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Mechanics and Function of the Pulmonary Vasculature: Implications for Pulmonary Vascular Disease and Right Ventricular Function

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Abstract

The relationship between cardiac function and the afterload against which the heart muscle must work to circulate blood throughout the pulmonary circulation is defined by a complex interaction between many coupled system parameters. These parameters range broadly and incorporate system effects originating primarily from three distinct locations: input power from the heart, hydraulic impedance from the large conduit pulmonary arteries, and hydraulic resistance from the more distal microcirculation. These organ systems are not independent, but rather, form a coupled system in which a change to any individual parameter affects all other system parameters. The result is a highly nonlinear system which requires not only detailed study of each specific component and the effect of disease on their specific function, but also requires study of the interconnected relationship between the microcirculation, the conduit arteries, and the heart in response to age and disease. Here, we investigate systems‐level changes associated with pulmonary hypertensive disease progression in an effort to better understand this coupled relationship. © 2012 American Physiological Society. Compr Physiol 2:295‐319, 2012.

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Figure 1. Figure 1.

Normal blood pressures of the systemic and pulmonary circulatory systems. Pulmonary circulation has much lower pressures and pulsations extend into the capillaries. (Redrawn, with permission, by Devon Scott.)

Figure 2. Figure 2.

Diagram of pulmonary vascular tree.

Figure 3. Figure 3.

Impedance modulus in healthy (A) and pulmonary hypertensive (B) children. As with other clinical studies of impedance, pulmonary hypertensive individuals displayed both larger values of , corresponding to higher PVR and larger values of the first several harmonics of impedance. Further, the first minimum of the curve is shifted rightward in the PH patients, corresponding to higher pulse‐wave velocities .

Figure 4. Figure 4.

Changes in mean blood pressure (MBP) (solid circle) and aortic pulse wave velocity (PWV) (open circle) for survivors and nonsurvivors of systemic hypertension in end‐stage renal disease. Patients underwent antihypertensive therapy and were tracked from inclusion to end of follow‐up .

Figure 5. Figure 5.

Mechanisms of arterial stiffening. Panels A, B, C, and D are discussed in detail in the text.

Figure 6. Figure 6.

Average hydraulic power of the inlet (IN, MPA) and outlet (OUT, pulmonary vein, near left atrium) of the pulmonary bed of anesthetized, open‐chest dogs. Regions above and below the hydraulic power = 0 line are both positive valued. Upper region contains pressure‐potential and kinetic energy terms associated with oscillatory component of blood flow. Lower region contains analogous terms for the steady‐flow component. Input and output hydraulic power values are shown in their respective columns with the difference between the two being the power dissipated (DISS) throughout the pulmonary bed during the cardiac cycle .

Figure 7. Figure 7.

Power dissipated as a function of heart rate for a constant pulmonary flow of 42.0 cm3/s measured in anesthetized dogs .

Figure 8. Figure 8.

Oscillatory component of input power (ordinate) at different levels of pulmonary blood flow (abscissa) for three different heart rates at constant stroke volume (solid line) and for three different stroke volumes at constant heart rate (solid line). Constant stroke volume curves are shown for three volumes (S = 10, 20, and 30 cm3/stroke) and constant heart rate curves are shown for three rates (f = 1.0, 2.0, and 3.0 beats/s). Constant stroke volume and constant heart rate curves are nearly equal for heart rates above 3 beats/s. Plot shows that pulmonary blood flow can be increased more efficiently by increasing heart rate than by increasing stroke volume .

Figure 9. Figure 9.

Effect of graded exercise on the increment in stroke volume (A), vascular resistance (B), aortic characteristic impedance (C), and external power (D) represented as mean change from resting values for young and old dogs at three different levels of exercise, *P = 0.05 (between young and old) .

Figure 10. Figure 10.

Schematic of pressure‐controlled isolated supported ventricle (PCISV). R, central reservoir; C2, C3, and C4, stopcocks; SL, supply container; OL, overflow system; RL, small reservoir; RP peripheral resistance; F, filter; RC characteristic impedance; and C capacitance .

Figure 11. Figure 11.

Schematic of volume controlled isolated supported ventricle (VCISV). A, coronary perfusion tube; AV, air vent; B, sealed box in which heart was placed for testing; BC, Bellofram cylinder; C, comparator; E, error signal; EDV, end diastolic volume; ESV, end systolic volume; HE, heat exchanger; LT, linear displacement transducer; LV, left ventricle; NP, negative pressure applied behind the diaphragm to reduce the compliance of the rolling diaphragm; PA, power amplifier; V, coronary venous return tube; VP, ventricular pressure measured by a miniature gage; VV, ventricular volume signal; W, hydraulic fluid (water) .

Figure 12. Figure 12.

Diagram of the Windkessel controlled isolated supported ventricle (WCISV). A linear motor and piston‐pump assembly allows for precise control of instantaneous ventricular volume. Loading system computes instantaneous ventricular pressure‐flow data in real time. Control system imposed real time pressure flow relationship based on three‐element Windkessel model through control of the linear motor .

Figure 13. Figure 13.

Example of typical Windkessel controlled isolated supported ventricle (WCISV) dataset. Experimental protocol consisted of first determining control values for the distal vascular resistance, characteristic impedance, and arterial compliance of the normal animal; which were 3.0 mmHg‐s/ml, 0.2 mmHg‐s/ml, and 0.4 ml/mmHg, respectively, for dogs weighing 20 to 22 kg. Arterial compliance and resistance were varied by 50% and 200% of control values while PV loops were generated at four end‐diastolic volumes for each experimental condition. Characteristic impedance was kept at control value. Heart rate was kept constant during all experiments (127 ± 9 beats/min) by pacing. Solid line at control indicates PV relationship at control conditions, dashed lines in other panels indicate transcribed PV relationship line from control. (B) and (C) End‐systolic pressure versus stroke with varying resistance and capacitance, symbols represent experimental data .

