**3.1 Elastic response of the arterial wall to changes in arterial pressure**

In both pulsatile and non-pulsatile flow the arterial wall showed a 3-phase elastic response to rising arterial pressure (see figures below). In the first phase, corresponding to sub-physiological pressure, the artery is relatively flaccid and distends easily with no thinning. In the second phase, corresponding to the normal physiological range of pressure, the stress/strain relationship is almost linear and over this linear

segment Young's modulus can be calculate at about 400–600 KPa and the wall begins to thin. As the pressure increases beyond the physiological range there is a marked loss of compliance with an 8 to 10 fold increase in Young's modulus. In this last phase the arterial wall thins to its minimum. **Figure 5** shows the proportional change in inner wall diameter and wall thickness of pig abdominal aortas (n = 5) subjected to stepwise changes in static (non-pulsatile) pressure over the range 0 – 250 mmHg.

The character of this 3-phase response to rises and fall in intralumenal pressure was explored using arterial hoop strips cut from the proximal end of the abdominal aortic segment.

**Figure 6** illustrates how Young's modulus measured in this way rises steeply once the upper limit of the physiological range of pressure is exceeded. The implications of this loss of wall compliance with rising arterial pressure are seen once pulsatile flow is introduced (**Figure 7**).

In the studies using pulsatile flow over a range of arterial diastolic and systolic pressures induced by varying the stroke volume load and the baseline diastolic pressure at a constant outflow resistance, a similar negative correlation was observed between the mean arterial pressure (MAP) and arterial wall compliance expressed as the proportional increase in cross-section per mm Hg pressure change (Spearman's R = −0.74, p < 0.001). **Figure 7** is a semi-log plot of the compliance versus MAP using 11 runs at different pressure settings in a single fresh pig abdominal aorta. The fall in arterial wall compliance with increased MAP follows the same three-phase response as that shown in **Figures 5** and **6**. As MAP approaches the upper limit of the physiological range there is a logarithmic reduction in compliance as the artery enters the third phase of stress/strain relationship and this is associated with corresponding rise in the pulse pressure, CTS, FI separation and the sharpness of the pressure peak.

#### **Figure 5.**

*3-phase elastic response of the arterial wall to rising static pressure (non-pulsatile flow), n = 5 +/*− *SEM. Throughout the physiological range of pressure the arterial diameter increases in response to rising pressure and the wall thins; at the upper limit of pressure the arterial diameter reaches an elastic limit and the wall its minimum thickness. A similar 3-phase stiffening of the arterial wall in response to mean arterial pressure is seen under conditions of pulsatile flow (Figure 7) and as the wall stiffens pulse pressure increases and the strain across the inner arterial wall rises proportionately.*

*Role of Arterial Pressure, Wall Stiffness, Pulse Pressure and Waveform in Arterial Wall… DOI: http://dx.doi.org/10.5772/intechopen.100048*

#### **Figure 6.**

*Changes of Young's modulus (Kpa) in hoops trips of arterial wall subjected to increasing tension. Equivalent lumenal pressure derived from the Young-Laplace formula is shown on the X axis. N = 5, runs 20.*

#### **Figure 7.**

*Under pulsatile flow conditions a rise in mean arterial pressure just above the normal range for the pig [21] gives rise to an exponential loss of wall compliance which is correlated with a corresponding increase in transmural strain. 11 runs in a single artery.*

#### **3.2 Arterial wall compliance under pulsatile flow conditions**

As arterial wall compliance drops, pulse pressure increases and the systolic peaks of the pressure wave sharpen. **Figure 8** compares the pressure traces where

#### **Figure 8.**

*Mean changes in pulse pressure and waveform profile with progressive loss of arterial wall compliance over a one-second pressure cycle. The key shows the period of exposure to formaldehyde vapour and resulting mean Young's modulus (Kpa) in relation to hoop strips cut from the proximal end of the test vessel after 6,9 and 24 hours of exposure. The volume load, cam profile and volume cycle and outflow resistance are held constant. n = 5, runs 20.*

the arterial wall compliance alone has been changed by progressive formaldehyde exposure, the volume load, baseline pressure, pulse rate and outflow resistance being held constant. The corresponding Young's modulus for each period of formalin exposure measured at the equivalent of 100 mmHg pressure load using hoop strips cut from the proximal end of the test artery is shown in the key.

