AHAFIT – Page 2 – The Early Career Voice

The Researcher’s Ultimate Toolkit: The PPI network Passion, Perseverance, and Interaction.

February 25, 2022February 22, 2022 Melody Chemaly, PhD

I had the pleasure of having a one-on-one virtual meet-up with Mabruka Alfaidi MD, PhD who won the ATVB Investigator in Training Award Competition during last year’s Vascular Discovery 2021 meeting based on her fascinating work on endothelial cells and IL-1b signaling pathway as well as her active involvement with the research community. We discussed her career path and her future projects which we couldn’t do without also going over the many hurdles that come our way as researchers. I decided to summarize the main themes that we tackled in a researcher’s toolkit which encompasses key ingredients to sustain a career in research: The PPI network.

Passion: Follow your passion, but it’s ok to be unsure

Mabruka Alfaidi is a postdoc at Louisiana State University and is currently an instructor seeking her research independence. For Mabruka, her passion for research started when she was a clinical cardiologist and when she realized that one needed to do more to save patients’ lives. Her PhD at the University of Sheffield in the UK opened her eyes to the field of IL1-b signaling in endothelial cells which further developed into her research passion and the basis on which she would like to build her future research career. Research without passion is unsustainable. Passion is the fuel which will motivate us to wake up in the morning (or in the night) and check the latest research, be inspired by the newest methods and design novel hypotheses. However, it is ok to be unsure sometimes when trying to figure out our next step; do we want to stay in academia, or should we venture into setting up this start-up that we always dreamed of? Nothing is really set in stone because research, just like our passion for it, is a dynamic process and it evolves.

Perseverance: It’s ok to fail

A career in basic research is impossible without facing failures and hardships. For Mabruka who started her research path with a medical background, failure, which is assimilated to losing a person’s life in medical practice, was not an option. However, life as a basic researcher is surrounded by failures. We have all struggled with experiments not working, manuscripts getting rejected, grant applications not receiving any interest and the list goes on. So, becoming a basic researcher coming from a medical background is definitely an adjustment. In those moments where doubt creeps into our heads and our confidence and self-esteem is at its lowest, it is important to be surrounded by the right people and inspiring mentors to give us this moral boost that we need to persevere and remind us that it is ok to fail.

Interaction: Network and share your experience, you are not alone

It is common for researchers to feel isolated in their own niche of research and drown in it. However, sharing one’s experience with the research community is important to learn from others and be presented with new opportunities. Mabruka’s experience with the AHA community helped in her career development as the organization provides funding opportunities for early career researchers as well as those seeking independence and is an important platform where basic and clinical researchers can communicate and find common ground. However, Mabruka’s involvement with AHA and other research communities is because she feels that it is important for a researcher to always ‘give back’ to the community as a way to acknowledge the help and contribution they received and carry on the flame.

“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 health matters. If you think you are having a heart attack, stroke, or another emergency, please call 911 immediately.”

The residency MATCH: a 101 guide to understand it

February 18, 2022February 14, 2022 Miguel Quintero-Consuegra, MD

The match, residency, ERAS. These terms become part of our everyday vocabulary, either as MS4 or IMG applying into residency. A cumbersome, long application process in which oneself that is going through seems lost most of the time. It is no wonder that our family or friends who are not in the medical field get confused about how the process occurs. To alleviate my anxiousness prior to the match and help our loved ones understand better what the process of applying to residency in the USA entails, I will make this quick 101 guide to understand it. And before we start, I will address a very common preconception; passing the steps1 and 2 does not mean we got into residency.

The beginning

Hello! If you are reading this behold, as a friend or family relative is about to embark into a couple of stressful, exciting, doubtful several months starting early June/July until matchday in March, yes, it this long, so please gives us love.

The process starts earlier than you might imagine. Before applying, you should have already decided what specialty you want to go into. Specialties in medicine could be divided in 3 big groups medical specialties (internal medicine, pediatrics,dermatology), surgical (neurosurgery, ophthalmology, plastic surgery), diagnostics (radiology, pathology). Once you have decided what specialty you want to apply to, the process begins.

Around June, ERAS will become the most searched website on your applicants one’s laptops. ERAS stands for Electronic Residency Application Service. This is the website where we will have to do a lot, so I will bullet point all that we have to get done on this website that gets quite stressful even with the calming blue colors of the ERAS banner.

CV: LONG standardized CV format where we will have to write in excruciating detail all our accomplishments, education background, hobbies (yes, super important). This is an essential part of the application because we have to look attractive for programs. Your applicant will spend several hours witting, re writing, and writing again this application for several months.
Letters of recommendation (LOR): It is pretty standard to put references down for a job, right? Well, I wish this was just to put down a name. The LORs are probably one of the most stressful parts of the application since it does not depend entirely on us. Our professors write these letters, mentors that want to support our residency application, and every word they write is taken very seriously by programs one applies to. There are two ways to upload a LOR as they are so important. One is to waive the right to see the letter (which is usually preferred) so that the person can freely write about you or upload the letter yourself (not recommended). So we reach a point where many students are asking the same attendings for LOR’s, that in addition to their busy clinical schedule, they have to write and upload in a platform for which they have to create an account. So you can imagine the stress one could go under while catching our mentors and pressuring them to write the LORs and upload them. Tip for future applicants, do this early in the season if possible.
Personal statement: I think my non-medical readers might be familiar with this part, as you must have read a couple of versions of the personal statement. In less than 28’000 characters, convey who you are, why you want the specialty you are applying to, and seem interesting enough to catch the attention of the selections committee. One goes on and on, and one writes several versions (I think I did about ten versions) and gets inputs from many people. So, brace yourself as you will be receiving personal statements any time soon to revise.
Medical School Performance Evaluation (MSPE): For American graduates, you are blessed; you don’t have to do much here as your medical schools are in charged. For my fellow IMG’s, this is where we go back to our alma mater across the world to ask for our medical school performance, and we all know how slow administrative requests are. Please do so in advance as we need to request them and translate them to English. I enjoyed this part as I got the chance to remember great memories from medical school.
Programs selection: Decision burnout, yeah, it might happen. How do I choose from so many programs? Which ones to apply to? This is where applicants will go over more than > 100 programs and read what each has to offer to decide which ones they want to apply. Usually, the limitans is, yes, you guessed it: money as applications to around 100 programs could cost up to $2000.

Congratulations! Once you have gathered all items on your ERAS application and decided which programs to apply, all is left is to use that plastic to pay thousands of dollars in applications and wait for the next phase of the match season.

The interview invitation season: two rules

ALWAYS HAVE YOUR PHONE TURNED ON WITH NOTIFICATIONS ON
Have a proxy that will be receiving emails when can not

Your application rests now in the people’s computers that might decide your future career. It is only normal that your applicant seems anxious during this time and is waiting impatiently for that [email protected] email at any time for an interview invitation.

Most programs will send out interview invitations at any time during the day, hence you will see your applicant glue to their phones, with an special alarm ready to receive these emails, and in constant cycle of checking to see if the email is working. This tends to become stressful for many reasons, as sometimes programs might send more interview invites than slots to interview, or if you don’t respond fast, you might have scheduling conflicts.

You will hear funny stories such as people jumping out of the shower once they hear an email notification. Thus, having a proxy answering your emails and scheduling your interviews when you won’t be able to be on your phone, like when flying on an airplane or while you are in other interviews. In my case, the funniest story was that I received an interview invitation while in the middle of taking step3, good energy boost but terrible timing. Shout out to my proxy Sebastian Gallo for scheduling that interview for me.

This time is mixed with extreme rushes of energy and enjoyment once you get that email that says you are invited to interview, sadness when a program you liked rejected you, and uncertainty when most of the programs you will apply for will neither invite you nor reject you.

Interviews: Game ON!

