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Increased Cardiovascular Risk in Patients With Human Immunodeficiency Virus Infection Under Highly Active Antiretroviral Therapy
Readers’ Comments
Figure 1. This graph is the predictive and therapeutic tool used by the author to predict and treat the population at risk for, or with extant, atherothrombotic disease. It incorporates a lipid arm, represented by the CRF, and a blood pressure arm, represented by SBP. Any CRF-SBP plot position above the threshold line represents risk for atherothrombotic disease. The graph works equally well at all levels of 2-hour postprandial glucose.
old line increases linearly with age, as does the percentage of those in the same population who develop atherothrombotic events. These lines run parallel, with a 40-year gap between the lines for men and a 20-year gap for women.2 Serial testing affords the opportunity to determine at what age a patient transgresses the threshold line and hence becomes at risk for a future atherothrombotic event. The higher the CRF, the earlier will occur the atherothrombotic event. Cigarette smoking also hastens the onset of atherothrombotic events. In conclusion, I submit that a targeted approach makes more sense than treating everyone with an LDL level ⱖ100 mg/dl (2.6 mmol/L). Although statins are relatively safe, when 100 million individuals are receiving them, even rare adverse events (such as rhabdomyolysis) will affect many. William E. Feeman, Jr., MD Bowling Green, Ohio 17 April 2008
1. Friedewald VE, Ballantyne CM, Nissen SE, Shah PK, Roberts WR. The Editor’s Roundtable: atherosclerosis regression. Am J Cardiol 2008;101:967–974. 2. Feeman WE Jr. Prediction of the population at risk of atherothrombotic disease. Exp Clin Cardiol 2004;9:235–241. 3. Feeman WE Jr. Prediction of angiographic stabilization/regression of coronary atherosclerosis by a risk factor graph. J Cardiol Risk 2000;7:415– 423. doi:10.1016/j.amjcard.2008.05.011
Increased Cardiovascular Risk in Patients With Human Immunodeficiency Virus Infection Under Highly Active Antiretroviral Therapy Schuster et al1 described a high frequency of subclinical cardiac abnormalities in patients seropositive for human immunodeficiency virus (HIV)–1 receiving highly active antiretroviral therapy (HAART). However, an exact mechanistic model to understand the pathways underlying the pathologic development involved is still absent. Inflammation and immune activation are well-known phenomena considered to play an important role in atherogenesis. Immune activation markers such as C-reactive protein and macrophage product neopterin have been shown to correlate with the extent and activity of coronary artery disease, and higher levels strongly predict unfavorable outcomes in addition to the traditional risk factors for cardiovascular disease.2,3 Data are well in line with the current understanding of atherogenesis, in which the activated macrophages play a crucial role, and thus immune activation could also be of greater relevance in the increased risk for myocardial infarction in patients infected with HIV who are receiving HAART. Higher neopterin concentrations are well established to significantly predict the future course of HIV infection,4,5
373
and as expected, the increased neopterin concentrations decrease rapidly during anti-HIV therapy.4,5 However, levels decrease from often very high baseline levels, so levels in most patients do not completely normalize under HAART and remain outside the normal range in many of them. So there exists a continuing inflammatory background in most patients, even under HAART, which may render patients at greater risk for myocardial infarction than healthy adults. We have described that lipid-metabolic changes in patients with untreated HIV infection are closely related to chronic immune activation.6 Increased neopterin production indicates macrophages activated by proinflammatory cytokines, such as interferon-␥, and thus is accompanied by various facets of the antiproliferative activity of this cytokine, which comprises the withdrawal of important nutrients such as tryptophan, iron, and also lipids and incorporation in macrophages. When HAART reduces virus production, immune activation ceases. Consequently, neopterin levels decrease, tryptophan levels increase, and iron is redistributed, as are lipids. This transient increase of lipids could, in addition to residual immune activation, contribute to precipitate myocardial infarction. Robert Zangerle, MD Dietmar Fuchs, PhD Innsbruck, Austria 17 April 2008
