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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: August, 2016
Aug 29, 2016

 

Carolyn:
Welcome to "Circulation on the Run", your weekly podcast summary and backstage pass to the journal and its editors. I'm Doctor Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. In just a moment, we will be discussing the very topical subject of wearable cardioverter defibrillators in patients at high risk of sudden cardiac death. Yes, this is the topic of our feature paper which really builds on prior US data using these devices and extends it, now, to a healthcare system outside the United States. First, here's the summary of this week's journal.

 
 
The first paper describes a novel class of mediators that may revolutionize the nonsurgical treatment of limb ischemia. This paper from first author Doctor Jung from University of Louisville School of Medicine and corresponding author Doctor Spite from Harvard Institute of Medicine and colleagues looked at resolvents. Resolvents are a family of lipid mediators synthesized from Omega-3 polyunsaturated fatty acids that promote the resolution of inflammation and have been shown to regulate the transition from inflammation to repair. Now, this is very relevant to limb ischemia because most other mediators that promote revascularization also exacerbate inflammation, thus potentially limiting their therapeutic use in chronic inflammatory diseases such as diabetes.

 
 
To assess the role of resolvents in revascularization and resolution of inflammation, the authors using a Murine model of hindlimb ischemia coupled with Laser Doppler profusion imaging, micro-computed tomography and targeted mass spectrometry. They identified that resolvent D2 is produced in the skeletal muscles of their Murine model of limb ischemia as well as in skeletal muscle biopsies of patients with peripheral artery disease. They showed that resolvent D2 increases tissue profusion by promoting arterial genesis that is collateral artery growth and, importantly, that it rescues defective revascularization in diabetic mice. These findings are important because they could inform the development of novel strategies for the clinical management of limb ischemia.

 
 
The next paper addresses food fortification with folic acid, which we all know prevents neural tube defects but may now even prevent congenital heart defects. This paper is from Doctor [Mule 00:02:53] and colleagues from The Center for Chronic Disease Prevention, Public Health Agency of Canada who studied approximately six million Canadian births from 1990 to 2011 and compared the prevalence rates and temporal trends in congenital heart disease sub-types before and after 1998 when folic acid fortification was mandated in Canada. They quantified the effects of folic acid fortification on the birth prevalence of specific non-chromosomal congenital heart disease sub-types, after controlling for concomitant changes in maternal age, pre-pregnancy diabetes, preterm pre-eclampsia, multiple birth and pregnancy termination. They found that there was an eleven percent reduction in non-chromosomal congenital heart defects following folic acid fortification. Specifically, folic acid fortification was associated with a twenty-seven percent reduction in conotruncal defects, a twenty-three percent reduction in coarctation of the aorta, a fifteen percent reduction in ventricular septal defects and an eighteen percent reduction in atrial septal defects. This large ecological study, therefore, provides evidence of a modest protective effect of folic acid fortification on congenital heart defects.

 
 
The last study suggests that in patients with ischemic cardiomyopathy and right ventricular systolic dysfunction, we should perhaps be taking a look at the mitral valve. This is work from first author Doctor Seib from the Beth Israel Deaconess Hospital and Harvard Medical School, corresponding author Doctor Kwon from the Heart and Vascular Institute of Cleveland Clinic Foundation and colleagues, who looked at over five hundred and fifty patients with ischemic cardiomyopathy, all of whom underwent cardiac MRI. They found that mitral regurgitation, as measured by effective orifice area, was a significant independent predictor of right ventricular ejection fraction. They further found that the relationship between right ventricular ejection fraction and mortality may be affected by mitral valve surgery in that a reduction in right ventricular ejection fraction was associated with increased mortality in non-repaired patients but not in patients who had undergone mitral valve repair.

 
 
The clinical take-home messages are that right ventricular function should be carefully assessed in patients with ischemic cardiomyopathy and if systolic dysfunction is found, patients should be assessed carefully for significant mitral regurgitation as well as other known risk factors such as right bundle branch block, right ventricular scar or a decreased left ventricular ejection fraction. The study suggests that mitral valve surgery may mitigate the relationship between right ventricular rejection fraction and mortality, however further studies are clearly needed.

 
 
Those were the summaries. Now, for our feature paper discussion.

 
 
I am thrilled to be joined by three guests today to discuss the feature paper on wearable cardio defibrillators in patients at high risk of sudden cardiac death. This is a real world experience all the way from Germany. Joining us today we have two authors of the paper, the first and corresponding author Doctor Nadine Visnic as well as author Doctor Ruth Strasser, both from the University of Dresden and Heart Center Dresden in Germany. Welcome, ladies.

 
Ruth:
Hello, how are you?

 
Carolyn:
Very good, thank you.

 
 
We have Doctor Mark Link, Associate Editor from UT Southwestern. Thank you for joining us, Mark.

 
Mark:
You're very welcome.

 
Carolyn:
Mark, let's start with a behind the scenes look. We have data from the United States describing the wearable cardio defibrillator. We have ample data on the implantable cardio defibrillators. What made the editorial board decide that this particular paper from Germany was so important?

 
Mark:
There are a number of aspects that we looked at for this paper. This is exciting new technology that is beginning to impact the daily lives of all the physicians in the states, the wearable defibrillator. This is a very nice prospective study from Germany that looked at a very large group of patients with this wearable defibrillator, gave us real world experience and it also fits in with the circulation mission of becoming a world wide cardiac journal, not just United States journal. We were very interested in the topic. We're very interested in the international collaboration and we're very excited to publish this paper.

 
Carolyn:
I love that. Practicing in a non US system, as well, I found this particularly special about this paper.

 
 
Nadiene, we're all wondering, could you describe the patient population, just so we know the kind of patients that your results are applicable to.

