and what they found was 3-hydroxybutyrate increased oxygen consumption without altering myocardial external energy efficiency. The response did not differ between HFrEF and age-matched volunteers.

Dr Greg Hundley:                             Wow, Carolyn, there was a lot of data in that study. So, what's your main take home?

Dr Carolyn Lam:                                In summary, 3-hydroxybutyrate, this ketone body, demonstrated dose-dependent beneficial cardiac and hemodynamic effects in patients with heart failure reduced ejection fraction without deteriorating mechano-energetic coupling and without causing any safety issues. And what's significant is that this opens the door to modulating circulating 3-hydroxybutyrate as a novel treatment option in patients with heart failure.

Dr Greg Hundley:                             Right, Carolyn, so I've got an interesting study from the world of basic science that's looking at the role of potassium channels as novel molecular targets and bradyarrhythmia’s and even, perhaps, in atrial fibrillation. This is from Yoshihiro Asano from Osaka University in Japan. So, the acetylcholine activated potassium channel is expressed in the sinus node, atrium, and atrioventricular node and contributes to heart rate slowing triggered by the parasympathetic nervous system. So the potassium, activated potassium channel is a heterotetramer of 2 inwardly rectifying potassium channel proteins encoded by two genes, KCNJ3 and KCNJ5, respectively.

Dr Carolyn Lam:                                Okay, so what did this study show?

Dr Greg Hundley:                             What it showed is a selective potassium acetylcholine channel blocker effectively inhibited a mutant potassium channel and up-regulated heart rate and bradyarrhythmias using a zebra fish model. And this is really interesting, Carolyn, because two conclusions are worth considering. First, future studies could determine the prevalence of bradyarrhythmias associated with dysfunctional mutation in this potassium channel. And, second, results raise the possibility that pharmacologic blockade of this channel might serve as a therapy for increasing heart rate and be especially beneficial for bradyarrhythmias in patients with gain of function mutations in the channel and, therefore, genetic testing for KCNJ3 and KCNJ5 in patients with bradyarrhythmias may provide a drug treatment option in lieu of an invasive surgical implantation of a pacemaker.

Dr Carolyn Lam:                                Fascinating! Thanks, Greg. What a great issue and now onto an even greater feature discussion.

Dr Greg Hundley:                             Welcome, everybody, to the second part of this interview. We've got a very exciting paper to discuss with you. Remember this is our backstage pass to Circulation and we've got today, Keith Ferdinand from Tulane University in Louisiana and our Associate Editor, our hypertensive expert, Dr Wanpen Vongpatanasin from the University of Texas Southwestern Medical School in Dallas. We're going to be discussing the anti-hyperglycemic and blood pressure effects of empagliflozin in African-Americans with type two diabetes and hypertension. Keith, we're going to start with you. What was your hypothesis for this study? Who's the study population? Review a little bit about your design and, importantly, what were your results?

Dr Keith Ferdinand:                         Well, my hypothesis was that one of the new classes of medications, the SGLT2 inhibitors, which have a mild diuretic effect and a mild natriuretic effect, may have benefits in self-described African-Americans in not only controlling glucose, but also controlling hypertension. These medicines are approved, of course, as medications for type 2 diabetes, but we had seen in some earlier trials that did not include self-defined African-Americans, that there may be a blood pressure effect. We know that diabetes is higher in blacks, almost twice that seen in the general population and, of course, hypertension and uncontrolled hypertension is disproportionate. So, here's a medication that may be even more beneficial in that population and we wanted to study it.

Dr Greg Hundley:                             And tell us a little bit about who was in the study and what was your design?

Dr Keith Ferdinand:                         The design was to be a placebo-controlled randomized trial using empagliflozin starting at 10 milligrams and force-titrating to 25 milligrams versus placebo on the background of conventional anti-hypertensive agents. Everyone was on one or more anti-hypertensive agents. We used the gold standard for blood pressure control with 24-hour ambulatory blood pressure and that was the means by which patients entered the study, although the primary endpoint was changed in hemoglobin A1c, we actually designed and powered the study to see if there would be a change in blood pressure. Additionally, we looked for changes in weight, losing calories with the effects of the SGLT2 inhibitors with glycosuria has translated in some preliminary trials to weight loss. So, this was a study looking at a population. Most of them had diabetes for approximately nine to 10 years, 59 years of age, definite hypertension, obesity, a high risk population, to see if a new class of medications would be beneficial.

Dr Greg Hundley:                             And what did you find?

Dr Keith Ferdinand:                         Fortunately, we did find an effect. It did lower the primary endpoint of a change in hemoglobin A1c, but remember it was powered also by blood pressure effect and fortunately, we did see that both with the ambulatory and clinic blood pressure, both at 12 weeks and 24 weeks. The clinic blood pressure was a trend, but the ambulatory blood pressure was positive at 12 weeks and both had a strong difference in terms of confidence intervals for blood pressure lowering. About five millimeters of mercury at 12 weeks and up eight millimeters of mercury at 24 weeks for the change in ambulatory blood pressure which, in a large population would translate into a significant blood pressure lowering, the hemoglobin A1c reduction was also significant. But, although that was the primary endpoint, my concern is as a cardiologist and cardiovascular specialist.

Dr Greg Hundley:                             And what dose did you select? Did you have to up-titrate this at all and, finally, were there any side effects?

Dr Keith Ferdinand:                         You know, with the SGLT2 inhibitors, you have an effect both in terms of glycosuria, some osmotic diuresis and some natriuresis, and with the loss of body weight. But the change in body weight really wasn't that much, about 1.2 kilos and the change in blood pressure was discordant with the change in body weight. So, we think that the effects in blood pressure may be from extended diuretic effect, but it may also be from effects on endothelial function that are outside those significantly related to diuresis, per se. Because you're urinating glucose, glycosuria, you would expect the potential for superficial infections, mycotic infections and that was seen. The rates were not prohibitive and not dissimilar to what's been seen in other studies. So, overall, the drug was well-tolerated. It did not have any significant adverse effects outside of a few mycotic infections, which are basically superficial fungal infections and that's been seen in other uses of the SGLT2 inhibitors, but nothing that I think would be unusually disturbing in this population.

Dr Greg Hundley:                             Outstanding. So, Wanpen, going to switch over to you and ask you to help us put this in the context of treating African-American men, women with hypertension. How do we think about using this new finding? How would we integrate it with other therapies that these individuals already might be taking?

Dr Wanpen Vongpatanasin:         Sure, so I think that this study is very intriguing and interesting that empagliflozin to me actually had more prominent benefit on lowering 24-hour blood pressure than the previous study that the true analysis showed the effects of 24-hour blood pressure is much less or almost half of four to five millimeters of mercury and that could be that this was not that significant in African-Americans and maybe this drug is particularly effective and, as you know, African-Americans tend to have more salt sensitive form of hypertension and I wonder if that could explain the results, but I think it's very encouraging because this drug class approved for treatment of diabetes and medication. African-American have higher blood pressures than other ethnic groups and having diabetes makes them prone to having more resistant hypertension. In this particular trial, almost 40% of the patients enrolled is already taking three or more antihypertensive medications, so adding this on top and having that benefit is as good as adding spironolactone, for example, and I didn't see from the manuscript, how many patients are taking spironolactone already, but I would be curious to see that, as well.

But I think that is something that physicians should think about and this drug is already FDA-approved for treating diabetes, so if you have a patient with difficult to control blood pressure and already needed something for diabetes, this could make a lot of sense to use it.

Dr Greg Hundley:                             Keith, do you have any thoughts on Wanpen's comment regarding the use of spironolactone in the study population?

Dr Keith Ferdinand:                         No, I don't have those specific data available at the time that we're speaking now, but that's certainly something that I will attempt to look at the database and get more information. But, I think Wanpen is absolutely right. If you look at some of the previous studies, for instance, EMPA-REG, the major outcomes trial that led to the indication of a decrease in cardiovascular death and heart failure, the blood pressure lowering wasn't that robust, maybe 4/2, but here we saw at week 24, 10 millimeters of mercury of blood pressure reduction and if you placebo subtract, which is what I mentioned in my first comments, you're talking about 8 to 8.5 millimeters of mercury reduction and that's a significant reduction, especially for ambulatory blood pressure measurement.

Dr Greg Hundley:                             Absolutely. So, I'm going to go with each of you separately, but taking this manuscript and this work that Keith, you've performed, we'll start with you. What do you think of the next steps in the research in this area, both from the perspective of using this family of agents in individuals with both diabetes and hypertension?

Dr Keith Ferdinand:                         What I would hope in the future is another outcome study is done with an SGLT2, any numbers of that class, that they particularly target enough African-Americans to see if this robust blood pressure reduction not only is found again, but also translates to decreased cardiovascular events. You know, NHLBI, for instance and ALLHAT, selectively over-represents African-Americans. They had 35% African-Americans in ALLHAT and the reason for that is you have a population that has a disproportionate degree of hypertension and a disproportionate degree of associated cardiovascular disease and renal disease, so you want to make sure that any medication that's been shown to be effective is effective in the higher risk population. So a future outcome study, regardless of whether they're renal-based or related to heart failure, I hope will target an increased population of blacks to see some of the robust reduction we have, translates in cardiovascular events.

