Cardiac diseases in AIDS pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2]

Overview

Many observational studies have shown that HIV-infected patients are at an increased risk for developing a variety of cardiac diseases. With the introduction of HAART, longevity of HIV-infected patients increased, in turn leading to increased prevalence of cardiac and allied diseases. Inflammation and immune regulation leading to atherogenesis, endothelial dysfunction and coagulation abnormalities have been proposed as the major factors in the pathogenesis of cardiovascular diseases in AIDS. Compared to age-matched uninfected controls, HIV-infected patients have a higher risk of myocardial infarction (MI) and cardiovascular death, even with effective anti-retroviral therapy.

Pathophysiology

Atherogenesis

Many observational studies have demonstrated an increased prevalence of subclinical atherosclerosis in HIV-infected patients. The pathology of subclinical atherogenesis is multifactorial and involves inflammation and immune dysregulation along with traditional risk factors like smoking, hypertension, dyslipidemia and diabetes mellitus (DM). Observational studies have shown that compared with uninfected controls, HIV-infected patients have higher intima media thickness (IMT), intra-luminal arterial plaque and coronary artery calcification resulting in increased over-all plaque burden [1][2][3][4]. Contributing factors for atherogenesis in HIV-infected patients include:

  • Active inflammation [5]
    • HIV infection is linked to elevated levels of several inflammatory markers like C-reactive protein (CRP), interleukin-6 (IL-6) etc.
    • Many studies have shown that elevated CRP is associated with increased risk of cardiovascular events.
    • In a small study, it was found that patients with HIV infection and elevated CRP levels have a four fold increased risk of MI compared with patients who have neither of them.
    • Elevated IL-6 levels are associated with HIV RNA viremia, CV events and all-cause mortality.
  • Endothelial dysfunction, as evident by elevated plasma markers like sICAM-1, sVCAM-1, E-selectin, tPAI-1, MPO and MMP9 [6][7]
  • Chronic viral co-infections

HIV drives inflammatory response via direct action by HIV RNA [8] and HIV-associated proteins like Tat and gp120 [9][10]. These proteins are known to promote endothelial dysfunction and apoptosis. It is a known fact that HIV inhibits T-cell responses, however, recent data indicate that HIV, as well as other viruses, induce changes via the activation of T cells into an immunosenescent and more atherogenic phenotype. In a study of 93 HIV infected and 37 uninfected subjects it was found that HIV-infected subjects had thicker carotid IMT compared to controls. It was also found that HIV patients had higher T-cell activation, hs-CRP levels, and CMV-specific T-cell responses and CMV-specific T-cell responses were independently associated with carotid intima media thickness [11][12].

Another mechanism by which HIV accelerates atherosclerosis is by causing alterations in cholesterol metabolism, resulting in redirection of cholesterol to extrahepatic tissues and impairment of cholesterol efflux from macrophages. This leads to accelerated foam cell formation, a characteristic feature of atherosclerosis [13].

Coagulation Abnormalities

Plasma levels of endothelial cell products like von Willebrand factor and soluble thrombomodulin, and D-dimer have been observed to be elevated in HIV-infected patients suggesting an increased risk of thrombosis [14][15]. However, a recent study of 278 HIV-infected patients found that HIV infection is associated with decreased thrombin generation, as measured by the endogenous thrombin potential, and an increased antithrombin level [16].

These findings suggest an unclear association between HIV infection and increased propensity towards clotting.

Cardiac Diseases in AIDS

Cardiac manifestations of AIDS include:

Pericarditis

Pericardial disease is the most common clinical manifestation of cardiovascular disease in patients with AIDS with Mycobacterium tuberculosis being the major infectious cause [17][18]. However, majority of the cases of pericarditis are of unknown etiology. Other causes of pericarditis in AIDS include [19][20][21][22]:

Myocardial Diseases

Major forms of myocardial diseases in patients with AIDS include[23][24]:

  • Focal myocarditis
  • Cardiomyopathy

Focal myocarditis is more of an autopsy finding[25][26] and is caused by opportunistic infections like Cytomegalovirus, Coxsackie virus, Epstein-Barr virus[26], bacterial, fungal and protozoal infections. Since the introduction of HAART for AIDS the incidence of myocarditis has reduced considerably [27].