As arterial wall compliance decreases under pulsatile flow conditions the separation of the FI during passage of the pressure wave increases and reaches its maximum during the transition from systole to diastole and vice-versa. **Figure 9** shows the timing of the mean separation of the FI from the underlying vessel wall observed using B/M mode ultrasound throughout the phases of the pulse pressure wave cycle measured in five representative arteries as the wall is progressively stiffened. When the arterial wall is relatively compliant little separation of the FI occurs: as it stiffens increasing "lifting" separation of the FI is seen during passage of the pressure wave and occurs out of phase with the pressure wave itself, initially only in systolic/diastolic transitions but as the vessel stiffens further both in systolic and diastolic transitions.

#### **3.3 Pulse pressure, centripetal strain and separation of the FI**

The pulse pressure is very closely directly correlated to the CTS (r = 0.907, p < 0.001) and to the internal displacement of the FI when controlled for peak pressure waveform. **Figure 10** shows the relationship controlled for slightly blunted peaks characterised by an area under peak pressure 3.5 mm2 (where each square represents 12 mmHg pressure over a period of 40 msec). Maximum proportional internal displacement of the FI is seen to occur as the peak pressure declines at the start of diastole (**Figure 9**) and is greatest when the pressure change is abrupt.

#### **3.4 Waveform profile, viscosity, pulse rate, and diastolic pressure**

No effect of pulse rate, or perfusate viscosity over the range 1 to 3.9 mPa.s on CTS or FI strain was observed independent of the effect of pulse pressure. This

*Role of Arterial Pressure, Wall Stiffness, Pulse Pressure and Waveform in Arterial Wall… DOI: http://dx.doi.org/10.5772/intechopen.100048*

#### **Figure 9.**

*Timing of strain response of the FI throughout the pressure cycle as the vessel wall is stiffened by progressive exposure to formaldehyde vapour. Figures in the key refer to corresponding mean Young's modulus derived from hoop strip tensiometry of the exposed formaldehyde vessels.*

#### **Figure 10.**

*Close relationship between pulse pressure and CTS controlled for the same waveform, area under peak (AUP) = 3.5 mm, n = 6 runs = 18.*

does not exclude the possibility that viscosity may affect *shear strain* acting on the endothelium in pulsatile flow conditions which was not measured. Increased vessel wall stiffness is reflected in sharpening of the peak pressure wave and increased pulse pressure and both are associated with increased CTS. A close correlation was found between pulse pressure, CTS and FI separation irrespective of pulse rate, baseline ("diastolic") pressure, waveform or fluid viscosity. However this correlation depended on comparing like waveform profiles. When waveform profiles alone were altered by changing the cam profiles and selecting identical pulse pressures

#### **Figure 11.**

*Relationship between peak waveform profile and CTS when the pulse pressure remains the same, MAP in range 75-100 mmHg. Sharper peaks give rise to a greater CTS in pulsatile flow, whilst with blunted ones the CTS is reduced.*

for analysis, the sharper the pressure transition the greater the CTS and false intima separation, (Spearman's R 0.93, p < 0.001), **Figure 11**).

### **4. Discussion**

Blood pressure along with age, smoking habits and serum low-density lipoprotein cholesterol concentration (LDL-C) is a risk factor in the development of ischaemic heart disease and the risk of atherosclerotic large and middle-sized arterial disease throughout the body [22]. Much attention has been paid to the clinical management of blood pressure and LDL-C. By comparison relatively little attention has been given to the haemodynamic inter-relationships whereby blood pressure and other variables such as blood viscosity, vessel wall stiffness and pulse pressure waveform may interact to stress the arterial wall and influence the development of vascular disease. The presence of cholesterol in atherosclerotic plaques, the results of experimental animal studies and the clinical effectiveness of statins have tended to concentrate attention on the cholesterol accumulation theory of atherogenesis perhaps to the detriment of the study of these biomechanical factors. Although LDL-C undoubtedly plays a part in the atherogenic process in relation to atherogenic inflammatory changes in the vessel wall, the clinical relevance of targeting blood cholesterol in itself remains unclear especially in the elderly [23–25]. Recent studies suggest that non-statin lowering LDL-C in itself is not necessarily useful [26] and that statins exert their effect via an anti-inflammatory rather than cholesterol-lowering pathway, a pathway in which mechanical stress is also implicated [27–29]. It follows that pursuing blood cholesterol targets in a patient already on an appropriate does of statins may be less productive than pursuing blood pressure and lifestyle targets. Bearing in mind the focal distribution of atheroma in the vascular tree at points of mechanical strain alluded to in the introduction, and the established role of inflammatory signalling in atherogenesis, it may also be appropriate now to reappraise atherosclerosis in terms

#### *Role of Arterial Pressure, Wall Stiffness, Pulse Pressure and Waveform in Arterial Wall… DOI: http://dx.doi.org/10.5772/intechopen.100048*

of a biomechanical-inflammatory disease akin to a repetition strain injury where similar inflammatory mediators and histological changes are involved [30, 31] rather than regarding it as a disease of principally metabolic origin.