 
Nadine:
The patients included in the register were regular patients we meet in clinic in every day life. No specific selection was made. For legal reason, of course, to analyze the data, they signed informed consent for the register. From April 2010 through October 2013, in total six thousand forty-three patients were using the wearable cardioverter defibrillator in Germany. All of these patients were registered into the life vest network, the registry to record demographic such as gender and age. Also, the cardiovascular indications and defibrillation treatments and daily wear time. The German population consisted of seventy-eight male and twenty-two female patients with median age of fifty-seven years.

 
Carolyn:
Great. What were the indications for the wearable defibrillators?

 
Nadine:
Most of the patients had to reduce the ejection faction by below thirty-five percent or even had experienced ventricular tachycardia as an indication. The largest group we had in our analysis was thirty-seven percent where those with newly diagnosed dilatative cardiomyopathy and ischemic cardiomyopathy accounted for twenty-seven of patients, especially forty days after myocardial infarction or after a high risk PCI or cabbage. Also, in total, we had twelve percent of patients that had an ICD explantation mostly due to infection situation. What is very special on that paper is that ten percent of all our patients had myocardidas as a diagnosis and was reason to use the WCD.

 
Carolyn:
Wow. That does sound very representative of the real world patients that we would put wearable defibrillators on, as well.

 
 
Ruth, could you tell us, what were the main results? Were there any differences by sub-groups?

 
Ruth:
Perhaps, we should first go on the compliance because this is very important to the daily wear time. This was more than twenty-two hours in ninety-four percent of the patients. Many patients who complained about the inconvenience but understanding that this life vest is a potentially life saving and only temporary treatment strategy made it acceptable to ninety-eight percent of the patients. As to the [inaudible 10:52] there is a difference, the younger patients, patients younger than forty-eight years of age or younger, they wear the life vest longer, sixty-six days. While the older patients, older than sixty-eight patients, this was statistically significant, wore it only forty-nine days. This difference was not used to compliance, because you do the description based on the cardiac diagnosis.

 
 
We also observed that the longer the cumulative wear of the life vest was, the longer day hours the patient had the life vest on. They were somewhat accustomed to it. One thing which is very, very important is, that in more than twenty-five percent of the patients, we could save the implantation of a permanent ICD due to the recovery of the ejection fraction. This was especially important for those patients who had the life vest, for example after myocardidas or after myocardial infarction, which is a very large population.

 
 
Also, which is important is that [full 12:06] shock treatment for reasons other then VT occurred only in point four percent, of less than one percent. Whereas those patients were successfully treated, this was one point six percent. They were treated in response to VT and VF. This means the incidence rate was eight point four per hundred patient years. This was even higher in those patients who had the life vest for the explantation. The life vest is very effective. It's a very effective strategy for general patient population with above indications. It can save the implantation, as I said already, in more than twenty-five percent in the population in Dresden itself. We could observe even a reduction of the need of implantation of permanent ICD more than thirty-five percent due to the recovery of the ejection. This is a very important treatment, especially for those patients who have an acute illness.

 
 
The German cohort is the first large cohort outside the US healthcare system. It confirms the overall value of the life vest and treatment pathways in Germany. Also, the cohorts analysis uncovered over two hundred forty-two sustained but self-terminated episodes of VT among seventy life vest patients, so that you have safely not treated because they were still conscious and could still press the response button. We found out that some of the self terminated VT episodes were even longer than eight minutes in duration time. All in all, we could see that the life vest is a device which is safe and which can prohibit shocks, as well.

 
Carolyn:
Thanks, Nadine. [Ruth 14:12]

 
 
Mark, though, for the readers, I'm sure we need to put in perspective, as well, because there are still patients where perhaps an implantable cardio defibrillator is still more important. Could you share some thoughts about that?

 
Mark:
Yeah. I think this is a very interesting, important study, for a number of regards.

 
 
One, is that there was a very high rate of compliance with using the life vest. To leave it on for twenty-three hours a day, for a mean of sixty days, is really quite impressive patient compliance. The data showed that it did recognize and treat VF in a small percentage, but in a important percentage, of people. This data does need to be put in perspective and the randomized trial is currently ongoing. The vest trial, which will randomize people, probably similar population to what the German study did, and look at the life vest performs in that population.

 
 
We look forward to further data from the vest trial and from other trials, that are looking at what the place of the wearable defibrillator will be in the future.

 
Carolyn:
Thank you, Mark and that's perfect take home message for all us out there.

 
 
Thank you, once again, Nadine, Ruth, Mark. It has been wonderful chatting with you.

 
 
To all of you out there, you've been listening to Circulation on the Run.

 
 
Thank you for joining us.

 
 

 

Aug 15, 2016

 

Carolyn:
Welcome to Circulation on the Run. Your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. I am so pleased to be joined this week by Dr. Judd Hollander and Dr. Deborah Diercks to discuss a problem that all of us, as cardiologists and emergency department physicians will recognize. This is a feature paper on the state of the art approach to the patient presenting to the emergency department with symptoms and signs suggestive of an acute coronary syndrome, but first here are the highlights of this weeks issue.

 
 
The first study is from first author's Dr. Wing and Dr. August from Grand Valley State University in Michigan who investigated whether social and physical neighborhood characteristics are related to progression of sub clinical atherosclerosis measured by coronary artery calcium. They studied this in almost six thousand adult participants of Mesa, a multi-ethnic study of atherosclerosis, followed over twelve years. The main result was that increases in density of neighborhood healthy food stores were associated with decreases in coronary artery calcium. This was significant even after adjusting for time varying demographic confiders, time varying behavioral risk factors and depression.

 
 
The next study from Dr. Hess and colleagues from the University of Colorado School of Medicine characterized rates of implantable cardioverter defibrillator or ICD counseling and ICD use among more than twenty-one thousand potentially ICD eligible hospitalized heart failure patients in the Get With the Guidelines heart failure program. This study had several notable findings. First, only twenty-two point six percent of patients received ICD counseling. This means that up to four out of five hospitalized heart failure patients, eligible for ICD counseling, did not receive it. Women were counselled less often than men and racial or ethnic minorities were counseled less frequently than white patients.

