**4. Conclusion**

resistance arteries, bradykinin, serotonin, and the alpha 2-adrenergic agonist clonidine evoked endothelium-dependent relaxations, which were fully (clonidine) or partially (serotonin) mediated by NO, while vasodilator response to bradykinin seems to be mediated by some other endothelium-derived mediator, different from NO [135]. Further, cold pressor test (CPT), in which the subject puts his hand into ice water, is another mode to assess epicardial vasoreactivity. In the study by Nabel et al., the response to CPT was assessed in patients with angiographically normal coronary arteries, in patients with mild coronary atherosclerosis and in patients with advanced coronary stenosis, using quantitative angiography and Doppler flow velocity measurements. Normal vessels exhibited vasodilation (partly related to betaadrenergic receptor stimulation and partly due to flow-mediated dilation or alpha-2 adrenergic receptor activation) while atherosclerotic vessels exhibited vasoconstriction in response to CPT, possibly due to altered sensitivity to adrenergic stimulation and/or some other impair-

Pulse wave velocity (PWV) is the velocity at which the pulse pressure wave spreads from the left ventricle (at the end of ventricular ejection) to the periphery. It results in an earlier return of the reflected wave which increases the pressure and subsequently the afterload of the left ventricle and reduces coronary artery perfusion pressure during diastole. One of the most frequently used noninvasive methods for the assessment of aortic stiffness is carotidfemoral (aortic) PWV [137]. It is a simple, noninvasive, and reproducible method which has been used as a gold standard and provides a predictive value of aortic stiffness for future cardiovascular events [138]. PWV has been used as significant marker of cardiovascular risk. Data indicate that increased arterial stiffness is being independently predictive of coronary artery disease, stroke, and cardiovascular events in general [139]. While PWV values are lower in healthy young individuals, the values of PWV increase with reduction of arterial

Applanation tonometry is another method that is used for pulse wave analysis. Rather than directly assessing aortic pulse wave, it estimates aortic pulse wave from the common carotid artery or the radial artery pulse waves. As the measurement is easier, radial artery tonometry has been the most commonly recommended approach [137]. Since the method can detect changes that might be related to vascular health, even before the onset of signs and symptoms, yet, the PWV analysis occupies an important place in clinical practice [141]. This method has some limitations that are related to associated comorbidities, such as metabolic syndrome, obesity, and diabetes, because the femoral pressure waveform may be difficult to record accu-

Carotid intima-media thickness (CIMT) is a method that evaluates extra-cranial carotid arteries by high-resolution ultrasound, and represents an important marker of subclinical atherosclerosis [142]. CIMT is increased in atherosclerosis and also correlates with

ment of endothelium-dependent vasodilation [136].

404 Endothelial Dysfunction - Old Concepts and New Challenges

*3.2.4. Pulse wave velocity*

elasticity [140].

rately in these patients [137].

*3.2.5. Intima-media thickness*

To find a specific and sensitive biomarker for any disease sometimes looks like a search for the Holy Grail—something precious but impossible to find. The reason for that could be those cardiometabolic diseases, all having a common point—endothelial dysfunction and it is likely that they have common underlying mechanisms leading to endothelial dysfunction. These mechanisms may be redundant and not activated at the same time and the same order, but certainly end up with impaired endothelium, and inappropriate vascular response to physiological stimuli with inability to compensate for pathophysiological events, finally leading to manifested disease and organ damage. One can only take with "a grain of salt" as many different biomarkers as possible and build up a picture of their relationship to the disease's etiopathogenesis, development, and prognosis.
