New treatments for cardiac hypertrophy, a thickening of the heart in response to pressure overload, could potentially treat or even reverse the condition after a new breakthrough discovery identified the mechanism that causes the heart's muscle to thicken, increasing the risk of irregular heart rhythms and heart failure.
The discovery by a team at the Victor Chang Cardiac Research Institute in Perth, Australia, showed that the molecule Piezo1 initiates the cardiomyocyte hypertrophic response to pressure overload in adult mice.
Published in Nature Cardiovascular Research, the study is a breakthrough in understanding one of the main drivers of heart disease, Michael Feneley, co-senior author of the paper, told BioWorld Science.
The discovery was a result of the collaboration between the three labs of Michael Fenley, Boris Martinac and Charles Cox that are housed within the Victor Chang Cardiac Research Institute.
"Cardiac hypertrophy is a key risk factor for premature cardiac death and is a major cause of heart failure," said Martinac, co-senior author of the paper.
"We have finally been able to pinpoint one of the key reasons why the heart muscle wall thickens and identified the molecules and the pathways that cause this process to take place."
Cardiac hypertrophy, which affects around one in every 500 people, is caused by many common conditions including abnormally high blood pressure and narrowing of one of the heart valves, also known as aortic stenosis.
This condition causes the wall of the left ventricle to thicken, and over time this thickening can cause abnormal heart rhythms and lead to heart failure. Once heart failure develops, the 5-year survival is less than 50%.
The new research identified the exact molecules in the heart muscle cells responsible and discovered how they were communicating with one another in a mouse model. They discovered that a molecule called Piezo1 triggered a signaling process, with another partner molecule, in cardiac muscle cells.
Causes of hypertrophy
The study was the culmination of 15 years of research on what causes hypertrophy, Feneley said, noting that hypertrophy is a response to stimuli, and there have been two different suspected pathways in the literature, one of which was from neuroendocrine hormones circulating like angiotensin 2 that acts to cause hypertrophy through a family of receptors call Gq receptors. The other pathway was through mechanical forces.
"Until recently, those stimuli were thought to activate two distinct calcium-dependent signaling pathways in the heart that ultimately lead to hypertrophy. One of them is called the calcineurin (calcineurin-nuclear factor of activated T cells) pathway and the other the CaMKII (calcium/calmodulin-dependent protein kinase II-histone deacetylase 4-myocyte enhancer factor 2) pathway," Feneley said.
An earlier study from Feneley's lab laid the foundation for this work that showed that by constricting the aorta, which is the most common way of simulating pressure overload on the heart, the mechanism of hypertrophy is dependent on activating the CaMKII pathway, but it does not require calcineurin activation, nor does it require Gq activation.
That experiment basically got rid of several candidates in one fell swoop, he said.
"We then showed that TRIPM4 was a key modulator of that pathway. At this stage, Boris and Charles and I started to collaborate to figure this out."
TRIPM4 (calcium-activated transient receptor potential melastatin 4) is activated by calcium but it is not activated by stretch itself, he said, stressing that once it was understood that these Gq receptors that respond to the neuroendocrine signal were not important to hypertrophy, "my major working hypothesis was that there had to be a molecule that detects the stretch itself."
"When we showed that TRIPM4 was important, we knew it couldn't be the first step, because it doesn't respond to stretch.
"Boris had shown in his lab that TRIPM4 didn't respond to stretch, so we knew the molecule was higher up on the chain that could respond to the stretch to activate TRIPM4, so that's what we were looking for."
The team picked Piezo1, which was discovered in 2010 by Ardem Patapoutian, who won the 2021 Nobel Prize in Physiology or Medicine along with David Julius for their work on Piezo1 and Piezo2, which are ion channels in the plasma membrane of neuronal cells that can be activated in response to stimuli such as mechanical force. These channels open to allow an influx of cations to depolarize the cell membrane and generate action potentials, which transmits signals along the neuron.
"This class of molecules had characteristics that we thought could work," Feneley said, noting Piezo1 is important in vascular biology as a stretch activator and is expressed in the heart.
Knocking out Piezo1
The group built knockout mouse models that knocked out Piezo in adult mice, "and when we did that, we found that got rid of the aortic pressure-induced hypertrophy."
"More than that, we found that the CaMKII pathway, which we knew was important in hypertrophy, was no longer activated. When you knocked out Piezo1, you didn't get activation of that pathway, so we knew that it both inhibited the hypertrophy, but it also failed to activate the CaMKII pathway.
"Piezo1 responds directly to the stretch and allows calcium into the cell, and the calcium activates TRIPM4, which amplifies the calcium signal. It is that amplified calcium signal that activates CaMKII. We knew all the details of the pathway from CaMKII down.
"Our study shows that Piezo1 is the initial sensor, and that is a brand-new finding because everyone had been looking for how the pathway ran.
"We showed that whole class of Gq sensors does not have any impact on hypertrophy, so we knew it was the activation of stretch.
Potential treatments could prevent hypertrophy
The discovery paves the way to develop a peptide that could stop these molecules from communicating with each other and prevent the heart muscle from thickening in the first place or stop any further thickening in those already affected.
Currently, there are few therapeutic options for severe hypertrophy. The traditional approaches include lowering blood pressure or replacing a stenotic aortic valve, neither of which can reverse the damage caused by hypertrophy.
In the future, treatments could potentially prevent or reverse hypertrophy, so protecting the pathway that runs the hypertrophy is a much more powerful approach, Feneley said.
Next steps will be looking at other types of hypertrophies due to scar tissue.
"We want to see if inhibiting Piezo is beneficial, and what the long-term effects might be," he said.
"When someone has a heart attack, many of their muscle cells will die and the heart loses its ability to pump as effectively, so it will compensate by thickening its muscle wall," Martinac said.
"A therapeutic that halted this process could be transformative for people who have a heart attack and prevent deaths in the longer-term post-heart attack.
"Whilst this is early days in our research, there are similar treatments showing promise in stroke victims, so we are incredibly excited about the potential of our discovery."