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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
17
Figure 3. Correlations between local PA stiffness indexes and pulsatile (Cp, pulmonary
arterial capacitance) and steady (PVR, pulmonary vascular resistance) pulmonary
afterload. (DC: cross-sectional distensibility; CC: cross-sectional compliance; EM:
elastic modulus).
Table 2. Comparative pulmonary artery stiffness in controls and PH
subjects
Controls
PH patients
CC (mm
2
/
mmHg)
DC (%/
mmHg)
EM
(mmHg)
CC (mm
2
/
mmHg)
DC
(%/mmHg)
EM
(mmHg)
Sanz,
2009 [72]
15(9-20)
3.1(2-4.3)
32(23-51)
3.9(2.8-5.5)
0.4(0.3-2.6)
245(156-321)
Domingo,
2014 [14]
0.5 ± 0.06
5.1 ± 1.6
21 ± 6
0.07 ± 0.06
0.65 ± 0.34
195 ± 84
Shen,
2016 [77]
0.42 ± 0.05
3.2 ± 0.4
44 ± 4
0.06 ± 0.07
0.6 ± 0.1
253 ± 22
Mean ± SD or mean (interquartile range). CC: cross-sectional compliance; DC: cross-
sectional distensibility; EM: elastic modulus.
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Juan C. Grignola, Antonio Roman and Enric Domingo
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Figure 4. Relationships between α and EM (nonlinear regression analysis) and cross-
sectional distensibility (linear regression analysis).
There are scarce data about the values of PA stiffness indexes in healthy
subjects. We compared the data of three studies that analyze PA stiffness
indexes of control subjects versus PAH of different etiologies (Table 2). Sanz
et al. measured the main pulmonary artery (24-26 mm) by CMRI, while
Domingo et al. and Shen et al. used IVUS, measuring elastic PAs of 2-5 mm
and 4.4 ± 0.2 mm, respectively [14, 26, 72, 77]. As it is expected, PA stiffness
of PH patients was significantly higher than the control group. We can observe
similar values of PA stiffness indexes among PH patients of the three studies,
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Pulmonary Arterial Stiffness
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except for the cross-sectional compliance of main PA versus distal PAs. By
contrast, Domingo et al. control group had lower PA stiffness indexes in
comparison to Shen et al. and Sanz et al. so the latter 'control' subjects could
have some degree of arterial remodeling. The effect of both, ageing stiffness
and/or inclusion of borderline PH subjects (20-24 mm Hg) cannot explain this
difference among the control groups since the age and range of mPAP are
similar (51 ± 6 years and 9-19 mmHg [14]; 50 ± 13 years and 14-18 mm Hg
[72] and 45 ± 16 years and 17.5 ± 3 mm Hg [77]). Probably, the control group
of Shen et al. had some degree of subclinical vascular remodeling, since it
included patients with connective tissue disease without PH.
Finally, we can observe that global distensibility α is correlated with
elastic modulus and cross-sectional distensibility (Figure 4). These data show
strong relationships between most indexes of PA stiffness and PH severity
(dynamic RV afterload).
Arterial Vascular Stiffening in Pulmonary Hypertension:
Cause or Consequence?
Recent studies have indicated that systemic arterial stiffening is a
precursor to hypertension and that hypertension, in turn, can perpetuate arterial
stiffening [55, 95].
RV adaptation to chronic pressure overload is related not only to the
levels of PVR (steady afterload) but also to PA stiffness (pulsatile
afterload). Increased PA stiffness is independently associated with adverse RV
remodeling and performance beyond the degree of PH determined by the
levels of PVR [83, 94]. This fact provides a potential mechanistic link between
PA stiffness and clinical outcome and raises the possibility that pulmonary
vascular stiffness is an important factor that must be addressed/treated if PH
outcome is to be improved. Besides, the degree of RV dysfunction, dilation,
and hypertrophy in CTEPH relative to idiopathic PAH is associated with PA
stiffness [8, 28]. The progressive increase in afterload overcomes the RV
adaptive reserve, and the ventriculo-arterial system becomes decoupled
(Figure 5) [71].
How distal and proximal arterial remodeling are related in PH remains
unclear. Current dogma suggests that distal changes in pulmonary vasculature
usually precede those associated with stiffening in the central vessels, though
recent data in pulmonary circulation suggest that vascular stiffening itself may
be the initial vascular change that begets subsequent remodeling [84].
