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Vegetations in endocarditis: big is bad, but is there more to it?
Editorial
Vegetations in endocarditis: Big is bad, but is there more to it? Christopher H. Cabell, MD, and Vance G. Fowler, Jr, MD, MHS Durham, NC
See related article on page 311.
Although infective endocarditis affects up to 20,000 new patients each year in the United States1 and carries a 1-year mortality rate that approaches 50%,2 it remains a poorly understood disease. One of the most important but least understood aspects of infective endocarditis (IE) is the development of thromboembolic events such as stroke. Stroke is often a catastrophic complication in patients with IE and occurs frequently. Studies have shown that thromboembolic events complicate the course of IE in 10% to 50% of patients,3,4 with the most precise estimated provided by Di Salvo et al,5 which found that 37% of patients with definite IE had evidence of thromboembolic events, 80% of which were clinically apparent. The majority of thromboembolic events in patients with IE are neurologic3,5 and patients with IE and neurologic events have a higher mortality rate.4,5 These studies provide evidence that elucidating strategies to identify high-risk populations for thromboembolic events and stroke is a research imperative. Advances in clinical characterization, microbiology, and imaging techniques have helped begin to define the populations at risk for stroke. Vegetation size has been evaluated in multiple studies. Although early data were inconsistent, recently several large studies4,5 and a careful meta-analysis have6 shown that vegetation size is a strong predictor of thromboembolic events. Despite this strong direct association between vegetation size and risk for thromboembolism, not all patients with large vegetations invariably had a stroke. Conversely, some patients with comparatively small vegetations sustained major thromboembolic events. Thus, it seems likely that factors other than vegetation size may also contribute to a particular patient’s risk for stroke.
From the Department of Medicine, Duke University School of Medicine, and Duke Clinical Research Institute, Durham, NC. Supported by NIH grants HL70861 (C.H.C.) and AI01647 (V.G.F.) and American Heart Association award 0265405U (C.H.C.). Reprint requests: Christopher H. Cabell, MD, Box 3850, Duke University Medical Center, Durham, NC 27710. E-mail: [email protected] Am Heart J 2003;146:189 –90. © 2003, Mosby, Inc. All rights reserved. 0002-8703/2003/$30.00 ⫹ 0 doi:10.1016/S0002-8703(02)00094-7
The current study by Mangoni et al7 was designed to evaluate the association between clinical, biochemical, and echocardiographic factors with thromboembolic events. These investigators prospectively identified 94 consecutive patients with definite IE, as defined by the Duke criteria8, over a 5.5-year period. The median age of the patients was 46.5 years, and 63% were male. Most study patients had native valve, left-sided IE. In the primary analysis, 5 risk factors were found to be associated with thromboembolic events: age, vegetation size, prothrombin activity, serum albumin, and C-reactive protein (CRP). In the subsequent multivariable analysis, age, vegetation size, and CRP were independent predictors of thromboembolic events. This study is important in a number of ways. It is consistent with previous work that has shown vegetation size as an important predictor of thromboembolic events and that overlap in vegetation size exists. These data also verify previous findings that vegetation size alone does not precisely identify a high-risk cohort of patients. The authors also evaluated a number of laboratory parameters and found that only CRP was independently associated with thromboembolic events when controlling for other important risk factors. The interesting finding that CRP was independently associated with risk for thromboembolism invites further study. Because of its role as a marker of the acute inflammatory cascade, is CRP simply “guilty by association” or does it directly contribute to the risk for stroke? Previous work has shown that CRP is an important marker of bacterial infection9 as well as an indicator of complications in patients with IE.10 Moreover, it has been hypothesized that CRP is directly involved in the inflammatory process in diseases such as ischemic heart disease, in which it localizes in atherosclerotic lesions promoting complement activation.11 Mangoni et al7 speculate that CRP may be related to thromboembolic events in patients with IE by inducing the inflammatory response and by a direct effect on platelets leading to more friable lesions at risk for embolization. Although basic bench research is needed to test this hypothesis, it is clear that new clinically identifiable factors may help to define risk factors for stroke among patients with IE more precisely. Humoral factors influencing thrombocyte adherence are one set of factors that may increase the risk of thromboembolism. Korkmaz et al12 found that circulating adhesion molecules are stronger predictors of thromboembolic
