Remodelling

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

4. Rearrangement Suppose 20% of material moves, but cross sectional area of media remains constant • If material moves from inside to outside: • Wall thickness  by 2% • Lumen area  4% • Circumferential stress  by 4% • Can sustain pressure  of 4% • 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. CHEMICAL COMPOSITION Consequences of remodelling MATERIAL E STIFFNESS inc STRUCTURE E h / R p FUNCTIONAL GEOMETRY STIFFNESS JUNCTIONS/ Z DISEASE C ELASTIC WAVE Pulsatile RESERVOIR REFLECTION HEART WORK Steady PERIPHERAL SMOOTH RESISTANCE MUSCLE

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

7. Pig pulmonary artery

9. 1.4 Pressure Flow 1.2 1.0 P and Q/Wt (relative to 1h values) 0.8 0.6 0.4 1D 2D 4D 1W 2W 4W 0.2 1 10 100 1000 Age (hr)

11. 40 Total Steady 30 Pulsatile 20 10 0 0 200 400 600 800 Right Heart Power [mW/kg] Age [hr]

12. 3 days 3 months

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

14. Change in flow  Change in lumen radius Shear Stress (µ Q/r3) less shear Intimal hyperplasia Q  radius  Stress normalised 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. Ring Freeze Freeze + Ring Distal/Proximal Time since treatment [days]

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

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

25. Methods • 30 four week old male Wistar rats • Left renal artery clipped, contralateral kidney untouched • 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 • Animals killed at age 9 weeks.Vasculature fixed at pressure of 100mmHg

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

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

28. Heart weight / body weight 0 . 0 0 7 0 p < 0.0001 0 . 0 0 6 5 0 . 0 0 6 0 0 . 0 0 5 5 0 . 0 0 5 0 0 . 0 0 4 5 0 . 0 0 4 0 0 . 0 0 3 5 1 2 5 1 5 0 1 7 5 2 0 0 2 2 5 2 5 0 Systolic BP (mmHg)

29. Medial thickness (mm) 0 . 1 4 p < 0.004 T h o r a c i c A o r t a 0 . 1 2 p < 0.003 A b d o m i n a l a o r t a p < 0.002 R i g h t r e n a l a r t e r y 0 . 1 0 0 . 0 8 0 . 0 6 0 . 0 4 0 . 0 2 0 0 1 2 0 1 4 0 1 6 0 1 8 0 2 0 0 2 2 0 2 4 0 2 6 0 1 Caudal artery systolic BP (mmHg)

30. p < 0.0002 T h o r a c i c A o r t a p < 0.05 A b d o m i n a l a o r t a R i g h t r e n a l a r t e r y p < 0.0008 Medial cross-sectional area (mm2) 0 . 9 0 . 8 0 . 7 0 . 6 0 . 5 0 . 4 0 . 3 0 . 2 0 . 1 0 . 0 1 0 0 1 2 0 1 4 0 1 6 0 1 8 0 2 0 0 2 2 0 2 4 0 2 6 0 Caudal artery systolic BP (mmHg)

31. T h o r a c i c A o r t a Lumen area (mm2) A b d o m i n a l a o r t a R i g h t r e n a l a r t e r y 3 . 0 2 . 5 2 . 0 1 . 5 1 . 0 0 . 5 0 1 0 0 1 2 0 1 4 0 1 6 0 1 8 0 2 0 0 2 2 0 2 4 0 2 6 0 Caudal artery systolic BP (mmHg)

32. NS T h o r a c i c A o r t a p < 0.02 A b d o m i n a l a o r t a NS R i g h t r e n a l a r t e r y Mean circumferential stress MNm-2 0.30 0.25 0.20 0.15 0.10 1 0 0 1 2 0 1 4 0 1 6 0 1 8 0 2 0 0 2 2 0 2 4 0 2 6 0 Caudal artery systolic BP (mmHg)

33. Number of cells per 5µm section 4 0 0 0 T h o r a c i c A o r t a 3 0 0 0 A b d o m i n a l a o r t a R i g h t r e n a l a r t e r y 2 0 0 0 1 0 0 0 0 1 0 0 1 2 0 1 4 0 1 6 0 1 8 0 2 0 0 2 2 0 2 4 0 2 6 0 Caudal artery systolic BP (mmHg)

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

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?