Pathophysiology of Vascular Function in CKD. INSERM U970 Hôpital Européen Georges Pompidou Paris

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1 Pathophysiology of Vascular Function in CKD Gérard M. London INSERM U970 Hôpital Européen Georges Pompidou Paris

2 Arterial Pathophysiology and Cardiovascular Diseases in CKD Systolic BP; Diastolic BP Arteriosclerosis Atherosclerosis (Decreased coronary perfusion) Adaptive LVH (Decreased coronary reserve) CORONARY ARTERY DISEASE Volume* Overload *Hgb; AVF; Na+ Maladaptive LVH Systolic/diastolic dysfunction HEART FAILURE SUDDEN DEATH CEREBROVASCULAR PERIPHERAL ARTERY DISEASE

3 Prevalence of discrete plaques on common carotid artery in control subjects and ESRD patients Controls ESRD Age (years) 48.5 ± ± 16 NS Plaques (%) 17.8% 56.3% < 0.01 Type of plaques Calcified 23.1% 91.5% <0.01 Soft/mixed 77% 9% <0.01 London et al Sem Dial 1999

4 Age related changes in arterial internal diameters Carotid artery diameter (mm) Age (years) Brachial artery diameter (mm) Age (years) Controls (r = 0.400; P < 0.01) Controls (r = 0.525;P < 0.01) ESRD (r = 0.438; P < ) ESRD (r = 0.277;P = 0.065) Controls ESRD patients

5 Evolution of Carotid diameter with progression of CKD stages Briet M. et al Kidney Int 2006

6 Age related changes in Carotid IMTh Common carotid art tery IMTh(mm) Age (years) Controls ESRD patients

7 Mechanical stresses in the blood vessel R σθ flow Q h circumferential wall stress sq = P x R h fluid shear stress t = 4 µ Q p R 3

8 Brachial artery characteristics Controls ESRD Baseline BA diameter (mm) 4.12 ± ± 0.11 < 0.01 BA compliance (m 2.kPa ) 0.45 ± ± 0.02 < 0.01 flow Q BA distensibility (kpa ) 3.5 ± ± 0.19 < BA incremental elastic modulus (kpa.10 3 ) 3.0 ± ± 0.42 < Baseline mean flow velocity (cm/s) 4.6 ± ± 0.30 < 0.01 Baseline mean flow (ml/min) 39 ± ± 3.6 NS Baseline mean SR (s 1 ) 53 ± ± 3.5 < 0.01 Baseline peak SR (s 1 ) 365 ± ± 26 < 0.05 Whole blood viscosity 3.57 ± ±0.06 <0.001 (cpoise) Baseline mean SS (dynes/cm 2 ) 19 ± ± 1.0 <0.001 Baseline peak SS (dynes/cm 2 ) 129 ± 9 83 ± 5 < Verbeke et al JASN 2007 t = 4 µ Q p R

9 Paracrine effect(s) of endothelial MPs predisposing to endothelial dysfunction in vivo Boulanger, C. M. et al. Hypertension 2006;48:

10 A. B CD144+ MPs (ev/µl) CD31+/41+ MPs (ev/µl) r = P < CD31+/41- MPs (ev/µl) Brachial artery shear stress (dynes/cm²) C. D r = P = Boulanger Ch et al Hypertension 2007 AnnexineV+ MPs (ev/µl) Brachial artery shear stress (dynes/cm²) r = P < r = P =

11 circumferential wall stress sq = P x R h 250 ESSYSTST T-Stress (kpa) Controls 100±16 ESRD patients 111±28 p<0.001 London GM (submitted)

12 Evolution of Carotid Circumferential wall stress with progression of CKD stages Briet M. et al Kidney Int 2006

13 0.26 Control population (n=104) Circumf.stress = 24.4± ESRD patients (n=163) Circumf.stress = 28.0±6.1 (p=0.027) Common Caro otid artery relative wall thic ckness (Th/r) R= P < R= P= Common Carotid artery systolic BP (mm Hg) London GM et al (submitted)

