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Circulation on the Run

Sep 16, 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: I'm Greg Hundley, associate editor from the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam: Greg, you know I'm vegetarian and any paper on plant-based diet will always interest me, and of course, we have one as a featured paper this week, very interestingly talking about changes in plant-based diet quality, meaning that there could be good plant-based diets and not so good plant-based diets. I mean we all know that potato chips, for example, are still plant-based. But, anyways, so this feature paper discusses the changes in these plant-based diet quality and association with total and cost-specific mortality. Neat, huh?

Dr. Greg Hundley: Yeah. I can't wait to hear about that one. I know that's a favorite topic of yours. How about if we have a sip of coffee and jump into our other articles?

Dr. Carolyn Lam: Sure. I'm sipping away, and have already picked my first paper. This talks about mutations in plakophilin 2, which are the most common cause of gene-positive familial arrhythmogenic right ventricular cardiomyopathy.

Dr. Greg Hundley: No quizzes for me on plakophilin 2, please.

Dr. Carolyn Lam: All right, well, let me tell you all about it. Plakophilin 2 is classically defined as a protein of the desmosome, which is an intracellular adhesion structure. Studies though have suggested that plakophilin 2 also translates information at the initiation. Recent studies have also shown that plakophilin 2 translates information initiated at the site of cell to cell contact into intracellular signals that maintain structural and electrical homeostasis. Now, the important thing is that mutations in plakophilin 2 associated with most cases of gene-positive arrhythmogenic right ventricular cardiomyopathy or ARVC. However, the molecular and cellular mechanisms responsible for arrhythmias in ARVC remain unclear.

Dr. Carolyn Lam: In today's paper, Doctors Delmar and Cerrone from New York University School of Medicine and their colleagues studied the role of cardiomyocyte plakophilin-2 expression in cardiac function. To do that, they utilized a cardiomyocyte-specific, tamoxifen-activated, plakophilin-2 knockout murine line. They found that loss of plakophilin-2 expression caused, as an early event and predominantly in the right ventricle, a non-transcriptional and likely arrhythmogenic, connexin-43-dependent disruption of calcium homeostasis.

Dr. Carolyn Lam: The phenotype included accumulation of calcium in three intracellular compartments, the junctional sarcoplasmic reticulum, the cytoplasm, and the mitochondria. Right ventricular myocytes also showed increased eagerness of ryanodine-receptor-2 channels to release calcium from the sarcoplasmic reticulum. Intrinsic ryanodine-receptor-2 properties were also modified further contributing to the pro-arrhythmogenic state. In summary, the authors postulated that disruption of calcium homeostasis in the right ventricle is a major arrhythmia trigger in patients with ARVC. The data identified both the ryanodine-receptor-2 channel and the connexin-43 hemichannel as targets for antiarrhythmic therapy in this population.

Dr. Greg Hundley: Very interesting that ARVC is such a worrisome concern, and gathering this mechanistic information is just so helpful.

Dr. Carolyn Lam: Exactly.

Dr. Greg Hundley: I have a basic science paper, but it was actually interesting because of the conduct was in many, many human subjects. It emanates from the large Million Veteran Program. There are a whole list of coauthors that are recognized as equal contributors, but Scott Damrauer actually serves as the corresponding author from the VA Medical Center. What it's addressing, about 13% of African American individuals carry two copies of the APOL1 risk alleles, G1 or G2, that are associated with a one and a half to two and a half fold increase in the risk of chronic kidney disease.

Dr. Greg Hundley: There've been conflicting reports as to whether an association exists between these APOL1 risk alleles and cardiovascular disease independent of the effects of the APOL1 on kidney disease. Here, the investigators thought to test the association of these G1 and G2 alleles with coronary artery disease, peripheral arterial disease, and stroke among African American individuals in the Million Veterans Program.

Dr. Carolyn Lam: Seems like a great study population and designed to look at this. What did they find?

Dr. Greg Hundley: Among 30,903 African American Million Veterans Program participants, 3,941 or about 13% carried the two APOL1 risk allele, high-risk genotype. Individuals with normal kidney function at baseline with the two risk alleles had a slightly higher risk of developing coronary artery disease compared to those with no risk alleles. Similarly, modest associations were identified with incident stroke and peripheral arterial disease. However, when modeling both cardiovascular and renal outcomes, APOL1 was strongly associated with incident renal disease while no significant association with the cardiovascular disease endpoints could be detected. In conclusion, what the authors are indicating is that the APOL1 risk variants display a modest association with cardiovascular disease, and this association is likely mediated by the already previously known association of APOL1 with chronic kidney disease.

Dr. Carolyn Lam: Interesting.

Dr. Carolyn Lam: My next paper also has to do with chronic kidney disease and this time looking at metformin use and clinical outcomes in patients with diabetes with or without heart failure or kidney dysfunction. We know that metformin is the first-line therapy for type 2 diabetes, although its effects on the cardiovascular system are actually, not fully proven. In this next paper, the authors examine metformin use in the SAVOR-TIMI 53 Trial.

Dr. Greg Hundley: Tell us a little bit about that SAVOR-TIMI 53 Trial. How is that organized?

Dr. Carolyn Lam: Just as a reminder, the SAVOR-TIMI 53 trial was a multinational, randomized, controlled cardiovascular outcomes trial that compared the dipeptidyl peptidase-4 or DPP4 inhibitor, Saxagliptin, with placebo, enrolling almost 16,500 patients with type 2 diabetes and cardiovascular disease or elevated cardiovascular risk.

Dr. Carolyn Lam: Now, in the current paper led by Dr. Bergmark from TIMI study group in Brigham and Women's Hospital and Harvard Medical School, the authors performed the post hoc analysis and looked at patients in SAVOR-TIMI 53 with baseline biomarker samples of whom there were more than 12,000 patients and classified these patients as ever versus never taking metformin during the trial period. The associations between metformin exposure and outcomes were estimated using inverse probability of treatment weighting, Cox modeling.

Dr. Carolyn Lam: They found that among patients with type 2 diabetes and high cardiovascular risk in the SAVOR-TIMI 53 trial, metformin use was associated with lower rates of all-cause mortality including after adjustment for clinical variables and biomarkers, however not lower rates of the composite endpoint of cardiovascular death, MI or stroke. This association was most apparent in patients without prior heart failure or moderate to severe chronic kidney disease.

Dr. Greg Hundley: Excellent.

Dr. Greg Hundley: I'm going to transition to another clinical trial and this one is looking at ezetimibe in elderly patients and looking at efficacy for preventing cardiovascular-related events. The paper comes from Yasuyoshi Ouchi from Toranomon Hospital in Japan. Evidence regarding the primary prevention of coronary artery disease events by LDL-C/lipid-lowering therapy in order individuals that are above the age of 75 years, is somewhat incomplete. This trial tested whether LDL-C lowering with ezetimibe is useful for the primary prevention of cardiovascular events in older patients. They implemented a multicenter, prospective, randomized but open-label, blinded, endpoint, however, evaluation design conducted among 363 medical institutions in Japan.

Dr. Greg Hundley: In the study, there're 3,796 patients that are aged greater than 75 years with elevated LDLC without a history of coronary artery disease that already were receiving dietary counseling. They're randomly assigned one-to-one to receive as ezetimibe 10 milligrams once daily versus usual care with their randomization stratified in a block design on age, sex, and baseline LDL-C. The primary outcome is the composite of sudden cardiac death, myocardial infarction, coronary revascularization, and stroke.

Dr. Carolyn Lam: Ooh, so tell us the results.

Dr. Greg Hundley: There were several patients that had to be excluded, so what ended up happening, there's 1,716 and then 1,695 that are included in each of the two respective arms for the primary analysis. What they found is that as ezetimibe reduced the incidents of the primary outcome. Then, regarding some secondary outcomes, the incidents of composite cardiovascular events and coronary revascularization were lower in the ezetimibe group than in the control group. But, there was no difference in the incidents of stroke, all-cause mortality, or adverse events in the two different groups.

Dr. Carolyn Lam: Can you sum it up for us, Greg? What should we take home regarding ezetimibe and what further do we need to do?

Dr. Greg Hundley: Good point, Carolyn. I think what we can take away from this study is that LDL-C lowering therapy with ezetimibe prevented cardiovascular events, suggesting the importance of LDL-C lowering for primary prevention in individuals greater than 75 years of age with an elevated LDL-C. However, remember, it was open label, so I think a placebo, controlled, randomized clinical trial will be required to validate the data that were obtained in this study. I think another study is probably going to be needed.

Dr. Carolyn Lam: Thanks, Greg. Well, let's move on to our feature discussion, shall we?

Dr. Carolyn Lam: Today's feature paper is of personal interest to me and I'm sure of widespread interest to everybody. Why? It's on plant-based diet. We've heard a lot about it. I'm vegetarian and very, very loudly self-confessed, but does the quality of a plant-based diet actually matter? Such an important question.

