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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_4012_Библиотеки_им_академика_М_И_Перельмана
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Pulmonary Arterial Stiffness
7
derive the value of the other [13]. In other words, it implies that Cp cannot
change independently of PVR and therefore would not be an important
independent determinant of outcome [29]. It has emerged that various
conditions are associated with significant alterations of RC-time. Shortened
empiric RC-times (0.47 ± 0.13 s; 0.43 ± 0.27 s; 0.39 ± 0.34 s) was documented
in subjects with normal pulmonary hemodynamics as compared with PAH
patients (0.56 ± 0.16 s; 0.53 -0.45 to 0.63- s) [29, 32, 40, 85]. Recently,
Tedford et al. documented shortened RC-times in post-capillary PH (0.28 ±
0.12 s, PAWP > 20 mm Hg), thus suggesting an increased pulsatile afterload
when compared to precapillary PH at a given PVR [86]. Very recently,
Oliveira et al. reported different age-dependent values of RC-time in normal
subjects (based on preserved exercise capacity). Subjects > 50 years have 0.48
± 0.12 s compared to 0.58 ± 0.4 s for subjects ≤ 50 years [62].
While it is clear that RC-times can no longer be considered constant when
precapillary PH, postcapillary PH and controls are compared. Constancy of
RC-time has been suggested within a given disease subgroup [13, 29]
implying a narrow range of RC-time values. However, RC-time constancy
paradigm is not supported by most of the data, which show a large SD and a
large coefficient variation (more than 25%) [13]. Pre-operative operable
chronic thromboembolic PH (CTEPH) is characterized by a more predominant
wave reflection than idiopathic PAH. The isobaric steady-component analysis
explains the disproportionately lower Cp with a downward and leftward
displacement of the inverse hyperbolic relationship between PVR and Cp in
the CTEPH patients and a significantly lower RC-time with respect to the
idiopathic PAH cohort (0.5 ± 0.13 versus 0.6 ± 0.3 s) [28]. Accordingly,
operable CTEPH increased mPAP with an increase in systolic PAP that was
proportionally more than in idiopathic PAH patients, while dPAP increased
less [24]. Therefore, dynamic right ventricular afterload in CTEPH patients
was higher than idiopathic PAH and correlated with the higher RV end-
diastolic diameter. Therefore, emerging evidence show that RC-time can
become shorter in PH, not only due to a stiffer pulmonary arterial tree caused
by increased pulmonary venous pressure (left heart dysfunction-PH) but also
an increased wave reflection caused by the presence of proximal pulmonary
obstructions (operable CTEPH), increasing dynamic right ventricular afterload
at the expense of the pulsatile component [13, 23].
RV total power (Wtot) is the sum of steady power (Ws) and oscillatory
power (Wosc) (Wtot = Ws + Wosc). Ws corresponds to the energy required to
move blood forward and maintain cardiac output. Wosc represents the extra
energy wasted to accelerate blood in a pulsatile fashion and is related directly
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to the amount of wave reflection. Wosc can be expressed as a fraction of Wtot
(Wosc/Wtot). The higher the Wosc/Wtot, the greater the waste of Wtot on
pulsatile work. There is a negative correlation between RC-time and the
Wosc/Wtot [29]. The lowest RC-time would determine an increase of Wo,
with a decline of the global cushioning function of pulmonary circulation
and ventricular-arterial coupling. These differences show that the different
processes of vascular remodeling that take place in PH may be associated
with different RC-times. This fact challenges the “monotonous” adaptation
hypothesis of pulmonary circulation in the disease (changes of PVR determine
proportional changes of Cp) [23, 58, 74]. According to that, Chemla et al.
propose a new formula for estimating systolic work of RV, which does not
only takes into account oscillatory work, but also the variability of its relative
weight in the total systolic work. These authors estimate that Wo can vary
from 20 up to a 55% from Wt according to the values of mPAP and right
auricular pressure [12].
