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Clinical Science

Brief Report: Differences in Types of Myocardial Infarctions Among People Aging With HIV

Crane, Heidi M. MD, MPHa; Nance, Robin M. MSa; Whitney, Bridget M. PhDa; Heckbert, Susan R. MD, PhDa; Budoff, Matthew MDb; High, Kevin MD, MSc; Landay, Alan PhDd; Feinstein, Matthew MDe; Moore, Richard D. MDf; Mathews, William Christopher MDg; Christopoulos, Katerina MDh; Saag, Michael S. MDi; Willig, Amanda PhD, RDi; Eron, Joseph J. MDj; Kitahata, Mari M. MDa; Delaney, Joseph A. C. PhDa,k; for the Centers for AIDS Research Network of Clinical Information Systems

Author Information
JAIDS Journal of Acquired Immune Deficiency Syndromes: February 1, 2021 - Volume 86 - Issue 2 - p 208-212
doi: 10.1097/QAI.0000000000002534

Abstract

BACKGROUND

There are many unanswered questions regarding a myocardial infarctions (MIs) in people living with HIV (PLWH). The Universal Definition of MI classifies MIs into 5 types according to the mechanism of myocardial ischemia.1,2 For example, type 1 MIs (T1MIs) result spontaneously from atherosclerotic plaque instability, and type 2 MIs (T2MIs) are secondary to causes other than atherosclerotic plaque rupture, including sepsis, hypoxia, and stimulant-induced spasm resulting in increased oxygen demand–supply mismatch. Type 3 MIs are deaths occurring with symptoms suggestive of MI; however, cardiac biomarkers are not measured. Type 4 and 5 MIs occur in the setting of coronary revascularization procedures.

Different MI types may indicate different prognoses and optimal medical management.3 In the general population, most MIs were believed to be T1MIs; estimates of T2MI incidence vary depending on the population and event ascertainment methods, but most general population studies suggest T2MIs are a minority of MIs.4–12 By contrast, we previously demonstrated that almost half of MIs among PLWH in care at our clinics across the United States are T2MIs.13 We also demonstrated that there are important differences in demographic and clinical characteristics among PLWH with T1MIs vs. T2MIs.13 Furthermore, we demonstrated that there are prognostic differences, whereby T2MIs are associated with higher mortality than T1MIs among PLWH14; this pattern was also recently shown in the general population, with higher T2MI-associated mortality than T1MI-associated mortality.15 However, many previous studies have not differentiated MI types limiting the ability to understand MI characteristics and prognosis in PLWH.

General population studies have demonstrated that those with T1MIs are younger than those with T2MIs.16,17 However, little is known about how age might vary by MI types in PLWH. We conducted this study to compare MI incidence rates by type and age among PLWH. We hypothesized that increases in rates with older age would differ by MI types, and that in contrast to the general population, T2MIs would be more common in younger individuals due to the different pattern of causes of T2MI among PLWH than the general population. In addition, we hypothesized that there would be a measurable rate of T1MI among young adult (<30 years old) PLWH.

METHODS

Study Setting

A longitudinal observational cohort study at the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS), a multisite clinical cohort of PLWH receiving HIV care at sites across the United States.18

Study Participants

PLWH aged ≥18 years receiving HIV care at 6 CNICS sites after MI adjudication began (inclusion dates varied by site, ∼2000–2019). Site locations included Seattle, Birmingham, Chapel Hill, Baltimore, San Diego, and San Francisco. We excluded individuals with information suggesting a previous MI before the start of MI surveillance in CNICS to focus analyses on first incident MI events alone.

Data Sources

The CNICS Data Repository integrates comprehensive clinical data from outpatient and inpatient encounters including information on demographic characteristics, clinical and laboratory data, and medications.

CNICS has an established state-of-the-art approach to MI adjudication13,19 with MIs categorized by type based on the Universal MI definition.1,2 We identified potential MIs in the centralized CNICS data repository using a comprehensive set of MI diagnostic and procedure codes and elevated cardiac biomarker values to optimize ascertainment sensitivity as previously described.13,19 For each potential MI, sites assembled a deidentified packet that included available provider notes, electrocardiograms, laboratory results, and imaging and procedure results, including from cardiac catheterizations. Two physicians with expertise in adjudicating cardiac disorders reviewed each packet, followed by a third reviewer if discrepancies occurred. Reviewers categorized MIs by type, identified causes for a T2MI, and also identified PLWH without an MI but with coronary interventions, such as a coronary artery bypass graft surgery or percutaneous transluminal coronary angioplasty. We grouped coronary interventions with a T1MI, based on previous work evaluating the similarity of PLWH with adjudicated T1MIs and coronary interventions.13 MI types other than T1MIs and T2MIs are not discussed further because of the low event numbers (there have been <10 type 4 and 5 MIs in CNICS to date).