Clinical dilated cardiomyopathy is seen in 1-3% of patients with AIDS. It was proposed that HIV-associated cardiomyopathy may be related either to a direct action of HIV on the myocardial tissue or to an autoimmune process induced by HIV even in association with other cardiotropic viruses. In a prospective echocardiographic study in 296 HIV infected adults it was found that dilated cardiomyopathy was strongly associated with a CD4 cell count of < 100 x 10(6)/l [28]. Other factors that contribute to LV dysfunction and cardiomyopathy include[29][23]:

Endocardial and Valvular Heart Diseases

Common endocardial diseases in patients with AIDS include:

  • Marantic endocarditis: Marantic endocarditis consists of sterile vegetations and is diagnosed at autopsy. It is clinically silent but may occasionally cause systemic embolization.
  • Infective endocarditis: Infective endocarditis (IE) in AIDS is almost always exclusively due to IV drug use. The most common culprit organism is Staphylococcus aureus and the most common valve involved is tricuspid valve.

With the introduction of HAART the incidence of both marantic endocarditis and infective endocarditis declined drastically and no cases of marantic endocarditis in AIDS patients have been reported since 1989.

References

  1. ↑ Grunfeld C, Delaney JA, Wanke C; et al. (2009). "Preclinical atherosclerosis due to HIV infection: carotid intima-medial thickness measurements from the FRAM study". AIDS (London, England). 23 (14): 1841–9. doi:10.1097/QAD.0b013e32832d3b85. PMC 3156613. PMID 19455012. Unknown parameter |month= ignored (help)
  2. ↑ Lo J, Abbara S, Shturman L; et al. (2010). "Increased prevalence of subclinical coronary atherosclerosis detected by coronary computed tomography angiography in HIV-infected men". AIDS (London, England). 24 (2): 243–53. doi:10.1097/QAD.0b013e328333ea9e. PMC 3154841. PMID 19996940. Unknown parameter |month= ignored (help)
  3. ↑ Fitch KV, Lo J, Abbara S; et al. (2010). "Increased coronary artery calcium score and noncalcified plaque among HIV-infected men: relationship to metabolic syndrome and cardiac risk parameters". Journal of Acquired Immune Deficiency Syndromes (1999). 55 (4): 495–9. doi:10.1097/QAI.0b013e3181edab0b. PMC 2974783. PMID 20720497. Unknown parameter |month= ignored (help)
  4. ↑ Pereyra F, Lo J, Triant VA; et al. (2012). "Increased coronary atherosclerosis and immune activation in HIV-1 elite controllers". AIDS (London, England). 26 (18): 2409–12. doi:10.1097/QAD.0b013e32835a9950. PMID 23032411. Unknown parameter |month= ignored (help)
  5. ↑ Subramanian S, Tawakol A, Burdo TH; et al. (2012). "Arterial inflammation in patients with HIV". JAMA : the Journal of the American Medical Association. 308 (4): 379–86. doi:10.1001/jama.2012.6698. PMID 22820791. Unknown parameter |month= ignored (help)
  6. ↑ Kristoffersen US, Kofoed K, Kronborg G, Giger AK, Kjaer A, Lebech AM (2009). "Reduction in circulating markers of endothelial dysfunction in HIV-infected patients during antiretroviral therapy". HIV Medicine. 10 (2): 79–87. doi:10.1111/j.1468-1293.2008.00661.x. PMID 19200170. Unknown parameter |month= ignored (help)
