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Setting Expectations for AI Models in Medicine

Artificial intelligence is a hot topic in every field, and these algorithms are being widely used in scientific research. Particularly in my field of genetics and genomics, machine learning methods are invaluable for gleaning insights from large amounts of highly dimensional data. But there are many things to consider before applying AI and ML in a clinical setting, when real people are on the other end of the predictive model. It is important to set expectations for what AI can and cannot accomplish and what is needed for a broad application of AI in medicine in the future. In the session “Hype or Hope? Artificial Intelligence and Machine Learning in Imaging”, presenters gave a great overview of the applications of AI, its limitations, and the advancements that are needed for a wide application of AI in medicine.

Dr. Geoffrey Rubin described many different scenarios in which AI can be deployed. Specifically, he talked about how AI can be used in predictive analytics to make test selection and imaging more efficient, in image reconstruction to reduce noise, in image segmentation to identify regions of interest and provide quantitative analysis, and in interpretation to derive unique characteristics that cannot be measured directly, identify abnormalities, and create reports. In addition, Dr. Tessa Cook explained in greater depth how AI can be used as clinical decision support to incorporate diverse data types and aid in proper test selection. Dr. Damini Dey also discussed how AI can improve diagnosis and prediction, characterize disease, and personalize therapy. Overall, it is important to determine where AI can provide the greatest value while introducing the least amount of risk.

However, there are many limitations to AI and ML models. First, as Dr. David Ouyang noted, because these models are trained by humans, they can only perform tasks that a human could theoretically do. AI just performs these tasks faster, more consistently, and at a larger scale. He noted that these models are not effective unless trained on broad underlying datasets, and that unless explicitly programmed, they do not accurately weight rare significant events. AI models can easily become uninterpretable black boxes, keeping experts from recognizing where they are failing. Dr. David Playford emphasized that due to these and other limitations, AI models are not yet clinically accurate in all areas.

There are many steps that must be taken before AI models can achieve wide use in clinical settings. Dr. Ouyang suggests standardized baselines and open access to measure advancements among tools. Dr. Cook implements a “trust and value” checklist to assess how each tool was trained and tested, as well as what it can and cannot do, before using it for clinical decision support. Dr. Playford advocates for randomized trials to establish proof-of-concept and compare outcomes to the current standard of care. Most importantly, steps must be taken to reduce bias in AI models, which can negatively impact the care of underrepresented populations. Multidisciplinary collaborative teams can ensure that the data aligns with the clinical question being tackled, diverse yet consistent training datasets are being used, and methods such as transfer learning are implemented to produce more accurate predictions on previously unseen datasets. While AI can be an important tool in clinical decision making, it is ultimately the responsibility of each physician to ensure that AI tools are serving their patients as effectively as possible.

“The views, opinions and positions expressed within this blog are those of the author(s) alone and do not represent those of the American Heart Association. The accuracy, completeness and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them. The Early Career Voice blog is not intended to provide medical advice or treatment. Only your healthcare provider can provide that. The American Heart Association recommends that you consult your healthcare provider regarding your personal health matters. If you think you are having a heart attack, stroke or another emergency, please call 911 immediately.”

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The Impact of COVID on Medical Education

Since the beginning of the COVID-19 pandemic, our lives have been significantly affected on every level. Different countries reacted in various ways and almost everybody was under lockdown at a certain point. With time, everyone has adapted to the new “normal”. Masks are on all the time, no handshakes or hugs, and if anyone gets slightly closer physically, we tend to get extremely uncomfortable. On the professional side, all health care workers were impacted too. At the very beginning, all elective procedures were delayed, there were long working hours, more stress, and a lack of personal protective equipment. Patients who were legitimately sick did not seek medical advice and hospitals were at full capacity. Additionally, didactics were canceled, medical students were asked to stay at home, in-person national and international conferences were canceled, and many more. As a result, training and education were disrupted but the medical community stepped up to the challenge and explored different avenues to ensure steady and proper education for all healthcare workers.

In the past several months, all professional societies (AHA, ACC, ESC, TCT, ASE, and many more) did a phenomenal job in reducing the impact of the pandemic on medical education. All conferences were switched to a virtual platform, different ideas were applied to keep everyone engaged, registration fees were reduced significantly or completely waived. I must point out that now it is possible to attend all national and international conferences from the comfort of your living room, listen and interact with experts in the field, and attend the sessions that you have missed at your convenience. Additionally, for grand rounds and didactics, remote education facilitated learning from experts from all over the world. Although all these efforts helped mitigate the effect of the pandemic on education, however, everyone is still hoping for in-person conferences. Unfortunately, the ESC has decided to deliver its full portfolio of congresses and events virtually up to the ESC Congress in September 2021. Moreover, the ACC annual meeting was pushed back to May 2021 and it is expected to be in-person and virtual. Although recently, promising news about the vaccine has been published however it is unclear for how long will the pandemic last. In my opinion, the COVID pandemic expedited the development of remote education and eventually, it will become a cornerstone in medical education. In the time being, we have to work on overcoming this pandemic without impacting our education and most importantly staying safe.

