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: .
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 acorrelation between vascular stiffness and outcomes the temporal and causal interrelationships withaging, hypertension, atherosclerosis and the progression to heart failure are not fully understood.Aortic stiffening increasessystolic load on the left ventricle contributing to ventricular hypertrophy and leading toincreased myocardial oxygen demand, as well as indirectly promotingcoronary disease and impaired perfusion.1Arterial 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, 3Increasing vascular stiffness precedes the onset of hypertension and may promote alterations in wall stress that accelerate atherosclerosis.4This body of evidence has generated renewedinterest in discovering whether arterial stiffness is more than a correlated risk factorand 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.6With 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 myocardiumand endothelium driving unfavourable outcomes.7Genetic 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.8An 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.9Age-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.10Ohyama et al’s new data indicatethat 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 implicatingaortic stiffness in adverse cardiac remodeling and impaired myocardial function. A previous longitudinal MESA study investigated 5960 participantsusing 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.11It has been argued that systolic load ultimately determines LV remodelingand the indirect effects of aorticmechanical properties are of secondary importance, but measures of aortic stiffness are also relatively less confounded by the degree of LV dysfunction.12A 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.13These 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 thesame 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.15Measurement of aortic wall stiffness could provide a sensitive indicator for the initiation of vascular disease, but interventional studies have yet to determinewhether a lowering of PWV leads to a reduction in cardiovascular events independent of alterations to classical risk factors.16Endothelial cells are mechanosensitive and directly respond to stiffening of the extracellular matrix leading to enhanced permeability and uptake of cholesterol into the vessel wall.17Endothelial 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.18Ohyama et al’sobservational study, taken with other longitudinal data, providesupportive 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.1In 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 cross-sectional 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 functionto that observed in the systemic circulation.23
Convincing data are still required on theputative 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 thatRho kinase (ROCK) inhibition, including pleiotropicactionsof statins, may prevent atherosclerosis due to vessel wall stiffening.17Aortic 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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