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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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Preface
ix
of cardiovascular events exists for pulse wave velocity (PWV) and carotid-
femoral PWV (cfPWV) is considered as gold standard for PWV measurement.
Recommended cut-off values for PWV are established for cfPWV (regional
arterial stiffness). Although regional and local PWV values correlate well, the
authors have found that regional PWV is significantly higher than local PWV.
These findings should be carefully taken into account when using this
technique in the clinical setting. According to expert consensus documents
local AS could be measured either at the common carotid, brachial or femoral
arteries. They were able to demonstrate, however, that AS parameters
measured at the brachial artery do not correlate either with common carotid or
with femoral artery indices. The authors also found that there is good
interobserver correlation of AS parameters when they were measured at the
carotid or femoral artery. The values of AS indices at the brachial artery
however show considerably large interobserver variation. On the basis of data
provided by the scientific literature and our personal experiences, they suggest
that: 1. AS is a useful parameter for evaluation of patients with arterial
hypertension and to follow-up on the effectiveness of therapy; 2. Reference
cut-off values for cfPWV cannot be applied to local PWV data; 3. Regarding
local AS measurement – brachial artery is not a suitable site for the evaluation
of AS indices and carotid or femoral arteries should be used instead.
Chapter 3 – Cardiovascular diseases represent an important cause of
mortality in patients with chronic obstructive pulmonary disease (COPD). The
increased prevalence of cardiovascular diseases is partly linked to common
risk factors, such as smoking and ageing. Patients with COPD have an
increased risk of cardiovascular morbidity and mortality, which is independent
of classical risk factors. Moreover, reduced FEV1 independently predicts
cardiovascular risks in general population and in patients with COPD. Arterial
stiffness is an independent predictor of cardiovascular risk, and aortic PWV
provides strong evidence concerning the prognostic significance of large artery
stiffening. In COPD patients, arterial stiffness is increased compared to
controls matched for classical cardiovascular risk factors. The mechanisms
responsible for the association between pulmonary and vascular diseases are
not completely understood. Age related degradation of elastin in lungs is
involved in emphysema, but ageing may also cause disruption of elastin in
arterial walls with excess collagen production and stiffening of arteries.
Besides modifications determined by age, some other mechanisms, such as
systemic inflammation, oxidative stress or neurohormonal activation, may be
responsible for both pulmonary and arterial diseases. This chapter reviews the
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Becky Chavez
x
processes involved in pathogenesis of arterial stiffness in COPD, and the
possible role of COPD therapy in vascular alterations.
Chapter 4 – Arterial stiffness is associated with medial arterial
calcifications which are commonly observed in certain patient groups such as
elderly, diabetic and chronic kidney disease patients and is a significant
predictor of cardiovascular morbidity and mortality, independent of well-
established traditional cardiovascular risk factors. The underlying pathogenetic
mechanisms are complex and not yet clearly defined; however, recently
research has focused on the link between disordered bone turnover and
arterial calcifications and stiffness and the regulatory factors and molecular
pathways of this process. The inhibitors of the canonical Wnt/β-catenin
signaling pathway of the osteoblasts, sclerostin and Dickkopf-1 related
protein (DKK-1), exert anti-anabolic activity in bones and have been related
to vascular calcifications, arterial stiffness and adverse clinical outcomes.
Osteoprotegerin, a negative regulator of osteoclast activity via RANKL
inhibition, has also been associated with vascular calcifications and
arterial stiffness. Moreover, recent epidemiologic data indicate that the
aforementioned molecules, despite their opposing actions in bone turnover,
may exhibit an additive effect on extra-osseous bone formation. Clearly,
further research is needed to identify the exact molecular interactions between
bone turnover and arteriosclerotic vascular changes which would hopefully
introduce new therapeutic strategies against cardiovascular disease.
