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Types of Myocardial Infarctions in HIV+ - Type 2 vs Type 1 MIs
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"half of all MIs among HIV-infected individuals were type 2 MIs caused by heterogeneous clinical conditions, including sepsis or bacteremia and recent use of cocaine or other illicit drugs....A higher proportion of patients with type 2 MIs were younger than 40 years....Type 1 MI events (T1MI) result spontaneously from instability of atherosclerotic plaque. Type 2 MI events (T2MI) are secondary to causes other than atherosclerotic plaque rupture, including hypotension, hypoxia, and stimulant-induced spasm, resulting in increased oxygen demand or decreased supply....Sepsis or bacteremia (100 [34.7%]), vasospasm induced by use of cocaine or other illicit drugs (39 [13.5%]), and hypertensive emergency (28 [9.7]%) were the most frequently identified likely causes of T2MI....T1MI and T2MI may require different approaches for prevention and treatment in HIV-infected individuals."
March 2017
Types of Myocardial Infarction Among Human Immunodeficiency Virus-Infected Individuals in the United States
JAMA Cardiol
Key Points
Question How common are type 1 vs type 2 myocardial infarctions (MIs) among human immunodeficiency virus (HIV)-infected patients, and do patient characteristics differ by MI type?
Findings Among patients with HIV, type 2 MIs occur almost as often as type 1 MIs; sepsis and vasospasm induced by use of cocaine or other illicit drugs are the most common causes of type 2 MIs. Patients with HIV who experience type 2 MIs are younger, with less traditional cardiovascular disease risk factors, than those who experience type 1 MIs.
Meaning Type 2 MIs are common among HIV-infected individuals and are caused by heterogeneous clinical conditions; differences in demographic and clinical characteristics among those who experience type 1 and type 2 MIs suggest the need to specifically consider type among HIV-infected individuals to further understand MIs and guide prevention and treatment.
Abstract
Importance The Second Universal Definition of Myocardial Infarction (MI) divides MIs into different types. Type 1 MIs result spontaneously from instability of atherosclerotic plaque, whereas type 2 MIs occur in the setting of a mismatch between oxygen demand and supply, as with severe hypotension. Type 2 MIs are uncommon in the general population, but their frequency in human immunodeficiency virus (HIV)-infected individuals is unknown.
Objectives To characterize MIs, including type; identify causes of type 2 MIs; and compare demographic and clinical characteristics among HIV-infected individuals with type 1 vs type 2 MIs.
Design, Setting, and Participants This longitudinal study identified potential MIs among patients with HIV receiving clinical care at 6 US sites from January 1, 1996, to March 1, 2014, using diagnoses and cardiac biomarkers recorded in the centralized data repository. Sites assembled deidentified packets, including physician notes and electrocardiograms, procedures, and clinical laboratory tests. Two physician experts adjudicated each event, categorizing each definite or probable MI as type 1 or type 2 and identifying the causes of type 2 MI.
Main Outcomes and Measures The number and proportion of type 1 vs type 2 MIs, demographic and clinical characteristics among those with type 1 vs type 2 MIs, and the causes of type 2 MIs.
Results Among 571 patients (median age, 49 years [interquartile range, 43-55 years]; 430 men and 141 women) with definite or probable MIs, 288 MIs (50.4%) were type 2 and 283 (49.6%) were type 1. In analyses of type 1 MIs, 79 patients who underwent cardiac interventions, such as coronary artery bypass graft surgery, were also included, totaling 362 patients.
Sepsis or bacteremia (100 [34.7%]) and recent use of cocaine or other illicit drugs (39 [13.5%]) were the most common causes of type 2 MIs. A higher proportion of patients with type 2 MIs were younger than 40 years (47 of 288 [16.3%] vs 32 of 362 [8.8%]) and had lower current CD4 cell counts (median, 230 vs 383 cells/µL), lipid levels (mean [SD] total cholesterol level, 167 [63] vs 190 [54] mg/dL, and mean (SD) Framingham risk scores (8% [7%] vs 10% [8%]) than those with type 1 MIs or who underwent cardiac interventions.
