Home Made Treatment for Congenital Heart Disease-Aymara Women Knit Devices to Close the Patent Ductus Arteriosus

| 27 March 2017

"The most complex problems in our time can be solved with simple techniques, if we are able to dream." - Dr. Franz Freudenthal

The ductus arteriosus is a vital fetal blood vessel. We all had a ductus in utero but at birth it disappears in 99%+ of all people (and that’s a good thing). Before birth, blood flow to the fetal lungs is minimal. Oxygen is provided to the fetus by the mother through the placenta (why supply blood to lungs that are not breathing?). The question for Mother Nature was, how to devise a structure that would avoid blood going from the right ventricle to the fetal lung BUT retain the ability to suddenly divert blood coming from the right ventricle to the lungs at birth. Nature’s elegant solution is the ductus arteriosus (DA), a remarkable bypass vessel, with a built-in oxygen sensor, that is programmed to close and disappear when the newborn baby breathes and oxygen enters the lungs. The ductus allows blood ejected from the right ventricle to flow from the pulmonary artery (PA) directly into the aorta without ever entering the lung circulation. (See below).

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On left: A fetus gets its oxygen (red) from the placenta. On right: CT scan showing the DA. In the womb the DA allows blood that was oxygenated by the mother’s placenta to move from the right ventricle and PA to bypass the unventilated lungs. After passing through the DA, blood proceeds to the aorta, where it provides oxygen to vital organs. At birth the baby breathes, oxygen levels rise, and this causes the DA to constrict and close. The newborn lung takes over the role served by the placenta.

Inside the mother the fetus experiences low oxygen levels (called hypoxia). The DA is actively held open by hypoxia. The oxygen tension in the fetus (PO₂) is only 30-40 mmHg, much lower than the PO₂ in the mother’s blood (which is 90-100mmH). In this regard, the fetus lives in a hypoxic world akin to that experienced by mountain climbers or other residents of high altitude. This similarity between the fetus and high altitude resident will become relevant later in the blog.

At birth, the infant inhales their first breath and their lungs expand. Oxygen levels skyrocket from 30 to 90 mmHg. The smooth muscle cells in the wall of the DA sense this change in oxygen supply and the DA constricts, blocking blood flow. At the same time (and this is fascinating) the oxygen sensors in the lung circulation tell lung arteries to relax and open, preparing them to receive all the blood that was previously diverted through the DA. Ductal constriction occurs within minutes of birth and changes the circulation to the adult pattern. The placenta is gone and the baby’s own lungs become its oxygenator- (bye Mom, I’m an “air breather” now). This functional closure (due to DA vasoconstriction) precedes anatomical closure, which occurs over the next days. Anatomical closure involves cell growth and scarring and ultimately completely blocks the hole in the DA (the lumen) through which blood once passed. In adults we have a fibrotic thread where our DA once connected the pulmonary artery and the aorta. It is called the ligamentum arteriosum. However, no mechanism is perfect. In some infants, particularly those born at high altitude or born prematurely, the DA fails to close. Failure to achieve early functional closure results in a common form of congenital heart disease, persistent DA, which causes extra-cardiac shunting, cyanosis and failure to thrive. Half of preterm infants born before 28 weeks of gestation require medical or surgical closure of the patent DA. Although medical closure of the DA can be accomplished using Prostaglandin H synthase inhibitors (e.g. ibuprofen) in 70% of cases, interventional or surgical closure is required in the remaining infants. The first surgical closure was reported by Gross and Hubbard, JP in 1939 (Surgical ligation of a patent ductus arteriosus. Report of first successful case. J. Am. Med. Assoc. 112:729, 1939). The first use of prostaglandin synthase inhibitors to treat the patent ductus occurred at Sick Kids Hospital in Toronto under the leadership of Dr. Peter Olley (Coceani, F., and P.M. Olley. The response of the ductus arteriosus to prostaglandins. Can. J. Physiol. Pharmacol. 60: 345-349, 1973). Increasingly, ductuses that fail to close with medical therapy are closed with devices (plugs) delivered by means of a catheter (rather than surgery). These plugs noninvasively block the ductus.

Since hypoxia keeps the DA open, it won’t surprise you to learn that residents of high altitude, who live in hypoxia all the time, give birth to babies who are ten times more likely to have persistent patency of the DA after birth. The ambient hypoxia deprives the DA of the signal to close. This story is about an innovative homemade solution to treat patent DA in La Paz, Bolivia. In La Paz (elevation 4000m), there is not only a high incidence of patent DA but the ductuses are enormous (the result of maternal hypoxia). This makes them hard to close either by drugs or the devices we use in North America (which are too small and too expensive). Bolivia is also financially poor and purchasing these types of closure devices is not a fiscal possibility.