My suspicion is that self-defined African-American versus a genetic factor, describes the phenotype of patients who tend to be more obese, have more salt sensitivity, perhaps subclinical kidney disease and will respond to a medication that has some diuretic natriuretic effects and effects with endothelial dysfunction and sympathetic discharge.

Dr Greg Hundley:                             Very good, well I heard sympathetic discharge. Wanpen, any comments there? That's your area.

Dr Wanpen Vongpatanasin:         I think that definitely needs to be studied. To my knowledge, there was only one small study that published that tried to measure sympathetic nerve activity directly, but unfortunately that study after a very short-term treatment for like four or five days, so I’m sure that there will be more studies to come and also hope that the future study will shed light on any particular markers with surrogate that will identify patients that will respond better, for example, PATHWAY-2 trials that were done to test the effects of spironolactone on resistant hypertension they found that the lower the reading, the more likely you can have better response to Aldactone and I wonder if this might apply to empagliflozin and be something else. I think the fact that the blood pressures continued to decline from the week 12 to week 24 is very, very interesting when the body weight effect doesn't necessarily go down much further. This really tells us there's something else beyond weight and perhaps glucose that would explain this.

Dr Greg Hundley:                             Very good. Well, I certainly want to thank you both for this outstanding discussion. Keith, we want to thank you for bringing this manuscript to Circulation and identifying this new application for this therapy in African-Americans. Wanpen, thank you also for your time and comments.

On behalf of Carolyn and myself, we really appreciate you listening. Have a great week and we look forward to seeing you next week.

Dr Carolyn Lam:                                This program is a copyright of American Heart Association 2019.


Apr 22, 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, associate editor as well at Circulation, and director of the Poly Heart Center in Richmond, Virginia, at VCU Health. Well, I'm going to talk about anti-hyperglycemic agents and look at a very important meta-analysis.

Dr Carolyn Lam:                Those are the rage: GLP-1 receptor agonists and SGLT-2 inhibitors. But first, let's talk about psychosocial stress and cardiovascular health. So what is the joint impact of multiple stressors on racial or ethnic disparities in cardiovascular health?

                                                Well, this question was tackled by Dr Albert, from University of California San Francisco Center for the Study of Adversity and Cardiovascular Disease and her colleagues. They basically studied more than 25,000 women participating in the women's health study follow-up cohort, and examined the relationship between cumulative psychosocial stress and ideal cardiovascular health as defined by the American Heart Association Strategic 2020 Goals.

                                                As a reminder, this health metric includes smoking, BMI, physical activity, diet, blood pressure, total cholesterol and glucose, and higher levels indicate more ideal cardiovascular health and less cardiovascular risk.

                                                So, they found that both cumulative psychosocial stress and ideal cardiovascular health varied by race or ethnicity. Mean cumulative psychosocial stress scores were higher in Hispanic, Black, and Asian women compared to white women, even after adjusting for age, socioeconomic status and psychological status such as depression and anxiety. The mean ideal cardiovascular health scores remained worse in blacks and better in Asians compared to whites, despite taking into account socioeconomic factors and cumulative psychosocial stress.

Dr Greg Hundley:             So Carolyn, how should clinicians incorporate this information in what we do every day?

Dr Carolyn Lam:                Although the cumulative psychological stress and socioeconomic status did not fully explain the racial or ethnic differences in ideal cardiovascular health that we saw, clinicians should be informed by these data that psychosocial stressors are social determinants of health that have different prevalence according to race and ethnicity. I think that's what we need to learn. And of course these data support the need for additional work that addresses the joint impact of multiple social determinants of health on cardiovascular disease and in diverse populations.

Dr Greg Hundley:             Very good, Carolyn. That was really an interesting article. Well, I'm going to switch gears and talk about the role of red blood cells in promoting vascular calcification. My article is from Dimitrios Tziakas from the Department of Cardiology in Thrace, Alexandropoulos, in Greece.

                                                Now, the presence of extravasated erythrocytes in human atherosclerotic lesions was described several years ago, but little is known about a possible active role of red blood cells during these cardiovascular disease processes. Clinical studies suggest that intraplaque hemorrhage may be associated with the progression of coronary, carotid, and atherosclerotic lesions and degenerative calcific aortic valve stenosis. So, in the present study, the authors examined the contribution of erythrocytes to vascular and valvular lesion progression, focusing on the effects of red blood cells on the osteoblastic transdifferentiation of smooth muscle cells in calcification.

Dr Carolyn Lam:                Interesting. So, what did they find?

Dr Greg Hundley:             So, lysed erythrocytes, and in particular their membrane faction, enhanced human and murine arterial smooth muscle cell mineralization and vascular aortic ring calcification. Red blood cell membranes injected in the vascular regions of atherosclerotic-prone mice also promoted calcification and red blood cells were found to co-localize with osteoblast like cells in human atherosclerotic plaques, stenotic aortic valves, and abdominal aortic aneurysms. And so, the study demonstrated that intra plaque hemorrhage promotes atherosclerotic and valvular lesion calcification and membranes of extravasated lysed red blood cells appeared to play an important role in the process. The investigators also showed a mechanism, that nitric oxide derived from erythrocyte endothelial nitric oxides synthase is involved, at least in part, in mediating the effects of red blood cells on vascular calcification.

Dr Carolyn Lam:                Thanks, Greg. Now back to another, well, clinical paper with the next one asking, do mid-life biomarkers of heart and kidney damage associate with the level of and decline in physical capability with aging? Dr Kuh and colleagues from MRC Unit of Lifelong Health and Aging at University College London used data on 1,736 men and women from the oldest British birth cohort study. And, looked at their walking speed, chair rise speed, balance time, and grip strength. Assessed at ages 60 to 64 and 69 years. They tested the associations between Cystatin C, NT-proBNP, interleukin-6, and E-selectin all at ages 60 to 64 years with their performance at 69 years. And what they found was the lower levels of NT-proBNP in interleukin-6 in middle aged adults were independently associated with better physical capability up to nine years later. And all these associations were stronger than those observed for conventional risk factors: including lipids, blood pressure, and glycemia, and were not explained by the onset of cardio vascular and kidney disease or diabetes.

Dr Greg Hundley:             Carolyn, is this saying we should now measure these biomarkers in mid-life?

Dr Carolyn Lam:                Ah, before considering the use of NT-proBNP and IL-6 or interleukin-6 for risk stratification, we really do need further research to untangle whether these associations exist because the biomarkers are an integrated measure of accumulated exposures to stressors. Or, whether they are really capturing early an organ damage. Or, whether they are marking additional risk pathways. So, this and more is discussed in a great accompanying editorial entitled "Putting the Measurement of Physical Capacity in Older Adults in its Place". And that's by Dr Kritchevsky from Wake Forest School of Medicine.

Dr Greg Hundley:             That's a favorite of my heart, Caroline. The old institution Wake Forest. But, I'm going to switch now and tell you a little bit about plasma ceramides and this is an article from Wei Zhao from the Department of Epidemiology in Population Health at Albert Einstein College of Medicine in Bronx, New York. The study evaluates the role of ceramides and what are those? Well, they're a class of bio-active lipids composed of sphingosines and fatty acids. And are involved in the development of cardiovascular disease. Elevated circulating levels of ceramides have been shown to be associated with increased risk of cardiovascular events, cardiovascular death, and even so, after adjusting for other cardiovascular disease risk factors. Now, interestingly, ceramide metabolism has long been noted to be closely related to HIV infection. But, the relationship has not been fully understood. HIV infected cells may cause enhancement of sphingomyelin volume breakdown and accumulation of intercellular ceramides, whereas intercellular accumulation is associated with enhanced replication of HIV.

                                                So, what did this study do? They evaluated circulating levels of four ceramides species which have been investigated in previous studies of non-HIV populations. And were measured in 737 women and men, 520 HIV infected and 217 HIV uninfected from the Women's Intra-Agency HIV Study and the Multi-Center Aids Cohort Study. And they compared the relationships with the progression of carotid artery disease assessed by B-mode ultrasound over a seven year period.

Dr Carolyn Lam:                Interesting approach. So, what did they find?

Dr Greg Hundley:             Elevated ceramide levels were associated with anti-retroviral therapy use. Particularly, protease inhibitor use HIV infected individuals. All four ceramides were highly correlated with each other and significantly correlated with total cholesterol and LDL cholesterol. And of note, remember they were measuring four, but C16:0 and C24:1 ceramides rather that C22:0 and C24:0 ceramides were more closely correlated with specific modified activation and inflammation markers and, surface markers of CD4 t-cell activation. Elevated plasma levels of C16:0 and C24:1 ceramides were also associated with progression of carotid artery atherosclerosis. So, in summary, the results of this study provide new information on biological mechanisms that may involve the specific mono-site activation and inflammation beyond cardiovascular disease traditional risk factors like cholesterol levels. For the association between ceramides and CVD, particularly among individuals living with HIV infection.

Dr Carolyn Lam:                Fascinating. Thanks, Greg. Now that sets us up for beautifully for our featured discussion.

Dr Greg Hundley:             Welcome everyone, to our podcast. My name is Greg Hundley and we've got a very exciting paper for the second part of our program today. With us we have Dr Thomas Zelniker from Brigham and Women's Hospital. And then, also, a guest editor, Dr John McMurray from Glasgow, Scotland. We're going to be discussing a meta-analysis in type 2 diabetic patients. Thomas, can you tell us a little bit about the study population, your design, and what where the outcomes that you saw in this study.