Conclusions and Relevance Approximately half of all MIs among HIV-infected individuals were type 2 MIs caused by heterogeneous clinical conditions, including sepsis or bacteremia and recent use of cocaine or other illicit drugs. Demographic characteristics and cardiovascular risk factors among those with type 1 and type 2 MIs differed, suggesting the need to specifically consider type among HIV-infected individuals to further understand MI outcomes and to guide prevention and treatment.
Introduction
There are many unanswered questions regarding the risk of cardiovascular disease (CVD), including myocardial infarction (MI), in human immunodeficiency virus (HIV)-infected individuals. Studies have suggested that rates of MIs may be higher in HIV-infected individuals vs those without HIV.1- 4 Human immunodeficiency virus may affect lipid levels and endothelial function, leading to increased risk of CVD.5- 7 Antiretroviral therapy (ART) has reduced HIV-associated morbidity and mortality,8- 11 but some ART agents, particularly older ones, may increase the risk of CVD.12- 15 Previous studies have used unadjudicated MI outcomes and have not differentiated the types of MI.1,16,17 These limitations may have contributed to conflicting findings regarding CVD risk in HIV-infected populations.
The Second Universal Definition of Myocardial Infarction18 classifies MI into 5 types according to the underlying mechanism of myocardial ischemia. Type 1 MI events (T1MI) result spontaneously from instability of atherosclerotic plaque. Type 2 MI events (T2MI) are secondary to causes other than atherosclerotic plaque rupture, including hypotension, hypoxia, and stimulant-induced spasm, resulting in increased oxygen demand or decreased supply. Type 3 MIs are deaths occurring with symptoms suggestive of MI without measurement of cardiac biomarkers. Type 4 and 5 MIs occur in the setting of coronary revascularization procedures. Different MI types may portend a different prognosis and optimal approach to medical management.19
Studies are needed to understand the effect of HIV and its treatment on the frequency and types of MI. Understanding the types of MI will require clearly defined clinical end points with accurate event identification and categorization. We developed an MI adjudication protocol in the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) Cohort.20 We conducted this study to characterize MIs by type in a large and diverse cohort of HIV-infected individuals. We were interested in whether demographic and clinical characteristics, including CVD risk factors, would be similar for HIV-infected individuals with T1MI and those with T2MI. Although estimates of the incidence of T2MI vary in the general population, T2MIs account for a minority of MIs.21- 28 We hypothesized that T2MIs in HIV-infected individuals may be common and patients who experience them would have distinct demographic and clinical characteristics, including CVD risk factors, compared with HIV-infected individuals who experience T1MI. If confirmed, these hypotheses would lend support to the idea that T1MI and T2MI are distinct clinical entities that represent different biological phenomena and should be treated as such among those with HIV.
Discussion
We examined MI types in a large, nationally distributed cohort of individuals with HIV. Type 2 myocardial infarctions were common, comprising half of all MIs. We identified characteristics that differed between individuals with T1MI and T2MI. On average, individuals who had a T2MI were younger and had a lower CD4 cell count, higher viral load, and fewer traditional CVD risk factors, including less dyslipidemia, lower current rates of smoking, and lower CHD risk scores. Individuals with a T2MI were significantly different from those with a T1MI with regard to demographic and clinical characteristics, particularly CVD risk factors. Our results suggest that, in HIV-infected individuals, T1MI and T2MI may represent distinct clinical entities that require different approaches to prevention and treatment, as noted in the general population.19 To our knowledge, this study is the first to report a high proportion of T2MI occurring among HIV-infected individuals.
