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Human body is intertwined collection of lives of Individual organs.We believe death occurs when brain dies , respiration stops and circulation ceases . Curiously ,when life ends , these organs  don’t die as a single unit . These three events can happen in any of the six possible permutations.Each organ takes different times to die after loss of life.It is like a crashed computer , where the mother board /RAM memory may be transferred to another and be functional . Out of these three , heart function appears to be supreme as it can function without the need of brain (Science of brain-death) and keep the body alive with intact circulation. Though the concept  called heart dead organ donors is catching up as well. (John Gill et all Use and Outcomes of Kidneys from Donation after Circulatory Death Donors in the United States    

The science of organ transplant has rapidly  evolved .We can transfer an organ from one who is dying or dead to another person who is also dying due to failure of a different organ. Though most organs can be transported and transplanted , we need to maintain life in a dead donor organ . A new and curious specialty  in medicine is emerging which could be named a  Critical Care of Dead or Critical Cadaveric Care Units !) till harvesting happens. Paradoxically ,after the harvest , the organ gains independent  life that has to be sustained.This is where the science of organ transport is waiting in to explode!

How to transport a dead man’s heart ?

There are two Ischemic times in organ donation.

  • Warm Ischemic time
  • Cold Ischemic time

Warm ischemic time refers to the amount of time that an organ remains at body temperature after its blood supply has been stopped or reduced. Cold ischemic time refers to the amount of time that an organ is chilled or cold and not receiving a blood supply. These times quiet vary with respect to different organs.

So far, we have been carrying organs in cold boxes with custodial solutions. (HTK*)

runtranslplant265x125_1234539

This makes the transport time a big limitation of success of the procedure. *HTK -histidine, tryptophan ,a-ketoglutarate, solution 

Whats new in organ transplant science ?

Trans medics is an exclusive company , that has pioneered  in this unique science of organ transport .They have developed separate organ care system for heart ,lungs and liver.

donor heart

It is the first portable heart perfusion system , which increase the time between the harvest to transplant . It avoids cold ischemic time ,replaced by warm perfusion with metabolic activity monitored till  it is transplanted.Ideal far long distance transplant .Soon one can expect trans-continental transplant as well !

This technology could make the difference between warm and cold Ischemic times blurred and in future one may expect to prolong the warm ischemic  period and there is near zero cold Ischemic time.

A heart is perfused by transmedics system while being transported

 

                                              A  lung breathing in transit

A link to a video

Final message

Modern medical technology can be seen in action , in so many ways and brings both accolades and agonies in equal proportion. While, even flimsy ones tend to get due attention , Transmedics , probably deserves a  grandest reward  for uplifting the science of organ donation . I would think this is the most unique service (playing God )  . . . shipping dead man’s organ  with assured life on delivery  !

 

Link to Transmedics website

ocs heart transmedics heart transplantation

http://www.transplantation.de/fileadmin/transplantation/txmedizin/txmedizin_2011_3/04_yeter.pdf

 

A middle aged women , with acute onset left sided chest pain and ECG changes was seen by a general physician. He had little hesitation in labeling the patient as  ACS( To be precious he reported the ECG as lateral wall Ischemia) and asked for an echocardiogram to rule out a heart attack  (This is how cardiology is practiced in many areas) .

This patient came to my lab  for the Echocardiogram .The echo window was poor , It showed a structurally normal heart and there was no pericardial effusion. I suspected something systemically wrong in this patient and asked for a X ray chest .

Subsequent scrutiny of this  patient revealed she had moderate left tuberculous effusion. ECG changes are attributed to this. We know pericardial disease can cause ECG changes that mimic ACS. While pericarditis can elevate the ST segment. Can pleuritis without effusion cause ECG changes.  What is the demarcation point between pleural from pericardial surface ?

What are the ECG features of pleural effusion ?

  • Low voltage qrs.
  • Poor R wave or even q waves
  • QRS axis shifts are due to true anatomical / electrical shifts
  • T wave inversion as in this patient

Mechanism of T wave inversion in plural effusion.

