Saturday, November 28, 2009

Welcome back to the NH Pediatric Cardiology blog.

We saw the historical development of Digoxin and Diuretics in the last 2 posts. In this post, we shall see the development of another important class of cardiac drugs: the Beta Blockers.

The huge laboratory of Eli Lilly in Indianapolis is a place for innovation. The recordings of events are so meticulous that serendipities are not unusual. In this lab, Irwin Slater was working on the analogues of isoprenaline to create long-acting bronchodilators. The agents were screened for their ability to relax tracheal strips contracted by pilocarpine to simulate the asthmatic bronchoconstriction. Adrenaline was used on these strips to ensure their responsiveness between the tests. Some strips were by chance got exposed to dichloroisoprenaline. Surprisingly, these strips did not relax when the adrenaline was added. For the first time, an antagonism to adrenaline was noted. In 1957, at a scientific meeting, Slater reported the phenomenon of dichloroisoprenaline antagonism.

This finding got the keen attention of Neil Moran, at Emory University in Atlanta. He requested Eli Lilly to provide samples of the new drug to investigate its effects on the heart. He was surprised to find that dichloroisoprenaline not only antagonised the changes in heart rate and muscle tension produced by adrenaline, it also mimicked the activity of the adrenaline to a certain extent. He reported his findings in a prominent journal.

It was the time when ICI Pharmaceuticals Division (now incorporated in AstraZeneca) had decided to make it big in the market. For this, they had caught a big man – James Black (Knighted in future, after winning the Nobel) Moran’s report caught the attention of James Black. The equipped Lab of ICI at Alderley Park in Cheshire was seeking a major breakthrough and had funded Black with a grant to further diversify his investigations into coronary artery disease.

Black had a phenomenal sense of first principles. He had for long believed that there exists an alternative way of treating angina. It would simply be to find a drug to reduce the oxygen demand of the heart. Black did not believe in merely increasing blood supply by vasodilators such as the nitrates. He sensed that treating a patient just symptomatically would not solve the issue. Black was in pursuit of a medication with longer, better and sustained effect that could increase the life span of the patient.

Black, by then, had realised the relationship between the heart rate and the oxygen demand. The influence of catecholamines on heart rate was well established. He was logical enough to correlate the effects of suppressing adrenaline and noradrenaline on heart rate and thereby the oxygen demand. But, his experiments along these lines till then had no gain.

On reading Moran’s paper a new wave of thought occurred to Black. He immediately realised the potential of this paper. His team had done extensive work on receptors which Raymond Ahlquist had described as beta-adrenoceptors. It should be possible to find an analogue of dichloroisoprenaline devoid of intrinsic action. This molecule can bind to the beta receptors in the heart.

Black entrusted his colleague John Stephenson to synthesise the drug of his ideas. The first effective beta-adrenoceptor blocker was synthesised in February 1960, by replacing the bulky chlorine atoms of dichloroisoprenaline with a second benzene ring to form pronethalol. The drug was orally active but short-acting. A small clinical trial on 30 patients confirmed the anticipated actions pronethalol in angina. The side effects noted were mild. It also gave pleasant surprises to the research team when its action went beyond the angina. Black had anticipated prevention of atrial fibrillation and atrial or ventricular tachycardias through diminution of the response to emotional or exercise-induced
sympathomimetic activity. This was confirmed in the trail. The drug also showed a marked hypotensive effect when taken for several months. This was totally unexpected but well desired. This led to the development of another trail in hypertensive patients. Pronethalol proved its value in reducing blood pressure also. Finally, the research team thought, the wonder drug was born!

But their happiness was short lived. Long-term toxicity testing in mice was received within few month of the trail of the drug and showed the association of pronethalol with cancer of the thymus gland. But such a big breakthrough could not be left alone. ICI decided to launch the drug late in 1963. Its use was limited to patients whose lives were seriously at risk. Today, the drug has become only a historical reference, but it started a new era in cardiac management.

No sooner the thymus carcinoma report arrived, the ICI research team started to improvise the drug. As a result, within a short time of the launch of pronethalol, the new drug propranolol was launched by ICI in 1964. It was found to be non-carcinogenic and ten times as potent as pronethalol. This marked the arrival of beta blockers in the therapeutic world and stood as the yardstick against which any improved version would be compared. All the other beta-blockers developed since then, retained the anti-anginal, anti-arrhythmic and antihypertensive properties of pronethalol.

The success of propranolol can be gauged by its existence in market even today.

Few hundred miles from ICI lab, one more team was evaluating the same compound – dichloroisoprenaline. But this centre called AB Hassle at Goteborg, Swedan was interested in potential anti-arrhythmic action. Short time after the launch of Propranolol, this centre developed and launched Alprenolol which very soon was acclaimed as an effective anti-arrhythmic with useful activity as anti-hypertensive medication. The success of this drug instigated other firms to take up active research in this group of drugs.

Another giant of a firm, Ciba, was successful in developing another beta-blocker called Oxprenolol, which retained partial agonist activity with beta1 and beta2-adrenoceptors. The advantage was immediately palpable. This agent did not produce as much bradycardia as the other beta-blockers, as this drug was capable of stimulating beta1-adrenoceptors in the heart. This property was termed as “instrinsic sympathomimetic activity” (ISA). This feature was useful in patients with peripheral vascular problems. Because of the ISA, oxprenolol did not cause feeling of coldness in extremities in patients with peripheral vascular disease, which was an undesirable feature of other beta-blockers. However, the stimulation of beta2-adrenoceptors in the lungs was suboptimal and oxprenolol was not proved sufficiently safe for use in asthmatic patients.

This led to the development of timolol, which which was initially used as antihypertensive. Some researchers found the utility of direct application of Timolol to the eye for the reduction of intraocular pressure in chronic simple glaucoma.

Few researchers kept Propranolol as the baseline drug and started improvising on it. The dihydro analogue of propranolol was the most promising and the compound was taken up by the Squibb Institute for Medical Research in Princeton. The ensuing compound led to nadolol. The dihydro component rendered it water soluble and less lipophilic. This property prevented it from entering the central nervous system, thereby reducing CNS side-effects such as sleep disturbance and nightmares associated with other beta-blockers. Also, low lipophilicity reduced the entry of the drug into liver cells. This reduced the rate of metabolism and ensured a longer duration of action.

The Mead Johnson lab could sense the potential market for beta-blokers by 1960. Their chief scientist, Larsen was a renowned name in the field of Sulfonamides. Logically, he used a sulphonamide side chain to isoprenaline in the place of phenolic group. This led to the development of Sotalol. Pharmacological evaluation showed all the components of beta-blockade. Also, as an added bonus, it also relaxed tracheal, uterine and intestinal muscles. Due to its hydrophilic nature, sotalol did not enter the CNS and had longer duration of action as nadolol.

The development of sotalol reached the ICI chemists. This led them to devise a series of its further analogues. Practolol was developed like this. Evaluation testing of Practolol had all the desired action on the heart but failed to antagonise the peripheral vasodilation caused by isoprenaline in anaesthetised dogs. For the first time a beta-blocker was selective for heart receptors. This literally caused a wave of elation in the medical community. This drug could avoid bronchospasm in patients with asthma or obstructive airways disease, which was actually a major clinical problem with beta-blockers. Practolol was marketed in 1970 for use in asthmatic patients with co-existing heart problems with much jubilation. But the excitement was short lived. Practolol on long term oral therapy could cause a serious oculomucocutaneous reaction, leading to blindness. This led to a seriously fast pursuit of alternative and better drugs and soon, practolol was abandoned. The new drug was Atenolol. As Practolol, it was relatively selective with regard to its action on beta2-adrenoceptors in the lung and on beta1-adrenoceptors in the heart. For a long time Atenolol was the most frequently prescribed beta-blocker and the third-best-selling drug in the world (after ranitidine and cimetidine). Its low lipophilicity prevented its entry into the CNS.

Atenolol, due to its phenomenal success, now stands as the baseline against which the new class of beta-blockers are developed. May & Baker developed acebutolol which could not replace Atenolol effectively. Acebutolol did not have much selectivity for cardiac receptors but it retained partial agonist activity.

Chemie Linz introduced a new developed beta-blocker compound called celiprolol. It was the first cardioselective beta-blocker with partial agonist activity. Labetalol was soon introduced by Allen & Hanbury, which had the added advantage of blocking the action of sympathomimetic amines both at beta-adrenoceptors and also at alpha1-adrenoceptors. Thus it was more effective anti-hypertensive at a lower level of adrenoceptor blockade.

Lateral thinking is a part of drug development industry! The scientists should analyse every bit of information to be better equipped to face challenges. Many drugs end up with severe side-effects, making the drug useless for the purpose. However sometimes the side-effects turn the table around – it becomes the main effect and form a therapeutic entity. Many such examples exist in the history of drug development. Beta-blockers have also contributed to this list. The side-effect associated with propranolol and other lipophilic beta-blockers was the vivid dreams or even hallucinations. The ICI scientists capitulated on this. When others in the world tried to reduce the lipophilicity to avoid CNS entry, brains at ICI prepared analogues of propranolol to increase lipophilicity further. This resulted in psychoactive drugs. In 1969 ICI patented viloxazine as an antidepressant drug. It was a relatively non-sedating antidepressant which inhibited both noradrenaline and 5-HT reuptake in the brain. The main use of this drug was in patients experiencing anticholinergic and cardiac side effects of antidepressant drugs such as imipramine and amitriptyline.

