Mar 11, 2019
Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr Greg Hundley: And I'm Greg Hundley, associate editor and director of the Pauley Heart Center at VCU Health, in Richmond, Virginia.
Dr Carolyn Lam: So Greg, are ARNI's now going to be used for functional, mitral regurgitation and heart failure? Well, we're going to be chatting all about that with our feature paper, coming right up after these summaries.
Greg, you've got a biggie to start with, haven't you?
Dr Greg Hundley: Oh yes, Carolyn, I'm really excited about this paper. The senior author Wanpen Vongpatanasin from University of Texas Southwestern Medical Center in Dallas and looking at high phosphate diets and their relationship to exercise intolerance. I really felt this was an exceptional study and combining that key that we have, for basic science papers and translation, where we're looking at data from both human and basic science, in both in a single manuscript.
So, this study focuses on inorganic phosphates and they are present in 40-70 percent of the foods, really as a preservative enhancer, in western diets. We see it in colas, meats, dry food mixes, bakery products.
For the human subject component of this study, the investigators examine the relationship between physical inactivity, assessed with ActiGraphs that were worn, and serum phosphate levels. They also obtained MRI measures of cardiac function and participants were recruited from the Dallas Heart Study too.
In animals, they looked at the direct effects of dietary, inorganic phosphate on exercise capacity, oxygen uptake, serum non-esterified fatty acids, and glucose was measured during exercise treadmill tests in mice fed either high inorganic phosphate diets or normal in-organic phosphate diets. And they were on that for 12 weeks.
To determine the direct effect of phosphate on muscle metabolism and expression of genes involved in fatty acid metabolism, additional studies in the differentiated myotubes were conducted after subjecting those cells to media with high or low phosphate conditions.
Dr Carolyn Lam: So, what did the study show?
Dr Greg Hundley: In the human part, among 1603 participants, higher serum in-organic phosphate was independently associated with reduced time spent in moderate to vigorous physical activity and increased sedentary time. And interestingly, there was no association between serum phosphate levels and left ventricular ejection fraction or volumes.
In the animal studies, mechanistic insight was obtained. Compared to controlled diets, consumption of high phosphate diet for 12 weeks did not alter body weight or left ventricular function, thereby confirming what we saw in the human subjects, but reduced maximal oxygen uptake, treadmill duration, spontaneous locomotor activity, fat oxidation, fatty acid levels, and led to down-regulations of genes involved in fatty acid synthesis.
So, the take-home on this is that the results of this study demonstrate a detrimental effect of dietary, phosphate excess on skeletal muscle, fatty acid metabolism, and exercise capacity, which is independent of obesity and cardiac contractile function.
And as such, dietary in-organic phosphate may represent a novel and modifiable target to reduce physical inactivity associated with the western diet. I think, Carolyn, we're going to see a large number of epidemiologic studies that are going to really look at this as something we might be able to modify in our diet to help impact some of these sedentary lifestyles and the harmful cardiovascular effects that we find associated with that lifestyle.
Dr Carolyn Lam: Yikes. Remind me again, so phosphates in colas, meats, dried food mixes, and bakery products and so on, the preservative. Wow, you're right; big paper.
Dr Greg Hundley: It's amazing. It's in 40-70 percent of the food products here in the United States. So, wow. Something really striking. So Carolyn, how about one of the papers that you liked?
Dr Carolyn Lam: Moving to related cardio metabolic disease, we know that patients with type 2 diabetes and prevalent atherosclerotic cardiovascular disease, there is a tenfold variation in future cardiovascular risk in these patients. The current paper actually analyzes data from EMPA-REG OUTCOME where the authors, led by David Fitchett from St. Michael's Hospital in Toronto, sought to investigate whether the beneficial effects of Empagliflozin, observed in the EMPA-REG OUTCOME trial, varied across the spectrum of baseline, cardiovascular risk.
What they found was that in patients with type 2 diabetes and atherosclerotic cardiovascular disease, the relative reductions in risk of cardiovascular death, all-cause mortality, 3-point MACE, and heart failure hospitalizations with Empagliflozin versus placebo, were consistent in patients with and without a prior, myocardial infarction, with and without a prior stroke, and across sub-groups by the 10-point TIMI Risk Score for secondary prevention at baseline.
Dr Greg Hundley: Does this suggest, Carolyn, that we use these inhibitors in all patients with type 2 diabetes?