Dr Thomas Zelniker:        As you know, the last half decade, members of two drug classes, GLP1 receptor agonists and SGLT2 inhibitors, so our goal was to provide clear context by comparing or contrasting the benefit of these two drug classes, and in particular to investigate the potential heterogeneity in the treatment site between patients with and without atherosclerotic cardiovascular disease. For that reason, we performed meta-analysis of all randomized partially controlled cardiovascular outcome trials of GLP-1 receptor antagonists and SGLT-2 inhibitors. We included data from more than 77,000 patients, nearly 43,000 patients coming from the five GLP-1 receptor antagonist trials and approximately 34,000 patients coming from the three SGLT-2 inhibitor trials. We tried to compare patients with those with known established atherosclerotic cardiovascular disease with those that have multiple risk factors for but no evident ASCVD. And as you can see, our interests included MACE, or major atherosclerotic cardiovascular events, and its individual components, MI, stroke and cardiovascular death. And then we looked at hospitalization for heart failure and progression of kidney disease. The progression of kidney disease was defined as one of the broad composites consisting of new onset of macroalbuminuria, worsening of eGFR, end-stage kidney disease, or death due to renal cause. And then we also had a more narrow kidney outcome which excluded macroalbuminuria.

Dr Greg Hundley:             Thomas, did you observe differences in the types of events between the two agents, as they would have impacted hospitalization for heart failure or the progression of renal disease?

Dr Thomas Zelniker:        Right. So foremost both trial analyses reduced the risk of MACE, major atherosclerotic events, but the reduction of MACE was actually confined to those patients with atherosclerotic cardiovascular disease. We saw a 40% reduction in patients with known ASCVD, where neither of these groups reduced the risk of MACE in patients with only multiple risk factors but without ASCVD. Now, in terms of the individual components of MACE, both trial analyses reduced the risk of myocardial infarction cardiovascular death but only GLP-1 receptor agonist reduced the risk of stroke. In contrast, as SGLT-2 inhibitors vastly reduced the risk of hospitalization with heart failure by more than 30%, where there was only a non-significant 7% relative risk reduction with GLP-1 receptor antagonist.

                                                GLP-1 receptor antagonists also reduced the broad kidney composite outcome. However, this effect was mainly driven by reduction macroalbuminuria. When excluding macroalbuminuria we found a non-significant relative risk reduction by 8% and this stands in contrast to a very robust relative risk reduction with SGLT-2 inhibitors of more than 45%.

Dr Greg Hundley:             Thomas, you mentioned there was a difference in benefit for those with existing cardiovascular disease versus no-known cardiovascular disease upfront. What do you think the reason for that might be, and then did you have the same number of patients in the non-cardiovascular disease group? Did you have enough events in that group? And finally, do you think we might need to follow that patient population a little bit longer in time, to see those events as they didn't have pre-existing cardiovascular disease?

Dr Thomas Zelniker:        These are fantastic points. I personally think it's biologically plausible that both drugs and receptors have the same benefit in both patient population to treatment effect may just require more time to become evident in patients with lower risk. You also mentioned a very good point, we had substantially more events in the patient cohort with ASCVD.

Dr Greg Hundley:             Very good. So John, we want to turn to you now. Can you help us put those results of this study in perspective? Can you put this into context for us with other published reports using these particular ages?

Dr John McMurray:         Certainly Greg, and I'd like to congratulate Thomas on what very important and very timely meta-analysis because, of course, what Thomas and his colleagues have done Greg, is to put all these studies together, to give us what meta-analysis does, which is much more power to look, for example, at components of composite outcomes, and we will in that way compare and contrast the differences and similarities between these two treatments. And as Thomas has mentioned, so interesting differences stand out but there are also some similarities that perhaps were not clear from the individual trials and I suppose the one that would perhaps stand out to me and might not have been realized by many of our readers, is myocardial infarction, that seems to be reduced to pretty much a similar extent by both GLP1 receptor antagonists and SGLT-2 inhibitors.

                                                I think there had perhaps been a view out there from the individual trials, that maybe GLP-1 receptor antagonists have more effect on atherosclerotic events and SGLT-2 inhibitors more effect on heart failure and renal events and to some extent that's true, both agents seem to reduce myocardial infarction to approximately the same extent. Which in itself is interesting, perhaps raises some mechanistic questions. I mean, the differences that stood out is stroke is reduced by GLP-1 receptor antagonists but not by SGLT-2 inhibitors and conversely heart failure which is the opposite, which is by SGLT-2 inhibitors, but not by GLP-1 receptor antagonists in this meta-analysis.

                                                So, I suppose, in summary what this tells us is that these drugs have complementary, perhaps additive cardiovascular benefits. Together, they potentially reduce the whole spectrum of the adverse cardiovascular events that occur in our patients with Type 2 diabetes, especially those who've got established cardiovascular disease.

Dr Greg Hundley:             And so, just a last question here, for both Thomas and John, if you're considering in your practice, you have a diabetic patient that's not on these, one of these agents, and they have existing cardiovascular disease, how do you go about considering the addition or the switch to this type of medicine, and what practices do you use to effect that change?

Dr Thomas Zelniker:        I guess, looking at patients, so we know that both drug classes have great benefits from MACE, right, but to people on antagonists having also reductions in stroke. So probably the associated risk is in the focus, I would probably rather go with the GLP-1 receptor antagonist. While looking at it from the heart failure perspective, or from the renal perspective, we see obviously bigger advantages attributed to inhibitors.

Dr Greg Hundley:             And John, how about you?

Dr John McMurray:         I would agree with Thomas' perspective, although I might add just a little caveat which is, of course, that the prevention of heart failure which is what, I think, the clear benefit of SGLT-2 inhibitors is, prevention of heart failure is different to the treatment of heart failure. So, patients at risk of heart failure sadly, an SGLT-2 inhibitor would make sense, but when it comes to patients with established heart failure event, of course we will get that answer because one of the great things about this recent incredible development of new therapies for diabetes, is that now there are now more studies underway including remarkable five trials in patients with different heart failure phenotypes, patients hospitalized, patients in the community, so we will learn a lot more about the use of these drugs, in particular cardiovascular populations.

Dr Greg Hundley:             Excellent. I want to thank both Thomas Zelniker from Brigham and Women's Hospital and John McMurray, guest editor from Glasgow, Scotland for helping us work through this just fantastic meta-analysis study pointing us in a new direction for utilizing medications to treat diabetes and those that we see every day, with cardiovascular disease.

                                                On behalf of Carolyn and myself, have a great week and we look forward to seeing you, next week.

Dr Carolyn Lam:                This program is copyright American Heart Association, 2019.


Apr 15, 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 in Duke National University of Singapore.

Dr Greg Hundley:             And I'm Greg Hundley, also associate editor of Circulation and director of the Poly Heart Center at BCU Health in Richmond. Carolyn, we've got a really exciting interview to follow our coffee chat and it's evaluating individuals with low complexity congenital heart disease. We often think of those with high complexity congenital heart disease and looking at their cardiovascular events. We're going to hear a little bit about low complexity congenital heart disease.

                                                Now you've got a paper you wanted to talk about first.

Dr Carolyn Lam:                Absolutely. You've got to hang on for that because I'm going to delve into chromatin architecture in heart failure, and it's in this paper from corresponding author Dr Foo from Genome Institute of Singapore.

                                                So, as background, the human genome actually folds in 3D to form thousands of chromatin loops within the nucleus encasing the genes and assists regulatory elements for accurate gene expression control. Now, these physical tethers of loops are anchored by the DNA binding protein CTCF, also known as the weaver of the genome and the cohesion ring complex. Now, the role of CTC in binding and changes in chromatin structure in heart failure are not well understood. Well, until today's paper.

                                                What the author said is they undertook an independent analysis of chromatin organization with mouse pressure overload model of myocardial stress or transverse aortic constriction, and a cardiomyocyte specific knockout of CTCF. So, interestingly, they found that the cardiac chromatin architectural in adult terminally differentiated cardiomyocytes was unchanged in pressure overload from transverse aortic constriction. Now this was completely unlike the CTCF knockout model where they verified that there was generation of vast genome-wide loss of genomic insulation and near complete abolition of the CTCF chromatin loops.

                                                Instead of chromatin rewiring on the scale of that knockout, the myocardial stress response appeared to proceed through enhancer H3K27 acetylation epigenetic changes and gene network co-regulation driven largely by fixed cardiac 3D chromatin architecture. In other words, a stable chromatin architecture really set the stage for accurate enhancer promoter interactions required for basal gene expression control and induction of the classical myocardial stress gene response.

Dr Greg Hundley:             So Carolyn, are there therapeutic implications here for this?

Dr Carolyn Lam:                Now of course, that was preclinical work, but it really opens the door to consider these epigenetic regulators that control disease expression changes and interacting gene sets in heart as potential future targets for novel heart failure therapy.

Dr Greg Hundley:             Very interesting. So, I'm going to review and switch gears a little bit and focus on diabetic cardiomyopathy and mitochondria associated endoplasmic reticulin membranes. And this paper is from Shengnan Wu from the Center for Molecular and Translational Medicine at Georgia State University here in the US in Atlanta, Georgia. So as we all know, mitochondria are essential for cellular energy production, but when they're damaged, they become a major source of reactive oxygen species and pro-apoptotic factors. In particular, increasing evidence suggests that mitochondrial dysfunction is a central event in diabetic cardiomyopathy.