Figure 14. Figure 14.

pressure‐controlled isolated supported ventricle (PCISV) model showing the effect that changes in resistance and compliance have on the left ventricular pressure, aortic pressure, and aortic flow measured from cat left ventricle. Distal resistance was increased from a control value of 28.5 g/(cm4s) to 61 and 137 g/(cm4s). Aortic compliance was decreased from a control value of 43 cm4s2/g to 14 and 3.6 cm4s2/g. Heart rate was maintained constant at 153 beats/min by pacing. Results from this model for aggregated data from six feline PCISV hearts exposed to a 208% increase in resistance and a 21% decrease in compliance are given in Table . Similar results were obtained for changes in the resistance and compliance parameters of PCISV hearts from dogs .

Figure 15. Figure 15.

The experimental approach was to increase the distal resistance from a control value of 28.5 g/(cm4s) to 61 and 137 g/(cm4s) and to decrease the aortic compliance from a control value of 43 cm4s2/g to 14 and 3.6 cm4s2/g while maintaining a constant heart rate of 153 beats/min.

Figure 16. Figure 16.

Stiff arteries may extend high flow pulsatility into the pulmonary microcirculation, whereas in a normal compliant artery the capillaries experience semisteady flow.



Figure 1.

Normal blood pressures of the systemic and pulmonary circulatory systems. Pulmonary circulation has much lower pressures and pulsations extend into the capillaries. (Redrawn, with permission, by Devon Scott.)



Figure 2.

Diagram of pulmonary vascular tree.



Figure 3.

Impedance modulus in healthy (A) and pulmonary hypertensive (B) children. As with other clinical studies of impedance, pulmonary hypertensive individuals displayed both larger values of , corresponding to higher PVR and larger values of the first several harmonics of impedance. Further, the first minimum of the curve is shifted rightward in the PH patients, corresponding to higher pulse‐wave velocities .



Figure 4.

Changes in mean blood pressure (MBP) (solid circle) and aortic pulse wave velocity (PWV) (open circle) for survivors and nonsurvivors of systemic hypertension in end‐stage renal disease. Patients underwent antihypertensive therapy and were tracked from inclusion to end of follow‐up .



Figure 5.

Mechanisms of arterial stiffening. Panels A, B, C, and D are discussed in detail in the text.



Figure 6.

Average hydraulic power of the inlet (IN, MPA) and outlet (OUT, pulmonary vein, near left atrium) of the pulmonary bed of anesthetized, open‐chest dogs. Regions above and below the hydraulic power = 0 line are both positive valued. Upper region contains pressure‐potential and kinetic energy terms associated with oscillatory component of blood flow. Lower region contains analogous terms for the steady‐flow component. Input and output hydraulic power values are shown in their respective columns with the difference between the two being the power dissipated (DISS) throughout the pulmonary bed during the cardiac cycle .



Figure 7.

Power dissipated as a function of heart rate for a constant pulmonary flow of 42.0 cm3/s measured in anesthetized dogs .



Figure 8.

Oscillatory component of input power (ordinate) at different levels of pulmonary blood flow (abscissa) for three different heart rates at constant stroke volume (solid line) and for three different stroke volumes at constant heart rate (solid line). Constant stroke volume curves are shown for three volumes (S = 10, 20, and 30 cm3/stroke) and constant heart rate curves are shown for three rates (f = 1.0, 2.0, and 3.0 beats/s). Constant stroke volume and constant heart rate curves are nearly equal for heart rates above 3 beats/s. Plot shows that pulmonary blood flow can be increased more efficiently by increasing heart rate than by increasing stroke volume .



Figure 9.

Effect of graded exercise on the increment in stroke volume (A), vascular resistance (B), aortic characteristic impedance (C), and external power (D) represented as mean change from resting values for young and old dogs at three different levels of exercise, *P = 0.05 (between young and old) .



Figure 10.

Schematic of pressure‐controlled isolated supported ventricle (PCISV). R, central reservoir; C2, C3, and C4, stopcocks; SL, supply container; OL, overflow system; RL, small reservoir; RP peripheral resistance; F, filter; RC characteristic impedance; and C capacitance .



Figure 11.

Schematic of volume controlled isolated supported ventricle (VCISV). A, coronary perfusion tube; AV, air vent; B, sealed box in which heart was placed for testing; BC, Bellofram cylinder; C, comparator; E, error signal; EDV, end diastolic volume; ESV, end systolic volume; HE, heat exchanger; LT, linear displacement transducer; LV, left ventricle; NP, negative pressure applied behind the diaphragm to reduce the compliance of the rolling diaphragm; PA, power amplifier; V, coronary venous return tube; VP, ventricular pressure measured by a miniature gage; VV, ventricular volume signal; W, hydraulic fluid (water) .



Figure 12.

Diagram of the Windkessel controlled isolated supported ventricle (WCISV). A linear motor and piston‐pump assembly allows for precise control of instantaneous ventricular volume. Loading system computes instantaneous ventricular pressure‐flow data in real time. Control system imposed real time pressure flow relationship based on three‐element Windkessel model through control of the linear motor .



Figure 13.

Example of typical Windkessel controlled isolated supported ventricle (WCISV) dataset. Experimental protocol consisted of first determining control values for the distal vascular resistance, characteristic impedance, and arterial compliance of the normal animal; which were 3.0 mmHg‐s/ml, 0.2 mmHg‐s/ml, and 0.4 ml/mmHg, respectively, for dogs weighing 20 to 22 kg. Arterial compliance and resistance were varied by 50% and 200% of control values while PV loops were generated at four end‐diastolic volumes for each experimental condition. Characteristic impedance was kept at control value. Heart rate was kept constant during all experiments (127 ± 9 beats/min) by pacing. Solid line at control indicates PV relationship at control conditions, dashed lines in other panels indicate transcribed PV relationship line from control. (B) and (C) End‐systolic pressure versus stroke with varying resistance and capacitance, symbols represent experimental data .



Figure 14.

pressure‐controlled isolated supported ventricle (PCISV) model showing the effect that changes in resistance and compliance have on the left ventricular pressure, aortic pressure, and aortic flow measured from cat left ventricle. Distal resistance was increased from a control value of 28.5 g/(cm4s) to 61 and 137 g/(cm4s). Aortic compliance was decreased from a control value of 43 cm4s2/g to 14 and 3.6 cm4s2/g. Heart rate was maintained constant at 153 beats/min by pacing. Results from this model for aggregated data from six feline PCISV hearts exposed to a 208% increase in resistance and a 21% decrease in compliance are given in Table . Similar results were obtained for changes in the resistance and compliance parameters of PCISV hearts from dogs .



Figure 15.

The experimental approach was to increase the distal resistance from a control value of 28.5 g/(cm4s) to 61 and 137 g/(cm4s) and to decrease the aortic compliance from a control value of 43 cm4s2/g to 14 and 3.6 cm4s2/g while maintaining a constant heart rate of 153 beats/min.



Figure 16.

Stiff arteries may extend high flow pulsatility into the pulmonary microcirculation, whereas in a normal compliant artery the capillaries experience semisteady flow.

References
 1. Alexander RS. The influence of constrictor drugs on the distensibility of the splanchnic venous system, analyzed on the basis of an aortic model. Circ Res 2: 140‐147, 1954.
 2. Avolio AP, Chen SG, Wang RP, Zhang CL, Li MF, O'Rourke MF. Effects of aging on changing arterial compliance and left ventricular load in a northern Chinese urban community. Circulation 68: 50‐58, 1983.
 3. Badesch DB, Champion HC, Sanchez MA, Hoeper MM, Loyd JE, Manes A, McGoon M, Naeije R, Olschewski H, Oudiz RJ, Torbicki A. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol 54: S55‐S66, 2009.
 4. Balzer DT, Kort HW, Day RW, Corneli HM, Kovalchin JP, Cannon BC, Kaine SF, Ivy DD, Webber SA, Rothman A, Ross RD, Aggarwal S, Takahashi M, Waldman JD. Inhaled nitric oxide as a preoperative test (INOP test I): The INOP Test Study Group. Circulation 106: I76‐I81, 2002.
 5. Barra JG, Armentano RL, Levenson J, Fischer EI, Pichel RH, Simon A. Assessment of smooth muscle contribution to descending thoracic aortic elastic mechanics in conscious dogs. Circ Res 73: 1040‐1050, 1993.
 6. Barst RJ, McGoon M, Torbicki A, Sitbon O, Krowka MJ, Olschewski H, Gaine S. Diagnosis and differential assessment of pulmonary arterial hypertension. J Am Coll Cardiol 43: 40S‐47S, 2004.
 7. Benetos A, Gautier S, Ricard S, Topouchian J, Asmar R, Poirier O, Larosa E, Guize L, Safar M, Soubrier F, Cambien F. Influence of angiotensin‐converting enzyme and angiotensin II type 1 receptor gene polymorphisms on aortic stiffness in normotensive and hypertensive patients. Circulation 94: 698‐703, 1996.
 8. Levy BI. Artery changes with aging: Degeneration or adaption? Dial Cardio Med 6: 104‐111, 7, 2001.
 9. Blacher J, Asmar R, Djane S, London GM, Safar ME. Aortic pulse wave velocity as a marker of cardiovascular risk in hypertensive patients. Hypertension 33: 1111‐1117, 1999.
 10. Borlaug BA, Kass DA. Invasive hemodynamic assessment in heart failure. Heart Fail Clin 5: 217‐228, 2009.
 11. Bradlow WM, Gatehouse PD, Hughes RL, O'Brien AB, Gibbs JS, Firmin DN, Mohiaddin RH. Assessing normal pulse wave velocity in the proximal pulmonary arteries using transit time: A feasibility, repeatability, and observer reproducibility study by cardiovascular magnetic resonance. J Magn Reson Imaging 25: 974‐981, 2007.
 12. Budhiraja R, Tuder RM, Hassoun PM. Endothelial dysfunction in pulmonary hypertension. Circulation 109: 159‐165, 2004.
 13. Castelain V, Herve P, Lecarpentier Y, Duroux P, Simonneau G, Chemla D. Pulmonary artery pulse pressure and wave reflection in chronic pulmonary thromboembolism and primary pulmonary hypertension. J Am Coll Cardiol 37: 1085‐1092, 2001.
 14. Cattan V, Kakou A, Louis H, Lacolley P. Pathophysiology, genetic, and therapy of arterial stiffness. Biomed Mater Eng 16: S155‐S161, 2006.
 15. Ceravolo R, Maio R, Pujia A, Sciacqua A, Ventura G, Costa MC, Sesti G, Perticone F. Pulse pressure and endothelial dysfunction in never‐treated hypertensive patients. J Am Coll Cardiol 41: 1753‐1758, 2003.
 16. Chae CU, Pfeffer MA, Glynn RJ, Mitchell GF, Taylor JO, Hennekens CH. Increased pulse pressure and risk of heart failure in the elderly. JAMA 281: 634‐639, 1999.
 17. Champion HC, Michelakis ED, Hassoun PM. Comprehensive invasive and noninvasive approach to the right ventricle‐pulmonary circulation unit: State of the art and clinical and research implications. Circulation 120: 992‐1007, 2009.
 18. Chemla D, Castelain V, Herve P, Lecarpentier Y, Brimioulle S. Haemodynamic evaluation of pulmonary hypertension. Eur Respir J 20: 1314‐1331, 2002.
 19. Chesler NC, Roldan A, Vanderpool RR, Naeije R. How to measure pulmonary vascular and right ventricular function. Conf Proc IEEE Eng Med Biol Soc 2009: 177‐180, 2009.
 20. Cheung N, Sharrett AR, Klein R, Criqui MH, Islam FM, Macura KJ, Cotch MF, Klein BE, Wong TY. Aortic distensibility and retinal arteriolar narrowing: The multi‐ethnic study of atherosclerosis. Hypertension 50: 617‐622, 2007.
 21. Chien S. Mechanotransduction and endothelial cell homeostasis: The wisdom of the cell. Am J Physiol Heart Circ Physiol 292: H1209‐H1224, 2007.
 22. Chien S. Effects of disturbed flow on endothelial cells. Ann Biomed Eng 36: 554‐562, 2008.
 23. Christensen KL. Reducing pulse pressure in hypertension may normalize small artery structure. Hypertension 18: 722‐727, 1991.
 24. Christensen KL, Mulvany MJ. Location of resistance arteries. J Vasc Res 38: 1‐12, 2001.