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Juan C. Grignola, Antonio Roman and Enric Domingo
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Proximal conduit PAs stiffening increases flow pulsatility which impacts all
layers of the distal small vessels wall leading to intimal inflammation and
fibrosis, medial hypertrophy and adventitial remodeling. Inflammation may
induce structural changes in the arterial wall through the breakdown of elastin,
proliferation of smooth muscle cells and fibroblasts and changes in the
composition of the ECM. Some experimental observations support that elastin
peptides, generated in the setting of PH in the media of large elastic PAs,
perpetuate pro-inflammatory gene programs in monocytes/macrophages [75].
Figure 5. Changes in distal pulmonary arteries stiffness secondary to the increased
proximal stiffness vessels begin a positive feedback cycle advancing the progression of
PAH and ultimately leading to increased RV oscillatory and steady workload, impaired
ventriculo-arterial coupling and RV failure (PAEC: pulmonary arterial endothelial cell;
mPAP and pPAP: mean and pulsatile pulmonary arterial pressure, respectively).
The distal and proximal PAs communicate with one another in a cycle of
positive feedback leading to remodeling progression, elevating vessel stiffness
through a combination of increased ECM production and rearrangement and
augmented intercellular force transmission (Figure 5) [5].
Very recently, Shen et al. evaluated an average of 8 PA segments from the
four lobes in the lower left and right lung branches in each of the 40 PAH
patients that underwent RHC + IVUS study (total PA segments measured =
320). Each vessel was subdivided into two segments, a distal segment with a
diameter < 5mm and a proximal segment with a diameter > 5mm [77]. They
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Pulmonary Arterial Stiffness
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defined two subtypes of remodeling according to the percentage of mean
wall thickness (WTP): if the WTP of the distal PA segment was greater
than the proximal segment WTP, the patient was assigned to the distal
remodeling subtype group (n = 22), and vice-versa, if the distal segment
WTP was smaller than the proximal WTP, the patient was assigned to the
proximal remodeling subtype group (n = 18). There were no differences
between both subtypes in age, mPAP, PVR and PA stiffness indexes.
However, all the five patients who died in the follow-up (median of 40
months) were from the distal remodeling group (23% versus 0%, P < 0.05).
The authors proposed that this subtype remodeling classification may be an
indicator of disease duration: the distal remodeling subtype indicates a later
stage of PAH and is characterized by higher mortality [77]. In a certain way,
this finding would support the fact that the increase of proximal PA stiffness
could be the first event in the development and/or perpetuation of the PA
remodeling that characterize PAH [41].
Stiffening of the PAs (both proximal and distal) occurs in all forms of
PAH to some degree or another. Unraveling the cellular and molecular
mechanisms that drive the interactions between proximal and distal PAs could
lead to new drug targets capable of preventing disease progression in the early
stages of PAH development and help break the positive feedback cycle that
makes PAH so intractable to traditional therapies [84].
Pulmonary Arterial Stiffness and Acute Vasorreactivity
Detection of acute pulmonary vasoreactivity is important for the
evaluation of patients with PAH in different scenarios [88]. However, the
clinical relevance of acute vasoreactivity testing in PAH for identifying
patients with a marked vasoreactive component, who may thus benefit from
chronic calcium channel blocker therapy, has been established only in IPAH
[22]. The criteria for identifying responder and non-responder patients with
IPAH have been changed in the last twenty years [88]. Nowadays, according
to the retrospective study of Sitbon et al., a positive response is defined as a
decrease in mPAP > 10 mm Hg, reaching an absolute mPAP < 40 mm Hg with
an unchanged or increased CO [79]. However, the acute response to a
vasodilator agent is not an all-or-nothing phenomenon, since different degrees
of vasoreactivity are present in all patients with PAH, even in those defined as
non-responders by the revised current criteria [10]. Pathophysiologically, the
different criteria used throughout time to define a positive response may
identify patients with different degrees of vascular remodeling. It has been
suggested that the currently used criteria of acute responder might identify
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those patients with a predominant vasoconstriction, a better hemodynamic
profile and less remodeling of the vascular wall [10].