                                                Well, the mitochondria and the endoplasmic reticulum are key players that regulate many cellular functions and their structural and functional interactions are essential for cellular homeostasis. The contact points, however, through which the endoplasmic reticulum communicates with mitochondria, they're known as mitochondria associated endoplasmic reticulum membranes, or MAMS. Importantly, MAMS play a pivotal role in calcium signaling, lipid transport, energy metabolism and cell survival, and they've been implicated in a variety of diseases, including Alzheimer's Disease, cancer, lysosomal storage diseases, diabetes, obesity induced mitochondrial dysfunction and other metabolic disorders.

                                                But the role of these MAMS in the initiation and progression of Diabetic Cardiomyopathy is really unknown. So now, FUNDC1 is a highly conserved protein that's exclusively localized to the mitochondria. And this group had previously demonstrated that FUNDC1 was essential for maintaining the structure of MAMS and ensuring appropriate calcium transfer from the endoplasmic reticulum to the mitochondria normal hearts. Moreover, cardiac specific deletion of FUNDC1 induced cardiac dysfunction by inhibiting MAM formation.

Dr Carolyn Lam:                Interesting. So that was their prior work? What did the current study show?

Dr Greg Hundley:             Right, so what the investigator showed in this study is that high glucose driven inactivation of AMP-activated protein kinase increased FUNDC1 stability, but resulted in aberrant MAM formation, impaired mitochondrial calcium increase, mitochondria dysfunction and then cardiac dysfunction. And additionally, AMP-K activation reverses Diabetic Cardiomyopathy by suppressing high glucose induced MAM formation, mitochondrial calcium increase and mitochondrial dysfunction.

                                                And interestingly, Metformin, an AMP-K activator, used exclusively for Type 2 Diabetes, might be effective in treating Diabetic Cardiomyopathy in individuals with Type 1 Diabetes. So a very interesting mechanistic study providing some information of how MAMS, mitochondrial function and endoplasmic reticulum could be important in understanding how to prevent Diabetic Cardiomyopathy.

Dr Carolyn Lam:                Indeed. And you know, that last note that you made on Type 1 Diabetes, also links very well with the next paper that I chose. Which really asks the question, in Type 1 Diabetes, what are the relative prognostic importance and optimal levels of risk factors for mortality and cardiovascular outcomes? And this comes from Dr Rawshani and colleagues from the Swedish National Diabetes register who studied more than 32,600 patients with Type 1 Diabetes in their national observational cohort study from the Swedish National Diabetes register, with a mean follow-up of 10.4 years and a mean duration of diabetes of 17.9 years.

                                                They found that the most important predictors for outcomes were HP-A1C, albuminuria, duration of diabetes, systolic blood pressure and low-density lipoprotein cholesterol, or LDL cholesterol. Now, the lower levels of HP-A1C, systolic blood pressure and LDL cholesterol than contemporary target levels were associated with lower risk for outcomes. Albuminuria was associated with a two to four times greater risk of cardiovascular disease and death. And each millimole increase of LDL cholesterol was associated with 35 to 50% higher risk for outcomes.

Dr Greg Hundley:             Boy, Carolyn, those are interesting results. So, what do we take away from this in clinical management of patients?

Dr Carolyn Lam:                The take home message is that in patients with Type 1 Diabetes, the strongest predictors for mortality and cardiovascular disease, with the exception of age, were mostly conventional and modifiable cardio-metabolic risk factors. And this in turn suggests that increased clinical focus on these risk factors, particularly in primary prevention, may result in the largest relative risk reduction for mortality and cardiovascular disease, even in Type 1 Diabetes. So, future clinical trials may be designed to test these findings.

Dr Greg Hundley:             Very good. Well, Carolyn, my next paper, I'm going to talk about five year outcomes after off-pump versus on-pump coronary artery bypass grafting in those over the age of 75 years. And this paper comes from Anno Diegeler from Bad Neustadt in Germany. From June of 2008 to September of 2011, they evaluated a total of 2,539 patients that were 75 years or older, who had been randomly assigned to undergo off-pump or on-pump coronary artery bypass grafting across 12 centers in Germany.

                                                And the primary outcome was all cause mortality at five years, and the secondary outcome included a composite of death, myocardial infarction and repeat revascularization. What did they show in this study? Well, after a median follow up of five years, the hazard ratio for off-pump versus on-pump coronary artery bypass grafting was 1.03, confidence interval 0.81 to 1.19, no difference. The composite outcome of death, myocardial infarction and repeat revascularization, the same. Hazard ratio 1.03, confidence interval 0.89 to 1.18, P-value 0.7.

                                                So, first take-home message, no difference if you had your surgery off-pump or on-pump, if you're over the age of 75. Now, another outcome related to incomplete revascularization. And what was striking I this study is whether you underwent on-pump or off-pump bypass, if you were incompletely revascularized, that was associated with both the primary as well as the secondary outcomes. So, in elderly patients, in summary, greater than or equal to 75 years, the five year survival rates as well as the combined outcome of death, MI and repeat revascularization, was similar for on-pump versus off-pump CABG. And incomplete revascularization was associated with a lower five year survival rate, irrespective of the type of surgery that was performed.

Dr Carolyn Lam:                Interesting. Beautifully summarized, Greg. Thank you.

Dr Greg Hundley:             Absolutely. And let's head on to that featured article.

                                                Well, welcome everyone to the second half of our program. We are very excited today to have Dr James Priest, from Stanford University School of Medicine. And also our associate editor Gerald Greil from University of Texas Southwestern School of Medicine in Dallas. And we're going to be discussing the article, Substantial Cardiovascular Morbidity in Adults with Lower Complexity Cardiovascular Disease.

                                                So, James, first could you tell us a little bit about what constitutes low complexity congenital heart disease? And then a little bit about your study population, your design, and the results that you found with your study?

Dr James Priest:                So, low complexity congenital heart disease really derives from definitions of congenital heart disease in adults that are grown up and have different complexity of lesions. And so high complexity congenital heart disease, you see things that, as people may remember, adult cardiologists may remember from their training. People remember from medical school, things like single ventricle disease, hypoplastic left heart, tetralogy of fallot, transposition of the great arteries. But, non-complex, so our low complexity disease, really constitutes a relatively simple malformation. Things like atrial septal defects, ventricular septal defects, patent ductus arteriosus. Things that are treatable with a single surgery.

                                                You close the hole, you ligate the vessels, you dilate the valve, and the patient is affectively cured. So relatively low complexity diseases that can be treated with typically, a single surgery or minimal interventions to restore completely, or essentially normal, cardiovascular physiology.

                                                So, the study was based upon a very large you know, volunteer data set, the UK Biobank. It comes from the United Kingdom where 500 thousand individuals enrolled, and from those individuals there is genetic information, medical histories dating back to the 1990s, self-reported history. A variety of functional and neuropsychiatric measures. And if you get a group of 500 thousand individuals from anywhere, there's going to be some congenital heart disease in there. And so, we looked to see what types of congenital heart disease were in there. And in fact, there was lower complexity individuals.

                                                And because I spent some time on the research side of things with my adult colleagues, the first thing we looked at were from the common adult cardiovascular outcomes, things people write about in Circulation all the time. Coronary artery disease, atrial fibrillation, heart failure. We know these things are problems in adults with complex cardiovascular disease, but nobody had really looked for the most part in adults with low complexity or non-complex disease. And we were surprised to see such high event rates for these common adult cardiovascular conditions.

Dr Greg Hundley:             So, what type of events did you appreciate in the population in follow up?

Dr James Priest:                So, we really appreciated about a two-fold rate of let's say, acute coronary syndrome relative to the general population. Up to almost 13 fold risk of atrial fibrillation and heart failure, relative to the general population. So, really substantial and very impactful event rates.

Dr Greg Hundley:             Very good. And so, just a couple points of clarification. Do you think that the events you observed, were they related to the congenital heart disease, per se? Or could it have been a result from the surgical procedure to treat that heart disease?

Dr James Priest:                So, that's a great question. I think, in some ways, that's the fundamental question that the paper leads to. So, we thought of it in two different ways. You know, one, were these events, and they're perioperative events, for individuals receiving some type of care for their congenital heart disease, during their adulthood? And we performed a sensitivity analysis where we basically looked at those events and then looked for events occurring within a year of adult interventions. And we saw no difference in those event rates. So, they weren't perioperative or postoperative events in adults receiving adult congenital heart disease care.

                                                The second part of the question is really more of an existential question in some ways. You know, is there some fundamental relationship between the care these people received as children? Or the genetic basis of congenital heart disease in the first place that is somehow put people at risk long term for adult cardiovascular disease, acquired adult cardiovascular disease? And I think there's indeed a lot of different ways to try and get at that question and explore that more, which we're currently working on.

Dr Greg Hundley:             So, Gerald, I wanted to turn over to you now and, in your practice that encompasses those that are young adults that have this low complexity congenital heart disease, how do you manage them now? And how might the results of this study suggest, potentially, a different management strategy?

