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Available online at www.sciencedirect.com
www.elsevier.com/locate/tcm
Editorial Commentary
Increased cardiovascular risk in subjects with a low prevalence of classic cardiovascular risk factors: The inflammatory bowel disease paradox Luca Zanoli, MD, PhDn, Gaetano Inserra, MD, and Pietro Castellino, MD Department of Internal Medicine, Policlinico Universitario, University of Catania, Catania, Italy
Inflammatory bowel disease is characterized by an uncontrolled immune response within the intestine, which results in chronic low-grade flogistic response and peaks of acute inflammation during the relapses of the disease. Accumulating evidence suggests that inflammation plays a role in atherogenesis. An increased risk of coronary heart disease has been linked to several diseases characterized by chronic inflammation [1]. Inflammation has been linked to increased aortic stiffness, a well-accepted cardiovascular risk factor and a marker of target organ damage, in both healthy subjects [2] and hypertensive patients [3], as well as in subjects with chronic inflammatory disorders [1,4–6]. Little is known regarding the cardiovascular risk faced by patients with inflammatory bowel disease. The article by Rungoe et al. [7] in this issue of Trends in Cardiovascular Medicine provides an update of the existing literature pertaining to the relationship between inflammatory bowel disease and the risk of cardiovascular disease, particularly coronary artery disease. It is now well accepted that the risk of cardiovascular events is higher among subjects with an elevated burden of classic cardiovascular risk factors; on the other hand, an amelioration of the risk factors profile is associated with a reduction of the cardiovascular risk. However, the cardiovascular risk could be also increased in subjects without a classic cardiovascular risk profile. To explain this discrepancy, several non-traditional cardiovascular risk factors have been identified, such as C-reactive protein, homocysteine, and pulse wave velocity. Several inflammatory disorders including rheumatoid arthritis, systemic vasculitis, and systemic All authors have contributed significantly to the submitted work. No conflicts of interest are reported. n Corresponding author. Tel.: þ39 095 378 2736; fax: þ39 095 378 2376. E-mail address: [email protected] (L. Zanoli). http://dx.doi.org/10.1016/j.tcm.2015.04.001 1050-1738/& 2015 Elsevier Inc. All rights reserved.
lupus erythematosus are characterized by various clusters of these non-traditional cardiovascular risk factors. Apparently, the positive relationship between the burden of the classic cardiovascular risk factors and the risk to develop cardiovascular events has not been confirmed among patients with IBD. Several studies have described a lower prevalence of classic cardiovascular risk factors among patients with IBD compared with the general population, including lower body mass indices and lipid levels [8–11], as well as lower prevalence of diabetes, obesity, and hypertension [11]. Therefore, we would anticipate a decrease in cardiovascular morbidity and mortality in patients with IBD compared with the general population. Surprisingly, it has been reported that in IBD, the standardized mortality ratio is not decreased [12]; Rungoe et al. [7] in this issue of Trends in Cardiovascular Medicine conclude that most studies are indicative of a modestly increased relative risk of coronary artery disease among patients with both ulcerative colitis and Crohn's disease; the risk appears to be higher in women. The majority of studies regarding the risk of cardiovascular disease in the setting of IBD did not stratify based on IBD subtypes (ulcerative colitis or Crohn's disease). The few that did separately analyze the risk in the setting of ulcerative colitis and Crohn's disease determined that the risk was similar between the two groups of patients. Taken together, these results suggest that as an alternative to the traditional cardiovascular risk factors, other factors may be associated with the cardiovascular risk of patients with IBD. Chronic inflammation has recently been linked to an increased risk of cardiovascular disease. In contrast with other chronic
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inflammatory disorders characterized by a prevalence of classic cardiovascular risk factors comparable with that of the general population, the low prevalence of classic cardiovascular risk factors among patients with IBD may partially counterbalance the increased cardiovascular risk associated with chronic inflammation. An improved understanding of these concomitant but opposing effects, which is not routinely taken into account in the cardiovascular risk stratification of patients with IBD, may assist clinicians with the planning of specific programs of intervention aimed at decreasing the cardiovascular risk in these patients. In IBD, increased aortic stiffness and endothelial dysfunction [6,13] may represent a link between chronic low-grade inflammation and the cardiovascular risk. However, as suggested by Rungoe et al. [7] in this issue of Trends in Cardiovascular Medicine, additional studies are warranted to confirm the preliminary data demonstrating that a reduction of inflammation (with anti TNF-α therapy) is associated with reduced arterial stiffness and improved endothelial function in the setting of IBD [14,15] and other chronic inflammatory disorders [6]. In addition, it will be of great clinical relevance to determine if reduced arterial stiffness and improved endothelial function may be associated with a decrease of the risk of cardiovascular events in patients with IBD. It has been recently reported that counter-regulatory processes are deficient in IBD and thereby contribute to either the pathogenesis or the maintenance of inflammation. One of such mechanisms involves transforming growth factor-β1, an inhibitor of T-cell proliferation and differentiation, macrophage activation, and dendritic-cell maturation. Recent evidence suggests that in patients with active Crohn's disease, an oral antisense oligonucleotide can induce remission and clinical response restoring TGF-β signaling and reducing proinflammatory cytokine production [16], thus providing an alternative pathway to modulate inflammation. In the future, it will be of interest to evaluate if this new promising therapy could have an impact on arterial stiffness, endothelial function, and the cardiovascular risk of subjects with IBD.
