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!

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