Shining a New Light on Cardiac Arrhythmias

With a few flicks of a light switch Stanford University’s Oscar Abilez is one step closer to changing the lives of millions.

Currently, four million Americans suffer from some degree of cardiac arrhythmia. In some, the heart beats too slowly, in others, too quickly or at irregular intervals, resulting in shortness of breath, fainting and even death.

While pacemakers and implanted defibrillators can be used to correct arrhythmias, these small mechanical devices come with risks. Patients must undergo invasive surgical procedures to permanently implant the devices, which can cause cardiac tissue damage. There are other challenges too, such as lifestyle limitations and the occasional battery malfunction.

“It’s like using a cannon to kill an ant,” says Leon Esterowitz, director of the National Science Foundation’s Directorate for Engineering’s Biophotonics program.

Doctors and patients alike have been searching for a better solution.

And now they may have one.  Abilez, a cardiovascular physician with a doctorate in bioengineering, and his team have demonstrated that they can control the rhythm of the heart using light alone. In laboratory experiments the Stanford scientists are able to make heart cells expand and contract simply by switching light on and off.

This novel biological pacemaker was one of 40 new projects funded by the National Science Foundation’s INSPIRE initiative.

The project, Optogenetic Control of the Human Heart-Turning Light into Force, involves two seemingly disconnected and developing technologies: optogenetics and stem cells.

At first glance optogenetics seems more like a magic trick than science, using just flashes of light to control a targeted group of cells.

Only a few organisms, such as algae, have naturally light sensitive cells. In 2002, however, scientists in Germany were able to isolate the genes for the proteins – called opsins – responsible for cells’ light sensitivity and modify the genetic code of other cells so that they too would produce opsins.

Once produced, the opsins act like small hatches on the surface of a cell. When light shines on them, the hatches either open or close depending on the type of opsin they are. If the hatches open, electrical signals are able to flow through the cell and be translated into some action, such as regulating a heart.  In 2005, Karl Deisseroth MD, PhD and colleagues, also at Stanford, were able to genetically introduce opsins into neurons and control these cells with light; this work and subsequent work has led to the field of optogenetics.

Abilez’s grand vision is to take stem cells from a person suffering from cardiac arrhythmia and convert the cells into light sensitive cells that are responsible for pacemaker functions in the heart. These genetically modified cardiomyocytes would then be grafted onto a person’s heart and enable doctors to control the heart’s rhythm using light.

“The applications can be of very high reward,” says Natalia Trayanova, director of John Hopkins University’s Computational Cardiology Lab. “Current high-energy defibrillation is painful, traumatic and has been associated with a higher rate of mortality. Wouldn’t it be nice to be able to shine a light on someone’s chest and defibrillate them painlessly?”

Abilez has already successfully grown light sensitive cardiomyocytes. His next step is to test whether the lab-grown cells are accepted when coupled with a larger body of non-stem cell derived heart cells. If they are, then Abilez will be on his way to creating a less-invasive, longer-lasting treatment for arrhythmias.

Moreover, Abilez will have paved the way for optogenetic success in other fields. If he can successfully couple light-sensitive cells with normal cells, then his method of creating light-sensitive stem cells could be used by other researchers to grow any type of light-sensitive cell they wanted, from brain to pancreatic cells.

Optogenetics has huge implications for medicine. Researchers have already shown that they can stop a seizure, cure anxiety and even implant fake memories into the minds of mice.

There still are risks involved in cardiac optogenetics. Such risks, exist not with the treatment itself but with the feasibility of its development and there are still major hurdles to overcome before any applications can be realized.

Abilez acknowledges such risk, saying that there is a chance the team will discover that their light-sensitive stem cells cannot control the heart as well as they hope. A large part of the research’s difficulty is that the team is in uncharted waters – they have no prior research on which to base their efforts.

“We have to invent things along the way. We don’t have any precedent,” Abilez says.

