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
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 !