 
 
Among counseled patients, a totally of sixty-two point six percent of patients received an ICD or had a documented plan for ICD placement. Women were just as likely as men to receive an ICD, however, ICD used differences by race and ethnicity persisted. The clinical implications of this study are that future quality improvement initiatives should incorporate culturally competent ICD counseling and elevating ICD counseling to a full performance measure and publicly reporting it by sex or race or ethnicity may need to be considered.

 
 
The next paper is from first author Dr. Resconey and corresponding author, Dr. Catalucci and colleagues from the Institute of Genetic and BioMedical Research in Milan, Italy. These authors looked at the voltage dependent [inaudible 00:03:31] calcium channel which is a key mediator of interest [inaudible 00:03:34] calcium entry associated with various cardiovascular conditions such as hypertrophy, atrial fibrillation, hypertension and diabetic cardio myopathy. The author's aim to address the problem that [inaudible 00:03:47] approaches aimed at enhancing calcium current and inotropism in heart failure have also frequently been found to favor arrhythmogenesis and diastolic dysfunction. Thus, limiting their clinical use.

 
 
The novel hypothesis addressed in this study is that a peptidome emetic therapeutic approach may overcome the arrhythmogenic limitations of current channel activator inotropes. To test this hypothesis, the author's used a whole host of methods to dissect new regulatory pathways modulating the [inaudible 00:04:24] tight calcium channel life cycle. This included yeast, two hybrid screenings, biochemical and molecular evaluations, protein interaction essays, fluorescence, microscopy, and structural molecular modeling and functional studies. Having uncovered a novel mechanism involving the [inaudible 00:04:44] tight calcium channel, calcium beta two chaperon, the author's then generated a mimetic peptide that specifically targets this calcium beta two chaperon. Thereby controlling the channel assembly and density of the plasma membrane while preserving its physiological channel function.

 
 
Finally, they showed that delivery of this mimetic peptide into a mouse model of diabetic cardiomyopathy restored calcium balance and recovered cardiac function. This study is so significant because it provides the proof of concept for the exploitation of novel therapy based on mimetic peptide technology. Really opens the field to mimetic peptides being used as innovative therapeutic tools for the treatment of cardiac disease.

 
 
The last study is from Dr. Cammel from the Feil Family Brain and Mind Research Institute in New York and colleagues who studied the association between pregnancy and aortic complications such as dissection or rupture. They used data on all emergency department visits and acute care hospitalizations at nonfederal health care facilities in California and New York between the period of 2005 to 2013. This was a cohort crossover study where they authors defined the period of risk as six months before delivery until three months after delivery. Compared each patient's likelihood of aortic complications during this high risk period to an equivalent control period of two hundred and seventy days exactly one year later.

 
 
Among more than six and a half million pregnancies in almost five million women, they identify thirty-six cases of aortic dissectional rupture during the high risk pregnancy period and nine cases during the control period. This gives the rate of aortic complications a five point five per million patients during pregnancy compared to one point four per million during the equivalent period one year later. Thus, pregnancy was associated with a significantly increased risk of aortic dissectional rupture with an incidence rate ratio of four compared to the control period one year later.

 
 
Furthermore, absolute risks were particularly elevated in those with a documented diagnosis of hypertension or a connective tissue disease. These findings have clinical implications for the counseling of patients at high base line risk of aortic complications and they also further suggest that clinicians may need to have a lower threshold for initiating diagnostic testing for symptoms of a possible aortic dissection or rupture in pregnant or postpartum patients and especially in those with connective tissue disorders or hypertension.

 
 
Our feature paper this week discusses a problem that impacts twenty million patients in North America and Europe every year. What am I talking about? These are patients presenting to the emergency department with symptoms and signs suggestive of an acute coronary syndrome. Who am I talking with? Well, today we have first author Dr. Judd Hollander from Thomas Jefferson University and Dr. Deborah Diercks associate editor from UT Southwestern. Welcome Judd and Deborah.

 
Dr. Deborah:
Thank you.

 
Dr. Judd:
Thank you.

 
Carolyn:
Let's start with a behind the scenes look at this paper. It's an in depth review that was invited by the editorial team. Deborah, can you tell us how this idea came about?

 
Dr. Deborah:
I think one of the goals of the editorial board of circulation is really to provide great clinical reviews that really could benefit the members. I have a unique aspect in that I'm an emergency physician. This idea was really brought about by discussion of really what can we merge cardiology and emergency medicine with. What would be the most clinically issue we're challenged with right now? You can't get two emergency physicians in a cardiologist's room together without some discussion and challenge around the [inaudible 00:09:11].

 
 
There's been so many changes in the last decade and so much more information about how we can use these in a clinically relevant way. It really fit nicely into a really great review article and I am really happy that we are able to invite Judd who's well known to the US and one of the leaders in the United States in this area and also an international group inviting a cardiologist from Europe and also an emergency physician from New Zealand to participate in it.

 
Carolyn:
Judd, what is the take home message of this in depth review from your point of view?

 
Dr. Judd:
I think the biggest take home message is we have known for decades and decades that if we rely on our clinical judgement we miss too many patients. We send home people that will be having acute coronary syndromes and acute myocardial infraction and the challenge over the last decades of trying to find ways where we're not going to spend a ton of money over admitting people to the hospital because of a fear of missing an event that may happen five percent of the time.

