Download The heart in concert: do other organs matter?

The heart in concert:
do other organs matter?
Gut in heart failure
Dr Anja Sandek
Applied Cachexia Research, Dpt. of Cardiology,
Charite-University Medical School, Berlin,
Germany, Campus Virchow-Clinic
No conflicts of interest or financial disclosures to declare
Overview
Inflammation in Chronic heart failure (CHF)
 Role of the gut
Gut morphology
 Arterial blood flow
 Bowel wall thickness
 Histology
Gut function
 Symptoms
 Intestinal barrier & absorption
 Cachexia
Inflammation in CHF
 CHF patients have levels of proinflammatory cytokines that
predict poor survival.
Levine et al., N Engl J Med 1990, Rauchhaus et al., Circulation 2000
 The sources of inflammation are not well understood.
 Translocation of bacterial endotoxin may contribute to this
inflammation.
Anker et al., Am J Cardiol 1997, Niebauer et al., Lancet 1999
Translocation of bacterial endotoxin
Monocytes
Hormones
LPS
CD 14
- circulating
- in tissues
(heart,
periphery)
Tissue Hypoxia
TLR 4
Thoracic
Duct
Bacteria or LPS
Portal
Vein
Anker SD et al., Am J Cardiol 1997
Gut Wall
Release of:
IL-1, IL-6, IL-8, IL-10
IFN-g TGF-b, TNF,
chemokines,
adhesion
molecules
Niebauer et al., Lancet 1999
Bacterial endotoxin in edematous heart failure
Variable
TNF [pg/mL]
sTNF-R1 [pg/mL]
sTNF-R2 [pg/mL]
LPS [EU/mL]
Controls
(n=8)
2.3  0.3
966  80
1785  219
0.37  0.03
p-Value
non-edematous
controls vs.
patients (n=8)
non-edematous
0.3
0.2
0.09
0.1
3.0  0.4
1605  380
2849  472
0.31  0.01
p-Value
non-edematous
vs. edematous
0.03
0.03
0.06
0.0009
edematous
CHF (n=12)
4.4  0.5
2611  343
3875  366
0.46  0.04
p-Value
edematous
vs. controls
0.003
0.002
0.001
0.056
Edema
=
Highest blood LPS
=
Inflammation
Sandek A, Bjarnason I, Anker SD et al. Int J Cardiol. 2010
Cardio-intestinal syndrome
Cardio-intestinal syndrome
Inflammation
endothelial
dysfunction
Myocardium
contractility
apoptosis
Congestion
intestinal
microcirculation
LPS decreases after recompensation
baseline
after diuretic treatment
Edematous gut wall & Epithelial dysfunction
Translocating LPS
Niebauer J et al., Lancet, 1999 & Sandek A, Bjarnason I, Anker SD et al., Int J Cardiol. 2010
Mesenteric ischaemia during exercise in CHF
patients
controls
 tonometry during rest and exercise stress testing
Higher intragastric PCO2 (iPCO2) in patients with CHF
Krack A, Richartz BM, Gastmann A, et al., Eur J Heart Fail. 2004
Lower intestinal arterial blood flow
Superior mesenteric artery
Inferior mesenteric artery
Mean systolic flow mL / min
Mean systolic flow mL / min
1000
p<0.0002
800
180
p<0.0001
p<0.002
800
60
200
0
2000
1200
100
400
Mean systolic flow mL / min
1600
140
600
Coeliac trunk
400
controls
n=24
CHF
n=63
20
0
controls
n=23
CHF
n=53
0
controls
n=21
CHF
n=53
The same applies to peak systolic arterial flow in all 3 vessels (all p< 0.002).
Sandek A, Bauditz J, Anker SD et al., in submission
Higher Bowel Wall Thickness in CHF
Bowel wall thickness [mm]
6
CHF
p<0.006
p<0.004
Controls
5
p<0.007
p<0.009
4
p=0.001
3
2
1
n=23
0
n=59
Terminal
Ileum
n=23
n=61
Ascending
Colon
n=23
n=60
Transverse
Colon
n=23
n=62
Descending
Colon
n=24
n=64
Sigmoid
Sandek A, Bauditz J, Swidsinski A et al., JACC 2007
Histology
Collagen accumulation in the small intestine
CHF patient
Relative area
occupied by
collagen [%]
Control subject
controls NYHA I-II NYHA III-IV cachexia
n=18
n=18
n=9
n=18
Distance between
the basal wall of
the enterocyte &
the capillary wall
[µm]
controls
n=18
NYHA I-II NYHA III-IV cachexia
n=18
n=9
n=18
Greater relative collagen
area correlated with lower
percentage of body fat
(r = − 0.88, p < 0.05).