Chapter 5 – The ambulatory arterial stiffness index (AASI) and pulse
pressure (PP) was analyzed during pregnancy and three months after delivery
in type 1 diabetes mellitus (T1DM) compared to non-diabetic, pregnant
controls. The study was performed prospectively in 176 women with T1DM
and 54 control women at a tertiary centre. Blood pressure (BP) was measured
using a portable oscillometry monitor and AASI was calculated as 1 minus the
regression slope of diastolic BP on systolic BP obtained from 24-hour
monitoring. Main outcome measures were AASI and PP associated with
diabetes vasculopathy and blood pressure measurements during and after
pregnancy. The authors found that AASI and PP were higher in 2
nd
and 3
rd
trimester during pregnancy in T1DM compared to post partum and
significantly associated with albumin excretion rate. The AASI was positively
correlated with night-day ratio during and outside pregnancy in diastolic BP
and in 1
st
trimester and outside pregnancy in systolic BP. The higher the AASI
the lower was the coefficient of determination. Thus, AASI showed a strong
association with albuminuria, PP, and circadian rhythm during pregnancy in
T1DM women and it seems even more pronounced than after pregnancy. The
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Preface
xi
diastolic and systolic BP displays non-linear behaviour and increasing random
variability with stiffing arteries measured as AASI.
Chapter 6 – Introduction-Aim: Large arterial pulse wave velocity
(PWV) demonstrates a predictive value of aortic stiffness for cardiovascular
events in general population and in dialysis patients. The authors observed the
effect of non-adjusted and adjusted for confounding factors carotid-femoral
pulse wave velocity (c-fPWV) on cardiovascular morbidity and mortality rate
in patients on renal replacement therapy during a median follow up time of 60
months. Methods: They studied 73 patients on on-line hemodiafiltration.
Dialysis adequacy was defined by Kt/V for urea. The authors performed a
Kaplan-Meier curve to examine the impact of high or low c-fPWV on
mortality rate. Additionally, they built Cox regression analyses to investigate
the relationship between both, coronary disease and overall mortality and non-
adjusted and adjusted c-fPWV for confounders. Also, the authors examined
the relationship between c-fPWV and measured i-PTH, hsCRP, serum
bicarbonate concentrations and hydration status. Results: Kaplan-Meier
analysis for the impact of higher or lower than the mean value of c-fPWV
(11.3 ± 1.83m/s) on overall mortality was found non-significant. Cox-
regression analysis revealed significant predictive effect of non-adjusted and
adjusted for confounders c-fPWV on coronary disease and overall mortality. c-
fPWV was positively associated with i-PTH, hsCRP and pulse pressure (PP),
but inversely with serum bicarbonate concentrations (r = 0.261, p = 0.02, r =
0.400, p=0.001, r = 0.346, p = 0.003 and r=-0.719, p = 0.001 respectively).
Conclusion: Carotid-femoral pulse wave velocity was found as a significant
predictor for coronary disease and overall mortality in dialysis patients. The
hydration status, bone disease, inflammation and uncorrected metabolic
acidosis state may be the main variables which impact on arterial stiffening
and mortality of these patients.
Chapter 7 – Exaggerated elevation of systolic blood pressure (SBP) during
aerobic or resistance exercises is a marker for early cardiovascular disease.
Moreover, arterial stiffness is an essential characteristic of the vascular system,
directly affecting blood pressure. In addition, arterial stiffness indirectly
influences blood pressure, since stiffening of the aortic arch and carotid
arteries, which contain stretch-sensitive baroreceptors, deteriorates the
cardiovagal baroreceptor reflex sensitivity (BRS). The authors hypothesized
that aging-related increase in arterial stiffness and decrease in cardiovagal
BRS exaggerate the elevation of SBP and rate-pressure product (RPP) during
resistance exercise. To test this hypothesis, we investigated the blood pressure
response to resistance training in 45 individuals aged between 45 and 76 years.
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The following were measured: SBP and RPP during arm and leg resistance
exercises, aortic pulse wave velocity (PWV, a traditional index of central
arterial stiffness), and cardiovagal BRS. SBP and RPP during resistance
exercises were correlated with age, aortic PWV, and cardiovagal BRS. In
particular, stepwise regression analysis revealed that aortic PWV was an
independent predictor of SBP and RPP during exercise. They concluded that
elevations of SBP and RPP during arm and leg resistance exercises are higher
in elderly individuals than in middle-aged individuals. Higher SBP and RPP
elevations during resistance exercise may be associated with increased arterial
stiffness in elderly individuals.