Pulmonary Vascular Distensibility (α)
The normal pulmonary circulation is thin walled and distensible, capable
of handling increases in CO and transmural pressures through distension and
recruitment of vessels result in an increase in the total vessel cross-sectional
area. This, in turn leads to a reduction in PVR and Cp and explains that
mPAP-flow relationships in health can display a slight curvilinearity [57]. In
vitro measurements have shown that the distensibility (α, fractional diameter
change/mm Hg pressure) of pulmonary vessels of several mammalian species,
including humans, is ~0.02 for isolated large and small arteries [51]. This
means that normal pulmonary arteries distend ~2% of their initial diameter for
each millimeter mercury increase in transmural pressure. Linehan et al.
developed a distensible vessel hemodynamic model in the isolated perfused
dog lung to calculate values of α that agreed with published values for α in
isolated vessels [51]. Distensibility (α) is a mechanical property of the
pulmonary vasculature that could be useful to estimate the vascular response
to the distending pressures secondary to changes in flow. In other words,
distensibility is a mechanical descriptor of vascular distension. The model
assumed that local pressure drop was directly proportional to both local
vascular resistance and flow. Integrating the equation over the entire vascular
volume from pulmonary artery to pulmonary vein is:
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Pulmonary Arterial Stiffness
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where Ro was total pulmonary resistance (TPR, mPAP/CO at rest, Wood
units) and Q was mean pulmonary flow (L/min). α is calculated using the
method of successive iterations: given values of Ro and the measured values
of PAWP and Q at rest and during exercise, we varied α until we found the
value that gave the minimal average difference and standard deviation between
measured and calculated mPAP over the whole range of available Q [65].
Reeves et al. have showed that normal values of α in young subjects were
similar to those measured in vitro (0.02 ± 0.006; ranged from 0.006 to 0.035
with a coefficient of variation -SD/mean- of 0.3). α values decreased in
chronic hypoxia and with aging where vascular remodeling or vascular wall
stiffening was expected [65]. Thus the normal lower limit of α (mean - 2SD)
can be estimated at 0.8%/mm Hg.
Very recently, Lau et al. demonstrated that the loss of α during exercise
occurs before resting PH in pulmonary vascular disease (PVD). They showed
that distensibility α was lowest in the PVD-PH patients, intermediate in the
PVD-noPH patients, and highest in control subjects (0.25 ± 0.14%/mm Hg vs
0.45 ± 0.24%/mm Hg vs 1.4 ± 0.45%/mm Hg, P < 0.001) [44]. The value of α
from the control group slightly lower than 2.0%/mm Hg value described
previously in healthy young subjects [65] and from in vitro animal vessels [51]
can likely be explained by the older age of the control group employed. Since
subjects with PVD without PH display markedly reduced distensibility, they
proposed α as a vascular index for an improved description of the functional
state of the pulmonary circulation and early detection of pulmonary vascular
remodeling.
Since α is a physical description of the distensibility of the pulmonary
vessels, it would be interesting to know its relationship with PVR and Cp.
While α is a dynamic measurement recovered from multipoint mPAP/CO
plots, Cp and PVR are measured at rest. In accordance with Lau et al., we
found that Cp and α were related linearly, and that PVR showed a curvilinear
relationship with α (Figure 1, unpublished data) [44]. α of the control group
was 2.12 ± 0.98 %/mm Hg (range from 1.1 to 3.5) versus 0.24 ± 0.15 %/mm
Hg (range 0.054-0.66) of the PAH group, P < 0.001.
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Figure 1. Relationship between α and total pulmonary capacitance, Cp (Linear
regression analysis) and pulmonary vascular resistance, PVR (nonlinear regression
analysis).