While the most stressful part is the first month and a half to receive interview invitations, by this time, your applicant will most likely start to interview. We will all do our interviews virtually as we are going through the COVID-19 pandemic, which makes things somewhat more accessible. Before the pandemic, applicants had to travel all over the United States to interview their desired programs, wild, right?

Before the interview, applicants will carefully study the program, the attendings that will be interviewing them, and reviewing their own application as anything they have written could be asked whether that been a hobby or a paper. This period is full of excitement, they are interviewing for their dream job! You will probably be asked to help them with mock interviews and to practice with them for a few times to be able to shine during the interviews. So be there for them and cheer them through this interview season that will last from October until probably mid-February.

Ranking order and match day

The interviews are over, by this time you probably have a sense of which programs your applicant liked more and you have asked, so when do you get the job offer? Well unfortunately this is not a direct hiring process. After the programs have interviewed the applicants and applicants have interviewed at all of their programs, each one of them well sit down and write something called the Ranking Order List (ROL). This is a list of preferences in descending order of which one is the program they liked the best to the least, or even not rank places they did not like. Programs will do the same to rank in order of preference applicants or not rank them at all if they did not seem like a good fit. Once the lists are done, they will be submitted to the NRMP platform. On this platform, the Gale-Shapley matchmaking algorithm, which earned them the 1995 Economic Nobel Prize, will dictate where you will spend the next 3 to 8 years of your life and be the most crucial part of your training as a physician; an algorithm will be determining our life’s.

So, the best way to explain this is to make an analogy with Tinder or any dating app. You swipe right when you like someone, and if the other person also swipes right, you will both match! It is similar in that if the number 1 ranking in your list is a program that also ranked you first or within the number of positions available, you will have a perfect match and train in your most desired program.

But if that program ranks you in a lower position than there are available slots, things get a bit complicated. So let’s set a fictional hospital, Greys Sloan Memorial, and our two dear applicants, Derek and Meredith.

Let’s say Greys Sloan Memorial has eight spots for General Surgery, and our imaginary applicants Derek ranked Greys Sloan as his number 1 residency program and Meredith as her 4th choice. Derek was ranked in the position 9 and Meredith was ranked as their # 1 out of the 60 people they interviewed. He was certainly ranked high, but for Derek to match in Greys Sloan Memorial, at least 1 of the other applicants that are above him must have either matched elsewhere or not have ranked Greys Sloan. Meredith on the other hand would have directly matched into Grey Sloan, right? They have 8 spots, and she was first! However, Grey Sloan wasn’t her first choice. Since the algorithm favors applicants, the system will first try to match Meredith into her other top 3 hospitals. For Meredith to match into Greys Sloan, she must not have been able to match in her top 3 choices. She would go ahead and match at Greys Sloan.

As you can see, Meredith matching into this program might mean that Derek will not be able to match into his top choice thus the outcome of the match is dependent on the ROL from each of the hundreds of applicants and the programs.

MATCH week: The reveal!

After submitting and editing the ROL endlessly, the second week of March of each year will be a life-defining week for most applicants. On Monday, we will receive an email stating if we were accepted for residency or matched into a program. If so, we will receive another email on Friday, AKA Match Day, that will tell us where we will be doing a residency for the next 3-7 years.

Of note, the match in March occurs only for most specialties, except for urology that happens in January and ophthalmology that happened this past Tuesday.

This was a brief overview of the tumultuous process of applying for residency. It goes without saying that having friends, significant others, and family through this time is paramount, and I take this opportunity to say thank you for the unwilling support anyone has brought me until this point. I want to specially thank my mentor Dr. Nestor Gonzalez, my family, and my friends (Sebastian Gallo, Sandra Saade, Andy Serrano and Juan Esteban Velez) for putting up with my anxiety through these months.

Clinical Practice Guidelines Part 1: Why and How Are They Developed

February 16, 2022February 14, 2022 Ahmad Ozair, MD

Clinical practice guidelines find extensive usage worldwide amongst both researchers and clinicians. In 2021, I had the opportunity to act as one of the trainee members of two guideline groups of the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) with the experience being transformative. The following will be a multi-part series on the why’s and how’s of guidelines, getting behind the scenes on their development.

Need for Clinical Practice Guidelines

The American Heart Association (AHA) and the American Stroke Association (ASA), often in conjunction with the American College of Cardiology, produce major clinical practice guidelines (CPGs) that are both widely utilized as professional practice standards globally and used extensively for research. For instance, the guideline papers on ‘Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults’ by the AHA/ACC Task Force on CPGs, which were published in multiple journals simultaneously, have been cited thousands of times by the end of 2021 since their publication in 2017, while having been utilized by millions of clinicians worldwide [1].

These guidelines are critically valuable tools for practitioners, many of whom lack the time to appraise the primary literature themselves. The latter becomes an especially challenging endeavor given the increasing amount of publications along with the expanding number of low-quality studies. In her book, Trisha Greenhalgh had quoted Stephen Lock, who had described in 1979 as the editor of the British Medical Journal, “Few things are more dispiriting to a medical editor than having to reject a paper based on a good idea but with irremediable flaws in the methods used” [2]. In 1994, Douglas Altman, one of the pioneers of the EBM movement, had written those widely quoted words that “We need less research, better research, and research done for the right reasons” [3]. A decade later, John Ioannidis had published his landmark work ‘Why most published research findings are false’ [4].

Twenty years after Altman’s editorial in BMJ, the editor of BMJ wrote how little had changed since then [5]. Chalmers and Glasziou have classically described the four stages of research waste [6], which coupled with the predicted doubling time of medical knowledge reaching 73 days in 2020 [7], leads to the increasing difficulty of reading and synthesizing the primary evidence for oneself. Thus, in an age of information overload, appropriately developed and concisely written guidelines in one part of the world often become a critically valuable tool globally.

Guidelines also help define the value judgments we assign to the primary evidence. For instance, for acute management of ischemic stroke, different anticoagulating drugs may be drugs, with one negative outcome assessed in the literature being the risk of intracranial hemorrhage. Here one value judgment is the significance we assign to the occurrence of intracranial hemorrhage. Finally, for outcomes where high-quality primary evidence is lacking, guidelines may still provide conditional recommendations with low certainty, which are useful to the frontline healthcare worker.

Evolution of Clinical Guidelines

Guideline development has come a long way from before the advent of the evidence-based medicine (EBM) movement to after the widespread utilization of the same. Colloquially, the old approach to guideline development was the GOBSAT model, i.e. ‘Good Old Boys Sitting Around A Table’ [8,9]. This typically was based on a panel of experts (typically males) who would be invited by a professional society to convene for a few days. They would provide their opinion and discuss their clinical practice, and their consensus would get written up as the professional society guideline to be followed worldwide. Many times, this gathering would occur in a hotel or trip funded by a pharmaceutical corporation [9].

In addition, this approach majorly ignored conflicts of interest amongst the experts themselves, since no rules existed on who could participate as a panel member based on their competing interests. Experts, who were paid speaking fees or honoraria related to certain medications by pharmaceutical corporations, would overwhelmingly represent members of the task force making the guidelines on diseases where those drugs would get utilized [9]. These competing interests meant that guideline development had significant bias from the start.

Finally, even if subject matter experts did not have competing interests, it was still likely that their perspective of the literature in totality on the PICO was biased, as was well captured in seminal papers by Mulrow in BMJ and Antman et al in JAMA [10,11]. These authors demonstrated that traditional narrative review-based consensus opinions of experts greatly lagged behind and sometimes significantly differed from effect estimates from well-performed meta-analyses. In one of their classic examples, Antman et al used the process of cumulative meta-analysis to show that data was consistently building up regarding the futility of lidocaine in improving survival in acute myocardial infarction for many years, yet most major traditional reviews continued to wholeheartedly recommend this medication even after 1990 [11].