Outcomes

We examined T1MIs and T2MIs.

Analyses

We used χ2 and t tests for categorical and continuous variables, respectively, to assess differences in demographic and clinical characteristics among PLWH with a T1MI or cardiac intervention vs. T2MI. By decade of age, we calculated T1MI and T2MI incidence rates and jackknife confidence intervals (CIs) per 1000 person-years of follow-up. Time at risk for an MI started at the initial CNICS visit or the site-specific MI surveillance date, whichever was later. Follow-up continued until the earliest of MI, death, last CNICS visit, or laboratory plus 9 months or administrative censoring date by site. Incidence rate ratios (IRRs) and 95% CIs were subsequently calculated to compare rates of T2MI vs. T1MI by decade of age. For PLWH <30 or 70 years or older, we combined all individuals because of smaller numbers of PLWH. Analyses were performed using STATA version 14.2.

RESULTS

Among 28,741 PLWH, 875 PLWH were adjudicated to have had an MI during a median follow-up of 5.3 years [interquartile range (IQR) 2.2–9.4 years]. Among those with an MI, 79% were men, the median age was 51 (IQR, 44–57) years, 50% were African American, 78% were on antiretroviral therapy (ART), and the current median CD4 cell count was 355 cells/mm3 (IQR 144–584); the current CD4 count was based on measures drawn during care; a median of 49 days before the MI (IQR 15–114 days).

Among the 875 MIs, 462 were T1MIs (53%) and 413 were T2MIs (47%); included as part of T1MIs were 122 (14%) events adjudicated not to have met MI criteria but were PLWH with severe enough atherosclerotic disease that they underwent a coronary intervention, such as a percutaneous transluminal coronary angioplasty or coronary artery bypass graft. A higher proportion of PLWH who had a T1MI were aged >40 years, men, White, on ART, on a statin, and had higher total cholesterol or low-density lipoprotein cholesterol levels compared with those with a T2MI (Table 1). The median CD4 cell count was higher among those with a T1M1 vs. T2MI (423 vs. 253 cells/mm3, P <0.001).

TABLE 1. - Clinical and Demographic Characteristics of People Living With HIV at 6 Sites Across the United States by MI Type
Characteristic No MI (N = 27,866), N (%) T1MI* (N = 462), N (%) T2MI (N = 413), N (%) P
Age, yrs median (IQR) 47 (38,55) 52 (46,58) 50 (43,56) <0.001
Age, yrs by decade <0.001
 <30 2254 (8) 2 (<1) 20 (5)
 30–39 6101 (22) 30 (6) 47 (11)
 40–49 8187 (29) 152 (33) 134 (32)
 50–59 7816 (28) 189 (41) 147 (36)
 60–69 2935 (11) 68 (15) 45 (11)
 ≥70 573 (2) 21 (5) 20 (5)
Sex <0.001
 Male 22,561 (81) 393 (85) 301 (73)
Race/ethnicity <0.001
 White 11,529 (41) 225 (49) 106 (26)
 African American 11,245 (40) 175 (38) 264 (64)
 Hispanic 3605 (13) 45 (10) 34 (8)
 Other/unknown 1487 (5) 17 (4) 9 (2)
HIV transmission risk factor <0.001
 Heterosexual 7071 (25) 106 (23) 123 (30)
 Men who have sex with men 14,427 (52) 239 (52) 127 (31)
 Injection drug use 5018 (18) 97 (21) 147 (36)
 Other/unknown 1350 (5) 20 (4) 16 (4)
ART <0.001
 Yes 22,100 (79) 390 (84) 298 (72)
CD4 count closest to event, cells/µL <0.001
 0–200 4480 (16) 92 (20) 170 (41)
 201–350 4107 (15) 82 (18) 75 (18)
 >350 19,199 (69) 287 (62) 168 (41)
Nadir CD4 cell count, cells/µL 0.06
 Median (IQR) 223 (70,390) 150 (41,298) 98 (17,242)
HIV-1 RNA closest to event, copies/mL <0.001
 <500 21,181 (76) 339 (74) 229 (55)
 500–100,000 4900 (18) 97 (21) 121 (29)
 >100,000 1617 (6) 25 (5) 63 (15)
Lipid levels mean (mean, SD)
 Total cholesterol, mg/Dl 172 (42) 188 (53) 164 (58) <0.001
 HDL, mg/dL 46 (16) 41 (14) 43 (20) 0.06
 LDL, mg/dL 98 (34) 108 (41) 86 (39) <0.001
 Triglycerides 156 (132) 213 (183) 192 (223) 0.2
Statin use <0.001
 Yes 5403 (19) 228 (49) 103 (25)
Blood pressure (mean, SD)
 Systolic, mmHg 126 (16) 131 (20) 129 (23) 0.2
 Diastolic, mmHg 79 (11) 80 (13) 79 (14) 0.1
Antihypertensive medication use 0.3
 Yes 10,685 (39) 323 (70) 273 (67)
Diabetes 0.3
 Yes 3429 (12) 113 (24) 113 (27)
Ever smoking 0.3
 Yes 10,152 (36) 216 (47) 180 (44)
Body mass index (mean, SD) <0.001
 Body mass index, kg/m2 27 (6) 27 (6) 25 (6)
Risk score (mean, SD) 0.7
 ASCVD (%10 yr event risk) 8 (10) 14 (12) 14 (14)
Demographic and clinical characteristics at time of MI or at end of follow-up.
*T1MI also includes patients with coronary interventions.
Comparing T1MI with T2MI.
ASCVD, atherosclerotic cardiovascular disease risk score; HDL, high-density lipoprotein cholesterol; LDL, low-density lipoprotein cholesterol.