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In: Advances in Arterial Stiffness Research ISBN: 978-1-63485-838-0
Editor: Becky Chavez © 2016 Nova Science Publishers, Inc.
Chapter 1
PULMONARY ARTERIAL STIFFNESS:
TOWARD A PREDICTOR OF PAH AND A KEY
PARAMETER TO MAKE PH REVERSIBLE
Juan C. Grignola
1,2
, Antonio Roman
3
and Enric Domingo
4,5
1
Dept Pathophysiology, Hospital de Clínicas,
Universidad de la República, Uruguay
2
Pulmonary Hypertension Unit, Hospital Maciel,
Ministerio de Salud Pública, Uruguay
3
Servei de Pneumologia i CIBERES,
Hospital Universitari Vall d’Hebron, Spain
4
Area del Cor, Hospital Universitari Vall d’Hebron, Spain
5
Dept Physiology, Universitat Autonoma Barcelona, Spain
ABSTRACT
Right ventricular (RV) adaptation to increased pulmonary arterial
(PA) load is a critical determinant of outcomes in pulmonary
hypertension (PH). Pulmonary vascular resistance (PVR) and total
pulmonary vascular capacitance (Cp) assess global resistive and elastic
properties of the pulmonary arterial vasculature, respectively. They show
an inverse relationship that is usually described by a hyperbolic fit in both
health and disease states including arterial PH (PAH). Conflicting data is
supporting PVR to be prognostic value in PH. However, Cp is a strong
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Juan C. Grignola, Antonio Roman and Enric Domingo
2
independent predictor of mortality in patients with PAH. Cp depends on
the prevailing mean pulmonary arterial pressure (mPAP) and on a
genuine change in the arterial wall stiffness as a result of vascular
remodeling. At present, we lack a complete understanding of the process
of large/proximal and small/distal PA stiffening during the course of PH
disease. Current dogma suggests that distal changes in the pulmonary
vasculature usually precede those associated with stiffening in the central
vessels. However, recent data have provided evidence that conduit
systemic arterial stiffness is an independent predictor of blood pressure
progression and incident hypertension. Similarly, data in pulmonary
circulation suggests that vascular stiffening itself may be the initial
vascular event that begets subsequently remodeling. Accordingly, human
data seem to indicate that pulmonary intimal lesions are associated with
the severely increased mPAP in the late stage of the disease. Recent
evidence shows that large PA stiffening impairs its buffering function and
increases distal vasculature flow pulsatility leading to distal PA
remodeling and stiffening. Although PAH remains an incurable disease,
animal models of PH and emerging human data put on doubt the concept
of the pulmonary vascular remodeling irreversibility and emphasize
efforts that experts must make for early detection of pulmonary vascular
disease. We will address the PVR-Cp product of the pulmonary
circulation as a global estimate of RV afterload, the assessment of
the local arterial stiffness indices and its relationship with PVR and Cp,
and finally, we put forward the cause-effect relationships between
large/conduit stiffening and distal/resistive vascular disease, analyzing if
it is possible the reversible remodeling in PAH.
Keywords: pulmonary artery, elastic modulus, pulmonary hypertension,
intravascular ultrasound
INTRODUCTION
Overall cardiac performance is determined by two pumps in series, and
cardiac output (CO) is only as good as the worst ventricle. Therefore, it is not
surprising that right ventricular (RV) function is an important prognostic
marker either in pulmonary vascular disease, such as pulmonary hypertension
(PH), as conditions that have traditionally been regarded as primarily left
ventricular dysfunction, such as heart failure and acute myocardial infarction.
Nowadays, RV has become the “barometer” of cardiovascular symptoms and
outcomes for two main reasons: first, RV function represents the coupling or
interaction between afterload (from both left ventricular filling pressures and
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Pulmonary Arterial Stiffness
3
pulmonary vascular impedance) and RV contractile reserve and second, these
downstream loads can be further stressed during an increase of CO (i.e.,
exercise), so that RV afterload increases disproportionately compared with that
of the left ventricle (LV) [21, 50].
In PH, the increased pulmonary arterial load is a key determinant of RV
dysfunction and failure, which in turn is strongly related to patient outcome.