Current Model of Guideline Development: An Overview

One of the most widely cited definitions for CPGs or ‘guidelines’ was given by an influential Institute of Medicine (IOM) report which referred to them as “statements that include recommendations, intended to optimize patient care, that are informed by a systematic review of evidence and an assessment of the benefits and harms of alternative care options” [12]. This definition can be broken down into two parts: (A) a systematic review of the primary evidence, which is the groundwork of the guideline, and (B) a set of recommendations, which incorporates both the evidence and the value judgments. The systematic review is typically informed by one of more key questions, that are structured in the PICO format, i.e. Population, Intervention, Comparator, Outcome(s).

Guidelines today are developed by a multidisciplinary panel of experts, which include but are not limited to, subject matter experts (which were the only members of guidelines previously), guideline methodologists, health economists, statisticians, librarians, patient representatives, amongst others (Figure 1). The goal now is to have guidelines that focus on what matters to the patients, and therefore, the outcomes used for decision-making in the guidelines have shifted gradually towards patient-reported outcomes (PROs). Instead of conventional outcomes like blood loss, PROs include pain score, quality of life, time to return to activities of daily living, etc.

Figure 1: Overview of the guideline development process, as seen from the Guideline International Network (GIN)-McMaster Checklist. Reproduced from Piggott T, Langendam M, Parmelli E, et al. Bringing two worlds closer together: a critical analysis of an integrated approach to guideline development and quality assurance schemes. BMC Health Serv Res. 2021;21(1):172. Published 2021 Feb 24. doi: https://doi.org/10.1186/s12913-020-05819-w under CC BY-NC-SA 4.0 license (https://creativecommons.org/licenses/by-nc-sa/4.0/).

Guidelines, including those of the AHA/ACC now explicitly attempt to reduce distortions, biases, and competing interests. They aim to minimize this by following a pre-specified, explicit, and transparent set of rules, that apply to all guidelines published by that organization. These guidelines have their foundation as the best available systematic review of the primary evidence. The goal is to use this systematic review and provide recommendations with ratings of the quality of evidence (high, low) along with the strength of recommendation (strong, conditional) [13]. Guidelines in the current age are expected to provide clear descriptions of the relationships between health outcomes and different care options.

Finally, guidelines today are revised regularly as deemed appropriate (by a designated group of individuals) to ensure new evidence gets incorporated in a timely manner [13]. For instance, the 2017 ACC/AHA Guidelines on hypertension [1], received an update through an AHA Scientific Statement published in 2021 on the management of stage 1 hypertension in patients with low ASCVD risk.

In the next part of this series on guidelines, we will continue with what principles guide guideline development.

PCSK9: From Bench to Bedside

February 14, 2022February 4, 2022 Devika Aggarwal, MBBS

(Image by sinclair.sharon28 from Creative Commons)

The proatherogenic role of low-density lipoprotein (LDL) cholesterol is well established and reduction of LDL cholesterol is one of the central pillars of management and prevention of atherosclerotic cardiovascular disease. The prevention of atherosclerotic events directly correlates with the reduction in LDL cholesterol and growing evidence supports the notion that the lower the LDL, the better the outcome.¹ Statins are the backbone of lipid-lowering therapy and are indispensable for primary and secondary prevention. Despite trials showing no significant difference versus placebo in terms of serious adverse events, statin intolerance is commonly encountered in clinical practice.² Additionally, patients on intensive statin therapy can have significant residual risk that can be minimized by additional lipid-lowering interventions.³ Hence, there was an urgent need for new strategies to lower LDL cholesterol levels.

In 2003, Abifadel and colleagues first reported a gain-of-function mutation in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene in a French family with autosomal dominant hypercholesterolemia, ⁴ a condition associated with significantly increased LDL cholesterol levels and risk of cardiovascular disease. Studies in mice subsequently delineated the underlying pathway: the PCSK9 gene encodes its namesake protein produced primarily in the liver.⁵ This protein binds to LDL receptors on the surface of hepatocytes, leading to their internalization and degradation. Reduced uptake of LDL particles by the hepatocytes leads to higher circulating levels of LDL cholesterol, increasing the risk of atherogenesis. Similar mechanisms are reported in humans. An analysis from the longitudinal Atherosclerosis Risk in Communities (ARIC) database showed that genetic variations in PCSK9 associated with lower levels of LDL cholesterol attenuated the risk of coronary heart disease.⁶ Studies also showed a reduction in triglyceride levels in patients with loss-of-function of PCSK9.⁷

These findings inspired the research and development of therapies targeting the PCSK9 pathway to achieve a reduction in LDL cholesterol levels. In 2009, Chan and colleagues developed a neutralizing antibody to PCSK9 that showed a significant reduction in LDL cholesterol in mice and monkeys.⁸ Within a decade of the discovery of the PCSK9 pathway, the race for human trials was on. In 2012, REGN727, a human monoclonal antibody, now known as alirocumab (Praluent®, by Regeneron and Sanofi) was shown to safely reduce LDL cholesterol levels.⁹ Similar results were seen with AMG145, later named evolocumab (Repatha®, by Amgen).¹⁰ Additional studies confirmed the ability of the two drugs to reduce LDL cholesterol by upto 60% without any serious adverse events. This led to FDA approval for both alirocumab and evolocumab as adjunct therapies to reduce LDL cholesterol in patients with (1) familial hypercholesterolemia and (2) established cardiovascular disease in 2015. Importantly, large randomized placebo-controlled trials, including the FOURIER and ODYSSEY trials, have shown remarkable reductions in the incidence of the composite clinical outcome of cardiovascular death, myocardial infarction, stroke, and hospitalization for acute coronary syndrome.^11,12 Initial concerns of neurocognitive impairment with PCSK9 inhibitors have been allayed. The clinical use of PCSK9 inhibitors has been reassuring in terms of both safety and efficacy. The primary limitations to their use are high cost and the need for twice weekly or monthly subcutaneous injections. While the reduction in annual costs from around $14,000 to $5,800 is encouraging, high co-pays and frequent need for prior authorization continue to prevent many patients from reaping the benefits of PCSK9 inhibitors.

The recent FDA approval of inclisiran (Leqvio®, Novartis) was met with enthusiasm throughout the medical community, and rightly so. Inclisiran is a novel small interfering RNA (siRNA) based therapy that blocks the synthesis of PCSK9 from the liver. The ORION trials showed a 50% reduction in LDL cholesterol levels as compared to placebo in patients with atherosclerotic cardiovascular disease on maximally tolerated statin therapy.¹³ A major advantage of inclisiran is the biannual dosing as compared with the every 2-4 week dosing with PCSK9 inhibitors. Novartis, the company behind the drug is proposing a ‘buy-and-bill’ model where the drug will be administered in the office, which will likely improve adherence.¹⁴ The convenience factor might just provide inclisiran leverage over existing therapies. Many real-world challenges still need to be addressed including long-term safety data and ensuring cost-effective and equitable distribution of this potentially life-saving drug. Despite these concerns, the approval of inclisiran is an important landmark in the field of cardiovascular disease prevention. The trajectory of PCSK9 from a newly discovered molecule to a novel siRNA-based therapy in 20 years is inspiring and reinforces the importance of basic science and translational research.\

References:

Koskinas KC, Siontis GCM, Piccolo R, et al. Effect of statins and non-statin LDL-lowering medications on cardiovascular outcomes in secondary prevention: a meta-analysis of randomized trials. Eur Heart J. 2018;39(14):1172-1180. doi:10.1093/eurheartj/ehx566
Tobert JA, Newman CB. Statin tolerability: In defence of placebo-controlled trials. Eur J Prev Cardiol. 2016;23(8):891-896. doi:10.1177/2047487315602861
Reith C, Armitage J. Management of residual risk after statin therapy. Atherosclerosis. 2016;245:161-170. doi:10.1016/j.atherosclerosis.2015.12.018
Abifadel M, Varret M, Rabès JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34(2):154-156. doi:10.1038/ng1161
Wiciński M, Żak J, Malinowski B, Popek G, Grześk G. PCSK9 signaling pathways and their potential importance in clinical practice. EPMA J. 2017;8(4):391-402. doi:10.1007/s13167-017-0106-6
Cohen JC, Boerwinkle E, Mosley TH, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354(12):1264-1272. doi:10.1056/NEJMoa054013
Handelsman Y, Lepor NE. PCSK9 Inhibitors in Lipid Management of Patients With Diabetes Mellitus and High Cardiovascular Risk: A Review. J Am Heart Assoc. 2018;7(13):e008953. doi:10.1161/JAHA.118.008953
Chan JCY, Piper DE, Cao Q, et al. A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates. Proc Natl Acad Sci U S A. 2009;106(24):9820-9825. doi:10.1073/pnas.0903849106
Stein EA, Mellis S, Yancopoulos GD, et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N Engl J Med. 2012;366(12):1108-1118. doi:10.1056/NEJMoa1105803
Dias CS, Shaywitz AJ, Wasserman SM, et al. Effects of AMG 145 on low-density lipoprotein cholesterol levels: results from 2 randomized, double-blind, placebo-controlled, ascending-dose phase 1 studies in healthy volunteers and hypercholesterolemic subjects on statins. J Am Coll Cardiol. 2012;60(19):1888-1898. doi:10.1016/j.jacc.2012.08.986
Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017;376(18):1713-1722. doi:10.1056/NEJMoa1615664
Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. N Engl J Med. 2018;379(22):2097-2107. doi:10.1056/NEJMoa1801174
Ray KK, Wright RS, Kallend D, et al. Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol. N Engl J Med. 2020;382(16):1507-1519. doi:10.1056/NEJMoa1912387
Pricey Inclisiran Is Rolling Out: a ‘Buy-and-Bill’ Model May Smooth Its Path. TCTMD.com. Accessed February 3, 2022. https://www.tctmd.com/news/pricey-inclisiran-rolling-out-buy-and-bill-model-may-smooth-its-path

“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.”

Space traveling and CVD risk: RACE to MACE

February 7, 2022February 4, 2022 Melody Chemaly, PhD

Picture Reference: https://twitter.com/glitchandgrace/status/711782004497326081 @glitchandgrace

Lately, the space race has been the talk of the town and while it might seem that we are on the verge between science-fiction and reality, there is a long way to go before humans can overcome the health hazards associated with space travel and adapt to their new environment. Humans will likely be exposed to many health hazards emerging from the “space exposome” during their journey into space. Many of these health hazards can affect the cardiovascular (CV) system.

Astronauts are required to undergo an extensive training program including engineering and paramedic courses, intensive health check and various assessments to see how they can cope under stressful conditions. From the start, there is a specific selection process to identify the most ‘fit’ of people who can qualify for space travel. However, even the most ‘fit’ of people can’t escape the health hazards that are awaiting us when we leave mother Earth.

One of the most prominent health hazards associated with long distance space travel affecting the CV system is space radiation. Space radiation usually consists of solar radiation and, the more dangerous, cosmic radiation. Among the components of cosmic radiation, the HZE ions are the most hazardous to the human body because they are highly penetrating and can even generate secondary particles when they interact with shielding materials such as spacecraft or spacesuit. Space radiation damages DNA either directly by energy absorption leading to clustered DNA damage, mutations, chromosome exchanges, carcinogenesis and apoptotic cell death, or indirectly via the production of reactive oxygen species (ROS) from the radiolysis of water molecules.

Exposure to various types of radiation can lead to radiation-induced cardiovascular disease (RICVD) which is a known complication in patients undergoing radiation therapy to treat thoracic cancers and in Japanese atomic bomb survivors. RICVD following space radiation exposure can develop acutely in the form of pericarditis or chronically leading to myocardial remodeling and fibrosis, accelerated development of atherosclerosis, cardiomyopathies, valve abnormalities, arrhythmias and conduction disorders. RICVD can also develop 10-15 years following exposure.

The number of astronauts that have surpassed the low Earth Orbit, where the space radiation amount becomes significantly higher, were only from the Apollo mission which limits the amount of data available. Therefore, several studies to investigate RICVD have been done in animal models using different types of radiations to mimic, to a certain degree, RICVD in humans. These studies have shown that ⁵⁶Fe ions, the most prominent heavy ion found in cosmic radiation, lead to cardiac hypertrophy and myocardial remodeling. In addition, people that have been exposed to higher levels of radiation compared to the general population had increased risk of myocardial infarction due to atherosclerosis. Mouse models further showed that the effects of irradiation are rather local than systemic where atherosclerosis developed in the areas which were specifically subject to irradiation using ⁵⁶Fe ions. Plaques in these mice had a thickened intima (carotid), indicating a damage to the arterial wall, and a large necrotic core (aortic root) which increases the risk of instability and thrombogenic complications. The biological processes that have been suggested to induce RICVD include endothelial dysfunction leading to a pro-inflammatory and a pro-fibrogenic environment, apoptotic cell death of various cardiovascular cell types and alterations in DNA methylation.

To date, extensive research is going into improving the shielding methods to protect astronauts from the effects of space radiation. The administration of anti-oxidants such as N-acetyl cysteine (NAC), ascorbic acid (vitamin C), vitamin B, coenzyme Q10 and vitamin E can complement the vitamin deficiencies that humans are subject to during space travel and also remove the generated ROS limiting DNA damage and protecting from space radiation exposure. Some drugs such as angiotensin converting enzyme (ACE) inhibitors and statins have also shown to reduce radiation-induced cardiopulmonary complications and radiation induced atherosclerosis in animal models respectively but need further exploration. Of note, altered DNA methylation can serve as an early biomarker for space radiation exposure and might lead to personalized treatment based on the level of altered DNA methylation after exposure. Space radiation can also increase the risk of cancer and diseases of the central nervous system such as impaired motor function, neurobehavioral changes, Alzheimer’s disease or accelerated aging which can complicate an existing CVD.

Apart from space radiation, other health hazards are also associated with space traveling. Prolonged exposure to microgravity induces bone and muscle atrophy as well as cardiovascular deconditioning. This requires humans to exercise constantly to remain healthy which could be beneficial for CV outcomes. Being confined in a closed environment, disrupted circadian rhythms and the stress for being away from mother Earth also add another layer of psychological and mental challenges to be overcome when venturing into space.

References:

Meerman M, Bracco Gartner TCL, Buikema JW, Wu SM, Siddiqi S, Bouten CVC, et al. Myocardial Disease and Long-Distance Space Travel: Solving the Radiation Problem. Front Cardiovasc Med. 2021;8:27.
Patel ZS, Brunstetter TJ, Tarver WJ, Whitmire AM, Zwart SR, Smith SM, et al. Red risks for a journey to the red planet: The highest priority human health risks for a mission to Mars. Npj Microgravity. 2020 Nov 5;6(1):1–13.
Patel S. The effects of microgravity and space radiation on cardiovascular health: From low-Earth orbit and beyond. IJC Heart Vasc. 2020 Oct 1;30:100595.
Delp MD, Charvat JM, Limoli CL, Globus RK, Ghosh P. Apollo Lunar Astronauts Show Higher Cardiovascular Disease Mortality: Possible Deep Space Radiation Effects on the Vascular Endothelium. Sci Rep. 2016 Jul 28;6(1):29901.
Glitch And Grace Art. Love #glitchandgrace #watercolour #watercolor #space #anatomical-heart #lovewins https://t.co/RIugIHw13W [Internet]. @glitchandgrace. 2016 [cited 2022 Jan 11]. Available from: https://twitter.com/glitchandgrace/status/711782004497326081

Sleep and Ideal Cardiovascular Health

February 4, 2022January 28, 2022 Ayana April Sanders, PhD

During the AHA’s Scientific Session 2021, heart health, defined by the Life’s Simple 7 metric, was often woven into health equity conversations.