 

“The views, opinions and positions expressed within this blog are those of the author(s) alone and do not represent those of the American Heart Association. The accuracy, completeness and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them. The Early Career Voice blog is not intended to provide medical advice or treatment. Only your healthcare provider can provide that. The American Heart Association recommends that you consult your healthcare provider regarding your personal health matters. If you think you are having a heart attack, stroke or another emergency, please call 911 immediately.”

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Highlights from AHA20

AHA20 is wrapping up today with the final sessions. It’s been another excellent meeting with tons of new data that was presented. One consistent theme remains, debates continue to drive the conversation in the management of patients with cardiovascular diseases.

  1. The ISCHEMIA trial did not disappoint again. It led to great discussions regarding the contemporary management of patients with stable ischemic heart disease.”- First, the debate regarding PCI vs optimal medical therapy rages on. Dr. Sripal Bangalore and Dr. William Boden make their case for their approach to managing these patients.

The post ISCHEMIA world left us with burning questions about the optimal approach to imaging.

– CT vs SPECT for the evaluation of patients with SIHD

Guidelines will be surely updated after this landmark trial, but what remains certain is that a patient-centered approach to imaging is the key to optimal decision making.

 

  1. Optimizing GDMT in HF patients with more pills. How much is too much?

This year’s sessions added to our armamentarium in the management of patients with Heart failure and reduced ejection fraction (HFrEF). The GALACTIC-HF trial enrolled 8256 patients with LVEF <35% and pro-BNP >400 pg/ml to receive Omecamtiv Mercabil vs. placebo. With a primary composite outcome of cardiovascular death or CHF event, those enrolled to receive the selective cardiac myosin activator in addition to GDMT demonstrated a reduction in the primary composite outcome, driven by a reduction in CHF events.

The results of this trial brought on questions regarding where newer agents in our HFrEF patients would rank in importance. Do we run the risk of polypharmacy and non-adherence with each newer agent? How much bang for our buck can we expect to receive?

Key takeaways from the discussions regarding GDMT include:

  1. Early initiation and up-titration of medical therapy improve outcomes in HF patients.
  2. Recognize signs of worsening HF and decompensation
  3. Referral to advanced heart failure cardiologists when you need help.

Debates trigger conversations, conservations lead to action. Action in this setting leads to improved patient outcomes. AHA 2020 Scientific Sessions was no different and provided great examples of this rhetoric.

One thing not up for debate at this year’s Scientific Sessions was clear. It was the call to action against structural and institutionalized racism, the fight for diversity, equity, and inclusion for all. From the opening address to the final sessions, AHA 2020 made it a point to bring these conversations to the forefront to impact change. At the end of these 5 days, I feel re-invigorated and optimistic that our actions moving will speak louder than our words. Here’s to hoping we can meet again in person at next year’s Scientific Sessions.

“The views, opinions and positions expressed within this blog are those of the author(s) alone and do not represent those of the American Heart Association. The accuracy, completeness and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them. The Early Career Voice blog is not intended to provide medical advice or treatment. Only your healthcare provider can provide that. The American Heart Association recommends that you consult your healthcare provider regarding your personal health matters. If you think you are having a heart attack, stroke or another emergency, please call 911 immediately.”

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Developing Your Career as an Academic Physician

For all early-career physicians out there, I am sure you were not only looking for the latest in science at AHA 2020 but also some guidance on career development, and the session “Developing your Career as an Academic Physician” was just perfect.  Here I will review some of the fantastic talks from this session.

It started with “Pearls for Becoming an Academic Leader” by Dr. Jennifer S. Lawton, chief cardiac surgery at Johns Hopkins University, and offered the perfect blend of inspiration, encouragement, and advice on being an academic leader. I am sharing some pearls from this talk:

  • DECIDE: Decide if leadership is right for you and why you want to be a leader?
  • PREPARE: Prepare to be a leader (leadership books/courses), gain experience (program director, lab director, multidisciplinary teams, write protocols for your institution), learn time management for different roles (clinical, academic, leadership, mentorship), and build your credibility.
  • COMMUNICATE: Keep your CV updated and make it available at a moment’s notice and be ready to articulate your 5 and 10-year goals.
  • ATTACH: Attach yourself to mentors and learn from their success/failures and seek their advice regularly. Find sponsors who can open doors for you.
  • 70/20/10 Rule: Being an academic leader is 70% on the job training, 20% is learned from mentors/sponsors and 10% is formal leadership training.

The follow-up amazing talk was “What Really is Work-Life Balance” by Dr. Sasha Shillcutt, Tenured Professor of Anesthesiology at the University of Nebraska Medical Center. Loss of control over work is an important reason for burnout and this talk really re-framed my concept of Work-Life balance as it emphasized the concept that we are in the “driver’s seat” of our career. Two main concepts that were presented are:

  • Time Management Traps & Myths: Learn to say “No” to tasks that no longer interest you and success is directly linked to saying no.
  • Set Boundaries: Successful health care workers set boundaries that are intentional, efficient, and healthy. It takes practice and planning to set boundaries but they make your life easy.

“Maintaining Clinical Skills While Working in the Lab” is a challenge faced by physician-scientists and Dr. Emily MacKay from the University of Pennsylvania discussed some remarkable strategies for this.