There are two major hemodynamic components of pulmonary arterial load, a
steady component and a pulsatile component, which depend on different parts
and properties of the pulmonary arterial tree [11, 43]. The steady component
of load can be represented by mean pulmonary arterial pressure (mPAP),
which depend by the caliber of small resistive arteries as reflected in the
pulmonary vascular resistance (PVR). The pulsatile component of the load can
be represented by pulsatile pulmonary arterial pressure (pPAP), which is
influenced by the elastic properties of the pulmonary arterial tree as reflected
by the total arterial compliance (Cp).
Pulmonary arterial hypertension (PAH) is a life-threatening disease
characterized by a progressive increase in pulmonary blood pressure that often
leads to RV failure and death [19]. Although PAH is classically viewed as a
proliferative remodeling of the distal small resistive vessels, the rise in RV
afterload results from an increase in PVR as well as a reduction in Cp [13, 42].
The aim of the present work is to analyze PVR and Cp as a global
estimate of RV afterload and to address the assessment of the local arterial
stiffness indices and its relationship with PVR and Cp. We also put forward
the cause-effect relationship between large stiffening and distal small
resistive vascular disease and finally, we will debate about pulmonary vascular
reversibility in PAH.
COMPONENTS OF THE RIGHT VENTRICULAR LOAD
In a hydraulic system where the flow is pulsatile, the relationship between
pulsatile flow and pulsatile pressure not only depends on the resistance to flow
afforded by friction but also on the opposition to flow due to both vascular
elasticity and inertia of blood mass [43]. The arterial hydraulic load can be
described completely by the so-called pulmonary arterial input impedance that
accounts for the relationship between pulsatile pressure and flow. However,
this description is not only difficult to derive but also complex to interpret
[61]. So, several simplified descriptions of the arterial circulation have been
proposed. One such description is the two-element Windkessel model which
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Juan C. Grignola, Antonio Roman and Enric Domingo
4
consists of physiologically easily interpretable parameters and describes the
hemodynamics in terms of resistance and compliance. The resistance of the
model is the PVR. PVR is mainly located in the small arteries and arterioles
since resistance strongly depends on vessel diameter. The compliance of the
model (Cp) is the storage capacity of all arteries and arterioles taken together.
Cp is related to arterial wall elasticity and vessel size (i.e., radius and wall
thickness). The normal pulmonary circulation is characterized by its low
resistance and high compliance vasculature with great capabilities for
distension and recruitment in reserve. It is estimated that the pulsatile
component of the pulmonary arterial load accounts for ~25% of RV power on
average, as compared with ~10% in the systemic circulation [73].
Clinicians usually define RV afterload in terms of PVR and this measure
is often used as an end-point in clinical studies. Both PVR and Cp have been
demonstrated to be prognostic value in PH, although the data supporting PVR
is conflicting. The French registry did not find PVR to be an independent
predictor of prognosis in PAH, and the American REVEAL registry showed
that from a PVR > 32 Wood units was associated with higher mortality in
PAH [3, 35]. By contrast, Cp is a strong predictor of mortality in patients with
PAH and scleroderma-related PAH [7, 52]. It was hypothesized that Cp is an
integrated measure of RV afterload that may be superior to PVR in explaining
RV failure.
Pulmonary Vascular Resistance
PVR is a measure of the extent to which the pulmonary circulation resists
to mean flow and depends on the blood viscosity and the size and number of
vessels [60]. The mean driving pressure of mean pulmonary flow is the
transpulmonary pressure gradient (TPG), namely mPAP minus pulmonary
arterial wedge pressure (PAWP) or left atrial pressure, which is usually
assumed to assess the mean downstream zero-flow pressure (Pzf). The
standard formula for calculating PVR is as follows (based on Ohm's law
electrical circuits):
PVR is a component of the current diagnostic criteria for precapillary PH,
which is defined by mPAP ≥ 25 mmHg, PAWP ≤ 15 mmHg and PVR > 3
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Pulmonary Arterial Stiffness
5
Wood units [33]. There are some limitations of the standard PVR equation. In
pulmonary vascular disease leading to precapillary PH, Pzf is significantly
above PAWP, which is supported by the high gradient between diastolic PAP
(dPAP) and PAWP and the pressure intercept of the mPAP-CO linear plots or
the PAP decay curve after balloon occlusion [16, 38]. Therefore, the true PVR
will be overestimated if one uses the previous equation. Another conceptual
limitation includes assumptions that blood behaves as a Newtonian fluid
and that arteries behave as rigid tubes while they are both collapsible and
distensible [60, 65].