Dr. Carolyn Lam: I'm so pleased to have the authors of this very remarkable paper, Dr. Megu Baden as well as Dr. Shilpa Bhupathiraju, both from the Harvard T.H. Chan School of Public Health; and our associate editor, Dr. Mercedes Carnethon from Northwestern University Feinberg School of Medicine. Welcome, ladies. What a nice chat we're going to have on this very personal topic to me as well.

Dr. Carolyn Lam: First of all, maybe, could I ask, Shilpa, do we need another study on plant-based diet? Could you tell us the rationale for what you did this time?

Dr. Shilpa Bhupathiraju: Like you said, when we talk about plant-based diets and what people usually think is, well, it's vegetarian or not. But, I think there's much more to a vegetarian diet. It's the quality that matters. Previous studies really then differentiate the quality of a vegetarian diet.

To this extent, we developed plant-based diet indices, which actually capture the quality of a plant-based diet, so we have an overall plant-based diet index which captures the amount of plant-based foods; a healthy plant-based diet index, which captures the quantity of healthy plant-based foods; and again, the unhealthy plant-based diet index, which captures the quantity of unhealthy, plant-based foods.

Dr. Carolyn Lam: Thanks. Meg, if you don't mind, I know everybody is asking this as they're listening. Could you give us some examples of what an unhealthy plant-based diet index would consist of compared to healthy? Then, perhaps, tell us a little bit about your study and what you found.

Dr. Megu Baden: First of all, let me explain again. In this study, we use three versions of plant-based diet indices that can assess the quality of plant foods in general population. The first index is an overall plant-based diet index, PDI for short. A second one is a healthful plant-based diet index, HPDI. The third one is an unhealthful plant-based diet index, UPDI. In order to create these indices, we divide all food groups into three larger categories. One is the healthy plant foods, which contains whole grains, fruits, vegetables, nuts, legumes, vegetable oils, tea, and coffee; less healthy plant foods such as fruits juice, refined grains, potatoes, sugar-sweetened beverages, and sweets or desserts; and animal foods, which is animal food, dairy, eggs, fish, meat, miscellaneous animals-based food.

Dr. Megu Baden: We investigated the association between preceding trailblazing changes in these indices and subsequent total and cause basic mortality in two large US cohorts. We found that compared with participants whose diet remained stable, the hazard ratio for total mortality, among those risks, the greatest increase in PDI was 0.95; for the greatest increase in HPDI, the healthful versions of the PDI was 0.90; and the greatest increasing in unhealthful PDI was 1.12. In contrast, the hazard ratio among participants with the greatest difficulty is in PDI, was 1.09; the greatest decrease in healthful PDI was 1.10; and the greatest decreasing in unhealthful PDI was 0.93. For CVD mortality, the risk was 7% lower for our 10 point increase in PDI, and 9% lower for HPDI and 8% higher for UPDI.

Dr. Megu Baden: In summary, we found that improving plant-based diet quality over a 12-year period was associated with a lower risk of total and CVD mortality, whereas increased consumption of unhealthful plant-based diet was associated with a higher risk of total and CVD mortality.

Dr. Carolyn Lam: Could I ask, Shilpa, to maybe add a line of ... have you applied this information in any way yourself or with patients, or is there an overwhelming take-home message you'd like people to remember?

Dr. Shilpa Bhupathiraju: Yeah, I'm not a clinician myself, but I'm a public health researcher. I'm in India currently and I'm giving a talk to South Asians and the emphasis on vegetarianism. But, again, the quality of the vegetarianism is important. Being a vegetarian is not enough, but what goes into it is really important. If it's a white rice and sugar-sweetened beverages, it's not good, so really the emphasis should be on whole grains, consuming more nuts and legumes. I think that's important.

Dr. Carolyn Lam: Oh, that's great. Mercedes, we've discussed this paper as associate editors, so proud to be publishing this in circulation. Could you share some of your thoughts on the implications of these findings?

Dr. Mercedes Carnethon: The authorship team has done an outstanding job of clarifying a very complicated issue. I think what we really like about this and the ways in which it really adds to the literature, what you point out, that every vegetarian diet isn't the same. I was very impressed with the thought that went into classifying vegetarian foods as healthy or unhealthy. I would be interested in hearing more from the authors, particularly, since I feel they did a good job of how they dealt with complicated foods or mixed foods. I think one example given was a pizza, which has tomato sauce, but it also has other things, so I would love to hear from the authors how they classified complicated foods.

