Dr.S.Venkatesan MD

Cath labs are probably the best place to practice preventive cardiology . . .

Practice of medicine is primarily guided by Infinite Information , plenty of Intuition, little bit of Intelligence and unquantifiable amount of Ignorance.The science of coronary reperfusion is standing example for variable mix of the above.The term no reflow is a jargan used liberally in cath labs right from first year fellow to super consultant without knowing what exactly they mean by it.

What really is No-reflow then ?

The academic definition :According to Kloner no-reflow is defined as suboptimal myocardial reperfusion through a part of coronary circulation without angiographic evidence of mechanical vessel obstruction.( Kloner RA, Ganote CE, Jennings RB. “The “no-reflow” phenomenon after temporary coronary occlusion in the dog.” Journal of Clinical Investigation, 1974; 54: 1496–1508.)

With due credits to his seminal paper, I always wonder what exactly Dr Kloner meant when he labelled it as No-reflow!

No is ok , Flow is ok , What does the adjective “re” mean to you ?

Re stands for repeat ? recurrent ? Yes , it may mean any one of it. It may mean nothing in many patients as their post PCI flow is same or found to be no better than pre PCI flow with no significant forward flow at all ! In this situation No-reflow is same as No-flow (Never flown ) in physiological terms irrespective of epicardial patency.

Literally, the term no re-flow tell us, there has been a dramatic procedure related*( or preexisting ) destabilization in distal blood flow. It can be any downgrading of basal TIMI flow. ( Example : TIMI 3 becoming Zero , or TIMI 1 becoming 3 then back to 1 or Zero.) The terms slow flow, low flow, stuttering or trickle of flow all fall under the common  category No reflow. In a crude manner one may conclude no reflow to be  masquereding term  for failed PCI.

*Mind you , No reflow can also occur with pharmacological lysis as well.(Less common)But personal experincee suggest it has a less benign course.

Mechanism of No- reflow

Many mechanisms has been proposed and disposed by experts. However , all suggested mechanisms end up in the final common theme ie micro vascular obstruction.

Can no-reflow precipitate a fresh ACS ?

Could be yes . How ? The distal thrombus migration clogs the active collateral channels at its entry point.This is probably the most unrecognised concept which is difficult to prove though.The problem is , we may not realise this as it could be silent or may just present as LV dysfunction , Infarct extension, or Ischemic cardiac failure.

Why is treatment of no reflow is so dismal ?

I think, by now you can guess the answer and get it right too !

Is no flow better than No-reflow?

It may seem a foolish question one could come across in coronary hemodynamics. The prevailing coronary doctrine, as we understand is , all ATOs need to be opened in STEMI in an emergent fashion. (Other wise patients or their myocardium can’t be salvaged )But, we also realise ATO do get converted to CTOs in a safe manner following a STEMI in a significant number. It’s the ultimate myocardial mystery when we realise even the ATO fails to damage the myocardium significantly in some patients.

Presence of acute collateralisation to IRA from non IRA is observed instantaneously and spreads rapidly towards myocardium in distress.It is observed in atleast 40% of all patients.(Ref 2,3).

The anatomical and physiological codecs of acute collaterals in ACS is secretly located close in the God’s domain.But, Interfering with it, is definitely in human domain.

Should we need to worry about the impact of PCI on these acute collaterals ?

It is estimated up to 5 grams of thrombus could spilled over to the distal coronary bed. Mind you thrombus formation is not a one time process.Can you guess where these thrombus lodge in ? We don’t know what is thrombus clearing capacity of LAD/LCX/RCA vascular bed. But. we have observed naturally formed thrombus is less likely to disseminate and migrate than the catheter and wire induced.My presumption is , coronaries show their dissent and disapproval in the only way they know, ie non stop generation of thrombus (Not withstanding our DAPT/2b 3a /Bivaluridins etc)

Acute collateral shutdown : A new concept

We are not sure if there is a collision between two streams of reperfusion that happens after a STEMI. One spontaneous from the collateral and other from antegrade(Either spontaneous or man made)

Is it benefitial, detrimental or neutral ? We don’t know the answer for sure. My understanding is some of subset of critical STEMI are heavily dependent on this life line however miniscule it may be.

