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Why is it difficult to produce myocardial relaxants ?

Posted Dec 13 2009 9:30am

  • Skeletal muscle relaxants – Available
  • Smooth muscle relaxants -Available
  • Cardiac muscle relaxants -Not available !

Cardiac failure is the number one killer of mankind.  So far we have believed the major function of the heart is to contract . Relaxation was thought to be a passive process  .Now we know,   for myocardium to relax properly the calcium which was  pumped in to acto myosin complex, has to be taken back into the  sarcoplasmic reticulum during diastole  .This is mediated by SERCA 2 , Phospholamban  the active  calcium uptaking kinase.Clinical diastolic dysfunction as a concept has been disputed for too long that has delayed our knowledge  gap .

Myocardial relaxation is much more complex than  we think !

We have given too much importance to calcium kinetics and diastolic dysfunction .While impaired relaxation and diastolic dysfunction are used interchangably by both researchers and clinicians  resting myocardial stiffness is an important parameter that has been overlooked .

The myocardium is made up of not only myocytes  , in fact it has more non myocytic components than myocytes themself. Myocytes constitute only 33 % of cardiac mass . The interstitial cells, fibroblasts  the extracellular matrix (This is in fact a vague terminology in use !) It is nothing but  sheets of tissues made up of collagen criss crossing the myocardial planes.  The type 1 collagen is as powerful as stainless steel . Type 3 collagen is little more flexible. The issue here is , how to flex these rigid collagens without compromising it’s contractile role. One can realise , how  ignorant   it would be be ,  if we thought altering calcium kinetics within the myocardium is the ultimate answer to tackle diastolic dysfunction .

So our aim is to reduce  the resting stiffness of  cardiac muscle in pathological states like SHT/LVH/CAD etc  . . .

How to do augment myocardial relaxation ?

Altering calcium kinetics within the cell is one option. But as we have discussed  much of the stiffness comes from cells which do not have calcium at all  (Fibroblasts) or from life less molecules like collagen etc

The proliferation of interstitial cells and fibroblasts  make the myocardium stiff.So drugs which inhibit these reactive events may help.ACE inhibitors, ACE receptor blockers, anti aldosterone (Spirinolactone) are vigorously tried by respective patent holders to bring in another indication for these drugs namely positive  lusiotropic agents .But the crux of the issue and the fact of the matter is we have not made any break through in finding a positive lusiotropic drug. (Milrinone was shownto have some promise !)

We need to try new concepts instead of  trying the existing band of drugs .

The following are some  of the options

Collagen  – The interstitial collagen may be modified.The so called MMP matrix metalloprotinase which lyse collagen cross linkages can make the myocardium agile and fit.Tissue inhibitors of MMP has a role.

One should remember we can not afford to play the dangerous game of manipulating  myocardial structural protein frames . If  the myocardium becomes too flabby it will forget it’s  primary job  that is contraction

Final message

There are thousands of  articles in cardiology literature that cry fowl over diastole and few  hundred of them   devoted to quantify diastolic dysfunction by various imaging technique .

It is unfortunate  there is no single drug or intervention that has a meaningful impact  on this entity. We look forward for cardiac scientists to divert the resources to find an answer to this problem instead of simply  documenting the presence of it .

Common sense has taught us the most effective  method that can reverse established diastolic dysfunction is  by simple , regular exercise .Exercise  not only make the skeletal muscles  agile & fit it does the same to cardiac muscle too !

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