Ventricular arterial stiffening: integrating the pathophysiology.

Vascular stiffening of the large arteries is a common feature of aging and is exacerbated by many common disorders such as hypertension, diabetes, and renal disease. This change influences the phasic mechanical stresses imposed on the blood vessels that in turn is important to regulating smooth muscle tone, endothelial function, and vascular health. In addition, the heart typically adapts to confront higher and later systolic loads by both hypertrophy and ventricular systolic stiffening. This creates altered coupling between heart and vessel that importantly affects cardiovascular reserve function. In this overview, I discuss the notion of a coupling disease in which stiffness of both heart and arteries interact to limit performance and generate clinical symptoms. This involves changes in the mechanical interaction of both systems, changes in signaling within the arteries themselves, and alterations in coronary flow regulation. Lastly, I briefly review recent development in de-stiffening strategies that may pave the way to treat this syndrome and its clinical manifestations.

[1]  D. Kass,et al.  Combined Ventricular Systolic and Arterial Stiffening in Patients With Heart Failure and Preserved Ejection Fraction: Implications for Systolic and Diastolic Reserve Limitations , 2003, Circulation.

[2]  Michael D. Schneider,et al.  Pressure-independent cardiac hypertrophy in mice with cardiomyocyte-restricted inactivation of the atrial natriuretic peptide receptor guanylyl cyclase-A. , 2003, The Journal of clinical investigation.

[3]  A. Tedgui,et al.  Differential Regulation of Vascular Focal Adhesion Kinase by Steady Stretch and Pulsatility , 2005, Circulation.

[4]  D. Kass,et al.  Age and gender affect ventricular-vascular coupling during aerobic exercise. , 2004, Journal of the American College of Cardiology.

[5]  H. Hod,et al.  External counterpulsation therapy improves endothelial function in patients with refractory angina pectoris. , 2003, Journal of the American College of Cardiology.

[6]  John M. Tarbell,et al.  Interaction between Wall Shear Stress and Circumferential Strain Affects Endothelial Cell Biochemical Production , 2000, Journal of Vascular Research.

[7]  C. H. Chen,et al.  Verapamil acutely reduces ventricular-vascular stiffening and improves aerobic exercise performance in elderly individuals. , 1999, Journal of the American College of Cardiology.

[8]  A P Avolio,et al.  Effects of aging on arterial distensibility in populations with high and low prevalence of hypertension: comparison between urban and rural communities in China. , 1985, Circulation.

[9]  D. Kass,et al.  Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy , 2005, Nature Medicine.

[10]  A. Cerami,et al.  An advanced glycation endproduct cross-link breaker can reverse age-related increases in myocardial stiffness. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[11]  D. Kass,et al.  Improved Arterial Compliance by a Novel Advanced Glycation End-Product Crosslink Breaker , 2001, Circulation.

[12]  R. Busse,et al.  EDHF: bringing the concepts together. , 2002, Trends in pharmacological sciences.

[13]  H. Struijker‐Boudier,et al.  Current Perspectives on Arterial Stiffness and Pulse Pressure in Hypertension and Cardiovascular Diseases , 2003, Circulation.

[14]  M E Safar,et al.  Pulse pressure and aortic pulse wave are markers of cardiovascular risk in hypertensive populations. , 2001, American journal of hypertension.

[15]  M. Zaccolo,et al.  cGMP Catabolism by Phosphodiesterase 5A Regulates Cardiac Adrenergic Stimulation by NOS3-Dependent Mechanism , 2004, Circulation research.

[16]  A. Dyer,et al.  Pulse Pressure Compared With Other Blood Pressure Indexes in the Prediction of 25-Year Cardiovascular and All-Cause Mortality Rates: The Chicago Heart Association Detection Project in Industry Study , 2001, Hypertension.

[17]  M. Quiñones,et al.  Simvastatin Induces Regression of Cardiac Hypertrophy and Fibrosis and Improves Cardiac Function in a Transgenic Rabbit Model of Human Hypertrophic Cardiomyopathy , 2001, Circulation.

[18]  D. Kass,et al.  Mechanisms, pathophysiology, and therapy of arterial stiffness. , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[19]  R Tominaga,et al.  Pulsatile flow enhances endothelium-derived nitric oxide release in the peripheral vasculature. , 2000, American journal of physiology. Heart and circulatory physiology.

[20]  Peter P. Liu,et al.  Elafin-overexpressing mice have improved cardiac function after myocardial infarction. , 2004, American journal of physiology. Heart and circulatory physiology.

[21]  D. Kass,et al.  systolic flow augmentation in hearts ejecting into a model of stiff aging vasculature. Influence on myocardial perfusion-demand balance. , 1995, Circulation research.

[22]  D. Kass,et al.  Pulse pressure-related changes in coronary flow in vivo are modulated by nitric oxide and adenosine. , 1996, Circulation research.

[23]  K. Node,et al.  Statins as antioxidant therapy for preventing cardiac myocyte hypertrophy. , 2001, The Journal of clinical investigation.

[24]  A. Dart,et al.  Intensive cholesterol reduction lowers blood pressure and large artery stiffness in isolated systolic hypertension. , 2002, Journal of the American College of Cardiology.

[25]  N. Alp,et al.  Regulation of Endothelial Nitric Oxide Synthase by Tetrahydrobiopterin in Vascular Disease , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[26]  W. White,et al.  Effects of the Selective Aldosterone Blocker Eplerenone Versus the Calcium Antagonist Amlodipine in Systolic Hypertension , 2003, Hypertension.