Empirical evidence consistently supports AHA’s recognition of these seven risk factors that people can avoid or improve on through lifestyle changes to help achieve ideal cardiovascular health. Regardless of how challenging this goal is for the average American, Life’s Simple 7 is an essential benchmark for staying heart-healthy.

More attention is now being directed at the role of sleep in maintaining heart-healthy lifestyle practices. Sleep plays an important role in overall health and well-being. In-kind, there exists a reciprocal relationship between the quality of one’s diet, physical activity, and stress on the quality of sleep achieved. Ideally, sleep needs to be deep and restorative to support good cardiovascular health. Specifically, the Centers for Disease Control and Prevention recommend that adults between 18-65 years aim for at least seven hours of quality sleep per night. However, sleeping well is not common. 4 in 10 adults report consistently good sleep at night, and 50 million to 70 million American adults suffer from chronic sleep problems or sleep disorders.

As an early career epidemiologist, who was not too long ago a pre-doctoral candidate, I am familiar with several factors that contribute to trouble with sleep. These have included staying up late to work on an analysis or drafting a manuscript whose internal deadline was already past due; following up on emails while binging a popular streaming series and munching on some snacks; juggling a busy household with two young children that always find a reason to wake up sometime after midnight. Perhaps these experiences are relatable. Often lifestyle choices, poor sleep habits, stress, and medical conditions can play a role in why you can’t sleep.

Alcohol

A glass of wine before bed might not interfere with your ability to drift off but indulging in more servings of alcohol before bedtime may impair your sleep by interfering with your sleep cycle, especially REM sleep. This leads to fragmented, unrefreshing rest.

Poor Sleep Habits

Habits that make it harder to fall and stay asleep may include (1) staying up late, (2) watching television in bed, (3) playing or browsing on your phone in bed, (4) having an irregular sleep schedule. Simple lifestyle changes to your nightly routines could help to remedy these issues.

Bed Sharing

Whether with a partner, child, or pet, reduced sleep quality can be caused by sharing your bed. Anything that can make you uncomfortable (i.e., snores, crowding, pulled covers, or mismatched sleep condition preferences like temperature, light, or noise level) will disrupt your sleep.

Poor Sleep Environment

Sleeping environments that are too hot or too cool will disrupt your sleep. Sleep experts recommend a bedroom temperature at a moderate climate between 65 to 72 degrees Fahrenheit at night. The body needs to cool at night for the most refreshing sleep, but a too-cold room will cause you to wake up. Don’t forget about light exposure. Whether it’s from a reading lamp, television, streetlight, or even the glow from a device, this could be enough to signal your brain to wake up.

Caffeine

Some folks may argue that coffee has no effect on their ability to sleep at night and will enjoy a cup before bed. However, caffeine has a half-life of three to five hours, so even a late afternoon caffeinated beverage can disrupt your sleep later that night.

Stress

Often the events of the day that creep back into our minds at night are not the positive experiences but the ones that fill our minds with worry and stress. Stress is one of the most cited symptoms of sleep problems.

Exercise

Exercise, like an evening walk, is excellent for fostering better sleep. But intense, heart-pumping, and sweat-inducing cardio workouts within three hours of your bedtime may be too much. Both your body temperature and heart rate naturally drop as you fall asleep. Exercise stimulates your entire nervous system and raises these two body functions making it difficult to sleep.

Snack Choices

Snacks or meals high in fat or protein consumed right before bedtime can overstimulate your digestive system, cause heartburn and make it difficult to sleep. A late-night sugar rush can also lead to hunger pangs and drops in blood sugar, causing you to wake up.

Sleep Disorders and Mental Health

Importantly other factors like sleep disorders and mental health problems can make it difficult to sleep. You should talk with your doctor if you suspect that a medical or mental health condition may be contributing to your poor sleep.

Insufficient sleep and poor sleep quality, in addition to sleep disorders, are linked to a wide range of adverse health effects. Major physical and mental health consequences include anxiety, bipolar disorder, hormone imbalances, weakened immune system, cardiovascular disease, and major heart disease risk factors like obesity, inflammation, Type 2 diabetes, high blood pressure. Additionally, poor sleep is linked to overall decreased quality of life and increased mortality risk.

If good sleep habits are not currently part of your daily routine, consider some useful strategies to alleviate some of the factors that have interfered with your quality and quantity of sleep. Here in this infographic are a few tips and techniques developed by AHA to help those who do not have a sleep disorder make small daily changes to establish healthier sleep habits.

Working to alleviate factors that contribute to insufficient sleep and poor sleep quality may also be another critical metric for cardiovascular health. Preliminary findings presented at the AHA’s 2021 Epidemiology and Prevention/Lifestyle and Cardiometabolic Health Scientific Sessions recommended revising the AHA’s Life’s Simple 7 to include sleep as a metric creating a new “Simple 8 or Essential 8” metric measuring cardiovascular health. The study’s lead investigator, Nour Makarem, Ph.D., explained that while sleep is a health behavior that people engage in every day, like diet and exercise, it has received far less attention. However, increasing evidence links sleep to heart disease and risk factors for cardiovascular disease.

Along with her team of investigators, Dr. Makarem assessed whether a cardiovascular health score that includes the Life’s Simple 7 combined with sleep metrics would be more strongly associated with cardiovascular disease than the Life’s Simple 7 score. The study found that when at least one measure of sleep was added with the Life’s Simple 7 measures, the new heart health score was more strongly associated with cardiovascular disease than the traditional Life’s Simple 7. The results were compelling and showed, for example, that study participants who received seven to eight hours of sleep a night in addition to meeting Life’s Simple 7 guidelines had up to 61% lower odds of having heart disease. Those who got less than six hours of sleep scored lower for overall cardiovascular health and had a higher prevalence of overweight and obesity, Type 2 diabetes, and high blood pressure. Sleep duration and the other sleep metrics included in the study made the cardiovascular health scores more predictive of cardiovascular disease risk than the seven metrics alone.

Like several current Life’s Simple 7 measures, clocking 7-9 hours of sleep per day can be challenging. However, the traditional cardiovascular health metric may need to be revisited for a potential upgrade in providing yet another vital benchmark for predicting and promoting ideal cardiovascular health.

References:

Lloyd-Jones, Donald M., et al. “Defining and setting national goals for cardiovascular health promotion and disease reduction: the American Heart Association’s strategic Impact Goal through 2020 and beyond.”Circulation 4 (2010): 586-613.
https://www.heart.org/en/health-topics/sleep-disorders/sleep-and-heart-health
https://www.heart.org/en/news/2020/03/06/sleep-should-be-added-as-measure-of-heart-health-study-says
https://www.verywellmind.com/reasons-for-not-sleeping-well-and-how-to-fix-350760
https://www.heart.org/en/healthy-living/healthy-lifestyle/sleep/sleep-well-infographic
https://www.ahajournals.org/doi/10.1161/circ.141.suppl_1.36

Electronic Cigarette Customization Matters.

