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Cardiovascular Disease in the Multicenter AIDS Cohort Study (MACS)

Cardiovascular Disease in the Multicenter AIDS Cohort Study (MACS). Wendy Post, M.D., M.S. Professor of Medicine and Epidemiology Cardiology Division Ciccarone Center for the Prevention of Heart Disease Johns Hopkins University School of Medicine. 100. 100. % Patients on HAART

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Cardiovascular Disease in the Multicenter AIDS Cohort Study (MACS)

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  1. Cardiovascular Disease in the Multicenter AIDS Cohort Study (MACS) Wendy Post, M.D., M.S. Professor of Medicine and Epidemiology Cardiology Division Ciccarone Center for the Prevention of Heart Disease Johns Hopkins University School of Medicine

  2. 100 100 % Patients on HAART Combined rate of AIDS and death 80 60 CombinedAIDS and Death Rates Patients % 10 40 20 0 1 Sept 1994 Sept1999–March 2000 Sept 2000–March2001 Sept1998–March 1999 March 1995–Sept1995 Sept 1995–March1996 March 1996–Sept 1996 Sept 1996–March1997 M<arch 1995 March 1997–Sept1997 Sept1997–March 1998 March 1998–Sept 1998 March 2000–Sept2000 Sept 2001–onwards Decreases in AIDS and Death Since the Introduction of HAART Mortality across Europe, Israel and Argentina in 9803 patients: EuroSIDA March 2001– Sept 2001 March 1999– Sept 1999 Mocroft A, et al. Lancet2003;362:22

  3. DEATHS Overall HIV-Related Non-HIV-Related Cardiovascular-Related Cancer-Related Substance Abuse-Related 900 N=68,669 800 700 600 500 400 Age-adjusted Mortality Rateper 10,000 Persons With AIDS 300 200 100 30 20 10 2001 2002 2003 2000 1999 2004 Cardiovascular-related Disease is a Leading Cause of Non-HIV-related Death Age-adjusted Mortality Rate in HIV+ by Underlying Cause of Death, New York City (1999-2004) Sackoff, et al. Ann Int Med. 2006;145:397-406.

  4. Potential CVD Risk in HIV Patients HIV Infection Inflammatory Response Non-HIV Traditional CVD Risk Factors Treatment of HIV Anti-retroviral Therapy Metabolic side effects

  5. Multicenter AIDS Cohort Study(MACS) • Prospective observational cohort study of natural history of HIV in MSM at 4 sites in the US (Baltimore/Washington D.C., Chicago, Los Angeles, Pittsburg) • 6972 men since 1984 • Includes both HIV+ and HIV- men • Semi-annual visits for standardized interview, clinical evaluation, laboratory tests

  6. MACS CVD2 Study Specific Aim One: To determine whether there is a difference in the prevalence of subclinical CVD between HIV+ and HIV- men. Procedures: CT Coronary artery calcium CT Coronary angiography Carotid ultrasound NHLBI RO1- Post PI

  7. Specific Aim Two: To determine potential mechanisms leading to subclinical CVD in this population. Procedures: CT abdomen- subcutaneous and visceral fat CT thigh- subcutaneous fat Hepatic fat Pericardial and epicardial fat Blood assays Traditional CVD risk factors

  8. MACS CVD3 Inclusion criteria for enrollment 1) Active MACS participant 2) Age 40- 70 years at time of enrollment Exclusion criteria for enrollment 1) History of cardiac surgery (CABG or valve surgery) 2) History of coronary angioplasty ± stent placement 3) Weight > 300 pounds (due to limitations for CT) Exclusion for contrast • Kidney disease- eGFR < 60 mg/ml/m2 • Contrast allergy

  9. Non-Contrast Cardiac CT Scans No Calcification Severe Calcification LAD PA LAD Aorta Left Main Left Main LA LCX

  10. Coronary MDCT

  11. Cardiac CTANormal Coronary Arteries

  12. Mixed Plaque Plaque but no significant stenosis

  13. Calcified Coronary Arteries

  14. Examples of Coronary Plaque Mixed Plaque Calcified Plaque Non-calcified Plaque

  15. Methods:Coronary artery stenosis graded in each coronary segment • No stenosis or plaque present • Plaque present < 25% stenosis – minimal 25 to 49% stenosis - mild 50 to 70% - moderate > 70% stenosis - severe

  16. Methods:Plaque size and composition graded in each coronary segment Size of each plaque Small - 1 Medium- 2 Large- 3 Total Plaque Score= sum of plaque in each coronary segment Plaque composition Non-calcified Mixed Calcified

