Pulmonary vascular wall stiffness: An important contributor to the increased right ventricular afterload with pulmonary hypertension.

2011·1.4 MB·English

by  Wang, Zhijie

Review Article
Pulmonary vascular wall stiffness: An
important contributor to the increased
right ventricular afterload with pulmonary
hypertension
Zhijie Wang and Naomi C. Chesler
Department of Biomedical Engineering, University of Wisconsin-Madison, Wisconsin, USA
ABSTRACT
Pulmonary hypertension (PH) is associated with structural and mechanical changes in the pulmonary vascular bed that increase
right ventricular (RV) afterload. These changes, characterized by narrowing and stiffening, occur in both proximal and distal
pulmonary arteries (PAs). An important consequence of arterial narrowing is increased pulmonary vascular resistance (PVR).
Arterial stiffening, which can occur in both the proximal and distal pulmonary arteries, is an important index of disease progression
and is a significant contributor to increased RV afterload in PH. In particular, arterial narrowing and stiffening increase the RV
afterload by increasing steady and oscillatory RV work, respectively. Here we review the current state of knowledge of the
causes and consequences of pulmonary arterial stiffening in PH and its impact on RV function. We review direct and indirect
techniques for measuring proximal and distal pulmonary arterial stiffness, measures of arterial stiffness including elastic modulus,
incremental elastic modulus, stiffness coefficient b and others, the changes in cellular function and the extracellular matrix proteins
that contribute to pulmonary arterial stiffening, the consequences of PA stiffening for RV function and the clinical implications of
pulmonary vascular stiffening for PH progression. Future investigation of the relationship between PA stiffening and RV dysfunction
may facilitate new therapies aimed at improving RV function and thus ultimately reducing mortality in PH.
Key Words: biomechanics, impedance, vascular-ventricular coupling, right ventricular dysfunction, hypertrophy
INTRODUCTION
mechanical changes in the pulmonary vasculature that
occur as a consequence of PH are referred to as pulmonary
Pulmonary hypertension (PH) is a complex disorder vascular remodeling. Structurally, these changes include
that manifests as abnormally high blood pressure in smooth muscle cell (SMC) proliferation, changes in
the vasculature of the lungs. Based on the causes of PH, extracellular matrix (ECM) protein content, composition
the World Health Organization (WHO) has classified the and cross-linking, and either dilation or constriction of
disease into five categories including Group I, pulmonary vessels, depending on their location in the circulation.
arterial hypertension (PAH) resulting from increased The mechanical consequences of these structural changes
pulmonary vascular resistance, Group II, PH associated are increased resistance and decreased compliance. The
with left heart disease, Group III, PH associated with lung increase in pulmonary vascular resistance (PVR) that
diseases and/or hypoxemia, Group IV, PH due to chronic occurs with pulmonary arterial hypertension (PAH) is well
thrombotic and/or embolic[ 1d]isease, and Group V, other studied and characAtcecreiszse tdh ibs ya rnticalrer oonwlinieng of small arteries
miscellaneous causes of PH. The chronic structural and Quick Response Code: Website: www.pulmonarycirculation.org
Address correspondence to: DOI: 10.4103/2045-8932.83453
Naomi C. Chesler, PhD
Associate Professor of Biomedical Engineering How to cite this article: Wang Z, Chesler
University of Wisconsin at Madison NC. Pulmonary vascular wall stiffness:
2146 ECB; 1550 Engineering Drive An important contributor to the increased
Madison WI 53706-1609 USA right ventricular afterload with pulmonary
Phone: [phone] hypertension. Pulm Circ 2011;1:212-23.
Fax: [phone]
212 Pulmonary Circulation | April-June 2011 | Vol 1 | No 2
Wang and Chesler: Pulmonary artery stiffening in PH
and arterioles. However, the decrease in compliance we review direct and indirect techniques for measuring
(i.e. increase in stiffness) is also important and affects proximal and distal pulmonary arterialb stiffness, metrics
the entire vasculature. Both narrowing and stiffening of arterial stiffness including elastic modulus, incremental
contribute to increased right ventricular (RV) afterload. elastic modulus, stiffness coefficient and others, the
changes in cellular function and the extracellular matrix
RV afterload is a critical metric of PH progression because proteins that contribute to the pulmonary arterial
typically the cause of death in PH is right heart failure stiffening, and the consequences of PA stiffening for RV
due to RV overload. Left untreat[e2]d , the estimated median function. We also discuss the coupling between RV and
survival of PAH is 2.8 years. Conventionally, mean pulmonary circulation and interactions between the
pulmonary arterial pressure (mPAP) is used to diagnose proximal and distal vascular beds. Finally, we recommend
and predict survival in PH. Because of the dominating directions for future studies to better understand
influence of small artery narrowing on increases in mPAP, pulmonary vascular stiffening and its relationship to RV
a traditional strategy for PH treatment has been to reduce function, dysfunction and failure in PH.