 
 
The beauty of the advances in troponins is we now have troponins that now have increasing sensitivity whether they be the non high sensitivity troponins used in the US or the high sensitivity troponins that are actually used in Europe and the rest of the world. We can use those better [inaudible 00:10:29] and combine them with clinical decision rules to create accelerated diagnostic pathways which is a big term. For now, if we put a blood test together with a structured clinical decision rule, we can, with more than ninety-nine percent negative predictor value, find patients who are safe to send home.

 
Carolyn:
Judd, I really have to congratulate you on such a beautiful paper. You really did cover all of that but what I love most is the way that you've managed to summarize very clearly a whole wealth of information because when you talk about biomarkers, there's so many out there and there's zero hour, one hour, two hours, this score and that score. I'm actually looking at table one now where you show a summary of the biomarkers strategies and then, in table two, you show a summary of the risk scores and then the performance measures of each of these scores. That must have taken quite a lot to put together.

 
Dr. Judd:
I think that's why Deb was very smart and invited authors from around the world. We have Christian Muller from Switzerland and Martin Tann from New Zealand which, literally, means we're all on different time zones and we were able to work around the clock to do that. There as always somebody awake. Getting more series, the nice thing is that my colleagues on this paper are some of the leaders in doing this kind of research. In fact, they are the leaders in doing this kind of research.

 
 
What I think is very challenging for the average cardiologist or the average emergency physician is there have been so many different approaches and many of them actually work. The challenge for us was to try and make it relatively simple so you can choose the approach at your institution and put it into a structured pathway and pick the one that works best for you. You can get a ninety-nine percent negative predicted value using the right essays with samples that the time of presentation and one hour later, you can get a ninety-nine percent negative predictor value at zero and two hours. You can combine it with an accelerated diagnostic pathway and do that at zero and two hours and zero and three hours.

 
 
I think the important thing is you need to figure out what will your clinicians use? Certain clinicians may be very comfortable with one risk score and not another and then they need to combine the timing of testing with the risk score their comfortable with in order for us to achieve the great possibilities we have with these new tasks. I think when you try and do a one size fits all, there are going to be people who push back because they don't like one component of the risk score. Really what we're trying to do and we didn't say everybody should do A, B or C but we present the data on five or six different options and let people choose what is most feasible for them.

 
Carolyn:
How wonderful. Deborah, what were you thinking when you were reviewing this paper and trying to structure it for the clinician out there who wants to use this information?

 
Dr. Deborah:
I think that, overall, we were really impressed by the clarity and the ease that a reader can take this information home. There is so much information out there and there are so many different ways to apply it that we're really impressed how the authors put it in a really pretty clear manner so you can actually see the risk stratification tools that are out there, what they're used with and what type of troponins. Think about your own clinical practice and what you can adapt really based on the evidence that is out there.

 
Carolyn:
I couldn't agree more. Judd, how about this issue of the coronary CT angiogram and where that falls?

 
Dr. Judd:
That's really an interesting question because there's been a lot of publicity and a lot of editorializing in recent years that maybe you can make a decision with your two troponins and your biomarkers and decrease the number of people that need downstream testing. One of the dilemma with this, like I said before, is we know we're not really good at predicting who has acute coronary syndrome based on clinical things and for that reason the European Society guidelines as well as the American AHAACC guidelines have always said you need to do two things. You need to rule out acute myocardial infraction and you need to risk stratify patients for underlying coronary disease. When a patient comes into the emergency department, if I'm going to be guideline compliant with the recommendations in the world, I need to do both things.

 
 
The paper, we summarize really clearly ways you can get out of the woods with biomarket testing and clinical pathways but then you still want to risk strategy for coronary disease. There are sometimes where you might not need that downstream testing but what coronary CTA really lets us do is it makes us more efficient than a stress test. A stress test I like to say is a next day test; although there is data that you can do it when the patient's in the emergency department rapidly. It certainly is not the standard practice.

 
 
There are people afraid of putting people on the treadmill too soon in case they have unstable angina but a coronary CTA lets me look at the coronary arteries, immediately, when they're in the emergency department. There's very few areas in emergency medicine where there are three large randomized control trials that all give the same results. It doesn't say coronary CTA is better than a next day stress test but it does say you can avoid admission and, hence, save some dollars. It says you can send patients home sooner and, hence, save some angst that the patients may feel while they're in that diagnostic indecision area.

 
Carolyn:
That's such a practical summary and, in fact, it really reflects the entire paper which is really so clearly presenting the information. Judd, one last thing, could I check is this correct, in my understanding, that the main difference between this and say the guidelines that you just measured is that what you do here is really give the readers all the information? As you say, allow the readers to choose what suits them best. This is not making recommendations, it's summarizing all the information. Is that right?

 
Dr. Judd:
Yeah, that's exactly right. If you look, I think it's table number four, where we go through each one of the decision aids and how many or what percent of patients actually fit into that decision aid and what the negative predictive value is for that decision aid combined with troponin. Then what type of troponin was used to achieve those results, you'll see that about half the studies are done with, what we call, the contemporary troponin or just the regular sensitivity troponin that we use in the United States. The other half of the data we show is with high sensitivity troponins. It would not be a good idea for somebody creating their quality program in their emergency department to take something that was tested with a high sensitivity troponin and validate it there and then apply it in an emergency department in the United States where we don't have those [inaudible 00:17:18].

 
 
We thought it was critically important to lay out the data and as the high sensitivity troponins come on the market, hopefully in the next year in the US, people can begin with something now and switch to something else later if they want. If we made a recommendation that was firm, the world changes too fast. I don't think we would be doing the best for our patients.

 
Carolyn:
That is such a great statement to end this on. Thank you so much Judd and Deborah. This was an excellent discussion.

 
Dr. Judd:
Thank you.

 
Dr. Deborah:
Thank you.

 
Carolyn:
You've been listening to Circulation on the Run. Thank you for joining us this week and don't forget to tune in next week for more exciting cardiology needs from all over the world.