  17. Results- Demographics and Characteristics

  18. Lipids

  19. HIV Clinical Characteristics * Among men with detectable HIV RNA

  20. Non-contrast CT Scans

  21. Associations between HIV and Presence of Coronary Artery Calcium Prevalence Ratio calculated using multiple poisson regressions with robust variances comparing HIV + to HIV - men *Adjusted for age, race, CT scanning center and MACS cohort (pre- vs. post-2001) † Additionally adjusted for systolic BP, antihypertensive medication use, diabetes medication use, fasting glucose, total cholesterol, HDL cholesterol, use of lipid-lowering medications, BMI and smoking (pack-years)

  22. Coronary CTA Plaque and Stenosis Prevalence

  23. Associations between HIV and Presence of Coronary Artery Plaque on CT Angiography Plaque present = plaque score >0 Separate multiple poisson regressions with robust variances comparing HIV + to HIV - men

  24. SummaryPlaque Prevalence • There is a greater prevalence of coronary artery calcium (CAC), any plaque on CT angiography, non-calcified and mixed plaque in HIV seropositive men than HIV seronegative men. • These associations persist after adjustment for CVD risk factors for non-calcified plaque and any plaque on CT angiography.

  25. Associations between HIV and Extent of Coronary Artery Plaqueamong men with plaque present Mean difference calculated using separate multiple linear regressions with log transformed scores comparing HIV + to HIV – men, among men with plaque present

  26. Prevalence (%) of Coronary Artery Stenosisand Associations with HIV (N= 759) PR= 1.20 (0.70, 2.05), p=0.51 Adjusted for age, race, center, and cohort PR= 0.76 (0.44, 1.30), p=0.31 Also adjusted for CVD risk factors PR= 1.48 (1.06,2.07), p=0.02 Adjusted for age, race, center, and cohort PR= 1.23 (0.86, 1.75), p=0.26 Also adjusted for CVD risk factors

  27. Associations between HIV Clinical Factors and Coronary Artery Stenosis > 50% among HIV+ Men

  28. SummaryCoronary Artery Stenosis (Blockage) • There is a greater prevalence of stenosis > 50% in HIV seropositive men. • This association is no longer apparent after adjusting for CVD risk factors. • Stenosis > 50% is independently associated with duration of HAART and nadir CD4 count.

  29. Summary/Conclusions • Non-calcified plaque is more prevalent and extensive in HIV-infected men, suggesting increased risk for cardiovascular events. • Men with more advanced HIV infection, as demonstrated by low nadir CD4+ T cell count and a greater number of years on HAART have a higher prevalence of clinically significant coronary stenosis > 50%. • Additional studies are needed to identify how best to prevent progression of atherosclerosis in this unique population and correlation with future events. • Although coronary CT angiography is not indicated as a screening test in asymptomatic individuals, these results emphasize the importance of assessing and modifying traditional cardiovascular risk factors in this population, especially in men with a history of a low nadir CD4+ T cell count.

  30. R01 HL125053 (Post) 08/07/2014 – 04/30/2018 Progression of Coronary Atherosclerosis in MACS Does coronary atherosclerosis progress more rapidly in HIV Patients? • Primary outcome: Relative change in total volume of non-calcified plaque over time. • State-of-the-art, validated, semi-automatic plaque analysis software • More precise data regarding plaque composition and volume than the semi-quantitative method available previously for our cross-sectional analysis • Assessment of “vulnerable” plaque characteristics • Low attenuation plaque • Positive remodeling • Spotty calcification

  31. Development of focal calcification in LAD (2010- 2015)

  32. Proportion of men with CAC = 0 50% Number of men N=225 48% N=148 50% 52% N=225 N=167 N=450 N=309 Metkus T, et al. HIV Medicine; 2015 In press

  33. HIV is associated with presence of non calcified plaque in men with CAC=0 • * Adjusted for age, race, center • † Adjusted, in addition, for systolic BP, antihypertensive medication use, diabetes medication use, fasting glucose, total cholesterol, HDL cholesterol, use of lipid-lowering medications, BMI and smoking (pack-years) • There were no associations between NCP and markers of HIV control, including nadir CD4 cell count, years of ART and detectable HIV RNA Metkus T, et al. HIV Medicine; 2015 In press

  34. HIV+ Men at Low Calculated CVD Risk Have Excess Atherosclerosis: MACS HIV+ vs HIV- OR=1.6 (0.7, 3.6) Odds of Plaque on Coronary CTA among 754 Men (450 HIV+/304 HIV-) in the MACS Age 40-70 2010-2013 HIV+ vs HIV- OR=2.0*, 3.4) HIV+ vs HIV- OR=1.3 (0.7, 2.7) Monroe A, Haberlen S, Post W, Brown T, et al. Unpublished data.

