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