 
 

Aug 8, 2016

 

Carolyn:
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 National Heart Center and Duke National University in Singapore. Joining me today will be Dr. Katherine Mills and Dr. Andrew Moran to discuss the very striking findings of a new study on global disparities of hypertension prevalence and control, but first, here's the summary of this week's original papers.

 
 
In a study by first author, Dr. [Lu 00:00:42], corresponding author, Dr. Denny, from the Harvard TH Chan School of Public Health in Boston, Massachusetts and colleagues, authors aimed to investigate how the risk of cardiovascular disease is distributed among whites and blacks in the United States and how interventions on cardiovascular risk factors would reduce these racial disparities. To achieve these aims, the authors used a nationally representative sample of more than 6,000 adults, age 50-69 years of age, in the United States and developed a risk prediction model that was calibrated separately for blacks and whites.

 
 
The main results were that were substantial disparities in the risk of fatal cardiovascular disease; 25% of black men and 12% of black women were at high risk of fatal cardiovascular disease compared to only 10% of white men and 3% of white women, respectively. A large proportion of these fatal cardiovascular events among blacks were concentrated among this small proportion of the population. Now, whereas, population wide and interventions focused on single risk factors did not reduce black/white disparities in fatal cardiovascular risk and intervention that focused on high-risk individuals and reduced multiple risk factors simultaneously could indeed reduce black/white disparities in fatal cardiovascular disease by a quarter in men and a third in women.

 
 
These results really emphasize that focusing preventative interventions on the high-risk individuals has a large potential to improve overall cardiovascular health and reduce racial disparities in the United States.

 
 
The next paper is from first author, Dr. Lee, corresponding author, Dr. Federer, from Ohio State University Wexner Medical Center in Columbus Ohio and colleagues who looked at the issue of adenosine-induced atrial fibrillation and aimed to elucidate the molecular and functional mechanisms that may underlie this problem. To achieve this aim they integrated panoramic optical mapping and regional immunoblotting to allow them to resolve the protein expression of the two main components of the adenosine signaling pathway, mainly the A1R and GIRK4. They found that these signaling pathways were 2-3 times higher in the human right atrium compared to the left atrium leading to a greater right atrial action potential duration shortening in response to adenosine.

 
 
Furthermore, they showed that sustained adenosine-induced atrial fibrillation is maintained by re-entrant drivers localized in the lateral right atrial regions with the highest A1R and GIRK4 expression. Finally, the authors demonstrated that selective GIRK channel blockade successfully terminated and prevented atrial fibrillation. Thus, suggesting that the arrhythmogenic effect of adenosine in human atria may be mediated by activating GIRK channels. The take-home message, therefore, is that specific blockade of the GIRK channels may offer a novel mechanism to prevent adenosine mediated atrial fibrillation in patients.

 
 
The next study is from Dr. Nielsen and colleagues from the Copenhagen University Hospital of Bispebjerg in Copenhagen, Denmark, who aimed to assess the optimal blood pressure in patients with asymptomatic aortic valve stenosis. To achieve this aim, the authors used data from the simvastatin, ezetimibe in aortic stenosis or SEAS trial of 1,767 patients with asymptomatic aortic stenosis and no manifest atherosclerotic disease. Outcomes that were studied included all-cause mortality, cardiovascular death, heart failure, stroke, myocardial infarction, and aortic valve replacement. The main findings were that an average diastolic blood pressure above 90 and a systolic blood pressure above 160 millimeters mercury were associated with a poor outcome.

 
 
Furthermore, low systolic blood pressure was also related to adverse outcomes while low average diastolic blood pressure was harmful in moderate aortic stenosis. In summary, the optimal blood pressure, which was associated with the lowest risk of adverse outcomes, were the systolic blood pressure between 130 and 139 and a diastolic blood pressure between 70 and 90 millimeters mercury. The clinical take-home message is that in the scarcity of randomized controlled evidence, these results may assist clinicians in their decisions in blood pressure measurements in patients with aortic stenosis, meaning that a blood pressure above 149D may be treated while a blood pressure lower than 120 systolic or 60 diastolic may be recognized as a warning signal for poor outcomes.

 
 
That was the summary of this week's original papers. Now for a discussion of our feature paper.

 
 
I am so excited to be joined by two guests today to discuss our feature paper entitled Global Disparities of Hypertension Prevalence and Control, a systematic analysis of population-based studies from 90 countries. We are so pleased to have the first author, Dr. Katherine Mills, from Tulane University School of Public Health and Tropical Medicine in New Orleans. Welcome, Katherine.

 
Katherine:
Thank you. Good morning.

 
Carolyn:
And a very special occasion indeed, we have an editorialist joining us, as well, in none other than Dr. Andrew Moran from Columbia University Medical Center in New York. Welcome, Andrew.

 
Andrew:
Good morning. Thank you, Carolyn.

 
Carolyn:
It's wonderful to have you discuss this. This paper has so many key findings that really struck me. If you don't mind, I am just going to summarize some of these. For example, Katherine, you reported globally more than 30% of the adult population, amounting to almost 1.4 billion people have hypertension in 2010, and the prevalence of hypertension was higher in low and middle income countries than in the high income countries, making it, therefore, that approximately 75% of people living with hypertension live in the low and the middle income countries. Yet, hypertension awareness, treatment, and control were much lower in the low and middle income countries compared to the high income countries. That is really striking. Katherine, I'd really love for you to share with us what was the inspiration to look at this and what do you think was the most striking finding?

 
Katherine:
We know that hypertension is a very important risk factor for cardiovascular and kidney disease. It's the leading cause of cardiovascular disease in the world and for premature death. A previous study in our research group found that about 26% of the world's adult population had hypertension in 2000, but since then there really hasn't been any global estimate made. Basically, since 2000, a lot of studies from individual countries and high income countries have shown a leveling off or decrease of hypertension prevalence, but studies from individual low and middle income countries have actually shown an increase in hypertension prevalence.

