Association of Growth Differentiation Factor 15 with Arterial Stiffness and
Endothelial Function in Subpopulations of Patients with Coronary Artery
Disease: A Proof-of-Concept Study
Authors: Mourouzis Konstantinos , Siasos Gerasimos , Bozini Nikoleta , Oikonomou Evangelos , Zaromitidou Marina , Tsigkou Vasiliki , Kokkou Eleni , Bletsa Evanthia , Stampouloglou Panagiota , Vavuranakis Manolis , Tousoulis Dimitris 
Published: November 2022

Background:
Growth-differentiation factor-15 (GDF-15) is a biomarker belonging to
the transforming growth factor-beta cytokine superfamily, which is linked to many pathological
conditions, including inflammation and myocardial injury. Pulse wave velocity (cfPWV) and
augmentation index (AIx) are indices of arterial stiffness, which are associated with the severity of
coronary artery disease (CAD). Flow-mediated dilatation (FMD) is a well-studied surrogate marker
of endothelial-dependent dysfunction and systemic inflammation.

Objective:
In this proof-of-concept study, we aimed to investigate the relationship between circulating
GDF-15, endothelial dysfunction, and indices of arterial stiffness in different settings of
coronary artery disease and myocardial injury.

Methods:
In this cross-sectional single-center study, we enrolled patients (n = 22) after interventional
treatment for acute myocardial infarction (AMI), patients (n = 11) admitted with chest pain
and elevated cardiac enzymes but without evidence of obstructing CAD (MI-NOCAD) in percutaneous
coronary angiography (CAG), and patients (n = 20) who underwent CAG according to indications
without evident obstructive CAD in CAG (NOCAD). FMD was assessed at the brachial
artery. AIx of the central aortic pressure and cfPWV were estimated by applanation tonometry at
the radial and carotid-femoral site, respectively, with a validated acquisition system (Sphygmo-
Cor, AtCor Medical, Sydney (NSW), Australia). ELISA was used to determine circulating GDF-
15 serum levels (R&D Systems, Minneapolis, MN). Clinical and demographic data and values of
routine biochemical biomarkers were obtained. The highest high-sensitive cardiac Troponin I
(hsTpnI) value during hospitalization was also recorded. Left ventricular ejection fraction (LVEF)
was assessed with a transthoracic echocardiogram.

Results:
Patients with AMI were older, had worse LVEF, higher values of hsTpnI and increased
circulating GDF-15 levels. Importantly, AMI patients had increased cfPWV values, deteriorated
AIx values, blunted FMD and worse serum creatinine levels compared to MI-NOCAD and NOCAD
patients, respectively, whereas MI-NOCAD and NOCAD did not differ from each other significantly
on these biomarkers. Both AMI and MI-NOCAD patients presented a higher but comparable
white blood cell count than NOCAD patients. A strong linear correlation between GDF-15
and cfPWV, hsTpnI, AIx, white blood cell count and creatinine but not with FMD was demonstrated
in the general study population.

Conclusion:
This proof-of-concept study showed that higher circulating levels of GDF-15, an inflammatory
biomarker, were associated significantly with increased arterial stiffness only in AMI patients,
whereas elevated GDF-15 demonstrated a linear relationship with the severity of the myocardial injury.