In this context the study of haemodynamic variables in relation as to how they may interact to cause mechanical stress becomes relevant.

The weaknesses in the present model are that it is an in vitro study involving fresh specimens maintained as far as possible in physiological conditions. The haemodynamic parameters and dimensions of porcine vessels are similar but not identical to those of their human equivalents [21]. The model examines pulsatile flow in a moving column of fluid but the nature of the pulsatility and the flow may be different from that encountered in vivo. In terms of the broad principles the experimental set-up nevertheless provides a thought-provoking model of the stress/strain response of a major artery similar to the human equivalent. With this caveat in mind the principle mechanical findings, namely: (a) a rise in mean arterial pressure above the physiological range results in a precipitate increase in transmural strain consequent upon the vessel wall stiffening in response to pressure and (b) that this increased strain is proportional to pulse pressure and is affected by the shape of the pulse pressure peak and vessel wall compliance provide theoretical support for concentrating on blood pressure management and in particular on management of pulse pressure in the reduction of clinical risk both from atherogenesis and from plaque detachment. Artificially increasing vessel wall stiffness to the extent seen in hypertension also increases transmural strain and emphasises the central role of loss of large vessel compliance, whether caused by hypertension or disease, in the physical strain across the vessel wall under pulsatile flow conditions. Measures to preserve large vessel compliance such as regular exercise, blood pressure and diabetic control thus logically becomes a key element in the management of cardiovascular risk [32, 33] and in the reduction of the risk associated with onward transmission of damaging pressure waves to vulnerable distal vessels [34]. The possible role of heat therapy and garlic extracts in this respect requires further confirmation [35, 36]. In summary the parameters showing an effect in regard to CTS are: mean arterial pressure, pulse pressure, wall compliance and pressure waveform.

There is an interplay between these factors; this interplay with some postulated clinical correlations is illustrated in **Figure 12**.

With regard to further study it would be interesting to look into the effect of changing the characteristics of pulsatile flow in respect to pulse pressure and waveform on the expression of adhesion molecules, oxygen free radicals and nitric oxide by the endothelium, and to investigate further the possible repetitive strain nature of hypertensive atherogenesis. This experimental set-up may also prove useful in investigating the role of biomechanical variables in atheromatous plaque detachment and in helping to develop newer more compliant materials for arterial grafts and stents.

The postulated role of pulse pressure and pulse waveform in atherogenesis would be further supported if it could be shown in clinical studies that subjects with relatively low pulse pressure and rounded pulse pressure waveforms, such as those with untreated mild congenital aortic stenosis, had a lower burden of atheroma in distal vessels than in comparable controls. The role of blood pressure in the initiation of inflammatory changes in the vessel wall might be further explored by examining whether good blood pressure control reduces the expression of inflammatory mediators associated with cardiovascular risk such as CRP.

#### **4.1 Clinical implications**

The conclusion of the present study is a hypothesis based on observational evidence and *in-vitro* experimentation. Should the hypothesis be confirmed by

**Figure 12.**

*Postulated relationship between vessel wall stiffness, blood pressure and mechanisms involved in the pathophysiology of atherosclerosis and cardiovascular risk.*

clinical studies these findings provide theoretical support for the following clinical measures: control of mean arterial pressure and pulse pressure are particularly appropriate targets for prevention; large vessel wall compliance is important, and in a vessel already stiff, the transmural strain and hence the mechanical contribution to the risk of plaque separation is determined by pulse pressure and the sharpness of the systolic peak. The choice of treatment should be determined accordingly, and efforts to reduce the diastolic pressure in elderly hypertensive patients may be misplaced: the rational targets should be mean arterial pressure, pulse pressure and waveform. A key element is the role of arterial wall compliance in large vessels.

In brief it may be helpful to consider atherosclerosis as a disease of mechanicalinflammatory origin to which metabolic elements contribute a part rather than concentrating on the contribution of metabolic elements alone.