January 31, 2022January 28, 2022 Jessica Monterrosa Mena

Electronic nicotine delivery systems (ENDS) are increasingly popular as an alternative to standard ‘combustion’ cigarettes. ENDS come in a large variety of forms and offer adulterant choices that enhance the user’s experience, such as flavors, humectants, and nicotine in different concentrations. There is a common perception that vaping is a safer alternative to traditional tobacco cigarettes as the ‘smoke’ lacks tars and other toxicants found in cigarette smoke⁽¹⁾. That may be true to some extent, however the ability of users to modify ENDS, like adjusting the power wattage, changing the type of heating element, and use of e-liquids with different flavor and nicotine concentrations, will influence the amounts of toxic chemicals in the inhaled aerosol. Under normal circumstances, the vapor contains, contrary to popular opinion, some of the same toxic compounds (formaldehyde, acetaldehyde, acrolein…) that are found in CCs ⁽²⁾. The ability to add custom adulterants to the vape fluid can add to the complexity of assessing potential risks. How modifications, or customizations might contribute to health effects and the generation of harmful chemicals is a topic that deserves more attention.

Devices are usually composed of a heating element, often a disposable metal heating coil, and atomizer tanks which directly produce the vapor. The most common heating coils and atomizer units can be comprised of different metals, such as stainless teel, nickel-chromium or nichrome, Kanthal nickel, or titanium. At usual setting these all work well, however they degrade with extended use. In some devices, users can set temperatures sufficiently high that degradation products of the device hardware such as metals are aerosolized and inhaled along with the vaporized e-liquid containing nicotine, flavoring, and solvents ⁽³⁾. Environmental metal contaminants are known risk factors for cardiovascular disease. Users of eC devices could inadvertently select vaping profiles that promote chemical reactions with the normally low-toxicity e-liquid to generate harmful chemicals in the aerosol they are inhaling at levels even exceeding traditional cigarettes.

Many studies have already brought insight into how device settings can generate levels of metals in inhaled aerosol that are unique to the modifiable aspects of eC devices. One study found increased concentrations of metals such as arsenic (As), chromium (Cr), copper (Cu), iron (Fe), manganese (Mn), nickel (Ni), lead (Pb), antimony (Sb), tin (Sn), and zinc (Zn) concentrations in eC aerosols when the device power is increased from low (20 Watts) to intermediate (40 Watts) settings ⁽⁴⁾. These exposure levels to metals like Ni from ENDS could exceed those of traditional reference cigarettes. It is interesting to note that ENDS from different manufactures emit different concentrations of metals, suggesting that heating and cooling patterns of individual devices could influence the amount of metals released. A similar study also found higher metal levels in aerosol and e-liquid after it comes in contact with the metal heating coil, compared to the original e-liquid in the dispenser vial ⁽⁵⁾. Elevated levels of metal biomarkers such as Cu, Cr, Sn, and Pb were found in the urine of electronic cigarette users. These studies highlight the need to further study how the unique customizable aspects of ENDS technology contribute to the formation of varying levels of contaminants in the inhaled aerosol. There is no question that smoking is a risk factor for cardiovascular disease and can increase blood pressure, heart rate, among other health outcomes. Educating the public about the health burden that ENDS pose and informing users about the potential dangers of vaping at elevated temperatures or using degraded heating components can be a step towards reducing use of new tobacco products.

References:

Benowitz, N. L., & Burbank, A. D. (2016). Cardiovascular toxicity of nicotine: Implications for electronic cigarette use. Trends in cardiovascular medicine, 26(6), 515–523. https://doi.org/10.1016/j.tcm.2016.03.001
Perraud, V., M.J. Lawler, K.T. Malecha, R.M. Johnson, D.A. Herman, N. Staimer et al.: Chemical characterization of nanoparticles and volatiles present in mainstream hookah smoke. Aerosol Science and Technology 53(9): 1023-1039 (2019)
Wylie, B. J., Hauptman, M., Hacker, M. R., & Hawkins, S. S. (2021). Understanding Rising Electronic Cigarette Use. Obstetrics and gynecology, 137(3), 521–527. https://doi.org/10.1097/AOG.0000000000004282
Zhao, D., Navas-Acien, A., Ilievski, V., Slavkovich, V., Olmedo, P., Adria-Mora, B., Domingo-Relloso, A., Aherrera, A., Kleiman, N. J., Rule, A. M., & Hilpert, M. (2019). Metal concentrations in electronic cigarette aerosol: Effect of open-system and closed-system devices and power settings. Environmental research, 174, 125–134. https://doi.org/10.1016/j.envres.2019.04.003
Olmedo, P., Rodrigo, L., Grau-Pérez, M., Hilpert, M., Navas-Acién, A., Téllez-Plaza, M., Pla, A., & Gil, F. (2021). Metal exposure and biomarker levels among e-cigarette users in Spain. Environmental research, 202, 111667. Advance online publication. https://doi.org/10.1016/j.envres.2021.111667
Bhatnagar A, Whitsel LP, Blaha MJ, Huffman MD, Krishan-Sarin S, Maa J, Rigotti N, Robertson RM, Warner JJ; on behalf of the American Heart Association. New and emerging tobacco products and the nicotine endgame: the role of robust regulation and comprehensive tobacco control and prevention: a presidential advisory from the American Heart Association. 2019;139:e937–e958. doi: 10.1161/CIR.0000000000000669.

Zooming In: The Impact of the COVID-19 Pandemic on PhD Interviews

January 28, 2022January 21, 2022 Khairunnisa Semesta, MA

The COVID-19 pandemic has brought significant changes to multiple layers of academia, including the biological and biomedical sciences PhD admissions process in the United States. Typically, prospective applicants are selected to interview in-person at the destination campus not only as a part of the evaluation process, but also as an opportunity for the applicants to gauge program fit. The travel disruptions caused by the pandemic put this opportunity on hold in 2020, and for many programs, lasted into the 2021 admissions cycle. As such, many programs opted for virtual interviews instead.

Rama Alhariri, a PhD student in the Human Genetics and Molecular Biology program at Johns Hopkins University, was unable to visit the universities she applied to when she was choosing PhD programs in 2020. All her interview processes took place virtually. Although there was slight variation in the format, she had an opportunity to talk to current students and faculty members about their research interests and the PhD program in general. In addition to the interviews, her virtual programs included sessions introduce applicants to the university and the city itself, such as a panel session about things to do in the area and a live virtual tour of the program. However, this experience did not quite resemble the in-person visits.

“I would’ve liked a higher quality of the tour of facilities as some programs lacked that altogether or it was a little unclear. Additionally, I would’ve liked a greater interaction with other interviewees without the presence of upper-class students or faculty so that we can get to know one another better, the way we might if we were in an in-person interview. It is unfortunate because it’s these interactions that also shape how well you might integrate with other students,” she added.

When asked about how she gauged the fit of the PhD program, Alhariri said that she tried to focus on her interactions with the students, faculty, and other interviewees. From these conversations, she was able to get a glimpse into the campus culture and the overall level of formality and professionalism among the faculty members and students.

“Ultimately the program I chose, while it was also the highest ranking one, was the one in which I felt most comfortable with the upper-class students as well as those that could potentially be within my cohort. I sought an environment with a good balance between professional and somewhat relaxed, which would be the best fit for me.”

Although virtual interviews have become more common in the PhD admissions process in the past two year, they are not new. International students who reside in other countries, for example, typically have limited opportunities to travel due to visa issues and a lack of financial reimbursement for long-distance travel. When I was choosing a PhD program to commit to in 2018, I was finishing up my undergraduate studies outside of the United States. Because of that, my campus visits were limited to places that I could afford flying to. Additionally, my virtual interviews were limited to conversations with faculty members, which was not enough to give me a comprehensive picture.

Alhariri shared a few tips for current applicants who are unable to visit campuses in-person, “It’s hard to make a decision on what program you want to choose based off limited virtual interactions. I say trust your gut and try to support your intuition with evidence. I obtained information about living in the city through online searching. Because faith is important to me, I also checked social media sites of the Muslim student faith group – I wanted to know that there was a large enough Muslim community within the city and even within the university at large, not limited to just my program.”