or attempt to reverse this aspect of pulmonary vascular MEASUREMENTS OF PULMONARY
remodeling. However, it is becoming apparent that mPAP ARTERIAL STIFFENING
does not correlate with either the severity of symptoms
or survival. More recently, parameters reflecting RV
Direct measurements
functional status, such as RV mass and size, mean right
atrial pressure, ejection fraction and cardiac ind[2e,4x-8,] have
been shown to be strong predictors of survival. As a
Direct measurement of pulmonary vascular stiffness can
consequence, there is growing interest [9i]n therapies that be performed in vivo and in vitro by quantifying arterial
act directly on the RV to restore function. Importantly, RV
diameter as a function of pressure to generate pressure-
function depends not only on the state of the heart muscle
diameter relationships or PD curves[1. 5]In large animals,
itself (oxygen supply and demand, metabolic status, etc.)
large and small arteries can be tested;[16-1 i8n] small animals,
but also the vascular bed to which it is coupled, which
typically only large arteries are tested. In vivo, usually
represents its afterload.
either inner or outer diameter is measured as a fun[c19t]ion
of pressure and wall thickness is either assumed or
RV afterload results from a dynamic interplay between
resistance, compliance and wave reflections. It can be ignored. In vitro, both inner and ou[t2e0]r diameter can be
measured by hydraulic load or hydraulic power, which measured as a function of pressure, as well as fac[2t0o- 2r3s]
that influence the mechanical behavior of the tissue.
is work per unit tim[10e] generated by the heart to sustain
forward blood flow. The power provided by RV consists The most direct technique to[ 1m5-1e8,2a4s]ure stiffness is an
isolated vessel mechanical test in which the vessel
of two components: the steady power required to produce
inner and outer diameter are measured over a range of
net forward flow and the oscillatory pow[1e1]r required to
physiological and pathological pressures. This type of test
produce zero-mean oscillations in flow. Historically,
allows fine control of the test conditions such that the
the increase in RV afterload in PAH has been attributed to
effect of single parameter (e.g., SMC tone, collagen and/
increased PVR, which only reflects the steady component
or elastin content, drug treatment, etc.) on stiffness can
of total RV power. However, over a third of the RV w[1o2]rkload
increase in PH is caused by large artery stiffening, which be determined. Biaxial (in two directions) tests of arterial
mostly influences the oscillatory RV power. In clinical sections and uniaxial (in one direction) tests[ 2o5, f2 6t]issue
studies, an increase in PA stiffness was found to be[1 3a,1n4] either in strips or rings can also be performed.  Most
excellent predictor of mortality in patients with PAH, biaxial and strip test methods do not allow the effects
which suggests an important role of PA stiffening in right of smooth muscle cell (SMC) tone to[ 1b7,1e8 ,2i7n-2v9e]stigated
heart failure. Thus, to obtain a comprehensive view of but isolated vessel and ring tests do. Indirect
the contributions of the pulmonary vascular bed to RV measures of proximal and distal arterial stiffness also
function, one must consider the complete arterial tree exist, which we will review in the next section.
and investigate both steady and oscillatory components
of the RV power, which are determined by steady and The most commonly used approach for assessing structural
oscillatory components of pulmonary hemodynamics. mechanical properties of arteries is PD curves. If wall
Pulmonary artery stiffness is an important determinant of thickness is measured optically or histologically, material
the oscillatory component of pulmonary hemodynamics. properties can also be calculated. Because transmural
pressure results in circumferential stretch of the arterial
In this review, we will focus on the current state of wall, most mechanical properties are characterized in
knowledge of the impact of pulmonary arterial remodeling the direction of circumference and sometimes derived
(narrowing and stiffening) on RV afterload during PH from calculation of circumferential wall stress and
pPruolmgroensasryio Cnir,c wuliatthio na |p aArptriilc-Juulnaer 2fo0c1u1 s| o Vno ls 1ti f|f eNnoi 2ng. To do so, strain. However, recent studies on systemic arteries2 h1a3ve
Wang and Chesler: Pulmonary artery stiffening in PH
consider[e30d-3 2c]hanges in longitudinal stretch with disease may be applied to individual sections. The best example is
as well. Calculated parameters either represent elastic modulus, E, which for most arteries is low in a low
the whole vessel stiffness but dependent on geometry, strain range due to loading of elastin and high in a high
[17,33- 35]
such as pressure-strain modulus (Ep), stiffness strain range due to collagen engagement. Thus, low and
[36,37] [23,38-41]
con[s2t3a,38n,4t2 -β44,] distensibility (D) and compliance high strain moduli (E[l1o7w,2 6a,4n7d] Ehigh respectively) are often
calculated separately.