Upper Limits of Normal Resting and Exercise Pulmonary
Hemodynamics
Reports indicate that PVR increases and extensibility of main pulmonary
artery decreases with advancing age [15, 30]. Because current era PH
demographics have shifted to an older population, we have to differentiate
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Pulmonary Arterial Stiffness
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older patients with “age-related stiffness” in the pulmonary vessels from those
who are truly PVD. Besides, it is unclear how to define the pulmonary
vascular response to exercise as “abnormal” especially in subjects > 50 years
old, whose pulmonary vasculature may respond differently to exercise than
younger people. It is very important to define the abnormal pulmonary
vascular response to exercise in subjects with normal resting hemodynamics
since several studies have suggested exercise PH may be mild, early and
perhaps more treatable stage of established resting PH [18, 59, 87].
Very recently, a cohort (n = 66) of consecutive normal subjects (based on
preserved exercise capacity and normal resting supine hemodynamics) who
underwent an invasive cardiopulmonary exercise testing for unexplained
exertional intolerance was evaluated [62]. Subjects aged > 50 years old (n =
41) were compared with subjects ≤ 50 years old (n = 25). pPAP, PAWP, PVR,
and Cp showed significant differences, with similar mPAP, right atrial
pressure, and CO at rest supine right heart catheterization (RHC). PVR was
0.96 ± 0.31 versus 1.27 ± 0.33 Wood units and Cp was 8.2 (6.9-11.2) versus
6.6 (5.2-8.0) mL/mm Hg for subjects ≤ 50 years old and > 50 years old,
respectively (P < 0.05) [62]. This is in agreement with the reported values of
distensibility between young (16 to 40 years old, 2.1 ± 2.0 %/mm Hg ) and old
(61 to 83 years old, 1.5 ± 1.0 %/mm Hg) subjects (P < 0.05) [65].
Although peak exercise mPAP (23 ± 5 versus 22 ± 4 mm Hg) and PAWP
(9 ± 5 versus 9 ± 4 mm Hg) was not different for subjects > 50 and ≤ 50 years
old, peak CO and Cp was lower and peak PVR was higher in older subjects
compared with younger subjects [62]. The upper limits of normal (ULN) for
maximum upright exercise pulmonary hemodynamics are shown in Table 1.
We can highlight two main observations: a) the requirement of a
preserved maximal oxygen uptake and maximal CO ≥ 80% in this study likely
excluded subjects with clinically relevant exercise-induced pulmonary venous
hypertension, in which peak mPAP ULN would be affected by pathologic
elevations of the PAWP during exercise and b) the significant differences in
PVR, Cp and mPAP/CO slope are explained by the different peak CO and
stroke volume between both groups. As a result of the observed decrease in Cp
and PVR, RC-time decreased by almost 50% without significant differences
between subjects >50 and ≤50 years old. Further work will be necessary to
better define any age-related causal relationship of the intrinsic RV function
response to exercise.
Finally, these exercise hemodynamic ULNs are in agreement with the new
definition of exercise PH: mPAP > 30 mm Hg and total pulmonary resistance
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> 3 mm Hg
.
min
.
mL
-1
, which demonstrated to reduce the number of false
positive exercise-PH diagnoses in healthy subjects [31, 39].
Table 1. ULN for maximum upright exercise pulmonary hemodynamics
≤50 years (n = 25)
>50 years (n = 41)
RAP, mm Hg
13
13
mPAP, mm Hg
30
33
PAWP, mm Hg
19
17
TPG, mm Hg
21
22
DPG mm Hg
14
12
PVR, Wood units
1.34
2.1
TPR, Wood units
2.11
3.16
Cp, mL/mm Hg
4.6
3.4
mPAP/CO slope, mm Hg/L/min
1.95
2.73
DPG: diastolic pulmonary gradient; RAP: right atrial pressure; TPG: transpulmonary
gradient; TPR: total pulmonary resistance. ( P < 0.001 comparing subjects > 50
and ≤ 50 years) [62].