T wave represents ventricular repolarisation. To be frank I am not able to give an exact mechanism of such  defects in pleural effusion.

The following mechanisms are  suggested

  1. Left sided pleural effusion can closely mimic pericardial effusion .One can get low voltage QRS in lateral chest leads .
  2. Anatomically I would guess the plural fluid also hugs the heart and the inflamed pleuro-pericardial Interface (Is there fibrous continuity ?) result in some degree of epicardial interference or reversal in electrical polarity.
  3. The true effects of mediastinal shifts with large effusions  on ECG is not clear(Lead V 3 and V4 may pick V5 / V6 signals in left sided effusions )
  4. Fluid altering the electrical conduction property
  5. Associated minimal pericardial effusion and  effectively causing epi-pericarditis as a part of poly-serositis .
  6. After ruling out all plausibility one may think primary ischemic changes as well.

Teaching points and potential error

To label  a left-sided pleuritic pain with ECG changes as ACS can never be considered as a serious error.However , rushing such patients to cath lab or   lytic therapy along with heparin leads to more trouble. ER physicians should always keep in mind T wave inversion in isolation is indeed a rare cause* of ischemia. Still,  as a physician first , we need to have a check list to rule out common non cardiac conditions. Pneumothorax is one another entity that can exactly mimic a STEMI with ST segment shifts and q waves.It’s also possible left sided pleural effusions produce q waves and mimic an old MI as this case report reveals.(Constatine A Manthous Chest 1993)

I think  X-ray chest is least used modality in a coronary care unit for various reasons . Still ,the utility of which can never be undermined and should be used diligently . 

*Of course we shouldn’t  forget a sinister form of ACS  referred to as Wellen’s LAD  syndrome which may present with dynamic T inversion.

Reference

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 !

 

intra-coroanry-thrombus (2)

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 

Time window in stemi 6 hour 12 hour or 90 minutes

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

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!)

Reperfused myocardium

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 twoOnset 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 !

 

 

 

 

 

We learn from basic physiology  lessons that human body is made up of 60 % water. What about heart ? There is no reason for the heart should behave differently from rest of the body . If my  assumptions are correct when the normal heart weighs 300g  , 180g of which should be  be water. The same thing could be applicable for LV mass( * Reference requested)

Is there myocardial congestion in cardiac failure ?

Genesis of edema in any tissue depends on local hydrostatic pressures, tissue resistive forces, osmotic balance, and cell membrane permeability. In the myocardium individual contribution of above factors are not known. Apart from total myocardial water content  , myocardial water logging depends upon the trans myocardial venous gradient and the coronary sinus exit pressure in right atrium.Technically ,any severe right heart failure should lead to myocardial congestion at least to some degree.Unlike the lungs , the myocardial edema fluid doesn’t produce crackle , (May cause S -3 gallop instead) . However ,we have modern technology to image water inside the myocardium. Yes, it is called proton / hydrogen imaging or simply called MRI .

This is especially evident In chronic kidney disease , where in the fractional water content within the myocardium is expected to increase further as the whole body is water logged.

 

myocardial edema by mri in ckd 2

We have seen time and again patients with CKD  improve in LV function immediately  after dialysis . It happens like a magic . The mechanism  is simple .The over-hydrated cardiac Interstitium  threatening to drown the myocytes  is promptly dehydrated by dialysis. This was my wild guess  until I came across this paper which proved the exact points.

myocardial edema in ckd chronic renal failure recovery of lv function after dialysis

 

Other situations  where myocardial edema may play a significant clinical Impact  (*Includes increased permeability of myocardial capillaries)

  1. Myocarditis
  2. Transplant rejection
  3. Stress cardiomyopathy (Takotsubo)
  4. Congestive heart failure
  5. Acute ischemic injury
  6. No Reflow situation after PCI

Final message

Myocardial interstitial edema in cardiac failure is a grossly under diagnosed  entity.  A water-logged myocardium is classical at least in CKD. We know it can severely compromise the LV function especially, the diastolic function that explains the all too common flash pulmonary edema in CKD.