Dr Carolyn Lam: Remember the EMPA-REG OUTCOME; all patients had established atherosclerotic cardiovascular disease. This paper really adds to the understanding of the gradient of risk within these patients who had atherosclerotic cardiovascular disease and says Empagliflozin could be beneficial. But remember, there are patients with type 2 diabetes without established, cardiovascular disease and I think there's still equipoise in this primary prevention population.
Dr Greg Hundley: That was great, Carolyn. Now I'm going to grab another sip of coffee and go onto my next paper.
Dr Carolyn Lam: Sure, as long as it's not cola. No phosphates.
Dr Greg Hundley: Right, thank you very much, Carolyn. I'm going to talk about screening for small and medium abdominal aortic aneurysms. This particular study comes from the surveillance of the National Health Service screening program by Dr Earnshaw. Basically, population screening for abdominal, aortic aneurysms has been shown to reduce AAA-related mortality by up to 50%. Most men who screen positive have a AAA below 5.5 centimeters in diameter, and that's really our current referral threshold for treatment. When they have smaller diameter aneurysms they're entered into an ultrasound surveillance program.
In this study, the investigators looked and reviewed those that had small, 3-4.4 centimeter diameter aneurysms or medium ,4.5 up to 5.4 centimeter aneurysms, and they were followed. They were looking at the risk of rupture in these under surveillance.
They had a total of 18,652 men and the risk of rupture overall per annum was 0.03% for men with small, abdominal aortic aneurysms and 0.28% for medium size. That was just below the threshold for the 5-5.4 centimeters, which was 0.4% over time. The risk of abdominal aortic aneurysm surveillance is below .5% per year and that is just below our current referral threshold for surgery, which is 5.5 centimeters.
This is a study that really confirms, Carolyn, that the target mark or diameter that we've selected is appropriate.
Dr Carolyn Lam: Nice. These just confirm the current guidelines?
Dr Greg Hundley: Yeah, they do and Gil Upchurch from University of Florida, a surgeon, had a very nice editorial. The point he wants to make is yep, diameter of 5.5 is the threshold, but a couple key points. As patients are coming in for these visits, we need to continue to emphasize to them other factors related to growth of abdominal aortic aneurysms and their rupture. So, tobacco cessation, treatment of your lipids, management of your hypertension.
The other point that he makes, is we really don't need to be operating on those individuals with an abdominal aortic aneurysm diameter of less than 5.5 centimeters. He makes an argument here that's in some countries with fee-for-service reimbursement, up to 30% of AAA repairs are for aneurysms less than this diameter of 5.5 centimeters. This over utilization of resources can add considerable costs to the healthcare system for managing this condition and is unlikely to increase the overall survival of these patients.
A nice study confirming that what we're doing, really in terms of size and diameter, is correct, but also emphasizing this patient population often has a lot of other cardiovascular co-morbidities that we need to aggressively manage. How about your next paper?
Dr Carolyn Lam: From one very clinically, applicable paper to another. This one answers the question, what's the optimal duration of emergency department and post-emergency department rhythm monitoring among patients with syncope. And the authors, led by Dr Thiruganasambandamoorthy and his colleagues from the Ottawa Hospital Research Institute, prospectively studied adults presenting within 24 hours of syncope at six emergency departments. They collected baseline characteristics, the time of syncope, the time of emergency department arrival, and the Canadian Syncope Risk Score, risk category. They followed subjects for 30 days and adjudicated the primary outcome, which was serious arrhythmic conditions and that includes arrhythmias or interventions for arrhythmias and unexplained death.
Their results showed that the overall arrhythmia risk, and the risk after two hours of emergency department arrival from Canadian Syncope Risk Score, low-risk patients, was indeed very low. Similarly, the overall risk and after six hours of emergency department arrival for medium and high-risk patients was moderate and high, respectively. No low-risk patients suffered ventricular arrhythmia or unexplained death and most of the arrhythmias among the non-low-risk patients occurred within 15 days of the index syncope.
Dr Greg Hundley: Carolyn, what's the take home message here?
Dr Carolyn Lam: The results really support brief monitoring in the emergency department for two hours for Canadian Syncope Risk Score low-risk patients, and six hours for medium and high risk patients followed by selective admissions and the results also support a 15-day outpatient monitoring for medium-risk patients at a selected threshold and for all high-risk patients. So very practical advice.
Dr Greg Hundley: Very good. Until next week, I'm going to watch out for phosphates.
Dr Carolyn Lam: Indeed, and let's go on now to our featured discussion.
