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Archive for January, 2023

Welcome back to the big molecular science of PCSK and its antagonist Evolocumab, a monoclonal antibody designed to target and prevent the LDL receptor catabolism inside the lysosomes. Evolocumab was approved by FDA for aggressive lowering of LDL, following a  customary study published in NEJM 2017, that released this double-edged anti-lipid molecule into the human domain with all fanfare.

It aimed to reduce the LDL as low as possible in selected patients with familial LDLemia & and those who don’t tolerate statins.  Now, a study was silently released in BMJ open, at the fag end of 2002, which is causing ripples in the pharma world in the new year.

In fact, this paper can’t be called a study. It looks more like an FIR. It questions the missing death counts, which were not included in the landmark trial, that led to its approval.  It took time for the news to sink into the world lipid community. 

Final message

I am surprised at the reactions to the reanalysis of FOURIER data. Any reasonably experienced cardiologist will agree, getting regulatory approval with manipulated data and analysis is more of a norm and not an exception (Ref 1). In a trillion-dollar pharma industry, do you think hiding deaths is a big crime? Is there a solution to this menace?  Yes, let us hope so, with movements like this one (Doshi P et all, Restoring invisible and abandoned trials: A call for people to publish the findings 

 

Counterpoint (Q&A)

Q  

Damn this post. Don’t blame a phenomenally successful scientific breakthrough that intercepts the immune destruction of LDL receptors. Instead of being cynical, try to come up with a scientific analysis of the FOURIER study. Please read this rebuttal from the TIMI group, https://www.tctmd.com/news/study-alleges-mortality-miscount-fourier-trial-timi-group-disagrees

 A 

I agree, let us not blame Evolocumab. It is an innocent and intelligent molecule. Culprits are elsewhere. It is a reserve drug in a highly selected population with refractory LDLemia.The lesson from the FOURIER  to all the clinical trialists is, when credibility is lost every thing is lost, even truths can become a casualty. We have to live with that. 

Reference

Marcia Angell,the former NEJM editor’s  book

 

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Pardon ,this video is nothing to do with cardiology. It is from the archives of the United nations library .This can teach some important lessons in art of communication , sharing to all folks, especially medical students. It was recorded in 1959 in Newyork, UN head quarters.Four 17 year old school girls & boys were invited for a debate on a complex topic. Does God exist ? How do you pray ? and what is the purpose of different religions ?

I keep wondering , how these youngsters accumulated so much wisdom and express it in such a polite manner too. Mind you, this was recorded , when learning happened with out any digital aids.The word Internet was unheard off. No ego, no bluntness, no diatirbes that has become a norm in many debates now. I got a punching lesson from this clip, be gentle when taking extreme views in any topic.

I wish, every medical debate in class rooms should happen this way.The key to succesful debate is, to accumulate knowedge, willingness to question the convention, and respecting the oppositie point of view.

The highest point of talk show, (for me) was, when the Brazilian girl(due respects, she should be nearing 80 years now) tell us casually some things are not meant to be understood in life .I tell the same when some patients ask too many questions about their illness which may not have an answer.

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Management of recurrent ventricular tachycardia has developed a lot in recent times. Anti-arrhythmic drugs(AADs) were a cornerstone for most recurrent and refractory VTs till recently. Surgeries including CABG,  repair of the aneurysm, and subendocardial resection has helped to control many post-MI ischemic VTs. Soon they became obsolete. Realistically, PCIs had little impact on post-MI VT for some unknown reasons. However, with the advent of ICDs and RF, ablation, a new dimension is added to this field. 