 
 
Given these trends in individual countries and the importance of hypertension prevalence and treatment and control, to prevent cardiovascular disease, we really wanted to look and see what the disparities were in high income compared to low and middle income countries. I think the most striking findings to me was that we found that over 75% of adults with hypertension globally are in low and middle income countries, and that's over a billion people. We also found that only 7.7% of those people with hypertension and low and middle income countries have controlled hypertension. That represents a huge global public health problem that could lead down the road to a large burden of cardiovascular and kidney disease if it's not effectively addressed.

 
Carolyn:
Katherine, I could not agree with you more because it's actually a living reality that I'm seeing where I come from in Asia. We have just so much hypertension, and what struck me was that from 2000 to 2010, while the prevalence increased here, it decreased in high income countries. Yet, this is where the greatest need is and where the control is the lowest. That was striking. Can you just articulate a bit further how your data now add to the knowledge that was there before your paper?

 
Katherine:
Basically, this is the first paper to show that the prevalence of hypertension is higher in low an middle income countries compared to high income countries. It's the first paper since 2000 to quantify the global burden of hypertension, and it's the first paper to really compare rates of awareness, treatment, and control comparing high income to low and middle income countries.

 
Carolyn:
That is fantastic and really striking. I think that's why the Circulation Editorial Board to invite an editorial by Andrew to discuss this. Andrew, your editorial was entitled Still on the Road to Worldwide Hypertension Control, and even in the first sentence of your editorial, you mention that hypertension is a preventable risk factor, and that's why this is so important. I really like that your first subheading has this big word, action. Maybe you could tell us a bit more. What are the implications of these findings for worldwide hypertension control and actions that we can take?

 
Andrew:
There's a growing attention to noncommunicable diseases worldwide as a lot of maternal and fetal deaths, those rates have improved worldwide, and so really as the world population ages, problems like hypertension and related noncommunicable diseases are becoming a bigger and bigger health problem for people around the world, not just in high income countries. As a matter of fact, recently the World Health Organization set a 25 by 25 goal, meaning to reduce deaths from noncommunicable diseases by 25% by the year 2025. A big part of that effort is going to be an effort to control hypertension. The World Heart Federation has set a goal of improving hypertension control by 25% as part of that overall effort.

 
Carolyn:
Yes. You mentioned that I think in the editorial, as well, but are there some action steps that we could take globally as a community?

 
Andrew:
Yes. It's striking to me as a practicing physician that something so basic as measuring blood pressure and recommending treatment for people with elevated blood pressure, which is so integral to our daily practice in medicine, that we still have so far to go in achieving control both in high income settings and low and middle income country settings. One of the most basic cornerstones of achieving control is proper measurement of blood pressure. I think one of the goal efforts has to involve making sure that primary care settings and even community centers have available well-calibrated and validated blood pressure measurement devices and that people know how to measure blood pressure accurately.

 
 
The other problems that come up with controlling hypertension are for people who have a diagnosis that is accurately made, are they able to follow up with a primary care provider to monitor their blood pressure, and do they have medications available to them that are affordable? It's important to note that especially in low and middle income countries, most people have to pay for their medications out of their own pockets, so the affordability and availability of medications is a really important part of achieving our goals. I think it's important to see that low and middle income countries, even though it can seem like a daunting setting in which to implement improvements in the quality of healthcare delivery, there also important places to experiment with improving the quality of care delivery worldwide.

 
 
For example, the concept of having a community health worker make home visits and reach out into the community was something that was developed in low and middle income countries and now is becoming a popular and effective method of delivering care in all countries worldwide.

 
Katherine:
One thing I would add is that I think we really need collaborations from the international level because so many of these low and middle income countries have very limited healthcare resources, and there still dealing with a lot of infectious diseases, so I think it really is going to take an international effort to address this problem in low and middle income countries.

 
Carolyn:
Thank you so much for joining us for another episode of Circulation on the Run. Tune in next week for more summaries and highlights.

 
 

Aug 1, 2016

Carolyn:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm doctor Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Joining on me in just a moment are two guests to discuss a very exciting new category of papers, known as the white paper. The topic for today is an evolution within the field of current day percutaneous coronary intervention that of the treatment of higher risk patients with an indication for revascularization. But first, here is your summary of this week's journal.

 
 
The first study is from first author doctor Jolis and corresponding author doctor Grainger, from the duke clinical research institute in Durham, North Carolina. These authors describe the American Heart Association Mission: Lifeline, STEMI Systems Accelerator. This exciting project represents the largest effort ever attempted in the United States to organize ST segment elevation myocardial infarction care across multiple regions, including 484 hospitals, 1,253 emergency medical services across sixteen regions and involving more than 23,800 patients.

 
 
Indeed, this project aims to organize coordinated regional reperfusion plans so as to increase the proportion of patients treated within guideline goals, that is a first medical contact to devise time of less than 90 minutes for STEMI patients directly presenting to PCI capable hospitals and less than 120 minutes for transferred patients.

 
 
The authors observed that during the study period of July 2012 to December 2013, there was a significant increase in the proportion of patients meeting these guideline goals, including an increase from 50% to 55% of STEMI patients directly presenting via emergency services and from 44% to 48% of those transfer patients. The authors concluded that these improvements, while modest, suggest the potential for reductions in total ischemic time and happily observe corresponding trends towards lower in-hospital mortality compared with the national data towards the end of the measurement period. Indeed, the tickle message is that the findings support continued efforts to implement regional STEMI networks.

 
 
The next study is by first author doctor Hidari and corresponding author doctor Kuang from the Brigham and Women's Hospital in Boston, Massachusetts. They describe the OMEGA-REMODEL randomized clinical trial. This is a multi-center, double-blinded, placebo control trial of 358 participants presenting within acute myocardial infarction who are randomized to six months of high dose omega-3 fatty acids at four grams daily versus placebo.