The number of studies in this  topic (Myocardial Hydrology !)  is minuscule compared to other areas of research in cardiology literature.There is a need to involve both  Nephrologist and cardiologists to explore this curious concept of  dialysable  left ventricular mass in CKD/Cardio renal syndromes !

medical quotes new idea

One more area of research 

It is reasonable to believe,  cardiomegaly in cardiac failure  is primarily related to the increased end diastolic volumes .Still , we are not clear whether there is net increase in cardiac mass as the surface area of the heart increases with dilatation. (Even in DCM ? ) Whenever myocardial mass increases relative increase water is likely. Does the beneficial effect of diuretics in cardiac failure , and the restoration of  LV dimension is due to myocardial interstitial diuresis as well ?

Reference

myocardail edema water content congestion mri n myocardial diuresis interstitial

2.Andrés-Villarreal, M., Barba, I., Poncelas, M., Inserte, J., Rodriguez-Palomares, J., Pineda, V., & Garcia-Dorado, D. (2016). Measuring Water Distribution in the Heart: Preventing Edema Reduces Ischemia-Reperfusion Injury. Journal of the American Heart Association5(12), e003843. doi:10.1161/JAHA.116.003843

3.Cardiovascular magnetic resonance of myocardial edema using a short inversion time inversion recovery (STIR) black-blood technique: Diagnostic accuracy of visual and semi-quantitative assessment Darach O h-Ici, John P Ridgway, Titus Kuehne , Journal of Cardiovascular Magnetic Resonance 2012, 14:22  

 

Evening cardiac clinic is generally a relaxing place until an occasional patient  with vague chest discomfort present with this sort of an ECG .

He was a 68 y old hypertensive and was on Tablet Amlodipine .After a cursory look at his ECG , eyes wandered to look for some specifics. Suddenly ,my  ECG reading skill was stretched . Is it really LVH ? or Ischemia ? I asked for any old ECG which he couldn’t provide. I had to blink  more than a moment , before asking him to describe his chest pain in detail one more time . I got almost convinced it was not ACS  since he was having only localized pain over left side of chest. Still , I didn’t have the courage to send him home. An Echo was done.

Curious to know what the Echo showed ?

 

Yes , you also probably guessed right . It is LVH and there is no wall motion defect either.

How to differentiate between Ischemia and LVH ?

This is a common question asked in the board exams.There are number of ECG clues to differentiate the two .Mostly it will help  fellows  to pass exams. Academics rarely comes to your rescue when patients land with  chest pain  especially at odd hours.

Find the answer in this link

https://drsvenkatesan.com/2009/12/12/how-to-differentiate-lv-strain-pattern-from-primary-lv-ischemia/

 

Now comes the real twister , Does presence of LVH  exclude Ischemia in any way ?

Why can’t be ACS in a patient with LVH ?

When I posed these questions , some one suggested global longitudinal strain  with speckle  tracking to rule out ischemic wall motion defect, my resident suggested  high sensitivity Troponin and Ischemia modified albumin.

Whatever is the technological assistance , one thing  is certain,  we need to finally fall back  on patient’s symptoms . Unstable angina is neither an ECG diagnosis nor biochemical  or Echo diagnosis . (Its all about patient description about his angina , that clinches the  diagnosis !)

It remains a fact normal spot Troponin can never rule out  ACS on time ,( Even patients with unstable angina who  harbor  tight  LAD lesion can be both ECG /Enzyme negative )

When we are not sure ,the traditional coronary care dictum  shall operate .It demands admit, observe, with serial ECGs and enzymes. This protocol cant’t be followed strictly for a variety of reasons . We may have to rely entirely on our clinical Intuition accrued over the years.

A modern-day cardiologist might have a different dictum .The simplest solution in such situations is a diagnostic radial snap shot coronary angiogram .It is an easy way out  . . . , and avoids the trouble of spending wasteful minutes of personal conversation with the patient .The ethics of outsourcing history taking , patient record review or even clinical examination has pushed the definition of professional competence in coronary care into murky grey zone.