ICDs, though an attractive device, don’t prevent a VT but vow to nullify the consequence of VT. This is problematic. ICDs in spite of their ability to prevent SCD effectively, it has little say in preventing non-sudden deaths of in any form of cardiomyopathy. (In fact, there is some evidence ICDs might increase myocardial damage with inappropriate shocks )

Hence, RF ablation can be called as true curative therapy by extinguishing hot spots of VT genesis. Still, we need to understand ablation is technically creating new dead myocardium (in alreadly  damaged myocardium) and hence, can’t avoid a consequence. More importantly, ablation as a modality is technically more demanding. We have accumulated huge experience with the help of electro-anatomic imaging and cutting-edge hardware in the last few decades. Still, we find it difficult to zero in the target area of RF ablation, with all available techniques of mapping (Activation, substrate, entrainment, and pace mapping) The reason is,  VT circuits can be really complex ones. Not only different loops but also it can travel deep into the myocardium (Intramural or epicardial) making a single approach endocardial often futile. Success rates vary between 60 -70% (Some may claim 90 +)

This post wants the young fellows to take on this fundamental issue and learn in-depth about the arrhythmia circuit.(Get Inspired by Dr. Samuvel Asirwatham of Mayo clinic work )

What is the best site to ablate ventricular tachycardia?

  1. Exit point 
  2. Central isthmus
  3. Entrance 
  4. Inner loop
  5. Outer loop
  • Though logic would tell us we can intercept an arrhythmia by ablating anywhere in the circuit. But the issue here is we need to permanently ablate it. not just interrupting. 
  • The best site to ablate is the exit point or entry point. Maybe isthmus. I am not really sure. But, one thing is clear, the outer and inner loops are not important. Further, live tissues are the culprits and not the scars and infarcted zones. 
  • One more possible answer is to try to ablate all (or maximum) points in the circuits.

How to identify entry points and exit points?

Not a simple answer .EPs apply their life experience to do that, assisted by technology. Not everyone who has a Carto -GPS can do that.

One simple answer for the fellows is, in entrainment mapping,  critical sites can be somewhat arbitrarily labeled as exit, central isthmus, or entrance on the basis of the Stimulus-QRS interval relationship to the TCL. Exit sites will show an S-QRS interval < 30% TCL (QRS onset shortly after pacing), central isthmuses will show an S-QRS interval of 30% to 50% TCL (some delay in QRS onset after pacing), and entrance sites will show an S-QRS interval of 50% to 70% TCL 

Ruairidh Martin et all Circulation: Arrhythmia and Electrophysiology. 2018;11:e006569

Final message 

Key to the successful ablation of VT is the accuracy in choosing the target site. Locating the target is meaningless if we can’t reach that site. Reaching the site is again futile unless we are able to deliver adequate burning or icing with sufficient contact.

Meanwhile, AADs can never be ignored in spite of the apparent side effects, for the simple reason they reach the VT circuits without any fuss. The Pharma industry has almost lost its interest in AAD research and the hyper-talented EP guys are squarely responsible for this unintended consequence.

Future directions

RF energy modification and newer catheter designs will help. While cryoablation shows a promising advantage over RF, it is still to prove its sustained efficiency. Meanwhile, other ablation modes are being tried. Transvascular ethanol ablation and stereotactic radio ablation have both shown promise for arrhythmias that fail other ablation strategies.

Some more questions

  • What is the difference between arrhythmia focus of origin and entry point? 
  • Once the VT is set in, what is the relevance of its origin? 

Reference

One of the very good reviews on the topic.

1.Gustavo S. Guandalini, Jackson J. Liang, Francis E. Marchlinski, Ventricular Tachycardia Ablation: Past, Present, and Future Perspectives,
JACC: Clinical Electrophysiology, Volume 5, Issue 12, 2019, 1363-1383,
2;,W.G. Stevenson, H. Khan, P. Sager, et al.  Identification of reentry circuit sites during catheter mapping and radiofrequency ablation of ventricular tachycardia late after myocardial infarction Circulation, 88 (1993), pp. 1647-1670










3.M.E. Josephson, L.N. Horowitz, H.L. Waxman, et al.Sustained ventricular tachycardia: role of the 12-lead electrocardiogram in localizing site of origin Circulation, 64 (1981), pp. 257-272

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The term Ischemic heart disease (IHD) was once very popular, but many abandoned it as it became an academic cliche.  CAD & CAHD are the other terms that are equally popular and prevalent. Stable IHD was in vogue till recently, which was again replaced by “chronic coronary syndrome’ now. Honestly, I feel the original term IHD to be restored however outdated it may look. it encompasses the entire spectrum of clinical cardiac disorders.