  • Cognitive Reframing: The idea is to reframe your perspective about a challenge into an opportunity while the objective facts of the situation remain the same. For researchers that spend most of their time in the lab, make the most of your clinical time and develop “deliberate practice” where the focus is on quality, attention to detail, mindful and purposeful performance of procedures.
  • Context Switching: If you hit roadblocks with one problem where the solutions are not obvious you can physically distance yourself from the problem, and then come back to it later and this will help you find a solution.
  • Handling Commitment: Using the Eisenhower matrix to identify tasks that are urgent and important and need to be handled quickly vs tasks are urgent but not important and can be delegated or tasks that are important but not urgent and can be scheduled.

I will encourage all early careers to watch this session and take notes as it is full of pearls for career development.

 

“The views, opinions and positions expressed within this blog are those of the author(s) alone and do not represent those of the American Heart Association. The accuracy, completeness and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them. The Early Career Voice blog is not intended to provide medical advice or treatment. Only your healthcare provider can provide that. The American Heart Association recommends that you consult your healthcare provider regarding your personal health matters. If you think you are having a heart attack, stroke or another emergency, please call 911 immediately.”

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The Era of Misinformation: A Constant War of Science vs. Fiction

“Covid19 is a hoax”, “vaccines poison your body”, “the earth is flat.” Various conspiracy theories and misinformation statements have existed throughout history. Though some might seem absurd and often put into the spotlight to ridicule them as they are improbable to be accurate, like the earth being flat, this comedian aspect shifts to a sinister black connotation when the conspiracy theories, and misinformation infect the medical field.

As the first doctor of my family, it is not uncommon to get questions about a new drug that was promoted on TV, or regarding a bold scientific claim, such as someone curing cancer. However, during this year, amid the Covid19 pandemic, the spread of misinformation has been almost as incontrollable as Covid19 cases in the United States of America. With great concern, I saw that several acquaintances, friends, and family, most of them with higher education degrees, shared and contributed to spread false information on the treatment of Covid19, its origin, or questioning if this was part of a bigger plot to control humanity.

The spread of misinformation has contributed to mistrust towards medical healthcare personnel, to the point of being violent towards them,1  not following their advices, or falsely claiming overdiagnosis of Covid19 with the sole purpose of getting “more money,” claim that unfortunately gets backed up by the Highest Office in the Land.2

However, this problem isn’t new in the medical community, as Dr. Anne Marie Navar stated in her conference during the Scientific Sessions lecture “How Misinformation Steers Patients off Course.” She mentions that the Covid19 pandemic highlighted and made more evident the dire problem misinformation has brought to medical compliance with treatments. She focuses on the misinformation campaigns that have been occurring around statins, were social media personalities with doubtful medical claims such as the questionable Dr. Joseph Mercola, and unscrupulous social medial like Infowars pretend to scare and deter patients from taking statins, while promoting their products such as diets, supplements (Omega-3), that are commercialized with misleading labels, and lies about the efficacy of their products.

But how likely are statements made by doubtful doctors or non-healthcare providers likely to affect patient compliance? Would patients believe more something they read or see on social media than following the physician’s recommendations to whom they trust their health?  Unfortunately, it is quite likely. Dr. Navar highlights a prospective cohort study from Denmark that included 674.900 individuals > 40 years old, that were on statin therapy ( a drug used for patients with high cholesterol levels) from 1995-2010, and followed until December 31 of 2011, to test the hypothesis if statin-related news were associated with early statin discontinuation.3

This prospective cohort showed that early statin discontinuation increased with negative-statin related news, and early discontinuation was associated with increased risk of myocardial infarction and death from cardiovascular diseases (fig 1). Also, a sensitivity analysis showed that  negative statin-related news stories were associated with an odds ratio of 1.15 (CI: 1.09-1.21) for early discontinuation of antihypertensive medication (fig 2).3

Fig 1. Early statin discontinuation vs. continued use and cumulative incidence of myocardial infarction (top panel) and death from cardiovascular disease (bottom panel).

Fig 2. Statin-related news stories and early discontinuation of statin, antihypertensive medication, and use of insulin among statin users.

It is worrisome that patients’ very own life might be at stake due to misleading propaganda that feeds from the fear of exaggerating adverse events for specific treatments (drugs, vaccines, etc.). To have these very own propaganda makers, in an ungracious second act, pretending to be messiahs, to promise patients the “healthiest” option available for their disease, thus creating widely successful businesses by selling non-effective products at the expense of putting the populations’ health at risk.

But this misinformation phenomenon has been more impactful and dreadful during the pandemic since we are dealing with a highly transmissible disease, where the cost of disinformation results in more people getting infected with Covid19 ,or dying because of Covid19.

But what can we do as healthcare professionals?  As scientists? The first thing to do is to speak up. We must not be silent as false and misleading information spreads. The truth tends not to be soothing, hopeful, nor easy to process, and during this cumbersome year, this might become a more challenging task when coming to terms with “the new normal.” The evidence does not change because of our feelings, thus making it imperative to face the facts. Our role as physicians, healthcare workers, and scientists is to be modern versions of Prometheus, and reside on the frontline to fight back misinformation by being leaders that defend the torch truth, and share it with the world.

Dr. Anthony Fauci is the perfect example of the leadership we all must show as bearers of the torch of truth, as his statements are based on hard facts and science.  Nonetheless, his remarks often failed to reassure people during these unprecedented times since he has been very cautious by avoiding making any premature conclusions regarding the effectiveness of a treatment or on the efficacy of a vaccine without proper evidence, as it should be.