(C), or describe the material properties of the [w34a,4l5l]
independent of geometry, such as elastic[2 1m,45o,4d6]ulus (E)
and incremental elastic modulus (Einc). Sometimes Besides these structural and material properties that can
be measured from PD and sometimes pressure-length
the geometric-dependent mechanical properties are
curves, other parameters that require less information
termed “extrinsic” since they depend on the amount of
wall material whereas the geometry-independent material and thus are more feasible for clinical measurements
properties are termed “intrinsic” since they depend only have been introduced to investigate PA stiffening
on the constitutive materials themselves. For example, two during PH pro[g14r]ession. One example is the relative area
arteries made of the exact same material but different wall change (RAC). RAC is calculated as the relative cross-
thicknesses would have the same intrinsic properties but section area change (ΔA/A) of the proximal PA from
different extrinsic properties. A summary of commonly systole to[1 4d]iastole and it is reduced significantly in PH
used arterial intrinsic and extrinsic mechanical and patients. RAC shows a moderate inverse curvilinear
material properties are presented in Table 1. Consistently, relationship with mPAP and predicts mortality better
pulmonary artery[1 w6-1a8,l2l6 s,4t7i,4f8f]ness is found to increase during than area distensibility. Interestingly, RAC does not
PH progression. require knowledge of the distending pressure, so it is
neither a material nor structural property; instead it is a
It is important to note that all of these parameters are geometrical property.
linear approximations of non-linear relationships. That
is, for sufficiently large changes in stress and strain (for It is well known that blood vessels are not purely
E) or volume and pressure (for D), a single calculation (of elastic but in fact viscoelastic materials, which means
E or D) will be a poor approximation of the true material the elastic deformation under dynamic loads exhibits
or mechanical behavior. In a physiological pressure range, time-dependent behavior. A consequence of arterial
most of the above metrics are good approximations but viscoelasticity is pressure energy loss. When a purely
when testing is performed over a larger range, curve fits viscous material is deformed, all the energy is dissipated
Table 1: Summary of parameters commonly used to measure arterial elasticity
Definition (unit) Formula Notes
Pressure-strain modulus Ep (Pa) E = ∆PR Rm ecachna anliscoa lb per oreppelratcyed with diameter (D). Extrinsic
p ∆R
Elastic modulus E (Pa) The slope of stress-strain (σ-ε) curve, assuming
σ
E = linear homogeneous, incompressible wall material.
ε
Thin-wall or thick-wall assumptions lead to different
calculations of σ and ε. Intrinsic material property
Incremental elastic modulus1 Einc ∆P 2(1−ν2)R2R Ro and Ri are external and internal radii and can be
(Pa) E = i o replaced with corresponding diameters (D). Assum-
inc ∆R (R2−R2)
o o i ing locally linear, homogenous, incomepressible (if
ν=0.5) wall material. Thick wall assumption. Intrinsic
material property
Incremental elastic modulus2 Einc ∆P 2D2D 2PD2 Modified Einc, assuming orthotropic cylindrical tube.
(Pa) E = i o + o Intrinsic material property
inc ∆D (D2−D2) (D2−D2)
o o i o i
Stiffness constant β (dimension- P and P are systolic and diastolic pressures. Radius
s d
less) ln(P /P) R can be replaced with diameter (D). Assume homo-
β = s d
(R /R −1) geneous, incompressible, isotropic material. Extrinsic
s d
mechanical property
Distensibility D (1/Pa) V (volume) can be replaced with A (area). Extrinsic
∆V mechanical property
D=
V⋅∆P
Compliance C (m3/Pa) ∆V V (volume) can be replaced with A (area). Extrinsic
C = mechanical property
∆P
P: pressure; R: radius; D: diameter; V: volume; A: area
214 Pulmonary Circulation | April-June 2011 | Vol 1 | No 2
Wang and Chesler: Pulmonary artery stiffening in PH
and none is returned. When a purely elastic material that can be obtained by in vivo and ex vivo methods are
is deformed, all the energy is returned, like a spring. A rSeteviaedwye dp rbeeslosuwr.e-flow relationships