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190 Cabell and Fowler
events in patients with IE than vegetation size. In addition, antiphospholipid antibodies, coagulation parameters, and endothelial cell activation have been found to be associated with the risk for thromboembolic events.13 Platelets also appear to offer a key target for these investigations. Platelets are an integral component of thrombus formation, are found abundantly in vegetations, and play an important role in the host defense against infecting organisms.14 To improve the care of patients with IE, it is critical to develop risk models that allow appropriate stratification of patients. Clinical and echocardiographic features will need to be added to new studies that incorporate measurable factors (eg, CRP and soluble adhesion molecules) to develop a sound prediction model. Once an accurate risk stratification system is developed, treatment strategies can be tested in highrisk patients. These strategies may include novel antithrombotic agents, new anti-infective strategies, and early aggressive surgery in patients at risk for untoward events. The reduction in adverse outcomes, particularly the rate of stroke and mortality, is the leading clinical imperative in the modern management of infective endocarditis. Unfortunately, clinically useful predictors of thromboembolic events have been difficult to recognize consistently. Mangoni et al have added important data to our understanding of risk factors in patients with IE. From this work and that of others, it is clear that large vegetations are associated with thromboembolic events and additional factors, such as CRP, may help identify this risk more precisely. To facilitate an evidence-based approach to the treatment of the patient with IE, large, cooperative, multicenter studies are needed. These studies should aim to (1) characterize in detail contemporary patients with endocarditis and examine regional variation in their characteristics; (2) identify predictors of thromboembolic events and death; and (3) identify potential host determinants of complications in endocarditis. These studies should develop prognostic models that will be validated in an independent patient population. Such large, cooperative, multicenter studies would provide important insights into the pathogenesis of IE and offer a unique infrastructure of investigators through
which definitive randomized trials could ultimately be conducted.
References 1. Bayer AS, Scheld WM. Principles and practice of infectious diseases. In: Mandell GL, Bennett JE, Dolin R, editors. 5th edition. Philadelphia: Churchill Livingstone; 2000. p. 857–902. 2. Cabell CH, Jollis JG, Peterson GE, et al. Changing patient characteristics and the effect on mortality in endocarditis. Arch Intern Med 2002;162:90 – 4. 3. Steckelberg JM, Murphy JG, Ballard D, et al. Emboli in infective endocarditis: the prognostic valve of echocardiography. Ann Intern Med 1991;114:635– 40. 4. Cabell CH, Pond KK, Peterson GE, et al. The risk of stroke and death in patients with aortic and mitral valve endocarditis. Am Heart J 2001;142:75– 80. 5. Di Salvo G, Habib G, Pergola V, et al. Echocardiography predicts embolic events in infective endocarditis. J Am Coll Cardiol 2001; 37:1069 –76. 6. Tischler MD, Vaitkus PT. The ability of vegetation size on echocardiography to predict clinical complications: a meta-analysis. J Am Soc Echocardiogr 1997;10:562– 8. 7. Mangoni ED, Adinolfi LE, Tripodi MF, et al. Risk factors for “major” embolic events in hospitalized patients with infective endocarditis. Am Heart J 2003;146;311– 6. 8. Durack DT, Lukes AS, Bright DK. New criteria for diagnosis of infective endocarditis: utilization of specific echocardiographic findings. Am J Med 1994;96:200 –9. 9. Lindback S, Hellgren U, Julander I, et al. The value of C-reactive protein as a marker of bacterial infection in patients with septicaemia/endocarditis and influenza. Scand J Infect Dis 1989;21: 543–9. 10. Olaison L, Hogevik H, Alestig K. Fever, C-reactive protein, and other acute-phase reactants during treatment of infective endocarditis. Arch Intern Med 1997;157:885–92. 11. Lagrand WK, Visser CA, Hermens WT, et al. C-reactive protein as a cardiovascular risk factor: more than an epiphenomenon? Circulation 1999;100:96 –102. 12. Korkmaz S, Ileri M, Hisar I, et al. Increased levels of soluble adhesion molecules, E-selectin and P-selectin, in patients with infective endocarditis and embolic events. Eur Heart J 2001;22:874 – 8. 13. Kupferwasser LI, Hafner G, Mohr-Kahaly S, et al. The presence of infection-related antiphospholipid antibiotics in infective endocarditis determines a major risk factor for embolic events. J Am Coll Cardiol 1999;33:1365–71. 14. Kupferwasser LI, Yeaman MR, Shapiro SM, et al. In vitro susceptibility to thrombin-induced platelet microbicidal protein is associated with reduced disease progression and complication rates in experimental Staphylococcus aureus endocarditis: microbiological, histopathologic, and echocardiographic analyses. Circulation 2002;105:746 –52.