 25. Cox RH. Mechanics of canine iliac artery smooth muscle in vitro. Am J Physiol 230: 462‐470, 1976.
 26. Davies PF. Endothelial transcriptome profiles in vivo in complex arterial flow fields. Ann Biomed Eng 36: 563‐570, 2008.
 27. Davies PF. Hemodynamic shear stress and the endothelium in cardiovascular pathophysiology. Nat Clin Pract Cardiovasc Med 6: 16‐26, 2009.
 28. Davies PF, Spaan JA, Krams R. Shear stress biology of the endothelium. Ann Biomed Eng 33: 1714‐1718, 2005.
 29. DeLoach SS, Townsend RR. Vascular stiffness: Its measurement and significance for epidemiologic and outcome studies. Clin J Am Soc Nephrol 3: 184‐192, 2008.
 30. Dobrin PB, Rovick AA. Influence of vascular smooth muscle on contractile mechanics and elasticity of arteries. Am J Physiol 217: 1644‐1651, 1969.
 31. Drexler ES, Quinn TP, Slifka AJ, McCowan CN, Bischoff JE, Wright JE, Ivy DD, Shandas R. Comparison of mechanical behavior among the extrapulmonary arteries from rats. J Biomech 40: 812‐819, 2007.
 32. Durmowicz AG, Orton EC, Stenmark KR. Progressive loss of vasodilator responsive component of pulmonary hypertension in neonatal calves exposed to 4,570 m. Am J Physiol 265: H2175‐H2183, 1993.
 33. Elzinga G, Westerhof N. Pressure and flow generated by the left ventricle against different impedances. Circ Res 32: 178‐186, 1973.
 34. Fagan KA, Oka M, Bauer NR, Gebb SA, Ivy DD, Morris KG, McMurtry IF. Attenuation of acute hypoxic pulmonary vasoconstriction and hypoxic pulmonary hypertension in mice by inhibition of Rho‐kinase. Am J Physiol Lung Cell Mol Physiol 287: L656‐L664, 2004.
 35. Feihl F, Liaudet L, Waeber B. The macrocirculation and microcirculation of hypertension. Curr Hypertens Rep 11: 182‐189, 2009.
 36. Finkelstein SM, Collins VR, Cohn JN. Arterial vascular compliance response to vasodilators by Fourier and pulse contour analysis. Hypertension 12: 380‐387, 1988.
 37. Franklin SS, Khan SA, Wong ND, Larson MG, Levy D. Is pulse pressure useful in predicting risk for coronary heart Disease? The Framingham heart study. Circulation 100: 354‐360, 1999.
 38. Galie N, Manes A, Negro L, Palazzini M, Bacchi‐Reggiani ML, Branzi A. A meta‐analysis of randomized controlled trials in pulmonary arterial hypertension. Eur Heart J 30: 394‐403, 2009.
 39. Galie N, Simonneau G, Barst RJ, Badesch D, Rubin L. Clinical worsening in trials of pulmonary arterial hypertension: Results and implications. Curr Opin Pulm Med 16 Suppl 1: S11‐S19, 2010.
 40. Gan CT, Lankhaar JW, Westerhof N, Marcus JT, Becker A, Twisk JW, Boonstra A, Postmus PE, Vonk‐Noordegraaf A. Noninvasively assessed pulmonary artery stiffness predicts mortality in pulmonary arterial hypertension. Chest 132: 1906‐1912, 2007.
 41. Gao F, Liao D, Drewes AM, Gregersen H. Modelling the elastin, collagen and smooth muscle contribution to the duodenal mechanical behavior in patients with systemic sclerosis. Neurogastroenterol Motil 21: 914‐e968, 2009.
 42. Garcia‐Cardena G, Comander J, Anderson KR, Blackman BR, Gimbrone MA Jr. Biomechanical activation of vascular endothelium as a determinant of its functional phenotype. Proc Natl Acad Sci U S A 98: 4478‐4485, 2001.
 43. Garde E, Mortensen EL, Krabbe K, Rostrup E, Larsson HB. Relation between age‐related decline in intelligence and cerebral white‐matter hyperintensities in healthy octogenarians: A longitudinal study. Lancet 356: 628‐634, 2000.
 44. Gow B. Circulatory correlates: Vascular impedance, resistance, and capacity. Comprehensive Physiology: John Wiley & Sons, Inc., pp. 353‐408, 1980.
 45. Guerin AP, Blacher J, Pannier B, Marchais SJ, Safar ME, London GM. Impact of aortic stiffness attenuation on survival of patients in end‐stage renal failure. Circulation 103: 987‐992, 2001.
 46. Guntheroth WG, Gould R, Butler J, Kinnen E. Pulsatile flow in pulmonary artery, capillary, and vein in the dog. Cardiovasc Res 8: 330‐337, 1974.
 47. Guyton AC. In: Schmitt W, editor. Medical Physiology. Philadelphia: Saunders, 2000.
 48. Hall J, Schmidt G, Wood L, Taylor C. In: Hall JB, Schmidt GA, Wood LDH, editors. Principles of Critical Care. New York: McGraw‐Hill, 2005.
 49. Haneda T, Nakajima T, Shirato K, Onodera S, Takishima T. Effects of oxygen breathing on pulmonary vascular input impedance in patients with pulmonary hypertension. Chest 83: 520‐527, 1983.
 50. Hardziyenka M, Reesink HJ, Bouma BJ, de Bruin‐Bon HA, Campian ME, Tanck MW, van den Brink RB, Kloek JJ, Tan HL, Bresser P. A novel echocardiographic predictor of in‐hospital mortality and mid‐term haemodynamic improvement after pulmonary endarterectomy for chronic thrombo‐embolic pulmonary hypertension. Eur Heart J 28: 842‐849, 2007.
 51. Harris P, Heath D, Apostolopoulos A. Extensibility of the human pulmonary trunk. Br Heart J 27: 651‐659, 1965.
 52. Howell W. In: Patton Harry D, Fuchs Albert F, Hille Bertil, Scher Allen M, Steiner Robert, editors. Textbook of Physiology Excitable Cells and Neurophysiology (21st ed). Philadelphia: W.B. Saunders, 1989.
 53. Huang PJ, Chien KL, Chen MF, Lai LP, Chiang FT. Efficacy and safety of imidapril in patients with essential hypertension: A double‐blind comparison with captopril. Cardiology 95: 146‐150, 2001.
 54. Huez S, Brimioulle S, Naeije R, Vachiery JL. Feasibility of routine pulmonary arterial impedance measurements in pulmonary hypertension. Chest 125: 2121‐2128, 2004.
 55. Hughes JMB, Morrell NW. In: Anderson Robert H, editor. Pulmonary Circulation: From Basic Mechanisms to Clinical Practice. London: Imperial College Press, 2001.
 56. Hunter KS, Lee PF, Lanning CJ, Ivy DD, Kirby KS, Claussen LR, Chan KC, Shandas R. Pulmonary vascular input impedance is a combined measure of pulmonary vascular resistance and stiffness and predicts clinical outcomes better than pulmonary vascular resistance alone in pediatric patients with pulmonary hypertension. Am Heart J 155: 166‐174, 2008.
 57. Hyvelin JM, Howell K, Nichol A, Costello CM, Preston RJ, McLoughlin P. Inhibition of Rho‐kinase attenuates hypoxia‐induced angiogenesis in the pulmonary circulation. Circ Res 97: 185‐191, 2005.
 58. Ishide N, Shimizu Y, Maruyama Y, Koiwa Y, Nunokawa T, Isoyama S, Kitaoka S, Tamaki K, Ino‐Oka E, Takishima T. Effects of changes in the aortic input impedance on systolic pressure‐ejected volume relationships in the isolated supported canine left ventricle. Cardiovasc Res 14: 229‐243, 1980.
 59. Jeffery TK, Morrell NW. Molecular and cellular basis of pulmonary vascular remodeling in pulmonary hypertension. Prog Cardiovasc Dis 45: 173‐202, 2002.
 60. Kaebnick BW, Giridharan GA, Koenig SC. Quantification of pulsatility as a function of vascular input impedance: An in vitro study. ASAIO J 53: 115‐121, 2007.
 61. Kass DA. Ventricular arterial stiffening: Integrating the pathophysiology. Hypertension 46: 185‐193, 2005.
 62. Kassab GS, Navia JA. Biomechanical considerations in the design of graft: The homeostasis hypothesis. Annu Rev Biomed Eng 8: 499‐535, 2006.
 63. Klein R, Klein BE, Tomany SC, Cruickshanks KJ. The association of cardiovascular disease with the long‐term incidence of age‐related maculopathy: The Beaver Dam eye study. Ophthalmology 110: 636‐643, 2003.
 64. Kobs RW, Muvarak NE, Eickhoff JC, Chesler NC. Linked mechanical and biological aspects of remodeling in mouse pulmonary arteries with hypoxia‐induced hypertension. Am J Physiol Heart Circ Physiol 288: H1209‐H1217, 2005.
 65. Kussmaul WG III, Altschuler JA, Herrmann HC, Laskey WK. Effects of pacing tachycardia and balloon valvuloplasty on pulmonary artery impedance and hydraulic power in mitral stenosis. Circulation 86: 1770‐1779, 1992.
 66. Lajemi M, Gautier S, Poirier O, Baguet JP, Mimran A, Gosse P, Hanon O, Labat C, Cambien F, Benetos A. Endothelin gene variants and aortic and cardiac structure in never‐treated hypertensives. Am J Hypertens 14: 755‐760, 2001.
 67. Lammers SR, Kao PH, Qi HJ, Hunter K, Lanning C, Albietz J, Hofmeister S, Mecham R, Stenmark KR, Shandas R. Changes in the structure‐function relationship of elastin and its impact on the proximal pulmonary arterial mechanics of hypertensive calves. Am J Physiol‐Heart C 295: H1451‐H1459, 2008.
 68. Launer LJ, Ross GW, Petrovitch H, Masaki K, Foley D, White LR, Havlik RJ. Midlife blood pressure and dementia: The Honolulu‐Asia aging study. Neurobiol Aging 21: 49‐55, 2000.
 69. Lavoie TL, Dowell ML, Lakser OJ, Gerthoffer WT, Fredberg JJ, Seow CY, Mitchell RW, Solway J. Disrupting actin‐myosin‐actin connectivity in airway smooth muscle as a treatment for asthma? Proc Am Thorac Soc 6: 295‐300, 2009.
 70. Lehoux S, Tedgui A. Cellular mechanics and gene expression in blood vessels. J Biomech 36: 631‐643, 2003.
 71. Li M, Chiou KR, Bugayenko A, Irani K, Kass DA. Reduced wall compliance suppresses Akt‐dependent apoptosis protection stimulated by pulse perfusion. Circ Res 97: 587‐595, 2005.
 72. Li M, Scott DE, Shandas R, Stenmark KR, Tan W. High pulsatility flow induces adhesion molecule and cytokine mRNA expression in distal pulmonary artery endothelial cells. Ann Biomed Eng 37: 1082‐1092, 2009.
 73. Li M, Stenmark KR, Shandas R, Tan W. Effects of pathological flow on pulmonary artery endothelial production of vasoactive mediators and growth factors. J Vasc Res 46: 561‐571, 2009.
 74. Lieber B. Arterial Macrocirculatory Hemodynamics. In: Bronzino J, editor. Boca Raton: CRC Press, LLC, 2000.
 75. Loutzenhiser R, Bidani A, Chilton L. Renal myogenic response: Kinetic attributes and physiological role. Circ Res 90: 1316‐1324, 2002.
 76. Lucas CL, Wilcox BR, Ha B, Henry GW. Comparison of time domain algorithms for estimating aortic characteristic impedance in humans. IEEE Trans Biomed Eng 35: 62‐68, 1988.
 77. Macchia A, Marchioli R, Marfisi R, Scarano M, Levantesi G, Tavazzi L, Tognoni G. A meta‐analysis of trials of pulmonary hypertension: A clinical condition looking for drugs and research methodology. Am Heart J 153: 1037‐1047, 2007.
