Link between a mitochondrial defect and heart disease

Diet rich in fatty acids can prevent heart disease and
increase survival of the mice with this condition, study shows

:A defect in mitochondria in the heart
causes dilated cardiomyopathy, leading to heart disease and early death,
according to a new study. The research shows that a diet rich in fatty acids
can prevent heart disease and increase survival of the mice with this
condition. Given the links between a high-fat diet and the risk of
atherosclerosis, more research is needed to show if the result could translate
into a benefit for a specific patient group.Share:

A defect in a vital mitochondrial process in heart cells
causes a type of dilated cardiomyopathy, a heart condition that in humans leads
in most cases to heart disease and premature death. The research was undertaken
by teams at the Centro Nacional de Investigaciones Cardiovasculares Carlos III
(CNIC) in Madrid and at the Research Institute CECAD/Max Planck in Cologne
(Germany), with the participation of the University Hospital Fundación Jiménez
Díaz and the CEU in Madrid. The study, published today in Science,
uncovers the key role of the protein YME1 in the regulation of the number, type
and shape of mitocondria, and demonstrates that its absence induces a metabolic
defect typical of patients with heart disease. The study also shows that
metabolic strategies based on diet are sufficient to restore correct heart
function, opening the possibility of future treatments for patients with this
disease.

The heart is the organ responsible for pumping blood and
supplying nutrients and oxygen to all organs and cells of the body. The cells
charged with these functions are the cardiomyocytes, explains Jaime
García-Prieto, joint first author of the study together with his counterpart in
Germany, Timothy Wai. Jaime points out that correct heart function requires
large amounts of energy; every day the heart burns approximately 20 times its
weight in the form of ATP (the molecular energy source), beats more than
100,000 times, and pumps approximately 8000 kg of blood. Therefore any failure
in the supply of energy to the heart results decreases the organ’s pumping
capacity, leading to heart failure and eventually death.

The major part of the energy necessary for cellular
activity is provided by mitochondria. These cellular structures act as ‘power
stations’, producing energy from the metabolism of organic ‘fuels’, including
sugars, lipids (fatty acids) and amino acids. Lack of a substrate or a failure
in the coordinated biochemical processes of energy production has lethal
consequences for the cell, and in the case of cardiomyocytes, for the patient.

A common disease

Dilated cardiomyopathy is a relatively common disease in
which the heart enlarges and loses contractile strength. In most cases, the
disease causes heart failure (the inability of the heart to efficiently pump blood
to meet the body’s needs), and in terminal phases a heart transplant is
required to avoid death. Although the condition can develop at any age, it is
most common in people aged 40 to 50 years and affects 3 to 10 per 100,000 of
the general population. There are currently no specific treatments, and it is
therefore essential to “understand the underlying mechanisms,”
explains Borja Ibáñez M.D., Ph.D., CNIC researcher, Cardiologist at the
University Hospital Fundación Jiménez Díaz, and joint lead author on the study
together with Thomas Langer of the Max Planck Institute.

In healthy people, cardiomyocytes consume much more fatty
acids than sugars, because of the higher energy content of lipids. This
situation is reversed in heart failure patients. Dr. Ibáñez explains that
“To date, this was thought to be a defense mechanism, but the prolonged
use of glucose by cardiomyocytes may instead be the cause of disease
progression.”

The research teams used several genetic and dietary
approaches to try to reverse this mitochondrial dysfunction and thus prevent
dilated cardiomyopathy. One approach involved feeding a high-fat diet to mice
with the mitochondrial defect. As García-Prieto explains, the goal was to
“force the heart cells to consume more fatty acids than sugars, and thus
‘bypass’ the mitochondrial defect.” The researchers observed that the
high-fat diet restored normal cell metabolism and that despite the presence of
the mitochondrial defect the heart regained its normal function. The results of
the study demonstrate that this approach impedes disease development and
increases the lifespan of mice with the mitochondrial defect.

Therapeutic implications

The prevention of dilated cardiomyopathy in a mouse model
by feeding a high-fat diet signals an advance in the understanding of the
mechanisms involved in heart disease and has implications for the future
development of treatments for this condition. Ibáñez considers that “this
result confirms the need to dedicate more resources to basic research that advances
knowledge of biological systems at the molecular level, in order to understand
them better and thus be able to resolve the problems that arise in
patients.”

Valentín Fuster, M.D., Ph.D., General Director of the
CNIC warns of the need for caution in the interpretation of these results:
“We know that a diet rich in fats is a threat to health because it
increases the incidence of atherosclerosis. The possibility that such a diet
might be beneficial in certain cases of heart disease is very provocative and attractive.
However, much translational research needs to be done before these results can
be considered definitive. Nonetheless, this multicenter research program should
continue, and perhaps over the medium term we will be in a position to answer
this question and perhaps eventually overthrow another established
paradigm.”

The next step is to research the effect of dietary
intervention in patients with dilated cardiomyopathy. This study will be
completed over the coming years, indicates Dr. Ibáñez, thanks to CNIC projects
run in partnership with specialist hospitals, such as the joint program between
the CNIC and the University Hospital Fundación Jiménez Díaz in Madrid. This
project, coordinated Ibañez, investigates the application and benefits in
patients with heart disease and other conditions. For Fuster, “This is a
clear example of the type of the collaborative and translational research
favored by the CNIC, in which research groups with different interests and
perspectives collaborate on clinical problems that would not be easily resolved
by teams working in isolation.”

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