T1MI vs T2MI in HIV-Infected vs Other Populations
Distinguishing T1MI from T2MI has been recommended since 2007 by the Second Universal Definition of Myocardial Infarction18 and endorsed by major cardiology societies32; however, differentiating between the 2 types can be challenging.19 Categorization of MI by type has increased over time, but the International Classification of Diseases coding system lacks distinct categories for T2MI,32 which likely limits capture of this diagnosis in clinical settings. However, nonspecific codes for other acute and subacute forms of ischemic heart disease (International Classification of Diseases, Ninth Revision code 411.89 and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision code I24.8) have been used for this purpose.33 Lack of data on MI type has been attributed to the relatively recent introduction of the Universal Definition of Myocardial Infarction, presumed underreporting of T2MI, and lack of consistency in T2MI criteria.32
Despite these limitations, studies have found that T2MIs are much less common than T1MIs in most populations, comprising less than 2% to 26% of all MIs, depending on adjudication methods and population,22- 28 but usually less than 10% of all MIs.23- 28 In a Danish study of hospitalized patients, there were 541 MIs, of which 26% were T2MI.22 In contrast, the proportion of T2MI in our population of HIV-infected individuals was almost twice as high as in the Danish study. This difference may be owing to an increased likelihood of bacteremia and infections, resulting in sepsis, and increased prevalence of the use of cocaine or other illicit drugs in those with HIV. In addition, the Danish study did not exclude individuals with prior MI: 27% of participants in the Danish study with T2MI had a history of MI, 17% prior percutaneous coronary intervention, and 10% prior coronary artery bypass graft.22 In contrast, we focused on initial events. Although more data are needed, our findings suggest that the proportion of T2MI among HIV-infected individuals is higher than in many other populations. These differences have important clinical implications.19 Prevention and treatment of atherosclerotic CVD, including statin use, antiplatelet agents, and coronary procedures, have been studied and disseminated in T1MI guidelines34,35; however, optimal management and prevention of T2MIs is unclear.
Causes of T2MI
We found that almost half of T2MIs were in the setting of sepsis or bacteremia or vasospasm induced by cocaine or other illicit drugs. Cocaine increases myocardial oxygen demand by increasing blood pressure, heart rate, and myocardial contractility and can also decrease myocardial blood supply by inducing coronary vasoconstriction.36 Factors that lead to T2MI have not been well characterized in the general population. The most common presumed causes of T2MI in the Danish study were anemia, arrhythmias, and respiratory failure.22 A New York study found that surgery, anemia, and sepsis were common presumed causes of T2MI.33 Arrhythmias were also a common presumed cause of T2MI in several studies of the general population.21,28,37 In contrast, we found that sepsis or bacteremia and use of cocaine or other illicit drugs were common with T2MI. These results suggest that HIV-infected individuals have a different set of presumed T2MI causes than the general population.21,28,37
T1MI vs T2MI
We found substantial differences in demographic and clinical characteristics among HIV-infected individuals who experienced a T1MI vs those who experienced a T2MI. Higher proportions of those with a T2MI were younger, female, and had poorer control of their HIV infection as measured by current CD4 cell count and viral load. This finding contrasts with population studies of individuals not infected with HIV in which patients with T2MI were older than those with T1MI.21,28 In the general population, people with T2MI tend to be seriously ill. We similarly found that those with a T2MI tended to be sicker than those with a T1MI in terms of HIV status.