In the next post we shall see the “Developmental History” of one more class of cardiac drugs!

On a personal note, we are experiencing the “side-effects” of expansion! Incorporation of peripheral institute for high-end services is a part of growth of corporate hospitals. But the peripheral centres would not accept newly recruited specialists. They want the same specialists in the original corporate institute to attend their clientage. When the number of specialists is scarce, such demands would put extra stress on the existing specialists. This is a “no-win” situation for everyone, but is a part of the problem faced by expanding corporates also. The management which should handle such situations are usually clueless on such issues and would conveniently transfer their responsibilities to the head of the concerned speciality team. “How to...” is the major issue. If find a solution, I shall let you know!

We are witnessing a surge of patients from a neighbouring state due to a newly launched insurance scheme by state Government. This is letting us see adolescent age group with a newly diagnosed complex CHD. We saw TAPVC in second decade, Truncus at 8 years, many cases of TOF in late second decade, Eisenmengered DORV and so on. All these children would never have had a diagnosis also, let alone treatment if not for the support from Government. After the phenomenal success of Yeshaswini health insurance scheme (www.yeshaswini.org) of Karnataka state, many states have tried to emulate it. A large amount of credit for the success of Yeshaswini should be shared by Narayana Hrudayalaya also. Dr Devi Shetty was instrumental in devising and executing the scheme, which was adopted by the Government of Karnataka in a big and “never before in the country” way. One can get the entire story from multiple sources including Harvard journals, London school of Economics website, Wall Street Journal website and so on. Those who interested in the success story of Yeshaswini can Google for it with Dr Devi Shetty’s name.

How fast can a subaortic membrane recur? We have a 3.5-year-old who underwent SAM excision 2 years back with minimal obstruction post-operatively. The toddler has come back with severe LVOT obstruction with recurrence of SAM now. What might be the cause of such a fast recurrence? To begin with, what was the cause of such severe SAM at 1.5-year-old? Are these dynamics different from SAM in older age group? When SAM excision has not worked for 2 years also, how long it would work now? Is the pathophysiology of such subgroups different? Is there an additional problem with LVOT? Do such subgroups require different lines of surgical management? Should a Konno be performed in them? Is only Konno enough or a Ross-Konno is required? Should such an extensive surgery be done at the inception or on Re-do if required? Are cases of re-do for SAM in such young age described? Any inputs on these issues? If anyone has any data, please let me know. If references are also provided (if any), it would be much appreciated.

We had a 5-year-old with Tricuspid atresia IIB. The cath data was in favour of surgical intervention. However, this baby had veno-venous collateral. It was deemed that the collateral can decompress the PA pressure and the actual PA pressure would be much more than the measured PA pressure in the cath (12mmHg). Is there any way of putting a correction factor for such situations? Can we just presume something and change our plans? What would be more logical in such cases? Please put in your thoughts.

When we look for reversibility of PVRI in the cath studies, we use oxygen or NO or both. If the post-oxygen data turns out be good by drop in the PVRI, we operate. However, such patients don’t live with higher concentration of oxygen after the surgery. So, what is the logic behind the using these agents to check the reversibility? This question was popped up in one of our sessions and a satisfactory answer could not be obtained by the house. Any references on this?
Has anyone done any research in this? What was the original explanation be the researchers who devised these techniques? Please let me know.

How does a combination of obstructive lesion and a shunt lesion behave? I had put this question for last two posts in the case of a VSD and Coarctation. Is the logic different for PDA with coarctation? We had a toddler with large PDA and severe coarctation. Cath data showed a Qp/Qs of <1 and a PVRI of 16 Wood units.However, he was deemed operable and taken up, despite the cath data. Same data in an adolescent with VSD and coarctaion was termed inoperable. Is it because of age or the dynamics are different? This question is getting more interesting and tougher at the same time. Please put in your comments on it.

We saw a 9-year-old with TAPVC with Truncus! I had never come across such a combination before. The age was surprising. More surprising was the fact that the child was not cyanosed! Two cyanotic lesions with high Qp have failed to produce cyanosis till this age either by mixing or by high PVRI. Few people have a strong combo of luck and ill-luck running parallel!

We saw an infant who was stable with no features of increased Qp. He had a single S2 with a click and a continuous murmur. It was a perplexing clinical scenario. On echo, we found a type 2 truncus with mid segment narrowing of both PAs! This is the first time I came across a type 2 truncus with bilateral PA narrowing. Good for the kid!

What is the worldwide mortality pattern of PA bands? Is this practiced extensively in the west? Our surgeons continue to have a tough time with these surgeries. One of our senior surgeons was in favour of abandoning these surgeries for some time! Aren’t the indications for these surgeries getting modified in the current era?How are the centres across Europe and American continents doing? If you know about it, please enlighten us!

Some news from the department to share: The stork visited the Alvas! Dr Rashmi and Dr Prem Alva are the proud parents of a lovely daughter now. Best wishes for the new parents. Let the Almighty bless the newborn with all His might!

Applications are invited for the Fellowship in Pediatric Cardiology affiliated to Rajiv Gandhi University of Health Sciences, Bangalore. The fellowship would be of 18to 24 months duration. The training would happen entirely at Narayana Hrudayalaya. Doctors with post-graduate qualification in Pediatrics (MD or DNB) or Cardiology (DM) would be eligible to take the entrance exam and interview. For further details please visit the NH website: www.narayanahospitals.com

Click your comments. If you find any difficulty, feel free to communicate with me at drkiranvs@gmail.com I shall post the contents of your mail in comments on your behalf.

Regards

Kiran

Saturday, November 21, 2009

Welcome back to NH Pediatric Cardiology blog.

In the previous post, we saw the History of Digoxin. In the present post, we shall see the development of another important life saving class of drugs: The Diuretics.

Mercury can be considered as one of the oldest of all drug prototypes. The majority of drug prototypes come from the animal and vegetable sources; mercury belongs to a minority that was derived from the minerals. An ancient Hindu work by Nagarjuna, named “Rasa Rathnakara” had masterly description of using the mercury and related compounds to strengthen the weak hearts. Mercury had also been employed by Paracelsus in the treatment of dropsy.

The first diuretics were organomercurials; toxic, but effective. Their introduction into clinical medicine was in the late 1880s. Mercury benzoate, was the initially chosen one because it was slightly soluble in water. The fusion with of inorganic mercury with an organic compound was aimed at reducing the irritancy and toxicity of inorganic mercurials and to obtain a slow, sustained release of mercuric ions from the organic complex. This was followed by the marketing of a number of injectable organomercurials. One such compound was introduced in 1912 by F. Bayer & Company for the treatment of syphilis. This was called merbaphen, a double salt of sodium mercurichlorophenyloxyacetate with barbitone.

Serendipitous use struck gold seven years after the introduction of merbaphen when Arthur Vogl, a third year medical student at the Wenckebach Clinic in Vienna’s First Medical University, had ordered a 10% solution of mercury salicylate to be prepared by the hospital pharmacy. When he did not get the preparation, he went to the pharmacy and was told that a solution in that concentration could only be prepared as an oily injection. A colleague suggested Vogl to use merbaphen injection instead and was done. As a routine, the meticulous nursing staff maintained the chart of the urine output of the patient. Vogl was surprised to see that, the patient who was struggling to pass 500 ml of urine in 24 hours had passed 1200 ml in 24 hours after the very first dose of merbaphen. After the third daily injection, this had increased to 2 litres in 24 hours; a feat which no other known medication of that time could achieve! Interested in creating a cause-effect relationship, Vogl withheld the medication for a few days and dramatically, the urine outflow decreased. On resumption of the injections, urine output improved again. Vogl decided to extend this use in other patients. He chose to administer merbaphen to another syphilitic patient with advanced congestive heart failure. Conventional diuretics of those times had no effect on this man. Vogl was not surprised this time to see his patient passing massive amount of almost colourless urine with the first dose of merbaphen. The flow continued throughout the day and the night and by the next morning the patient had passed about 10 litres with thorough exhaustion and elation at the same time! Vogl found that profound diuresis was produced in any patient injected with merbaphen. But other antisyphilitic mercurials could not produce any effect close to this. After confirming this in multiple subjects, Paul Saxl decided to conduct a thorough clinical evaluation. This transformed the treatment of the severe oedema of congestive heart failure, allowing it to recover to normal function. No other medication used hitherto had any activity comparable to this.

The joy was short lived. It was soon recognised that merbaphen injections posed a risk of severe renal damage or fatal colitis. But the effect was not ignorable. So, improvisation process began and soon, merbaphen was replaced by another antisyphilitic agent, mersalyl, which was administered on an intermittent schedule to minimise toxicity.

Around the late nineteenth century that mercury and mercurous chloride were introduced as oral diuretics. Tablets combining finely dispersed metallic mercury with digitalis remained on the market until rendered obsolete by the introduction of the thiazide diuretics in the 1950s.

The demand for a non-toxic, potent diuretic was critical and the challenge was accepted by a team of researchers from Sharp & Dohme, under the direction of Karl Beyer in the early 1950s. The then recent developments in renal physiology had convinced him that the moment had come to design a safe, effective diuretic. The renal physiology had proved the role of renal tubules in the reabsorption of water from the glomerular filtrate. It was understood that the efflux of sodium ions across the tubule wall was the responsible factor. It was believed that mercurial diuretics interfered with movement of ions by inhibiting dehydrogenase enzymes inside the tubular cells. This prompted the Sharp & Dohme scientists to try designing mercury-free inhibitors of dehydrogenases in order to avoid the toxic effects of mersalyl.