14 ESRD with absence of carotid artery calcifications ESRD with carotid artery calcifications Common Car rotid artery relative wall th hickness (Th/r) R= P = NS R= P< Common Carotid artery systolic BP (mm Hg) London GM et al (submitted)

15 Shroff et al Circulation 2008;118:

16 Control subjects ESRD patients ESRD carotid calcifications ESRD carotid calcifications + Common Carotid arter ry elastic modulus Common Carotid artery systolic BP (mm Hg) All categories P< London GM et al (submitted)

17 Evolution of Carotid elastic modulus with progression of CKD stages Briet M. et al Kidney Int 2006

18 **-** P < Age (years) Age (years) AGE vs HRPWV Aortic Pulse Wave Velocity (m/s) Brachial Pulse Wave Velocity (m/s) ** ** Aortic Pulse Wave Velocity (m/s) Age (years)

19 Aortic and arm pulse wave velocities as as function of age Pulse Wave ve elocity (m/s) 10 Arm Aorta Age Avolio et al Circulation 1983

20 Characteristics of arterial system in controls and ESRD patients Controls ESRD Peripheral/femoral PWV (m/s) 11.0 ± ±1.80 Age (years) 48.5 ± ± 16 Aortic PWV (m/s) 9.70 ± ±2.5**

21 1.00 Aortic PWV 1.00 Brachial PWV CV Survival χ²=72.8 P< >12 m/s Follow-up (months) 1.00 <9.7m/s >9.7 m/s CV Survival Femoral PWV χ²=1.78 P= Follow-up (months) st tertile 2nd tertile 3rd tertile CV Survival χ²=2.34 P= Follow-up (months) Pannier et al Hypertension 2005

22 Correlation between age and arterial calcium (Ca) concentration in the aorta and internal iliac artery in nonuremic control subjects Ca (mm mol/kg) * * * ** * ** * * * * * * * *** ** * ** * * ** *** * * * * Ibels et al. Am J Med Aorta (r=0.84) Internal Iliac (r=0.75) AGE (years)

23 Correlation between aortic calcification score and aortic PWV in ESRD patients 20.0 Aortic PW WV (ms) Abdominal aortic calcification score r = P < Pannier et al. Artery 2007

24 Aortic systolic BP (mm Hg) Diastolic BP (mm Hg) Aortic PWV (m/s) Aortic PWV (m/s) Aortic pulse pressure (mm Hg) Aortic PWV (m/s)

25 Common carotid artery Pulse pres. (mm Hg) R = P < Aortic PWV (m/s) Common carotid artery Pulse pres. (mm Hg) R = P < CCA Augmented pressure (mm Hg) (wave reflection) Common carotid artery Pulse pres. (mm Hg) R = P < Systemic reflection coefficient

26 Pressure wave analysis measured pressure wave forward/incident pressure wave reflected pressure wave pulse wave velocity

27 Reflected Wave SPTI DPTI SPTI DPTI

28 Correlation between left ventricular mass and aortic pulse wave velocity 200 Left ventricular mass (g/m 2 ) r = 0.52 p < London et al KI Aortic pulse wave velocity (cm/sec)

29 r = P< Aortic PWV (m/s) Subendocardial viability ration (DPTI/SPTI)

30 Arterial system as «hydraulic filter» Cyclic high and pulsatile pressure Continuous low pressure Pressure (mm Hg) Pressure (mm Hg) Aorta Microcirculation capillaries Flow (mls) Flow (mls) Cyclic highly pulsatile flow Continuous flow and perfusion

31 A. Systole In normally compliant arterial system important part of the stroke volume is stored in the arteries during ventricular systole stretching the arterial walls Left ventricle Arterial Compliance Peripheral Resistance B. Diastole During ventricular diastole the previously stretched arterial walls recoils with the stored volume insuring continuous perfusion of tissues and organs SYSTOL E Left ventricle Arterial Compliance Peripheral Resistance

