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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! [email protected]