The New England Journal of Medicine (NEJM) the premier journal in medicine originated two centuries ago, in 1811, when John Collins Warren, a Boston physician, along with James Jackson, submitted a formal prospectus to establish the New England Journal of Medicine and Surgery and Collateral Branches of Science as a medical and philosophical journal.
Subsequently, the Massachusetts Medical Society (MMS) purchased the Journal for US$1 and, in 1928, renamed it to The New England Journal of Medicine.
NEJM’s New Journey
It is 2022, after 200 years of providing explosive knowledge in medical science, MMS starts a new journal, fresh and bold. It is called NEJM Evidence. Can you guess, what is the need for such a journal now? I think the most battered word in science in current times is probably “ evidence”. It has a unique character of appearing most sacred as well as scandalous at the same time.
NEJM has remained the torchbearer of almost all advances in the medical field seen in the last two centuries. It is heartening to note the newborn is named as NEJM evidence. It has come at a critical juncture. I am sure, everyone will acknowledge that we are at difficult crossroads. Overwhelmed with unregulated scientific discoveries and publications, struggling to deal with self-inflicted knowledge pandemic. In the process, we have lost “not only” the ability to ignore trivial health issues “but also” failed to provide simple, cost-effective care to the real patients who desperately need it.
Let us hope, (& wish,) NEJM’s new prodigy will guide medical science towards a successful, meaningful, and ethically fulfilling journey for mankind. Meanwhile, let us pray for every medical scientist to be blessed with the required strength and courage to steer in the right direction, weeding off both academic and non-academic contaminants.
What is in store for the future of cardiology as of 2022?
Here is one of the rare lectures (A grand rounds by Houston Methodist) by legendary cardiologist Dr. Euegne Braunwald who shares his wisdom, vision, and research and finally his advice for the generation next cardiologist.
For those, who are short of time to listen to the father of modern-day cardiology, let me share a preview. The talk is divided into 6 subsets.
Polygenic risk score (PRS) Dr. Braunwald talks about how genetic risk profiling and risk factor interaction will help us identify susceptible populations. Here, he stresses also the importance of clinical risk assessment.
Primordial prevention of CAD:
Anti-lipid strategies:
He introduces a new concept of Cumulative LDL score & CHD threshold. Dr. Braunwald argues rigorous lipid control should go beyond statins and suggest once a year Injection Inclisiran(Small interfering RNA that prevents PCSK synthesis) will reset the lipids levels by 40% and prolong life by 30 years.
Anti -Inflammatory strategies: He reminds us Atherosclerosis is equally an inflammatory disease and new anti-inflammatory drugs like Canakinumab’s role could be vital.
Artificial Intelligence: Will be the guiding force in the future of preventive cardiology, as well as treatment. He tells us predicting Atrial fibrillation and even LV function from the resting ECG is possible.
Clonal hematopoiesis independent potential (CHIP) is a new risk factor by somatic mutations in leukocytes that accelerate atherosclerosis proven by canonical risk predicting models
It was a great one hour to spend on a Sunday, under Covid Lockdown. However, It was a surprise, the biggest Innovation in cardiology in the last century, PCI, and other exotic coronary and noncoronary interventions could not find a place in his one-hour lecture. I think there is a hidden message here.
He signs off with some important advice for the generation next cardiologist.
Here is a case report from Dr. Brugada’s group. What is your diagnosis?
Source & Courtesy Sergio Richter, Joseph Brugada et all , 100(1), 154–156. doi:10.1016/j.amjcard.2007.02.067
Whoever diagnosed AF in the above ECG need not feel bad. The rhythm is not AF, though it mimics very closely. In cardiology, especially in electrophysiology, we can get surprises on a daily basis. (Read below)
Why the ventricular rate is irregular in AF?
Atrial fibrillation (AF) may sound like a simple clinical arrhythmia until we ask this delicate question. The traditional and fairly accepted answer is that, AV node with all its collective decremental property filters the incoming atrial impulses (Which varies 400-600/mt) in a random fashion and allows only about 1/3rd of impulses. So, technically it is AV block of various degrees that makes the ventricular response irregular.
Any other explanation possible?