However, this lack of reassurance opens a door for opportunistic scientists and medical doctors such as America’s Frontline Doctors, that earlier during the year claimed that Covid19 could be treated with hydroxychloroquine, widely tested as being not useful.4,5 This bold claimed amid the uncertainty lived in the beginning of the pandemic, unleashed an incontrollable confirmation bias, as people would feel reassure when “doctors” tell them there is a cure for this virus; despite the fact that the “doctors” making such claims were not infectious disease experts, nor did they have any real evidence to support those claims. This mere example highlights the importance of raising our voices to spread real facts to prevent landslides of false information spread.

We must be empathetic to those that are sharing or commenting on false information. When seen friends or family doing this, please give them the benefit of the doubt, as people share information thinking of their well-being and that of others and, most of the time, is not out of a primary motive to harm or do wrong. When I have encountered my family or friends doing this, I try to reach out to them and ask them what they learned from the information they are sharing and explain to them the inaccuracies of all the misleading content on the news they are spreading. At last, I tell them to send me privately all the videos, chats, news they get so we can discuss them before sharing them. By doing this, the fake news chain will break, and more people will start acquiring critical thinking before sharing news from a field that is unknown or unfamiliar to their area of expertise, in this case, medical and healthcare related news.

Finally, I would like to share a pamphlet on how to fight misinformation from Dr. Tim Caufield from the University of Alberta that outlies four main steps, help stop the spread, and craft a message to counter misinformation, promote a regulatory response, and debunking (fig 3).  Let us all unite our voices so they can be loud enough to bury misinformation.


Fig 3.  Fighting misinformation pamphlet (https://www.ualberta.ca/law/faculty-and-research/health-law-institute/fighting-misinformation.html)

Acknowledgments
I would like to thank Dr. Anne Marie Navar for her conference “How Misinformation Steers Patients off Course” As it encouraged me to write todays blog on this pressing issue. I encourage you all to see her conference on the Scintific Sessions website.

References

  1. Medellin. Personal médico del Hospital General fue agredido por caso de covid-19. El Tiempo. https://www.eltiempo.com/colombia/medellin/coronavirus-en-medellin-denuncian-agresion-a-personal-medico-del-hospital-general-de-medellin-527090. Published 2020. Accessed.
  2. Griffin J. Medical professionals push back after Trump says COVID-19 cases are inflated to ‘get more money’. Daily Herald 2020.
  3. Nielsen SF, Nordestgaard BG. Negative statin-related news stories decrease statin persistence and increase myocardial infarction and cardiovascular mortality: a nationwide prospective cohort study. Eur Heart J. 2016;37(11):908-916.
  4. Boulware DR, Pullen MF, Bangdiwala AS, et al. A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19. New England Journal of Medicine. 2020;383(6):517-525.
  5. Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19. New England Journal of Medicine. 2020.

 

 

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AHA 2020 Delivers on Virtual Conference Experience

As we near the close of the American Heart Association’s 2020 Scientific Sessions, I’d like to reflect on the virtual conference experience. I must admit, despite the high quality research and programming schedule, I was skeptical going into this year’s virtual conference. It was my first (of many?), and I had reservations about the ability of any organization to recreate the live experience that we all love so dearly. Looking back, the AHA put on a phenomenal show, filled with groundbreaking research, high profile panelists and even networking. For this blog, I’m going to focus on the networking, as this was the area that I was most skeptical of. How can you provide ample networking opportunities for clinicians, trainees and vendors when they’re all at home watching? Well, first, let me share the AHA’s plan to tackle this, then I’ll share some examples.

VIDEO: Networking Opportunities at AHA (Don Lloyd-Jones MD and Manesh Patel MD)

The AHA successfully delivered on their promise to fulfill the networking needs of its attendees in the following ways:

  1. AI-powered networking. The AHA brilliantly utilized burgeoning artificial intelligence technology to match like-minded individuals to each other as well as to programming that matched their interests. The AI then facilitated the organization of virtual meetings amongst interest-matched attendees. Wow!

  1. Fireside chats and FIT Virtual Lounge. The AHA continued its focus on providing mentorship to early career cardiologists and trainees. The experience was as engaging, and some would argue more engaging, than the live sessions. The democratization of commentary afforded by virtual communication was evident, as even the most reserved participants were able to ask questions and exchange ideas with established leaders in the field.

 

 

 

 

 

 

 

 

 

  1. Scavenger Hunt. Even the scavenger hunt was preserved! The AHA managed to provide a scavenger hunt experience via QR codes hidden throughout the conference programs for attendees to scan and WIN. This also further cultivated the relationship between the AHA and its industry partners.
  2. In line with its commitment to foster group wellness and health activities, the AHA organized morning yoga, exercise, and mental health sessions for attendees to virtually participate in together. This is a trend that has been popular since the start of the pandemic and hopefully will continue long after COVID-19 is gone.

In conclusion, my AHA 2020 experience has been rewarding in many ways. With quality education and networking opportunities, this year’s conference proved that the AHA is prepared to weather the challenges brought on by the COVID-19 pandemic. I look forward to future programming, and will certainly be an active participant.