It doesn’t require a double blinded study to prove what would happen when a hurried cardiologist attempt hurried PCI who often has to a change his target to thrombus instead of myocardium .

When aggression is shown on the thrombus, it’s more likely you end up in no reflow . One possible new mechanism(Proposed by the author) of No reflow is distal dissemination of thrombus debri that plugs the lateral entry points of collaterals.

This is the time , no reflow shows its violent face. Invariably hemodynamic deteriation occurs and the entire reperfusion team would seem to count their luck than expertise.

Can we perceive, predict and prevent this ?

We should , we need to , but how ? Since we know the true success rate of no reflow is miniscule, serious introspection to be done. Funnily (but realistically) one can take a famous cue from the most underrated medical specialty Social and preventive medicine .

Yes it’s “Prevention is better than cure” and mind you, if there is no cure, how important prevention becomes.Strangley , preventive cardiology is meant for lesser professionals , who and talk about diet, excercise and lifestyle.

No , it’s not . Preventive medicine needs a new defintion , rather new understanding .Its’ all about preventing an expected or unexpected adverse event anywhere.

How many of us really believe there is no effective cure for No-reflow and it is directly related to aggressive thrombus clearance strategies .

Should we argue new age Interventionists to practice preventive cardiology right inside the cath lab and do away with non-academic temptations.(Surprise , this is exactly mega trials on thrombus aspiration told us (Class 3 Indication for routine thrombus meddling)

Final message

Stable and comfortable, late ATOs need not be opened like defusing a time bomb. We will never know which side of the bomb the cardiologist is sitting.

The incidence of new onset No-reflow can be higher than what we presume.Further it can trigger a fresh ACS by whipping up the injured and resting myocardium.(Mostly attributed to late reperfusion Injury and the acute collateral shutdown.)

Postample and Counterpoint

As an interventional cardiologist, No-reflow is one among the expected complications , which are part of the profession.Never bother about these unscientific utterrings . That’s the job of critics. You go ahead and fight with the coronary artety in every case of ACS. Only weak minded unprofessionals would love to sit on a case of ACS and play a waiting game in CCU. True professionals shall look for multiple criminal targets beyond thrombus, myocardium, IRA , non IRA, doesn’t matter . Do it with confidence.Hope for the best, don’t bother too much about the endpoint.

Mind you, that’s what , we are trained and paid for and possibly respected too in this most glamorous subspecialty of Medicine.

Coming next

*Is Catheter, Guidewire Induced thrombus radically different from natural denovo thrombus ?

*How common is angiographically blind No reflow.(TIMI 3 with good and bad blush included)

*What are the residual defects and long term myocardial sequale ? (Inspite of successful tackling of No reflow )

Reference

1.Claire Bouleti et all The no-reflow phenomenon: State of the art Le no-reflow : état de l’artArchives of Cardiovascular Disease (2015) 108, 661—674
2.L YJ,Masuyama T,Mishima M, et al Effect of pre-reperfusion residual flow on recovery from myocardial stunning: a myocardial contrast echocardiography study. J Am Soc Echocardiogr 2000;13:18–25. doi:10.1016/S0894-7317(00)90038-5

The prime job of cardiologists is to restore coronary blood flow in an emergency fashion. While we do this with reasonable success ,there is still a missing link between our Initial aim and achieved goal.

It’s all too common situation in any busy cath lab , to see two similar STEMI patients with identical time window & proximal LAD as IRA , in totally different scenarios. In the first patient we find a trickle of flow in LAD , who is relatively comfortable  with normal LV function (In whom , emergency primary PCI might appear redundant.) While the other patient , even after rapidly established TIMI 3 flow , LV wouldn’t look good at all . All our efforts to reperfuse is found wanting.  Ultimately LV goes in a downward spiral , ends up in irreversible cardiogenic shock or fatality inspite of Impellas, ECMOs and other LV assist exotica !

I can promise , you can never guess from the angiogram whether this ACS patient was very much comfortable or he is in cardiogenic shock on ventilator  unless I reveal the history. Am I right ? That is the mystery of coronary circulation and hence its so critical to serve the myocardium what it wants ? Never treat a coronary artery in isolation !

What is the possible explanation ?