How about AV node playing out a silent game with Atria, deciding to block everything and start its own fast escape rhythm, rather than leaking out selectively atrial impulses. Some think this is fictional, some others feel it can be real too. When this happens it can be referred to as irregular junctional tachycardia or AF with varying AV blocks. It has been tough, to prove it is only the atrial impulses penetrating through the AV node complex and exiting on the ventricular side unscathed?
Understanding AV node is not easy
AV node morphology and function still remain a mystery.( Katritsis DG. Arrhythm Electrophysiol Rev. 2020)The AV node shows huge variation in its size, shape, orientation with LV long axis and AV plane in short axis. The approach to slow pathways with multiple inferior nodal extensions makes a dual (or even poly ) AV pathway in any human being real. How common is dualism or multilateralism within the AV node in the general population? (More than 30-40 % ?) . Let us also mind the traffic in this busy & complex AV flyover can change on a moment-to-moment basis based on neurohormonal and autonomic tone.
Any tachycardia can become irregular if the AV node wishes so !
Though rare ,multiple physiological splits in the AV node make it possible for a single atrial impulse can generate 2 or 3, even more, ventricular impulses. (1: 2 or 3 AV conduction) Since these pathways are dynamic they can make the ventricular response irregular as well (Unlike the regularly coupled Echo beats in classical AVNRT substrate ). Hence, any supraventricular tachycardia can masquerade as AF if AV nodal pathways decide to split and share the impulses this way. It is also interesting to note there has been a documented link between AVNRT and AF (.Ref 2) . Also, adenosine-induced AF is known (James E. Ip et al Circulation: Arrhythmia and Electrophysiology. 2013;6:e34–e37)
Final message
Irregular RR interval with absent/or invisible P waves is not always AF. It can be due to the aberrant behavior of the AV node.( anatomical or functional) It is termed Pseudo Atrial fibrillation as in the above case report. Why do we need to be aware of this entity? We need to be cautious, as any overzealous efforts to ablate the pulmonary veins in such patients will go in vain.
A 5-minute session: Answers are my own. Please cross-check.
1. Is Brugada syndrome clinical or ECG diagnosis?
Always clinical. Never get confused on this.
2. Spontaneous type 1 vs Induced Type 1 (from type 2) which carries more risk?
Both are risky since they are close cousins. But, spontaneous type 1 is the dreaded devil.
3. Is Brugada primarily a defect of myocardial depolarization or repolarisation?
Not clear. Often in both. In fact a mismatch between them. (Don’t ask how Na+ Channel defect affects repolarisation !)
4. Is Brugada VT is monomorphic, polymorphic?
Both. What determines morphology is not clear though. (All de-nova monomorphic VT will degenerate to polymorphic en route to cardiac arrest)
5. Should Fever induced Brugada pattern be investigated further?
Better, it is not to be reported in ECG. May not be important in the majority if there is no adverse family history. (If the patient is well educated and afflicted by Dr.Google and cardiologists can’t escape from ordering sophisticated tests)
6. What is the overlap between ERS and Brugada?
It is all about the Idiosyncrasy of the K+ channel phenotypes ( Transmural dispersion heterogeneity )
7. Is a benign Brugada better than a malignant ERS?
Yes, it would seem so. (Inferior or Infero -lateral ERS prone for primary VF in case they develop ischemic / ? also non-ischemic stress)
8. How important is the link between Brugada and Long QT 3 syndrome?
A rare entity, but It is double jeopardy for VT risk. The entire action potential width is vulnerable right from phase 0 to 3 or 4 A case report Sandhu A Clin Case Rep. 2017;5(8):1315-1319.
9. Is Amiodarone really contraindicated in VT?
Not really. Though Amiodarone unmasks Brugada, it can still be used during episodes of VT in patients with manifest or unmanifest Brugada. Maybe in Long QT 3 overlap, it may perpetuate the VT.
10. How important is the structural myocardial defect in Brugada?
Not important in the majority. Though localized RVOT abnormalities are noted in some..RV abaltion can be succesful in odd case.
11. What happens to the ST segment in Brugada during exercise stress?
Obviously not. But, definitely life-saving in high-risk survivors. I guess definitive therapy is possible for future generations through the science of genetic reprogramming of Na+ channels. (Of course, our planet shouldn’t succumb to man-made climatic arrhythmia, by then )
14. Does widespread genetic testing & screening of families help in the management and reduce anxiety?
Cracking the genomic code of cardiac ion channels is the ultimate sophistication (Blueprint of fate ?) However, there is no guarantee this information is going to ease out the family members who harbor a genocopy with or without a phenocopy.
