Elevated serum endothelin-1 is an independent predictor of coronary microvascular dysfunction in non-obstructive territories in patients with coronary artery disease

Abstract

Objective: Endothelin-1 contributes to the constrictor response of the coronary arteries in patients with ischemia with normal coronary arteries. There is thus increasing evidence that endothelin-1 plays a role in coronary microvascular dysfunction (CMD). We investigated whether elevated endothelin-1 is associated with CMD in patients with coronary artery disease (CAD). Methods and Results:We prospectively studied 49 consecutive CAD patients with 1or 2-vessel disease (age 71 ± 10 yrs, 43 males). Myocardial blood flow (MBF) was measured by 15 O-water PET/CT at rest and during stress, and the coronary flow reserve (CFR) was calculated by dividing the stress MBF by the rest MBF. A CFR of less than 2.0 in non-obstructive regions was defined as a marker of CMD. Eighteen out of 49 (37%) CAD patients had CMD. Endothelin-1 in patients with CMD was significantly higher than in those without CMD (2.27 ± 0.81 vs. 1.64 ± 0.48 pg/mL, P = 0.001). Accordingly, univariate ROC analysis showed that the continuous endothelin-1 levels significantly discriminated between the presence and absence of CMD (area under the curve = 0.746 [95%CI 0.592-0.899]). The dichotomous treatment of elevated endothelin-1 as 4 1.961 pg/mL or more yielded the optimal discriminatory capacity, with a sensitivity of 72.2% and a specificity of 71.0%. High endothelin-1 was still a significant predictor of CMD after adjusting for diabetes mellitus (odds ratio = 6. 64 [1.75-25.22], P = 0.005). Conclusion:Endothelin-1 is associated with CMD in non-obstructive territories in patients with CAD, suggesting that endothelin-1 is a potential target for treating CMD in CAD patients.

Effects of Physical Prehabilitation on the Dynamics of the Markers of Endothelial Function in Patients Undergoing Elective Coronary Bypass Surgery

“…At the same time, serum ET-1 was positively associated with the myocardial blood flow, estimated using positron emission tomography and pharmacological stress testing. According to the authors’ conclusions, these results support a pronounced decrease in coronary flow velocity reserve due to stress in patients with coronary heart disease and elevated ET-1 [ 43 ].…”

Molecular Hallmarks of Ischemia with Non-Obstructive Coronary Arteries: The “INOCA versus Obstructive CCS” Challenge

“…The main pathogenic mechanisms of CMD are represented by endothelial dysfunction, smooth muscle cell dysfunction, and vascular remodeling [ 2 ]. Endothelin-1 (EDN1) has been investigated as responsible for CMD and endothelial dysfunction [ 37 , 38 ]. However, in CMD, due to a low-grade inflammatory response, several inflammatory biomarkers have been involved (TNF, IL-6 and hs-CRP) [ 38 , 39 , 40 , 41 ].…”

Endothelin-1 axes in the framework of predictive, preventive and personalised (3P) medicine

“…To them belong: Maintaining versus diminishing physical well-being [ 1 , 2 ] Regulation of stress reactions and mental health: chronic as well as episodic psychosocial factors provoke social, environmental and emotional stress reactions; elevated plasma endothelin-1 (ET-1) influences individual differences in autonomic and hemodynamic responses to stress [ 3 , 4 ] Female and male health [ 5 – 8 ] Pregnancy and embryonic development [ 9 – 12 ] Wound healing [ 13 – 16 ] Regulation of senses [ 17 – 20 ] amongst others. On the other hand, shifted ET homeostasis may influence and predict the development and progression of: Suboptimal health conditions [ 1 , 18 – 24 ] Ageing and related pathologies [ 5 , 25 – 28 ] Vascular stiffness and ageing, cardiovascular diseases and “young” ischemic stroke [ 1 , 29 – 35 ] Metabolic impairments with cascading complications [ 1 , 36 – 38 ] Neurodegenerative disorders [ 39 – 42 ] Particularly aggressive subtypes of cancer such as metastasing breast and prostate malignancies [ 7 , 20 , 43 – 50 ] ET-1 axes are involved in thermoregulation and attenuate the heat loss, modulate pain and drug sensitivity [ 20 , 51 – 55 ], therapy response [ 56 – 58 ] and individual outcomes of both non-communicable [ 59 ] and infectious diseases, such as during the current COVID-19 pandemic [ 60 – 63 ]. …”

“…ET-1 axes are involved in thermoregulation and attenuate the heat loss, modulate pain and drug sensitivity [ 20 , 51 – 55 ], therapy response [ 56 – 58 ] and individual outcomes of both non-communicable [ 59 ] and infectious diseases, such as during the current COVID-19 pandemic [ 60 – 63 ].…”