viscoelastic material is both viscous and elastic so some
of the energy provided to the material during loading is
dissipated during unloading and some is returned. Since Increases in mPAP that occur with increases in flow
most in vitro measurements do not perform dynamic whether in vivo (due to exercise or drugs) or ex vivo (due
loading-unloading tests such as occur in the intact to imposed flow waveforms) can provide insight into distal
animal or human due to physiological pulsatile pressure arterial stiffness. If one imagines the distal pulmonary
waveforms, mechanical properties obtained from in vivo arterial bed to be a parallel network of rigid tubes, then
or dynamic in vitro experiments are more realistic and any increase in flow will lead to a proportional increase in
physiological. For example, the compliance measured pressure. If more rigid tubes open as a result of increased
from static PD curves is less than that measur[e49d] form the flow (i.e., are recruited), then the increase in pressure
dynamic PD curves under the same pressures. Although will be less at high flows. If these rigid tubes increase in
not well recognized, the characterization of arterial diameter with increased flow (i.e., by the mechanism of
mechanical behavior including elasticity and viscosity flow-induced vasodilation), then the increase in pressure
may be of clinical importance in PH. at high flows will be less still. Finally, if the tubes are
not in fact rigid but can distend, then the pressure-flow
In systemic arteries, viscosity has been shown to curve may plateau at high flow. A theoretical approach
change with a[g50in-52g], with atherosclerosis and systemic to measuring this distal arterial distensibility, assuming
hypertension.  The effect of acute PH on arterial
a fully recruited and dilated pul[m73o] nary vasculature, was
vAirsmcoenstitayn oh. [a53s,5 4b] eOeunr ginrovueps,t itgoa oteudr kbnyo wthleed ggreo, uisp t hoef f i r s t d e smcrPiAbePd= by[( L1i+nαePhva )n5 +et 5 aαl.R0(:H ct)CO] 1 / 5 -1 (1)
α
only one that has investigate[d16 ,c47h,5a5]nges in proximal PA
viscoelasticity in chronic PH. Traditionally, SMCs
are consi[2d9e,56r]ed to be the primary source of arterial
viscosity but our results suggest that SMCs may where Pv is pulmonary venous pressure, CO is cardiac
not be the only determinant. The dampi[n16g,4 7c,5a5]pacity of output, R0 is the total pulmonary vascular resistance
large PAs increases after chronic hypoxia and th[5i5s] (mPAP/CO) at rest, Hct is the hematocrit, and α is the
increase correlates with the accumulation of collagen. pulmonary arterial distensibility, which is assumed to be
The clinical implications of increased PA viscosity during constant throughout the pulmonary vascular bed.
PH are unclear, but ar[5t6e]rial viscosity likely increas[e57s] [7,74] [75]
circulatory energy loss and affects wave reflections, In vivo and ex vivo studies have demonstrated that
thus impairing dynamic interactions between heart and PH decreases α. However, whether distal arterial stiffening
lIunndgi raencdt i nmcreeaassiunrge RmV eafntetsrl oad. impairs exercise capacity in PH by exacerbating flow-
iPnudlusacetidle in pcrreeassseusr ein- fmloPwA Pr erelamtiaoinnss hunipksnown.
Both proximal and distal pulmonary arterial stiffness can
be measured indirect[l5y8- 6f3r]om pulmonary pressure-flow From pulsatile pressure-flow relationships obtained
relatio[n63s-6h9i]ps in vivo or ex vivo in isolated whole either in vivo or ex vivo, indirect measurements of
lungs. Advantages of the isolated, perfused and proximal arterial stiffness can be obtained. In addition,
ventilated lung preparation are that pres[s60u]re-flow other characteristics of the pulmonary circulation can
relation[5s9]hips are not affected by anesthesia, volume be determined such as PVR and wave reflections. Two
status a[n58d] level of sympathetic nervous system approaches to analyze these pulsatile pressure-flow
activation. In addition, the effect of drugs on the relationships are commonly used: a frequency domain
pulmonary vasculature can be investigated independent mImeptheodda;n acned ( Fa rteimquee dnocmy adionm maeitnh aodn.a lysis)
o[70f ]the effects of those drugs on the systemic vasculature.