Adjudication
Central adjudication is preferable to local adjudication with or without secondary central review.20 Clinical definitions of MI have changed over time.38 In particular, events that used to be characterized as unstable angina would now be considered an MI. We therefore ascertained potential MIs using cardiac biomarkers in addition to diagnoses. Although diagnoses alone, such as from billing data, are commonly used for ascertainment, possibly with concomitant verification using other data elements,1,4,16,39- 41 the sensitivity of this approach is not optimal.42 A previous study has demonstrated that using clinical diagnoses alone results in missing substantial numbers of patients with T2MI.20 This finding is not surprising since there is no relevant International Classification of Diseases code to document myocardial injury owing to severe extracardiac causes, such as sepsis.32,43 Experts have advocated the development of distinct diagnostic codes for T2MI.19 Studies with cardiac biomarkers in their ascertainment criteria therefore likely more accurately capture T2MIs vs studies that rely on diagnoses alone. The Universal Definition of Myocardial Infarction has not established what constitutes a significant level of hypertension, hypotension, and other risk factors; therefore, identifying T2MI must rely on clinical judgment.21
Strengths and Limitations
The CNICS cohort is large and geographically and ethnically diverse, with comprehensive clinical data. We ascertained for potential MI events using both abnormal cardiac biomarkers and clinical diagnoses to increase the sensitivity of ascertainment and more fully capture the burden of MI in HIV. However, this method may make comparing rates of T2MI with rates in other cohorts ascertained with a less sensitive approach challenging. Adjudication facilitates capturing MI type and potential causes of T2MI.
Our study has some limitations. Silent T1MI can be missed, and T2MI may be missed in critically ill people in whom cardiac biomarkers are not assessed. We did not systematically examine results of ECGs to identify silent events; however, this approach has been shown to have a low probability of detecting MIs.44 Ascertainment may be incomplete for events that occur outside CNICS sites, although we requested medical records. We used troponin assays; however, they have become more sensitive over time and are not biologically equivalent owing to biochemical differences in assays and the reference populations used to determine upper reference limits.45 Although we categorized MI by type using carefully reviewed clinical data, there is debate regarding what criteria should be used to categorize an event as T2MI,32 and correctly classifying falsely positive events vs T2MI can be difficult. However, events were reviewed independently by 2 physicians and resolved by a third reviewer in case of disagreement, ensuring consistency in our approach to diagnosis and classification. Cardiac catheterization to verify obstructive coronary disease was frequently not performed for patients with T1MI and rarely done for those with T2MI. It is therefore unknown whether most patients with T2MI had obstructive disease. Finally, because our study is the first to describe MI types in patients with HIV, the findings have not been replicated, although the pattern of T1MI and T2MI in approximately half the patients was seen across the 6 CNICS sites.
Future Studies
Type 2 myocardial infarctions are increasingly recognized in the general population, and additional research is needed to better define and manage these events.46 The importance of applying ECG classifications, such as ST-segment elevation MI vs non-ST-segment elevation MI, to categorizing T2MI is unclear, as these classifications are intended to help guide decisions regarding clinical reperfusion therapy in patients with T1MI.32
Research is needed to better understand the complex association between traditional and HIV-specific CVD risk factors, the genetic predisposition to develop MI and potential interactions with ART, and the role of behavioral factors. Further evaluation is needed to understand the role of sepsis and risk for T2MI. Such information can guide interventions to alter these associations and improve prognosis, as well as improve risk prediction and risk reduction strategies. Differentiating MI type is important clinically, as it is likely that optimal interventions, such as the use of anticoagulation therapy, will differ by type. It is unclear if T1MI or T2MI will decrease in the current era now that ART is initiated earlier and with potentially less metabolically active regimens. Classification of MI type will result in a better understanding of these important outcomes among those with HIV.
Conclusions
Our large cohort study of HIV-infected individuals across the United States demonstrates that approximately half of MIs are T2MI. Individuals with T2MI were younger and sicker in terms of their HIV but had lower Framingham CHD risk scores than those with T1MI, suggesting these events may be owing to different mechanisms among different populations. These findings have important implications for studying MIs, understanding the higher MI rates, and determining whether the extent burden of MI can be reduced by modification of CVD risk factors among HIV-infected individuals, particularly given the unknown role, if any, of atherosclerosis in T2MI. Understanding types of MI may help clarify unanswered questions regarding risk factors, risk scoring, and prognosis. Most important, these findings are important clinically, as T1MI and T2MI may require different approaches for prevention and treatment in HIV-infected individuals.
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