Although, in theory, they had proved the requirement, practically, it was a daunting task that took many years of intensive research. After series of failures, they decided to reaffirm their hypothesis. They went back to understand the correct action of mercurials. This turned out to be the turning point. It was the realised that both merbaphen and mersalyl possessed a phenoxyacetic acid moiety. When an unsaturated ketone was attached to the 4-position of the benzene ring, potent hydrogenase inhibitor was obtained. When they sought the influence of additional substituents, it was shown that chlorine or methyl groups attached to the benzene ring further enhanced potency. Ultimately, ethacrynic acid emerged as a safe, orally active diuretic in 1962, five years after a separate group of Sharp & Dohme chemists had announced their discovery of the thiazide diuretics with similar properties.

Thaddeus Mann and David Keilin were the researchers working at the University of Cambridge in 1940. They had had isolated in an enzyme in pure state a year before which was known to play an important role in the output of carbon dioxide by the lungs. The enzyme was called carbonic anhydrase. They observed the fall in carbon dioxide binding power of the blood caused by some of the recently discovered antibacterial sulphonamides. They carried out an experiment to determine whether this could be accounted for by inhibition of carbonic anhydrase. The experiment confirmed their suspicions. Sulfanilamide was the prototype.

At the Harvard Medical School, researcher Horace Davenport discovered large amounts of carbonic anhydrase in the kidneys. Earlier, Rudolf Hober had observed alkaline diuresis in patients who had been given massive doses of sulphanilamide. Now it could be accounted for by increased excretion of sodium bicarbonate caused by carbonic anhydrase inhibition. The resorption of water from the tubules of the kidney depended principally on the absorption of sodium ions from the lumen. When the enzyme was inhibited, sodium ions were excreted in the urine because the process responsible for their reabsorption was blocked.

Davenport informed the data to Richard Roblin at the Lederle Division of the American Cyanamid Company and sought a more potent inhibitor of carbonic anhydrase from them. Thiophen-2-sulfonamide was provided in the belief that it would be more acidic than conventional sulfonamides and that this would enhance its ability to compete with carbon dioxide for the active site on the enzyme. It was about 40 times more potent than sulphanilamide in inhibiting carbonic anhydrase.

Boston physician William Schwartz in 1949 experimented with oral sulfanilamide to obtain diuretic effect. But he had to abandon this due to toxic side effects. But, this observation prompted Roblin’s interest in carbonic anhydrase inhibitors again. He and James Clapp restarted their experimentation and within a year, acetazolamide was synthesised. It was about 330 times more potent than sulfanilamide as an inhibitor of the enzyme.

Acetazolamide was available as orally active diuretic in 1952. Soon, it was noticed to have a variety of complications. The only way to use acetazolamide was on an intermittent schedule. Serendipitously, the inhibition of carbonic anhydrase in other parts of the body was turned to advantage, as in the treatment of glaucoma. Acetazolamide remains in use for this purpose even today.

Karl Beyer could not be left behind for long. Leading a new project for Merck, Sharp and Dohme, he analysed the problem with sulphanilamide. He found that that it inhibited carbonic anhydrase at the distal end of the renal tubules, rather than solely at the proximal end. This could be accounted for the increased excretion of bicarbonate. He sought a carbonic anhydrase inhibitor that acted in the proximal portion. Such a drug would have the advantage of being useful antihypertensive agent. It was the time when low salt diets were believed to be an effective means of controlling high blood pressure. The first carbonic anhydrase inhibitor that Beyer came out with the name of carzenide. But, in humans it was poorly absorbed from the gut and had weak diuretic activity. It still inspired James Sprague and Frederick Novello to research further. This led to the introduction of clofenamide which was a potent carbonic anhydrase inhibitor. Further medication of this was dichlorphenamide which produced an increase in chloride secretion in humans.

Dichlorphenamide served as a baseline drug for the future research. Further research was aimed at achieving better dieresis with no further reduction in chloride ion excretion.

Novello and colleagues made the N-formyl analogue with formic acid. This resulted in an unplanned ring closure to form a benzothiadiazide. As a matter of routine, this novel compound was entered in the screening programme. It was a matter of surprise and delight to the team when it was found to be a potent diuretic which did not increase bicarbonate excretion. Clinical tests confirmed the safety of this orally active diuretic with marked saluretic activity.

With the first reports in 1957 it was termed ‘chlorothiazide’. It had duration of action of 6–12 hours. Literally overnight, singlehandedly, it rendered mercurial diuretics obsolete for the treatment of cardiac oedema associated with congestive heart failure. Chlorothiazide still remains in use because of its low price.

On the other side, Ciba scientists led by George De Stevens replaced the formic acid used to produce chlorothiazide with formaldehyde and thereby obtained hydrochlorothiazide, which was ten times as potent as chlorothiazide. Since then, many other thiazides have been developed.

Dichlorphenamide was still the baseline drug for the research. Some modifications in the acidic side of it and replacement with a carboxyl group gave a new molecule. This led Hoechst to introduce frusemide (also known as ‘furosemide’) in 1962. It had a quicker onset of activity, more intense and of shorter duration than any other diuretic. Frusemide had a different site of action within the kidney tubule and became known as a loop diuretic because it acted in the region known as the loop of Henle. Loop diuretics were valuable in patients with pulmonary oedema arising from left ventricular failure. Despite thiazides being indicated for most patients requiring a diuretic, frusemide is widely prescribed.

Bumetanide is a more potent loop diuretic introduced by Leo researchers ten years after frusemide. Hoechst introduced its analogue known as piretanide when their patent on frusemide expired.

In the next post, we shall see the fascinating history of one more class of drugs.

On a personal note, the work at NH is getting heavier with all the addition of Tamil Nadu government insurance schemes. We ended up doing echoes for patients with eye burning, skin infections and healed fractures! The screening does not happen at any place for such patients. Most of them would like to take the advantage of the free services and would insist on getting all the investigations done free of cost. The ensuing load on doctors and the compromise in the quality of investigations done are nobody’s concern. We insisted on putting up a higher limit to the numbers everyday for the scheme patients. But, eventually, we would end up seeing loads of children who would probably not require echocardiography otherwise. I don’t know how much of quality compromise has happened due to extension of echo and OPD timings by at least 2 hours every day!

Is it possible to a Fontan repair in a case of interrupted IVC? The usual protocol is to do a Kawashima repair, which does not involve incorporation of hepatic veins into the venous circuit. The chances of AV fistulae are higher possibly due to the lack of hepatic factors. But, if by any chance we can incorporate the hepatic veins into the venous circuit, would this be called Fontan repair? In case of one such boy, our surgeons evaluated the cath images and were of the opinion that a Fontan repair can be done. Any inputs?

How often do we find a diverticulum in the RV? We had one such patient with DORV of single ventricle physiology. His RV angiogram showed an outpouch of contractile nature. The close DD would be an aneurysm which would be devoid of any contractile elements. Atrial diverticulae and LV diverculae are known. But this is first RV diverticulum we have come across in recent times.

In cases of older children with Tetralogy, if PA sizes are small and eventual McGoon ratio is low, should we consider Brock’s procedure? It is said that, as the age progresses, the PA sizes cannot improve with BTT shunt. Is the improved antegrade flow the best way of improving PA sizes? If so, can Brock’s be the way? It is true that the patient would through for bypass for this. But, if it has the potential to prepare the patient for the future complete correction, is it not worth it? Are there any repots of using Brock’s procedure for such a purpose? It is a “third world” problem and developed countries may not have seen such an eventuality. If anyone’s got any data or experience on this, please let me know.

Is there an oral inotrope that is as effective as IV? Can levosimendan qualify? In cases of chronic ventricular failures, the patients cannot be on IV inotropes for long. They can have some solace if they can be treated at home with some oral inotropes. The traditional drugs with inotropic action may not suffice all the times. If anyone had any personal experiences with their patients, please let me know.

In the last post, I had put up the case of sequential lesions. Our patient had a VSD and severe coarctation. The query was the operability assessment of VSD in the presence of severe Coarctation. We decided to balloon the coarctation and check for VSD operability. After successful balloon coarctoplasty, we found that the VSD had a PVRI of 18 wood units. Is there a way of assessing the same thing prior to coarctation intervention? Any experiences? Please let me know.

How many times do we come across cyanosis in ASD in children? It is a typical exam question and most of us know about 5 to 6 causes. But, we happened to see one child with ASD and cyanosis. The subcostal windows were suboptimal. All the causes we knew were verified, but with no gain. At last, we decided to do a contrast study and found to our surprise that the RSVC was entering directly into LA! There was no LSVC or PAPVC or TAPVC. How common is such a situation? I came across such a lesion for the first time.

We happened to see one 18-year-old boy with unobstructed TAPVC and dTGA with ASD and intact IVS. Is there any advantage of doing any surgical procedures now? Is it ethical leaving him as he is? Again, these are the “third world” dilemmas! What is the natural history of an untreated dTGA? Does the co-existing TAPVC has changed the course? Any inputs?

I would be happy to see your inputs. In case of any difficulty in posting a response, please send it to my email drkiranvs@gmail.com I shall post your response on your behalf.