Ultimately, completing a PhD is a long-term commitment, and the decision making to commit to a program looks different from person to person. Self-introspection can help a lot in this case: what is important for you? Will the environment nurture your academic curiosity? Do you like the idea of living in the area for several years? Based on my own experience of interviewing virtually, I would suggest doing the following things. First, try to talk to as many people in the PhD program as you can. Do not hesitate to ask to be connected to faculty members you are interested in working with and current students to get more information about the culture of the university. Second, try to connect with previous applicants who ended up choosing a different program to understand their perspectives and add information to your decision making. Lastly, if you are moving to a new environment, do some research about the area itself – including cost of living and things to do beyond academic work – to ensure that you will adapt well.

A Scientific Statement from the American Heart Association on the Management of Cardiovascular Risk Factors for Adults with Type 2 Diabetes

January 26, 2022January 21, 2022 Gaganpreet Kaur

The prevalence of diabetes is increasing at an alarming rate, with more than 34 million Americans suffering from diabetes¹. Patients with type 2 diabetes make up 90% to 95% of total diabetes cases¹. Cardiovascular diseases (CVD) are the principal cause of death and disability in type 1 and type 2 diabetes patients². American Heart Association (AHA) recommends a comprehensive and patient-centered approach involving lifestyle management and pharmacological interventions to manage cardiovascular risk factors, such as smoking, obesity, glycemia, blood pressure (BP), and lipid abnormalities, in type 2 diabetes patients³.

A healthy lifestyle can substantially lower the risk of CVD events in type 2 diabetic patients. Lifestyle management involves physical activity, nutrition, psychological and emotional well-being, and smoking cessation³. The lifestyle interventions using meal replacement products and at least 175 minutes of moderate-intensity physical activity /week, with a calorie goal of 1200 to 1800 kcal per day (with <30% from fat and >15% from protein), resulted in weight loss and hemoglobin A1c. Individuals with either ≥10% reduction in their body weight or >2 metabolic equivalent increase in fitness experienced reductions in cardiovascular outcomes; however, the rate of a major adverse cardiovascular event (MACE) was not reduced⁴. Mediterranean, vegetarian, low-carbohydrate, and diets rich in protein and nuts can lower blood glucose and body weight in type 2 diabetes patients³. Mediterranean diet over 4.8 years exhibited the highest benefits in blood glucose regulation and 29% of CVD events^3,5. Further, increased exercise and physical activity can improve blood glucose, blood pressure, insulin sensitivity, lipid profile, and inflammation in type 2 diabetes³. American Diabetes Association (ADA) has recommended more than recommends ≥150 minutes/week of moderate-to-vigorous intensity aerobic activity with no more than 2 days of inactivity in diabetes patients^3,6. Including 2-3 sessions/week each of resistance and balance training is also recommended. Further, vigorous activity for a short duration (>75 minutes/week) or interval training is beneficial^3,7. Patients with BMI ≥27 kg/m2 can use US Food and Drug Administration (FDA) approved weight loss medication. Orlistat, lorcaserin, liraglutide, naltrexone/bupropion are some of the weight management drugs approved by FDA have demonstrated ability to lower A1c³. Liraglutide at a lower dose can reduce cardiovascular risk in high-risk patients⁸. However, medicines should be immediately stopped if weight loss after 3 months is less than 5% or any safety concerns arise. Patients with BMI ≥40 kg/m2 or BMI 35.0 to 39.9 kg/m2 with no benefit with nonsurgical methods can consider metabolic surgery³. The long-term effects of weight-loss drugs and metabolic surgery on reducing cardiovascular events are yet to be studied.

Smoking is linked with abnormal lipid profile, worsening of glycemic measures, and increased pro-inflammatory marker in type 2 diabetes. Therefore, cessation of smoking is recommended³. Interestingly, light to moderate alcohol consumption compared to no drinking, particularly wine, has been associated with fewer heart attacks, whereas heavy alcohol consumption increases CVD risk³. Despite the benefits of moderate alcohol intake, non-drinks should not be advised to drink, and adults with diabetes should be mindful of the risk of hypoglycemia, weight gain, and hypertension. No more than 1 drink/day for women and 2 drinks/day for men are recommended³. In America, 12-ounce beer or 5-ounce wine, or 1.5 ounces of distilled spirits are considered as one drink.

In addition to lifestyle management, intensive glycemic control can be valuable to prevent cardiovascular disease events in diabetes patients. Randomized trials involving intensive glucose control using insulin reported a 17% reduction in myocardial infarction (MI), 15% reduction in coronary heart disease, 16% reduction in nonfatal MI, but no effect on stroke or all-cause mortality³. However, tight glucose control increases the two-fold risk of severe hypoglycemia and 47% risk of heart failure³. The research involving intensive glucose control using new anti-hyperglycemic agents is undergoing. Some newer agents are Dipeptidyl peptidase-4 (DPP4) inhibitors, GLP-1 receptor agonists, and sodium-glucose cotransporter-2 (SGLT-2) inhibitors. DPP4 inhibitors inhibit the DPP4 enzyme, thereby prolonging the action of incretin hormone GLP-1 and insulinotropic polypeptide, which ultimately results in increased insulin secretion and lower glucose. DPP4 inhibitors agents successfully lowered A1C but showed no reduction in MACE, and one of the agents was associated with an increased risk of heart failure³. GLP-1 receptor agonist stimulates insulin release and slows down gastric emptying to decrease glucose absorption. The intervention with GLP-1 receptor agonists resulted in a significant reduction in MACE, heart attack, stroke, and cardiovascular death; however, it had no beneficial effect on heart failure. The use of GLP-1 receptor agonists is associated with increased heart rate, pancreatitis, pancreatic cancer, thyroid cancer, and retinopathy. SGLT-2 inhibitors limit glucose reabsorption in the renal tubules³. SGLT-2 inhibitors lower the risk of hypertensive heart failure by 27-35%, MACE BY 11%, heart attacks by 11%, and cardiovascular death by 16%. SGLT-2 inhibitors are associated with genital and urinary infections, polyuria, acute kidney injury (with a higher dose), and reduction in bone mineral density³.

CVD risk increases with low and high blood pressure in patients with type 2 diabetes. When initiated at baseline (BP > 140/90 mmHg), Antihypertensive therapy resulted in CVD risk reduction but did not have a robust effect in type 2 diabetes patients compared to patients without diabetes³. ADA does not recommend a specific BP target but suggests risk classification to avoid overtreatment and polypharmacy³. In addition to BP abnormalities, an altered lipid profile is also a central risk factor for CVD in diabetes. The most common lipid abnormalities encountered in diabetes include:

Increased serum triglycerides.
Triglyceride-rich, very-low-density lipoprotein.
Mild increase in small dense low-density lipoprotein cholesterol (LDL-C).
Decreased HDL-C.

The lipid therapies include lowering LDL with statin/ non-statin, lowering triglycerides, and increasing HDL. Statin therapies reduce cardiovascular risk by 25%⁹, but HDL raising therapies had no effect³.

Lastly, clinical care only accounts for 10-20% of health outcomes; the rest 80-90% is contributed by social determinants, including socioeconomic factors, racism, environment, and individual behavior³. Therefore, we need a multifaced approach to address social determinants to eliminate disparities in CVD health. AHA recommends using a patient-centered approach and considering the patient’s family, community, and society while planning their cardiovascular risk management³. ADA and AHA have initiated a “Know Diabetes by Heart” program to improve CVD and outpatient care of type 2 diabetes patients. The program raises awareness about the link between diabetes and CVD, supports clinicians in patient engagement, and empowers patients³.