However, in most isolated, ventilated, perfused lung
preparations, only steady pressure-flow relationships are The relationship between pulsatile bloo[7d6] pressure and
obtained, from which only distal arterial stiffness can be flow can be quantified by the impedance. Its calculation
derived. Our group has used pulsatile flow waveforms to requires synchronized pulmonary arterial pressure and
obtain pulsatile pressure-flow relationships, which allow flow measurements, which are typically obtained w[77i,t7h8]
estimates of proximal artery stiffness to be made, although a right heart catheterization an[d79 ,e80i]ther ultrasound
these are still difficult to compare to in vivo mea[s68u,7r0e-7m2]ents or a catheter-based flow sensor in vivo or by direct
obtained with physiological flow waveforms. The recording of pressure and flow ex vivo. From these
mPeultmriocnsa royf Cpirrcouxlaimtioanl |a Anpdr idl-iJsutnael 2p0u1lm1 |o Vnoalr 1y |a rNtoe r2ial stiffness data, a comprehensive measurement of RV afterlo2a1d5 is
Wang and Chesler: Pulmonary artery stiffening in PH
given by pulmonary arterial input impedance (PVZ). in proximal PA radius decreases Zc, whereas an increase
The calculation of PVZ requires a spectral analysis of in stiffness has the opposite effect. These relationships
the pulmonary arterial pressure waveform P and flow are described theoretically by:
rEh
waveform Q and a mathematical elaboration (Fourier Z = (4)
c 2p2r5
analysis) to derive a PVZ spectrum, which is expressed as
the ratio of P to Q mod[7u6]li and a phase angle (θ), both as a
function of frequency :
P(ω) r
PVZ(ω)= (2) whereE ,h , andr are proximal PA elastic modulus, wall
Q(ω)
thickness and lu[8m7,8i8n]al radius, respectively, and is the
density of blood. [6 8Z,7c6 ,i8s9 ]usually found to remain constant
q(ω)=Φ(ω)−f(ω) (3)
in subjects with PH, which ma[1y6 ,b17e,2 a6,4 c7o]mbined result
o[14f ,1i6n]creased proximal PA stiffness and diameter.
This observation suggests that during PH, the RV and
where ω is the frequency, Φ is the pressure phase and φ pulmonary vasculature adapt to main[7t6a,8i9n] the mechanical
is the flow phase. This approach has been adopted in PH load on the RV and conserve energy. However, Zc has
animal m[1o9d,68e,7ls8, 8u1-s8i3n]g in vivo and ex vivo techniques and in also been found to change (increase or decrease) with
patients. Details of how to calculate impedance PH depending on the animal m[61o,6d2,e81l, 82u,8s8e,9d0,9 1o]r different
for the pu[2lm3,84o,8n5]ary circulation have been reviewed pathological mechanisms of PH.
previously.
A third parameter that can be derived from [t7h6e,9 2i]mpedance
The impedance spectra in systemic and pulmonary spectrum is pulse wave reflection (Г), which is
circulations share a similar, classic pattern of a high 0-Hz calculated by Z −Z
Γ= c (5)
value (Z0) followed by a local minimum and oscillations Z +Z
0 c
at high frequencies (Fig. 1). Z0 increases during PH
0
progression and this parameter is equal to total PVR. Like
PVR, Z0 is essentially as a measure of distal pulmonary [68,93]
resistance; it is the input impedance in the absence of flow The wave reflection increases significantly with PH,
oscillations. The average of the impedance modulus at which suggests a bigger impedance mismatch between
higher harmonics is used as an estimation of characteristic the proximal and distal pulmonary vasculature and may
impedance (Zc), which is the input impedance in the have detrimental effects on the RV [f1u0]nction as reported
absence of wave reflection. Zc is determined principally to occur in the systemic circulation.
by the r[7a6t,8i6o] of stiffness of the proximal arteries to fluid
inertia. It is dependent on both the size and material Overall, PVZ has the potential to be a better prognostic
properties of the proximal PAs. For example, an increase indicator than PVR alone because it captures both static
and dynamic characteristics of the opposition to flow in
the pulmonary circulation. PVR is typically a single-value
measurement assuming a linear relationship between
the pressure difference ΔP (ΔP = Pulmonary arterial
pressure – left atrial pressure) and the flow (Q). When
left atrial pressure is normal, total PVR can be measured
by the ratio of mean pulmonary pressure and mean
pulmonary flow (mPAP/Q). Both PVR and total PVR
characterize the steady, time-averaged hemodynamics
and represent only the static component of RV afterload.
It is well known that progressive pulmonary artery
remodeling during PH increases PVR. However, PVR is
likely limited as a prognostic parameter because [P94V]R alone
is not sufficient to measure total RV afterload. In fact,
more and mor[1e3 ,1e4v,8i3d] ence suggests that a global stiffness
measurement that includes both static and dynamic
components is a better representative and potentially
pTrimogen doostmica pianr aamnaeltyesri sfor PH progression.
Figure 1: Representative pulmonary vascular impedance (magnitude
Z and phase θ) spectra in a healthy mouse.
Although the rapid development of new technologies
216 Pulmonary Circulation | April-June 2011 | Vol 1 | No 2
Wang and Chesler: Pulmonary artery stiffening in PH
and instrumentation may allow more widespread use
of impedance analysis in the frequency domain, current
clinical applications are limited because of the complexity
of performing and interpreting the frequency domain
analysis and results, respectively. Instead, the time domain
analysis of the pulse pressure waveform is a useful
surrogate for assessing Z0, Zc and oth[e8r4, 9c5l,9i6n]ical indices of
pulsatile pulmonary hemodynamics.