 
 
Cardiac magnetic resonance imaging was used to assess cardiac structure and tissue characteristics at baseline and following therapy with the primary study in point being a change in left ventricular systolic volume index. Indeed, the authors reported that compared to placebo, patients who received four grams daily omega-3 fatty acids experienced significant improvements in both left ventricular and systolic volume and surrogate measures of non-infarct myocardial fibrosis during the six months of treatment.

 
 
These remodeling benefits further followed a dose response relationship with the rise in the in vivo omega-3 fatty acid levels as quantified by your red blood cell index. They concluded that four grams daily of omega-3 fatty acid is a safe and effective treatment in improving cardiac remodeling in patients receiving current guideline based post-myocardial infarction therapies. Indeed, this does warrant perspective clinical studies.

 
 
The third study is by first author doctor Liu and corresponding author doctor Sia from University of Texas, Houston Medical School and Colleagues, who sought to understand the molecular basis underlying adaption to high altitude hypoxia. By conducting both human high altitude and most genetic studies, the authors identified a novel functional role of CD73-dependent elevations in extracellular adenosin signolin in response to high altitude hypoxia.

 
 
This led to sequential activation of a readthrough site AMP-activated protein kinase, which in turn resulted in increased 2,3-bisphosphoglyceric production and enhanced oxygen release capacity to peripheral tissues. Thus, reducing tissue hypoxia, inflammation and pulmonary injury. These findings have significantly added to our understanding of the molecular mechanisms underlying adaption to hypoxia. Thereby, opened novel therapeutic possibilities for the prevention and treatment of hypoxia related conditions.

 
 
The final study is from first author doctor Yen and corresponding author doctor Chen from the National Taiwan University and Colleagues, who aimed to determine the effect of betel nut chewing and paternal smoking on the risks of early metabolic syndrome in human offspring. The author studied more than 13,000 parent-child trios identified from more than 238,000 Taiwanese aged 20 years or older screened in two large community based screening cohorts.

 
 
The main finding was that pre-fatherhood habits of both betel nut chewing and cigarette smoking led to a 77% and 27% increase in risk of early metabolic syndrome in their offspring respectively. In fact, they even observed a dose-response relationship where the risk was higher with an increase in duration of exposure as well as with earlier age of starting exposure. These findings interestingly suggest that genetic or epigenetic changes due to exposure to both betel nut and cigarette smoking before birth can contribute to early occurrence of metabolic syndrome in offspring. In fact, these findings really support education for avoidance of these habits or cessation of these habits.

 
 
That was your weekly summary. Now, for our feature paper. Our feature paper this week is a white paper regarding the treatment of higher risk patients with an indication for revascularization and evolution within the field current-day percutaneous coronary intervention. To join me in this discussion, I'll have the first and corresponding author doctor Ajay Kirtane from Colombia University Medical Center, New York Presbyterian hospital, as well as doctor [Manus Brelaques 00:08:22], associate editor from UT Southwestern. Welcome, Ajay and Manus.

 
Ajay:
Thanks so much for having us.

 
Manus:
Thanks Carolyn.

 
Carolyn:
Great. Manus, I would love if we could start by talking about the concept of the white paper and what circulation is looking in these white papers.

 
Manus:
Of course. It is a very exciting part of the new circulation which is for topics that are very timely and important, but at the same time there's not enough populous data and populous literature to be able to address it in a more formal systematic review way. The concept is that establish the leaders in the field. I'm going to provide their perspectives which have derived through their clinical practice and be able to inform us of what the current issues are, how can they best be addressed and what are the next steps forward.

 
Carolyn:
That's great, and what a great example to start with with this paper by Ajay. Ajay, maybe I could just start by asking you to make it crystal clear to us the kind of patients you're referring to in this higher risk and the context and the scope of the problem that you're talking about in your paper.

 
Ajay:
Absolutely. First of all, I'm honored that you would consider that's both timely and important and that this will be one of the new papers in the series on behalf of all the [cohorts 00:09:44] is we're really pleased to be able to discuss it. I think the reason that we find this really critical at this juncture is because what we're sort of saying is an evolution in current-day [catlab 00:09:53] practice. There are many patients now who were seen that have either been turned down for cardiac surgery of have highly complex disease that we know merit revascularization.

 
 
In other words, medical therapy has failed for them either from the symptomatic standpoint or because it puts them at too high risk given the complexity of their coronary anatomy and where these lesions are located. Yet at the same time, in order to be able to treat these patients effectively, we need to grasp not only advanced techniques in terms of how to do it, but also need to be able to select the patients appropriately so that they can undergo these procedures safely and to drag the benefit that we'd like to be able to offer them.

 
 
Just one brief thing to mention is that we certainly know that over the past 10 years or so, there's been a lot of criticism of the PCI procedures they could perform, particularly here in the United states. Some of them were perhaps unnecessary or some of them were not necessarily benefiting patients. The good news is we've curtailed a lot of that, but yet at the same with that curtail we've sort of seen a decline in these types of cases that we refer to in the paper where patients really could benefit from revascularization, but for whatever reason or not being offered it.

 
Carolyn:
Listeners might be wondering though, what is the difference between what you're talking about high risk, and we read a lot of papers about complex procedures and complex PCI, you want to make that differentiation just slightly clearer?

 
Ajay:
Sure. I think that complex PCI has been something that carries the historical definition and usually involves lesion subsets like the left main, chronic total occlusion, bifurcations, that require more than just a simple predilatation stent implantation. The concept of procedural risk though while it overlaps with complexity, to some extent actually has other inputs. For instance, the ventricular function of the patient whether or not the other circulation is also compromised, so it's a larger ischemic territory, and similarly some things that were previously complex with an evolution of techniques actually don't offer or confer that much greater risk on patients.