Saturday, November 14, 2009

Welcome back to NH Pediatric Cardiology Blog

I started feeling a kind of vacuum after the History of Pediatric Cardiology was completed. A couple of sessions with Nobel prize winners could do no good to my feelings, as the research involved was neither extensive, nor satisfying. I sought suggestions from my team; and as usual, very few came in! I was suggested to go with some of the musings we came across in the wards and OPD. True life incidents involving parents’ feelings and doctors’ dilemmas were suggested. Incidents which changed our outlooks towards something was another suggestion. Miraculous survivals or an improvement in some of the patients and possible causes of it was another suggestion. All these are no doubt good, but they lack the sustenance value. They may be inserted as snippets, but cannot sustain an entire post. Also, their frequency is less. Nevertheless, I have received all these suggestions with great fervour, and hope to do justice to them sometime in future.

I have known people who are into pharma research. I happened to meet some of them, who have spent years together in developing an elusive drug, just to see nothing at the end of it! But, what a zest they have! I always had the admiration for the creators. It is in this spirit that I will be writing on the history of development of some of the cardiac drugs. They should read like a proper story albeit a true one. It is an ode to the people who have made it for all of us.

It might be prudent to make a beginning with the most famous and equally controversial yet indispensible drug of cardiology. Yes, the mighty DIGOXIN!

Foxglove (Digitalis purpurea Linn) was a folk remedy introduced into medicine in the 18th century. It grew throughout Europe. The term “Fox” was a misnomer as this shrub was originally known as the folksglove due to the shape of its flowers. The shape of the flowers and the colour gave its scientific name, which is derived from what was given to it in AD 1539 by Hieronymus Bock. He explained that
‘digitalis’ was an allusion to the German word fingerhut (finger stall), since the blossoms resembled the fingers of a glove.

Foxglove has a long history of folk use. The Ancient Celtic tribes know about it and made use of its medicinal properties. A family of 13th century Welsh healers applied it to the body by inunctions to relieve headache, abscesses and cancerous growths. It was also listed among herbs used by Edward III of England in the 14th Century.

In 1775, the English physician and botanist William Withering (1741–1799) was asked his opinion of a herbal tea prepared by an old lady on countryside for the relief of dropsy. Her medicinal preparation boasted of phenomenal success to dropsy, for which the then medical world did not have a proper remedy. The cause of dropsy was then unknown, so the possible explanation of the treatment was explained by expulsion of the excess body fluid. Withering, who was a trained botanist, very soon realised that among the 20 or so ingredients in the herbal tea, it was the foxglove that was most likely to be causing the violent vomiting and purging if taken in excess. During the next nine years, Withering treated 158 patients with it, of whom about two-thirds responded favourably. In 1785, he wrote his treatise entitled “An Account of the Foxglove, and Some of its Medical Uses: with Practical Remarks on Dropsy, and Other Diseases”. The write up was not only a list of his observations, but also, a description of how to determine the correct dosage, which was highly relevant since foxglove was a potent poison that was ineffective unless administered at near the toxic dose level. He took care to standardise the doses he used, to a level for determining the correct dosage for each patient. He also discussed different ways of preparing foxglove, preferring the use of powdered leaves.
However, what Withering did not realise was that the stimulant action of Foxglove on the heart which was responsible for its beneficial role in dropsy. It was paradoxical that in the year 1799, the year of his death, Ferriar suggested that the increased urinary output was of secondary importance compared with the power of foxglove to reduce the pulse rate.

Although it was not in great use at that period, some minds could identify the importance of this drug very soon. The need for isolating an active principle from digitalis was recognised and attempts were made in the 1820s for the same. To stimulate research, the Paris Pharmacological Society offered a prize of 500 francs for the isolation of a pure principle from the plant. As per the prevailing financial rule, this sum was to be doubled every five years if no claimant came forward. But, in 1841, the French pharmacists E. Homolle and Theodore Quevenne won the award for their isolation of an impure crystalline material which consisted mainly of impure digitoxin. They called this ‘digitalin’, a name also applied to various products obtained by other workers.

However, the principal cardiotonic glycoside present in the leaves of Digitalis purpurea which was termed Digitoxin, was isolated in 1875 by Schmiedeberg at the University of Strassburg in Germany. He obtained crystals from digitalis leaves.

It was an era when the apparent clinical success would not pave for the regular use of medicines. Because of the lack of a clear understanding of how it was able to affect dropsy, foxglove was rarely used as a cardiac stimulant during the 19th century. German pharmacologist Ludwig Traube revealed the stimulating effect of foxglove on heart muscle in 1850. But it was around 1901 that a clear understanding of the effects of foxglove on heart was revealed by the development of the polygraph by the Scottish physician James Mackenzie and the electrocardiograph by the Dutch physician Willem Einthoven. Subsequent investigations along these lines revealed some of the correct indications for the use of digitalis: atrial fibrillation or in certain forms of heart failure in sinus rhythm.

In 1920, Max Cloetta in Zurich hydrolysed digitoxin under acid conditions and isolated the aglycone, digitoxigenin, which had weak cardiotonic activity. Adolf Windaus finally obtained pure digitoxin in 1925, at the University of Gottingen.

The structure of digitoxigenin was determined by Walter Jacobs and his colleagues at the Rockefeller Institute in New York, but it was not until 1962 that chemists at Sandoz in Basle elucidated the structure of the sugar residue and hence that of the entire molecule of digitoxin.

In the late 1920s, it was discovered that the powdered leaves of Digitalis lanata, once popularly known as ‘woolly foxglove’, had greater physiological activity than those of Digitalis purpurea. This led Sydney Smith of Burroughs Wellcome in London to isolate digoxin. This is now used more than either powdered digitalis leaves or digitoxin since it does not bind as strongly to proteins in the tissues and plasma, resulting in less delay before a therapeutic concentration of unbound drug can build up. Clearance from the body is also faster as only unbound drug is filtered by the kidneys; consequently digoxin is less cumulative and thus safer to use. It has become the standard digitalis preparation in current usage.

Thanks to the painstaking efforts of Withering, experimental medicine was now able to exploit the single greatest breakthrough in the history of drug discovery. Progress from prehistoric times until then had been pitiful because two essential factors were missing: access to chemical compounds with consistent potency and effective methods of clinical investigation. Access to these during the past two hundred years has made it possible to identify and exploit beneficial drugs, free from the dogmatic teachings that were the legacy of the past and a major obstacle in the path of drug discovery. The discovery of Digoxin paved a new revolution in the field of drug discovery and its scientific analysis. The nature hides millions of such drugs, waiting for the mankind to explore with open mind. We need more “Witherings” to do it!

If we can name one more class of drugs used to a great extent in the clinical cardiology, it must be diuretics. The journey till the point of high ceiling diuretics has been equally fascinating. It all started with experimental medicine with keen eyes and mind with meticulous observations. We shall see the development of Diuretics in the next post.

On a personal note, we were wondering how much challenges this small filed of pediatric cardiology can pose! Someone had once told me, “You have 4 valves and 4 chambers. How much is there to learn in Pediatric Cardiology?” With every new challenge, I remember that person!

We saw an 11-year-old boy in our OPD with NYHA class 2 symptoms. On examination, he had RV apex, RV forces, wide fixed split, PSM at RLSB. Also had an ESM at RUSB. Except for the ESM, everything was fitting into the diagnosis of ASD. What we saw in echo was surprising. The IAS was intact. RV was hypertensive and dysfunctional. There was a severe TR. Further, the IVS was intact. MPA continues as RPA with absent LPA. RPA had a gradient of around 50mmHg. The fixed split and PSM were thus explained. Also, the ESM could find a place. But, what started first? Was it the RPA stenosis (which is underestimated now) the primary event? What might have caused RV dysfunction? We have no previous records. In such cases how to explain the chronology of events?

We saw a 17-year-old boy with Tetralogy of Fallot. Though echo windows were compromised, we could see a dilated origin of Left coronary artery. We subjected him for cath study, which showed a large Left coronary to PA collateral. This was second such instance we had seen such an anatomy with TOF. However, in this boy, the PAs were small. McGoon ratio was 1.2 How to go about? This boy had SO2 of 86%. BTT shunt is unlikely to improve his saturation or PA sizes. He had no angina pain and no indication of coronary steal. Dr Sunita suggested Treadmill test for inducible ischemia. TMT was terminated due to effort intolerance, but no angina. TMT did not show any ST-T changes. This boy had achieved 6.5 METS. The surgical team is keen on ligation of coronary to PA collateral and creation of BTT shunt. But the question remains same: Has the patient earned his surgery? Can we wait? Is it advantageous or not to wait? Please let me know your takes on this situation.

The enigma of sequential lesions never ends amusing us. We have a 4-year-old boy with VSD and a tight coarctation of aorta. Cath data is obviously has its limitations and usually not accepted well by surgeons. In this case, the cath data showed PVRI of 14 Wood units with oxygen. We suggested balloon dilatation of CoA and reassessment of VSD. However, the surgical team was in favour of doing both of them together. Is there any concrete data in determining operability in such sequential compound lesions? I would like to know the opinion from experienced. Also, please quote some references if anyone has.

What baseline saturation in OPD is the cut-off for Eisenmengarization? At OPD, we get both baseline SO2 at rest and with exercise whenever deemed necessary. Sometimes, the data does not match with the cath data. Is there a reasonable cut-off for the OPD saturation below which the cath is not necessary? If anyone knows any number for this, please let me know the reference.

Perloff defines the Anamolous Pulmonary Venous connection and Anamolous Pulmonary venous drainage separately. We happened to see an infant with all 4 pulmonary veins draining independently into the right atrium. The LA was fed by an ASD. There was no common confluence. Is it an abnormal connection or drainage? We have seen such a pattern earlier also, but never pondered on the embryological basis for such an anomaly. If anyone knows any case reports, please let me know.

Thanks to Dr Amit Misri for the comments. I have posted them on the comments section on the previous post.

I shall also welcome our new follower, Dr Sanjay Panda. Can you please introduce yourself for the others, Sir? The team would love to hear more about you.

Please send your inputs. Feel free to send it to my email drkiranvs@gmail.com I shall post it on your behalf.

Regards

Kiran

Sunday, November 8, 2009

Welcome back to the NH Pediatric Cardiology blog

We had seen some of the Nobel achievers in Cardiology. We would see the final instalment of this now.

American physician Dickinson Woodruff Richards Jr was born in 1895 in Orange, New Jersey. He received a B.S. degree from Yale University in 1917. Following service in the United States Army in World War I (1914-1918), he entered the College of Physicians and Surgeons of Columbia University, receiving an M.D. degree in 1923. Richard's association with Columbia as a researcher and professor of medicine began in 1928 and continued until his retirement in 1961, after which he became Emeritus Lambert Professor.
In the early 1930s Richards teamed with André Frédéric Cournand at New York's Bellevue Hospital, one of Columbia's teaching facilities, to investigate the interrelated functions of the heart, lungs, and circulatory system. One of Richards's key objectives was to measure precisely the changing levels of oxygen and carbon dioxide in blood as it circulated through the heart and lungs. Richards and Cournand had read of the experiments of Werner Forssmann, who a few years earlier had experimented with cardiac catheterization on himself. Richards and Cournand refined Forssmann's work, performing catheterization first on animals and then, in 1941, on humans. The ability to place a sensing device directly into the heart, where it could be safely left for hours, provided a wealth of new information on heart and lung function. Exact concentrations of carbon dioxide and other gases could be determined in specific locations of the heart. They made it possible to obtain precise measurements of blood pressure and blood volume in the heart and lungs. Richards and his collaborators gained new insight into many disorders such as those caused by malfunctions in the heart's valves. Later, during World War II (1939-1945), they performed crucial research on how the heart, lungs, and blood are affected by shock in reaction to injury.
Through his improvements to the procedure of cardiac catheterization, Richards greatly advanced the knowledge of how the heart and lungs function. Cardiac catheterization was an obscure and largely untried procedure before Richards and his colleagues refined it into the essential diagnostic tool. For their advancements in cardiac catheterization and circulatory system functions, Richards and French American physiologist André Frédéric Cournand were awarded the 1956 Nobel Prize in physiology or medicine, which they shared with German surgeon Werner Forssmann.
Richards also made important studies of the effects of the drug digitalis, given to patients to stimulate a weakened heart.

André Frédéric Cournand , the French-born American physician was born in 1895 at Paris. He received his B.S. degree from the Sorbonne, University of Paris, in 1913. He remained there to begin his medical studies, which were interrupted by World War I (1914-1918). After service in the French Army during the war, Cournand resumed his medical studies, finally receiving his M.D. degree in 1930. He then moved to the United States and an internship in the Columbia University division of Bellevue Hospital in New York City. In 1934 he joined the teaching staff of the Columbia College of Physicians and Surgeons, remaining there until his retirement in 1964. He became a U.S. citizen in 1941.
In the 1930s Cournand, along with his colleague Richards, set out to study how the heart, lungs, and circulatory system work together as an integrated unit. They believed that the technique of cardiac
catheterization, pioneered in Germany a few years earlier by Werner Forssmann, might provide the best tool for their research. Forssmann had demonstrated the safety of inserting a catheter into the heart by performing such procedures on himself. Cournand and Richards worked to improve Forssmann's procedure by experimenting with catheterization on laboratory animals. Within a few years, they had advanced the technique considerably, demonstrating that a catheter could remain in the heart for hours without harmful effect. The way was open to experiment with the procedure on humans. In 1941 Cournand and his colleagues performed their first catheterization on a human patient. Very soon, as their research progressed, their findings were providing a wealth of information on cardiopulmonary function and the interrelated action of the heart and lungs. For example, the catheter permitted the drawing of blood from directly inside the heart, providing samples that had never before been available. Using devices on the tip of the catheter, the researchers could also make precise readings of blood pressure, and measurements of oxygen and carbon dioxide in the circulating blood as it moved through the heart and lungs. Later Cournand and his colleagues used catheterization to study how the heart, lungs, and blood function during the state of shock brought on by traumatic injury. In short, the work of Cournand and his collaborators did much to clarify the workings of the heart and circulatory system in healthy subjects as well as in those suffering from cardiopulmonary disorders. Today cardiac catheterization remains an essential tool in cardiology.
Cournand and his colleagues helped clarify many important aspects of how the heart and lungs function. For their advances, Cournand and American physician Dickinson Woodruff Richards, Jr. received the 1956 Nobel Prize in physiology or medicine, which they shared with German physician Werner Forssmann.
In addition to the Nobel Prize, Cournand's other distinctions include the prestigious Albert Lasker Basic Medical Research Award of the American Public Health Association in 1949.

German physician Werner Forssmann was born in 1904 at Berlin. He completed his medical training at that city's Friedrich Wilhelm University in 1929. He then joined the Eberswalde Surgical Clinic near Berlin, where his key experiments with catheterization took place. Later in his career, as a surgeon specializing in urology, Forssmann was associated with hospitals in Berlin, Dresden, and Düsseldorf.
At Eberswalde, Forssmann was convinced that methods for diagnosing heart disorders and for injecting drugs directly into the heart could be improved. Having read earlier accounts of cardiac catheterization in laboratory animals, he began experimenting with this technique on human cadavers. In 1929 Forssmann performed a cardiac catheterization on himself as its first trial in a living human. Inserting a catheter into a vein in his arm, he pushed the tube up the vein until it entered the right side of his heart, where he observed it by means of a fluoroscope.
After continuing his research, Forssmann published a summary of his findings in 1931. The German medical establishment, however, refused to accept the validity of Forssmann's work, regarding his
experiments as stunts rather than as legitimate research. After being dismissed as a charlatan, Forssmann abandoned his catheterizaton experiments and in 1932 began training as a urological surgeon. Meanwhile, physiologists in the United States, including Cournand and Richards, read Forssmann's writings and continued to develop cardiac catheterizaton, achieving unprecedented insight into the workings of the heart and lungs. For his contribution to cardiac catheterization, Forssmann was jointly awarded the Nobel Prize in physiology or medicine along with French-American physiologist André Frédéric Cournand and American physician Dickinson W. Richards in 1956.

British pharmacologist Sir James Whyte Black was born in 1924. Working at the King's College Medical School in London, he developed several drugs for treating peptic ulcers and heart disease. Black shared the 1988 Nobel Prize in physiology or medicine with American biochemists Gertrude Belle Elion and George Herbert Hitchings.
Propranolol was the drug created by Black and his research team in 1964, binds to beta-receptors. Usually these beta-receptors bind to epinephrine and norepinephrine, hormones that stimulate the heart. For heart patients, too much stimulation of the heart is dangerous, and propranolol relieves this stress. Propranolol is also used to treat heart attacks, high blood pressure, and migraine headaches. Today this class of drugs is known as a beta-blocker. Black also developed cimetidine, for the treatment of ulcers.
In 1981 Black was knighted by Queen Elizabeth II of England for his service to medical research.

American chemist Gertrude Belle Elion was born in 1918 at New York city. Elion received an M.S. degree from New York University and began her long tenure (1944-1983) at the Burroughs Wellcome pharmaceutical company at the height of World War II (1939-1945). Before the 1940s few women worked as scientific researchers, but the war afforded more opportunities for women as men were called to the battlefront. At Burroughs Wellcome, Elion teamed up with American chemist George Herbert Hitchings. Together, they developed many drugs that have been proven effective against previously untreatable diseases. Elion and Hitchings shared the 1988 Nobel Prize in physiology or medicine with British pharmacologist Sir James Whyte Black.
Elion and Hitchings compared the functioning of normal human cells with that of bacteria, viruses, and cancer cells in order to find ways to inhibit or kill harmful invading cells without damaging healthy body cells. Elion and Hitchings concentrated on how cells synthesize the building blocks of deoxyribonucleic acid (DNA) called nucleotides. They successfully blocked the manufacture of new DNA in harmful cells; this stopped the cells from multiplying. The researchers accomplished this feat by developing chemical compounds that would fill in for key nucleotides. Because different sequences of nucleotides are manufactured by different cells, Elion and Hitchings were able to fabricate compounds that would attack the DNA only of the dangerous cells.
Over nearly four decades of research, Elion and Hitchings developed drugs for the treatment of many diseases and conditions, including cancer, malaria, leukemia, herpes, gout, heart disease, autoimmune diseases, bacterial infections, and transplant rejections. Their techniques are now standard in the pharmaceutical industry, but were revolutionary in the 1940s when they were first developed.
After her retirement in 1983, Elion taught, held various advisory positions, and continued consulting for the Burroughs Wellcome Company. In 1991 President Bush presented Elion with the National Medal of Science.