In the time domain analysis, Z0 is calculated as mean
pressure divided by mean flow, which is the same as in
the frequency domain, andd ZPc is calculated as
Z = (6)
c dQ
Figure 2: An illustrative example of pressure waveform and the
derivation of pulse pressure (PP) and augmentation index (AI). Pi
where dP and dQ are pressure and flow increases taken is the inflection point, which may present either in the systolic or
prior to when flow rea[c9h7,9e8s] 95% of its maximal value diastolic phase.
during one cardiac cycle. Because of the raid upstroke
of the waveforms at this early ejection phase, the reflected
waves do not have time to return to the proximal bed [79,89,93,96,109]
and thus the system is [r97e]asonably assumed to be free reflection. AI can differentiate different types of
from wave reflections. From Zc, the instantaneous PH, i.e., chronic pulmonary thromboembol[i9s5m,96] (CPTE) and
pressure waveform is decomposed into forward (Pf) and primary pulmonary hypertension (PPH) but it may
backward (Pb) trav[e99l]ing waves using the linear wave be more sensitive to the proximal arteries than the whole
separation method. The global wave reflection index vascular bed a[1n0d0,1 c0a1]n be confounded by other factors such
(RQ) is then calculated as the ratio of the amplitude of Pb as heart rate. Finally, the relationship between AI
to Pf. In contrast to the wave reflection (Γ) that is m[o10s0t] and the severity of PH remains unknown.
applicable for simple systems of one or two tubes
and thus characterizes mismatch between proximal and A potentially more useful parameter is compliance, which
distal beds, R[Q1 0c1a]ptures the wave reflections of the whole conceptually is the inverse of stiffness. Compliance[ 1(1C0),1 1i1s]
vascular bed. calculated as the ratio of stroke volume (SV) to PP.
Similar parameters measured in the systemic circulation
Correlation between impedance measurements performed have been shown to be related to conduit artery stiffening
using frequency and time domain analyses requires and correlated with m[1o12r]tality in patients with left
further investigation. Our preliminary results[1 0h2a]ve shown ventricular dysfunction. In PAH patients, compliance,
good agreement between the two methods. which is sometimes called capaci[t1a3,1n1c3]e, has been shown
to have prognostic value as well. It is important to
Pulse pressure (PP) is often measured in the time domain point out that unlike in the systemic circulation where
analysis of pulmonary hemodynamics and[1 0h3,a10s4 ]been arterial compliance is mainly localized to the aorta, arterial
found to be a useful indicator of heart health. PP is compliance in pulmonar[y1 1c1]irculation is distributed over
defined as the difference between systolic and diastolic the entire vascular bed. An interesting relationship
pressure (Fig. 2) and is determined by the characteristics between compliance and resistance (PVR) has recently
of ventricular ejection and proximal arterial stiffness. In been observed in the pul[2m3,9o1n,11a1r,1y14 c]irculation: the product
both systemic and pulmonary circulations, PP is elevated of PVR and C is constant. In particular, Lankhaar
when large arterie[1s0 5s-1t0if8f]en, even without changes in the et al. have shown that the product of[ 9P1V] R and C is a constant
distal vasculature. for patients with and without PH an[1d1 4t]hat treatment
does not change this time constant Importantly,
Another parameter derived from the pressure waveform these results explain why changes in PVR alone do not
is the augmentation index (AI, Fig. 2), defined as the ratio reflect the clinical outcomes of PH patients. PH leads to
of the height from the inflection point (Pi) to peak systolic increased PVR and decreased C; but for a similar decrease
pressure (ΔP), which is an estimate of t[h96e] magnitude of PVR due to therapy, the patients with higher starting
of the reflected pressure wave to the PP, which may PVR (more severe PH) will have a smaller increase in C
correlate with proximal PA stiffness. In normal subjects than the patients with lower starting PVR (milder PH).
thPuelrmeo insa rvye Cryirc luitlattlieo nw |a Avper ril-eJfulneec t2i0o1n1, a| nVdo lP 1H | iNnoc r2eases wave Thus the former group of patients has improve2m1e7nt
Wang and Chesler: Pulmonary artery stiffening in PH
mainly in steady RV power requirements (due to a the neonatal period is associated with significant elastin
decrease in PVR) whereas the latter group of patients has production [i1n23 ]the pulmonary trunk even in normoxic
improvement in both steady and oscillatory RV power conditions, elastin synthesis may be particularly
requirements (due to comparable decrease in PVR and sensitive to modulation by hypoxia during this time of
increase in C). rapid growth. Another study using a set of transgenic and
CELLULAR AND MOLECULAR
knockout mice with graded elastin insufficiency found that
CONTRIBUTORS TO PULMONARY reduced elastin content in large PAs predispos[1e24d] the mice
ARTERIAL TIFFENING to elevated RV pressures and RV hypertrophy. With the
genetic deficiency in elastin, peripheral PAs developed
muscularization and proximal PAs exhibited increased
overall stiffness, but the Einc remained constant over a
The arterial remodeling that occurs in the progression of wide range of pressure change (0-90 mmHg). However, the
PH involves all three layers of the arterial wall. Histological extent of pathological remodeling of heart and pulmonary
evidence of remodeling consists of intimal fibrosis, vasculature was limited compared to those with similar
increased medial thickness, accumulation of extracellular pressure elevation induced by hypoxia, which suggests an
matrix proteins such as collagen, increased adventitial adaptation occurred during the development from fetus
thickness, pulmonary arteriolar occlusion and plexiform to adult. Therefore, it is likely that different mechanisms
lesions. The process is characterized by proliferative (elastin vs. collagen) may dominate the development of
and obstructive changes that involve cell [t1y2,p11e5s] such as PH, depending on the type of disease.