15. Is Brugada getting undue attention in cardiology literature compared to many other common arrhythmias?
Yes sir, It was acute decompensated LV failure, Patient was in impending pulmonary edema. In fact, he developed. He is fine now,
How did he come around? He was too sick I thought.
“Just pushed 60 mg Frusemide IV, luckily he also had good BP, so with an infusion of NTG, titrated Carvedilol a little bit, he came out nicely. I guess it is Ischemic DCM”.
“Good, You have done a nice job”
“Don’t make me embarrassed sir. It is such a routine in our ER.
To make him curious, I asked “Which drug do you think that saved him”?
“Obviously, Frusemide sir. He was frothing out. I thought he will require a ventilator. It was a matter of 20 minutes, sort of flushing out 500 ml lung fluid through the urine”.
“No, you are wrong. As a professor and cardiologist, I need to tell you this. Diuretics never save lives heart failure.
Sir, I guess, you are not kidding. Does this statement apply to acute heart failure? We have saved 100s of lives with Frusemide, both in acute, acute on chronic, and even in chronic cardiac failures with metolazone.
Hmmm, I agree with you my dear student, Frusemide has saved not hundreds but lakhs of lives in the past decades in all forms of heart failure. It continues to do this fabulous job even now. But, don’t say it in exams or scientific forums. It has no evidence to show survival benefits. You can’t credit a drug without evidence. Also realize, saving lives by unscientific means by a cheap generic is not something to boast upon. We need the blessings of RCTs, or Kaplans Mayer curves, or Forrest blobbograms. Unfortunately . that is the current principle of practice of medicine.
But sir, who is preventing whom, to do such studies. Why they are not comparing diuretics one to one with these modern drugs of inotropes, calcium modulators, or SGLTis, etc?
I am not sure. My guess is, there are no good friends in the cardiac failure research community for this old warrior drug.
Loop diuretics
Till 1960s, toxic mercurial compunds was the only option to drain water in heart failures. The Invention of Na+/K+ /Cl channel blocker Frusemide, ( In the thick ascending limb of the loop of Henle) is the single most important event, that changed the way we manage cardiac failure in both acute and chronic settings. Still, the current evidence creators hesitate to call it a life-saving drug,
The meteoric rise of SGLT-2 Inhibitors
Meanwhile, a few micrometers down the hairpin bend of Henle, drugs called phlorizin are doing wonders. These Apple root barks derivatives were since been invaded by Glyflozins Industry. They are made into a powerful glycosuric drug that drags water out of the system along with glucose. This seems to be the biggest revolution in cardiac pharmacology ever since DaVinci drew the heart and Harvey made it functional. I think we need a supercomputer to count the number of papers and analyze the data from Dapa & Empaglyflosin. It is now concluded officially, as an evidence-based life saver in HF.
I asked one Gen X Pharma-geek, “How do these magic drugs perform this miracle in heart failure”? He said beamingly, It is not merely Glyco-diuresis, as you academicians think, it is some mystery action from heaven, still not decoded. What a revelation I thought.
Continuing Medical Education: Choosing the correct path is never easy!
Final message
Loop diuretics are powerful drugs that aid the failing heart to reduce both pre and after-load. It is a fact, indiscriminate use of these drugs leads to some electrolytes and metabolic issues. But, hiding behind a hazy and shaky evidence base, and trying to ridicule these life-sustaining drugs, is the height of senselessness in cardiac failure literature.
Reference
(There is a tug of war of evidence between benefits and risks. I guess someone will bring out the truth, which is written clearly on the walls)
It is to be noted,Eplerenone (EPHESUS trial ) & Finerinone (FIDELIO-DKD trial) are new generation K + sparing diuretics and mineralocorticoid antagonists may have better cardioprotection in cardiac failure.(Part of RAAS blockade)
Recognizing the clinical importance of AF and the need to rule out a systemic cause is the key, Further, a genuine bedside debate about the pros and cons of simple vs aggressive treatment discussion is welcome.
The nomenclature issue of valvular vs non-valvular has finally seemed to have settled. The latter is banished for good reason. (Funny to note Aortic valve was considered as not a valve for so long !)