Vegetations in endocarditis: Big is bad, but is there more to it? Christopher H. Cabell, MD, and Vance G. Fowler, Jr, MD, MHS Durham, NC
See related article on page 311.
Although infective endocarditis affects up to 20,000 new patients each year in the United States1 and carries a 1-year mortality rate that approaches 50%,2 it remains a poorly understood disease. One of the most important but least understood aspects of infective endocarditis (IE) is the development of thromboembolic events such as stroke. Stroke is often a catastrophic complication in patients with IE and occurs frequently. Studies have shown that thromboembolic events complicate the course of IE in 10% to 50% of patients,3,4 with the most precise estimated provided by Di Salvo et al,5 which found that 37% of patients with definite IE had evidence of thromboembolic events, 80% of which were clinically apparent. The majority of thromboembolic events in patients with IE are neurologic3,5 and patients with IE and neurologic events have a higher mortality rate.4,5 These studies provide evidence that elucidating strategies to identify high-risk populations for thromboembolic events and stroke is a research imperative. Advances in clinical characterization, microbiology, and imaging techniques have helped begin to define the populations at risk for stroke. Vegetation size has been evaluated in multiple studies. Although early data were inconsistent, recently several large studies4,5 and a careful meta-analysis have6 shown that vegetation size is a strong predictor of thromboembolic events. Despite this strong direct association between vegetation size and risk for thromboembolism, not all patients with large vegetations invariably had a stroke. Conversely, some patients with comparatively small vegetations sustained major thromboembolic events. Thus, it seems likely that factors other than vegetation size may also contribute to a particular patient’s risk for stroke.
From the Department of Medicine, Duke University School of Medicine, and Duke Clinical Research Institute, Durham, NC. Supported by NIH grants HL70861 (C.H.C.) and AI01647 (V.G.F.) and American Heart Association award 0265405U (C.H.C.). Reprint requests: Christopher H. Cabell, MD, Box 3850, Duke University Medical Center, Durham, NC 27710. E-mail: [email protected] Am Heart J 2003;146:189 –90. © 2003, Mosby, Inc. All rights reserved. 0002-8703/2003/$30.00 ⫹ 0 doi:10.1016/S0002-8703(02)00094-7
The current study by Mangoni et al7 was designed to evaluate the association between clinical, biochemical, and echocardiographic factors with thromboembolic events. These investigators prospectively identified 94 consecutive patients with definite IE, as defined by the Duke criteria8, over a 5.5-year period. The median age of the patients was 46.5 years, and 63% were male. Most study patients had native valve, left-sided IE. In the primary analysis, 5 risk factors were found to be associated with thromboembolic events: age, vegetation size, prothrombin activity, serum albumin, and C-reactive protein (CRP). In the subsequent multivariable analysis, age, vegetation size, and CRP were independent predictors of thromboembolic events. This study is important in a number of ways. It is consistent with previous work that has shown vegetation size as an important predictor of thromboembolic events and that overlap in vegetation size exists. These data also verify previous findings that vegetation size alone does not precisely identify a high-risk cohort of patients. The authors also evaluated a number of laboratory parameters and found that only CRP was independently associated with thromboembolic events when controlling for other important risk factors. The interesting finding that CRP was independently associated with risk for thromboembolism invites further study. Because of its role as a marker of the acute inflammatory cascade, is CRP simply “guilty by association” or does it directly contribute to the risk for stroke? Previous work has shown that CRP is an important marker of bacterial infection9 as well as an indicator of complications in patients with IE.10 Moreover, it has been hypothesized that CRP is directly involved in the inflammatory process in diseases such as ischemic heart disease, in which it localizes in atherosclerotic lesions promoting complement activation.11 Mangoni et al7 speculate that CRP may be related to thromboembolic events in patients with IE by inducing the inflammatory response and by a direct effect on platelets leading to more friable lesions at risk for embolization. Although basic bench research is needed to test this hypothesis, it is clear that new clinically identifiable factors may help to define risk factors for stroke among patients with IE more precisely. Humoral factors influencing thrombocyte adherence are one set of factors that may increase the risk of thromboembolism. Korkmaz et al12 found that circulating adhesion molecules are stronger predictors of thromboembolic
American Heart Journal August 2003