M
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[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
r e f e r e n c e s [15] [1] [2]
Roman MJ, Salmon JE. Cardiovascular manifestations of rheumatologic diseases. Circulation 2007;116:2346–55. Yasmin, McEniery CM, Wallace S, Mackenzie IS, Cockcroft JR, Wilkinson IB. C-reactive protein is associated with arterial stiffness in apparently healthy individuals. Arterioscler Thromb Vasc Biol 2004;24:969–74.
[16]
25 (2015) 705–706
Pietri P, Vyssoulis G, Vlachopoulos C, Zervoudaki A, Gialernios T, Aznaouridis K, et al. Relationship between low-grade inflammation and arterial stiffness in patients with essential hypertension. J Hypertens 2006;24:2231–8. Booth AD, Wallace S, McEniery CM, Yasmin, Brown J, Jayne DR, et al. Inflammation and arterial stiffness in systemic vasculitis: a model of vascular inflammation. Arthritis Rheum 2004;50:581–8. Roman MJ, Devereux RB, Schwartz JE, Lockshin MD, Paget SA, Davis A, et al. Arterial stiffness in chronic inflammatory diseases. Hypertension 2005;46:194–9. Mäki-Petäjä KM, Hall FC, Booth AD, Wallace SM, Yasmin, Bearcroft PW, et al. Rheumatoid arthritis is associated with increased aortic pulse-wave velocity, which is reduced by anti-tumor necrosis factor-α therapy. Circulation 2006;114: 1185–92. Rungoe C, Andersen NN, Jess T. Inflammatory bowel disease and risk of coronary heart disease. Trends Cardiovasc Med 2015;25:699–704. Geerling BJ, Badart-Smook A, Stockbrugger RW, Brummer RJ. Comprehensive nutritional status in recently diagnosed patients with inflammatory bowel disease compared with population controls. Eur J Clin Nutr 2000;54:514–21. Levy E, Rizwan Y, Thibault L, Lepage G, Brunet S, Bouthillier L, et al. Altered lipid profile, lipoprotein composition, and oxidant and antioxidant status in pediatric Crohn disease. Am J Clin Nutr 2000;71:807–15. Jahnsen J, Falch JA, Mowinckel P, Aadland E. Body composition in patients with inflammatory bowel disease: a population-based study. Am J Gastroenterol 2003;98:1556–62. Yarur AJ, Deshpande AR, Pechman DM, Tamariz L, Abreu MT, Sussman DA. Inflammatory bowel disease is associated with an increased incidence of cardiovascular events. Am J Gastroenterol 2011;106:741–7. Dorn SD, Sandler RS. Inflammatory bowel disease is not a risk factor for cardiovascular disease mortality: results from a systematic review and meta-analysis. Am J Gastroenterol 2007;102:662–7. Zanoli L, Cannavò M, Rastelli S, Di Pino L, Monte I, Di Gangi M, et al. Arterial stiffness is increased in patients with inflammatory bowel disease. J Hypertens 2012;30:1775–81. Zanoli L, Rastelli S, Inserra G, Lentini P, Valvo E, Calcagno E, et al. Increased arterial stiffness in inflammatory bowel diseases is dependent upon inflammation and reduced by immunomodulatory drugs. Atherosclerosis 2014;234: 346–51. Schinzari F, Armuzzi A, De Pascalis B, Mores N, Tesauro M, Melina D, et al. Tumor necrosis factor-α antagonism improves endothelial dysfunction in patients with Crohn’s disease. Clin Pharmacol Ther 2008;83:70–6. Monteleone G, Neurath MF, Ardizzone S, Di Sabatino A, Fantini MC, Castiglione F, et al. Mongersen, an oral SMAD7 antisense oligonucleotide, and Crohn's disease. N Engl J Med 2015;372:1104–13.
