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Stiff arteries, stiff ventricles: correlation or causality in heart failure?
Declan P. O’Regan FRCR PhD
From the MRC Clinical Sciences Centre (CSC), Du Cane Road, London W12 0NN
Correspondence to: Dr Declan P O’Regan, MRC Clinical Sciences Centre (CSC), Du Cane
Road, London W12 0NN, UK. E-mail: [email protected].
Keywords:
Pulse wave velocity
Cardiac magnetic resonance imaging
Aortic stiffness
Heart failure
Diastolic dysfunction
The biophysical properties and neuro-hormonal regulation of arterial function are influential
mediators of cardiovascular disease. Over the last three decades the prognostic importance of
arterial stiffness, as a measurable indicator of arterial function, has been recognized in both
unselected populations and amongst patients with cardiovascular risk factors. Although there
is a correlation between vascular stiffness and outcomes the temporal and causal
interrelationships with aging, hypertension, atherosclerosis and the progression to heart
failure are not fully understood. Aortic stiffening increases systolic load on the left ventricle
contributing to ventricular hypertrophy and leading to increased myocardial oxygen demand,
as well as indirectly promoting coronary disease and impaired perfusion.1 Arterial stiffness
and wave reflection effects augment systolic blood pressure and place additional mechanical
load on the heart leading to diastolic dysfunction and myocardial fibrosis.2, 3 Increasing
vascular stiffness precedes the onset of hypertension and may promote alterations in wall
stress that accelerate atherosclerosis.4 This body of evidence has generated renewed interest
in discovering whether arterial stiffness is more than a correlated risk factor and if it could
play a role in the causative pathway to adverse cardiovascular events.
The proximal elastic arteries serve as capacitance vessels that distend to accommodate the
stroke volume as it is transferred from the heart to the circulation and maintain efficient
coupling with the mechanical properties of the myocardium.5 During systole a pulse wave is
propagated along the aorta that travels at a velocity which is an accurate surrogate for arterial
stiffness.6 With advancing age elastin fibers in the tunica media become degraded and
fragmented leading to a less compliant collagen-dominant state with an associated rise in
pulse wave velocity (PWV) and reflected pressure waves. Endothelial dysfunction plays a
pivotal role in the progression to heart failure with neuro-hormonal interactions between the
myocardium and endothelium driving unfavourable outcomes.7 Genetic factors are also
influential but, although the heritability of carotid femoral PWV is around 40%, the genetic
variants that independently influence vascular stiffness are not well defined.8 An important
unanswered question in cardiovascular medicine is what role aortic stiffness may play in the
initiation of myocardial dysfunction and subsequent progression to heart failure in the general
population.
See Article by Ohyama et al
In this issue of Circulation: Cardiovascular Imaging, Ohyama et al explored the relationship
between aortic PWV and left ventricular (LV) function using phase contrast imaging and
strain analysis of tagged cardiac magnetic resonance (CMR) imaging in a large multi-ethic
cohort.9 Age-related changes in proximal aortic stiffness have previously been associated
with LV mass and concentricity independent of central blood pressure and conventional
cardiovascular risk factors.10 Ohyama et al’s new data indicate that higher aortic arch PWV is
also associated with impaired circumferential systolic strain and diastolic function in a
community-based population. This study provides further evidence implicating aortic
stiffness in adverse cardiac remodeling and impaired myocardial function. A previous
longitudinal MESA study investigated 5960 participants using radial artery tonometry and
found that the magnitude of wave reflections was strongly predictive of new-onset heart
failure, but did not assess PWV itself.11 It has been argued that systolic load ultimately
determines LV remodeling and the indirect effects of aortic mechanical properties are of
secondary importance, but measures of aortic stiffness are also relatively less confounded by
the degree of LV dysfunction.12 A Framingham cohort study of 2539 middle-aged to elderly
adults followed for a median of 10.1 years reported that carotid-femoral PWV was associated
with an increased risk of incident heart failure – and comparable risk was conferred by PWV
in heart failure patients with either preserved or reduced ejection fraction.13 These data would
suggest that, as there is no treatment for heart failure with preserved ejection fraction of
proven benefit, modulating vascular function may be a promising target for intervention.14
Recent observational longitudinal data, also from the same MESA investigators, suggest that
blood pressure control may be effective in halting the progression of aortic stiffening and
breaking the vicious circle between hypertension and vascular aging.15 Measurement of aortic
wall stiffness could provide a sensitive indicator for the initiation of vascular disease, but
interventional studies have yet to determine whether a lowering of PWV leads to a reduction
in cardiovascular events independent of alterations to classical risk factors.16 Endothelial cells
are mechanosensitive and directly respond to stiffening of the extracellular matrix leading to
enhanced permeability and uptake of cholesterol into the vessel wall.17 Endothelial
dysfunction is not irreversible and a number of emerging non-pharmacological and
pharmacological therapeutic strategies are under investigation that aim to reduce oxidative
stress and promote nitric oxide release.18 Ohyama et al’s observational study, taken with
other longitudinal data, provide supportive evidence of the role that declining arterial
elasticity may have in the development of subclinical impairment of both systolic and
diastolic function.
There are number of approaches and technologies used to assess vascular stiffness which
present both challenges and opportunities for advancing our understanding of hemodynamic
factors in heart disease.1 In Ohyama et al’s study the velocity of the propagating systolic
wavefront in the aorta was determined using phase contrast imaging – a non-invasive
approach for assessing vascular stiffness that offers good agreement with intra-aortic pressure
measurements.19 Phase contrast imaging depends on adequate temporal sampling of the flow
waveform particularly when model-fitting the systolic upstroke to minimise the influence of
wave reflection effects.20 The most relevant blood pressure metric is also debatable as,
although 24 hour ambulatory monitoring may better represent the cumulative exposure to
hypertension, transient changes in vascular stiffness also occur with acute variations in blood
pressure. Another factor not addressed in this study is the variation in elastic properties of the
aorta as the pulse wave travels distally, as both extracellular matrix composition and
expression of vascular disease vary in different territories. A limitation of the tagged
deformation imaging used is the absence of data on long axis function which is an
independent predictor of survival, after adjustment for clinical variables and short axis
function, in patients with heart failure.21 It would be appealing to combine complementary
CMR datasets from the MESA cohort, including feature-tracking for strain assessment in
each axis, to establish a comprehensive picture of longitudinal adaptations in LV mass,
function and aortic stiffness – findings which may not always be congruent with crosssectional associations.22 The right heart is also an important determinant of outcome in heart
failure, and there is emerging evidence that a similar relationship exists between pulmonary
artery stiffness and right ventricular function to that observed in the systemic circulation.23
Convincing data are still required on the putative feedback mechanisms between aortic and
ventricular dysfunction, what processes might initiate and amplify the progression to heart
failure in the general population, or any certainty as to whether outcomes in heart failure may
be improved by modifying aortic elasticity independent of conventional risk factors.
Pharmacological approaches to treat vascular stiffness, including angiotensin converting
inhibitors and calcium channel blockers, have achieved only modest results but there is
promising data that Rho kinase (ROCK) inhibition, including pleiotropic actions of statins,
may prevent atherosclerosis due to vessel wall stiffening.17 Aortic PWV improves risk
stratification independently of conventional cardiovascular risk factors, but its clinical value
will ultimately depend on whether it can be proven to guide treatment and improve
outcomes.24
Conflict of Interest Disclosures
None
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