American pharmacologist Robert F. Furchgott was born in 1916 at Charleston, South Carolina, Furchgott earned his bachelor’s degree in chemistry in 1937 at the University of North Carolina and completed his doctoral studies in 1940 at Northwestern University in Illinois. Since 1956 he has been a professor in the Department of Pharmacology at the State University of New York (SUNY) Health Science Center in Brooklyn. In 1988 he earned the title of Distinguished Professor at the center. He is now Distinguished Professor Emeritus.
Furchgott helped demonstrate that nitric oxide (NO), a molecule produced in the form of a gas in the cells of humans and other life forms, can act as a signaling molecule. Signaling molecules are released by cells and transmit messages to other cells. Furchgott found that messages transmitted by NO play essential roles in the regulation of blood pressure and other cardiovascular functions.
His contributions opened an active field of research into the properties and actions of NO. This research has shown that NO is involved in many physiological processes, including memory and other nervous-system functions, as well as certain responses of the immune system to infection.
Furchgott’s breakthrough studies with NO can be traced to the late 1970s, when he investigated the relaxation of smooth muscle in the blood vessels of rabbits. He discovered that the blood vessels would not dilate unless the inner cellular lining of the vessel—a layer called the endothelium—was intact. He surmised that the endothelial cells produced a substance that acted as a signal to the smooth muscle cells surrounding the blood vessels, causing the muscles to relax and the vessels to dilate. Furchgott called this hypothetical agent endothelium-derived relaxing factor (EDRF). He then set out to identify this signaling molecule.
Meanwhile, other researchers were working on pieces of the same puzzle. Among them was American pharmacologist Ferid Murad, whose work at the University of Virginia and at Stanford University had demonstrated that nitroglycerin and other so-called vasodilators cause blood vessels to dilate by releasing NO. During the early 1980s, Furchgott began working on the theory that EDRF and NO were identical. At the time, the NO molecule was known primarily as an air pollutant resulting from the burning of nitrogen, for example, in fumes from automobile exhaust, and Furchgott’s theory seemed farfetched. Nevertheless, he officially proposed the theory at a meeting of biomedical scientists in July 1986. Another American pharmacologist, Louis J. Ignarro of the University of California, Los Angeles, who had been working independently of Furchgott, made the same proposal at the meeting. Subsequent research supported their theory.
Scientists have since intensively investigated NO and its properties. Now NO is known to play many roles in the body. Some types of brain cells, for example, communicate by releasing or receiving NO. White blood cells of the immune system release the gas to fight bacterial infection. Among its many cardiovascular functions, NO is involved in the blood flow involved in penile erection. The drug Viagra, which has helped millions of men overcome impotence, owes its success in part to the NO research sparked by Furchgott.
In 1998, the importance of Furchgott’s work was acknowledged with science’s highest honor, the Nobel Prize. Furchgott shared this prize with Ignarro and Murad. Furchgott’s other distinctions include the Gairdner Foundation International Award in 1991, the Wellcome Gold Medal from the British Pharmacological Association in 1995, and the Albert Lasker Basic Medical Research Award, which he shared with Murad in 1996.

American pharmacologist Louis J. Ignarro was born in 1941 at Brooklyn, New York. Ignarro earned his bachelor’s degree in pharmacy from Columbia University in 1962. He earned his Ph.D. degree in pharmacology in 1966 from the University of Minnesota. Between 1979 and 1985, Ignarro was a professor in the pharmacology department at the Tulane University School of Medicine in New Orleans, Louisiana. Since 1985 he has been a professor in the Department of Molecular and Medical Pharmacology at the University of California, Los Angeles, School of Medicine. Ignarro’s research helped solve a mystery first uncovered in the late 1970s by American pharmacologist Robert F. Furchgott. Furchgott noted that blood vessels would expand, or dilate, only if a specific cellular layer surrounding the vessels—the endothelium—was intact. He proposed that cells in the endothelium released a chemical factor that caused smooth muscle cells around the vessel to relax, with the result that the vessel would dilate and blood flow would increase. Ignarro set out to identify this agent, which Furchgott had named endothelium-derived relaxing factor (EDRF).
Ignarro’s experiments led him to suspect that EDRF might be the gas NO. The prospect seemed unlikely because at the time NO was known primarily as an air pollutant. Ignarro pressed on with his research,however, and at a meeting of biomedical scientists in 1986, he officially proposed his theory that EDRF was NO. Furchgott, who had independently pursued the same theory, presented the same proposal at the meeting. Subsequent research supported their conclusion. In the years following Ignarro and Furchgott’s discovery that EDRF and NO were the same substance, interest in NO virtually exploded. Based on the increasing knowledge of NO and its actions, scientists are pursuing new therapies for heart disease, cancer, septic shock, and other diseases. Even the celebrated anti-impotence drug Viagra owes a debt to Ignarro’s work. Viagra increases the blood flow in the penis, helping to produce an erection.
In 1998 Ignarro’s discoveries were honored with the Nobel Prize in physiology or medicine. He shared the prize with Furchgott and the American pharmacologist Ferid Murad, who had also achieved insights into NO’s cardiovascular function. He helped illuminate the cardiovascular role of nitric oxide. Ignarro was among the first to suggest that NO serves as a molecular signal—a substance that is released by one cell and influences the function of another cell. He also helped identify NO as a crucial agent in the process by which blood vessels widen, or dilate. Scientists now recognize that NO not only regulates blood pressure and other cardiovascular functions but also plays a role in many other processes. These processes are helping the body fight bacterial infection and sending messages between cells in the nervous system.
Other honors received by Ignarro include the Merck Research Award in 1974 and the Lilly Research Award in 1978.

American physician and pharmacologist Ferid Murad was born in 1936 at Whiting, Indiana. He earned his medical degree in 1958 from the medical school at Western Reserve University (now known as Case Western Reserve University). He remained at that institution to complete a doctoral degree in pharmacology, awarded in 1965. Murad has since held academic posts at the University of Virginia School of Medicine, Stanford University, and Northwestern University Medical School. During the early 1990s he served as a corporate officer in two Illinois-based biotechnology companies—first at Abbott Laboratories, and later at Molecular Geriatrics. In 1997 he returned to academic medicine by joining the faculty of University of Texas Medical School at Houston. In 1977, while at the University of Virginia, Murad sought to determine the physiological mechanism by which the drug nitroglycerin helps relieve heart-related chest pain. He found that nitroglycerin and related drugs produce NO in the cells surrounding blood vessels. The NO acts as a signal to other cells, causing the smooth muscle tissue in blood vessels to relax. In the process, the vessels dilate, or widen, increasing the flow of blood. In 1978, Murad formally published his theory that NO is a signalling molecule.
Since Murad’s initial discoveries, the investigation of NO has become an extremely active area of biomedical research. Scientists now recognize that NO is involved in many processes, such as the action of the nervous system and the immune system. Based on this knowledge, new treatments are being developed for heart disease, septic shock, and other diseases. In 1998 Murad received the Nobel Prize in physiology or medicine for his discoveries related to NO. He shared the award with American pharmacologists Robert F. Furchgott and Louis J. Ignarro, who had independently performed key NO research during the early 1980s. His work helped to demonstrate the role in the body of nitric oxide (NO), a gas produced in the cells of humans and other organisms. Murad determined that NO is a signaling molecule—a molecule that transmits messages from one cell to another. Murad investigated the action of NO in the blood vessels of the cardiovascular system. Thanks to extensive research that his findings helped to stimulate, scientists now know that NO plays a role not only in blood pressure and other cardiovascular functions but also in many of the body’s systems.
Murad has also been honored with the Albert Lasker Basic Medical Research Award, which he shared with Furchgott in 1996.

The above list is nowhere complete and exhaustive. They serve only as a matter of information, so that it helps in generating further interest.

On a personal note, our latest meeting on academic publication was a mixture of many sentiments! Although we were all falling short of our given deadlines, there were many who had completely forgotten about their assignment! Few of the team who have left for their future to other places also were not spared. An immediate phone call went to them so as to remind them of their due responsibility! Everyone enjoyed the plight of the other, till their turn came in! Just hope if we had one tenth of enthusiasm of our boss, Dr Sunita. Sometimes I feel how long we would take to match the energies of Dr Sunita!

What are the options in cTGA with VSD, PAH with Ebsteins malformation of TV with severe TR in a 2-month-old? Everything depends on how repairable the TV is. Is the age OK for any kind of repair? What would the plan B be? Let me know your take on it.

We have often come across the VSD and PDA with severe PAH in the same patient. When the VSD shunts bi-directional, the PDA would be predominantly left-to-right in the absence of PS. How to explain this analogy? Is it only the color dominance or any other explanation also exists?
We often come across masses in RA. Are they always pathological? Some of them may be thrombi or fungal mass. Sometime back, we had seen an organized mass in the RA. If it is of an acute origin, does it always require medication even in the absence of systemic symptoms and signs? Any guidelines?

Rheumatics continue to pose both diagnostic and therapeutic challenges. Not every child fulfils the Jones criteria. Many a times, parents would not be intelligent enough to observe and recall the symptoms. There are no clear cut guidelines on diagnosing RHD on echo. The impaired mobility of PML is not always found. Sometimes, children would fulfil Jones criteria, but the heart would show normal mobility of PML with regurgitant mitral valve. The involvement of aortic and mitral valves together in a young child also poses diagnostic challenges. The problems of third world find no guidelines on a regular basis.

Please send your inputs. Feel free to send it to my email drkiranvs@gmail.com I shall post it on your behalf.

Regards

Kiran

Tuesday, November 3, 2009

Welcome back to NH pediatric Cardiology.