 78. Mahapatra S, Nishimura RA, Sorajja P, Cha S, McGoon MD. Relationship of pulmonary arterial capacitance and mortality in idiopathic pulmonary arterial hypertension. J Am Coll Cardiol 47: 799‐803, 2006.
 79. Mauban JR, Remillard CV, Yuan JX. Hypoxic pulmonary vasoconstriction: Role of ion channels. J Appl Physiol 98: 415‐420, 2005.
 80. McDonald DA, Taylor MG. The hemodynamics of the arterial circulation. Prog Biophys Chem 9: 107‐173, 1959.
 81. McDonald DA. In: McDonald Alison, Nichols Wilmer W, Milnor William R, editors. Blood Flow in Arteries (2nd ed). London: Edward Arnold Ltd., 1974.
 82. Mecham RP, Stenmark KR, Parks WC. Connective tissue production by vascular smooth muscle in development and disease. Chest 99: 43S‐47S, 1991.
 83. Medley TL, Cole TJ, Gatzka CD, Wang WY, Dart AM, Kingwell BA. Fibrillin‐1 genotype is associated with aortic stiffness and disease severity in patients with coronary artery disease. Circulation 105: 810‐815, 2002.
 84. Medley TL, Kingwell BA, Gatzka CD, Pillay P, Cole TJ. Matrix metalloproteinase‐3 genotype contributes to age‐related aortic stiffening through modulation of gene and protein expression. Circ Res 92: 1254‐1261, 2003.
 85. Milnor WR. Arterial impedance as ventricular afterload. Circ Res 36: 565‐570, 1975.
 86. Milnor WR. In: Nancy Collins, editor. Hemodynamics (2nd ed). Baltimore: Williams & Wilkins, 1989.
 87. Milnor WR, Bergel DH, Bargainer JD. Hydraulic power associated with pulmonary blood flow and its relation to heart rate. Circ Res 19: 467‐480, 1966.
 88. Milnor WR, Conti CR, Lewis KB, O'Rourke MF. Pulmonary arterial pulse wave velocity and impedance in man. Circ Res 25: 637‐649, 1969.
 89. Mitchell GF. Increased aortic stiffness: An unfavorable cardiorenal connection. Hypertension 43: 151‐153, 2004.
 90. Mitchell GF. Effects of central arterial aging on the structure and function of the peripheral vasculature: Implications for end‐organ damage. J Appl Physiol 105: 1652‐1660, 2008.
 91. Mitchell GF. Arterial stiffness and wave reflection: Biomarkers of cardiovascular risk. Artery Res 3: 56‐64, 2009a.
 92. Mitchell GF. Clinical achievements of impedance analysis. Med Biol Eng Comput 47: 153‐163, 2009b.
 93. Mitchell GF, DeStefano AL, Larson MG, Benjamin EJ, Chen MH, Vasan RS, Vita JA, Levy D. Heritability and a genome‐wide linkage scan for arterial stiffness, wave reflection, and mean arterial pressure: The Framingham Heart Study. Circulation 112: 194‐199, 2005.
 94. Mitchell GF, Vita JA, Larson MG, Parise H, Keyes MJ, Warner E, Vasan RS, Levy D, Benjamin EJ. Cross‐sectional relations of peripheral microvascular function, cardiovascular disease risk factors, and aortic stiffness: The Framingham Heart Study. Circulation 112: 3722‐3728, 2005.
 95. Morrell NW, Adnot S, Archer SL, Dupuis J, Jones PL, MacLean MR, McMurtry IF, Stenmark KR, Thistlethwaite PA, Weissmann N, Yuan JX, Weir EK. Cellular and molecular basis of pulmonary arterial hypertension. J Am Coll Cardiol 54: S20‐S31, 2009.
 96. Moudgil R, Michelakis ED, Archer SL. Hypoxic pulmonary vasoconstriction. J Appl Physiol 98: 390‐403, 2005.
 97. Murgo JP, Westerhof N, Giolma JP, Altobelli SA. Aortic input impedance in normal man: Relationship to pressure wave forms. Circulation 62: 105‐116, 1980.
 98. Naeije R, Huez S. Reflections on wave reflections in chronic thromboembolic pulmonary hypertension. Eur Heart J 28: 785‐787, 2007.
 99. Nagaoka T, Fagan KA, Gebb SA, Morris KG, Suzuki T, Shimokawa H, McMurtry IF, Oka M. Inhaled Rho kinase inhibitors are potent and selective vasodilators in rat pulmonary hypertension. Am J Respir Crit Care Med 171: 494‐499, 2005.
 100. Nakayama Y, Nakanishi N, Hayashi T, Nagaya N, Sakamaki F, Satoh N, Ohya H, Kyotani S. Pulmonary artery reflection for differentially diagnosing primary pulmonary hypertension and chronic pulmonary thromboembolism. J Am Coll Cardiol 38: 214‐218, 2001.
 101. Nichols Wilmer W., O'Rourke Michael F.. In: Joana Koster, editor. McDonald's Blood Flow in Arteries: Theoretical, Experimental, and Clinical Principles (5th ed). London: A. Hodder Arnold, 1998.
 102. Nichols WW, Conti CR, Walker WE, Milnor WR. Input impedance of the systemic circulation in man. Circ Res 40: 451‐458, 1977.
 103. Nichols WW, O'Rourke M, Kenney W. In: Joana Koster, editor. McDonald's Blood Flow in Arteries: Theoretical, Experimental, and Clinical Principles. (5th ed). London: A Hodder Arnold, 1998, p. 607.
 104. O'Rourke M. Arterial stiffness, systolic blood pressure, and logical treatment of arterial hypertension. Hypertension 15: 339‐347, 1990.
 105. O'Rourke MF. Vascular impedance in studies of arterial and cardiac function. Physiol Rev 62: 570‐623, 1982.
 106. O'Rourke MF, Mancia G. Arterial stiffness. J Hypertens 17: 1‐4, 1999.
 107. O'Rourke MF, Safar ME. Relationship between aortic stiffening and microvascular disease in brain and kidney: Cause and logic of therapy. Hypertension 46: 200‐204, 2005.
 108. Ooi H, Chung W, Biolo A. Arterial stiffness and vascular load in heart failure. Congest Heart Fail 14: 31‐36, 2008.
