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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 References 1. Townsend RR, Wilkinson IB, Schiffrin EL, Avolio AP, Chirinos JA, Cockcroft JR, Heffernan KS, Lakatta EG, McEniery CM, Mitchell GF, Najjar SS, Nichols WW, Urbina EM, Weber T. Recommendations for Improving and Standardizing Vascular Research on Arterial Stiffness: A Scientific Statement From the American Heart Association. Hypertension. 2015;66:698-722 2. Russo C, Jin Z, Palmieri V, Homma S, Rundek T, Elkind MSV, Sacco RL, Di Tullio MR. Arterial Stiffness and Wave Reflection: Sex Differences and Relationship With Left Ventricular Diastolic Function. Hypertension. 2012;60:362-368 3. Rommel KP, von Roeder M, Latuscynski K, Oberueck C, Blazek S, Fengler K, Besler C, Sandri M, Lucke C, Gutberlet M, Linke A, Schuler G, Lurz P. Extracellular Volume Fraction for Characterization of Patients With Heart Failure and Preserved Ejection Fraction. J Am Coll Cardiol. 2016;67:1815-1825 4. Kaess BM, Rong J, Larson MG, Hamburg NM, Vita JA, Levy D, Benjamin EJ, Vasan RS, Mitchell GF. Aortic stiffness, blood pressure progression, and incident hypertension. Jama. 2012;308:875-881 5. Borlaug BA, Kass DA. Ventricular-vascular interaction in heart failure. Heart Fail Clin. 2008;4:23-36 6. Wagenseil JE, Mecham RP. Elastin in large artery stiffness and hypertension. Journal of Cardiovascular Translational Research. 2012;5:264-273 7. Marti CN, Gheorghiade M, Kalogeropoulos AP, Georgiopoulou VV, Quyyumi AA, Butler J. Endothelial Dysfunction, Arterial Stiffness, and Heart Failure. Journal of the American College of Cardiology. 2012;60:1455-1469 8. Proust C, Empana JP, Boutouyrie P, Alivon M, Challande P, Danchin N, Escriou G, Esslinger U, Laurent S, Li Z, Pannier B, Regnault V, Thomas F, Jouven X, Cambien F, Lacolley P. Contribution of Rare and Common Genetic Variants to Plasma Lipid Levels and Carotid Stiffness and Geometry: A Substudy of the Paris Prospective Study 3. Circ Cardiovasc Genet. 2015;8:628-636 9. Ohyama Y, Ambale-Venkatesh B, Noda N, Chugh AR, Teixido-Tura G, Kim J, Donekal S, Yoneyama K, Gjesdal O, Redheuil A, Liu C, Nakamura T, Wu C, Hundley G, Bleumke DA, Lima JAC. Association of Aortic Stiffness with Left Ventricular Remodeling and Reduced Left Ventricular Function Measured by MRI: The Multi-Ethnic Study of Atherosclerosis (MESA). Circulation: Cardiovascular Imaging. 2016 10. Redheuil A, Yu WC, Mousseaux E, Harouni AA, Kachenoura N, Wu CO, Bluemke D, Lima JA. Age-related changes in aortic arch geometry: relationship with proximal aortic function and left ventricular mass and remodeling. J Am Coll Cardiol. 2011;58:1262-1270 11. Chirinos JA, Kips JG, Jacobs DR, Jr., Brumback L, Duprez DA, Kronmal R, Bluemke DA, Townsend RR, Vermeersch S, Segers P. Arterial wave reflections and incident cardiovascular events and heart failure: MESA (Multiethnic Study of Atherosclerosis). J Am Coll Cardiol. 2012;60:2170-2177 12. Fernandes VR, Polak JF, Cheng S, Rosen BD, Carvalho B, Nasir K, McClelland R, Hundley G, Pearson G, O'Leary DH, Bluemke DA, Lima JA. Arterial stiffness is associated with regional ventricular systolic and diastolic dysfunction: the MultiEthnic Study of Atherosclerosis. Arterioscler Thromb Vasc Biol. 2008;28:194-201 13. Tsao CW, Lyass A, Larson MG, Levy D, Hamburg NM, Vita JA, Benjamin EJ, Mitchell GF, Vasan RS. Relation of Central Arterial Stiffness to Incident Heart Failure in the Community. J Am Heart Assoc. 2015;4:e00218 14. Canepa M, AlGhatrif M. From Arterial Stiffness to Heart Failure: Still a Long Way to Go. J Am Heart Assoc. 2015;4:e002807 15. Ohyama Y, Teixido-Tura G, Ambale-Venkatesh B, Noda C, Chugh AR, Liu CY, Redheuil A, Stacey RB, Dietz H, Gomes AS, Prince MR, Evangelista A, Wu CO, Hundley WG, Bluemke DA, Lima JA. Ten-year longitudinal change in aortic stiffness assessed by cardiac MRI in the second half of the human lifespan: the multi-ethnic study of atherosclerosis. Eur Heart J Cardiovasc Imaging. 2016;[Epub ahead of print] 16. Antonini-Canterin F, Carerj S, Di Bello V, Di Salvo G, La Carrubba S, Vriz O, Pavan D, Balbarini A, Nicolosi GL. Arterial stiffness and ventricular stiffness: a couple of diseases or a coupling disease? A review from the cardiologist's point of view. European Heart Journal - Cardiovascular Imaging. 2009;10:36-43 17. Huynh J, Nishimura N, Rana K, Peloquin JM, Califano JP, Montague CR, King MR, Schaffer CB, Reinhart-King CA. Age-related intimal stiffening enhances endothelial permeability and leukocyte transmigration. Sci Transl Med. 2011;3:112ra122 18. Schnabel RB, Wild PS, Schulz A, Zeller T, Sinning CR, Wilde S, Kunde J, Lubos E, Lackner KJ, Warnholtz A, Gori T, Blankenberg S, Munzel T. Multiple endothelial biomarkers and noninvasive vascular function in the general population: the Gutenberg Health Study. Hypertension. 2012;60:288-295 19. Grotenhuis HB, Westenberg JJM, Steendijk P, van der Geest RJ, Ottenkamp J, Bax JJ, Jukema JW, de Roos A. Validation and reproducibility of aortic pulse wave velocity as assessed with velocity-encoded MRI. Journal of Magnetic Resonance Imaging. 2009;30:521-526 20. Dogui A, Redheuil A, Lefort M, DeCesare A, Kachenoura N, Herment A, Mousseaux E. 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Ben-Shlomo Y, Spears M, Boustred C, May M, Anderson SG, Benjamin EJ, Boutouyrie P, Cameron J, Chen CH, Cruickshank JK, Hwang SJ, Lakatta EG, Laurent S, Maldonado J, Mitchell GF, Najjar SS, Newman AB, Ohishi M, Pannier B, Pereira T, Vasan RS, Shokawa T, Sutton-Tyrell K, Verbeke F, Wang KL, Webb DJ, Willum Hansen T, Zoungas S, McEniery CM, Cockcroft JR, Wilkinson IB. Aortic pulse wave velocity improves cardiovascular event prediction: an individual participant metaanalysis of prospective observational data from 17,635 subjects. J Am Coll Cardiol. 2014;63:636-646