PULMONARY ARTERIAL STIFFNESS
AND PULMONARY HYPERTENSION
PA stiffness is an important factor governing dynamic afterload. There is
evidence that pulmonary vascular stiffness may be a better predictor of
outcome than PVR. It has also been reported that proximal PA stiffness may
increase early in the course of PH, suggesting a potential contributory role of
PA stiffness in the development and progression of PH. The association
between vascular stiffening and disease severity is believed to be due to
several factors: a) stiffening reduces the windkessel effect of the elastic
arteries, leading to impair the buffering function; b) stiffening increases RV
afterload independent of PVR; c) the degree of RV dysfunction in PH is
independently related to PA stiffness; and d) changes in the flow and pressure
waveforms due to stiffening of the pulmonary circulation have been shown to
stimulate cellular signaling pathways in distal vessels and the lungs that
aggravate the existent vascular disease [41, 83]. Increased stiffness observed in
PAH may be secondary to elevated distending pressures or/and to structural
changes of the PA wall. Although the increased stiffness of the conduit arteries
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Pulmonary Arterial Stiffness
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contributes to disease progression, proximal arterial compliance comprises
only 15 to 25% of the total Cp, with the reminder distributed across the
entirely of the arterial bed. Changes in Cp affect the entire pulmonary
vasculature with the largest portion of that occurring in vessels distal to the
lung hilium. Furthermore, because Cp is a critical determinate of RV
oscillatory work, a greater understanding of the mechanisms by which Cp is
decreased in PAH will assist the development of new therapies [5].
Mechanobiology of the Increased Arterial Stiffness in PAH
In general, the aspects of vascular remodeling responsible for increasing
vessel stiffness include changes in the content and organization of the
extracellular matrix (ECM) proteins (elastin, collagen, proteoglycans and
glycoproteins), increased transmission of force between the ECM and vascular
cells, and an intrinsic stiffening of the cells themselves driven by changes in
cytoskeletal organization [5]. At present, we lack a complete understanding of
the process that leads to increases in the stiffness of the large and small
vessels. Remodeling of distal PA vessels in patients with PH is characterized
by intimal thickening and concentric and/or eccentric fibrosis, medial
hypertrophy, muscularization of arterioles and adventitial thickening and
fibrosis [64, 89]. Remodeling of the conduit PAs includes dilatation of the
vessels with the accumulation of inflammatory cells in the vessel wall,
degradation of the elastin in the media and deposition of collagen with
increased crosslink. All these changes, determine the vessel wall thickened and
neointima formations. In general, proximal changes are more consistent across
species and groups of PH compared to the wide variability of changes
observed in the distal vasculature [75].
The content and arrangement of the ECM are critical regulators of blood
vessel mechanics. While collagen imparts rigidity to the vessel wall, elastin
determines compliance. Normally, collagen engagement occurs gradually as
stress is applied to the vessel wall, progressively heightening the vessel's
resistance to deformation. Regarding to the content of the ECM, collagen
accumulation occurs both in the vessel media and in the adventitia of proximal
and distal arteries in PAH, increasing resistance to strain at both early and
late deformations. The cellular source of this collagen accumulation are the
PA smooth muscle cells and fibroblasts in the vessel media and adventitia,
respectively [68]. By contrast, vascular elastin expression is variable,
exhibiting an inverse relationship with the increase mPAP [78]. Respecting to
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the arrangement of ECM, collagen fiber organization is regulated by the
balanced activity of matrix metalloproteinase (MMP) and tissue inhibitors of
MMPs (TIMMP). Elevated expression and activity of MMP-2, MMP-3,
MMP-9 and TIMMP-1 and type III and IV collagen degradation products
correlate well with PAH disease severity and PA stiffness. The increased
collagen synthesis and breakdown coupled with disordered alignment
contributes to increased stiffness. The increased elastin degradation secondary
to the upregulated serine elastase in PAH also contributes to increased vessel
stiffness because it causes a transfer of load bearing to the stiffer collagen
fibers [5]. Alterations in the TGF-β/BMP signaling axis, chronic inflammation
and disrupted serotonin signaling would be responsible for the altered ECM
content and remodeling in PAH [90].