One more reason we should hesitate to rush these patient to cath lab is the detection of  incidental insignificant CAD (Which will loom larger than life when they are wheeled in from  ER)  that will  lead on to  further inappropriate chain of events.

How relevant is clinical acumen in modern era ?

Clinical acumen in medicine can never be taught in class rooms or read in text books. It is the innate ability to  combine  knowledge, experience ,skill  and  lastly (and most importantly) courage to ignore conflicting and pervasive data from new generation Investigations. Instead of helping us ,they often directly affect our increasingly vulnerable native medical cognition.

Even if some one is blessed with a good clinical acumen it seems to have little value many times as power of Investigations and fear of missing a event will prevail over it ! I have been victim of this phenomenon many times and not able to follow what my mind preach me !

What happened to this patient ?

I had to admit him against my  wish (Of course I was safe!)  He too got admitted reluctantly and was observed till morning , spent Rs 5000 for pack of investigations and stay , was discharged without any issues with a diagnosis of simple Hypertension and LVH.

The non academic bug  didn’t stop there  . . . again  contrary to my conscience  I had to suggest  optional coronary angiogram to rule out true CAD as a precautionary statutory advisory !

 

Counterpoint 

How do you know this is really not CAD  ? I won’t believe unless and until I see the CAG and its normal.

Ok, Let me post his angiogram if he decides to  undergo it.

We know pleural effusion (hydrothorax) is disproportionately more common on right side in cardiac failure.Though its a well observed phenomenon, the mechanism of which  has not been clear to us. It could be due to multiple  anatomical , physiological factors.

 

*The are  right and left lymphatic (Thoracic) ducts that drain the corresponding lungs and pleural space . There can be overlap and contribute to the differential occurrence of pleural effusion

 

Reference 

A meticulous paper written some 75 years ago (1946) from Harvard medical school teach us some important points in this phenomenon.

There is still lot, to be understood about pleural effusion in cardiac failure. We need to know why some pleural effusions tend to occur independent of hydrostatic forces.  It is also noted long-standing transudative effusions can become true exudates. Role of local pleural capillary hypoxia resulting increasing permeability is underestimated.Hepatic congestion and trans-abdominal seepage of fluid is a distinct possibility.

One more area we are not clear is  the relationship  between the  genesis of  pericardial effusion in cardiac failure and concomitant pleural effusion. Post operatively , after univentricular repair (as in Fontan ), pleural effusions can be much problematic with high venous pressure interfering with  pleural drainage.

Impact on symptoms

Finally, even mild pleural effusion can increase the work of breathing and result in dyspnea which is out of proportion to cardiac dysfunction.While we expect the diurteics to clear the effusion of cardiac failure, it doesn’t happen always arguing for a non transudative mechanism in at least some of them.

Further reading

Discerned readers are advised to study the pleural space dynamics in detail.

Link to the original Article of Edgar Mcpeak and Levine 1946

 

 

 

Though heart is known primarily as a pump, it is the four cardiac valves that ensures the critical , non-stop unidirectional flow that sustain the circulation . It is to be recalled these valves originate in the very early days of cardiac development when the primitive heart tube loops , even as the chambers expand from primitive ventricle. Mesenchymal differentiation controlled by various genes that cleaves the valve from myocardial tissue.

While heart by itself is the supreme vascular organ ,  its surprising  few structures inside the heart , like the valves are quiet avascular ( or is it really so ?)

The valves that beat average of 30 billion time in life time ,seem  to get its nourishment from Nowhere ?

Layers of heart valve 

 

Image source : Huk D., Lincoln J. (2017) Oxidative Stress in Cardiac Valve Development. In: Rodriguez-Porcel M., Chade A., Miller J. (eds) Studies on Atherosclerosis. Oxidative Stress in Applied Basic Research and Clinical Practice. Humana Press, Boston, MA

It’s primarily made up of  complex stratified connective tissue covered by endothelial cells with intervening interstitial cells. The extracellular matrix (ECM) layers are rich in elastin proteoglycan (spongiosa) and collagen (fibrosa). It has been found myocytes and dormant fibroblasts are scattered in the valve leaflets. This forms the basis of focal origins of  Cuspal Ventricular tachycardia J Cardiovasc Electrophysiol. 2002 Jun;13(6):551-6.  from electricaly activated myocytes.