 

“The views, opinions and positions expressed within this blog are those of the author(s) alone and do not represent those of the American Heart Association. The accuracy, completeness and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them. The Early Career Voice blog is not intended to provide medical advice or treatment. Only your healthcare provider can provide that. The American Heart Association recommends that you consult your healthcare provider regarding your personal health matters. If you think you are having a heart attack, stroke or another emergency, please call 911 immediately.”

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Fish Oils versus Statins?

Hypercholesterolemia remains a significant risk factor for cardiovascular disease. Management of hypercholesterolemia has entailed the use of statins and non-statins, such as omega-3 fatty acid supplements. Common side effects related to fish oil supplements have included reports of gastrointestinal upset and difficulty in swallowing the fish capsules. Common side effects of statin therapy have included reports of muscle aches, abdominal pain, dizziness, leading to non-adherence and termination of therapy.

The debate on the use of omega-3 fatty acids over statins in the management of blood cholesterol continues, calling for more studies.1  Day 3 of this year’s AHA Scientific Conference highlighted results from recent trials on the use of non-statins and statins in the reduction of cardiovascular events. Here are some takeaways from three studies: the STRENGTH Trial, the OMENI study, and the SAMSON study.

The STRENGTH (Outcomes Study to Assess STatin Residual Risk Reduction With EpaNova in HiGh CV Risk Patients With Hypertriglyceridemia) trial – This phase III international study evaluated the use of a medication derived from fish oil, containing the omega-3 fatty acids EPA and DHA, more than 13,000 people who had existing heart disease or who were at high risk of heart disease due to other medical conditions.2

  • The medication did not reduce the risk of cardiac events compared to a corn oil-based placebo.
  • Atrial fibrillation, an abnormal heart rhythm, occurred more frequently in participants taking the omega-3 CA medication.

The OMENI (OMega-3 fatty acids in Elderly patients with Myocardial Infarction) trial – a study of more than 1,000 patients in Norway investigated whether adding 1.8 grams of omega-3 fatty acids to standard treatment prevented further cardiovascular events among elderly participants with recent heart attacks.

  • When compared to placebo, omega-3 fatty acids supplement in addition to statin therapy and/or a blood thinner did not reduce the number of cardiac events in the participants.

The SAMSON (The Self-Assessment Method for Statin Side-effects Or Nocebo) Trial – The study, conducted in London, enrolled adults who had previously taken one or more statins but stopped taking them due to side effects. The participants had self-reported symptoms measured throughout a 12-month period of randomly alternating months of statin use, placebo, and no medications.

  • The participants who reported side effects from statins also reported the same side effects when they unknowingly took placebo pills.
  • The side effects appeared to be mostly due to psychological rather than pharmacological effects of statins since the reported symptoms were consistent when taking the placebo.

In the discussion led by Dr. Karol E. Watson, statins remain the mainstay in the reduction of Low-Density Lipoprotein (LDL) and Atherosclerotic cardiovascular disease (ASCVD) risk.  As also recommended in the 2018 AHA/ACC/ AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol, non-statin therapies should be considered in high-risk patients with LDL above thresholds.  Heart-healthy lifestyle changes should be also considered as important measures in the reduction of LDL and triglycerides in patients at risk for ASCVD. The heart-healthy lifestyle should include diet, weight control, and physical activity.4  It will be important to observe the outcome of future studies including the combined effects of heart-healthy lifestyle interventions and non-statin/statin therapy among those considered to be at high risk for ASCVD. Future discussions should also center on intervention studies to address patients’ perceptions of statin/non-statin therapies.

 

 

References

  1. Tummala R, Ghosh RK, Jain V, Devanabanda AR, Bandyopadhyay D, Deedwania P, Aronow WS. Fish Oil and Cardiometabolic Diseases: Recent Updates and Controversies. Am J Med. 2019 Oct;132(10):1153-1159. doi: 10.1016/j.amjmed.2019.04.027. Epub 2019 May 8. PMID: 31077653.
  2. Nicholls SJ, Lincoff AM, Bash D, Ballantyne CM, Barter PJ, Davidson MH, Kastelein JJP, Koenig W, McGuire DK, Mozaffarian D, Pedersen TR, Ridker PM, Ray K, Karlson BW, Lundström T, Wolski K, Nissen SE. Assessment of omega-3 carboxylic acids in statin-treated patients with high levels of triglycerides and low levels of high-density lipoprotein cholesterol: Rationale and design of the STRENGTH trial. Clin Cardiol. 2018 Oct;41(10):1281-1288. doi: 10.1002/clc.23055. Epub 2018 Sep 28. PMID: 30125052; PMCID: PMC6489732.
  3. Kalstad AA, Myhre PL, Laake K, Tveit SH, Schmidt EB, Smith P, Trygve Nilsen DW, Tveit A, … Effects of n-3 Fatty Acid Supplements in Elderly Patients after Myocardial Infarction: A Randomized Controlled Trial. Circulation. 2020 Nov. https://doi.org/10.1161/CIRCULATION AHA.120.052209Circulation.
  4. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT, de Ferranti S, Faiella-Tommasino J, Forman DE, Goldberg R, Heidenreich PA, Hlatky MA, Jones DW, Lloyd-Jones D, Lopez-Pajares N, Ndumele CE, Orringer CE, Peralta CA, Saseen JJ, Smith SC Jr, Sperling L, Virani SS, Yeboah J. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/ AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019 Jun 25;73(24):e285-e350. doi: 10.1016/j.jacc.2018.11.003. Epub 2018 Nov 10. Erratum in: J Am Coll Cardiol. 2019 Jun 25;73(24):3237-3241. PMID: 30423393.

