A new therapeutic target for the prevention of aortic stenosis-induced heart failure

Scientists at the National Center for Cardiovascular Research (CNIC) have discovered a new therapeutic target that can prevent heart failure
caused by aortic stenosis.
The study was led by Dr.
Ibáez, a cardiologist and director of clinical research at CNIC, at the University Hospital Fundación Jiménez Díaz, a member of
the Spanish Cardiovascular Research Network (CiberCV).
Studies have shown that overexpression of β-3 adrenergic receptors, a member of the β-adrenergic system, in cardiomyocytes can prevent or even reverse heart failure in mouse models of aortic stenosis, a condition for which there are currently few
treatment options.

In the United States, the CNIC team employed an innovative gene therapy approach to boost the expression of this receptor in the heart, thereby enhancing its beneficial effects
.
"Gene therapy has great potential
in treating heart disease.
The next step will be to study this approach in animals with hearts more similar to humans, such as pigs, and then design a pilot clinical trial to translate these promising results into patients," explains
Dr.
Valentín Fuster, co-author of the study and director general of CNIC.

Aortic stenosis refers to the progressive narrowing of the aortic valve, which is the "gate"
through which blood flows from the heart to the rest of the body.
Progressive aortic valve occlusion blocks the supply of blood to organs in the body, leading to increased
pressure in the heart.
The extra force required to expel blood with each heartbeat creates physical stress that worsens the heart muscle
.
Current treatment is to replace the damaged valve with a prosthesis
.

While valve replacement techniques are much less invasive and successfully restore valve function, Dr.
Ibáez explains that the heart muscle cannot be restored
under years of stress.
Unfortunately, treatments that can improve myocardial function and thus relieve heart failure
caused by long-term aortic stenosis.

In addition to the CNIC team led by Dr.
Ibáez's team, the study received input
from teams from Italy and the United States.
The study took advantage of the beneficial properties of stimulating the -3 adrenergic receptors, which are abundant in adipose tissue and the bladder but weakly expressed in the heart
.
Previous studies have shown that despite the low expression of this receptor in the heart, stimulation of it has a potentially beneficial effect
on heart disease.

Using cultured rat cardiomyocytes (cardiomyocytes), the researchers found that forced expression of β-3 adrenergic receptors inhibited the hypertrophic growth
of these cells when these cells were exposed to hormone stimulation.

Through collaboration with the CNIC Cardiovascular Development and Disease Intercellular Signaling Group, led by Dr.
Jose Luis de la Pompa, transgenic mice
overexpressing β-3 adrenergic receptors in cardiomyocytes were bred.
"When these mice had supravalvular aorta stenosis, they developed less
cardiac hypertrophy and fibrosis than mice with normal expression levels.
The genetically modified mice also did not have heart failure, they were metabolically more efficient and consumed less glucose," explains
Dr.
Andrés Pun, lead author of the study.

These results prompted scientists to study the mitochondria of cardiomyocytes, the center
of energy production in cells.
"Because the heart muscle has a high energy demand, any damage to its mitochondria can lead to catastrophic consequences, which often occurs in heart failure," Dr.
Pun said
.

In a healthy heart, mitochondria primarily burn fatty acids, which efficiently produce large amounts of energy
.
However, Dr.
Pun said, "failed hearts often turn to glucose, a much less efficient source of energy, which leads to the progression
of the disease.
" ”

In addition, the mitochondria of a failed heart cannot fuse effectively, so they are smaller in size and more likely to accumulate damage
.
The researchers found that the mitochondria of cardiomyocytes in genetically modified mice were larger and healthier
.

Because the transgenic technology used to grow these mice did not work for patients, the researchers developed a gene therapy that injects a harmless virus into mice that delivers the β-3 adrenergic receptor gene specifically to cardiomyocytes to produce the receptor
safely and efficiently.

Working with the CNIC viral vector group, the team designed a harmless virus capable of entering cardiomyocytes and driving elevated expression of β-3 adrenergic receptors in the hearts of non-GMO adult mice
.
When these mice suffered from aortic stenosis, they had the same protective effect against heart failure as genetically modified mice that overexpressed the receptor before birth
.

In the final test, the team injected the virus into non-GMO mice with long-term aortic stenosis and heart failure
.
In these mice, gene therapy-induced β-3 adrenergic receptor overexpression restored cardiac function, reduced cardiomyocyte hypertrophy, restored normal mitochondrial size and normal expression of mitochondrial fusion proteins in the heart, and increased animal survival
.