Low BDNF protein levels in blood may indicate right heart failure
But animal work suggests these levels are its consequence, not cause
Low blood levels of a protein called brain-derived neurotrophic factor (BDNF) are associated with right heart failure in people with pulmonary arterial hypertension (PAH), a study reports.
Experiments in mouse models of PH, however, suggest that the low BDNF levels are a consequence, and not the cause, of right heart failure.
The study, “Decreased plasma levels of the brain-derived neurotrophic factor correlate with right heart congestion in pulmonary arterial hypertension,” was published in the journal ERJ Open Research.
BDNF is released by muscle cells that enable heart to pump blood
PAH is characterized by structural alterations to blood vessels, called remodeling, that promotes an increase in the blood pressure in the pulmonary arteries. As a result, the heart’s right ventricle needs to work harder to pump blood. This narrowing of the pulmonary arteries is driven by proliferation and migration of pulmonary artery smooth muscle cells (PASMCs).
BDNF has been shown to boost the proliferation of PASMCs. While neurotrophic factors such as BDNF are known for their effects on nerve cells, BDNF is released by several other cells, including cardiomyocytes, the contractile muscle cells of the heart that enable it to pump blood. However, the exact role of BDNF in the development of PH and right ventricle failure is not known.
Researchers in Germany investigated whether BDNF could be a biomarker and treatment target for PAH and right ventricle failure.
The scientists first measured BDNF levels in blood samples from patients with three distinct types of pulmonary hypertension (PH) — idiopathic, or unknown cause, PAH; combined pre- and post-capillary PH; and isolated post-capillary PH — compared with levels in a control group of patients. People in both groups were part of the Giessen Pulmonary Hypertension Registry in Germany.
Of note, combined pre- and post-capillary PH and isolated post-capillary PH are both forms of PH due to left heart disease.
After adjusting for body mass index (a measure of body fat), age, and sex, only idiopathic PAH patients showed significantly lower circulating levels of BDNF.
BDNF levels showed a positive correlation with the cardiac index of all PH patients, meaning that lower BDNF levels are associated with a lower cardiac index. The cardiac index represents the amount of blood ejected by the heart in a unit of time divided by the body’s surface area.
In contrast, a negative correlation was found between BDNF levels and both central venous pressure (CVP) — the blood pressure in the vena cava, near the top right chamber of the heart — and the resistance of pulmonary vessels to blood flow (PVR). A negative correlation means that lower BNDF levels associate with a higher CVP and PVR.
Researchers then assessed how BDNF levels correlated with right ventricle remodeling and function in a second group of idiopathic PAH patients. These people were enrolled in the Right Heart 1 trial (NCT03403868), sponsored by the University of Giessen.
For this purpose, the team used findings from cardiopulmonary exercise testing (CPET) — an evaluation of the cardiopulmonary system — echocardiograms, or MRI and conductance catheter measurements. Of note, conductance catheter assesses the volume of the heart’s left pumping chamber (left ventricle) using electrical signals.
Results again showed that blood BDNF levels correlated with CVP and with parameters of right ventricle size. However, in contrast to the first group of patients, no association was found with PVR or heart function. The researchers speculated that this could be due to differences in blood work analyses between the two groups of PAH patients.
An analysis conducted after adjusting for certain variables showed a significant correlation between circulating BDNF levels and right ventricle function, specifically blood volume in the right ventricle at the end of contraction (systole) and the beginning of filling (diastole). A correlation with the CVP also was found, but not with cardiac index.
Work in mice raises question of consequence rather than cause
Using healthy (wild-type) mice and a mouse model genetically engineered to have lower BDNF levels, the researchers performed a procedure called pulmonary arterial banding (PAB) that restricts blood flow to the pulmonary artery.
Three weeks after the procedure and compared with wild-type mice, mice with lower BDNF levels had lesser right ventricle dilatation after banding.
In another group of mice engineered to lack BDNF specifically in smooth muscle cells, the researchers found that right ventricle dilatation was attenuated, although PH developed similarly to animals with normal BDNF levels in response to low oxygen levels.
While in idiopathic PAH patients low blood levels of BDNF associate with right ventricle dilatation and CVP, experiments in animals linked low BDNF levels with “mild protective effects on RV [right ventricle] dilatation,” the researchers wrote.
These findings “suggest that low BDNF levels detected in IPAH patients do not cause RV dysfunction, but are rather a consequence of right heart congestion,” they concluded.
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