Dr Gerald Greil:                 Usually these patients, they're kind of thought to be cured or only needed minimal follow up in the past. So, if you take a patient with a VSD, rarely during childhood, young adult or even kind of in 20s and 30s, you have any major difficulties. And as a pediatric cardiologist, you rarely experience any major follow up problems with these patients. I think, particularly in the US, and I work actually for more than 10 years in the UK, the problem in the US is how can you organize follow up in these patients?

                                                There're insurance issues, there're issues about moving into different areas, and since these patients were kind of labeled as being healthy and close to normal, they were lost for follow up, particularly in the US. I think this study raises some concerns, we should probably be more careful and cautious and follow these patients up kind of in a lifelong session. And take care of them. This is definitely something, which is a new finding, and what the cause is, how we are following up, that's the question. I guess it could be a good question for future studies.

Dr Greg Hundley:             You mentioned future studies. Specifically, what type of future studies do you think we need to perform next? This shows us that the events are occurring, are we ready yet for randomized trials to perform prevention? Do we need studies that have more frequent observation? What are your thoughts there? And I'll get your answer and then we'll come back to James and get his thoughts on the same question.

Dr Gerald Greil:                 Yeah, I think the major thing is we need close follow up of these patients. And it will be a combined effort between pediatric and specialized adult cardiologists, with a special interest in patients with congenital heart disease. Once again, coming back to it, a closer follow up is a little bit dependent on the medical system, which you have. If you take Canada and the UK, it may be easier in these patients are under close follow up. And this allows large multicenter studies, large data bases like UK Bio Bank are kind of exemplary. And we should try to get something similar within the US or in other countries.

                                                I think that's the lesson what we take from that, we need larger data bases, probably more granular than what we have right now. I mean, James probably can comment in a second about the shortcomings and what can be done better in the UK Bio Bank to allow more detailed conclusions than we have currently from his study.

Dr Greg Hundley:             James?

Dr James Priest:                I would agree with that. I think as a person who does not, clinically speaking, take care of adults with congenital heart disease, my colleagues and I, or I have the impression from my colleagues that for most of the time, in most of these patients in the Unites States adults who had VSD or ASD repair as a child, they were essentially said, oh, you're cured. And they perhaps had some follow up during childhood, but then were otherwise discharged to live the rest of their lives.

                                                And so, in many cases I'd say the first step before performing any studies is to simply identify who these patients are, and figure out you know, what their risk factors otherwise for cardiovascular disease might be. Now, that being said, I think that was one of the powerful things about the UK Bio Bank study is that there's a large population in which all these traditional cardiovascular risk factors you know, obesity, lipid levels, hypertension, smoking status, all these things were uniformly measured in both the individuals with congenital heart disease, the adults with congenital heart disease. And of course the control population.

                                                And so that allowed us to make some estimates about what proportion of disease was attributable to these traditional cardiovascular risk factors. And what was attributable to other factors related, potentially, to the congenital heart disease. But all those things being said, I think the first questions that I often to tend to receive about these studies from the pediatric cardiologists and the adult congenital heart disease doctors, reflects the sorts of data sets that we're used to looking at.

                                                Well, what sort of an intervention did this person have? Did they have a ventriculostomy? When did they receive their diagnosis and their repair? Details of the surgical care and the perioperative of course, are not available in this data set because it's not a particularly pediatric cardiology focused data set. It's a broad population based data set. And so the relationship specifically the details of their perioperative care and diagnosis are not able to be attained. And so we'll need larger data sets that include that information to fully start to develop those sorts of relationships over time.

Dr Greg Hundley:             So, we want to thank our lead author, Dr James Priest from Stanford University School of Medicine, and our associate editor, Gerald Greil from the University of Texas Southwestern Medical School in Dallas. And reviewing this very interesting article on lower complexity cardiovascular disease and its association with an increased risk of cardiovascular events. And thank you both so much for clarifying. It sounds like an opportunity to collect more data through registries, et cetera, that we may need to expand around the world.

                                                Thank you everyone for listening to Circulation on the Run. Remember that's your back stage pass to our journal. And we'll see you next week.


Apr 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 VCU Health Systems, the Poly Heart Center in Richmond, Virginia.

Dr Carolyn Lam:                So arrhythmogenic cardiomyopathy that will make most of us think of right ventricular disease and fatty infiltration of the muscle, but could arrhythmogenic cardiomyopathy really be a bi-ventricular disease? Well you've got to stay tuned to find out more in a fantastic interview coming right up after our little coffee chat. So Greg, what are your picks this week?

Dr Greg Hundley:             My first paper is from Chris Lim at NYU in New York. And it's looking at the relationship between Mediterranean diet, air pollution and cardiovascular events.

                                                So, it's unknown whether usual individual dietary patterns can modify the association between long-term air pollution exposure and health outcomes. And so, in this large cohort with detailed diet information at the individual level, they had 548000 individuals across six states and two cities within the U.S. and a follow up period of 17 years. And that occurred between 1995 and 2011. And they evaluated whether a Mediterranean Diet modified the association between long-term exposure to ambient air pollution and then cardiovascular disease and mortality risk. And so, the average exposures to parts per billion and nitric oxide air pollution that the residential census track level were measured, and the investigators found that for the particulate matter there were elevated significant associations with cardiovascular disease. So, a hazard ratio of 1.13, ischemic heart disease similar hazard ratio and cerebrovascular disease with also a similar hazard ratio.

                                                For the nitric oxide, there were also significant associations with cardiovascular disease, as well as ischemic heart disease. And then the analysis indicated that Mediterranean diet modified the relationships. Those with a higher Mediterranean diet score had significantly lower rates of air pollution related mortality. These results therefore indicate Carolyn, that Mediterranean diet reduce cardiovascular disease mortality related to long-term exposure to air pollutants in a large perspective, U.S. cohort. Can you believe increased consumption of foods rich in antioxidant compounds actually may aid in reducing the considerable disease burden associated with ambient air pollution?

Dr Carolyn Lam:                Oh wow. That is hugely interesting. Gosh, what do we do about this clinically now?

 Dr Greg Hundley:            Remember, first of all, this is an associate study, so we can't infer cause effect. And what we need next are some more independent studies from other cities around the world, prospective cohorts, examinations of clinical outcomes and randomize interventions. And so, I think the results add to a growing body of literature suggesting that dietary patterns may help reduce cardiovascular events in these high air pollution exposure areas. And how does this work? Well, potentially through augmenting antioxidants and reducing oxidative stress.

Dr Carolyn Lam:                That's really cool. So from one region, talking about air pollution to another region that often reports about air pollution and that's China. But this study from China is actually the largest registry study to evaluate sex related differences and hospital management and outcomes of patients with acute coronary syndrome in China.

                                                This is from corresponding author Dr Zhao from Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Disease. With colleagues of the improving care for cardiovascular disease in China, Acute Coronary Syndrome project, which is an ongoing nationwide registry of the American Heart Association and the Chinese Society of Cardiology. So, the authors use data from this project and evaluate at sex differences in the acute management, medical therapies for secondary prevention and in hospital mortality in more than 82000 patients admitted for acute coronary syndrome in 192 hospitals across China from 2014 to 2018.

Dr Greg Hundley:             What did they show in this study?

Dr Carolyn Lam:                They showed that women hospitalized for acute coronary syndrome in China less frequently received acute treatments and strategies for secondary prevention and had a higher in hospital mortality rate than men. Now the observed sex differences in this in hospital mortality were likely due to older age, worse clinical profiles and fewer evidence base acute treatments provided to women. And that's because the sex differences were no longer observed after adjustment for these clinical characteristics and acute treatments.

                                                What this all means though is specifically targeted quality improvement programs may be warranted to narrow these sex related disparities in patients with acute coronary syndrome in China.

 Dr Greg Hundley:            Very interesting. I'm going to take sort of the next paper and it's looking at a different aspect of acute myocardial infarction. And these papers from Yong Wang from the Division of Molecular and Translational Cardiology at Hannover Medical School in Hanover, Germany.

                                                Now as we know, the heart can undergo deleterious changes and left ventricular geometry and function during that vulnerable period before scar formation has stabilized the infarct area. And so inflammatory cell trafficking from hematopoietic organs like the spleen to sites of tissue injury is coordinated by chemokine chemokine receptor networks. Therapeutically modulating these chemokine chemokine receptor interactions may promote infarct healing by limiting excessive inflammation induced tissue damage or by enhancing the recruitment of angiogenic cell populations to the infarct or the wound. Inflammatory cell trafficking after a myocardial infarction is controlled by a CXC motif chemokine ligand 12 or CXCL12 and its receptor CXC motif chemokine receptor 4. CXC receptor 4 antagonists, mobilize inflammatory cells and promote infarct repair. But the cellular mechanisms are unclear.

                                                So, what do these investigators do? In mouse models, the investigators found that inflammatory cell trafficking between a hematopoietic organs and sites of tissue injury is controlled by CXCL12 and its receptor CXC receptor 4. And bolus injectives of a highly selected peptidic macrocycles CXC receptor 4 antagonist, enhanced tissue repair and functional recovery after re-perfused acute myocardial infarction in mice. And interestingly, the therapeutic effects require a dendritic cell priming and we're specifically mediated by t-regulator cells. Intermittent CXC R4 blockade mobilized the t-regulator cells from their splenic reservoir. Leading to their enhanced recruitment to the infarct region.

Dr Carolyn Lam:                So bring it home for us, Greg. What does this mean clinically for MI management in humans?