[27]  D. Ingram,et al.  A cross-link breaker has sustained effects on arterial and ventricular properties in older rhesus monkeys. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[28]  D. Kass,et al.  Effect of reduced aortic compliance on cardiac efficiency and contractile function of in situ canine left ventricle. , 1992, Circulation research.

[29]  I. Shiojima,et al.  Role of Akt Signaling in Vascular Homeostasis and Angiogenesis , 2002, Circulation research.

[30]  W. Sessa,et al.  Simvastatin upregulates coronary vascular endothelial nitric oxide production in conscious dogs. , 2000, American journal of physiology. Heart and circulatory physiology.

[31]  D. Webb,et al.  Noninvasive assessment of arterial stiffness and risk of atherosclerotic events. , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[32]  P. Cahill,et al.  Sustained pulsatile flow regulates endothelial nitric oxide synthase and cyclooxygenase expression in co-cultured vascular endothelial and smooth muscle cells. , 1999, Journal of molecular and cellular cardiology.

[33]  M. Safar Pulse pressure, arterial stiffness, and cardiovascular risk. , 2000, Current opinion in cardiology.

[34]  C. Vlachopoulos,et al.  Effect of sildenafil on arterial stiffness and wave reflection. , 2009, Vascular medicine.

[35]  U. Laufs,et al.  Impact of HMG CoA reductase inhibition on small GTPases in the heart. , 2002, Cardiovascular research.

[36]  D. Hayoz,et al.  Nitric oxide synthase expression in endothelial cells exposed to mechanical forces. , 1998, Hypertension.

[37]  R. Busse,et al.  Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation , 1999, Nature.

[38]  Daniel Levy,et al.  Systolic Blood Pressure, Diastolic Blood Pressure, and Pulse Pressure as Predictors of Risk for Congestive Heart Failure in the Framingham Heart Study , 2003, Annals of Internal Medicine.

[39]  I. Shiojima,et al.  The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. , 2000, Nature Medicine.

[40]  M. Chen,et al.  Endothelial nitric oxide production during in vitro simulation of external limb compression. , 2002, American journal of physiology. Heart and circulatory physiology.

[41]  T. Gillebert,et al.  Afterload induced changes in myocardial relaxation: a mechanism for diastolic dysfunction. , 1999, Cardiovascular research.

[42]  D. Kass,et al.  Specificity of synergistic coronary flow enhancement by adenosine and pulsatile perfusion in the dog , 1999, The Journal of physiology.

[43]  B. Sumpio,et al.  Cyclic strain activates the pro-survival Akt protein kinase in bovine aortic smooth muscle cells. , 2001, Surgery.

[44]  R. Ramasamy,et al.  Protein Glycation: A Firm Link to Endothelial Cell Dysfunction , 2004, Circulation research.

[45]  Karl Swedberg,et al.  Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial , 2003, The Lancet.

[46]  L. Rowell,et al.  Disparities Between Aortic and Peripheral Pulse Pressures Induced by Upright Exercise and Vasomotor Changes in Man , 1968, Circulation.

[47]  D. Kass,et al.  Role of Calcium-Sensitive K+ Channels and Nitric Oxide in In Vivo Coronary Vasodilation From Enhanced Perfusion Pulsatility , 2001, Circulation.

[48]  G. Mitchell,et al.  Arterial stiffness and wave reflection in hypertension: Pathophysiologic and therapeutic implications , 2004, Current hypertension reports.

[49]  Hirofumi Tanaka,et al.  Aging, Habitual Exercise, and Dynamic Arterial Compliance , 2000, Circulation.

[50]  D. Kass,et al.  In vitro system to study realistic pulsatile flow and stretch signaling in cultured vascular cells. , 2000, American journal of physiology. Cell physiology.

[51]  D. Kass,et al.  Adverse influence of systemic vascular stiffening on cardiac dysfunction and adaptation to acute coronary occlusion. , 1996, Circulation.

[52]  C H Chen,et al.  Coupled systolic-ventricular and vascular stiffening with age: implications for pressure regulation and cardiac reserve in the elderly. , 1998, Journal of the American College of Cardiology.

[53]  D. Kass,et al.  Frequency- and Afterload-Dependent Cardiac Modulation In Vivo by Troponin I With Constitutively Active Protein Kinase A Phosphorylation Sites , 2004, Circulation research.

[54]  M. Safar,et al.  Increased Carotid Wall Elastic Modulus and Fibronectin in Aldosterone-Salt–Treated Rats: Effects of Eplerenone , 2002, Circulation.

[55]  D. Kass,et al.  Hemodynamic effects of unloading the old heart. , 1999, American journal of physiology. Heart and circulatory physiology.

[56]  Saptarsi M. Haldar,et al.  Wall Stiffness Suppresses Akt/eNOS and Cytoprotection in Pulse-Perfused Endothelium , 2003, Hypertension.

[57]  W. Hundley,et al.  Cardiac cycle-dependent changes in aortic area and distensibility are reduced in older patients with isolated diastolic heart failure and correlate with exercise intolerance. , 2001, Journal of the American College of Cardiology.

[58]  R. Pilz,et al.  This Review Is Part of a Thematic Series on Cyclic Gmp–generating Enzymes and Cyclic Gmp–dependent Signaling, Which Includes the following Articles: Regulation of Nitric Oxide–sensitive Guanylyl Cyclase Cyclic Gmp Phosphodiesterases and Regulation of Smooth Muscle Function Structure, Regulation, and , 2022 .