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33 Oxygen Limitation Model Blood Velocity (NOT capillary recuitment) Capillary Transit Time Normally 2-3 seconds O 2 Extraction Smaller Fraction of O 2 Available for Metabolism

34 Hanon O et al. Stroke 2005;36:2193

35 Scuteri A et al. J Hypertens 2007;25:1035

36 Correlation Between CCr (C-G formula) and Aortic PWV Aortic PW WV (m/s) r = 0.30 P< Creatinine clearance (ml/min/m²) Bortolotto et al KI 2001

37 Arterial Impedance Gradients Zc-characteristic impedance; Zr-peripheral resistance Reflection Coefficient ( Γ) = Z Z R R - Z + Z C C = P P b f Zc P b P f Z R P t PWV=6 m/s PWV=10 m/s Pb P f P t PWV=12 m/s PWV=11 m/s Aorta Peripheral arteries Resistance vessels

38 Pressure transmission in the presence of arterial stiffness gradients 120 Pre essure mm Hg Incident pressure Reflected pressure Terminal pressure Aorta PWV 6 m/s Large arteries PWV=10 m/s Resistance vessels Microvascular network

39 Pressure transmission in low peripheral resistance organs (kidney; brain) when arterial stiffness gradient is decreased or abolished 140 Pre essure mm Hg Reflected pressure Incident pressure Reflected pressure Terminal pressure Aorta PWV 11 m/s Large arteries PWV=10 m/s Resistance vessels Microvascular network

40 Systemic Reflecti ion Coefficient r= P< London GM (submitted) (Aortic PWV/Brachial PWV) 0.5

41 0.95 Systemic reflect tion coefficient r = P < Age (years) London GM (submitted)

42 r = P = Age (years) Distance from the aortaa to reflecting sites ( % of body height ) London GM (submitted)

43 Characteristics of arterial system in controls and ESRD patients Controls ESRD Forward pressure (mm Hg) 38 ± ± 16** Wave reflection (% of PP) 17 ±17 25 ±15*** Reflected pressure (mm Hg) 11 ± 6 14 ± 8* Reflected wave arrival time (ms) 128 ± ± 16** Zr (dynes.s.cm-5) 2309 ± ±1175 Zc (dynes.s.cm-5) 179 ± ±103** Γ (reflection coefficient) 0.85 ± ±0.06** Aortic PWV (m/s) 9.70 ± ±2.5** Peripheral/femoral PWV (m/s) 11.0 ± ±1.80 *P<0.05; **P<0.01; ***P<0.001 ESRD: fmin=4.62hz ; Control: fmin=3.90hz

44 1.8 P < 0.01 Aortic PWV/fem moral PWV (ratio) Controls 0.84±0.15 ESRD 0.97±0.25

45 Schematic representation of reactive hyperemic response in the human forearm after five minutes of ischemia Forearm blood flow ml/100 ml/min * * ** * * A = Flow debt ml/100 ml Peak flow * * * Flow debt repayment=b/a B = Excess hyperemic flow ml/100ml Duration of hyperemia * ** *** * * ** ** * ** * baseline occlusion postocclusion Time,min

46 AoPWV (M/S) AoPWV (M/S) 0 Flow debt repayement (%) Duration of vasodilation (s) Minimal resistance (arbitrary units) AoPWV (M/S) AoPWV (M/S) Maximal blood flow (% from baseline)

47 Postischemic Flow debt repayement (%) r = P < Systemic Reflection Coefficient London GM (submitted)

48 Arterial changes in CKD Premature Aortic Aging: increased diameter and stiffness. Accelerated in the presence of calcifications Lost or Impairement of Hydraulic Filter : high Systolic and Pulse pressure in Aorta and Central arteries (LVH poor Coronary perfusions), and abnormal pressure transmission to microcirculation (impaired vasodilation)

49 Common Carotid Pulse Pressure and Cardiovascular mortality in ESRD patients (log rank p<0.0001) 1.00 Cardiovascu ular free events PPcc <50 mm Hg PPcc 75 mm Hg PPcc 70 mm Hg Cox model: P= adjusted for age and mean BP P<0.05 P<0.001 P< Follow-up (months) Safar et al Hypertension 2002