Is there a dynamic cell turnover within the valve tissue ? Where does it get the nourishment ? What is the effect of  aging and CAD on valve tissue ? 

There is growing evidence for valvular extra cellular  matrix are indeed dynamic. This explains valvular lesions in connective tissue disorders like Rheumatoid arthritis. Progressive degenerative changes of aging  involves  remodelling , tissue engineering . Calcification of cardiac valves in endocrine disorders like  hyperparathyroid states implies  cardiac valvular interstitium is in continuum of systemic metabolic pool. There has been very little published evidence  correlating  CAD and Ischemic degeneration of valve.

Evidence for vascularity of valves

It is surprising , this simple question of  vascular supply to cardiac valves has  confronted the scientists for too long.

1.Histopathological and  autopsy studies have revealed vascular channels.(Harper 1938 BMJ)

2.X-ray projection microscopy was used to image the valves after injecting radio opaque microparticles in the ascending aorta. This is probably the one of the few original studies done in UK in 1968 (Clarke et al ) it revealed significant  vascularity of the valve .It was found 16 % the tricuspid valve, in 10% of the mitral valve, and was maximum in Aortic valve (24%).

3.The fact that statins reach the Aortic valve tissue in lipomatous Aortic stenosis indicate significant vascular port of entry to valves.

Direct evidence : Why don’t we ask the surgeon ?

When I asked my surgical colleagues  Does the valve  bleed  as they cut it  ? Most of them were amused with my query , still Iam not sure I got the answer right. At least one of them said since the heart is on pump ,  it won’t bleed any way !

 

Conclusive evidence : From a 1968 study 

It is academically humiliating to note we have to go back 50 years in time to get a proof for vascularity in cardiac valve.(Or anything new I am missing ? readers may share !) I think , this is strongest proof  for valve cusps are supplied by end coronary arteries. However the penetrance is not deep into all layers of the valve and distally

Is hematogenous spread of Infective endocarditis(IE) occur ?

How does systemic infection reach the valves ? We still believe the IE is due to direct colonisation from circulating blood .Hematogenous spread of IE do occur but difficult to prove. It seems infection of valves primarily happen from outside initiated by  endothelial injury over the valves .

*There seems to be a contribution from  systemic bacteremia  reaching  from within through the pre-existing capillary twigs as well.(Evidence elusive !)

 

Final message

Is cardiac valves vascular ?  It is curious even in this era , we struggle to answer this query with certainity.

Yes, they are vascular structures , but at best it has partial vascular capillary network. It is also possible  the valves can live a durable life even without these vascular Innervation.(I haven’t heard of a condition called mitral valve infarct or necrosis in RCA/LCX STEMI which supply the base of the heart)

Still, this partial  vasculaity can become Important at times of pathology like infection or degeneration. Expecting more research in this unique area of valvular heart disease

Reference

1.JOHN A. CLARKE AN X-RAY MICROSCOPIC STUDY OF THE BLOOD SUPPLY TO
THE VALVES OF THE HUMAN HEART BY   From the Department of Anatomy, University of Glasgow, Glasgow Brit. Heart J., 1965, 27, 420

2.https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC1252531&blobtype=pdf

3.Dow, D.R. and Harper, W.F. The vascularity of the valves of the human heart. J Anat193266610–617

4.Ritter, S.A., Gross, L., and Kugel, M.A. Blood vessels in the valves of normal human hearts: from a study of 700 human hearts. Am Heart J19283433–446

5. Saini N, Saikia UN, Sahni D, Singh RS.  Vascularity of human atrioventricular valves: a myth or fact? J Thorac Cardiovasc Surg. 2014 Jan;147(1):517-21.