1. Schuster I, Thöni GJ, Edérhy S, Walther G, Nottin S, Vinet A, Boccara F, Khireddine M, Girard PM, Mauboussin JM, et al. Subclinical cardiac abnormalities in human immunodeficiency virus-infected men receiving antiretroviral therapy. Am J Cardiol 2008;101:1213– 1217. 2. Ray KK, Morrow DA, Sabatine MS, Shui A, Rifai N, Cannon CP, Braunwald E. Long-term prognostic value of neopterin: a novel marker of monocyte activation in patients with acute coronary syndrome. Circulation 2007;115:3071– 3078. 3. Kaski JC, Consuegra-Sanchez L, FernandezBerges DJ, Cruz-Fernandez JM, Garcia-Moll X, Marrugat J, Mostaza J, Toro-Cebada R, González-Juanatey JR, Guzmán-Martínez G, on behalf of the SIESTA Investigators. Elevated serum neopterin levels and adverse cardiac events at 6 months follow-up in Mediterranean patients with non-ST-segment elevation acute coronary syndrome. Atherosclerosis. In press. 4. Mildvan D, Spritzler J, Grossberg SE, Fahey JL, Johnston DM, Schock BR, Kagan J. Serum neopterin, an immune activation marker, inde-
374
The American Journal of Cardiology (www.AJConline.org)
pendently predicts disease progression in advanced HIV-1 infection. Clin Infect Dis 2005;40:853– 858. 5. Zangerle R, Widner B, Quirchmair G, Neurauter G, Sarcletti M, Fuchs D. Effective antiretroviral therapy reduces degradation of tryptophan in patients with HIV-1 infection. Clin Immunol 2002; 104:242–247. 6. Zangerle R, Sarcletti M, Gallati H, Reibnegger G, Wachter H, Fuchs D. Decreased plasma
concentrations of HDL cholesterol in HIV-infected individuals are associated with immune activation. J Acquir Immune Defic Syndr 1994;7:1149 –1156. doi:10.1016/j.amjcard.2008.04.023
Correction In “Approach to the Diagnosis and Initial Management of the Stable Adult
Patient With a Wide Complex Tachycardia,” by Goldberger et al, in the May 1, 2008 issue of the Journal, in Figure 6, on page 1462, leads aVR and aVF are incorrectly labeled. Lead aVR should be labeled “aVF,” and lead aVF should be labeled “aVR.” doi:10.1016/j.amjcard.2008.06.020
Figure 1. This graph is the predictive and therapeutic tool used by the author to predict and treat the population at risk for, or with extant, atherothrombotic disease. It incorporates a lipid arm, represented by the CRF, and a blood pressure arm, represented by SBP. Any CRF-SBP plot position above the threshold line represents risk for atherothrombotic disease. The graph works equally well at all levels of 2-hour postprandial glucose.
old line increases linearly with age, as does the percentage of those in the same population who develop atherothrombotic events. These lines run parallel, with a 40-year gap between the lines for men and a 20-year gap for women.2 Serial testing affords the opportunity to determine at what age a patient transgresses the threshold line and hence becomes at risk for a future atherothrombotic event. The higher the CRF, the earlier will occur the atherothrombotic event. Cigarette smoking also hastens the onset of atherothrombotic events. In conclusion, I submit that a targeted approach makes more sense than treating everyone with an LDL level ⱖ100 mg/dl (2.6 mmol/L). Although statins are relatively safe, when 100 million individuals are receiving them, even rare adverse events (such as rhabdomyolysis) will affect many. William E. Feeman, Jr., MD Bowling Green, Ohio 17 April 2008
1. Friedewald VE, Ballantyne CM, Nissen SE, Shah PK, Roberts WR. The Editor’s Roundtable: atherosclerosis regression. Am J Cardiol 2008;101:967–974. 2. Feeman WE Jr. Prediction of the population at risk of atherothrombotic disease. Exp Clin Cardiol 2004;9:235–241. 3. Feeman WE Jr. Prediction of angiographic stabilization/regression of coronary atherosclerosis by a risk factor graph. J Cardiol Risk 2000;7:415– 423. doi:10.1016/j.amjcard.2008.05.011