 

“The views, opinions and positions expressed within this blog are those of the author(s) alone and do not represent those of the American Heart Association. The accuracy, completeness and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them. The Early Career Voice blog is not intended to provide medical advice or treatment. Only your healthcare provider can provide that. The American Heart Association recommends that you consult your healthcare provider regarding your personal health matters. If you think you are having a heart attack, stroke or another emergency, please call 911 immediately.”

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Cardio-Oncology, Meet Your New Neighbor: Immunology

In this AHA session, an international group of physician scientists discussed ways to mitigate immune checkpoint inhibitor (ICI) induced myocarditis and future therapies. The session, moderated by Dr. Sakima Smith MD, MPH, FAHA (from THE Ohio State), and Dr. Doug Tiley highlighted studies by Drs. Burkhard Ludewig, DVM, Dr. Han Zhu, MD, Dr. Alcaide, PhD, Dr. Peter Liu, MD and Dr. Joe-Elie Salem, MD, PhD. The talk began with presenting the problem, basic-science T-cell mechanisms including involvement of microbiota, and ended with a possible targeted therapy, Abatacept. This is a hot topic in the cardio-oncology world considering the high mortality in those affected (up to 50%!) [1].

Source: Cardio-Oncology, Meet Your New Neighbor: Immunology| American Heart

ICIs (eg. ipilimumab, pembrolizumab) are effective targeted therapies in patients with PDL-1/PD-1 expression on tumor cells. Many cancer phenotypes are FDA approved for treatment which includes melanoma, renal cell carcinoma, non-small-cell lung cancer, Hodgkin lymphoma, and more[2]. Although these agents have shown to extend cancer survivorship[3] , they have inadvertent side effects that can lead to myocarditis and cardiomyopathy. ICIs act by “releasing the brake” of T cell immune proliferation. These monoclonal antibodies block PD1/PDL-1 ligands/receptors and allow for T cells to bind to tumor cells leading to reduced tumor burden[3]. Understanding the mechanism for ICI induced myocarditis is partially based on PDL1 knockout mice[4]. Unfortunately, there is cross-reactivity that occurs via binding to cardiac antigens (eg. myosin) leading to the inflammatory response[4].

Dr. Zhu informed us that the risk of this effect includes dual ICI treatment. In addition, early identification is key, considering 50% mortality. Patients may have a drop in their ejection fraction (EF), but have other signs of cardiac injury including brady and tachyarrhythmias. She highlighted that our current data is from FDA sponsored pharmacovigilance databases collected by Dr. Javid Moslehi, who is a pioneer and leading investigator on this subject. A registry created by Dr. Tom Neilan’s lab at Massachusetts General Hospital demonstrated an increased risk of MI and stroke after treatment with ICI[5]. Her group at Stanford along with renowned Dr. Ronald Witteles is using biobanking to identify patients with autoimmune myocarditis and controls to conduct downstream high-throughput immune repertoire analysis. Dr. Alcaide supplemented this talk by adding a novel mechanism. She discussed that reactive oxygen species (ROS) play a role in triggering downstream T cell expansion in the heart. Therefore, there may be a role in anti-oxidant therapy to reduce T cell response. Dr. Liu acknowledged our current pandemic and discussed the added risk of inflammation in the setting of concomitant COVID19 viral infection associated with myocarditis.

During this session, we learned about possible therapies to mitigate myocarditis. Dr. Ludewig discussed his teams work with an ICI mouse model. They explored T cell cross-reactivity that led to the lethality of the disease. There was a heart-gut connection! They found elevation of Bacteroides-specific CD4+ T cells in disease models which suggests that mimic peptides from commensal bacteria can promote inflammatory cardiomyopathy in genetically susceptible patients (those with HLA DQB1*03:01 polymorphisms) by showing increased reactivity against myosin 6 (MYH6) (cardiac antigen). His study suggests that the genetic susceptibility along with cross-reactivity antigens in the heart and potentially the intestine put patients at risk for fulminant myocarditis. Therefore, he proposed the use of antibiotics as a cardioprotective agent by blocking the cross-reactivity that leads to ICI induced myocarditis.

Source:  Ludewig: ‘Dangerous gut-heart liaison’| When it comes to matters of the heart, don’t always trust your gut/ Cruz et al. Microbiota-derived peptide mimics drive lethal inflammatory cardiomyopathy. Science 2019; 336, 881-886.