Arutyunov GP, et al., Int I Cardiol. 2008
Histology
Higher concentration of bacteria in mucosal biofilm in CHF
Highly colonised
large intestinal mucosa
CHF patient
Low colonised
large intestinal mucosa
Control subject
Sandek A, Bauditz J, Swidsinski A et al., JACC 2007
Histology
Higher adherence of bacteria to the mucosa in CHF
Concentration of bacteria (mL-1)
1012
1011
Bacteria in CHF are more
often adherent to the mucosa
(70% vs. 36%, p=0.03).
1010
Bacteria in CHF range over
a higher mean biofilm area
(35.5% ± 8.2% vs. 10.2 ± 3.7%,
p=0.006).
109
108
107
Serum IgA anti-LPS-antibodies
are higher in CHF (p=0.005).
106
105
104
Controls
(n=22)
CHF
(n=20)
Sandek A, Bauditz J, Swidsinski A et al., JACC 2007
Function
Additional gastrointestinal symptoms in CHF
Patients
n=59
Controls
n=18
p-value
Burping
Murmours from the intestine
25 % (15/59)
58 % (34/59)
0 % (0/18)
28 % (5/18)
0.016
0.027
Feelings of repletion
59 % (34/58)
22 % (4/18)
0.014
Flatulences
73 % (43/59)
44 % (8/18)
0.03
Bowel wall thickness sigmoid [mm]
p=0.03
5
Wall thickness descending colon [mm]
p=0.04
4
4
3
3
2
2
1
1
0 no murmors murmors
0 no murmors murmors
(n=25)
(n=34)
(n=25)
(n=34)
Sandek A, Bauditz J, Anker SD et al., in submission
Function
Intestinal barrier & absorption
Lumen
D-Xylose
3-OMG
(passive carrier)
(active carrier)
Sucrose, Lactulose,
Mannitol, Sucralose
(no carrier)
Function
Altered intestinal permeability in CHF
Permeability
Method
change p-value
Sucrose
0.7
Paracellular:
Gastroduodenum
Small intestine
Large intestine
Lactulose/Mannitol 21%
0.047
Sucralose
210%
0.04
Xylose
29%
0.003
Transcellular:
Carriermediated transport
Sandek A, Bauditz J, Swidsinski A et al., JACC 2007
Function
Reduced active and passive transport in CHF
Edematous patients
=
lowest
carrier-mediated transport
Sandek A, Bjarnason I, Anker SD et al. Int J Cardiol. 2010
Function
Lower protein and fat absorption in CHF
30
Fat, protein, %
25
20
protein
15
fat
10
5
0
controls
n=18
NYHA I-II
n=18
NYHA III-IV
n=18
cachexia
n=9
Protein loss
related to small intestinal fibrosis, r=0.9, p<0.05
Fat loss
adapted from Arutyunov GP, Kostyukevich OI, Serov RA et al., Int I Cardiol. 2008
Function
Nutritional deficiencies in CHF
intestinal
dysfunction
catecholamines
& cytokines
TNF, IL-1
diuretics
Malabsorption
Chronic
hypermetabolism
Inhibition
of food
intake
Loss of B
vitamin,
magnesium,
selenium,
calcium
Nutritional deficiencies in CHF
Wasting is a risk factor for mortality in CHF
CHF patients
13%
malnourished
59.6% at risk of malnutrition
27.4% normal nutritional status
Bonilla-Palomas JL, et al., Rev Esp Cardiol., 2011
16%
cachectic
Anker SD, Ponikowski P, Coats AJ, et al. Lancet, 1997
Conclusions I
 CHF is associated with impaired tissue perfusion
in the intestinal vascular bed.
 CHF is associated with a greater bowel wall
thickness.
 Patients with CHF show a greater bacterial biofilm
and higher level of IgA-LPS-antibodies.
Conclusions II
 Patients with CHF show an increased intestinal
permeability and a reduced specific intestinal absorption
 Mesenteric mal-perfusion in CHF may contribute to:




Bacterial overgrowth,
Chronic inflammation,
Gastrointestinal symptoms and
Cardiac cachexia.
Thank you!
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