In one of the crossword puzzles that we had for our fellows, the clue was: “The white man who discovered Beta blockers”. The answer was not that clear to everyone, despite a nearly give away clue. I gave an additional clue that the man had also won the Nobel Prize. Yet, I could see blank expressions. Our wonderful fellows, who would easily solve questions pertaining to the subject with great ease, were nearly clueless when it came to the person who discovered the medicine which is saving millions of lives. I am talking of best brains who would mark their presence in this field in near future. If Sir James Black does not find a place in their brilliant minds, I can imagine what would happen if talk of Alexis Carrel, Otto Loewi, Corneille Heymans, Dickinson Woodruff Richards, Robert Furchgott etc come up sometime. I felt a couple of posts should deal with the Nobel Prize winners in the field of Cardiology, albeit in brief. The first of this is below:

We can start with Ivan Pavlov; the name synonymous with “Conditioned reflex”. Russian physiologist Ivan Petrovich Pavlov was born in 1849, in Ryazan’, and educated at the University of Saint Petersburg and at the Military Medical Academy, Saint Petersburg; from 1884 to 1886 he studied in Breslau (now Wrocław, Poland) and Leipzig, Germany. He was serving as director of the department of physiology at the Institute of Experimental Medicine (part of the present Academy of Medical Sciences), Saint Petersburg, and professor of medicine at the Military Medical Academy, when the Russian Revolution broke out. His work was so famous and inspiring that despite his opposition to Communism, Pavlov was allowed to continue his research in a laboratory built by the Soviet Government in 1935. Pavlov is noted for his pioneer work in the physiology of the heart, nervous system, and digestive system. His most famous experiments, begun in 1889, demonstrated the conditioned and unconditioned reflexes in dogs, and they had an influence on the development of physiologically oriented behavioural theories of psychology. His work on the physiology of the digestive glands won him the 1904 Nobel Prize in physiology or medicine. His major work is Conditioned Reflexes was published in Russian in 1926 and translated to English in 1927. Pavlov’s work has helped us to understand the normal physiology of heart in great deal.

French surgeon Alexis Carrel was born in 1873. He was known for his keen research abilities on keeping animal organs alive outside the body. Born in Lyon and educated at the University of Lyon, Carrel went to the USA in 1905 but had to go back for service in the French army during World War I. He returned to USA and remained there until 1939. He worked at the Rockefeller Institute for Medical Research (now called Rockefeller University) in New York City. His development of a technique for suturing blood vessels in 1902 won him the 1912 Nobel Prize in physiology or medicine. In the early 1930s, he and the American aviator Charles Lindbergh invented a mechanical heart capable of passing vital fluids through excised organs. Various animal tissues and organs were kept alive for many years in this fashion. He is famous for his works Man the Unknown in 1935, expounding his elitist philosophy, and collaborated with Lindbergh on The Culture of Organs in 1938.

Danish physiologist Augustus Steenberg Krogh was born in 1874 at Grenå, Jutland (a peninsula that is part of Denmark). Krogh attended the University of Copenhagen, where he received his M.S. degree (1899) and his Ph.D. degree (1903) in zoology. As a young man, Krogh spent much time at sea, hoping for a career as a naval officer, although he ultimately decided to pursue scientific research. Still, he never lost his love for the sea. In fact, some of h is earliest physiological research was performed on marine organisms. Krogh also invented a device known as a microtonometer in 1901, an instrument for measuring gas pressure in fluids. For his doctoral thesis, Krogh examined respiration, studying the process by which oxygen and carbon dioxide are exchanged between cells and the external environment. Using his microtonometer to study respiration in frogs, Krogh and his colleagues demonstrated that oxygen and carbon dioxide pass through capillaries and other membranes by diffusion. Many scientists of the time believed that respiration involved active secretion by the lungs instead of passive diffusion. Krogh's observations settled this dispute. He made important discoveries about the action of capillaries. In 1916, Krogh noted that when a muscle is at rest, few capillaries are open. However, when the muscle becomes active, many capillaries open up, with the increased blood flow supplying more oxygen to the precise muscle tissues where it is needed. Krogh's research had a significant impact on the practice of medicine. In modern open-heart surgery, for example, the patient's body is cooled to lower-than-normal levels to slow the rate at which oxygen and other gases in the blood are exchanged. This practice derives directly from Krogh's work. For his work Krogh received the 1920 Nobel Prize in physiology or medicine.

Willem Einthoven is probably an exception to the general ignorance! This Dutch physiologist born in 1860 founded the modern field of electrocardiography. Born in Semarang, Java (in what is now Indonesia), Einthoven was ten when his family moved back to the Netherlands in 1870, settling in Utrecht. After receiving his Ph.D. degree in medicine in 1885 from the University of Utrecht, Einthoven became a professor of physiology at the Leiden University in the Netherlands, where he remained for the rest of his career. Although trained in medicine, Einthoven had a keen interest in physics and invented many devices to measure and record physiological activities in the human body (see Physiology). A key challenge for physiologists at that time was measuring the electrical activity associated with the beating heart. By the 1880s it was known that each contraction of the heart produces electrical changes throughout the body, but physiologists were unable to find a method for making immediate, reliable measurements of this activity. One device used a column of mercury that rose and fell with changes in the electric current, but measurements required so much time and so many calculations that the device was useless for making practical observations. Around 1903 Einthoven solved the problem by inventing his string galvanometer. The device consisted of a very thin wire of quartz held in a magnetic field (see Magnetism). Extremely sensitive, the wire would move in reaction to even the smallest electric current. By magnifying the wire and recording its movements on film, Einthoven could make precise measurements of the heart's electrical activity. As he improved the device and used it on greater numbers of patients, Einthoven came to recognize distinctive electrical activity that corresponded to damage or disturbances in specific areas of the heart. With knowledge of these electrical patterns, physicians vastly improved their ability to monitor and diagnose irregularities in heart function. Today, we use the same technology pioneered by Einthoven, to make detailed measurements of the heart's electrical activity. The resulting record, called an electrocardiogram, can help identify damage caused by birth defects, a heart attack, or diseases such as rheumatic fever. An ECG can also help doctors monitor the effects of heart drugs.
Einthoven's most important invention, the string galvanometer, made possible the precise measurements of the electrical activity produced by the beating human heart. Modern electrocardiograph machines are based on Einthoven's original invention. For his essential contributions to the development of electrocardiography, Einthoven was awarded the 1924 Nobel Prize in physiology or medicine.

Otto Loewi, a German American physiologist, pharmacologist was born in Frankfurt, Germany in 1873. He made important discoveries regarding the biochemical transmission of nerve impulses in the involuntary nervous system. For his work, Loewi shared the 1936 Nobel Prize in physiology or medicine with English physiologist Sir Henry Dale.
Loewi studied medicine at the University of Strasbourg (today part of France), receiving his medical degree in 1896. He could have easily made a career in clinical medicine but he favoured research, getting a post in the Department of Pharmacology at the University of Marburg. In 1906 he moved to Austria and Vienna University for the next three years, at which time he was appointed professor of pharmacology at Graz University. He remained there until the German occupation of Austria in 1938, just prior to the outbreak of World War II (1939-1945). Shortly thereafter, Loewi moved to the USA. He eventually settled in New York City, becoming a research professor of pharmacology at New York University and receiving U.S. citizenship in 1946.
During the early 1900s, in examining the workings of the nervous system, physiologists were beginning to explore the idea that the transmission of nerve impulses takes place, in part, via chemical means. Loewi decided to explore this idea. During a stay in London in 1903, he met Sir Dale, who was also interested in the chemical transmission of nerve impulses. However, for Loewi, Dale, and all the other researchers pursuing a chemical transmitter of nerve impulses, years of effort produced no solid evidence. In 1921 Loewi suspended two frogs' hearts in solution, one with a major nerve removed. Removing fluid from the heart that still contained the nerve, and injecting the fluid into the nerveless heart, Loewi observed that the second heart behaved as if the missing nerve were present. The nerves, he concluded, do not act directly on the heart—it is the action of chemicals, freed by the stimulation of nerves, that causes increases in heart rate and other functional changes. In 1926 Loewi and his colleagues identified one of the chemicals in his experiment as acetylcholine. This was indisputably a neurotransmitter—a chemical that serves to transmit nerve impulses in the involuntary nervous system. While the effects of acetylcholine had been observed in the involuntary nerves that control heart action, Loewi doubted that such neurotransmitters also operated in the voluntary nervous system. The matter was settled in England by Dale, who, in a series of experiments between 1929 and 1936, proved that acetylcholine also transmits impulses in voluntary nerves. Loewi and Dale continued their research, helping to identify still more neurotransmitters and clarifying their role in the nervous system.

Hope everyone still remembers Dale’s Vasomotor phenomenon. Sir Henry Hallett Dale, English physiologist who made important discoveries about the chemical substances within the body and how they regulate the function of nerves and other physiological processes, was born in 1875 in London. Dale studied the natural sciences at Trinity College, part of the University of Cambridge. He received his B.S. degree in 1903. Dale also studied medicine at Cambridge, earning his M.D. degree in 1908, but by that time he had chosen research over a career in medicine. Four years earlier, he had accepted a research position with the pharmaceutical firm of Burroughs Wellcome and company, London, where he remained until 1914. Subsequently, he was director of the National Institute for Medical Research from 1927 until his retirement in 1942. During his retirement he served as president of the Royal Society of London (1940-1945), director of the Royal Institute of Great Britain (1942-1946), and the chairman of the Scientific Advisory Committee of the War Cabinet. At Burroughs Wellcome and Company, Dale investigated the properties of ergot, a chemical extract from a species of fungus. By accident, he made a significant discovery, observing that ergot would reverse the effects of adrenaline, a hormone that ordinarily constricts blood vessels, causing blood pressure to rise. During the period from 1910 to 1914 he also studied the biochemical actions of histamine, a substance that plays a role in the swelling and inflammation resulting from a traumatic injury or the introduction of foreign substances, such as bee venom.
The research for which Dale is particularly noted, however, concerned acetylcholine, a substance that had been observed to widen the cavities of blood vessels. In 1921 Otto Loewi demonstrated that nerve impulses are transmitted by biochemical substances. Loewi's experiments centered on a substance later identified as acetylcholine. He observed that acetylcholine transmited nerve impulses in the autonomic, or involuntary, nervous system, which controls processes such as breathing and digestion. In a series of experiments between 1929 and 1936, Dale investigated the action of acetylcholine in the voluntary nervous system, which serves muscles under conscious control, such as those that move the arms and legs. Dale demonstrated that acetylcholine also serves as a neurotransmitter—a substance that transmits nerve impulses—in the voluntary nervous system. Responding to Dale and Loewi's findings, other researchers were able to discover a treatment for myasthenia gravis, a condition that involves a progressive weakening of muscles.
Dale was knighted with the Grand Cross of the British Empire in 1936. Much of his efforts later in life were devoted to developing standards for drugs and vaccines. For his work Dale shared the 1936 Nobel Prize in physiology or medicine with German American physiologist Otto Loewi.

Corneille-Jean-François Heymans, Belgian physiologist, pharmacologist, and Nobel Prize winner who demonstrated how reflexes in the nervous system regulate heart rate, blood pressure, and respiration, was born in 1892 at Ghent (Gent), Belgium. Heymans received the 1938 Nobel Prize in physiology or medicine for his discovery of the role the sinus and aortic nerves play in regulating respiration. Heymans studied medicine at the University of Ghent. After World War I (1914-1918) he returned as a decorated field officer to medical school, receiving his degree in 1921. The next year he was appointed to teach pharmacology at the University of Ghent, where his father, a professor of pharmacology, had founded the institute that bore his name, the J. F. Heymans Institute of Pharmacology and Therapeutics. The younger Heymans joined his father in investigating the cardiovascular and respiratory systems and how they are regulated.
In the early 1920s, as the two began their experiments, physiologists believed that the brain itself, without the intervention of the nervous system, controlled heart rate, blood pressure, and the concentrations of oxygen, carbon dioxide, and hydrogen in the circulating blood. Heymans and his father disproved this theory. They designed an experimental mechanism involving two laboratory dogs; the head of one dog was separated from its body except for selected nerves, with the body's circulation artificially maintained, while blood flow in the head was maintained by connection through tubes with the second dog. Thus, the head was completely isolated from the body except by the nerve connection. In one such experiment, only the aortic nerve, located in the abdomen, was left connected to the dog's brain. The Heymans observed that when the blood pressure in the dog's body was lowered with drugs, the respiratory center in the brain was stimulated, and breathing increased—the expected response. When blood pressure was elevated, breathing slowed, as was expected. However, when the aortic nerve was severed, these respiratory changes did not take place. Through this and similar experiments, Heymans and his colleagues demonstrated that nervous reflexes, and not the direct action of the brain, bring about changes in respiration, blood pressure, and heart rate. In later research, Heymans and his father identified key centers in the cardiovascular system containing receptors that sense changes in pressure and in the chemical composition of the blood. One such site is located in the carotid sinus, a slight enlargement in the carotid artery where it separates into its two branches. The combined ability of the nerve centers, brain, and lungs to receive information maintains proper levels of heart rate, blood pressure, and blood gases. Had the elder Heymans not died in 1932, he likely would have received a share of the Nobel Prize. Heymans's discoveries helped to elucidate many areas of biomedical research, such as heart disease, anemia, and carbon-monoxide poisoning.

(Ref: Few books on Nobel Prize winners and Wikipedia)

In the next post, we shall see more such achievers.

The cause of the delay of this post is our great BSNL broadband service. They woke up after two weeks of continuous complaining (just short of crying!) As per the great Indian tradition, we had to call up some of our personal connections in BSNL to get the things set again. Long live BSNL!

On a personal note, our cath discussions are getting more and more interesting. We look forward to the cath meets with great interest. Recently, we had a 9-year-old boy with DORV, restrictive subaortic VSD, supramitral membrane with NRGA. TransVSD gradient was about 70mmHg. This was despite a moderate MV inflow obstruction. In spite of our best efforts, we could not negotiate the catheter into the LV. Now the question was, “is it safe to enlarge the VSD?” The only way to route the LV to aorta is to enlarge the VSD. Doing it with a back up Permanent pacemaker is an option. If, by any chance, VSD cannot be enlarged, what are the other options? I had suggested excision of Supramitral membrane and creation of an ASD. But the surgical team felt that if VSD cannot be enlarged, then leaving the anomaly as it is would be wiser than creating a new anomaly. I shall inform the surgical sequel in future post. If anyone had an experience with such combinations, please let me know how you handled it.

We saw a newborn baby who came with features of LRTI. On echo, the septae were intact. But, all the vessels emerging out of heart were dilated and tortuous. This is the third time we are witnessing such a lesion. We made a diagnosis of arterial tortuosity syndrome. On detailed history, we found that the parents had lost a baby couple of years back with same diagnosis. We know the eventuality of such lesions, but the parents were pleading with us to do something. Highest number of such lesion is seen by the Pediatric Cardiology dept of Amrita Institute in Kochi. All that I could suggest was to visit the Amrita Institute for a second opinion. Any suggestions?

Recently, we happened to see a newborn with multiple rhabdomyomas. They were huge and multiple. In fact, one large rhabdomyoma occupied almost one-third of RV! There was one sitting prettily beneath the aortic valve on 2D. We were almost sure of obstruction to flow. The colour Doppler took us by pleasant surprise! Despite the huge numbers, size and strategic locations, there were no inflow or outflow obstructions to blood flow! The baby was hemodynamically stable. What are the chances of embolization of these masses? Please let me know your experiences.

How to tackle a child with smallish Tricuspid valve, but good sized RV (due to coexisting VSD)? We have a 7-month-old child with TV annulus at Z-score of minus 4 with non-restrictive ASD and VSD. There is no PS. The RV is well developed probably due to non restrictive feeding from VSD. Neither of the shunts can be closed. The only option we could think of was a PA banding. But, with the kind of risks involved, should we consider it or just settle for a medical management? Let me know your take on this.

What is the final word in the measurement of PA sizes? Echo? CT? Or Cath? Somtimes we have seen our surgical team getting rigid on not touching the patient when the McGoon is 1.4. The same surgical team is sometimes so generous to go ahead with a Glenn shunt even when McGoon is 1.0 on cath, quoting under filled PAs. Is there any better way of measuring the PA sizes? Let me know your experiences.

I should conclude this post with something that bothered us off late. At NH, we have an egalitarian approach to all patients – whether paying class, charity class, government sponsored insurance class or international patients. All or treated with same care, respect and concern. Right from admission to discharge, there is no discrimination; and we are extremely proud of our approach to humanity than to finances. All these patients stay in the same ward. A patient sponsored by government by insurance scheme, who is literally getting the complex cardiac surgery worth lakhs for free, stays in the bed adjacent to a patient whose parents have arranged the entire amount by hardship to get the surgery done.

The problem occurs at this point. The patients sponsored by government by insurance scheme are often from very poor socio-economic status; they have very poor hygienic standards; they do not understand the value of keeping them and their surroundings clean; their ignorance probably makes them very insensitive to the problems they are causing to others. They seldom realize the value of what they are getting virtually free of cost. Sometime back we wondered how a person who is paying the full kitty from his pocket feels staying with such company. A person who pays his hard earned money definitely expects a level of minimal comfort for the payment. One parent told me in confidence that he feels like sitting in an AC compartment of a train with his co-passenger spitting all over the coupé! We often quote that the journey should be as pleasant as the destination. How pleasant a journey are we giving to such patients?

We cannot change the living standards or the behaviour of the masses overnight. But, if we imagine ourselves in the position of paying patients, how would we feel? Most of such parents swallow their displeasure and keep silent for various reasons. May it be the policy of institute not to discriminate or the fear of being called insensitive. Few openly express their anguish, more so, when their child gets contaminated with some other infection due to the adjacent bed. We wondered what sort of picture they would carry back home? When they are made to express their opinion on the institute, we wondered what they would say about all these experiences of theirs. It is wonderful to be egalitarian; but why should we not think of the other side of the spectrum? Is it only the deprived class that needs attention? Are there no rights for the affordable class who are parting with their hard earned money? The issue is not very comfortable to discuss, as it involves lot of emotional factors. But it needs attention. All may go smooth when the choices of patients are minimal. But in the face of a stiff competition, things should change for better. It is time to find out a via-media solution for this complex problem. If anyone has any suggestions or criticisms please don’t hesitate. I have brought up this issue for the sake of clarity of opinion. Please note that I have only raised a problem. I am neither offering a solution nor suggesting rights or wrongs. It is open for debate.

Please send your inputs. Feel free to send it to my email drkiranvs@gmail.com I shall post it on your behalf.

Regards

Kiran