E N D S I N
C
A R D I O V A S C U L A R
M
E D I C I N E
25 (2015) 705–706
Available online at www.sciencedirect.com
www.elsevier.com/locate/tcm
Editorial Commentary
Increased cardiovascular risk in subjects with a low prevalence of classic cardiovascular risk factors: The inflammatory bowel disease paradox Luca Zanoli, MD, PhDn, Gaetano Inserra, MD, and Pietro Castellino, MD Department of Internal Medicine, Policlinico Universitario, University of Catania, Catania, Italy
Inflammatory bowel disease is characterized by an uncontrolled immune response within the intestine, which results in chronic low-grade flogistic response and peaks of acute inflammation during the relapses of the disease. Accumulating evidence suggests that inflammation plays a role in atherogenesis. An increased risk of coronary heart disease has been linked to several diseases characterized by chronic inflammation [1]. Inflammation has been linked to increased aortic stiffness, a well-accepted cardiovascular risk factor and a marker of target organ damage, in both healthy subjects [2] and hypertensive patients [3], as well as in subjects with chronic inflammatory disorders [1,4–6]. Little is known regarding the cardiovascular risk faced by patients with inflammatory bowel disease. The article by Rungoe et al. [7] in this issue of Trends in Cardiovascular Medicine provides an update of the existing literature pertaining to the relationship between inflammatory bowel disease and the risk of cardiovascular disease, particularly coronary artery disease. It is now well accepted that the risk of cardiovascular events is higher among subjects with an elevated burden of classic cardiovascular risk factors; on the other hand, an amelioration of the risk factors profile is associated with a reduction of the cardiovascular risk. However, the cardiovascular risk could be also increased in subjects without a classic cardiovascular risk profile. To explain this discrepancy, several non-traditional cardiovascular risk factors have been identified, such as C-reactive protein, homocysteine, and pulse wave velocity. Several inflammatory disorders including rheumatoid arthritis, systemic vasculitis, and systemic All authors have contributed significantly to the submitted work. No conflicts of interest are reported. n Corresponding author. Tel.: þ39 095 378 2736; fax: þ39 095 378 2376. E-mail address: [email protected] (L. Zanoli). http://dx.doi.org/10.1016/j.tcm.2015.04.001 1050-1738/& 2015 Elsevier Inc. All rights reserved.
lupus erythematosus are characterized by various clusters of these non-traditional cardiovascular risk factors. Apparently, the positive relationship between the burden of the classic cardiovascular risk factors and the risk to develop cardiovascular events has not been confirmed among patients with IBD. Several studies have described a lower prevalence of classic cardiovascular risk factors among patients with IBD compared with the general population, including lower body mass indices and lipid levels [8–11], as well as lower prevalence of diabetes, obesity, and hypertension [11]. Therefore, we would anticipate a decrease in cardiovascular morbidity and mortality in patients with IBD compared with the general population. Surprisingly, it has been reported that in IBD, the standardized mortality ratio is not decreased [12]; Rungoe et al. [7] in this issue of Trends in Cardiovascular Medicine conclude that most studies are indicative of a modestly increased relative risk of coronary artery disease among patients with both ulcerative colitis and Crohn's disease; the risk appears to be higher in women. The majority of studies regarding the risk of cardiovascular disease in the setting of IBD did not stratify based on IBD subtypes (ulcerative colitis or Crohn's disease). The few that did separately analyze the risk in the setting of ulcerative colitis and Crohn's disease determined that the risk was similar between the two groups of patients. Taken together, these results suggest that as an alternative to the traditional cardiovascular risk factors, other factors may be associated with the cardiovascular risk of patients with IBD. Chronic inflammation has recently been linked to an increased risk of cardiovascular disease. In contrast with other chronic
706
TR
E N D S I N
C
A R D I O V A S C U L A R
inflammatory disorders characterized by a prevalence of classic cardiovascular risk factors comparable with that of the general population, the low prevalence of classic cardiovascular risk factors among patients with IBD may partially counterbalance the increased cardiovascular risk associated with chronic inflammation. An improved understanding of these concomitant but opposing effects, which is not routinely taken into account in the cardiovascular risk stratification of patients with IBD, may assist clinicians with the planning of specific programs of intervention aimed at decreasing the cardiovascular risk in these patients. In IBD, increased aortic stiffness and endothelial dysfunction [6,13] may represent a link between chronic low-grade inflammation and the cardiovascular risk. However, as suggested by Rungoe et al. [7] in this issue of Trends in Cardiovascular Medicine, additional studies are warranted to confirm the preliminary data demonstrating that a reduction of inflammation (with anti TNF-α therapy) is associated with reduced arterial stiffness and improved endothelial function in the setting of IBD [14,15] and other chronic inflammatory disorders [6]. In addition, it will be of great clinical relevance to determine if reduced arterial stiffness and improved endothelial function may be associated with a decrease of the risk of cardiovascular events in patients with IBD. It has been recently reported that counter-regulatory processes are deficient in IBD and thereby contribute to either the pathogenesis or the maintenance of inflammation. One of such mechanisms involves transforming growth factor-β1, an inhibitor of T-cell proliferation and differentiation, macrophage activation, and dendritic-cell maturation. Recent evidence suggests that in patients with active Crohn's disease, an oral antisense oligonucleotide can induce remission and clinical response restoring TGF-β signaling and reducing proinflammatory cytokine production [16], thus providing an alternative pathway to modulate inflammation. In the future, it will be of interest to evaluate if this new promising therapy could have an impact on arterial stiffness, endothelial function, and the cardiovascular risk of subjects with IBD.