We examined incidence rates by age and found T1MIs occurred in all age decades, including young adults <30 years, among PLWH. The rates of T1MI increased for each decade of older age (Table 2) with much higher rates among those 70 years and older (9.32 T1MIs per 1000 person-years of follow-up). T2MIs also occurred in every decade of adult PLWH and rates increased with age among PLWH 40 years and older (Table 2).

TABLE 2. - Rates of Type 1 and Type 2 MIs per 1000 Person-Years of Follow-Up Among PLWH at 6 CNICS Sites Across the United States
Age Category Rate (CI) Type I MI Rate (CI) Type 2 MI IRR (CI) Type 2 vs. Type 1 MIs, P
<30 0.13 (0.03 to 1.32) 1.31 (0.86 to 2.11) 10.0 (2.43 to 88.24), 0.001
30–39 0.71 (0.50 to 1.03) 1.11 (0.84 to 1.49) 1.57 (0.97 to 2.57), 0.05
40–49 2.33 (1.99 to 2.74) 2.06 (1.74 to 2.45) 0.88 (0.69 to 1.12), 0.3
50–59 3.91 (3.40 to 4.53) 3.04 (2.59 to 3.59) 0.78 (0.62 to 0.97), 0.02
60–69 5.13 (4.07 to 6.56) 3.42 (2.58 to 4.63) 0.67 (0.45 to 0.98), 0.03
≥70 9.32 (6.16 to 14.78) 8.88 (5.80 to 14.26) 0.95 (0.49 to 1.85), 0.9

We compared incidence rates between T1MI and T2MI. T2MI rates were significantly higher than T1MI rates for PLWH <40 years (Table 2). In particular, the comparison of T2MI with T1MI rates demonstrated the highest relative difference in those <30 years (IRR = 10.0, 95% CI: 2.43 to 88.24, P < 0.001). Rates of T1MI and T2MI were not significantly different among those 40–49 years. However, among PLWH aged 50–59 and 60–69 years, T1MI rates were significantly higher (IRR = 0.78, 95% CI: 0.62 to 0.97, P = 0.02; IRR = 0.67, 95% CI: 0.45 to 0.98, P = 0.03, respectively).

We also examined causes of T2MIs. Sepsis (36%), cocaine or other drug-induced vasospasm (11%), and respiratory failure (10%) were the most frequently identified likely causes of T2MIs (see Figure 1, Supplemental Digital Content, https://links.lww.com/QAI/B550). In every decade, more T2MIs were associated with sepsis than any other T2MI cause. However, although sepsis was always the most common cause, the proportion of T2MI due to sepsis varied by age, with more T2MIs due to sepsis among younger adult PLWH (50% of T2MI among those <30 years) and older adults (50% of T2MI among those >60 years) and a lower percentage among those who were middle aged (27% of T2MI among those 40–49 years). Demographic characteristics of those with T2MIs due to sepsis resembled those with T2MIs due to other causes; however, CD4 counts, particular nadir counts of those with a T2MI due to sepsis who were younger than 50 years were very low (median 21 cells/mm3) (see Table 1, Supplemental Digital Content, https://links.lww.com/QAI/B550).

