1. Remodelling Ability of living tissue to adapt to its environment by changing its shape and structure Modifies mechanical properties Driven by tendency to maintain ‘optimal’ levels of stress and strain

2. The Response of Conduit Arteries to Chronic Changes in Pressure and Flow Remodelling: Chemical Cellular Morphological

3. If material added to outer surface: Wall thickness  by 19% Lumen area remains constant Circumferential stress  by 16% Can sustain pressure  of 16% Hypertrophy Suppose cross sectional area of media increases by 20% If material added to inner surface Wall thickness  by 21% Lumen area  by 4% Circumferential stress  by 19% Can sustain pressure  of 19%

4. If material moves from inside to outside: Wall thickness  by 2% Lumen area  4% Circumferential stress  by 4% Can sustain pressure  of 4% Rearrangement Suppose 20% of material moves, but cross sectional area of media remains constant If material moves from outside to inside: Wall thickness  by 2% Lumen area  by 4% Circumferential stress  by 4% Can sustain pressure  of 4%

5. SMOOTH MUSCLE WAVE REFLECTION HEART WORK MATERIAL STIFFNESS STRUCTURE ELASTIC RESERVOIR PERIPHERAL RESISTANCE FUNCTIONAL STIFFNESS GEOMETRY h / R JUNCTIONS/ DISEASE E inc E p Z C CHEMICAL COMPOSITION Pulsatile Steady Consequences of remodelling

6. Physiological Perinatal changes in: Pulmonary artery/aorta Aortic scleroprotein Internal/external iliac Distribution of intercellular junctionsPathological Hypertension Atheroma Growth retardation in early life P.S.D. Ageing Residual stress Large/small vessel differences in: Elasticity Scleroprotein Causes of Remodelling

7. Pig pulmonary artery

9. 1000100101 0.2 0.4 0.6 0.8 1.0 1.2 1.4 Pressure Flow Age (hr) P and Q/Wt (relative to 1h values) 1D2D4D1W2W4W

11. 8006004002000 0 10 20 30 40 Pulsatile Steady Total Age [hr] Right Heart Power [mW/kg]

12. 3 days3 months

13. “Pathological” remodelling of arteries l Pressure (circumferential stress or strain) –VSMC hypertrophy and or hyperplasia –Collagen (Elastin) synthesis l Flow (shear stress or strain) –Endothelial cell mediated –VSMC migration and proliferation –Intimal hyperplasia and hypertrophy l Mechanical damage –Combination of the two factors above –Acute or chronic

14. Shear Stress (  Q/r 3 ) less shearIntimal hyperplasia radius  Stress normalised Q  Change in flow  Change in lumen radius Optimal shear stress 15 dyne cm -2. (Glagov, S. et al. Frontiers of Medical & Biological Engineering, 1993. 5: 37-43.)

16. Post stenotic dilatation

18. Silver, super glue and X-rays

20. Topical application of nor-adrenalin before freezing

21. Nor-adrenaline after freezing

22. Distal/Proximal Time since treatment [days] Ring Freeze Freeze + Ring

23. Circumferential Stress (= Pr/h) Increased stretch Synthesis of protein etc. wall thickness  Stress normalised P  Change in Pressure  Change in medial thickness

24. Is there a relationship between the severity of hypertension and the degree of remodelling?

25. Methods l 30 four week old male Wistar rats l Left renal artery clipped, contralateral kidney untouched l Caudal artery systolic pressure measured using tail cuff and optical sensor –Three measurements made on separate days between 4 and 5 weeks after clipping, then averaged l Animals killed at age 9 weeks.Vasculature fixed at pressure of 100mmHg

26. l Tissue samples taken from –Thoracic aorta (5mm distal to 4th intercostal space) –Abdominal aorta ( 5mm proximal to external iliac branch) –Right renal artery l Paraffin embedded l 5µm sections cut and stained –Miller’s elastic stain for morphometry –Ehrlich’s haematoxylin for counting cell nuclei

27. Medial cross sectional area VSMC in outer half VSMC in inner half of media Lumen cross sectional area Medial thickness Mean values derived from measurements on 4 rectangular areas shown Morphometry

29. Medial thickness (mm) 0.02 0.04 0.06 0.08 0.10 0.12 0.14 1 00120140160180200220240260 Abdominal aorta Right renal artery Thoracic Aorta p < 0.004 p < 0.003 p < 0.002 Caudal artery systolic BP (mmHg)

30. 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 100120140160180200220240260 Thoracic Aorta p < 0.0002 Abdominal aorta p < 0.05 Right renal artery p < 0.0008 Medial cross-sectional area (mm 2 ) Caudal artery systolic BP (mmHg)

32. 100120140160180200220240260 0.15 0.20 0.25 0.10 0.30 Thoracic Aorta NS Abdominal aorta p < 0.02 Right renal artery NS Mean circumferential stress MNm -2 Caudal artery systolic BP (mmHg)

33. 0 1000 2000 3000 4000 100120140160180200220240260 Number of cells per 5µm section Abdominal aorta Right renal artery Thoracic Aorta Caudal artery systolic BP (mmHg)

34. 0 10 20 30 40 50 60 Number of cells/ 5µm section TAAARR Vessel Outer half Inner half

35. Summary & Conclusions Vascular response - hypertrophic in nature Correlates with the severity of hypertension No hyperplasia No difference in cell numbers between inner and outer halves of the aortic media Circumferential stress increases non significantly with hypertension in thoracic aorta and renal artery Significant increase in abdominal aorta Shear stress remains constant?