Arterial stiffness as predictive factor of cardiovascular diseases

<jats:p>nema</jats:p>


Introduction
Understanding the basic hemodynamic principles is necessary for the assessment of arterial stiffness and its possible clinical practice.Hydraulic and elasticity theory was established by Young in 1840, Moens in 1878, and Korteweg in 1878 1 .The main determinants of pulse wave velocity (PWV) relates to the velocity of pulse wave travel in a vessel to the distenbility of that vessel 2,3 : (PWV) = √(Eh/2Rρ), (E is the Young's modulus in the circumferential direction, h is the wall thickness, R is the vessel radius and ρ is the density of fluid).
Later, the doctors-physiologists, Marey in 1860, Mahomed in 1872 and Mackenzia in 1902, developed various types of Sphygmocor and, thus, made a significant progress in pressure waveform analysis 4 .Clinical application was discovered by Safar and O'Rourke 5,6 , which turned out to be very useful in the prognosis of the outcome and the correction of therapy.
In healthy persons, the peripheral arteries are stiffer than the central and that leads to an increase of amplitude of pulse wave in blood vessels, from heart to periphery, which is known as pressure amplification 6,7 .The stiffness of midsize arteries is assessed by a vasomotor tone which depends on the endothelial function or the sympathetic nervous system [8][9][10] or on renin-angiotensin system 11 .
Elastic properties of arteries vary along the arterial tree, with more elastic proximal and stiffer distal arteries.In humans, PWV increases from 4-5 m/s in the ascending aorta to 5-6 m/s in the abdominal aorta, and 8-9 m/s in the iliac and femoral arteries 11 .This difference in the arterial stiffness has the significant physiological and pathophysiological consequences.
Due to an increase of pulse pressure (PP) between the central and peripheral arteries, brachial PP should not be used as a replacement for aortic or carotid PP, especially in younger persons.
The stiffness of the common carotid artery is approximately six times higher in 70-year old persons than in a 20year old person 6,12 .In the older patients with hypertension or diabetes, the carotid arteries may become stiffer than the femoral or radial arteries which become slightly stiffer with age, or due to hypertension.

Noninvasive assessment of arterial stiffness
The regional and local arterial stiffness may be measured directly in a noninvasive manner, in various locations along the arterial tree and it is based on measuring the parameters which are directly connected to the arterial stiffness.

Local assessment of arterial stiffness
The arterial stiffness can be assessed locally through the use of ultrasound device which also provides precise measures of intima-media thickness (IMT) which allows the assessment of elastic properties of arterial vessel according to the Young's elastic modulus 13 .The assessment of carotid stiffness and thickness is important for the development of atherosclerosis.The local arterial stiffness of deep arteries such as aorta may also be measured by the magnetic resonance imaging (MRI), but this is not commonly applied in routine practice.Aortic PWV assessed by transformation of the brachial pressure waveform did not show a significant difference comparing with the cardiac magnetic resonancederived transit time method 14 .
Although the carotid-femoral PWV and carotid stiffness provide similar data on how age affects the stiffness of big arteries in healthy persons, this is not the case with the persons with hypertension and/or diabetes.With age and other cardiovascular risk factors, the aorta gets stiffer than the carotid arteries and that is why the aortic and carotid stiffness can not be used as the variable predictors of the high-risk patients 15 .

Regional assessment of arterial stiffness
Aorta is the main blood vessel of interest in the assessment of regional arterial stiffness, but all of the arterial branches have their own impact.Arteria brachialis, where the pressure is most often measured, and the lower extremity arteries get especially altered by atherosclerosis.Measurement of a local carotid stiffness may also provide a significant prognostic information since the carotid artery is often the place where atheroma appears.

Pulse wave velocity measuring
The PWV measurement is the simplest, noninvasive method for the assessment of arterial stiffness.Carotidfemoral PWV is a direct measurement and is considered a golden standard for the assessment of arterial stiffness, but it is important to measure precisely the distance between the carotid and femoral artery, because even small mistakes may affect the absolute value of PWV [16][17][18] .Measuring along the aorta or aortoiliac path is clinically the most relevant, since the aorta and its first branches are connected to the left ventricle and therefore are the most responsible for the majority of the arterial stiffness effects.Contrary to that, the PWV measured outside of aortic system, that is, in the upper extremities (brachial PWV) or lower extremities (femorotibial PWV) do not have a good predictive value in the patients with terminal kidney disease 19 .
It is difficult to register the femoral pressure waveform in persons with metabolic syndrome, excess body mass, diabetes and peripheral arterial disease 20 .In case of aortic, iliac, or stenosis of proximal segment of femoral artery, the pressure waveform may be delayed or reduced.Abdominal obesity, especially in men, and large breasts in women may cause an inaccurate measuring of distance 21 .