For today's featured paper, we are discussing the results of the PRIME Study and that is Angiotensin Receptor Neprilysin Inhibitor, or ARNIs, for functional mitral regurgitation. A terribly interesting study. So pleased to have with us an author Dr Sung-Hee Shin from Inha University Medical center in Incheon, Korea as well as our associate editor Dr Victoria Delgado from University of Leiden in the Netherlands.
Sung-Hee, what an interesting study. ARNI or Entresto for functional mitral regurgitation. Could you tell us what inspired this study and what did you find?
Dr Sung-Hee Shin: Our study was the designed to tell if ARNI or functional mitral regurgitation because secondary functional mitral regurgitation was developed as a result of a reduced function. Guideline-directed medical therapy for heart failure would be a mainstay for a therapy.
But despite use of the traditional drugs such as BETA blocker, ACE inhibitor or angiotensin receptor blockers, you know that the functional mitral regurgitation may be common and significant in the person having this functional mitral regurgitation would be related to increased morbidity and mortality.
So, that trial showed that trans-catheter mitral valve repair effectively reduced the function mitral patient and resulted in lower rate of heart related mortality among patients with heart failure and function mitral regurgitation.
In our blind trial, we also tried to tell whether an ARNI is more effective in improving function mitral regurgitation and randomly assigned 118 patients with heart failure and chronic secondary function mitral regurgitation lasting more than six months despite medical therapy and ejection fraction between 25% and 50% to receive either sacubitril/valsartan or valsartan in addition to standard medical therapy for heart failure.
What happened with that change of mitral regurgitation after 12 months which was assessed by means of transthoracic area ways echo. What we observed was that transthoracic area as well as the volume of mitral regurgitation saw a decrease much more effective in the sacubitril/valsartan group than valsartan group.
We also looked at the various other measures of the left ventricle remodeling and showed that the valsartan group had smaller left ventricle volume at 12 months and had a greater reduction of end-diastolic volume index.
Also, among the completers ARNI, for the reduced left ventricle volume and the yearly time than the control group. So, what we think is that these factors might contribute to greater reduction of function mitral regurgitation in patients in the sacubitril/valsartan group.
But our study was a mechanism study, but it was not designed to see outcomes. So further research and data would be necessary to check is this transthoracic echo end point can translate into better outcome in this population.
Dr Carolyn Lam: Sung-Hee, this is just so interesting to have hypothesized this about functional mitral regurgitation. And not only that, I mean, to my mind, this is the largest echo-based studies of patients before and after Entresto that I can think of. It's nice to know, on top of knowing in paradigm that we can improve outcomes in heart failure reduced ejection fraction, that we now can look at the heart and see what happens in so many dimensions.
So, congratulations.
Victoria, were you surprised by these results? And do you agree with the mechanisms that Sung-Hee suggested?
Dr Victoria Delgado: I think that this study is very important because in the field of functional mitral regurgitation, there is still a lack of consensus on how to treat these patients, which are very challenging.
If the patient needs revascularization they will be referred for certain. But it still should be CBR mitral regurgitation and moderate and mile mitral regurgitation are not considered.
I think that we discuss often which is the optimal medical therapy or the guidelines based medical therapy but it's not really consensus because the studies before have not been like this one. That large in order to answer a specifically that question.
I think that this article brings an important message and brings more evidence to our field that there is not that much data. So, I think it's very important for that research, in particularly after the research of the co-op and the mitral trial where it seems that the selection of patients is very important in order to identify the patients that will really benefit from those therapies.
Dr Carolyn Lam: That's such a good point. Going to that selection of patients, Sung-He, you mentioned very carefully the ejection fractions that you allowed up to 50% in these patients. Could you explain how you reasoned the selection of this patient cohort?
Dr Sung-Hee Shin: The reason why we chose the patients we did, the range of ejection fraction condition, was that we thought the reversibility of the left ventricle mortality and function mitral regurgitation might be more pronounced in these patients.
When we considered the fraction condition in mitral regurgitation with ejection fraction used under [inaudible 00:18:17] LV dysfunction, our inclusive criteria of ejection fraction between 25 to 50% might correspond to ejection fraction of 20 to 40% in patients with mitral regurgitation.
We concluded that if a patient had ejection fraction less than 25% because the reversibility of mortality and function mitral regurgitation might be smaller when all the LV dilation is too extreme and advanced heart failure is already established.
So, I just thing how it can be provided to the patient who have functional mitral regurgitation associated with too extreme LV dilation and LV ejection fraction too.