 
 
I would say when I did my fellowship training, left main was something that my heart rate got up for and we were worried about the patient in that respect. Now when we do left mains, it's actually something where we view it as one of the more simple things that we do relative to for instance the retrograde approach to a CTO revascularization. There's been an evolution and there's an overlap of what's complex and what's high risk.

 
Carolyn:
Very nicely put. Could you tell us a little bit about how your paper is structured? I really like for example the way your tables are laid out and so on, but maybe just give an overview?

 
Ajay:
Absolutely. I think we start off with just setting the scope of the problem. Basically, looking at coronary heart disease and the fact that there are subsets of coronary diseases for which has prognosticked the importance to revascularize. For instance, the publication of this ten-year result for the first trial [inaudible 00:12:45] revascularization as a whole. We talk a little bit about the assessment of procedural risk and then we sort of move on in the end to the various areas that interventionalists need to become better trained in order to deal with these types of patients. I have to give credit where credit is due. The tables that you like so much were actually the suggestion of the editors.

 
 
Because of the new theory, Manus had a lot to do with this. I think it's very important for people to understand, at least for this paper the role, the back-and-forth conversation between not only us, but also the editors and the reviewers play in bringing this manuscript to its final form. I really give them credit for it. What's in the tables are not only descriptions of the types of multidisciplinary teams that are needed in order to [affect 00:13:27] that we take of these patients. Also, the techniques that would be useful for interventionalists to know how to use and be [inaudible 00:13:33] to take care of these patients. Finally, a table looking at future directions because it's all good and fine for us to say this is a new area and we're moving into it, but we need to sort of generate the research and the evidence base to really support the treatment that we're trying offer or saying we can offer in the manuscript.

 
Carolyn:
Manus, you have to this describe some of this back-and-forth conversation that went on.

 
Manus:
Ajay, I wish that every author took the comments as well as you did because that's definitely not the case. I must admit that it was a pleasure working with you because again you were so open to all the comments and suggestions even though some were tough ones. I think the interaction and being so open I think made the paper better and we're very, very appreciative for your response to those.

 
Ajay:
I think at the end of the day when you have a new editor team taking over, there are going to be changes and some changes you learn how to grow through and other changes you basically adopt what the previous editors were doing. At least my experience, not to [despair 00:14:29], is the prior circulation editors at all, I actually had a great experience with them as well, but this was novel, and I think it's something that for many authors will find quite nice to experience because there was a lot of back and forth. Some parts were contemptuous, but these were all resolved. I wrote in my response back to the reviewers I really do feel the paper was better as a result.

 
Manus:
I think that's the idea that [inaudible 00:14:51] the language and the whole editorial team is trying to enforce and we're very happy with it and enjoyed.

 
Carolyn:
I couldn't agree more. Actually, Manus I was also going to ask the title is provocative. It says this is an evolution and even in the conclusion of the paper that this could be a new field of coronary interventional procedures. I really love your thoughts. Is this a beginning of a whole new field?

 
Manus:
I personally do believe and many people I think do believe that there's a tremendous evolution that is going on right now, continue to go on in the field compared to the early days of [inaudible 00:15:26] where we did simple angioplasty I think it has come a long way. But I think there is gap between what can be done right now in terms of technical possibilities, in terms of equipment we'll have and improved patients' quality and quantity of life.

 
 
Actually, what is being done because as you heard from Ajay, many of those patients who could benefit do not. Within the environment of trying to stop in a [inaudible 00:15:51] procedure, which is very appropriate, what happened exactly is that those more complex and high risk cases because of the fear of complications or sub-optimal outcomes led to offering less treatment to those complex patients.

 
 
I do believe it's an evolution in the field. I do believe that having access to these techniques, equipment and offering options to the patients and explaining there is benefit ratio can bring the patient's life, make them better and bring the field forward to the next step.

 
Carolyn:
Ajay, do you think you could elaborate a little bit more then on what those next steps you think are and what are the future areas of research?

 
Ajay:
Yeah, I'd certainly be happy to do so. I couldn't agree with Manus more. I know he and I share a lot of beliefs in terms of this. One of the things that's important to recognize is while we can all assess procedural risk, some of these advanced techniques are not commonly shared by all interventionalists here in the United States, particularly if you look at the overall case volumes of many interventionalists in the United States, there are folks who are just not going to have the requisite volume to be able to do complex CTO revascularization with a retrograde approach. For instance, they would bring procedural success rates up around 90%.

 
 
I think that some of this is education. You have to sort of understand what can and cannot be done, what can and cannot be done [faithfully 00:17:08] and what techniques you use or are necessary in order to be able to improve this rate of success. If for instance I can't do the procedure myself, then I need to be familiar with somebody who actually can because if the patient merits revascularization, in other words they could benefit from having a procedure done, they're not a surgical candidate and they could be helped by PCI, then rather than saying, "We should just do medical therapy because I can't do the procedure." The appropriate thing to do is to actually refer the patient to somebody who actually could do the procedure in a safe way and therefore ensure benefit for the patient.

 
 
That's an educational aspect. Some of it relates to training, but I think conceptually we do need to start understanding now that there is a sub-specialization within coronary intervention of interventionalists who are able to offer things that many interventionalists cannot. That's somewhat of a fundamental step many people have to take, but I think it's time to take that step and that was the whole point in writing this paper.

 
Carolyn:
I think that is a very effective first step that now you've brought it to light and we're so proud and privileged to be publishing this paper. Thank you so much Ajay, thank you so much Manus.

 
Ajay:
Thanks so much for having us.

 
Manus:
Thanks Carolyn.

 
Carolyn:
And thank you listeners. You've been listening to Circulation on the Run. Please tune in next week for more highlights and discussions.

 
 

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