50 Aorta Peripheral artery Amplification Aix Aix (mm Hg) Tsh recorded wave forward wave reflected wave

51 Superimposed simultaneous phasic recording of aortic (Ao), left ventricular (LV) pressures and coronary blood flow (CBF) (Buckeberg et al. Circ Res. 1972) BP (m mmhg) STTI DPTI Ao LV STTI DPTI Ao LA or PA Wedge 100 CBF (ml/min)

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53 Effects of age on arterial stiffness and wave reflections For males (circle and solid lines) and females (squares and dashed line) Augmentation index Augmented pressure Carmel M. McEniery et al.jacc 2005;46:1753

54 Controls 1.76±0.24 P = 0.03 ESRD 1.64±0.3 Aortic tapering (Aortic root/aortic bifurcation)

55 AoPWV (M/S) AoPWV (M/S) 0 Flow debt repayement (%) Duration of vasodilation (s) Minimal resistance (arbitrary units) AoPWV (M/S) AoPWV (M/S) Maximal blood flow (% from baseline)

56 Flow debt repayement (%) Time to flow debt repayement (s) (AoPWV/FTPWV) (AoPWV/FTPWV) Maximal blood flow (% from baseline) (AoPWV/FTPWV) 0.5

57 Postischemic Flow debt repayement (%) r = P < Systemic Reflection Coefficient London GM (submitted)

58 Clinical Characteristics Controls (n=59) ESRD (n=121) P-value Age (yrs) 48±13 51±15 NS Weight (kg) 76±15 64±13 < Height (m) 1.70± ±0.11 <0.001 Systolic BP ( mmhg) 144±21 152± Diastolic BP (mm Hg) 86±14 83±15 NS Mean BP (mm Hg) 105±15 106±18 NS Pulse Pressure (mm Hg) 58±15 68±24 <0.0001

59 Coronary Artery Calcification in Young Dialysis Patients Calcificati ion Score* N= *Determined by EBT Age (years) Goodman WG et al. N Engl J Med. 2000;342: Calcification scores nearly doubled in a majority of patients with positive initial scan when 59 rescanned at 20 months

60 Effect of arterial stiffness on timing of forward and reflected Waves PWV 8 m/sec PWV 12 m/sec Negative Aix Positive Aix Systolic Augmentation Pressure (Aix). T T Forward-traveling wave Backward-traveling reflected wave Actual (composite) wave T - traveling time of pressure wave to reflecting sites and back

61 Pressure wave analysis measured pressure wave forward/incident pressure wave reflected pressure wave pulse wave velocity

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63 Oxygen Limitation Model Blood Velocity (NOT capillary recuitment) Capillary Transit Time Normally 2-3 seconds O 2 Extraction Smaller Fraction of O 2 Available for Metabolism

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65 1.8 P < 0.01 Aortic PWV/fem moral PWV (ratio) Controls 0.84±0.15 ESRD 0.97±0.25

66 Controls 1.76±0.24 P = 0.03 ESRD 1.64±0.3 Aortic tapering (Aortic root/aortic bifurcation)

67 AoPWV (M/S) AoPWV (M/S) 0 Flow debt repayement (%) Duration of vasodilation (s) Minimal resistance (arbitrary units) AoPWV (M/S) AoPWV (M/S) Maximal blood flow (% from baseline)

68 Femoral artery PWV (m/s) (AoPWV/FTPWV) 0.5 Time to flow debt repayement (s) (AoPWV/FTPWV) Maximal blood flow (% from baseline) (AoPWV/FTPWV) 0.5

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70 Traub, O. et al. Arterioscler Thromb Vasc Biol 1998;18:

71 Mechanical stresses in the blood vessel R σθ flow Q h circumferential wall stress sq = P x R h fluid shear stress t = 4 µ Q p R 3

72 Postischemic Flow debt repayement (%) r = P < Systemic Reflection Coefficient London GM (submitted)