Additionally, transmission of force between cells of the vascular walls
plays an important role of vessel stiffness. Force transmission between cells
and their environment (mechanotransduction) is accomplished functionally
through integrins, a class of matrix-binding proteins. Elevated activity of the
protein kinase Src leads to greater transmission of force between cell and ECM
through a significant alteration of integrin expression in idiopathic and
hereditary PAH, leading to an increased PA stiffness [54].
Regrettably, there are no approved drugs and few under active clinical
investigation designed to target mechanisms responsible for increased PA
stiffness directly yet [91].
Assessment of Pulmonary Arterial Stiffness
Pulse pressure and arterial stiffness determine, together with the
geometrical characteristics of the vessel, the mechanical stress within the
arterial wall. Three types of arterial stiffness can be considered: systemic,
regional and local arterial stiffness. Systemic stiffness can be estimated by the
inverse of Cp (pPAP/SV) and regional arterial stiffness is classically assess by
the pulse wave velocity (PWV) [48]. PWV is defined as the speed of travel of
the pressure pulse along an arterial segment, and dependent on the elastic
modulus and geometrical factors of the vessel as derived by the Moens-
Korteweg equation:
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Pulmonary Arterial Stiffness
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where Einc is the Young's elastic modulus, h and r are the thickness and radius
of the vessel, is blood density. Human data of the PA PWV comes from
cardiovascular magnetic resonance imaging (CMRI) studies. The normal value
of PA PWV reported was 1.6 ± 0.5 to 3.8 ± 1 m/s, and increased significantly
in patients with PAH 6.9 ± 1.3 m/s [17, 36].
We will focus on local arterial stiffness indexes that are defined as wall
properties per unit of length, or cross-sectional area wall properties and are
derived from the pulsating arterial section area (Figure 2) and of the pPAP.
Figure 2. Schema showing the change in cross sectional area (systolic minus diastolic
areas; sA-dA) of the vessel during the cardiac cycle. (dD and sD: diastolic and systolic
diameters).
Pulsatility corresponds to the relative change in lumen area during the
cardiac cycle:
-
-
where maxA and minA are maximum and minimum cross-sectional areas,
which correspond to systolic (sA) and diastolic (dA) areas. Pulsatility can be
estimate by CMRI, echocardiography or intravascular ultrasound (IVUS) [6,
63, 72]. Pulsatility < 40% predicts PH with 93% of sensibility and 63% of
specificity [72]. In PAH, pulsatility < 10% predicts non-responders to acute
vasoreactivity testing (100% sensitivity; 56% specificity) [37]. It has been
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reported that a decreased pulsatility of both proximal (CMRI) and distal
(IVUS) PA is related to an increased long term mortality in patients with PAH
[20, 67, 72].
While the arterial pulsatility depends on intraluminal pressure and
viscoelastic properties of the arterial wall, the arterial stiffness depends on the
extent of wall remodeling.
So, because of the strong dependency of strain on underlying pressures,
quantification of pulsatility alone is insufficient to fully characterize PA elastic
properties, explaining the absence of its correlation with basic hemodynamic
parameters [67].
In clinical practice we can estimate the following local arterial stiffness
(elastic properties of the PA as a whole) [48]:
EM corresponds to the inverse of distensibility coefficient (the pressure
change driving an increase in relative cross-sectional area), DC corresponds to
the relative change in lumen area during systole for a given pressure change
and CC corresponds to the absolute change in cross-sectional area during
systole for a given pressure change (operating pressure).
In an experimental model of acute PH, we have demonstrated that
only those indexes of wall stiffness that simultaneously consider changes of
pressure and diameter of PA are correlated with the incremental elastic
modulus (the gold standard for the elastic properties of a vessel wall) [70]. We
have recently demonstrated that local elastic PA (2-5 mm diameter) stiffness
indexes normalized according to pPAP are correlated with Cp and
PVR (Figure 3) [26]. Accordingly, Sanz et al. showed a correlation
between hemodynamic parameters and proximal PA stiffness in patients
with PAH [72].
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