We have evaluated the relationship between PA wall stiffness, real
absolute vasodilatation, and vasoreactivity response (regarding conventional
vasoreactivity criteria) during the acute vasoreactivity testing in patients with
idiopathic PAH (RHC + IVUS). We have shown that patients with lesser PA
vascular wall remodeling (higher pulsatility and lesser EM) displayed a real
vasodilatation (an increase in the vascular lumen) during acute vasoreactivity
testing with epoprostenol. EM ≤ 190 mm Hg (median value) is a good marker
of a vasodilator response during acute vasoreactivity testing in patients with
idiopathic PAH. So, the patients with a positive vasoreactive response
according to actual criteria do not have necessary a real absolute vasodilatation
on IVUS [25].
Reversible Remodeling in PAH: Fiction or Fact?
Pulmonary Vascular Disease in PAH: How Early We Should Be for
Impact on Mortality
PAH remains an incurable disease associated with an unacceptably high
early mortality, despite advances in therapeutic options. However, early
diagnosis of PAH is associated with improved long-term survival [4, 9, 34].
Early detection of PAH remains a clinical challenge, particularly in the
case of a sporadic disease, in which patients have no often identifiable risk
factor. The majority (> 60%) of the pulmonary circulation must be obstructed
before resting mPAP rise above 25 mm Hg [47]. If we rely on the presence of
early symptoms related to PAH, most patients would be diagnosed at a very
advanced stage of the illness. Accordingly, different national registries have
reported that ~ 75-85% of patients with new cases of idiopathic PAH and SSc-
PAH presented in NYHA functional class III or IV at diagnosis.
There are several components to improve clinical outcomes through
diagnosis PAH at a preclinical stage and early intervention: a) the
understanding of pathobiology and natural history of disease (basic research);
b) the development of novel diagnostic tools; c) evidence-based screening
studies (patients with risk factors for PAH, like BMPR-2 mutation carriers and
first-degree relatives of patients with familial PAH, systemic sclerosis, Porto-
pulmonary hypertension, sickle-cell disease) and d) community awareness and
education [46].
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Pulmonary Arterial Stiffness
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Uncertainties exist about the definition and prognostic relevance of
borderline PH (resting mPAP between 21-24 mm Hg) and exercise-induced
PH, but accumulating evidence suggests that they can unmask clinically
important early disease [46, 47]. Normal resting mPAP is 14 ± 3 mm Hg, with
an upper limit of 20 mm Hg (14 + 2 SD). Therefore, resting mPAP of 21-24
mm Hg constitutes a gray zone in which hemodynamics falls outside normal
limits, but do not fulfill the criteria for the diagnosis of PH (defined as resting
mPAP ≥ 25 mm Hg). Patients with systemic sclerosis that present borderline
PH had an increased risk of developing resting PH on follow-up (HR 3.7, P <
0.001) [92]. Very recently, Lau et al. reported that exercise PH (defined by
mPAP > 30 mm Hg and TPR > 3 WU at maximal exercise) occurred in 86%
in patients with resting mPAP of 21-24 mm Hg and PAWP < 15 mmHg [45].
Decreasing levels of mPAP were associated with a lower prevalence of
exercise PH, which occurred in 60%, 39% and 8% of patients with mPAP of
17-20, 13-16 and < 13 mm Hg, respectively. Interestingly, they divided
exercise PH into a precapillary pattern when mean PAWP at peak exercise was
≤20 mm Hg and a postcapillary pattern when mean PAWP at peak exercise
was >20 mm Hg. This cut-off value is in accordance with the upper limits of
normal for maximum upright exercise pulmonary hemodynamics described by
Oliveira et al. [62]. The precapillary pattern of exercise PH predominates over
the postcapillary pattern. This may be related to the fact that 63% of the
patients had at least one risk factor for pulmonary vascular disease and that
only in 44% of patients were documented the presence of a risk factor for left
heart disease. Finally, among the possible predictors of exercise PH in patients
with borderline PH, a resting total pulmonary resistance of > 3.4 Wood units
had a sensitivity of 87% and specificity of 92% for the presence of exercise
PH [62].
Since 2009, Sanz et al. were reported that patients with exercise PH (based
on the old definition, mPAP > 30 mm Hg, even with false-positives cases [39])
have already shown an increased PA stiffness (low CC and DC with high EM)
in spite of normal resting hemodynamics [72]. We have shown in a cohort of
chronic obstructive pulmonary disease and interstitial lung disease candidates
for lung transplantation, that patients with normal resting hemodynamics have
a significant pulmonary vascular disease, with a significantly increased EM
(51 ± 5 mm Hg and 90 ± 7 mm Hg, respectively) [27]. Hilde et al. reported in
a cohort of COPD patients that patients without PH showed similar abnormal
hemodynamic responses to exercise as the PH group, with increased PVR,
reduced Cp and steeper slopes for mPAP/CO and mPAP/work [32].