Manifestation of Ischemia heart disease 

  1. Angina
  2. Infarction
  3. Cardiac failure
  4. Arrhythmias 
  5. Silent ischemia
  6. Sudden cardiac death

 The purpose of this post is to share some thoughts on the link between Ischemia and cardiac arrhythmia. 

 

 

What is the relation between  Ischemia and cardiac arrhythmia (especially VT)

A.Strong relation

B.Weak relation 

C.No relation 

D. Recurrent ischemia protects against arrhythmia.

The fact that. acute Ischemia triggers primary VT and VF and is the leading cause of electrical death is sufficient to fix the answer without any doubt. But, the  truth is, the link between Ischemia and cardiac arrhythmia is more complex  

If we could agree ischemia is a powerful trigger of ventricular arrhythmia, will every patient with chronic stable angina be at risk of  VT after walking a certain distance?  

So, where does cardiac arrhythmia fall in the Ischemic cascade of events? the fact that chronic ischemia on exertion rarely precipitates an arrhythmia conveys a strong hidden message. 

Coming back to, STEMI where the arrhythmic risk is powerful, still, if the same acute ischemia, presents as UA/NSTEMI, with severe compromise of resting blood flow, it doesn’t trigger a VT usually. This fact should baffle us and question why even acute ischemia carries low arrhythmic risk except when it happens with STEMI.

The potential mechanisms of lack of VT in UA* (No evidence /Class C evidence) 

  • In UA, ischemia is primarily subendocardial, and the neuronal innervation which is more in the epicardial plexus fails to get stimulated. This is in contrast to what happens in STEMI. Here It is transmural ischemia and the sub-epicardial is always involved.
  • In this context, the high prevalence of VT in Prinzmeal angina where there is subepicardial injury is a point to be noted. In young NSTEMI/STEMI crossover entities like Wallens and De-winters, there is a high adrenergic drive, which triggers the VT rather than ischemia per-se.
  • Finally, even in STEMI, only a minority of 15-20 % of myocardium become arrhythmogenic and face fatal complications. What protects the rest of the 75 %? is genetics, epigenetics, or fate.? 

The practical implication of this question

  1. The VT in ischemic cardiomyopathy is related more, to the scar burden, strategically placed islands of dead and live tissues, and the overall severity of LV dysfunction. This makes the Ischemic VT, as a term,  could be a misnomer.  In fact, it is the viable ischemic tissue that is a powerful trigger.
  2. If baseline chronic ischemia is less likely to trigger any VT, revascularisation in chronic CAD (PCI/CABG) is unlikely to give relief from it as well.

Anti-arrhythmic adaptation in chronic Ischemia 

We know about ischemic preconditioning and angina relief. It may apply to arrhythmic preconditions as well. Recurrent ischemia, while we expect to elevate the arrhythmic risk, it is a curious and exciting possibility it might work as an “anti-arrhythmia vaccination” at the molecular level. 

Final message 

So, what is the true relation between ischemia and cardiac arrhythmia?  

It is not as strong as one would believe it to be( Except in the early hours of STEMI and a very small subset of NSTEMI.

Curiously, in certain lucky beings, recurrent baseline ischemia may protect against future arrhythmias.

Reference 

1.A V Ghuran, A J Camm, Ischaemic heart disease presenting as arrhythmias, British Medical Bulletin, Volume 59, Issue 1, October 2001, Pages 193–210, https://doi.org/10.1093/bmb/59.1.193

2.Janse MJ, Wit AL. Electrophysiological mechanisms of ventricular arrhythmias resulting from myocardial ischemia and infarction. Physiol Rev 1989:  69 ; 1049 –169

Few more questions worth pondering 

Why do certain VTs struggle to become sustained?