The rate vs rhythm control debate still favors the former. (AFFIRM/RACE)
Stroke prevention is the concern & anticoagulation is the mainstay. OAC/DAPT /triple therapy has evolved a little more in the last decade. Though stoke is a major concern, we rarely see neurologists & cardiologists debate closely on risk profiling issues of such patients. (at least in this part of the world.)
Whether we have conquered AF or not we have become experts in creating an unlimited number of bleeding risk scores. Understanding and applying them at the bedside need specialmemory and expertise.
On the combative front, ablation strategies, however, advanced they look, are vested with the risk of injuring the surrounding structures. My biased opinion is that the risks are prohibitive except in very refractory and troublesome AFs. (with all these 4D, contact, cryo, etc) Recall the CABANA study. We are beginning to understand, the true embryological face of pulmonary veins insertion points is so variable, and residual sleeves are very rampant that will sustain the AF even after an apparently successful ablation.
LAA appendage closure studies again don’t look rosy as the device itself is prone to thrombus at least in the early periprocedural period. (Watchman requires more security and protection than the Inmates !)
Final message
AF is a simple arrhythmia in 9/10 patients. Please, let us not complicate it. We must ensure, systemic and non-permanent forms of AF should not drain our cardiac resources. We shall follow basic principles of managing a cardiac arrhythmia that will suffice in the majority. An occasional patient needs to be referred to an EP specialist.
If anyone asks to shortlist the best papers that were, ever published in clinical cardiology, I am sure, this one will reach the top ten. It was 1979, the field of cardiology is just waiting to explode. CAD was managed primarily with drugs and occasional CABGs. Coronary angiograms were an academic luxury. Both thrombolysis and PCI were unknown. Fortunately, Clinical cardiology was still alive and kicking. Dr. George Diamond and Dr. James Forrester from Cedars Sinai, New York worked together to bring this masterpiece. How and when to suspect CAD in the general population? For the first time probability was applied as a diagnostic tool.
The paper begins by analysing basic clinical symptoms, risk factors, then gradually dwell deep into the population-based likelihood ratio, of CAD with the help of stress ECG, Thallium, and fluoroscopic coronary calcium. It finally ends up with a magical fusion of the Bayesian theorem into clinical medicine. It essentially taught us how to accrue scattered knowledge, clinical judgment, and diagnostic acumen among physicians in a community and aggregate them to a powerful statistical evidence base.
A popular Inference from the DK model still asked in cardiology boards
It’s more than four decades since this paper was published. There have been some concerns about DF classification in the current era. It was compared with the new Duke risk and found to be less valuable in the low-risk CAD population.(Wasfy MM, et all AJC 2011) The concept of pre-test probability deciding the diagnostic value of screening tests is very much valid. We need to recalibrate the DF scale for the current population and new generation screening methods like MDCT etc..(Gibbons et al Jamanetwork 2021 )
Forget the pros and cons, DF study told us the importance of clinical judgment in the decision making process. Now, we are living in a glamorous new world of cardiology. Cath labs have become our 24/7 office suits, always in hot pursuit for instant fix solutions. Still, we often find ourselves desperately blinking at the doors of EBM, for the elusive answers to some critical queries. Why the same intervention seems to work in one large study and totally go wanting in another? (MITRA-FR vs COAPT)
Where are we erring?
The problem is the way evidence is created. It is often made up of data collected from poorly framed questions and methods, which are incompletely collected or wrongly interpreted. I wish, Bayesian theorem derivatives also address the probability of how pure is the pre-test (research) evidence base available in a scientific community. The core of truth in statistical science lies in, how we understand and define the number needed to treat, (NNT) and the number needed to harm (NNH) with any treatment or diagnostic modality.
Final message
Artificial intelligence and machine learning are projected to be the next big thing in medical science However, the probability of machines prevailing over, human clinical acumen, backed by a sound knowledge base and observation skills appears very minimal. Let us see. Meanwhile, I wish every young cardiologist to go through this paper by D&F to get enlightened.
It is not the number of publications in journals or getting those big awards or memberships in prestigious scientific societies. True success is “something else,” says the Nobel Medical Laureate Dr Willam Kaelin
Great thoughts. Just wondering, what are those elements beyond our controls he was alluding to?
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The author acknowledges all the queries posted by the readers and wishes to answer them .Due to logistic reasons only few could be responded. Inconvenience caused is regretted.
Dr.S.Venkatesan MD 