So although we won’t be seeing these biological pacemakers anytime soon we think we speak for all cardiac arrhythmia patients when we say “Let there be light!”

Be Still My Beating Heart! – Monty Python and the Holy Grail

Look up the term myocardial infarction (MI) in any medical dictionary and the definition will be something along the lines of –  the changes to the myocardium (heart muscle) that occur due to the sudden deprivation of circulating blood. The main change being necrosis, or death of myocardial tissue. Death of myocardial tissue.  As in dead, as in non-viable, as in beyond repair. Kind of reminds me of the infamous Monty Python Dead Parrot sketch… “Passed on! No more! Ceased to be! Expired and gone to meet ‘is maker!”….but I digress.

Fast forward from the British humor of December 1969 to an astonishing paper presented in Britain in April 2012  at the Frontiers in CardioVascular Biology meeting. In a keynote lecture, Dr Deepak Srivastava outlined results that have been described as a “game changer” with the potential to revolutionize the treatment of MI.   Srivastava used viral vectors to deliver genes directly into the hearts of adult mice that had experienced an MI. In his original “proof of principle” study, Srivastava was able to show that all that was needed for the direct  reprogramming of fibroblasts (a major component of scar tissue) into myocytes (the heart muscle cells responsible for  beating)  was the delivery of three genes.  The work , which took place in a Petri dish, was considered groundbreaking since it showed for the first time that unrelated adult cells could be reprogrammed from one cell type to another without having to go all the way back to a stem cell state. “Our ultimate hope is that, during the acute period following MI, patients will be able to receive direct injections of factors that transform the existing fibroblast cells in the “scar” into new myocytes. The resulting increase in muscle mass should help MI survivors to live more normal lives,” explained Srivastava.

Healthy heart tissue is composed of a mixture of several kinds of cells, including cardiomyocytes, which provide beating muscle and cardiac fibroblasts that provide architectural support to the myocytes. “When heart muscle cells become injured and die following an MI, patients have the major problem that these cells have little or no capacity for regeneration,” says Srivastava.  Part of the process of remodelling that occurs following the injury is that fibroblast cells migrate to the site and create the scar. At first, the process can be considered beneficial since without fibroblasts adding structural support damaged hearts would rupture. But later, difficulties arise when the fibrotic scar doesn’t contract like the muscle it has replaced. “Reduced global contractility means the heart has to work much harder, and the extra stress can ultimately lead to heart failure and even death,” said Srivastava.

One of the Holy Grails of cardiovascular research has been to replace these lost myocytes and return functionality to the heart.  Some of the first approaches to be investigated were the introduction of stem or progenitor cells to the sites of injury.  But many hurdles have been encountered including getting cells to integrate with neighboring cells in the heart, and there have been concerns that residual “rogue” cells could persist with the potential to keep dividing and give rise to tumors.

Srivastava, a pediatric cardiologist, explained how he got ahead of the game by “leveraging” knowledge from his work in embryo hearts. Over the past 15 years the focus of Srivastava’s lab has been to identify genetic factors responsible for the formation of embryonic hearts. From this work, his team identified 14 key genes that they felt were the major “on/off” switches for cardiac genetic programming. In this original study they were able to whittle things down to the three factors that were indispensible. The team then injected fibroblasts that had the three genes inserted directly into the scar tissue of mice.  They were able to show the fibroblasts differentiated into cardiomyocyte-like cells. In the latest study  they were able to take the process one step further by injecting a viral vector encoding the  3 genes directly into the scar tissue of mice who had just experienced an MI. “With these studies we’ve obtained even better results showing that the fibroblasts become more like cardiomyocytes and functionally couple with their neighbors. They could beat in synchrony and improve the function of the heart,” said Srivastava.

The next step will be to test the direct injection approach in a larger animal, such as a pig, whose heart is similar in size to a human.  But a big question remains “will the same combination of genes work in human hearts?” SRxA’s Word on Health will be watching and waiting. In the meantime…it’s back to Monty Python!