Increased Cardiovascular Risk in Patients With Human Immunodeficiency Virus Infection Under Highly Active Antiretroviral Therapy Schuster et al1 described a high frequency of subclinical cardiac abnormalities in patients seropositive for human immunodeficiency virus (HIV)–1 receiving highly active antiretroviral therapy (HAART). However, an exact mechanistic model to understand the pathways underlying the pathologic development involved is still absent. Inflammation and immune activation are well-known phenomena considered to play an important role in atherogenesis. Immune activation markers such as C-reactive protein and macrophage product neopterin have been shown to correlate with the extent and activity of coronary artery disease, and higher levels strongly predict unfavorable outcomes in addition to the traditional risk factors for cardiovascular disease.2,3 Data are well in line with the current understanding of atherogenesis, in which the activated macrophages play a crucial role, and thus immune activation could also be of greater relevance in the increased risk for myocardial infarction in patients infected with HIV who are receiving HAART. Higher neopterin concentrations are well established to significantly predict the future course of HIV infection,4,5
373
and as expected, the increased neopterin concentrations decrease rapidly during anti-HIV therapy.4,5 However, levels decrease from often very high baseline levels, so levels in most patients do not completely normalize under HAART and remain outside the normal range in many of them. So there exists a continuing inflammatory background in most patients, even under HAART, which may render patients at greater risk for myocardial infarction than healthy adults. We have described that lipid-metabolic changes in patients with untreated HIV infection are closely related to chronic immune activation.6 Increased neopterin production indicates macrophages activated by proinflammatory cytokines, such as interferon-␥, and thus is accompanied by various facets of the antiproliferative activity of this cytokine, which comprises the withdrawal of important nutrients such as tryptophan, iron, and also lipids and incorporation in macrophages. When HAART reduces virus production, immune activation ceases. Consequently, neopterin levels decrease, tryptophan levels increase, and iron is redistributed, as are lipids. This transient increase of lipids could, in addition to residual immune activation, contribute to precipitate myocardial infarction. Robert Zangerle, MD Dietmar Fuchs, PhD Innsbruck, Austria 17 April 2008
1. Schuster I, Thöni GJ, Edérhy S, Walther G, Nottin S, Vinet A, Boccara F, Khireddine M, Girard PM, Mauboussin JM, et al. Subclinical cardiac abnormalities in human immunodeficiency virus-infected men receiving antiretroviral therapy. Am J Cardiol 2008;101:1213– 1217. 2. Ray KK, Morrow DA, Sabatine MS, Shui A, Rifai N, Cannon CP, Braunwald E. Long-term prognostic value of neopterin: a novel marker of monocyte activation in patients with acute coronary syndrome. Circulation 2007;115:3071– 3078. 3. Kaski JC, Consuegra-Sanchez L, FernandezBerges DJ, Cruz-Fernandez JM, Garcia-Moll X, Marrugat J, Mostaza J, Toro-Cebada R, González-Juanatey JR, Guzmán-Martínez G, on behalf of the SIESTA Investigators. Elevated serum neopterin levels and adverse cardiac events at 6 months follow-up in Mediterranean patients with non-ST-segment elevation acute coronary syndrome. Atherosclerosis. In press. 4. Mildvan D, Spritzler J, Grossberg SE, Fahey JL, Johnston DM, Schock BR, Kagan J. Serum neopterin, an immune activation marker, inde-
374
The American Journal of Cardiology (www.AJConline.org)
pendently predicts disease progression in advanced HIV-1 infection. Clin Infect Dis 2005;40:853– 858. 5. Zangerle R, Widner B, Quirchmair G, Neurauter G, Sarcletti M, Fuchs D. Effective antiretroviral therapy reduces degradation of tryptophan in patients with HIV-1 infection. Clin Immunol 2002; 104:242–247. 6. Zangerle R, Sarcletti M, Gallati H, Reibnegger G, Wachter H, Fuchs D. Decreased plasma
concentrations of HDL cholesterol in HIV-infected individuals are associated with immune activation. J Acquir Immune Defic Syndr 1994;7:1149 –1156. doi:10.1016/j.amjcard.2008.04.023
Correction In “Approach to the Diagnosis and Initial Management of the Stable Adult
Patient With a Wide Complex Tachycardia,” by Goldberger et al, in the May 1, 2008 issue of the Journal, in Figure 6, on page 1462, leads aVR and aVF are incorrectly labeled. Lead aVR should be labeled “aVF,” and lead aVF should be labeled “aVR.” doi:10.1016/j.amjcard.2008.06.020