M
E D I C I N E
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
r e f e r e n c e s [15] [1] [2]
Roman MJ, Salmon JE. Cardiovascular manifestations of rheumatologic diseases. Circulation 2007;116:2346–55. Yasmin, McEniery CM, Wallace S, Mackenzie IS, Cockcroft JR, Wilkinson IB. C-reactive protein is associated with arterial stiffness in apparently healthy individuals. Arterioscler Thromb Vasc Biol 2004;24:969–74.
[16]
25 (2015) 705–706
Pietri P, Vyssoulis G, Vlachopoulos C, Zervoudaki A, Gialernios T, Aznaouridis K, et al. Relationship between low-grade inflammation and arterial stiffness in patients with essential hypertension. J Hypertens 2006;24:2231–8. Booth AD, Wallace S, McEniery CM, Yasmin, Brown J, Jayne DR, et al. Inflammation and arterial stiffness in systemic vasculitis: a model of vascular inflammation. Arthritis Rheum 2004;50:581–8. Roman MJ, Devereux RB, Schwartz JE, Lockshin MD, Paget SA, Davis A, et al. Arterial stiffness in chronic inflammatory diseases. Hypertension 2005;46:194–9. Mäki-Petäjä KM, Hall FC, Booth AD, Wallace SM, Yasmin, Bearcroft PW, et al. Rheumatoid arthritis is associated with increased aortic pulse-wave velocity, which is reduced by anti-tumor necrosis factor-α therapy. Circulation 2006;114: 1185–92. Rungoe C, Andersen NN, Jess T. Inflammatory bowel disease and risk of coronary heart disease. Trends Cardiovasc Med 2015;25:699–704. Geerling BJ, Badart-Smook A, Stockbrugger RW, Brummer RJ. Comprehensive nutritional status in recently diagnosed patients with inflammatory bowel disease compared with population controls. Eur J Clin Nutr 2000;54:514–21. Levy E, Rizwan Y, Thibault L, Lepage G, Brunet S, Bouthillier L, et al. Altered lipid profile, lipoprotein composition, and oxidant and antioxidant status in pediatric Crohn disease. Am J Clin Nutr 2000;71:807–15. Jahnsen J, Falch JA, Mowinckel P, Aadland E. Body composition in patients with inflammatory bowel disease: a population-based study. Am J Gastroenterol 2003;98:1556–62. Yarur AJ, Deshpande AR, Pechman DM, Tamariz L, Abreu MT, Sussman DA. Inflammatory bowel disease is associated with an increased incidence of cardiovascular events. Am J Gastroenterol 2011;106:741–7. Dorn SD, Sandler RS. Inflammatory bowel disease is not a risk factor for cardiovascular disease mortality: results from a systematic review and meta-analysis. Am J Gastroenterol 2007;102:662–7. Zanoli L, Cannavò M, Rastelli S, Di Pino L, Monte I, Di Gangi M, et al. Arterial stiffness is increased in patients with inflammatory bowel disease. J Hypertens 2012;30:1775–81. Zanoli L, Rastelli S, Inserra G, Lentini P, Valvo E, Calcagno E, et al. Increased arterial stiffness in inflammatory bowel diseases is dependent upon inflammation and reduced by immunomodulatory drugs. Atherosclerosis 2014;234: 346–51. Schinzari F, Armuzzi A, De Pascalis B, Mores N, Tesauro M, Melina D, et al. Tumor necrosis factor-α antagonism improves endothelial dysfunction in patients with Crohn’s disease. Clin Pharmacol Ther 2008;83:70–6. Monteleone G, Neurath MF, Ardizzone S, Di Sabatino A, Fantini MC, Castiglione F, et al. Mongersen, an oral SMAD7 antisense oligonucleotide, and Crohn's disease. N Engl J Med 2015;372:1104–13.