Dr Victoria Delgado: I think, Carolyn, it's a very good point what she explained because we are used to select patients based on ejection fraction, in particularly patients with functional mitral regurgitation, ejection fraction is rather misleading because actually it's just a change of volume in the ventricles emptying in a low pressure chamber which is the left atrium.
The moment that you correct that in mitral regurgitation sometimes then you face, or you see, the true ejection fraction of that ventricle. And if we wait too long, we may end up with ventricles that they don't have any more resource in order to improve ejection fraction after repair of the mitral valve.
So, I think that this study is important to also realize that concept. That ejection fraction in patients with functional mitral regurgitation may not be the most accurate parameter to assess the function of that ventricle.
Dr Carolyn Lam: Yeah. Exactly. And I thought that was a very clever part of the design. I'm glad you explained it and also so glad, Victoria, you invited the editorial by Dr Mullens, who also commented on that. So, just for the audience to understand that ejection fraction up to 50% was included and ejection fraction less than 25% was excluded.
So also, again, very consistent to your prior point, Victoria.
Could I ask you, I think Dr Mullens also spent quite some time talking about the potential mechanisms. What's your take of this Victoria? ARNI for functional regurgitation. How come?
Dr Victoria Delgado: For me, I'm much more from the side of the imaging point of view. When we have patients with functional mitral regurgitation I always try to see which is the capability that that ventricle has to recover.
Actually, first is always medical therapy, but we know that the [inaudible 00:20:59] only, for example, we just reduced the mitral regurgitation, but they don't really improve the function of that ventricle, while if you reduce the loading conditions of the ventricle in terms of blood pressure as well and favoring remodeling of the left ventricle, you can improve the condition of the mitral valve and reduce the mitral regurgitation.
How valsartan plus sacubitril works differently than valsartan alone that I don't think that I have enough knowledge to explain why but it could be that in a way there is more effective with sacubitril on top of valsartan can improve the loading conditions of the ventricle and improve the, or facilitate, the reversing of morbidity of that ventricle, reducing the mitral regurgitation and that, by itself, could also lead to reversing morbidity.
Like a little bit cardiac resynchronization we'd do, for example, in patients with an ejection fraction below 35% and based on the EEG you have the synchronous fraction of the papillary muscle or the walls of the ventricle which could lead to the mitral regurgitation at the moment that you resynchronize that mitral regurgitation can produce, you reduce part of the volume of the load of the ventricle and that can favor that reversing morbidity.
So, I think that this study raises a lot of questions and I think that further research is needed in order to confirm or to know more how these treatments work.
Dr Carolyn Lam: Goodness, that was so beautifully explained and in fact, many clues from Sung-Hee's study and the reversal of left ventricle end diastolic volume index greater with those treated with ARNI, the LA size and so on.
But maybe I should ask you, Sung-Hee, in line with what Victoria said, what are the next steps? Do you already know what are the next studies that you're going to be looking at in PRIME?
Dr Sung-Hee Shin: We're considering mark of monitoring such as NT pro-BNP or using auto imaging models such as echo and cardiac MRI to look at the change of mitral valve regurgitation in more detail.
This kind of study might be very helpful in understanding [inaudible 00:23:15] ARNI in functional mitral patient.
Dr Carolyn Lam: Yes, that's clever, too. And Victoria, before we end could you maybe give us some take home messages?
Dr Victoria Delgado: I think that the take home message from this study is that when we have patients with functional mitral regurgitation, we need to think what we can offer to them. Not consider mitral regurgitation just as a base standard. That it's going to respond only to diuretics. No. We need to do something on that left ventricle to help it to improve the function and to avoid the progress to more reduced function.
It's very important to understand the mechanism of the mitral regurgitation and to use the guidelines based medical therapy trying to go step by step in order to optimize the medication of that patient and later on, see all the potential treatments that are available right now such as cardiac synchronization therapy, which we should not forget, and then surgery if the patient needs catheterization and if the patient needs the benefit from mitral valve plasty or eventually, for example, trans catheter mitral valve therapies.
But we should avoid that the patient goes further down into heart failure with very dilated ventricles and very poor function because then probably we may face a point of no return.
Dr Carolyn Lam: Thank you so much, Victoria. Both you and Sung-Hee mentioned this is a mechanistic study. So many insights. But it's not saying that everybody with functional mitral regurgitation has to be treated this way now. It's calling for more work and it's certainly very, very important study.
Thank you listeners, for listening today as well. 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.