Compliance
The compliance of the arterial tree allows the arteries to expand passively
during systole and to recoil during diastole. The systolic storage of this
reservoir volume dampens pulsatile RV ejection and decreases RV stroke
work. Total arterial compliance is difficult to measure in vivo based on the
formula V/P, since there is blood leaving the arterial system through the
periphery (microcirculation) while cardiac ejection takes place. Therefore, V
estimated by stroke volume (SV) exceeds the reservoir volume of the
compliant pulmonary arteries, and Cp estimation in clinical practice as
SV/pPAP can overestimate true total arterial compliance up to 61% [56, 82].
Cp is determined by the prevailing mPAP and by the viscoelasticity of the
pulmonary arterial wall, which is mainly determined by the content of elastin
and collagen fibers and amount and degree of vascular smooth muscle
activation in the wall [2, 70]. So, a decrease in Cp can result on one side from
an increase in mPAP without a true change in the viscoelastic properties of the
PA wall and on other hand, from an increase in PA wall stiffness due to
vascular remodeling [94].
PVR-Cp Relationship in Pulmonary Circulation
There is an inverse relationship between PVR and Cp in both health and
disease states including PAH, chronic thromboembolic PH and left heart
disfunction-PH, and it is usually described by a hyperbolic fit [42]. The
inverse relationship between PVR and Cp can be explained by a number of
factors: a) the mPAP is the main determinant of Cp, b) the longitudinal
distribution of resistance and compliance vessels of the pulmonary circulation
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Juan C. Grignola, Antonio Roman and Enric Domingo
6
and c) the presence of mathematical coupling because SV appears in both
variables and that mPAP (PVR) and pPAP (Cp) have an almost 1:1 ratio [13].
The product of PVR and Cp has units of time (RC-time) and represents
the time-constant of the pulmonary circulation, which characterizes the
diastolic decay of PAP curve [13, 43]. This concept comes from the
Windkessel model where the decrease in diastolic pressure is governed by
PVR and total arterial compliance. However, as we mentioned before, empiric
estimates of PVR and Cp may prone to errors. The true PVR can be
overestimated if one uses the standard PVR equation because Pzf may be
significantly higher than PAWP (especially in precapillary PH) and SV/pPAP
also overestimates the true total arterial compliance, not only for SV, but for
the non-accurate measurement of pPAP using fluid-filled catheters. Thus, it
does not surprise the long RC-time reference values (empiric estimate) of
~0.5-0.7 s.
By contrast using the semi-logarithmic method, the recovered RC-time
averaged 0.16-0.39 s and 0.21-0.83 s in normal subjects and PH patients,
respectively [66, 76]. The semi-logarithmic method consists of a log-
transformation of the fitted single exponential function of time of the diastolic
PAP decay, according to the following equations:
where Po is the pressure at the onset analysis (t=0, corresponding to the time at
the pulmonary arterial dicrotic notch pressure) and P
asymptote
is the theoretical
pressure at the infinite time when the exponential decline is completed. The
PAWP or the LV filling pressure is used as P
asymptote
. The shorter RC-times
derived from the semi-logarithmic method would be more consistent with
more completed expression of the Windkessel function. Assuming a heart
period of 0.80 s (RV ejection time ~0.30 s, diastolic time ~0.50 s, and an RC-
time of 0.15 s implies that completion of the Windkessel function may be
observed after 0.45 s. By contrast, an RC-time of 0.60 s impedes a complete
expression of the Windkessel function, with RV ejection occurring at time
when pulmonary arterial emptying is not completed [13].
Beyond the methods of calculating the RC-time, is the RC-time constant?
[23]. Reasoning by the absurd, if RC-time is indeed constant, it suggests that
Cp and PVR are redundant measures since knowledge of one is sufficient to
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