DISCUSSION

We examined MI types by age in a large, nationally distributed HIV cohort. T2MIs were common, comprising half of all MIs observed during follow-up. PLWH with a T1MI were on average older, had a higher CD4 cell count, and were more likely to be on ART than those with a T2MI. We found that both T1MI and T2MI occurred in every age category including young adult PLWH (aged <30 years). T1MI incidence rates increased among adults with each decade of age, and T2MI incidence rates increased with each decade older than 40 years, resulting in higher T2MI vs. T1MI rates for PLWH younger than 40 years and higher T1MI vs. T2MI rates among PLWH 50–69 years. Sepsis was the most common cause of T2MI in every decade, although the proportion due to sepsis varied with age. These results highlight that a T1MI and T2MI represent distinct clinical entities that require different approaches to prevention and treatment, as noted in the general population and in our recent investigation of PLWH.3,13–15 Importantly, a T1MI vs. T2MI impact PLWH at different rates across the age spectrum, with implications for prevention and prognosis. This study is the first to report rates of T1MI and T2MI by age among PLWH.

A key finding from our study is that PLWH with a T2MI are on average younger than those with a T1MI. This is in contrast to general population studies where T2MIs account for a much smaller proportion of MIs and typically occur in older individuals. For example, a single center study of all patients (not limited to those with HIV) admitted with a non-ST segment elevation MI (NSTEMI) found that 75% were T1MIs vs. 25% were T2MIs. Furthermore, patients with a T2MI were older (median 73 vs. 65 years, P < 0.001).17 A Swedish study characterized ∼20,000 hospitalizations with MIs and found 7.1% were T2MIs. Furthermore, the mean age among those with a T1MI was 71.1 years vs. 75.9 years for those with a T2MI.11 A meta-analysis found that compared with those with a T1MI those with a T2MI were older (mean age 74 years for a T2MI vs. 70 years for a T1MI).20 We expect these differences are due, in part, to different causes driving T2MIs. For example, among a meta-analysis including a large number of T2MI, the most common cause associated with T2MIs was operative stress (20%), followed by sepsis (19%), arrhythmia (19%), heart failure (15%), and anemia (12%).20 By contrast, among PLWH we found that sepsis was the most common cause of T2MIs, although the percentage varied by decade of age ranging from 27% to 50% of T2MI.

This study has several strengths and limitations. Strengths include the use of centrally adjudicated MIs differentiated by types and the use of multiple ascertainment criteria to identify potential events. This is crucial given how poorly previous studies have found diagnoses codes alone work to accurately identify MIs, particularly given inadequacy of diagnosis codes for T2MIs.19,21,22 The large size and comprehensive clinical data are strengths, although the more limited number of women is not. The number of MIs is a limitation. Although >800 MIs allowed us to evaluate a T1MI and T2MI separately, T2MIs are due to heterogenous causes; a larger number of outcomes are needed to further separate T2MIs by cause. Finally, we focused on first incident MI for each PLWH. Although this approach has many advantages, it limits comparisons with some general population studies where those with T2MIs are more likely to have had a previous MI.

CONCLUSIONS

We found that among PLWH, T1MIs occurred in adults of all ages. T2MIs accounted for almost half of all MIs, and T2MIs occurred at a higher rate than T1MIs until age 40 years, differing from what is seen in the general population; rates of both T2MI and T1MI were very high among older PLWH. T2MIs were heterogenous with multiple causes, although sepsis was the most common cause across decades. The high proportion of T2MI highlights the importance of including both T1MI and T2MI in studies of PLWH. The age differences, as well as heterogeneous causes, highlight the importance of distinguishing MI types among PLWH. A better understanding of these important comorbidities, who is impacted, when, and why, is needed to further comprehend the underlying mechanisms and successfully intervene to improve long-term outcomes for older PLWH as the population in care continues aging.

ACKNOWLEDGMENTS

The authors would like to acknowledge all CNICS study participants and personnel for their contributions to this work.

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Keywords:

myocardial infarction; type 1 MI; type 2 MI; aging; HIV

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