  35. Monocyte Activation Markers Are Elevated in HIV-infected Men in MACS Serologic markers of monocyte activation measured at time of cardiac CT scanning in the MACS soluble CD163 (sCD163) soluble CD14 (sCD14) monocyte chemoattractant protein-1 (CCL2) McKibben RA et al. J Infect Dis. 2014 Oct 30. Epub ahead of print

  36. Monocyte Activation Markers Associated with Immunodeficiency and HIV Viremia McKibben RA et al. J Infect Dis. 2014 Oct 30. Epub ahead of print

  37. Elevated Monocyte Activation Markers Associated with Coronary Artery Stenosis Among HIV-infected Men n=566 for coronary artery calcium n=426 for coronary plaque subtypes Odds Ratio and 95% CI for associations between biomarkers (quintile 5 compared to quintile 1) and prevalence of coronary plaque, including coronary stenosis ≥50%, among HIV-infected men Models were adjusted for age, race, HIV serostatus and CVD risk factors Red lines indicate p<0.05. * trend across quintiles of biomarker p<0.05. ** trend across quintiles of biomarker p<0.01. McKibben RA et al. J Infect Dis. 2014 Oct 30. Epub ahead of print

  38. Predictors of Atherosclerosis in MACS CVD2(separate manuscripts) • Insulin Resistance • Lipids • ART • Inflammation markers (IL-6, sTNFRα 1 and 2) • Smoking • TMAO and microbiome • HDL Function • Testosterone • Adiponectin • Epicardial adipose tissue • Race • Monocyte Activation Markers (sCD163, sCD14, MCP-1) • HCV infection • Chronic Kidney Disease • Osteoprotegerin • Subcutaneous and Visceral Adipose Tissue Published Manuscripts, Submitted for Publication, Working on Pen Draft, Data Analyses

  39. HIV and Risk of Heart Failure Veterans Aging Cohort Study 8486 participants 28.2% HIV-infected 7.3 years of follow-up Adjusted HR 1.81 (95% CI, 1.39-2.36) Limited data on myocardial function Butt AA et al. Arch Intern Med 2011;171(8):737-743

  40. Myocardial fibrosis on cardiac MRI more common in HIV Myocardial fibrosis present HIV+ (on cART) 76% HIV- 13% Peak myocardial longitudinal systolic and diastolic strain were lower in HIV+ Small sample size N=39 N=90 P<0.001 Holloway CJ et al. Circulation 2013;128:814-822.

  41. Myocardial disease in HIV Do HIV+ patients have a greater prevalence of myocardial abnormalities that can predispose to sudden cardiac death or heart failure than HIV- individuals? Does use of drugs and alcohol confound these associations? • N= 400 • MACS (Baltimore/DC and Chicago), WIHS (DC), ALIVE (Baltimore) R01HL126552 (Post/WU – Multi PI) 09/15/14 – 07/31/18 Identifying Risk Factors for Subclinical Myocardial Disease in HIV Infection

  42. Summary • HIV patients are increased risk for CVD • Inflammation/immune activation contribute to risk for atherosclerosis and CVD independent of traditional CVD risk factors • Elevated sCD163 levels are associated with vascular inflammation and also coronary atherosclerosis in patients with HIV • Lower nadir CD4+ T cell counts associated with coronary stenosis

  43. Conclusions • Clinical trials are needed to inform HIV guidelines • REPRIEVE will test statin therapy • Need an aspirin clinical trial • Need data about CAC and risk • Until further data, use guidelines in place for general population (AHA/ACC guidelines) • Treat HIV+ patients with multiple CVD risk factors most aggressively

  44. Acknowledgements • CAMACS- Hopkins • Lisa Jacobson • Sabina Haberlen • Andrea Stronski • Xiuhong Li • Sandra Reynolds • Jennifer Deal • Richey Sharrett • Janet Schollenberger • Hemjot Kaur • AsiehGolozar • Frank Palella- Chicago PI • Larry Kingsley – Pittsburgh PI • Mallory Witt – LA PI • Matt Budoff - CT reading center • Katherine Wu • Todd Brown • Richard George • Adrian Dobs • Joseph Margolick • NIAID- MACS • NHLBI- R01HL126552 (Post/Wu) • R01HL125053 (Post) • RO1 HL095129 (Post)

  45. Thank You

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