Dr Greg Hundley:             Right. Highlighting the translational potential. What we might infer is that CXC receptor 4 blockade reduces infarct volume and improved systolic function in a porcine close chest model of re-perfuse acute myocardial infarction.

                                                And so, the results of both the mouse experiments and this sort of translational model in pigs should stimulate further research into therapeutic potential of CXC R4 blockade after MI and in other acute conditions were excessive, innate or adaptive immune responses cause immunopathology.

Dr Carolyn Lam:                Fascinating. So from one preclinical paper to another, but this time focused on heart failure. And focus specifically on titin. Titin is this giant elastic protein that spans the half-sarcomere from the Z-disk to the M band, and it acts like a molecular spring and a mechanosensor that has been linked to striated muscle disease. Now the pathways that govern tight independent cardiac growth and contribute to disease are diverse and have been really difficult to dissect. And so corresponding author Dr Gotthardt, from Max Delbruck Center for Molecular Medicine and the German Center for Cardiovascular Research and his colleagues aimed to study titin deficiency versus titin dysfunction.

                                                And how they did that is they generated and compared striatum muscles specific knockouts with progressive postnatal loss of the complete titin protein. And that's by removing Exxon 2. Or an M-band truncation that eliminates the proper structure and integration, but retains all the other functional domains. So they then evaluated cardiac function, cardiomyocytes mechanics, and the molecular basis of the phenotype. Now, what they found was that progressive depletion of titin led to sarcomere disassembly an atrophy in striated muscle. And in the complete knockout, remaining titin molecules had increased strain resulting in mechanically induce trophic signaling and eventual dilated cardiomyopathy.

                                                On the other hand, the truncated titin helped maintain passive properties and thus reduced mechanically and do signaling. In other words, truncations versus loss of titin, differentially affected cardiac pathology with atrophy versus dilated cardiomyopathy respectively. And together, these findings really contribute to the molecular understanding of why titin mutations differentially affect cardiac growth and have implications importantly for genotype, phenotype relations that support a personalized approach to the diverse titinopathy.

Dr Greg Hundley:             Interesting, Carolyn. All this information on titin. So why is it clinically important?

Dr Carolyn Lam:                Well, first of all, tightened mutations are the most common genetic basis of heart disease and the findings are clinically relevant, as I said, for understanding the genotype phenotype relations at the Titin mutation. But understanding the integration of Titin based signaling and sarcomere biology could indeed help personalize diagnostics by improved clinical decisions and maybe identify suitable therapeutic targets for these titinopathy. But that of course requires much further work. Well that brings us to the end of our summaries. Let's go to our feature discussion.

 Dr Greg Hundley:            Welcome everyone to our second segment of our program. We're discussing an interesting paper today entitled Sudden Death and Left Ventricular Involvement in Arrhythmogenic Cardiomyopathy. And we want to welcome our coauthors Elijah Behr and Mary Sheppard from St George's University in London. And also, our own associate editor, Sami Viskin to discuss this paper. Mary, can you tell us a little bit about your study design here, the population and the hypothesis and some of your results?

Dr Mary Sheppard:          I am a cardiac pathologist of 20 years and I have a special interest in sudden death. Over this time, I've established a national pathology database, where pathologists throughout the country when they have a sudden death, which is likely cardiac and non-ischemic, they will send the heart or tissue blocks insides to me for my opinion concerning the death. We have as a result developed a large number, over 5200 cases which has now built up to 6000. It's the largest pathological series in the world.

                                                And I was also discovering the pathologists were either under or over diagnosing all types of cardiomyopathy but particularly ergogenic cardiomyopathy. And that is why with Chris Miles, our research fellow, we looked in detail at what I had diagnosed, or the pathologist as ergogenic cardiomyopathy and we actually honed are pathological diagnostic criteria for this very important entity. Establishing that left ventricular is five and ventricular and left and ventricular is the norm almost. That right or left ventricular is unusual by themselves and even in 20%, one in five, the heart can look macroscopically normal. So that histology is essential when you're making this diagnosis. You cannot make the diagnosis pathologically without histologically examining the heart.

Dr Greg Hundley:             Very good, Mary. And did you also examine some genetic markers in some of the subsets of the patients? And how did you decide who those individuals would be that received the genetic analysis?

Dr Mary Sheppard:          A small subset and I will hand over to Elijah Behr, my colleague concerning that.

Dr Elijah Behr:                   The genetic tissue is only available in a minority of cases. We've developed a pipeline now with the referring pathologists who are increasingly they're sending samples of spleen suitable for DNA extraction that allow us then to do a retrospective postmortem genetic testing or molecular autopsy. But unfortunately, in this particular series we only had a small proportion. I think there were roughly about 24 out of the 202 cases, so just over ten percent. And interestingly, while we didn't necessarily mirror the expected yield of genetic testing that is seen in clinical cases, where you may see about 40% carrying pathogenic variance. We certainly picked up some important pathogenic variance, particularly those that are often associated with highly penetrant and more severe disease. In particular TMEM43 and desmoplakin. These findings may reflect the small size of the sample, but it also may reflect where the greatest risk for sudden death from ergogenic cardiomyopathy lies.

Dr Greg Hundley:             Elijah, getting back to some of the patients that experienced the sudden death in the study population Mary was referring to, were there characteristics that were associated with the sudden death? For example, those that might be related to gender or activity?

Dr Elijah Behr:                   So the majority of the cases were male. The majority has never had prior symptoms. These were unheralded deaths. The majority did not have a family history and I think the majority were addressed, but those that were athletes, we're much more likely to have died during exertion. So as we found with ergogenic cardiomyopathy in general and exertion is a trigger to sudden death. The risk was higher and compared to the athletes in death during exertion was associated with being younger as well. I think exertion and sports clearly play a role in ergogenic cardiomyopathy. It didn't appear to play a role in whether there was left ventricular involvement or not, but certainly a role at more severe presentation.

 Dr Greg Hundley:            Maybe both Mary and Elijah answering this. You found histopathological evidence of fibrosis and fatty infiltration. How extensive was that? And do you think that could be identified with a test like maybe magnetic resonance imaging?

Dr Mary Sheppard:          Yes. Our diagnostic criteria which is illustrated in the addendum is that it was at least two blocks of tissue. We always look at 10 to 12 to 15 blocks of tissue from both right and left ventricle. And at least two of the blocks had to have fibrosis with fat in 20% of the area examined. We did not include inflammation because inflammation is, an important histological criterion in our experience. We were very precise about that because you need that much at least to make the diagnosis. A little bit of fibrosis or a little bit of fat is not sufficient by itself.

Dr Greg Hundley:             When you mention a block, for us clinically, how much myocardium would that be? For example, on an imaging test like an echo or an MRI scan.

Dr Mary Sheppard:          One to two centimeters squared.

Dr Greg Hundley:             So quite a bit.

Dr Elijah Behr:                   You're looking at probably around two to four millimeters of potential depth of fibrosis. And what we've seen clinically in LV involvement of MRI scans is miss two epicardial late enhancement. Now the question is whether our scans are sensitive enough to pick that up? Given the technology available or a sense to the histopathology and I think that's why maybe some of the clinical studies have tended to miss the true proportion of left ventricular involvement. Because of the relative subtlety of the fibrosis compared to the technological ability to discriminate it. I mean certainly when you look at our cases that were diagnosed previously with cardiomyopathy, either they were arrhythmogenic or dilated, many did have imaging findings if MRI was performed, that would indicate or suggest some left ventricular involvement. But as you know, the task force criteria for arrhythmogenic cardiomyopathy having very much right ventricular focus. An LV imaging findings and LV ECG findings are just not part of those at the moment.

Dr Greg Hundley:             Was there a particular location within the heart where there was a predilection toward the findings of fibrosis and fat?

Dr Mary Sheppard:          In the posterior basal wall particularly, transmural involves going from the epicardium to the sub endocardium and also the interior walls of the left ventricular were the predilection areas.

Dr Elijah Behr:                   I think that's what we see on our MRI scans as well. When you look at these patients, that posterior basal area, is the one that tends to light up the most.

Dr Mary Sheppard:          It is believed that increased stress in that area gives more damage because of the stretching away from the septum.

Dr Greg Hundley:             Very interesting. So Elijah, you had mentioned task force criteria. I want to shift to Sami now and ask, Sami, can you help us put this in perspective relative to the existing task force criteria and then the findings in this study? And how that could lead to subsequent changes down the road?

 Dr Sami Viskin:                 Okay, so it is difficult to place this in the context of the task force because mentioned by Elijah, the taskforce are focused on a disease that is believed to be in the right ventricle. And the study shows that many of the sudden death cases will involve the left ventricle. One of the most important messages of this paper is importance of her forensic examination. And importance of making it for anything examination in the center of expertise. We know of patients that will travel a thousand miles to undergo surgery or an ablation procedure, but families do not think that way when there is casualty or family dies. You may take a postmortem as a given, but in many countries, including my own, most cases of sudden death would not be followed by a post mortem and will not go into center of expertise. And you cannot overemphasize the importance of doing that because then you have to know what you are looking for in the remaining relatives is extremely important.

Dr Greg Hundley:             Very good. How about from the perspective as an electrophysiologist? Does this impact in any way how you might evaluate a younger person with syncope?