Arterial stiffness measuring devices
SphygmoCor ® is a tonometric device; PWV is calculated on the basis of successive waves produced in short time interval in two arterial locations (most often the carotid and femoral artery) through use of R waves in the electrocardiogram (ECG) for the calculation of the delay 22 .
Measurements are most often done at the root of the left subclavian artery (suprasternal space on the skin) or close to abdominal aortic bifurcation (at the level of umbilicus).Transit time is automatically calculated by the recognition of the beginning of pulse.This method is used for the assessment of predictive value of aortic PWV for cardiovascular events in the patients with diabetes and it gives more precise assessment of aor-tic PWV when compared to the carotid-femoral PWV.The aortic brachial PWV is an important predictor of cardiovascular events in the patients with hypertension 23 .
TensioMed Arteriograph ® is a device for measuring stiffness of arterial blood vessels that works according to the patented oscillometric principle.Data received via arteriograph [augmentation index (AIx), PWV, central systolic blood pressure (SBP) and PP] match the data received via the brachial artery catheter.Comparison was also made with Applanation Tonometer Sphygmocor ® and no significant difference was observed.For the assessment of the arterial stiffness parameters with these devices, it is necessary to prepare the patient adequately: the use of alcohol 10 h before and the use coffee 3 h before the measurement are strictly forbidden; patients must be in a semisupine position 10 min before the measurement.The assessment is performed in supine position at the room temperature of 22 ± 1°C.The arteriograph device measures aortic PWV (PWVao), AIx and central blood pressure (SBPao) values simultaneously with the peripheral blood pressure.By inflating the cuff on the upper-arm to suprasystolic pressure the brachial artery becomes occluded.The brachial flow is stopped, therefore the brachial wall characteristics are excluded (no significant wall movement), consequently the gained information relate to the systematic circulation.For calculating the arterial function parameters the recorded pulse waveform is analyzed and the characteristic points of the first and reflected waves are determined.The true aortic length is estimated with the jugulum symphysis distance (Jug-Sy).
Besides the classic 24-h blood pressure measurement, the latest device with HMS CS program combined with the Mobil-O-Graph ® also has an integrated system for 24-h ambulatory monitoring of arterial stiffness through the use of oscillometric method.The Mobil-O-Graph ® measures standard blood pressure parameters, central aortic pressure, central PP, AIx standardized to a heart rate of 75 beats through empirical regression (AIx@75), PWV, cardiac output, cardiac index, and total vascular resistance reflection magnitude.Biolectrical impedance gives us these values at present time 24,25 .24-h monitoring both of arterial stiffness and hemodynamic enables the provision of more precise parameters in cardiovascular prediction.There is no specific preparation of patients for wearing this device and one advantage is that all parameters are monitored 24 h during usual the daytime and nighttime values.In addition, the therapeutic effect of medicine can be assessed much better, with a much better prognostic effect on damages of target organs.
The Mobil-O-Graph ® parameters are shown in Figure 1.
There is no difference in the value of central aortic pressure measured by using the oscillometric noninvasive method with the Mobil-O-Graph ® device and the tonometric method with the SphygmoCor ® device.The Mobil-O-Graph ® combines the advantages of assessing brachial pressure and central blood pressure in one measurement 20 .As with other populations, the acceptability of Mobil-O-Graph ® and SphygmoCor ® is evident for central SBP and AIx@75 in the Stojanov V, Radivojević N. Vojnosanit Pregl 2019; 76(9): 942-950.
dialysis patients; PWV is slightly underestimated by the Mobil-O-Graph 22 .Noninvasive 24-hour assessment of blood pressure level and blood vessel stiffness is of prognostic value for a cardiovascular risk 26 .According to the SAFER study, the left ventricular hypertrophy (LVH) is more associated with 24-hour aortic pressure than with 24-hour brachial pressure in the patients with hypertension 27 .Aortic pressure correlates better with all, especially cardiovascular mortality caused by the brachial artery pressure 28 .

