The heart in concert: do other organs matter?

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1 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

2 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

3 Inflammation in CHF CHF patients have predict poor survival. levels of proinflammatory cytokines that 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

Bacteria or LPS Gut Wall Release of: IL-1, IL-6, IL-8, IL-10 IFN-g TGF-b, TNF,

4 Translocation of bacterial endotoxin Hormones LPS Monocytes - circulating - in tissues (heart, periphery) CD 14 TLR 4 Tissue Hypoxia Portal Vein Thoracic Duct Bacteria or LPS Gut Wall Release of: IL-1, IL-6, IL-8, IL-10 IFN-g TGF-b, TNF, chemokines, adhesion molecules Anker SD et al., Am J Cardiol 1997 Niebauer et al., Lancet 1999

5 Sandek A, Bjarnason I, Anker SD et al. Int J Cardiol Bacterial endotoxin in edematous heart failure Variable Controls (n=8) p-value controls vs. non-edematous non-edematous patients (n=8) p-value non-edematous vs. edematous edematous CHF (n=12) p-value edematous vs. controls TNF [pg/ml] stnf-r1 [pg/ml] stnf-r2 [pg/ml] LPS [EU/mL] Edema = Highest blood LPS = Inflammation

6 Cardio-intestinal syndrome Cardio-intestinal syndrome Inflammation endothelial dysfunction Myocardium contractility apoptosis intestinal microcirculation Congestion

7 Niebauer J et al., Lancet, 1999 & Sandek A, Bjarnason I, Anker SD et al., Int J Cardiol LPS decreases after recompensation baseline after diuretic treatment Edematous gut wall & Epithelial dysfunction Translocating LPS

8 Krack A, Richartz BM, Gastmann A, et al., Eur J Heart Fail Mesenteric ischaemia during exercise in CHF patients controls tonometry during rest and exercise stress testing Higher intragastric PCO2 (ipco2) in patients with CHF

9 Sandek A, Bauditz J, Anker SD et al., in submission Lower intestinal arterial blood flow Superior mesenteric artery Inferior mesenteric artery Coeliac trunk Mean systolic flow ml / min Mean systolic flow ml / min Mean systolic flow ml / min 1000 p< p< p< controls CHF n=24 n= controls CHF n=23 n= controls CHF n=21 n=53 The same applies to peak systolic arterial flow in all 3 vessels (all p< 0.002).

10 Higher Bowel Wall Thickness in CHF Bowel wall thickness [mm] 6 CHF 5 4 Controls p<0.009 p<0.007 p<0.004 p< p= n=23 n=59 n=23 n=61 n=23 n=60 n=23 n=62 n=24 n=64 Terminal Ileum Ascending Colon Transverse Colon Descending Colon Sigmoid Sandek A, Bauditz J, Swidsinski A et al., JACC 2007

Histology Collagen accumulation in the small intestine CHF patient Relative

NYHA III-IV n=18 cachexia n=9 Distance between the basal wall of the

correlated with lower percentage of body fat (r = 0.88, p < 0.05).

11 Histology Collagen accumulation in the small intestine CHF patient Relative area occupied by collagen [%] Control subject controls n=18 NYHA I-II n=18 NYHA III-IV n=18 cachexia n=9 Distance between the basal wall of the enterocyte & the capillary wall [µm] Greater relative collagen area correlated with lower percentage of body fat (r = 0.88, p < 0.05). controls n=18 NYHA I-II n=18 NYHA III-IV n=18 cachexia n=9 Arutyunov GP, et al., Int I Cardiol. 2008

Low colonised large intestinal mucosa CHF patient

12 Histology Higher concentration of bacteria in mucosal biofilm in CHF Highly colonised large intestinal mucosa Low colonised large intestinal mucosa CHF patient Control subject Sandek A, Bauditz J, Swidsinski A et al., JACC 2007

13 Histology Higher adherence of bacteria to the mucosa in CHF Concentration of bacteria (ml -1 ) Bacteria in CHF are more often adherent to the mucosa (70% vs. 36%, p=0.03) Controls CHF (n=20) Bacteria in CHF range over a higher mean biofilm area (35.5% ± 8.2% vs ± 3.7%, p=0.006). Serum IgA anti-lps-antibodies are higher in CHF (p=0.005). (n=22) Sandek A, Bauditz J, Swidsinski A et al., JACC 2007

14 Function Additional gastrointestinal symptoms in CHF Burping Murmours from the intestine Feelings of repletion Flatulences Patients Controls n=59 n=18 25 % (15/59) 0 % (0/18) 58 % (34/59) 28 % (5/18) 59 % (34/58) 22 % (4/18) 73 % (43/59) 44 % (8/18) p-value Bowel wall thickness sigmoid [mm] p= Wall thickness descending colon [mm] p= no murmors murmors (n=34) (n=25) 0 no murmors murmors (n=25) (n=34) Sandek A, Bauditz J, Anker SD et al., in submission

15 Function Intestinal barrier & absorption Lumen D-Xylose 3-OMG (passive carrier) (active carrier) Sucrose, Lactulose, Mannitol, Sucralose (no carrier)

16 Sandek A, Bauditz J, Swidsinski A et al., JACC 2007 Function Altered intestinal permeability in CHF Permeability Paracellular: Gastroduodenum M eth o d S u c ro s e c h an g e p- v al u e 0. 7 Small intestine Lactulose/Mannitol 2 1 % L a rge intestine S u c ral o se 2 1 0% Transcellular: Carriermediated transport Xylose 2 9 %

17 Sandek A, Bjarnason I, Anker SD et al. Int J Cardiol Function Reduced active and passive transport in CHF Edematous patients = lowest carrier-mediated transport

18 Function Lower protein and fat absorption in CHF Fat, protein, % protein fat 5 0 controls n=18 NYHA I-II n=18 NYHA III-IV n=18 cachexia n=9 Protein loss Fat loss related to small intestinal fibrosis, r=0.9, p<0.05 adapted from Arutyunov GP, Kostyukevich OI, Serov RA et al., Int I Cardiol. 2008

19 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

20 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., % cachectic Anker SD, Ponikowski P, Coats AJ, et al. Lancet, 1997

21 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.

22 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.

23 Thank you!

Intestinal blood flow in patients with chronic heart failure a link with bacterial

Title: Intestinal blood flow in patients with chronic heart failure a link with bacterial growth, gastrointestinal symptoms and cachexia Short Title: Intestinal blood flow in chronic heart failure. Authors: