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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 32, No 2, March/April 2021
AFRICA
111
Letter to the Editor
Melatonin against pulmonary arterial hypertension:
is it ready for testing in patients?
Gerald J Maarman, Sandrine Lecour
Abstract
Pulmonary arterial hypertension (PAH) is a fatal disease
defined as a mean pulmonary artery pressure exceeding 25
mmHg when diagnosed with right heart catheterisation.
Its pathophysiology involves multiple molecular pathways,
including key components leading to an inflammatory and
oxidative stress environment that ultimately causes right
ventricular hypertrophy and failure. Compared to the devel-
oped world, the overall PAH prevalence is higher in devel-
oping countries, including Africa, where it is mostly associ-
ated with left heart disease, obstructive/restrictive pulmonary
disease, HIV and rheumatic heart disease. Current targeted
PAH treatments are expensive, not always available in devel-
oping countries, and have a limited impact on PAH progres-
sion and mortality rate. Therefore, there is an urgent need
for effective and affordable medications that can be used
as adjunct therapy against PAH in developing countries.
Recently, there have been mounting pre-clinical and clinical
data suggesting that melatonin may provide health benefits
against PAH.
Keywords:
pulmonary arterial hypertension, melatonin, adjunc-
tive therapy
DOI: 10.5830/CVJA-2021-008
Melatonin (N-acetyl-5-methoxytryptamine) is a hormone
present in vertebrates and produced mainly by the pineal
gland. Its production is dependent on the day–night cycle, and
serum physiological melatonin levels range from 10 to 180 pg/
ml, with a peak observed between 02:00 and 04:00.
1
Melatonin
exerts multiple cardiovascular benefits that are mediated, at
least in part, via its strong anti-oxidant, anti-inflammatory and
vasodilatory properties.
2
In patients with pulmonary arterial
hypertension (PAH), levels of melatonin are lower than in
healthy patients and this negatively correlates with an increase in
cytokine levels.
3
Of greater importance, lower levels of melatonin
correlate with a worse long-term survival rate of PAH patients.
4
Pre-clinical data fromour group and others have demonstrated
that melatonin inhibits PAH progression and ameliorates right
ventricular dysfunction.
5-7
It reduces inflammation, pulmonary
oedema, structural pulmonary damage, interstitial fibrosis and
oxidative stress, pulmonary vascular remodelling and pulmonary
vasoconstriction.
5-7
Taken together, pre-clinical and clinical
studies advocate a role for melatonin as a safe, affordable, adjunct
therapy that may improve PAH and confer cardioprotection in
patients.
However, before melatonin is tested in the clinical setting for
patients with PAH, we strongly believe that lessons should be
learned from previous clinical testing of melatonin in patients
with ischaemic heart disease. The MARIA trial showed no
effects after melatonin administration, while smaller trials have
suggested benefits.
8,9
These inconsistent findings have been
attributed to disputable study design and translational errors
in the treatment regimen.
10
Nevertheless, we do believe that a
clinical study to test melatonin in PAH is feasible and can be
effective if properly designed.
Of concern is the high dose of melatonin that is commonly
used in both clinical and pre-clinical studies without any
rationale for the selection of this dose. These doses (given
in the range of 10 mg of melatonin orally or intravenously)
increase blood melatonin levels up to 5 000 times higher than
physiological concentrations.
11
It is therefore possible that these
supraphysiological concentrations may negatively disturb the
physiological inflammatory and anti-oxidant balances, thus
resulting in the lack of protection.
Interestingly, melatonin is also present in foodstuffs, including
fruit, vegetables and wine. Regular and moderate consumption
of wine, pineapple, orange or banana all increase serum
melatonin levels to physiological values and offer anti-oxidant
properties (see review).
12
In a pre-clinical setting, we have been
able to demonstrate that chronic oral consumption of melatonin,
given at a concentration similar to the amount obtained via the
diet by drinking two to three glasses of wine (75 ng/ml given
in drinking water), confers cardioprotective benefits against
PAH by reducing cardiac interstitial fibrosis, right ventricular
hypertrophy and function, and reducing plasma oxidative stress.
7
Most importantly, this protective effect was observed whether
melatonin was given prior to the development of the disease
or after the PAH was established. This suggests that dietary
melatonin may benefit PAH patients whether it is given as a
preventative or a curative treatment.
7
Centre for Cardio-Metabolic Research in Africa (CARMA),
Division of Medical Physiology, Department of Biomedical
Sciences, Faculty of Medicine and Health Sciences,
Stellenbosch University, South Africa
Gerald J Maarman, PhD,
gmaarman@sun.ac.zaHatter Institute for Cardiovascular Research in Africa
(HICRA), Department of Medicine, University of Cape Town,
South Africa
Sandrine Lecour, PhD