Structural abnormalities of the heart and vascular system in CKD & Dialysis - Thick but weak

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1 Structural abnormalities of the heart and vascular system in CKD & Dialysis - Thick but weak Kerstin Amann Nephropathology, Dept. of Pathology, University of Erlangen-Nürnberg Krankenhausstr Erlangen, Germany

2 Cardiovascular pathology in CKD LVH atherosclerosis calcification fibrosis microarteriopathy reduction in capillarisation arteriosclerosis

3 Cardiovascular pathology in CKD - crosstalk between kidney and cardiovascular system LVH cardiac fibrosis impaired angioadaptation with reduced ischemia tolerance (role of VEGF and the sympathetic nervous system) accelerated arterio- and atherosclerosis (calcification and inflammation)

4 Cardiovascular pathology in CKD - crosstalk between kidney and cardiovascular system LVH: is very common and develops early on in CKD cardiac fibrosis impaired angioadaptation with reduced ischemia tolerance (role of VEGF and the sympathetic nervous system) accelerated arterio- and atherosclerosis (calcification and (micro-) inflammation)

5 Prevalence of LV disorders in CKD 16% normal LV 40% systolic sysfunction 16% LV dilatation concentric LVH 28% 84% of patients starting dialysis already show LV alterations time until development of end-stage heart failure (Parfrey et al, NDT 1996)

6 Uremic cardiomyopathy / cardiomyopathy in advanced CKD control CKD

7 Relative heart weight and left ventricular weight g/kg * * rel. heartweight (g/kg) rel. left ventricular weight (g/kg) * * 0 control (n=9) hypertension (n=9) uremia (n=9) (Amann et al, JASN 1998) (*:p<0.05 vs uremia)

8 Morphology of the myocardium in experimental CKD sham SNX LVH already present after 3 weeks (20-60% increase in LV weight) LV contractility: - 40% prevented and reversed (!) by ACE-i and mtor inhibition

9 LVH in SNX is accompanied by increased apoptosis and loss of cardiomyocytes SNX sham sham (n=10) * * SNX (n=8) number of myocytes per heart number of myocytes per volume myocardium Nakamura et al. 2010: cyclin D2, PCNA, CDK-inhibitor p27 (as novel markers of LVH) myocyte loss (-25%) in CKD predisposes to cardiac failure! experimentally prevented by ACE-i and mtor inhibition! (Amann Kidney Int 2003)

10 Cardiovascular pathology in CKD - crosstalk between kidney and cardiovascular system LVH cardiac fibrosis impaired angioadaptation with reduced ischemia tolerance (role of VEGF and the sympathetic nervous system) accelerated arterio- and atherosclerosis (calcification and (micro-) inflammation)

11 Increased volume density of the myocardial interstitial tissue in CKD *:p<0.05 vs uremia sham (%) * * SNX 5 0 control (n=9) hypertension (n=9) uremia (n=9) TGF- mrna early and specific activation of myocardial interstitial cells in CKD pathogenetic role of PTH, P, AngII and ET-1 (via TGF-ß) (Amann et al. JASN 1998)

12 Functional consequences of cardiac fibrosis reduced LV compliance altered stress strain relationship arrhythmia - interposition of fibrous tissue with high electrical resistance - local delay in spread of action potential - reentry type of arrhythmia sudden cardiac death

13 Cardiovascular pathology in CKD - crosstalk between kidney and cardiovascular system LVH cardiac fibrosis FGF23, a new kid on the block? impaired angioadaptation with reduced ischemia tolerance (role of VEGF and the sympathetic nervous system) accelerated arterio- and atherosclerosis (calcification and inflammation)

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15 (JCI 2011)

16 synergy of highphosphate diet, Klotho deficiency and aging on cardiac remodelling (JASN 2015)

17 + cardiac fibrosis - CKD

18 Cardiovascular pathology in CKD - crosstalk between kidney and cardiovascular system LVH cardiac fibrosis impaired angioadaptation with reduced ischemia tolerance (role of VEGF and the sympathetic nervous system) accelerated arterio- and atherosclerosis (calcification and (micro-) inflammation)

19 Decrease of myocardial capillarisation in CKD control patient mm/mm * *: p<0.05 vs uremia CKD patient * control (n=9) hypertension (n=9) uremia (n=9) (Amann et al. JASN 1998)

20 Myocyte-capillary mismatch in experimental CKD sham SNX - 25% reduction of capillary supply (can be prevented by blockade of the sympathetic nervous system and the ET system!)

21 Capillary rarefaction in SNX leads to increased myocardial damage after coronary artery ligation sham SNX Area of infarction (in % LV) : 18.8 ± 6.6 % in sham 30.6 ± 6.7 % in SNX (p<0.05) reduced myocardial ischemia tolerance in SNX! (Dikow et al, JASN 2004)

22 LDPI-ratio (hindpaw) Vascular maladaption in CKD under ischemic conditions sham SNX -25% 1.1 sham vs SNX, p<0.05 sham sham vs. SNX p= SNX 0.3 pre-op day1 day14 (Amann et al. 1992, 1996, 2000, Jacobi et al. 2005) sham SNX

23 Lack of adaptive VEGF-regulation in CKD under ischemic conditions (LVH and hind-limb) sham SNX VEGF mrna VEGF-protein 0,45 0,4 0,35 0,3 0,25 0,2 0,15 0,1 0,05 0 sham * 15 * * snx SNX sham SNX

24 anti-angiogenic effect of CKD serum with apoptosis of EC and (JASN NO 2009)

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26 Elevated sflt-1 levels reduce capillary density in the heart

27 Cardiovascular pathology in CKD - crosstalk between kidney and cardiovascular system LVH cardiac fibrosis impaired angioadaptation with reduced ischemia tolerance (role of VEGF and the sympathetic nervous system) accelerated arterio- and atherosclerosis (calcification and (micro-) inflammation)

28 Accelerated arteriosclerosis in CKD - Uremic arteriopathy fibrous or fibroelastic intimal thickening Epigastric artery of a 46y old patient at the time of renal transplantation

29 Wall thickening of coronary arteries in CKD mm 2 Control nierengesund 0,25 0,2 * * CKD chron. NI control 0,15 0,1 0,05 0 media thickness Mediadicke intima thickness Intimadicke CKD (Schwarz et al., NDT 2000)

30 Arterial wall thickening in CKD is acompanied by ultrastructural changes Normal morphology of aortic media (sham) Media thickening with hyperplasia of VSMC, increased ECM and reduced elastic fibre content (SNX) reduced vascular elasticity, increased vascular wall stiffness, RR, LVH, calcification (Amann et al., Am J Hypertens 1995)

31 Atherosclerosis in CKD? more common? more severe? specific characteristics?

32 Atherosclerosis in CKD number of cases no renal disease (n=27) renal disease (n=27) Ca x P Type I Type II Type III Type IV Type V Type VI Type VII Type VIII X-ray diffraction analysis of coronary plaques (Schwarz pro-inflammatory et al., 2000) phenotype of atherosclerotic plaques in CKD!

33 Cardiovascular pathology in CKD LVH atherosclerosis calcification fibrosis microarteriopathy reduction in capillarisation arteriosclerosis

34 Phenotypic alterations in uremia Intradialytic hypotension (Smith et al. 2009)

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36 Thank you very much! Glomunculus