Central pulse wave analysis
Arterial pressure waveform consists of the pulse wave initiated by the ventricular contraction and reflected wave.The waves are reflected from periphery, mostly from the branching point.In elastic blood vessels, due to the low PWV, reflected wave has a tendency to return to the aortic root during diastole.In case of stiff arteries, PWV increases and reflected wave arrives to the central artery earlier, where it acts as an enhancement to the initiated wave and increases systolic pressure.This phenomenon may be quantified through AIx which is defined as a difference between the second and first systolic peak (P2-P1) expressed as a percentage of PP (Figure 1) 4,16 .Regardless of high PWV, changes in the location of reflection may affect AIx.In clinical research, the main AIx determinants are not only diastolic blood pressure and height, but also age and aortic PWV.
Central AIx and central PP showed an independent predictive value when it comes to all-cause mortality in the dialysis patients 28 and cardiovascular events in the patients who underwent percentaneous coronary intervention, as well as in the patients with hypertension in the CAFE study 29 .
Figure 2 shows AIx which is defined as difference between the second and first systolic peak (P2-P1) expressed as a percentage of PP.

Central and peripheral systolic and pulse pressure
Peripheral pressure SBP and PP (measured on the brachial artery) should not be equated with central SBP and PP measured on carotids, since peripheral pressure is higher than the central and PP, especially in younger persons, due to the less stiff central artery in younger persons.

Central pulse pressure, augmentation index and arterial stiffness
Central SBP and PP, AIx and PWV increase with age, hypertension, diabetes mellitus and hypercholesterolemia, and they are connected with damage to target organs (LVH, microalbuminuria, carotid plaques, and endothelial dysfunction).Central SBP, PP and AIx depend on the speed at which the wave travels, amplitude of the reflected wave, point of reflection, duration and size of ventricular ejection, especially in relation to heart rate and ventricular contractility 30 , while aortic PWV which is the wave propagation speed, presents the internal arterial stiffness according to the Bramwell-Hill equation (Figure 2).Pathophysiological conditions and medicines can change central PP and AIx without changing aortic PWV, which shows the dominant influence of the reflecting wave, heart rate or ventricular ejection, without the change of arterial stiffness [30][31] .AIx is much more sensitive to heart rate than PWV.In the Anglo-Cardiff Collaborative Trial conducted in the general population, it is shown that younger than age of 50 years affects AIx more than it affects PWV in the people below 50 years of age, but it is the opposite after the age of 50 years 34 .
Central pressure and AIx have a significant predictive value in the patients with hypertension, coronary disease and kidney diseases 35 .
Figure 3 shows the foot to foot method for measurement of carotid-femoral PWV.

Pathophysiology
The stiffness of vascular wall depends on two main fiber proteins which are part of its composition: collagen and elastin.Excessive production of abnormal collagen and reduction of normal elastin plus their inadequate spatial organization lead to arterial stiffness 36 .
There are many risk factors for the increased arterial stiffness: age, low birth weight, menstrual cycle, menopause, lack of physical activity, genetic predisposition to hypertension, diabetes, myocardial infarction, genetic polymorphism, obesity, smoking, hypercholesterolemia 37 , glucose intolerance, metabolic syndrome, hyperhomocysteinemia, high levels of C-reactive protein (CRP).Also, cardiovascular diseases, such as coronary disease, congestive heart failure 2 , stroke, as well as non-cardiovascular diseases, such as moderate chronic kidney disease stage 3 38 , rheumatoid arthritis, systemic vasculitis and systemic lupus erythematosus 30 represent risk factors for the increased arterial stiffness.
The arterial stiffness and reflection of waves are important for an increase of systolic pressure in elderly persons, and they play an important role in the occurrence of cerebrovascular stroke and myocardial infarction.
The arterial stiffness causes premature return of reflected wave in early systole, which increases central PP and then systolic blood pressure which increases left ventricular burden and increases the need for oxygen.In addition, the arterial stiffness is combined with LVF 27 , which is a significant risk factor for coronary disease in the normotensive and hypertensive patients.The increase of central blood pressure and decrease of diastolic BP can directly cause subendocardial ischemia.The increase of aortic stiffness, together with aging and risk factors for cardiovascular diseases, is caused by various mechanisms including the degradation of elastic Stojanov V, Radivojević N. Vojnosanit Pregl 2019; 76(9): 942-950.fibers, collagen accumulation, fibrosis, inflammation, medial smooth muscle cell necrosis, calcification and diffusion of macromolecules across the arterial wall 29 .The increased arterial stiffness may increase the risk of stroke through several mechanisms, including the increase of central PP, influence on remodeling of intra-and extracranial arteries, increase of carotid wall thickness, and development of stenosis and plaques 29,30,39 , with plaque rupture and damage to the white matter of brain.In addition, the coronary disease and heart weakness with high PP and the arterial stiffness are risk factors for the occurrence of stroke.