  7. ↑ Neuhaus J, Jacobs DR, Baker JV; et al. (2010). "Markers of inflammation, coagulation, and renal function are elevated in adults with HIV infection". The Journal of Infectious Diseases. 201 (12): 1788–95. doi:10.1086/652749. PMC 2872049. PMID 20446848. Unknown parameter |month= ignored (help)
  8. ↑ Beignon AS, McKenna K, Skoberne M; et al. (2005). "Endocytosis of HIV-1 activates plasmacytoid dendritic cells via Toll-like receptor-viral RNA interactions". The Journal of Clinical Investigation. 115 (11): 3265–75. doi:10.1172/JCI26032. PMC 1253628. PMID 16224540. Unknown parameter |month= ignored (help)
  9. ↑ Huang MB, Khan M, Garcia-Barrio M, Powell M, Bond VC (2001). "Apoptotic effects in primary human umbilical vein endothelial cell cultures caused by exposure to virion-associated and cell membrane-associated HIV-1 gp120". Journal of Acquired Immune Deficiency Syndromes (1999). 27 (3): 213–21. PMID 11464139. Unknown parameter |month= ignored (help)
  10. ↑ Li JC, Yim HC, Lau AS (2010). "Role of HIV-1 Tat in AIDS pathogenesis: its effects on cytokine dysregulation and contributions to the pathogenesis of opportunistic infection". AIDS (London, England). 24 (11): 1609–23. doi:10.1097/QAD.0b013e32833ac6a0. PMID 20588103. Unknown parameter |month= ignored (help)
  11. ↑ Hsue PY, Hunt PW, Sinclair E; et al. (2006). "Increased carotid intima-media thickness in HIV patients is associated with increased cytomegalovirus-specific T-cell responses". AIDS (London, England). 20 (18): 2275–83. doi:10.1097/QAD.0b013e3280108704. PMID 17117013. Unknown parameter |month= ignored (help)
  12. ↑ Kaplan RC, Sinclair E, Landay AL; et al. (2011). "T cell activation and senescence predict subclinical carotid artery disease in HIV-infected women". The Journal of Infectious Diseases. 203 (4): 452–63. doi:10.1093/infdis/jiq071. PMC 3071219. PMID 21220772. Unknown parameter |month= ignored (help)
  13. ↑ Bukrinsky M, Sviridov D (2006). "Human immunodeficiency virus infection and macrophage cholesterol metabolism". Journal of Leukocyte Biology. 80 (5): 1044–51. doi:10.1189/jlb.0206113. PMID 17056763. Unknown parameter |month= ignored (help)
  14. ↑ Seigneur M, Constans J, Blann A; et al. (1997). "Soluble adhesion molecules and endothelial cell damage in HIV infected patients". Thrombosis and Haemostasis. 77 (4): 646–9. PMID 9134636. Unknown parameter |month= ignored (help)
  15. ↑ Armah KA, McGinnis K, Baker J; et al. (2012). "HIV status, burden of comorbid disease, and biomarkers of inflammation, altered coagulation, and monocyte activation". Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 55 (1): 126–36. doi:10.1093/cid/cis406. PMID 22534147. Unknown parameter |month= ignored (help)
  16. ↑ Hsue PY, Scherzer R, Grunfeld C; et al. (2012). "HIV infection is associated with decreased thrombin generation". Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 54 (8): 1196–203. doi:10.1093/cid/cis014. PMC 3309887. PMID 22438347. Unknown parameter |month= ignored (help)
  17. ↑ Maher D, Harries AD (1997). "Tuberculous pericardial effusion: a prospective clinical study in a low-resource setting--Blantyre, Malawi". The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union against Tuberculosis and Lung Disease. 1 (4): 358–64. PMID 9432393. Unknown parameter |month= ignored (help)