Dr. Joe Elie-Salem (making us jealous by Zooming in from Paris; Ca alors!) ended the session with the introduction of abatacept for therapeutic use in ICI induced myocarditis.  Corticosteroids are the mainstay of treatment; however steroid therapy is nonspecific and there are unintended off-target side effects. Specifically, there is a high association with concurrent myasthenia gravis-like syndrome with ICI myocarditis that presents a challenge with the use of steroids. Steroids can lead to an exacerbation of myasthenia crisis which can lead to significant respiratory failure[6].  Based on work with Dr. Moslehi, abatacept (a cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4] agonist, they found that in anti-CTLA4 and Anti—PDL-1  treated disease mouse models, treatment with abatacept reduced myocarditis induced death. This agent will be further explored in a Phase II trial titled: ACHLYS-trial: Phase II trial testing abatacept for ICI-myocarditis.

The take-home points for this session include: 1) ICI used to treat many cancer phenotypes are associated with incident myocarditis with up to 50% mortality 2) Cross-reactivity with cardiac antigens leads to myocyte dysfunction and the clinical sequelae of this includes cardiomyopathy (not always!) and brady/tachyarrhythmias 3) Understanding predisposing immune variants and microbiota (Bacteroides- B. theta) related to immune response associated with this disease is key to identifying all the possible therapies including antibiotics 4) Abatacept is a known T cell immunomodulator and it has a potential role in treating ICI induced myocarditis; especially in those at risk for corticosteroid effects (eg. myasthenia gravis), which will be further explored in a clinical trial.

REFERENCE

  1. Ball, S., et al., Cardiovascular Toxicities of Immune Checkpoint Inhibitors: JACC Review Topic of the Week. J Am Coll Cardiol, 2019. 74(13): p. 1714-1727.
  2. Zhou, Y.W., et al., Immune Checkpoint Inhibitor-Associated Cardiotoxicity: Current Understanding on Its Mechanism, Diagnosis and Management. Front Pharmacol, 2019. 10: p. 1350.
  3. Ferris, R.L., et al., Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med, 2016. 375(19): p. 1856-1867.
  4. Nishimura, H., et al., Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science, 2001. 291(5502): p. 319-22.
  5. Drobni, Z.D., et al., Association Between Immune Checkpoint Inhibitors with Cardiovascular Events and Atherosclerotic Plaque. Circulation, 2020.
  6. Xing, Q., et al., Myositis-myasthenia gravis overlap syndrome complicated with myasthenia crisis and myocarditis associated with anti-programmed cell death-1 (sintilimab) therapy for lung adenocarcinoma. Ann Transl Med, 2020. 8(5): p. 250.

“The views, opinions and positions expressed within this blog are those of the author(s) alone and do not represent those of the American Heart Association. The accuracy, completeness and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them. The Early Career Voice blog is not intended to provide medical advice or treatment. Only your healthcare provider can provide that. The American Heart Association recommends that you consult your healthcare provider regarding your personal health matters. If you think you are having a heart attack, stroke or another emergency, please call 911 immediately.”

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Buzzword Alert! Artificial Intelligence – Just the Hype Man or a Genuine Showstopper?

Conversations of the utility and promise of machine learning (ML) and artificial intelligence (AI) permeate all fields of medicine, and cardiology is no exception. A quick search shows that 69 posters containing the keywords “machine learning” made it into AHA’s Scientific Sessions 2020. But is it for real? Will we really see a future in with ML/AI factors into all aspects of clinical care and in fact, re-write the script on how we care for patients?

Below is some of the discussion points and imperatives that stood out to me today from the “Hope or Hype? Artificial intelligence and Machine Learning in Imaging.” session at #AHA20 featuring thought leaders Drs. Marielle Scherrer-Crosbie, Alex Bratt, David Ouyang, Tessa Cook, Damini Dey, David Playford, and Geoffrey Rubin.

  1. While awe-inspiring in its ability to make inferences and predictions human beings often cannot themselves, we must be aware that ML/AI algorithms can recreate and reinforce the bias pre-existing in our society. We must fight this by knowing it is a possibility, screening for it, and training algorithms on datasets that are truly representative. As much of the political landscape and national conversation right now centers on structural racism and bias in America, it’s is prudent to understand how the models we create can perpetuate this.
  1. Separate low hanging fruit from the unrealistic (at the moment) and consider the unrealistic tasks in the realm of discovery science. A quick rule of thumb provided by Dr. Ouyang, summarizing the words of Dr. Andrew Ng, first determines if it is possible for humans to do a task relatively quickly. If it is, we can probably automate it with AI now or in the near future.

  1. Scrutinize our data. How much do we trust it? High-quality data for ML/AI means broad, accurate, and plentiful. We need robust training labels, as free from subjectively as possible.
  2. How open is our data for inspection? Fields in computer science are far further along than medicine in deploying and improving ML/AI models because of open data sets and shared code, allowing groups to verify, tinker, and re-create to move the needle forward. Medical AI has not been so forthcoming.

  1. As new technology is rapidly evolving and making it into the clinical space, we need to be responsible for mistakes. This means we need to assess not only our model performance before deploying but also the consequences of using the model in real life. This may require RCTs and to consider ML/AI algorithms like we consider new therapeutics.

  1. What we really want is the AI running in the background saying “Hey, this task was automated and is now solved for you. Proceed as you see fit.” Humans and machines are in this shared space. The more we can integrate ML/AI to help us with tasks we are already doing, the better our results will be.

So where does this leave us? Most in our field believe ML/AI will play an important role in our future. Ideally, we will do it in a way that will make sure human intelligence is always paired with artificial intelligence to create a product neither of the two could be alone, will ensure our algorithms are free of bias and openly shared to allow for continuous improvement.