endothelial, smooth muscle and fibroblast. Detailed
The SMC tone changes significantly during PH development.
reviews on the cellular and molecular mechanisms of PA
This is especially prominent in the distal vasculature. It is
remodeling[1 i2n,11c6l]uding genetic factors have been reported
well accepted that the acute phase of PH is manifested by
previously.
vasoconstriction. In the chronic phase of PAH, remodeling
Stiffenin[g16 ,4o7f,4 8l,a11r7g,11e8 ]PAs is linked with accumulati[1o6n,26 ,4o7f] occurs with endothelial layer thickening (and formation
collagen and, in some studies, elastin. of plexiform lesions in severe PAH) and smooth muscle
However, if collagen and elastin concomitantly increase hypertrophy, which leads to reduced smooth muscle
during PH, one cannot discern which is more responsible contractility. The pro[1x7i,1m8,1a25l ]PAs seem to have limited
for arterial stiffening. A recent study suggests elastin changes in SM[2C7,2 8t,o12n6]e, but discrepant results are
remodeling contributes to PA stiffening in response to also reported. The impact of SMC tone on proximal
hypoxia-induce[2d6 ]pulmonary hypertension (HPH) in PA mechanical behavior in large animals or humans is an
neonatal calves, but discrepant observations are also important area of future research.
CONSEQUENCES/CLINICAL
reported in other species in adults. For example, there
RELEVANCE OF PULMONARY
was no change in [e48la,1s19t]in content in rodent large PAs after
chronic hypoxia. Our latestt mslt Jauedies using a novel ARTERIAL STIFFENING
transgenic mouse model (Col1a1 ) suggests changes
in collagen rather than elastin track la[1r7g]e PA stiffness Right ventricular overload and heart failure
during HPH progression and recovery. Furthermore,
we specifically examined the effects of collagen content vs.
cross-linking in the passive, dynamic mechanical behavior Right heart function is closely tied to survival in PH. For
of large PAs in chronic PH and fo[5u5n]d that collagen content instance, RV function assessed via right atrial pressure and
is critical to large PA stiffening. cardiac output is associated[ 2w] ith mortality in addition to
mPAP in patients with PAH. Previously, much attention
Differential impacts of elastin and collagen metabolism on has been paid to the pulmonary circulation and basic
PH progression may exist and can be attributed to the age mechanisms underlying pulmonary arterial dysfunction;
and type of PH developed. There is evidence suggesting however, little is known about the RV in health and
that elastin may play a more important role in PH in diseased states. It is recognized now that effective
newborns whereas collagen may have a larger impact treatment for PH should not only impact the pulmonary
in PH developed in adults. Studying the biomechani[c26s] vasculature but also improve RV function.
of newborn calf extralobar arteries, Lammers et al. 
showed a significant increase in low-strain elastic Stiffening of the pulmonary vascular bed can increase RV
modulus with chronic hypoxia that was dependent on workload, which may be caused by impaired conduit and
elastin. However, it is well known that newborn animals buffering function of the proximal PAs and early wave
develop more severe pulmonary hyperte[n12s0i-1o2n2] than reflections to the RV (Fig. 3). Under normal circumstances,
ad2u1l8ts with more dramatic vascular changes. Since the oscillPautlomroyn aRryV C iprcoulwateiorn |i sA parbil-oJuunte 22051%1 |o Vfo lt 1h e| Ntoo t2a l
Wang and Chesler: Pulmonary artery stiffening in PH
(oscillatory + steady) RV power, which is higher [t7h6,1a2n7]
the proportion in the systemic circulation (~10%). 
A recent study on the RV pulsatile hydraulic load in
PAH patients has shown that while both oscillatory RV
work and total RV work increase with[1 1P1A] H severity, the
proportion remains constant (~23%). The oscillatory
RV work correlates with pul[s12e7 ,p12r8e]ssure, which increases
with proximal PA stiffening. Therefore, PA stiffness
increases oscillatory RV work; however, the direct impact Figure 3: Hemodynamic interactions between the right ventricle
on RV function remains undefined. The effects of distal and proximal and distal pulmonary arteries. PA: pulmonary artery.