Reference

National Diabetes Statistics Report. Accessed January 14, 2022. https://www.cdc.gov/diabetes/data/statistics-report/index.html
Cheng YJ, Imperatore G, Geiss LS, et al. Trends and Disparities in Cardiovascular Mortality Among U.S. Adults With and Without Self-Reported Diabetes, 1988-2015. Diabetes Care. 11 2018;41(11):2306-2315. doi:10.2337/dc18-0831
Joseph JJ, Deedwania P, Acharya T, et al. Comprehensive Management of Cardiovascular Risk Factors for Adults With Type 2 Diabetes: A Scientific Statement From the American Heart Association. Circulation. Jan 10 2022:CIR0000000000001040. doi:10.1161/CIR.0000000000001040
Fox CS, Golden SH, Anderson C, et al. Update on Prevention of Cardiovascular Disease in Adults With Type 2 Diabetes Mellitus in Light of Recent Evidence: A Scientific Statement From the American Heart Association and the American Diabetes Association. Circulation. Aug 25 2015;132(8):691-718. doi:10.1161/CIR.0000000000000230
Esposito K, Maiorino MI, Bellastella G, Chiodini P, Panagiotakos D, Giugliano D. A journey into a Mediterranean diet and type 2 diabetes: a systematic review with meta-analyses. BMJ Open. Aug 10 2015;5(8):e008222. doi:10.1136/bmjopen-2015-008222
Association AD. 5. Facilitating Behavior Change and Well-being to Improve Health Outcomes:. Diabetes Care. 01 2020;43(Suppl 1):S48-S65. doi:10.2337/dc20-S005
Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 09 10 2019;140(11):e596-e646. doi:10.1161/CIR.0000000000000678
Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 07 28 2016;375(4):311-22. doi:10.1056/NEJMoa1603827
de Vries FM, Denig P, Pouwels KB, Postma MJ, Hak E. Primary prevention of major cardiovascular and cerebrovascular events with statins in diabetic patients: a meta-analysis. Drugs. Dec 24 2012;72(18):2365-73. doi:10.2165/11638240-000000000-00000

Elevated Lipoprotein A, are we ready to intervene?

January 19, 2022January 11, 2022 Reza Mohebi, MD

Lipid abnormalities can be classified into four clinical groups:1) elevated triglycerides, 2) low high-density lipoprotein cholesterol (HDL-C),3) elevated low-density lipoprotein cholesterol (LDL-C), and 4) elevated lipoprotein A. Lipoprotein A disorder has been the least lipid abnormality studied from a clinical standpoint. Although many mendelian and genome-wide association studies have shown an association between elevated lipoprotein A and risk of incident atherosclerotic cardiovascular disease (ASCVD), the causality relationship still lacks the final corroboration of a randomized Lp(a) lowering intervention clinical trial¹.

In 1963, for the first time, Kare Berg described the existence of Lp(a). Lp(a) consisted of apolipoprotein (a) bound to apolipoprotein B-100, an apolipoprotein also found on LDL-C particles. Distinct from other lipoproteins greatly affected by diet and genetics, Lp (a) is determined by more than 90% by individuals’ genetics. Lp(a) is synthesized in hepatocytes and is released into blood circulation. Plasma concentrations of Lp(a) are inversely associated with the size of apolipoprotein(a). It is postulated that small isoforms can be synthesized faster than large ones, and apolipoprotein(a) size can account for up to 70% influence on Lp(a) blood concentration. Other known factors include single nucleotide polymorphisms, sex hormones, inflammatory mediators, and dietary factors².

Many medications have been tested to lower Lp(a) concentration. A large-scale meta-analysis of 5,256 patients (1,371 on placebo and 3,885 on statin) enrolled in a randomized clinical trial showed that most statins significantly increase Lp(a) concentration by 8-24%³. Niacin may lower Lp(a) concentration by 20-30%. However, studies did not show any significant reduction in risk of ASCVD event, once niacin was added to the medication list of patients already receiving a statin. Estrogen can also lower Lp(a) concentration by 20%; however, the usage is limited due to concern about increasing the risk of thrombotic events. Proprotein convertase subtilisin Kexin type 9 inhibitors (PCSK9 inhibitors) have been shown to lower Lp(a) concentrations. In 2 major PCSK-9 inhibitors clinical trials- FOURIER and ODYSSEY OUTCOME- the fourth quartile of Lp(a) in the treatment arm was associated with a 25% increase risk of major adverse cardiovascular events. This implies the presence of residual risk of ASCVD despite very low LDL-C⁴. In a recent sub-analysis of ODYSSEY OUTCOME trial, alirocumab reduced Lp(a) concentration. Each 5mg/dl decrease in Lp(a) by alirocumab resulted in a 2.5% reduction in risk of cardiovascular events⁵. It should be noted that none of the above medications have primarily been initially designed to test the hypotheses of the beneficial effect of medication on Lp(a) concentration.

Genetic studies have shed light on the role of each allele on Lp(a) concentrations and have provided a base for pharmacological intervention. Antisense oligonucleotides (ASO) have revolutionized the treatment of Lp(a). ASOs are short DNA fragments designed complementary for a target messenger RNA. LPA gene transcribes the two alleles of apolipoprotein(a) mRNA. ASO like Pelacarsen binds to the mRNA and generates the mRNA-ASO complex. Hepatocytes recognized this complex as foreign objects, and RNase H1 cleaves the sense strand. Four clinical trials have been conducted to assess the efficacy of ASOs to lower Lp(a) concentrations. All the clinical trials have shown promising results, from 40% to up to 90% reduction in Lp(a) depending on the type of ASO, dosage, and frequency of administrations⁶.

Currently, the pivotal phase 3 of Lp(a)HORIZON⁷ (ClinicalTrials.gov Identifier: NCT04023552) randomized controlled trial is enrolling up to 8280 individuals, aged >18 years with Lp(a) ≥ 70 mg/dl and with a history of myocardial infarction, ischemic stroke, or symptomatic peripheral artery disease. Participants are double blindly randomized to receive TQJ230 80 mg injected monthly subcutaneously or placebo and will be followed for the primary outcome of MACE (CV death, non-fatal MI, non-fatal stroke, and urgent coronary revascularization). The estimated primary completion date is May 29, 2025. So, we need to be patient and wait to see if the causal relationship between Lp(a) and ASCVD will be established by 2025.

References:

Miksenas H, Januzzi JL, Jr. and Natarajan P. Lipoprotein(a) and Cardiovascular Diseases. JAMA. 2021;326:352-353.
Tsimikas S. A Test in Context: Lipoprotein(a): Diagnosis, Prognosis, Controversies, and Emerging Therapies. J Am Coll Cardiol. 2017;69:692-711.
Tsimikas S, Gordts P, Nora C, Yeang C and Witztum JL. Statin therapy increases lipoprotein(a) levels. Eur Heart J. 2020;41:2275-2284.
Ruscica M, Greco MF, Ferri N and Corsini A. Lipoprotein(a) and PCSK9 inhibition: clinical evidence. Eur Heart J Suppl. 2020;22:L53-L56.
Szarek M, Bittner VA, Aylward P, Baccara-Dinet M, Bhatt DL, Diaz R, Fras Z, Goodman SG, Halvorsen S, Harrington RA, Jukema JW, Moriarty PM, Pordy R, Ray KK, Sinnaeve P, Tsimikas S, Vogel R, White HD, Zahger D, Zeiher AM, Steg PG, Schwartz GG and Investigators OO. Lipoprotein(a) lowering by alirocumab reduces the total burden of cardiovascular events independent of low-density lipoprotein cholesterol lowering: ODYSSEY OUTCOMES trial. Eur Heart J. 2020;41:4245-4255.
Tsimikas S, Moriarty PM and Stroes ES. Emerging RNA Therapeutics to Lower Blood Levels of Lp(a): JACC Focus Seminar 2/4. J Am Coll Cardiol. 2021;77:1576-1589.
Assessing the Impact of Lipoprotein (a) Lowering With TQJ230 on Major Cardiovascular Events in Patients With CVD (Lp(a)HORIZON). https://clinicaltrialsgov/ct2/show/NCT04023552. 2019.