Thursday, January 14, 2010

Readers are welcome to the NH Blog. We are in the process of learning something about the developmental history of cardiac drugs. This time, we shall see the history of Aspirin in regard to the heart.

Before we start, I have some news which made us proud. Our boss, Dr Sunita Maheshwari was featured on the Cover of the prestigious India Today Woman in the January 2010 issue. (Incidentally, the accompanying regular issue of India Today had Aamir Khan on the Cover!) It was a matter of pride for the entire institute.

The second news was the glory we basked in the Madras Medical Mission. The annual teaching programme of MMM for the DM equivalents was held a week back. Our senior fellow, Dr Vishal Changela got the award for best case presentation. Our fellows literally dominated the session and no answer got missed from them. It stands as the solid testimony for our training and the quality of our fellows.
With this, lets go back to our regular content of blog.

One of the finest accounts of the history of a drug was written by a scientist who was directly involved in the development of the drug. Written in German, its English translation is as fascinating and soul-touching. The author of this historical account is Arthur Eichengrun, whose original article was published in 1949 in a German journal called Pharmazie. It is a “must read” for any enthusiast of medical history and (in my personal opinion) for everyone. The drug is the ubiquitous ASPIRIN. What we shall see is the development of cardiac utility of aspirin, skipping the anti-inflammatory history. For those who would be interested in the entire legacy of Aspirin history, I would strongly recommend a fantastic article by Walter Sneader in BMJ in the year 2000.

Lawrence Craven was a busy surgeon in California. His busy schedule would allow him minimal time to interact with patients and any question of personal touch was usually ruled out. On one of his busy day, he performed a tonsillectomy for a boy. Unable to get in touch with the surgeon after the surgery, the parents of the boy offered him a chewable aspirin for analgesia. The young patient started bleeding, worrying his surgeon for possibility of re-exploration. However, good sense prevailed and the surgeon decided to wait. Under some stern questioning, the parents spilled the beans and the surgeon went into a thinking mode! He made enquiries with other patients asking just 2 questions: Have you taken aspirin as post-surgical analgesia? If yes, did you experience any bleed? To his surprise, the OTC was consumed by many without his knowledge and universally had experienced visible bleed! The scientist in the surgeon made an appearance and he decided to investigate this further. He learnt that one Gibson had tried the use of Aspirin in a small number of patients with vascular diseases with equivocal response. Craven decided to make it big, but ended up being crude.

He tried around 8000 patients who consumed aspirin and came out with a claim that would surprise a seasoned physician! He claimed that none of these 8000 suffered a heart attack!! He could not publish his studies in any major journal as the trail was not a controlled study. The anticlimax of the study was reached when Craven himself died of a heart attack even after taking aspirin. The sceptics would have ended the saga of aspirin with this irony. However, good sense prevailed again and Harvey Weiss in New York could re-establish the role of Aspirin in 1967. He categorically demonstrated the acquired impairment of platelet aggregation in the subjects consuming aspirin by demonstrating prolonged bleeding time. He was the first to suggest the anti-thrombotic nature of aspirin and its use in clinical medicine. He urged the scientists to take up a larger trail in this regard. When it happened, there was no looking back. Aspirin was proved to be an effective anti-thrombotic agent. However, it took many years to come to the right dose that was minimal enough not to cause side-effects, but sufficient enough to provide the desired anti-thrombotic effect. As of today, aspirin stands as one of the most precious drugs in cardiac pharmacology.

With this, I am concluding the “Developmental history of Cardiac drugs”. I have not received any suggestions from any of the readers (if such a population exists!!) on what aspects of history to write next. May be, for next few sessions, I shall write only interesting cases and take up the historical aspects after some thinking.

On a personal note, the year 2010 is seeing lesser number of OPDs in Pediatric side. Possibly the festive season in Tamilnadu might be the reason. We should have taken this opportunity to relax a bit, but some of the events happening never let us!

I have posted this query in the past also, but it continues to haunt us on a regular basis. Hence, I am posting it again. This time, the patients are different, but the problem remains the same. We had one 16-year-old boy with Supramitral membrane with severe obstruction, Severe LVOT obstruction, large PDA and coarctation. The combination fits into Shone’s complex. The CoA was juxtaductal and the PDA was flowing right to left. The boy was desaturated in the lower limb with a significant drop in the LL saturation. His calculated baseline PVRI was 22 Wood units, which dropped to 9 Wood units with oxygen. Now the question remains the same. Is he operable? Isn’t the PVRI secondary to pulmonary venous hypertension reversible after correcting the cause? How much of PVRI is due to PDA and how much due to left heart obstruction? When put to vote, only a handful of people felt it was operable. The young guns of surgical team felt that the patient deserved to be operated as it might be his last chance for repair. However, the senior rung was not so much for it. They felt that the CoA was not much significant with PDA being the dominant lesion and it clearly shows inoperability. The decision was a bitter pill to swallow, but none of us have a concrete evidence for our stand. Such cases can be argued on either side. I questioned the need for cath study in such cases, as the pressure data and interpretations are dubious (may not be decision making in black and white) and the anatomical data might be much superior with a CT and a 3D reconstruction. However, the opinion favoured the cath study over CT. When I had to counsel the parents after the cath meet, I was choking for words. I personally felt that the boy should be given an opportunity to undergo surgery, accepting the high risk. However, the uneducated parents may not understand what we mean. I directed them to the surgical team. What bothers more is the fact that the next patient with similar problem would restart the enigma and we are no wiser by the experience of the present patient. Can anybody throw some light on this? I badly need some advice on management issues of such class of patients.

We came across an infant who had undergone artereial switch as a neonate. He is otherwise asymptomatic, except a murmur in the precordium. Echo showed bilateral branch PA stenosis. Cath showed a significant gradient in branch PAs. Is there a role of balloon dilatation in such cases? How far is it successful? The age may not permit us to stent. Is isolated balloon dilatation recommended? Should we go ahead with surgery directly or give a trail of ballooning? Put in your ideas.

This question has come up in the past, but is another case for lack of consensus. We have a 6-month-old boywith single ventricle physiology (DILV) with mild PS. His mean PA pressure in cath was 36mmHg. Now, should we be doing a PA band? How far can we offer a BDG for him in future? Is he better off as he is now? Our chief was in favour of a PA band so as to keep the future options open, but the surgical team vehemently argued against it. I thought of putting the issue with both possibilities to clear the concepts for myself! I questioned the surgical team if we can anticipate any progress in PS as a part of natural history in this subset. It was interesting to know that such incidents have happened when the level of obstruction was at restricting VSD to produce a PS in Holmes heart. My next question was on the naturally history of a scenario with present PA band, but not suitable for future BDG. Would the eventual pressure overload on single ventricle be worse than the otherwise natural history? The answer had 2 interesting facets to it. Not only such a scenario increases the pressure overload on the heart, it also increases the cyanosis, because the afterload of pulmonary circulation would be greater than that of systemic. The band enigma was another unresolved issue which made us not much wiser at the end of it.

Is it possible to have a TGA with normally related great arteries? We did see newborn with this picture. It had a clear VA discordance but the aorta came out of RV posteriorly, followed by the PA from LV, without the great arteries crossing each other. On the short axis, aorta was to the posterior and right with the PA anterior and left. Now, as per the segmental anatomy, they are {S,D,S}. Do they fit into NRGA? Is the component of crossing essential for defining normal relationship of great arteries? Can the term “Transposition” be applied if the vessels are normally related? Should we call it an isolated AV discordance or TGA? If anybody has seen such a picture before and had any thoughts gone into it, please enlighten us.

Does the definition of Shone’s complex involve the mitral valve, aortic valve and arch or does it involve left sided structures? We came across a case of corrected Transposition with sequential left heart obstruction. There was a tight supratricuspid membrane with subaortic membrane and a coarctation. Technically speaking, it does not fit the definition of Shone’s complex. This is the first time I have come across a cTGA with sequential left sided obstructive lesions. Our surgical team had a tough time operating this child. Tell me your experience if you have come across this combination anytime.

Send your comments. You can either use the comments section or use my email for posting your views and questions. Write about the issues you found perplexing and the way you have found the answer for them.



Thursday, January 7, 2010

Hearty welcome to NH blog again. We are in the process of learning something about the developmental history of cardiac drugs. This time, we shall see the development of Calcium Channel blockers.

The 1,4-dihydropyridines have an important role in the human biochemistry. Despite the role it played and the ease with which it can be evaluated, very surprisingly, minimal research had taken place involving this vital compound. The research scientists group of Bayer laboratories learnt this and started working on it. True to their research reputation, they did not leave any stone unturned. Once they had a lead, they tested for its organ efficiency and found a reasonable change in the cardiac output. They focused their energies on the molecular variant and ended up developing and testing more than 2000 analogues! The result was a patent application for a new drug called Nifedipine in the year 1967 by two scientists named Friedrich Bossert and Wulf Vater. They registered the drug for its supposed activity as coronary vasodilator.

With that started the hunt for the actual action of Nifedipine. Over a couple of years, they found that nifedipine acted by blocking calcium channels in the cardiac conduction tissue and in the smooch muscles of blood vessels. Thereby, Nifedipine led to the relaxation of the myocardial tissue and blood vessels. The resultant action was coronary vasodilatation and drop in both systemic and pulmonary vascular resistance. As an obvious result, this should have reduced the afterload and oxygen consumption. Thus, it was a drug with potential benefit in angina with hypertension. With this background, Nifedipine had a grand entry into the markets in 1975.

The major hitch of Nifedipine was its short duration of action. As the popularity of the drug picked up, this issue was to be sorted out. The research groups started the action in two sides.

The first was to develop analogues of nifedipine for longer duration of action. This would have the advantage of a sustained action on blood pressure. The result was the development of felodipine and amlodipine. In the same bargain, some more drugs were developed, which showed a higher specificity for Calcium channels of other organ systems. Nimodipine was one such development with effect on cerebral blood vessels. The advantage was its specificity, in which it did not affect the systemic blood pressure. However, all this new developments would take high levels of research and finances, not to mention the time.

The second approach was more logical and much simpler: creation of a sustained release preparation of Nifedipine. This happened quite fast and was marketed easily. With the popularity Nifedipine enjoyed, it was not difficult to make the presence for the sustained release preparation. However, the research team was aware of the short life of this strategy and had realised the effacement of molecule once the new preparations took over. But the gamble had paid off. The SR preparation effectively bridged the gap and made the constant market for the drug till the newer generation ones took over. Even today, the dihydropyridine analogues enjoy a great market presence in the field.

Compared to the systematic research of Nifedipine, the other calcium channel blocker, Verapamil was more of serendipitous in its invention. It was supposedly a takeoff from the atropine in the field of antispasmodics. In this group came mebeverine, which enjoyed some success. However, the other molecule called verapamil did not have such luck. It was synthesised by the famous Knoll pharma. Its chief of research, Ferdinand Dengel has been credited for its creation and discovery of possible uses. Once the initial trials were over, Dengel realised that the drug was nowhere near the antispasmodic action. What caught his attention was its potential action as coronary dilator. He led the research to take over towards the use in angina. The success of the trials led to the introduction of the drug in the market in 1968. Soon it was realised that the drug can cause depression of conduction activity. This action prompted Albrecht Fleckenstein at the University of Freiburg to evaluate the molecule on those lines. That explained why the drug failed as an agent for smooth muscle relaxation; it was more specific for cardiac muscles! The much more interesting finding of the research was the reversibility of its action by calcium. This led Fleckenstein to assume that the drug was indeed a calcium blocker. Further research showed that the assumption was correct and Verapamil blocked the movement of calcium ions into cardiac cells. It was credited as the first calcium antagonists. As better understanding of the cardiac physiology and the role of calcium channels became apparent, the anti-arrhythmic action of Verapamil was acknowledged in 1970s. Its action as the relaxation agent also became useful in controlling the hypertension, albeit the use is minimal for this purpose at present.

The other calcium channel blocker, Diltiazem has much more serendipitous history! It was supposed to be sought as a psychotropic drug by the Japanese. The Tanabe Seiyaku Company of Japan was working in this regard. After huge number of possible variations in the combination of the medicational research, what they ended up with was Diltiazem! The initial drug was a racemic mixture of many isomers of the drug. The research team ended up segregating each isomer and started testing them. As a part of serendipity, the dextro isomer showed great vasodilator effect. The team decided to conduct the trial for this molecule. It was finally shown to have vasodilatory action simulating papaverine on coronary circulation. Logically, they tested it against calcium ion movement across cardiac muscle membrane. It was found to be a positive blocker! Thus was born the first coronary vasodilator which was actually a calcium antagonist. Later, as a comparison with the other drugs of the group, it was tested for its action on cardiac rhythm. It was positive for that action also! Theoretically, it stood between the Nifedipine and Verapamil, with good qualities of both in the same drug. Its spectrum makes it a desired preparation even today for selective indications.

Next issue may be the last one for the history of drug development. If anyone has any ideas for future posts, please let me know.

On a personal note, we had our departmental “publication meet” recently. As usual, many a write ups are in the long process of preparation. Our mercurial boss got impatient about the delay of her lethargic team. I was advised to give up blogging and to get serious with research. I think it is a good advice for now, as the number of people reading my blog does not make any justice to my effort. I can as well concentrate on writing papers and getting credit for publication! If you find the frequency of the blog posts getting reduced in the future, you know whom to blame!!