190 Cabell and Fowler
events in patients with IE than vegetation size. In addition, antiphospholipid antibodies, coagulation parameters, and endothelial cell activation have been found to be associated with the risk for thromboembolic events.13 Platelets also appear to offer a key target for these investigations. Platelets are an integral component of thrombus formation, are found abundantly in vegetations, and play an important role in the host defense against infecting organisms.14 To improve the care of patients with IE, it is critical to develop risk models that allow appropriate stratification of patients. Clinical and echocardiographic features will need to be added to new studies that incorporate measurable factors (eg, CRP and soluble adhesion molecules) to develop a sound prediction model. Once an accurate risk stratification system is developed, treatment strategies can be tested in highrisk patients. These strategies may include novel antithrombotic agents, new anti-infective strategies, and early aggressive surgery in patients at risk for untoward events. The reduction in adverse outcomes, particularly the rate of stroke and mortality, is the leading clinical imperative in the modern management of infective endocarditis. Unfortunately, clinically useful predictors of thromboembolic events have been difficult to recognize consistently. Mangoni et al have added important data to our understanding of risk factors in patients with IE. From this work and that of others, it is clear that large vegetations are associated with thromboembolic events and additional factors, such as CRP, may help identify this risk more precisely. To facilitate an evidence-based approach to the treatment of the patient with IE, large, cooperative, multicenter studies are needed. These studies should aim to (1) characterize in detail contemporary patients with endocarditis and examine regional variation in their characteristics; (2) identify predictors of thromboembolic events and death; and (3) identify potential host determinants of complications in endocarditis. These studies should develop prognostic models that will be validated in an independent patient population. Such large, cooperative, multicenter studies would provide important insights into the pathogenesis of IE and offer a unique infrastructure of investigators through
which definitive randomized trials could ultimately be conducted.
References 1. Bayer AS, Scheld WM. Principles and practice of infectious diseases. In: Mandell GL, Bennett JE, Dolin R, editors. 5th edition. Philadelphia: Churchill Livingstone; 2000. p. 857–902. 2. Cabell CH, Jollis JG, Peterson GE, et al. Changing patient characteristics and the effect on mortality in endocarditis. Arch Intern Med 2002;162:90 – 4. 3. Steckelberg JM, Murphy JG, Ballard D, et al. Emboli in infective endocarditis: the prognostic valve of echocardiography. Ann Intern Med 1991;114:635– 40. 4. Cabell CH, Pond KK, Peterson GE, et al. The risk of stroke and death in patients with aortic and mitral valve endocarditis. Am Heart J 2001;142:75– 80. 5. Di Salvo G, Habib G, Pergola V, et al. Echocardiography predicts embolic events in infective endocarditis. J Am Coll Cardiol 2001; 37:1069 –76. 6. Tischler MD, Vaitkus PT. The ability of vegetation size on echocardiography to predict clinical complications: a meta-analysis. J Am Soc Echocardiogr 1997;10:562– 8. 7. Mangoni ED, Adinolfi LE, Tripodi MF, et al. Risk factors for “major” embolic events in hospitalized patients with infective endocarditis. Am Heart J 2003;146;311– 6. 8. Durack DT, Lukes AS, Bright DK. New criteria for diagnosis of infective endocarditis: utilization of specific echocardiographic findings. Am J Med 1994;96:200 –9. 9. Lindback S, Hellgren U, Julander I, et al. The value of C-reactive protein as a marker of bacterial infection in patients with septicaemia/endocarditis and influenza. Scand J Infect Dis 1989;21: 543–9. 10. Olaison L, Hogevik H, Alestig K. Fever, C-reactive protein, and other acute-phase reactants during treatment of infective endocarditis. Arch Intern Med 1997;157:885–92. 11. Lagrand WK, Visser CA, Hermens WT, et al. C-reactive protein as a cardiovascular risk factor: more than an epiphenomenon? Circulation 1999;100:96 –102. 12. Korkmaz S, Ileri M, Hisar I, et al. Increased levels of soluble adhesion molecules, E-selectin and P-selectin, in patients with infective endocarditis and embolic events. Eur Heart J 2001;22:874 – 8. 13. Kupferwasser LI, Hafner G, Mohr-Kahaly S, et al. The presence of infection-related antiphospholipid antibiotics in infective endocarditis determines a major risk factor for embolic events. J Am Coll Cardiol 1999;33:1365–71. 14. Kupferwasser LI, Yeaman MR, Shapiro SM, et al. In vitro susceptibility to thrombin-induced platelet microbicidal protein is associated with reduced disease progression and complication rates in experimental Staphylococcus aureus endocarditis: microbiological, histopathologic, and echocardiographic analyses. Circulation 2002;105:746 –52.