I was recently chairing a session at the University of California, San Francisco School of Medicine’s 10th International Conference of Neonatal and Childhood Pulmonary Vascular Disease, organized by Drs. Jeff Fineman and Ian Adatia (UCSF). One of the speakers, Dr. Franz Freudenthal, mentioned that to block the giant ductuses he faces in Bolivia he created new, large ductal occluder devices (or plugs). He mentioned in passing, that Aymara women, who are remarkable weavers, weave these complex medical devices. He said this so casually that I thought I misheard. In the question period when I was able to quiz him and ask if he really meant what he had said. To my shock he meant precisely what he said. He had created a company and contracted these talented women to “knit” the closure devices in a special clean facility…16^th century Art meets 21^st century Medicine! Dr. Freudenthal makes his own occluders or plugs using Nitinol, a remarkable alloy of nickel and titanium, which has shape memory and great flexibility. Large (ductus size) Nitinol structures can be shaped and then compressed for delivery into the baby through the lumen of a catheter. Once pushed out of the catheter into the ductus they expand and block the ductus. Decorative Image

Dr. Franz Freudenthal

While this story was news to me, the story of the Aymara weavers and Dr. Freudenthal has been told. According to a blog by Yara Simon “40 Aymara women create 250 to 300 devices monthly, and it’s a source of pride for the women. “I learned how to weave when I was a child,” said Julia Yapita Poma. “They teach us in the schools, and our mothers tell us we must learn how to weave. I never imagined I would work like this, saving people, saving kids. For me, it a blessing that fell upon me to work here. I feel proud.”Freudenthal’s company, PFM SRL, has sold 7,000 implants to patients in Latin America, the Middle East, and Europe. And it hopes to eventually donate one implant for each one sold.” Decorative Image

On left: Aymara Weaving. On right: Aymara-made closure device for ductus.

I subsequently found a story and film on this subject by the BBC. Thus, I can’t claim my blog is “news”. Nonetheless, I thought you might like the story. I found it inspirational. Local people using their traditional skills to do what humans do best-solve problems! Check out the movie below- it’s quite amazing.

If you’re interested in the molecular mechanism by which oxygen closes the DA read on: My laboratory has spent decades defining the molecular mechanism by which the DA constricts. I am afraid it is neither as inspirational or practical as Franz’s work…but humor me! Panel A: With colleagues Ken Weir, Evangelos Michelakis and Bernard Thébaud I studied how the DA closed on the molecular level. We were intrigued because while the pulmonary artery relaxes to oxygen at birth, the adjacent DA constricts. One of our early discoveries was that ductal constriction was due by a mechanism that resides entirely with its muscular layer. The ductus smooth muscle cells (SMC) can constrict to oxygen without requiring input from blood, nerves or other layers of the vessel wall). To prove this we conducted a “Wisdom of Solomon” experiment. We cut one baby’s ductus in half. One half received 4 chemicals that eliminated the effects of all substances from the endothelium that constrict or relax blood vessels; the other half we left alone. As shown below, both sides constricted equally to oxygen (labeled Normoxia). Ergo the endothelium is not essential for oxygen-induced ductal constriction).

Decorative Image Lancet Volume 356, No. 9224, p134–137, 8 July 2000

Panel B: We went on to identify the sensor (the structure that tells the ductal SMC that the oxygen has increased…time to constrict!). Oxygen-induced ductal closure is an elegant ballet. The first step in the dance involves division of mitochondria. These cellular powerhouses also sense oxygen. Recently it has been discovered they can divide (remember they were once bacteria!). Oxygen induced division (the scientific name for which is fission) releases signaling molecules called free radicals. Below are pictures of single ductal cells. The red lines are individual mitochondria. With increased oxygen the mitochondria divide and become fragmented (picture on right during normoxia). Within seconds this process, mediated by an enzyme called dynamin related protein 1 (Drp1) starts the cell on the path to constriction. Decorative Image

Images of ductus cells below from Hong, Z et al Circulation Research. 2013;112:802-815

Panel C: The free radicals close specialized protein pores in the cell membrane, called voltage-gated potassium channels. This traps positively charged potassium within the cell and depolarizes the membrane. We used an elegant technique involving a tiny glass electrode to record the electricity of the cell. This technique is called patch-clamping. Below you can see a recording of single potassium channel. Each deflection above the baseline is the current moving through 1 channel. Oxygen inhibits the opening of certain potassium channels in DASMC-those marked with the red arrow in the upper half of the tracing (note their absence in the lower trace when oxygen levels are high). This leads to depolarization of the DASMC plasma membrane. Decorative Image

This in turn increases the opening of another type of ion channel protein, called the L-type calcium channel. Once calcium flows into the ductal cell constriction occurs. This ionic mechanism of DA closure is not mature in preterm infants-one of the many reason their DAs do not close normally. Panel D: This initial ionic mechanism of vasoconstriction is ultimately reinforced by activation of rho kinase, which locks constriction in place. These events ultimately trigger ductal occlusion and it becomes a fibrous thread. If one disrupts oxygen-sensing and vasoconstriction (by inhibiting fission using a chemical blocker of DRP1, called mdivi1), the ductus fails to close even when one gives oxygen for 14 days (see below).

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Note the ductus at the bottom left has grown closed after 14 days on oxygen. The ductus at right had mitochondrial oxygen sensing disrupted and remains patent. In conclusion, the ductus is interesting both from the practical perspective (the ingenuity and impact of the Aymara weavers and their physician partners) and also from a purely scientific perspective (an example of the body’s specialized oxygen sensing system that is essential for life). Dr. Freudenthal's creation of the Aymara-made ductus occluder serves as a reminder to us all to consider what lies within our reach when we search for solutions in medicine, research and, more generally, in our everyday life. It encourages us to realize the talent and potential that surrounds us, and to find ways to utilize it in our constant pursuit of success in all domains. I hope you enjoyed these stories. Acknowledgement: Thanks to Dr. Kathie Doliszny and Ms. Jill McCreary for their editorial input.