Routine application of arterial stiffness
The aortic stiffness has an independent and more significant predictive value than classical risk factors for allcause and cardiovascular mortality in the patients with hypertension, type 2 diabetes, patients on dialysis and elderly persons, since it shows damage to blood vessel through risk factors during the longer time period 22 .
Aortic PWV has a better predictive value than the classical cardiovascular risk factors.Central AIx and PP showed an independent predictive value for all-cause mortality in the patients on dialysis, or after kidney transplantation and for cardiovascular events in the persons with hypertension and coronary disease, after percutaneous coronary intervention 40 .It was shown in meta-analysis that the aortic stiffness expressed as aortic PWV is a strong predictor of future CV events and all-cause mortality.The predictive ability of arterial stiffness is higher in the subjects with a higher baseline cardiovascular risk 41,42 .Also, aortic PWV may enable better identification of the high-risk populations that might benefit from more aggressive cardiovascular disease risk factor management 43 .

Predictive value of pulse wave velocity for cardiovascular event reduction
An important question is whether the reduction of PWV is associated with the accompanying reduction of cardiovascular events, regardless of the normalization of classical risk factors?
The reduction of arterial stiffness may indicate an actual reduction of damage to blood vessel wall, while blood pressure, glycaemia and lipids may be normalized in several weeks through medical therapy, resulting in a significant reduction of cardiovascular risk score, but without the improvement of atherosclerotic lesion and the arterial stiffness which require a long-term correction of biochemical parameters.Therefore, a temporary dissociation between the reduction of cardiovascular risk factor and further present arterial stiffness is to be expected.
It is still to be proven whether reduction of central PP is associated with the accompanying reduction of cardiovascular events, regardless of normalization of classical risk factors.There is indirect evidence of this.In the REASON study 38,44 , only the combination of perindopril/indapamide managed to significantly reduce reflection of carotid wave with the resulting relative reduction of central SBP and PP and subsequent reduction of LVH 42 as opposed to no reduction of carotid PP and LVH in the patients who used atenolol in their therapy.The CAFE study 40 and ASCOT study 45 showed that central pressure, AIx and PP were the independent predictors of cardiovascular events in the hypertensive patients and that reduction of central SBP and PP was higher in the amlodipine/perindopril group than in the atenolol/thiazide group, despite of similar reduction of SBP and PP of brachial artery.