  18. ↑ Dronda F, Suzacq C (1997). "[Pericardial tuberculosis complicated with heart tamponade as presentation form of acquired immunodeficiency syndrome]". Revista Clínica Española (in Spanish; Castilian). 197 (7): 502–6. PMID 9411548. Unknown parameter |month= ignored (help)
  19. ↑ Chen Y, Brennessel D, Walters J, Johnson M, Rosner F, Raza M (1999). "Human immunodeficiency virus-associated pericardial effusion: report of 40 cases and review of the literature". American Heart Journal. 137 (3): 516–21. PMID 10047635. Unknown parameter |month= ignored (help)
  20. ↑ Flum DR, McGinn JT, Tyras DH (1995). "The role of the 'pericardial window' in AIDS". Chest. 107 (6): 1522–5. PMID 7781340. Unknown parameter |month= ignored (help)
  21. ↑ Gouny P, Lancelin C, Girard PM, Hocquet-Cheynel C, Rozenbaum W, Nussaume O (1998). "Pericardial effusion and AIDS: benefits of surgical drainage". European Journal of Cardio-thoracic Surgery : Official Journal of the European Association for Cardio-thoracic Surgery. 13 (2): 165–9. PMID 9583822. Unknown parameter |month= ignored (help)
  22. ↑ Eisenberg MJ, Gordon AS, Schiller NB (1992). "HIV-associated pericardial effusions". Chest. 102 (3): 956–8. PMID 1516433. Unknown parameter |month= ignored (help)
  23. ↑ 23.0 23.1 Sani MU (2008). "Myocardial disease in human immunodeficiency virus (HIV) infection: a review". Wiener Klinische Wochenschrift. 120 (3–4): 77–87. doi:10.1007/s00508-008-0935-3. PMID 18322768.
  24. ↑ Sudano I, Spieker LE, Noll G, Corti R, Weber R, Lüscher TF (2006). "Cardiovascular disease in HIV infection". American Heart Journal. 151 (6): 1147–55. doi:10.1016/j.ahj.2005.07.030. PMID 16781213. Unknown parameter |month= ignored (help)
  25. ↑ Anderson DW, Virmani R, Reilly JM; et al. (1988). "Prevalent myocarditis at necropsy in the acquired immunodeficiency syndrome". Journal of the American College of Cardiology. 11 (4): 792–9. PMID 3351145. Unknown parameter |month= ignored (help)
  26. ↑ 26.0 26.1 Barbaro G, Di Lorenzo G, Grisorio B, Barbarini G (1998). "Cardiac involvement in the acquired immunodeficiency syndrome: a multicenter clinical-pathological study. Gruppo Italiano per lo Studio Cardiologico dei pazienti affetti da AIDS Investigators". AIDS Research and Human Retroviruses. 14 (12): 1071–7. PMID 9718123. Unknown parameter |month= ignored (help)
  27. ↑ Barbaro G (2005). "Reviewing the cardiovascular complications of HIV infection after the introduction of highly active antiretroviral therapy". Current Drug Targets. Cardiovascular & Haematological Disorders. 5 (4): 337–43. PMID 16101566. Unknown parameter |month= ignored (help)
  28. ↑ Currie PF, Jacob AJ, Foreman AR, Elton RA, Brettle RP, Boon NA (1994). "Heart muscle disease related to HIV infection: prognostic implications". BMJ (Clinical Research Ed.). 309 (6969): 1605–7. PMC 2542022. PMID 7819934. Unknown parameter |month= ignored (help)
  29. ↑ Lewis W (2000). "Cardiomyopathy in AIDS: a pathophysiological perspective". Progress in Cardiovascular Diseases. 43 (2): 151–70. doi:10.1053/pcad.2000.9031. PMID 11014331.
  30. ↑ Herskowitz A, Willoughby SB, Baughman KL, Schulman SP, Bartlett JD (1992). "Cardiomyopathy associated with antiretroviral therapy in patients with HIV infection: a report of six cases". Annals of Internal Medicine. 116 (4): 311–3. PMID 1733387. Unknown parameter |month= ignored (help)


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