Structural abnormalities of the heart and vascular system ... · Structural abnormalities of the...
Transcript of Structural abnormalities of the heart and vascular system ... · Structural abnormalities of the...
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. 8-10
91054 Erlangen, Germany
Cardiovascular pathology in CKD
LVH
fibrosis
reduction in capillarisation
atherosclerosis
microarteriopathy
arteriosclerosis
calcification
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)
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)
Prevalence of LV disorders in CKD
16%
16%
28%
40%
normal LV
systolic sysfunction
LV dilatation
concentric LVH
(Parfrey et al, NDT 1996)
time until development
of end-stage heart failure 84% of patients starting dialysis
already show LV alterations
„Uremic cardiomyopathy“ /
cardiomyopathy in advanced CKD
CKD
control
Relative heart weight and left ventricular
weight
0
1
2
3
4
5
6
7
8
9
10
control (n=9) hypertension (n=9) uremia (n=9)
g/kgrel. heartweight (g/kg)
rel. left ventricular
weight (g/kg)*
*
*
*
(*:p<0.05 vs uremia) (Amann et al, JASN 1998)
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
0
5000000
10000000
15000000
20000000
25000000
30000000
number of myocytesper heart
number ofmyocytes per volume
myocardium
sham (n=10)
SNX (n=8)**
LVH in SNX is accompanied by increased
apoptosis and loss of cardiomyocytes
sham SNX
(Amann Kidney Int 2003)
→ myocyte loss (-25%) in CKD predisposes to cardiac failure !
→ experimentally prevented by ACE-i and mTOR inhibition!
Nakamura et al. 2010:
↑cyclin D2, ↑PCNA, CDK-inhibitor
p27 (as novel markers of LVH)
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)
Increased volume density of the
myocardial interstitial tissue in CKD
0
5
10
15
20
25
30
35
control (n=9) hypertension (n=9) uremia (n=9)
(%)
*
*
*:p<0.05 vs uremia
(Amann et al. JASN 1998)
→ early and specific activation of myocardial interstitial cells in CKD
→ pathogenetic role of PTH, P, AngII and ET-1 (via TGF-ß)
sham
SNX
TGF- mRNA
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
Cardiovascular pathology in CKD - crosstalk
between kidney and cardiovascular system
LVH
FGF23, a new kid on the block ?
cardiac fibrosis
impaired angioadaptation with reduced ischemia tolerance (role of VEGF and the sympathetic nervous system)
accelerated arterio- and atherosclerosis (calcification and inflammation)
(JCI 2011)
(JASN 2015)
synergy of high-
phosphate diet,
Klotho deficiency
and aging on car-
diac remodelling
+ cardiac fibrosis
- CKD
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)
Decrease of myocardial capillarisation
in CKD
control
patient
CKD
patient
0
500
1000
1500
2000
2500
3000
3500
4000
control (n=9) hypertension (n=9) uremia (n=9)
*
mm/mm3
*
*: p<0.05 vs uremia
(Amann et al. JASN 1998)
Myocyte-capillary mismatch in
experimental CKD
SNX sham
→ - 25% reduction of capillary supply
(can be prevented by blockade of the sympathetic nervous system and
the ET system !)
Capillary rarefaction in SNX leads to increased
myocardial damage after coronary artery ligation
(Dikow et al, JASN 2004)
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 !
sham
SNX
Vascular maladaption in CKD under ischemic
conditions
sham SNX
-25%
LD
PI-
rati
o
(hin
dp
aw
)
sham vs SNX, p<0.05
0.3
0.5
0.7
0.9
1.1
sham vs. SNX
p=0.014
pre-OP day1 day14
sham SNX (Amann et al. 1992, 1996, 2000, Jacobi et al. 2005)
sham
SNX
Lack of adaptive VEGF-regulation in CKD
under ischemic conditions (LVH and hind-limb)
sham SNX
0
0,05
0,1
0,15
0,2
0,25
0,3
0,35
0,4
0,45
sham SNX
* *
0
5
10
15
20
25
30
35
40
45
sham snx
*
sham sham SNX SNX
VEGF mRNA VEGF-protein
(JASN 2009) → anti-angiogenic effect of CKD serum with ↑apoptosis of EC and NO
Elevated sFLT-1 levels reduce capillary density
in the heart
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)
Accelerated arteriosclerosis in CKD -
Uremic arteriopathy
fibrous or fibro-
elastic intimal
thickening
Epigastric artery of a 46y old patient at the time of renal transplantation
Wall thickening of coronary arteries in CKD
control
CKD
0
0,05
0,1
0,15
0,2
0,25
Mediadicke Intimadicke
mm2 nierengesund
chron. NI**
(Schwarz et al., NDT 2000)
Control
CKD
media thickness intima thickness
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)
(Amann et al., Am J Hypertens 1995)
→ reduced vascular elasticity, increased vascular wall stiffness,
RR ↑, LVH ↑ , calcification ↑
Atherosclerosis in CKD ?
more severe ? more common ?
specific characteristics ?
Atherosclerosis in CKD
0
2
4
6
8
10
12
14
16
18
20
Type I Type II Type
III
Type
IV
Type
V
Type
VI
Type
VII
Type
VIII
number of
casesno renal disease
(n=27)
renal disease
(n=27)
(Schwarz et al., 2000)
X-ray diffraction analysis of
coronary plaques
Ca x P
→ pro-inflammatory phenotype of atherosclerotic plaques in CKD !
Cardiovascular pathology in CKD
LVH
fibrosis
reduction in capillarisation
atherosclerosis
microarteriopathy
arteriosclerosis
calcification
Phenotypic alterations in uremia
(Smith et al. 2009)
Intradialytic hypotension
Glomunculus
Thank you
very much !