How to reduce arterial stiffness (arterial stiffness therapy)
Nonpharmacological and pharmacological therapies have an important place in the arterial stiffness reduction.
Pharmacological therapy includes the application of antihypertensive medicines and medicines for the cardiac insufficiency treatment: diuretics, beta blockers, angiotensinconverting-enzyme (ACE) inhibitors, type 1 angiotensinreceptor blockers (ARBs) and calcium antagonists, nitrates, hypolipidemic medicines such as statins and fibrates, antidiabetics such as thiazolidinediones as well as sildenafil 17,49 .
The majority of antihypertensive drugs have the main influence on the dynamic component of arterial stiffness and in some part on the structural component in the arterial wall remodeling 18 .
In general, the renin-angiotensin system inhibitors are superior to all other antihypertensive drugs in reducing arterial stiffness.One reason is the profibrotic action of the renin-angiotensin system, as the turnover of the extracellular matrix in the arterial wall per se leads to a change in the properties of the vessel 50,51 .
The REASON study showed the positive effects of ACE inhibitors on the arterial stiffness, especially on AIx.The effects lasted even after nine months of treatment 44,52 .Positive effects were shown for most drugs in this group, including for lisinopril 53 .
If reduction of AIx is in focus, losartan in the LIFE 54 , OPTIMAAL 55 study and candesartan 56,57 showed positive effect on reduction.Some others ARBs valsartan (VALUE study) 58,59 and telmisartan 60 reduce AIx and PWV, but increase PP.
Figure 4 shows the case from our practice (a -before therapy with losartan and b -six months on losartan therapy. Beta-blockers without the vasodilating effects have a weaker effect on the arterial stiffness and central pulsatile hemodynamics than vasodilating drugs of other antihypertensive groups.The mechanism of action is through the heart rate reduction, as this influences the viscoelastic properties of the arterial wall.Reduced heart rate also leads to increased wave reflections, a lower reduction in aortic than brachial systolic blood pressure and reduced PP amplification.Pe-Stojanov JV, Radivojević JN.Vojnosanit Pregl 2019; 76(9): 942-950.
ripheral vasoconstriction, achieved by atenolol, is an additional mechanism responsible for the negative effect on wave reflections 61,62 .New agents such as nebivolol, which have vasodilating effects, seem to be more effective in improving central pulsatility.These effects appear to be related to their ability to donate nitrit oxide (NO), which dilates the small resistance arteries.The effects observed lead to PP amplification, but AIx reduction [61][62][63] .
Calcium channel blockers also lower PWV and reduce wave reflections, but to a lesser degree than reninangiotensin inhibitors.The largest amount of evidence is for amlodipine.In the CAFE study 64, it was showed to reduce central blood pressure more than peripheral blood pressure; it amplified pulse pressure and reduced AIx.
Diuretics seem to have no beneficial effect on pulsatile hemodynamics.Hydrochlorothiazide showed a neutral effect on reduction of central blood pressure and a neutral effect on PP amplification 65,66 .

Arterial stiffness and damage to target organs
The arterial stiffness also provides data on the damage of target organs, which is of a great importance for the assessment of total cardiovascular risk in the patients with hypertension.
In case of primary coronary event in the hypertensive patients, the value of aortic PWV is much more important for the low-risk patients (first or second tertile of the Framingham risk score) than for the high-risk patients (third or fourth tertile), which shows that the population with low to medium risk benefits the most from the value of PWV 30 .The latest results showed that the increased aortic stiffness is an independent predictor of major adverse cardiac and cerebrovascular events (MACCE) after acute STelevation myocardial infarction.The assessment of aortic stiffness in addition to classical risk factors significantly improved an early risk stratification 67 .
Concerning diastolic dysfunction, the arterial stiffness was correlated with the elevated left ventricular filling pressure and it was shown that the increased level was associated with an elevated left ventricular filling pressure in the patients with the preserved systolic function.It was hypothesized that the increased arterial stiffness is of pathophysiological relevance for the diastolic dysfunction 68 .

Conclusion
The existing European and American 70 recommendations for the diagnosis and treatment of hypertension define LVH and albuminuria as evidence of target organ damage, as well as the arterial stiffness and reflection of waves.
The assessment of arterial stiffness and central pressure should be considered as a recommended test for assessment of cardiovascular risk, especially in the patients with the damages on the target organs that went undetected during the routine examinations.According to the recommendations of the American Society of Hypertension (ASH), the assess-ment of blood vessels stiffness should be performed by a hypertension specialists in the hypertension centers.Introduction of this diagnostic procedure in routine practice is still under the consideration 70 .
According to the European Society of Hypertension (ESH) guidelines of 2013, the stiffness of large arteries and wave reflection phenomenon are the important pathophysiological indicators of isolated systolic hypertension, and, together with PP, they increase with age 28,71 .Carotid-femoral PWV is a golden standard for measuring the aortic stiffness 71 .According to the common guidelines issued by the European Society of Hypertension and European Society of Cardiology (ESC) 72 , the PWV value of > 12 m/s indicates a significant deterioration of aortic function in the middle-aged hypertension patients.According to the recent research, due to the use of correct carotid-femoral distance and taking into consideration 20% anatomically shorter pulse wave distance, the PWV value of > 10 m/s indicates the increase of aortic stiffness 73 .Central pressure, especially central SBP and PP are more important predictors of occurrence of cardiovascular events and assessment of cardiovascular risk from brachial pressure 72 .For the valid measuring of central pressure, you can use not only the tonometric devices (Sphygmo-CorCP ® ) but also the oscillometric ones (SphygmoCor XCEL ® ) 74 , as well as the 24-hour arterial stiffness monitoring device, the Mobil-O-Graph ® 18 .

Fig. 3 -
Fig. 3 -The foot to foot method for measurement of carotid-femoral pulse wave velocity.