The first trickle (Say TIMI 1 which is usually spontaneous or lytic related ) is the one that’s going keep the muscle viable and possibly prolong the time window for the subsequent reperfusion strategies .Hence it is the timely TIMI 1 or 2 is much more critical than delayed TIMI 3 (Still rapid).

Time window woos :

Who fixed the reperfusion  time window as  6 to 12 hours ? Do you know on what basis  the acceptable delay of 30 to 60 mts related to primary PCI ? was made acceptable by  cardiology community ?  If you analyse the published data both are highly contentious and empirical. ( Suggest you scrutiny the data from DANAM2 , PRAGUE and AIR PAMI and come to your own conclusion) (*These are the 3 sacred studies done with few thousand patients  that redefined our approach  to STEMI and gave the licence to waste the golden hour ! )

I remember reading  the Robins pathology book (Bible of  pathology William Boyd as well ) in early days of medical school myocardium may die even within 1 hour with wavy necrosis, contraction bands etc. Looking back some times I  wonder how the clinicians have conveniently prolonged time window with whims and fancies of science Intact.

Concurring with the pathologists , we have learnt some harsh lessons inside the cath labs. One of them is that even ultra fast pPCI can fail to salvage  myocardium, meaning that time is not the ultimate thing in our race. (There should be other important determinants )

A brief journey back into our pathology classes : Have a look at this table 

Please note, Irreversible Injury might happen any time after 30 minutes .Of course it can vary . But, the question is how are you going to identify these patients with  ultra short  time windows? source : Robbins Basic Pathology 9th Edition.Elsevier

Other factors that influence myocardial cell survival

• Tendency of myocardium becoming electrically unstable
• Criticality of non IRA lesions
• Ischemic preconditioning
• Gender dependent reperfusion times
• Efficiency of collateral circulation
• Reperfusion Injury (R.A. Kloner, Ultrastructural evidence of microvascular damage and myocardial cell injury after coronary artery occlusion: which comes first?)
• Co-morbid conditions

Re-perfusion is not a single edged sword 

We may wish the concept of re-perfusion Injury is a myth : Unfortunately it is not ! Myocardium doesn’t relish (not always) the return of circulation in full dose. (May be it’s laying and taking the much needed rest with the initial Injury!)

Sudden gushes of blood leads to extravasation into the interstitium (due to damaged capillaries)  increases the Intra myocardial resistance and obstructs the microvascular flow. We have  witnessed more than a handful of patients going for cardiac arrest once IRA is opened (of course,  we might be  able to resuscitate many of  them )

Myocardial hypoxia resistance time

Please realise ,true  STEMI clock starts not with onset of symptoms but with time of total occlusion.There is more than subtle difference between the two. Onset of total occlusion to symptom time is not a well explored or understood Interval. We take it for granted that the onset of symptoms coincides with total occlusion.

But in multi vessel CAD, even a CTO can cause a STEMI through loss of distal collaterals. Further ,the presence and absence of pre-infarction angina (PIA*) , ischemic pre-conditioning (IPC*) sensitizing effect of  remote CAD , manifest vs recruitable  collaterals  all these make the fixed time windows with which we did our land mark studies of PCI / lysis academically  questionable.

* Both PIA  IPC are master confounders in the true time window calculations .We don’t know whether its due to ischemia tolerating myocytes or pain tolerating nerve fibres  responsible for this varying presentations.But the mystery is certain , when we  realise the angiographic  spectrum of ACS can range from silent ATOs to painful CTOs

Final message

Is timely reperfusion (and its favorable effect ) lies in God’s domain ? If you we  believe myocardial susceptibility , arrhymogenicity and recovery to hypoxia is genetically determined ,then the difference between fate and science Is much narrower than we think .Its appears we can change the former with the later with both positive and negative outcomes. So ,the  “f”  word may not be a forbidden at-least in the STEMI management. It resides not only  within the human genomic codecs written with double-helical nucleic acid fonts . . . but also  in the nimble and restless hands of both novice and experienced interventionists !

A study proposal 

Let me make a hypothetical statement .A significant subset of patients with STEMI have ultra short myocardial survival and we are unable to identify these hypoxia challenged hearts where primary PCI related delay could be a myocardial sin. Any one willing to prove or disprove this hypothesis ? If some body take this quixotically important study in STEMI management please give me some credit as a contributor !