VVC: ventricular-vascular coupling.
PA stiffening (loss of distensibility α) on RV afterload are
also unknown.
Increased RV afterload leads to augmented myocardial
oxygen demand and the RV adapts primarily by
hypertrophy. Hypertrophy serves to decrease the
ventricular wall stress and maintain cardiac output
initially and thus could be a healthy response. However,
during PH progression, severe hypertrophy reduces
cardiac output and cardiac index, which [a9]re the hallmarks
of right heart dysfunction and failure. The indicators
of the transition from healthy adaptive hypertrophy to
pathological maladaptive remodeling remain unknown.
To understand the molecular pathways that differentiate
adaptive from maladaptive ventricu[l1a29r] hypertrophy is an
iVmepnotrrtiacnutl aarre av aofs ccuurlraern tc roeusepalricnhg. (V VC) efficiency
Figure 4: An illustrative example of vascular-ventricular coupling
To understand how pulmonary vascular remodeling
analysis from pressure-volume (PV) loops. Ventricular end-systolic
affects ventricular output during PH progression,
elastance (Ees) and arterial effective elastance (E) are calculated
investigations into ventricular function alone or vascular from multiple loops by varying the preload. a
function alone are not sufficient. Ideally, vascular function
is efficiently matched to ventricular function, and vice
versa. Ventricular pressure-volume (PV[1)3 0l]oop analysis
was first developed by Sagawa et al. to describe (Ees/Ea), may reveal the mechanisms that differentiate
the coupling efficiency between the left ventricle and physiological and pathological ventricular remodeling.
systemic circulation, i.e., vascular-ventricular coupling During acute PH, the optimal ventricular-arterial coupling
(VVC). In this approach, the ventricular and arterial appears to be maintained re[8g2]ardless of species and the
dynamic behaviors are quantified by ventricular end- way in which PH is induced. As effective afterload (Ea)
systolic elastance (Ees, which represents contractility of increases, the ventricle increases contractility (Ees) such
the ventricle) and arterial effective elastance (Ea, which that optimal coupling (Ees/Ea) is maintained. However,
represents ventricular afterload), respectively, which are such a balance may not exist in chronic PH due to both
derived from the pressure-volume loops at different levels pulmonary vascular and right ventricular remodeling. Our
of preload (Fig. 4). The ratio of these two parameters (Ees/ recent study in mice demonstrated decreased pulmonary
Ea) yields a direct assessment of VVC efficiency. When vascular–right [v13e2n] tricular coupling efficiency after
the ventricle and vasculature are efficiently coupled, chronic hypoxia.
minimal energy is wasted in the pulse pressure and
maximal energy is transmitted in the mean pressure. The A potentially important consequence of PA wall stiffening
optimal coupling efficiency (Ees/Ea) has been iden[1t3i1f,i1e3d2] may be impaired VVC efficiency via increased Ea. Optimal
and is comparable for both sides of the heart. coupling between the RV and the pulmonary circulation in
Recently, there is increasing interest in PV loop analysis a healthy cardiopulmonary system is likely important to
for PH because RV contractility is a more reliable[ 84w]ay the adaptive response to acute stresses such as hypoxia or
to differentiate the effect of therapies than mPAP. In exercise. In conditions of impaired VVC, however, the RV
addition, the linkage between RV function and vascular may not be able to maintain cardiac output sufficiently to
function, which is characterized by coupling efficiency meet these challenges, leading to dysfunction and failure.
Pulmonary Circulation | April-June 2011 | Vol 1 | No 2 219
Wang and Chesler: Pulmonary artery stiffening in PH
Because very few studies have examined ventricular- at the cellular and molecular level, it would be useful to
vascular coupling and pulmonary arterial stiffening identify the cells and cellular signaling pathways that
concurrently, the linkage between changes in vascular control PA stiffening and should be targets of treatment.
and ventricular function is not established. For example, Finally, a better understanding of the impact of pulmonary
the arterial effective elastance (Ea) is thought to represent hemodynamics on RV function and vice versa may allow
the RV afterload presented by the pulmonary vasculature. more accurate prognoses of RV failure. That is, the
However, the influences of proximal arterial stiffness, hemodynamic indicators of the transition from adaptive
distal arterial stiffness and distal arterial narrowing on ventricular remodeling to maladaptive ventricular
Ea are not clear. Understanding the relationship between remodeling, the precursor of ventricular failure, may lead
right heart function and pulmonary vascular remodeling to better care and treatment for patients with PH.
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