Dr Sami Viskin:                  Well, it is difficult to conclude from this paper about how to evaluate patients with syncope because most of the cases in this series don't have symptoms at all. But this paper calls to very interesting investigations by Mario del Mar and others in New York. Looking about the electrophysiology consequences of a disease like right ventricle are like a bit mechanical in [inaudible 00:21:58] The tissues becomes editing the disease, the electrical properties how the patients in brugada can cause malfunction of this sodium channel and create a disease that is more like brugada and dysplasia at the beginning. So, the entire correlation between a morphologic disease and the metrical disease and we used to think they are two different things. And now we see that we can actually put them together and you can go through stages where one disease is before an electrical disease and only at later stages it becomes a morphological evident disease.

 Dr Greg Hundley:            A fantastic discussion on pathologic findings. Sami making the point that certainly in cases for young individuals having a postmortem examination performed at centers that have expertise such as what Mary's described, can be very important. And then Elijah, helping us to understand with arrhythmogenic cardiomyopathy, number one, findings are not, we shouldn't just be thinking about the right ventricle in isolation, but also the left ventricle. Fibro fatty infiltration, particularly in the posterior basal wall could be an important thing to look for, for those that are performing the magnetic resonance imaging exams. And then lastly, many of the patients in the study like this, the first presentation was of sudden death. And we need to be cognizant that this condition could be prevalent in the population and not necessarily appreciated by some of our current task force guidelines and examinations. So, what an outstanding discussion. And I think for today, we want to thank our authors and our associate editor and wish everyone a great week.

                                                On behalf of Carolyn and myself, we look forward to seeing you next week. Thank you very much.

Dr Carolyn Lam:                This program is copyright American Heart Association 2019.


Apr 1, 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 in Richmond, Virginia at VCU Health.

 Dr Carolyn Lam:               So, PCI or no PCI for chronic total occlusion. That is a perennial question, and we have the results of the decision CTO trial reported in this week's Journal. In fact, we're going to discuss it right after our little chat here.

                                                So, Greg, why don't you kick us off? What paper did you choose?

 Dr Greg Hundley:            Yeah, thanks so much Carolyn. My first paper is from Laura Benschop from the Department of Obstetrics and Gynecology at Erasmus Medical Center in Rotterdam, the Netherlands. It's going to focus on placental growth factor as an indicator of maternal cardiovascular risk after pregnancy.

                                                So, as we all know, pregnancy is accompanied by extensive maternal hemodynamic changes that allow for proper placental implantation, growth, profusion, and fetal development and this process requires a tight balance between pro-angiogenic factors like placental growth factor, and anti-angiogenic factors like soluble FMS like tyrosine kinase factors. So, in response to stress, the syncytiotrophoblast will decrease the production of placental growth factor and women with reduced placental growth factor and increased FLT-1, are more at risk of a complicated pregnancy. For example, like preeclampsia and spontaneous preterm birth.

                                                So, angiogenic placental growth factor concentrations can rise during pregnancy, peaking at the end of the mid-pregnancy. And low placental growth factor concentrations during pregnancy are associated with pregnancy complications with recognized later life cardiovascular risk. So here, the authors hypothesize that low placental growth factor concentrations, especially in mid pregnancy, identify not only a subset of women at risk for pregnancy complications, but also women with greater cardiovascular risk factor burden after pregnancy, regardless of their outcome.

                                                So, among 5,529 women, the authors computed gestational age adjusted and mid-pregnancy placental growth factor concentrations and pregnancy complications, like preeclampsia, small for gestational age, spontaneous preterm birth, was obtained from hospital registries.

 Dr Carolyn Lam:               Cool, and what did they find?

 Dr Greg Hundley:            So six years after pregnancy, the authors found that women with mid pregnancy low placental growth factors, in the lowest quartile, had larger aortic diameters, left atrial diameters, and LV mass, and a higher systolic blood pressure by an average of 2.3 millimeters of mercury. High mid-pregnancy placental growth factor concentrations were the opposite. They were associated with smaller aortic diameters, smaller left atrial diameters, lower LV mass by 3.9 grams, and lower systolic blood pressure. And these differences persisted after exclusion of women with complicated pregnancies.

                                                So, the results suggest that a woman's response to the cardiovascular changes of pregnancy, measured by pre-mid-pregnancy placental growth factor levels could provide insight into the path of physiological mechanisms leading to future cardiovascular disease in multiparous women.

 Dr Carolyn Lam:               Wow. That is really interesting. Well, the paper I chose really answers the question, are there racial differences in sudden cardiac death, and why? And this is from corresponding author Dr Guallar from Welch Center for Prevention, Epidemiology, and Clinical Research in Johns Hopkins Bloomberg School of Public Health and Colleagues.

                                                What they did is they compared the lifetime cumulative risk of sudden cardiac death among blacks and whites in the atherosclerosis risk in community study, or ARIC. They evaluated the risk factors that may explain racial differences in sudden cardiac death risk in this general population.

                                                What they found was that blacks had a much higher risk of sudden cardiac death in comparison with whites, with a sex adjusted hazards ratio of 2.12. Known factors explained 65% of the axis risk of sudden cardiac death in blacks compared to whites. The single most important factor explaining this difference was income, followed by education, hypertension, and diabetes. These racial differences were evident in both genders, but stronger in women than men.

 Dr Greg Hundley:            Hmm. So are there implications, and are there potential strategies that could help reduce this risk in African Americans?

 Dr Carolyn Lam:               Yeah, this is a really interesting study, and it really implies that efforts to reduce the sudden cardiac risk in blacks should perhaps focus on improving CPR outreach, medical care engagement in response to cardiac arrest, the quality of treatment in medical institutions in predominantly black neighborhoods, and factors such as that. Because remember the single most important factor explaining the difference was actually income and education.

 Dr Greg Hundley:            Oh, wow. Well, I'm going to switch gears a little bit here Carolyn, and we're going to talk about pulmonary hypertension. And this next paper is going to focus on pericytes. We'll learn a little bit about what pericytes are. So, the paper is from Vinicio de Jesus Perez, who's an assistant professor of medicine and pulmonary critical care at Stanford University Medical Center in California.

                                                What are pericytes? So, pericytes are specialized perivascular cells embedded in the basement membrane of blood vessels, where in conjunction with neighboring and endothelial cells, they support vessel maturation and stability. In the lung, pericytes are mostly found associated with small precapillary arteries, the capillaries, and then those post capillary venules. And it's thought that pericytes are responsible for regulation of vasomotor tone and structural support of these micro-vessels. When the vessels become muscularized, pulmonary vascular resistance increases, resulting in pulmonary artery hypertension.

                                                So recent studies have focused on pericytes in addition to pulmonary endothelial cells, smooth muscle cells, and fiberglass, but not much is known about the contribution of pulmonary pericytes to pulmonary arterial hypertension. Two genes are involved in Wnt planar cell polarity pathway that is responsible for coordinating complex cell movements during tissue morphogenesis. So, in this group, they have produced prior results that show that restoration of the Wnt planar cell polarity in pulmonary arterial hypertension, pericytes could partially restore recruitment to PNVECs and increase vessel stability.

 Dr Carolyn Lam:               Interesting, and so that was their past research, and what did the current paper show?

 Dr Greg Hundley:            Right. So Carolyn, what they found is that pulmonary microvascular endothelial cells isolated from pulmonary arterial hypertension patients, and endothelium from pulmonary arterial hypertension tissue have reduced expression of Wnt-5a. Healthy PMVECs produce and package Wnt-5a in the form of exosomes which regulate pericyte recruitment, motility, and polarity.

                                                And so, the overall implication is that promising therapeutic strategies that help can restore the Wnt/PCP, or planar cell polarity pathway, and endothelial pericyte communication could help prevent micro-vessel loss in patients with pulmonary artery hypertension.

 Dr Carolyn Lam:               Thanks, Greg. So, I'm going to take us to the cath lab for this next paper. And it's the results of the CANTIC study, which aimed to answer the question, does intravenous P2Y12 inhibitor Cangrelor have a role in bridging the gap in platelet inhibition in patients with STEMI undergoing primary PCI. And this is from corresponding author Dr Angiolillo from the University of Florida College of Medicine Jacksonville and Colleagues.

                                                Now, CANTIC was a prospective randomized double-blind placebo control parallel design investigation of the pharmacal dynamic effects of Cangrelor versus placebo in patients undergoing primary PCI, who were also treated with crushed Ticagrelor. So, after diagnostic angiography, patients were randomized to a blinded two-hour infusion of either Cangrelor or placebo. At the same time, 180 milligrams of crushed Ticagrelor was administered to both groups. Platelet reactivity was measured with Verify Now P2Y12 point of care testing, and with vasodilator-stimulated phosphoprotein, or VASP.

 Dr Greg Hundley:            So what did the trial show, Carolyn?

 Dr Carolyn Lam:               They found that addition of Cangrelor led to more prompt and potent platelet inhibitory effects, compared with crushed Ticagrelor alone in patients undergoing primary PCI. The significant differences were observed as early as five minutes post bolus administration, and persisted until the end of its two-hour infusion.

                                                Furthermore, after discontinuation of Cangrelor or the placebo infusion, there were no differences in levels of platelet reactivity between groups. And this importantly rules out a drug/drug interaction when Cangrelor and Ticagrelor are concomitantly administered. This lack of drug-drug interaction is important, as it supports a more versatile use of Ticagrelor with respect to timing of its administration in patients treated concurrently with Cangrelor.