 

“The views, opinions and positions expressed within this blog are those of the author(s) alone and do not represent those of the American Heart Association. The accuracy, completeness and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them. The Early Career Voice blog is not intended to provide medical advice or treatment. Only your healthcare provider can provide that. The American Heart Association recommends that you consult your healthcare provider regarding your personal health matters. If you think you are having a heart attack, stroke or another emergency, please call 911 immediately.”

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Late-Breaking Highlights: “To Screen Or Not To Screen And Then What? Studies of Detection and Treatment of AF”

This was an exciting session at AHA 2020 which focused on clinical trials of screening, monitoring, and early intervention in Atrial Fibrillation (AF). Screening of AF is a controversial topic and for individuals >65 years, current AHA guidelines give a Grade 2a recommendation for screening whereas USPSTF guidelines suggest that there is insufficient evidence for screening. In this article, I will be discussing studies that addressed AF screening and their implications on clinical practice with Dr. Stavros Stavrakis who is an electrophysiologist and Associate Professor at the University of Oklahoma Health Sciences Center, Oklahoma City.

Question: What are the important goals when we think about screening for AF?

Dr. Stavrakis: The important goals for screening in AF are to establish a diagnosis of new AF in patients at high risk of stroke so they can be anticoagulated, ultimately reducing the risk of stroke.

There were 3 important trials that addressed AF screening in different patient populations.

SEARCH AF

  • In patients who have undergone cardiac surgery and have a higher risk of stroke but no history of pre-operative or pre-discharge AF, what is the risk of developing AF/Aflutter in the sub-acute post discharge period?
  • 336 post-cardiac surgery patients (median CHADS2Vasc Score 4) but with little or no AF in the post-operative period (<24 hours of AF but no intent to anticoagulate at discharge) were randomized to continuous cardiac rhythm monitoring vs usual care during the sub-acute post discharge period.
  • In the enhanced cardiac rhythm monitoring group 19.6% participants developed AF/Aflutter as compared with 1.7% in the usual care group with an absolute rate difference 17.9% (p<0.001, NNS=6).

Question: What are the implications of this trial on clinical practice?

Dr. Stavrakis: Risk of POAF, although peaking at 48-72hours post-op, is not confined to the index hospitalization, continuous monitoring for POAF can identify AF in a significant proportion of patients (20%) that may need treatment with anticoagulation. Whether anticoagulation improves outcomes in these patients, remains to be determined.

VITAL-AF Trial

  • Among older adults (age>65) presenting to primary care visits, does point of care rhythm assessment with a single lead ECG result in increased diagnosis of AF?
  • 30,722 patients were randomized to screening vs control.
  • Screening did not significantly affect AF diagnosis in the overall study sample (1.74% vs 1.60%, p=0.33)
  • Increased likelihood of AF diagnosis at primary care encounter (p<0.02)
  • Effectiveness of screening varied by age with effective screening in age>85 (risk difference 1.88%, NNS=53)
  • Overall no difference in the initiation of anticoagulation

Question: What are the implications of this trial on clinical practice?

Dr. Stavrakis: There are 2 important implications from this trial.

  1. Screening everyone age>65 for AF at a single time point is not an efficient way to detect AF, especially if the usual care is very good in detecting AF by pulse palpation or BP device.Screening at age>85 may be more effective than usual care to identify silent AF, but it is uncertain if it changes management or outcomes

mSTOPS

  • Can screening for AF by wearing an ECG patch improve clinical outcomes at 3-years?
  • 1718 actively monitored participants vs 3371 matched observational controls with analysis of 3-year clinical outcomes.
  • Mean duration of follow-up was 29 months
  • 11.4% of actively monitored patients developed AF vs 7.3% of matched controls
  • No difference in anticoagulation prescription between both arms (45.2% vs 44%, p=0.84)
  • 3-year Primary combined end point (death, stroke, systemic embolism or MI) for entire cohort was 4.5 vs 5.5 per 100 person-year (HR 0.79, p<0.01) and for diagnosed AF patients it was 8.4 vs 13.8 per 100 person-year (HR 0.53, p<0.01).

Question: What are the implications of this trial on clinical practice?

Dr. Stavrakis: Clinical outcomes can be improved with AF screening provided these patients are followed up for extended periods of time. However, this was not a randomized trial and unknown confounders may have influenced the outcome.

Question: What are 3 important unanswered questions pertinent to screening of AF?

  1. What is the impact of AF screening on clinical outcomes? Large studies, adequately powered to detect clinical outcomes, are underway (SAFER, HEARTLINE, GUARD-AF).
  2. What is the optimal screening intensity that identifies AF which would benefit from anticoagulation?
  3. What is the minimum AF burden that, if identified with screening, would benefit from anticoagulation?

“The views, opinions and positions expressed within this blog are those of the author(s) alone and do not represent those of the American Heart Association. The accuracy, completeness and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them. The Early Career Voice blog is not intended to provide medical advice or treatment. Only your healthcare provider can provide that. The American Heart Association recommends that you consult your healthcare provider regarding your personal health matters. If you think you are having a heart attack, stroke or another emergency, please call 911 immediately.”