 109. Pantoni L, Garcia JH. Cognitive impairment and cellular/vascular changes in the cerebral white matter. Ann N Y Acad Sci 826: 92‐102, 1997.
 110. Pauca AL, O'Rourke MF, Kon ND. Prospective evaluation of a method for estimating ascending aortic pressure from the radial artery pressure waveform. Hypertension 38: 932‐937, 2001.
 111. Pauca AL, Wallenhaupt SL, Kon ND, Tucker WY. Does radial artery pressure accurately reflect aortic pressure? Chest 102: 1193‐1198, 1992.
 112. Peled N, Shitrit D, Fox BD, Shlomi D, Amital A, Bendayan D, Kramer MR. Peripheral arterial stiffness and endothelial dysfunction in idiopathic and scleroderma associated pulmonary arterial hypertension. J Rheumatol 36: 970‐975, 2009.
 113. Peng X, Haldar S, Deshpande S, Irani K, Kass DA. Wall stiffness suppresses Akt/eNOS and cytoprotection in pulse‐perfused endothelium. Hypertension 41: 378‐381, 2003.
 114. Pepine CJ, Nichols WW, Conti CR. Aortic input impedance in heart failure. Circulation 58: 460‐465, 1978.
 115. Piene H. Impedance matching between ventricle and load. Ann Biomed Eng 12: 191‐207, 1984.
 116. Piene H. Pulmonary arterial impedance and right ventricular function. Physiol Rev 66: 606‐652, 1986.
 117. Piene H, Sund T. Does normal pulmonary impedance constitute the optimum load for the right ventricle? Am J Physiol 242: H154‐H160, 1982.
 118. Qiu H, Zhu Y, Sun Z, Trzeciakowski JP, Gansner M, Depre C, Resuello RR, Natividad FF, Hunter WC, Genin GM, Elson EL, Vatner DE, Meininger GA, Vatner SF. Short communication: Vascular smooth muscle cell stiffness as a mechanism for increased aortic stiffness with aging. Circ Res 107: 615‐619.
 119. Reeves JT, Groves BM, Turkevich D. The case for treatment of selected patients with primary pulmonary hypertension. Am Rev Respir Dis 134: 342‐346, 1986.
 120. Remillard CV, Yuan JX. High altitude pulmonary hypertension: Role of K+ and Ca2+ channels. High Alt Med Biol 6: 133‐146, 2005.
 121. Rodes‐Cabau J, Domingo E, Roman A, Majo J, Lara B, Padilla F, Anivarro I, Angel J, Tardif JC, Soler‐Soler J. Intravascular ultrasound of the elastic pulmonary arteries: A new approach for the evaluation of primary pulmonary hypertension. Heart 89: 311‐315, 2003.
 122. Safar M. Arterial Stiffness in Hypertension. In: Safar M, O'Rourke M. editors. Edinburgh: Elsevier, 2006.
 123. Safar ME. Systolic blood pressure, pulse pressure and arterial stiffness as cardiovascular risk factors. Curr Opin Nephrol Hypertens 10: 257‐261, 2001.
 124. Safar ME. Pulse pressure, arterial stiffness and wave reflections (augmentation index) as cardiovascular risk factors in hypertension. Ther Adv Cardiovasc Dis 2: 13‐24, 2008.
 125. Safar ME, London GM, Plante GE. Arterial stiffness and kidney function. Hypertension 43: 163‐168, 2004.
 126. Safar ME, Struijker‐Boudier HA. Cross‐talk between macro‐ and microcirculation. Acta Physiol (Oxf) 198: 417‐430, 2010.
 127. Safar ME, Thuilliez C, Richard V, Benetos A. Pressure‐independent contribution of sodium to large artery structure and function in hypertension. Cardiovasc Res 46: 269‐276, 2000.
 128. Sanz J, Kariisa M, Dellegrottaglie S, Prat‐Gonzalez S, Garcia MJ, Fuster V, Rajagopalan S. Evaluation of pulmonary artery stiffness in pulmonary hypertension with cardiac magnetic resonance. JACC Cardiovasc Imaging 2: 286‐295, 2009.
 129. Saouti N, Westerhof N, Helderman F, Marcus JT, Boonstra A, Postmus PE, Vonk Noordegraaf A. Right ventricular oscillatory power is a constant fraction of total power irrespective of pulmonary artery pressure. Am J Respir Crit Care Med 182: 1315‐1320, 2010.
 130. Sokolis DP, Kefaloyannis EM, Kouloukoussa M, Marinos E, Boudoulas H, Karayannacos PE. A structural basis for the aortic stress‐strain relation in uniaxial tension. J Biomech 39: 1651‐1662, 2006.
 131. Stenmark KR, Davie N, Frid M, Gerasimovskaya E, Das M. Role of the adventitia in pulmonary vascular remodeling. Physiology (Bethesda) 21: 134‐145, 2006.
 132. Stenmark KR, Fagan KA, Frid MG. Hypoxia‐induced pulmonary vascular remodeling: Cellular and molecular mechanisms. Circ Res 99: 675‐691, 2006.
 133. Stenmark KR, McMurtry IF. Vascular remodeling versus vasoconstriction in chronic hypoxic pulmonary hypertension: A time for reappraisal? Circ Res 97: 95‐98, 2005.
 134. Stenmark KR, Mecham RP. Cellular and molecular mechanisms of pulmonary vascular remodeling. Annu Rev Physiol 59: 89‐144, 1997.
 135. Streeter VL, Keitzer WF, Bohr DF. Pulsatile pressure and flow through distensible vessels. Circ Res 13: 3‐20, 1963.
 136. Suga H, Kitabatake A, Sagawa K. End‐systolic pressure determines stroke volume from fixed end‐diastolic volume in the isolated canine left ventricle under a constant contractile state. Circ Res 44: 238‐249, 1979.
 137. Sunagawa K, Maughan WL, Burkhoff D, Sagawa K. Left ventricular interaction with arterial load studied in isolated canine ventricle. Am J Physiol 245: H773‐H780, 1983.