Dr. Shilpa Bhupathiraju: The decision to classify pizza as an animal food was somewhat, I would say, arbitrary. I do agree that there's lots of tomato sauce, but again, I think the decision that went to it, it does have a ton of cheese, processed cheese, I think that's why we classified that as an animal food. The other complicated foods are mixed dishes that we struggled with were cream soups. We thought about what the base was or what the general preparation of that would be. Given that heavy cream is a major ingredient, so those were again, classified as animal foods.

Dr. Mercedes Carnethon: I think there's a lot of logic in that and I really like the thought and care that you put into that. The other questions I have, I feel that you did a really nice job of, are even portion sizes. Tell me how you handled portions.

Dr. Megu Baden: We basically take the information from our food frequency questionnaire. All of them are per the serving sizes, so we considered how participants reported how often on average they had consumed each food of our standard portion size in the past year. I know it's difficult to indicate the portion size. Shilpa, would you add something for the portion size for that?

Dr. Shilpa Bhupathiraju: Yes. Like Megu said, we use standardized portioning sizes, so a cup of fruit, a cup of vegetables, an eight-ounce, or a cup of tea or coffee, so that's how we use what people use in general. The portion sizes are all specified on the food frequency questionnaire, so the nurses or the health professionals, they understand exactly what they're reporting. Is it a glass of fruit juice or half a glass? Then, we can word those frequencies into standardized serving sizes onto servings per day.

Dr. Carolyn Lam: Great. Shilpa, could I follow up from Mercedes very important question? How does the index account for portion size too, as an is too much of even a good thing become a bad thing? You know what I mean?

Dr. Shilpa Bhupathiraju: The index itself is a score. The way we capture it, as you know, everything is converted from frequencies into servings per day for each participant. Then, what we did was we divided the participants based on the distribution of the data into quintiles. Those in the highest category of the healthy plant foods received the highest points. The scoring varied a little bit based on which index we were calculating. But, in general, what we did was we divided everybody into five groups or quintiles. Then, the scoring varied depending on what we were calculating. For the HPDI, which is the healthy plant-based diet index, those in the fifth group or the highest intake received the maximum number of points, which was five. For the unhealthy plant-based diet index, those people received the reverse scoring, so they received zero points. Essentially, the participants were divided into quintiles and the scoring was done accordingly.

Dr. Carolyn Lam: Maybe I could ask you a question on a different track, and I'm not sure if you have some answers here, but I noticed that your study population was impressive, almost 49,500 women from the Nurses' Health Study, almost 26,000 men from the Health Professionals Follow-up Study. Did you find any sex differences?

Dr. Shilpa Bhupathiraju: We didn't find any sex differences. We did some sensitivity analysis by cohort and we didn't find a statistically significant interaction, which is I think good to note because we would expect the effects to be similar in men and women.

Dr. Carolyn Lam: I think both men and women need to hear that. None of us are excused from, I suppose, trying to gear towards a healthy plant-based diet. I think that's what I'm hearing. Mercedes, do you have more thoughts to add?

Dr. Mercedes Carnethon: I do. One thing I really like about this particular paper is the way the you acknowledge some of the limitations that we face when interpreting findings from observational studies, particularly observational studies of a health behavior when we know that health behaviors often cluster or correlate with other health behaviors. Can you tell us a little bit about some of the cautions and interpretation that you certainly acknowledged and presented very well?

Dr. Shilpa Bhupathiraju: Sure. Our primary analysis was looking at changes, so long-term changes. When people change a diet or their lifestyle, they change something else. As you can see from our paper, those who improve the plant-based diet quality, we're also, in general, tended to be healthier. This being an observational study, we tried to control for those as to the greatest extent possible, but again, they could be residual confounding. We maybe failed to measure for certain things that we were unaware of or that we did not measure. I think we really can't get at causality, but I think the consistency of the evidence from our previous papers and from this paper point to a suggestion that improving plant-based diet quality is definitely associated with better health outcomes and a lower risk of death. But, again, it is important to know that this is observational and there could be changes in other health behaviors that we did not measure that could explain this association. But, we did as well of a job as we could in trying to control for these changes and other behaviors, lifestyles or even health conditions.

Dr. Mercedes Carnethon: Thank you.

Dr. Carolyn Lam: Thank you so much, Meg and Shilpa. You've been listening to Circulation on the Run. Don't forget to tune in again next week.

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