Will discuss this later (Will need to talk about the diameter of the primary Rotor, the Curvature of rotors and source-sink mismatch, etc. )

How often  Ischemia triggers AF?

I haven’t heard of Ischemic SVT, or ischemic AF much. Trying to accumulate more Info on this.

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EHJ has listed the top 10 papers in cardiology in the year 2022 in its current issue. 

Kindly go through this when free. While each of the 10 has its own importance, one meta-analysis, I thought was a  real bright spot. Though the message it conveys is nothing new,  it reaffirms an important management principle in ACS. Getting curious? Before going into the paper, a mini pretest

What is your take on these 4 statements on ACS?  True or False

1. STEMI is an emergency, NSTE-ACS* is not an emergency

2. Both are true emergencies.

3. STEMI is definite, yes, but  NSTE-ACS may or may not be (Mind the GRACE score dude !)

4. Even STEMI can be a non-emergency if the patient reports after 24 -48 hours.

(Remind you, NSTEACS = UA+NSTEMI , still often used interchangeably)

Hope we don’t have difficulty in identifying the wrong response. Whatever the answer to this somewhat insulting question to our intellect, forget it. Now, read this paper, which is listed as one of the most read last year. It is about the impact of early invasive strategy in NSTE-ACS.

Kite TA, Kurmani SA, Bountziouka . Timing of invasive strategy in non-ST-elevation acute coronary syndrome: a meta-analysis of randomized controlled trials. Eur Heart J. 2022 Sep 1;43(33):3148-3161.

Conclusion is pasted for the busy guys.

Post-test

  1. What is overall NSTEMI in-hospital mortality? (Everyone knows for STEMI it is around 4-8 %, no one seems to be sure about NSTEMI. I think it can’t be estimated accurately, guess it is 1 -2% )
  2. Is there a primary PCI equivalent situation in NSTEMI?  What are they? (Left main UA with AVR ST elevation comes first on the list)
  3. Based on the urgency to treat how does the ultimate outcome change? (This is what this meta-analysis by Kite et all proved.It is not a new revelation though . Recall the landmark ICTUS study  of 2010 which was largely kept in the dark )

Final message

One lay definition of STEMI is, It is a mass of myocardium under fire. True UA/NSTEMI is, a mass of myocardium, that is threatening to go on fire. When firefighters are able to reach a smoky building before the onset of a fire, no doubt, it looks like a great & awesome response, Isn’t it? Unfortunately, the myocardial landscape is different and NSTEACS is such a heterogenous entity that doesn’t welcome unsolicited aggressive, emergency rescue missions. That’s one of the messages we get (at least I got )from this top-read paper in 2022. 

Reference

1.Emanuele Barbato, Margaret McEntegart, Tommaso Gori, The year in cardiovascular medicine 2022: the top 10 papers in interventional cardiology, European Heart Journal, 2023;, ehac778https://doi.org/10.1093/eurheartj/ehac778

2.Kite TA, Kurmani SA, Bountziouka V, Cooper NJ, Lock ST, Gale CP, Flather M, Curzen N, Banning AP, McCann GP, Ladwiniec A. Timing of invasive strategy in non-ST-elevation acute coronary syndrome: a meta-analysis of randomized controlled trials. Eur Heart J. 2022 Sep 1;43(33):3148-3161.

3.Damman P, Hirsch A, Windhausen F, et al. 5-Year Clinical Outcomes in the ICTUS (Invasive versus Conservative Treatment in Unstable coronary Syndromes) Trial. J Am Coll Cardiol. 2010 Mar, 55 (9) 858–864.https://doi.org/10.1016/j.jacc.2009.11.026

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Happy new year & memories of 2022 !

Wishing every one of you an Enlightening New year. As we begin a new journey around the sun, yet another time, let us re-dedicate ourself, to use science, for the welfare of our planet & people.

Thank you , for visiting this site and make all its worth.

Just one memory of 2022, lingers ! Retired and left Madras medical college,Chennai after 3 decades, which grew me up as a Cardiologist.

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