How does a restrictive VSD in Tricuspid atresia type II behave? If anyone says as IIb, they are obviously wrong; it becomes subaortic obstruction! It is clearly unlike that of type I. But a beginner needs to understand the finesse of anatomy and should not give feel that a restrictive VSD in Tricuspid atresia II is type b. We had earlier seen a report from outside in which the baby clinically had PAH, but the echo report said Tricuspid atresia IIb. The present baby we saw had a frank narrowed pulmonary valve with sever PS. We recalled the opportunity we had of learning from others mistake! We understood the importance of measuring the size of VSD in such cases and comparing it with aortic annulus. On cath study, this boy had a mean PA pressure of 16mmHg, which was not very much OK for BD Glenn. How about creating a Glenn and doing a PA band at the same time? What is the future of such a manoeuvre? Is there any experience of doing this combo procedure? We could also recall a baby with Tricuspid atresia IC, who had undergone a PA band at age of 4 months and at the age of 2 years, had a PVWP of 17mmHg. Do the post PA bands behave any different from type B physiology in Tricuspid atresia? Does the initial period of high flow change the pressure dynamics in post Glenn any way? Any role of creating a Glenn with PA band tightening here? Please send me your takes on these.

What are the indicators of RV failure in cTGA, VSD, PS physiology? Can the progressively increasing TR be an indicator? We had a 3-year-old baby with cTGA, VSD and PS with more than mild TR. Since the age of the baby is less than the institute acceptance for RV to PA homograft and the baby was symptomatic, it was the choice between BTT shunt Vs an early Senning + Rastelli. How would each of them go about? The chance of getting an optimal sized homograft and the possibilities of repeat procedure were the caveats for Senning + Rastelli. Compared to this, the BTT shunt would increase the RV volume load in a cTGA. Is it OK to load the fragile RV for another year or so? What would be the impact on eventual RV function? Would a failed RV permit us to proceed with any procedure in future? Is there any way of making a vis-to-vis comparison? Any data on this? Please let me know.

Can cTGA have the great arteries crossing each other? We had a 2-year-old with situs ambiguous, common atrium with ill-defined pulmonary venous connection with interrupted IVC. Now that the atrial morphology could not be defined, the upper floor anatomy was unclear. However, on the echo, the ventricles appeared to have d loop with the VA concordance. One of our team members pointed towards the dilemma of labelling ventricular cavities in AVCD. Hence, if the loop was presumed to be L, then it would be AV concordance with VA discordance! Now, can a discordant VA connection have crossing great arteries? Although I maintained that it is not possible, I was not very sure of my answer, more so in a situation with situs ambiguous! If you have any data on this, please post it.

What is the definition of cardiac TAPVC? The most common answer would be the pulmonary venous confluence draining into coronary sinus or rarely, to directly at SVC – RA junction. We had an infant who presented with features of TAPVC. On echo, we found the pulmonary veins forming a common confluence and going up via the left ascending vertical vein, which entered the persistent Left SVC. There was no bridging innominate vein in this boy. The LSVC came back to heart and opened into the RA via coronary sinus! Technically, it is common confluence opening into CS. Is the variant cardiac or supracardiac? The question is more etymological, as the surgical team had no reservations on surgery, whatever name we called it! But, as a matter of interest, we debated the name. I felt that the cardiac variant should always be in physical link with the surface of heart throughout its entire course and any deviation from it would not be a cardiac variety, more so if it comes with a vertical vein. One of our team members tried to improve my words by saying that the cardiac variant should always be intrapericardial. We would like to get an opinion from the readership. Does the definition involve only the destination or the journey too? Please write your take on it.

Coming back to TAPVC, we often come across mixed TAPVC. Less common but seen variants are the dual drainage, which involves the different pulmonary vein combinations entering RA via separate entry sites. Technically, dual drainage is different from mixed TAPVC. The question is, should they be considered as a separate entity? The traditional Darling’s classification of TAPVC does not mention dual drainage at all. What is the opinion from the surgical clan? Should the naming follow only when the management differs or should it be adherent to the embryological basis? Definitely, the embryological basis of dual drainage is different from that of other variants. What is your take on it? Pen your opinions.

Let me know your opinions on the issues raised or any issues you want to rise! The whole objective of the Blog is to encourage the exchange of opinions on the issues that may not have a straight forward answer. The opinions from your side would be very valuable to lot many for ages. Don’t hesitate to post questions if any genuine problem is bothering you. Let the enlightened readership be your guide to a “Yet to be opened door”. You can either use the comments section or use my email for posting your views and questions. Best of luck.