Targeting ‘microtubules’ could prevent heart failure
One of the most common causes of congestive heart failure is “stiff heart syndrome.”
According to Dr. Jerry Sokol — a cardiologist in Deer Park, NY — this causes fluid to build up and back up into the lungs.
This occurs “usually in patients older than age 60,” he says.
At the microcellular level, they revealed that stiff heart appears to be related to microtubules in the cells of the heart muscle.
By treating these microtubules with newly developed research and medications, cardiac surgeons will soon be able to more effectively treat patients with this type of congestive heart failure.
The new study was led by Dr. Ben Prosser — an assistant professor of physiology in the Perelman School of Medicine at the University of Pennsylvania in Philadelphia — and is a “continuation” of research carried out 2 years ago into how microtubules help to regulate heartbeat.
Investigating microtubules
“These findings provide compelling evidence from human samples for a new therapeutic target for heart disease,” says Dr. Prosser; his team aims to “develop therapies that seek out the damaged microtubules to reverse their harmful influence.”
Normally, microtubule cells in the heart have diverse structural and signaling roles. When these microtubules are altered, the result is believed to trigger heart disease.
Recent studies have suggested that chemical changes to the microtubules called detyrosination — that is, the removal of a tyrosine chemical group — control a person’s heartbeat.
Detyrosinated microtubules provide resistance that could “impede the motion of contracting heart muscle cells.” Dr. Prosser and his team tested single heart muscle cells to identify changes to the cell’s microtubules network and their consequences for normal heart function.
The analyzed tissues from the left ventricle of heart transplant patients revealed a consistent level of proteins that resulted in the stiffening of microtubules.
Thanks to super-resolution imaging, the researchers also found a “dense, heavily detyrosinated microtubule network in the diseased heart muscle cells.”
The researchers used a drug to suppress the detyrosinated microtubules, successfully restoring around 50 percent of the lost contractile function in the diseased cells. They also revealed that genetically lowering the microtubule detyrosination “softened” any diseased cells, therefore enhancing their ability to contract.
According to Dr. Sokol, unlike the usual type of congestive heart failure — typically caused by a weakened heart muscle (when the heart doesn’t contract well after pumping) — a stiff heart resulting in heart failure occurs because the heart doesn’t “relax” well after contracting.
“Also,” he says, “the more damaged [microtubules] one has, the weaker the heart. When the damaged microtubules are compressed, the heart functions better.”
Prior clinical data from the institution identified a “direct correlation between excess microtubule detyrosination and a decline in heart function” in patients who are living with hypertrophic cardiomyopathy.
In this condition, thickened heart muscle can lead to problems in maintaining both proper blood pressure levels and blood flow through one’s heart.
Information from transplants
For this study, the team cited research conducted by transplant cardiologist and study co-author Dr. Ken Margulies, a professor of cardiovascular medicine.
Dr. Margulies compared human heart tissue donated by heart transplant patients with normal heart tissue from other donors. The result was that detyrosination was greater in diseased hearts.
Therefore, cells from diseased hearts contain more microtubules, and these microtubules possess greater detyrosination.
This process meant impaired function in this patient population; their hearts, prior to transplant, had a lower ejection fraction (a marker of heart health designed to measure the blood pumped out of heart ventricles with every contraction) that matched up with greater detyrosination.
Currently, the team is seeking ways to target only heart muscle cell microtubules. By utilizing the Penn Gene Vector Core, the scientists are refining gene therapy approaches to transport “an enzyme to the heart that reverses detyrosination within heart muscle cells.”
Dr. Sokol adds, “Congestive heart failure is one of the most serious types of heart disease and increasingly common with age in both men and women.”
“This new research from Penn is in infancy stages,” he concludes, “but will hopefully prevent congestive heart failure in patients, resulting in healthier lives.”
Source: Read Full Article