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Finally, in a large patient cohort with cardiovascular disease (n = 21727),
Maron et al. demonstrated for the first time a continuum of risk according to
mPAP level and that borderline PH is associated with increased mortality and
hospitalization even though after excluding patients with PAWP > 15 mm Hg
[53].
Although two longitudinal studies involving few patients with systemic
sclerosis showed that not all patients with precapillary PH on exercise
invariably develop resting PAH within the medium-term duration of follow-
up, it is now undeniable that both, borderline PH and exercise PH patients
have some degree of pulmonary vascular disease, probably expressed by a PA
stiffness increase. So, alternative tools are required to make the diagnosis at a
preclinical stage of PAH. Among them, the assessment of PA stiffness might
have utility in the identification of early pulmonary vascular disease. While
arterial pulsatility can be assessed non-invasively by CMRI, we must obtained
the PA pressures concomitantly by an invasive RHC to assess the different
local PA stiffness indexes. Therefore, although invasive, IVUS it is also a
valuable technique (Figure 6).
Figure 6. Relationship between PH on exercise and borderline PH and resting PAH.
Borderline PH and exercise PH as precursors to resting PAH is a physiologically
rational concept, but data on the natural history of this entity is scarce.
At present, the relative high cost, lack of widespread availability, and
special expertise required for this imaging techniques limit its potential
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Pulmonary Arterial Stiffness
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application as a preclinical screening method for asymptomatic patients. The
efficacy of actual PAH therapy for delaying disease progression for patients
with borderline PH or exercise PH is also unknown.
Reversible or Irreversible Remodeling in PAH
Pulmonary vascular remodeling is characterized by thickening of all three
layers of the blood vessel wall. Such thickening is due to hypertrophy and/or
hyperplasia of the predominant cell type within each of the layers (fibroblasts,
smooth muscle cells, and endothelial cells, as well as increased deposition of
ECM). Cytokines and immune cells appear to play a significant role in
the initiation and progression of PH. Although vascular inflammation in PH
has traditionally been considered an “inside-out” response driven by the
endothelium-expressed adhesion molecules, growing evidence supports an
“outside-in” alternative paradigm, in which vascular inflammation is initiated
in the adventitia and progress inward toward the media and intima [89].
Some studies have demonstrated irreversible PAH in congenital
heart disease to be strongly associated with impaired apoptotic regulation of
endothelial cells, with endothelial damage and with increased circulating
endothelial cells counts [49, 80]. Besides, it is suggested that the proliferative
state of smooth muscle cells may be reversible [69].
The development of neointimal lesions, concentric laminar intimal fibrosis
and plexiform lesions, in particular, is believed to indicate a completed
transition from early-stage, “reversible” to advanced “non-reversible” or
progressive PAH. Very recently, Allen et al. developed an allometric model
that integrates diameter branching complexity between pulmonary arterioles of
generation n and the main PA via a power-law exponent (X) [1]. Comparisons
of X between PAH-free and diverse forms of PAH subjects demonstrated early
decrements in X which alters the arteriolar shear stress load from a low-shear
stress to a high-shear stress phenotype, leading to endothelial dysfunction and
injury before clinically PH. They concluded that the evaluation of X may be of
use in identifying reversible and irreversible phases of PH in the early course
of the disease process [1].
At least two molecular mechanisms have been proposed to play a critical
role in the progression of PH and the development of irreversible neointimal
lesions. Both the increase pulmonary vascular Egr-1 expression and
endothelial-to mesenchymal transition are relevant to vascular remodeling and
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are important as we consider new therapies aimed at reversing pulmonary
vascular remodeling [81, 93].
The question about which forms of pulmonary vascular remodeling are
reversible continues. Further studies are necessary to characterize pulmonary
vessel phenotypes to determine the reversibility of vascular remodeling and to
stop angiogenesis in PAH [69]. It will be important to increase knowledge of
the role of vascular stiffening in PH. Understanding the molecular mechanisms
by which the cells and ECM of the PAs stiffen are necessary for the
identification of possible points of intervention to prevent or reverse the
process [75].
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