                                                Overall, the results are reassuring and demonstrate reduced platelet reactivity, and no high on treatment platelet reactivity with Cangrelor in combination with Ticagrelor in primary PCI patients. Of course, the implications of these pharmacal dynamic findings really warrant investigation in an adequately powered clinical trial.

                                                And that brings us to the end of our summaries. Let's go to our featured discussion.

                                                So PCI, or no PCI for chronic total occlusion, that is a perennial question isn't it? Especially nowadays when procedural results for PCI and CTO have improved in recent years, and PCI strategies have moved towards more complete revascularization. Yet the evidence is clearly lagging behind for us to make decisions on this. And that's why we're so happy that our featured paper today is the DECISION-CTO trial from Korea, and so happy to have the first author, Dr Seung-Whan Lee from ASA Medical Center to tell us about this, as well as our associate editor, Dr Manos Brilakis from UT Southwestern.

                                                So Dr Lee, could you tell us about the DECISION-CTO trial?

Dr Seung-Whan Lee:       Yeah, in our trial our multicenter, randomized, noninferiority trial, PCI-eligible patients were assigned to receive either one of two strategies; PCI or no PCI or CTO. We did the option for PCI of the other. The primary endpoint as you know the composite outcome of deaths, myocardial infraction, stroke, or any revascularization. As related to quality of life was assessed up to three years. However, because of the slow recruitment, the trial was stopped before completion. We started 208 planned enrollments. For six years 834 patients there were randomly assigned to the CTO PCI versus no CTO PCI strategy.

                                                Among the patients assigned to the no CTO PCI strategy, nearly 20 percent of patient cross over to the CTO PCI. That is our big limitation, as you know. Anyways, the primary end point was assessed per year, and then, finally, we founded the per year risk of the major adverse cardiac events there’s no difference in contributor composite outcome, MI, revascularization, and stroke.

                                                However, in our trial, in some detail, in CTO PCI was success rate around 91 percent. However, complication is very low, .6 percent of patient is complication. Very surprisingly the coheir is up to the three, and no difference between CTO PCI versus no CTO PCI.  

                                                I think our main message is our patient is a relatively low-risk population, including the syntax score 20 and the score 22%. The majority of patient preserved LV function and single-vessel disease 25%. The relative low risk population CTO PCI versus no CTO PCI clinical outcome is no difference of the per year from the two groups.

                                                I think that our trial is make the reposition with the medical law in the CTO patient. That’s my summary.

Dr Carolyn Lam:                Thank you. Manos, could you maybe paint the background and let us know why this was so important for us to publish in Circulation? Why is it so difficult to do these trials?

 Dr Manos Brilakis:           This is the largest study on CTO PCI so congratulations on getting this accomplished. I know it was many years and a lot of effort.

                                                I think a couple of things on the background. As Dr Lee said as well, CTO PCI success rates have been improved, and now at experienced centers you can get 85 to 90 percent success fairly consistently.

                                                The complication rates are low. .5 to 3 percent is the average rate. We do have a tool right now. The procedure is mature, and it's time test in the randomized trials.

                                                The question has always been for CTO PCI, "How does it help?" Does it improve symptoms? Does it improve the heart outcomes? Myocardial Infarction?  This is what DECISION CTO was trying to answer.

                                                Couple of I think limitations that we should take into account when interpreting the results. The first one is that these were notations with an isolated CTO, but a significant proportion had also multi-vessel disease. They were enrolled before treating the other vessels, which were subsequently treated.

                                                Sometimes it's hard to know how much the residual ischemia or symptoms would be present after the other lesions were treated. That's one thing.

                                                The second is that there was a significant crossover for about 1 in 5 patients that randomized to medical therapy immediately crossed over to the CTO PCI group. And that always uses the power and creates difficulty in interpreting the results.

                                                In my mind, the question still remains, in low risk populations it's possible that CTO PCI doesn't improve symptoms, but the ones that were expected to improve, the heart outcomes dec-MI, would be the high-risk patients with significant ischemia. Ideally, studies in the future should actually look specifically at patients who have high ischemia, significant symptoms when looking at heart outcomes.

 Dr Carolyn Lam:               Dr Lee, I think you did mention as well in your manuscript that a viability test was not mandatory for patient enrollment. I mean, clearly it was such as work of labor enrolling such patients. If you put even more criteria it would have been impossible, I suppose. Do you have some thoughts there on maybe future studies?

Dr Seung-Whan Lee:       Yeah, as you know, the currently ongoing CTO PCI process medical treatment is nobel CTO and ischemia CTO is assessed at the reduction of the ischemia burden in CTO PCI. I think there maybe two studies that give us some answer for the low level of the CTO PCI for the reduction of the ischemia.

                                                So, I think the larger ischemic burden the patient is maybe high risk to make the however we don’t know exactly the cut off… ischemic burden in CTO patient. Usually instable angina any kind…coronary disease…3 years circulation showed more than 10 percent of ischemic burden is really predictive of future cardiac event. However, we don't know exactly the can be applied to CTO patient. We don't know exactly.

 Dr Manos Brilakis:           Can I ask Dr Lee a question regarding the study and his interpretation as well. Now the study was borrowed for hard end points dec MI. What his is perception, based on the DECISION CTO, and, of course, everything else in the literature and the CTO study with symptomatic benefit...Dr Lee, what is your conclusion about, or your kind of thoughts about, the effect of CTO PCI on improving symptoms, which is a more accepted indication for the procedure right now?

Dr Seung-Whan Lee:       As you know, the university trials symptom assessment was done after the no CTO PCI. However, our trial is a pragmatic trial, initial approach to the CTO vessel and the vessels that is patient.

                                                At this moment, I think the other vessel, other no CTO vessel intervention and OMT may improve the patient symptom and then CTO vessel is the intervention including the CI patient completely…improve the symptom status. However, analysis showed up to the 3 year, maybe no difference between two groups in the CTO PCI versus medical treatment.

                                                Our trials of the CTO PCI symptom, we don't exactly the role of the after no CTO PCI. We don't know exactly the CTO based symptom assessment was not done, because of the symptom assessment was done before the intervention.

                                                I think that our trials are more practical, because of the initial…multivessel… CTO. Our trials, maybe, completely vascularization including CTO and no CTO vessel revascularization without the CTO intervention. Sometimes the patient to complain of symptom multivessel with the CTO I think we can wait if we continue the patient symptom…

                                                However, in this trial showed CTO specific intervention trial, because of the symptom assessment was done after no CTO vessel intervention. There is some improvement of the… receptor treatment satisfaction of the angina stability. I think that the CTO intervention is maybe reserved for the symptom control after the medical treatment failure of patient.

                                                I fully agree the symptom control is possible with the CTO PCI.

 Dr Manos Brilakis:           Wonderful. Thank you. I think that's a critical differentiation that the DECISION CTO is not specific for CTO, but it's multi-vessel disease plus CTO. Thanks for clarifying. That's very important for the leaders and the entire community to understand that part.

                                                One more question, if it's okay. I know that in Asian countries bypass patients are relatively less. I think in the U.S. 50 percent. Any comment on that? I know people get less bypass in Asia than they do in the United States. How may that affect the interpretation of the DECISION CTO?

Dr Seung-Whan Lee:       Initially, I introduced my studies to our patients syntax score under 20. As you know, the U.S. Registry shows the syntax score more than I think the 20, and the tester score around 46. Quite different in population, because the risk factor is quite different. U.S. patient is hypertension and diabetic are more prevalent than the Asian patient. Bypass surgery is 40 percent in Asian patients. Bypass surgery is around 102 percent in CTO registry. Quite big difference of the base rank, risk factor, and morbidity.

                                                I cannot apply to U.S. population exactly the same ... Not same situation. We cannot apply directly to the U.S. population. I fully agree with your suggestion, though. Lowest population is maybe ... Our trial is maybe lowest population. We agree.

 Dr Carolyn Lam:               I'm just learning so much listening to both of your interventionists. What do you think are the take-home messages from this? Maybe, could I start with Dr Lee, and then give Manos the last word?

Dr Seung-Whan Lee:       CTO PCI critical outcome, it should be tested as a large random trial. Maybe Manos already mentioned about the high-risk population, because our population is the lowest population. However, in some large random trial with a high-risk population we have consider some random trial because they are not easy.

                                                Maybe not easy to test in high-risk population. However, you must do that, because of the two established CTO PCI law in the current practice.

 Dr Carolyn Lam:               Manos?

 Dr Manos Brilakis:           Yeah, I would agree with that. I think the main conclusion regarding the field of CTO PCI is that still right now, the key indication remains symptom improvement. We do have the trials at this point showing that you do CTO PCI in terms of improving mortality. However, CTO PCI is a tool. It's a revascularization tool. Patients who have severe, complex, coronary disease, multi-vessel disease, may be best served with bypass in the first place. Those who have multi-vessel disease that's less complex and don't have significant symptoms after fixing the non-CTO lesions, then they may not benefit from CTO PCI as well. But those who have CTO lesions and have significant symptoms, this is the population for which I think there is general agreement, and I the decision that CTO is good with that, that those patients could benefit from CTO intervention.

 Dr Carolyn Lam:               Thank you so much for sharing your insights.

                                                Thank you, listeners, 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.