 138. Tagawa H. Pulmonary arterial input impedance in patients with chronic pulmonary diseases. Nihon Kyobu Shikkan Gakkai Zasshi 27: 1031‐1039, 1989.
 139. Taylor MG. Wave‐travel in a non‐uniform transmission line, in relation to pulses in arteries. Phys Med Biol 10: 539‐550, 1965.
 140. Tobise K, Haneda T, Onodera S. Changes in the pulmonary vascular input impedance in patients with atrial septal defect after surgical correction. Jpn Circ J 54: 175‐182, 1990.
 141. Travis AR, Giridharan GA, Pantalos GM, Dowling RD, Prabhu SD, Slaughter MS, Sobieski M, Undar A, Farrar DJ, Koenig SC. Vascular pulsatility in patients with a pulsatile‐ or continuous‐flow ventricular assist device. J Thorac Cardiovasc Surg 133: 517‐524, 2007.
 142. Tuder RM, Abman SH, Braun T, Capron F, Stevens T, Thistlethwaite PA, Haworth SG. Development and pathology of pulmonary hypertension. J Am Coll Cardiol 54: S3‐S9, 2009.
 143. Tuder RM, Marecki JC, Richter A, Fijalkowska I, Flores S. Pathology of pulmonary hypertension. Clin Chest Med 28: 23‐42, 2007.
 144. Undar A, Zapanta CM, Reibson JD, Souba M, Lukic B, Weiss WJ, Snyder AJ, Kunselman AR, Pierce WS, Rosenberg G, Myers JL. Precise quantification of pressure flow waveforms of a pulsatile ventricular assist device. ASAIO J 51: 56‐59, 2005.
 145. Uren NG, Oakley CM. The treatment of primary pulmonary hypertension. Br Heart J 66: 119‐121, 1991.
 146. Vermeer SE, Prins ND, den Heijer T, Hofman A, Koudstaal PJ, Breteler MM. Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med 348: 1215‐1222, 2003.
 147. Vernooij MW, van der Lugt A, Ikram MA, Wielopolski PA, Niessen WJ, Hofman A, Krestin GP, Breteler MM. Prevalence and risk factors of cerebral microbleeds: The Rotterdam Scan Study. Neurology 70: 1208‐1214, 2008.
 148. Veyssier‐Belot C, Cacoub P. Role of endothelial and smooth muscle cells in the physiopathology and treatment management of pulmonary hypertension. Cardiovasc Res 44: 274‐282, 1999.
 149. Waldstein SR, Rice SC, Thayer JF, Najjar SS, Scuteri A, Zonderman AB. Pulse pressure and pulse wave velocity are related to cognitive decline in the Baltimore Longitudinal Study of Aging. Hypertension 51: 99‐104, 2008.
 150. Weinberg CE, Hertzberg JR, Ivy DD, Kirby KS, Chan KC, Valdes‐Cruz L, Shandas R. Extraction of pulmonary vascular compliance, pulmonary vascular resistance, and right ventricular work from single‐pressure and Doppler flow measurements in children with pulmonary hypertension: A new method for evaluating reactivity: In vitro and clinical studies. Circulation 110: 2609‐2617, 2004.
 151. Willum‐Hansen T, Staessen JA, Torp‐Pedersen C, Rasmussen S, Thijs L, Ibsen H, Jeppesen J. Prognostic value of aortic pulse wave velocity as index of arterial stiffness in the general population. Circulation 113: 664‐670, 2006.
 152. Wohrley JD, Frid MG, Moiseeva EP, Orton EC, Belknap JK, Stenmark KR. Hypoxia selectively induces proliferation in a specific subpopulation of smooth muscle cells in the bovine neonatal pulmonary arterial media. J Clin Invest 96: 273‐281, 1995.
 153. Wolinsky H, Glagov S. Structural basis for the static mechanical properties of the aortic media. Circulation Research 14: 400, 1964.
 154. Wuyts F, Vanhuyse V, Langewouters G, Decraemer W, Raman E, Buyle S. Elastic properties of human aortas in relation to age and atherosclerosis: A structural model. Phys Med Biol 40: 1577‐1597, 1995.
 155. Yin FC, Weisfeldt ML, Milnor WR. Role of aortic input impedance in the decreased cardiovascular response to exercise with aging in dogs. J Clin Invest 68: 28‐38, 1981.
 156. Zhang YH, Dunn ML, Drexler ES, McCowan CN, Slifka AJ, Ivy DD, Shandas R. A microstructural hyperelastic model of pulmonary arteries under normo‐ and hypertensive conditions. Ann Biomed Eng 33: 1042‐1052, 2005.
 157. Zieman SJ, Melenovsky V, Clattenburg L, Corretti MC, Capriotti A, Gerstenblith G, Kass DA. Advanced glycation endproduct crosslink breaker (alagebrium) improves endothelial function in patients with isolated systolic hypertension. J Hypertens 25: 577‐583, 2007.
 158. Zuckerman BD, Orton EC, Latham LP, Barbiere CC, Stenmark KR, Reeves JT. Pulmonary vascular impedance and wave reflections in the hypoxic calf. J Appl Physiol 72: 2118‐2127, 1992.
 159. Zuckerman BD, Orton EC, Stenmark KR, Trapp JA, Murphy JR, Coffeen PR, Reeves JT. Alteration of the pulsatile load in the high‐altitude calf model of pulmonary hypertension. J Appl Physiol 70: 859‐868, 1991.
 160. Zulliger MA, Rachev A, Stergiopulos N. A constitutive formulation of arterial mechanics including vascular smooth muscle tone. Am J Physiol Heart Circ Physiol 287: H1335‐H1343, 2004.

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Steven Lammers, Devon Scott, Kendall Hunter, Wei Tan, Robin Shandas, Kurt R. Stenmark. Mechanics and Function of the Pulmonary Vasculature: Implications for Pulmonary Vascular Disease and Right Ventricular Function. Compr Physiol 2012, 2: 295-319. doi: 10.1002/cphy.c100070