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Original Investigation |

Acute Myocardial Infarction in Human Immunodeficiency Virus–Infected Patients FREE

Shlomo Matetzky, MD; Michelle Domingo, BA; Saibal Kar, MD; Marko Noc, MD, PhD; Prediman K. Shah, MD; Sanjay Kaul, MD; Eric Daar, MD; Bojan Cercek, MD, PhD
[+] Author Affiliations

From the Divisions of Cardiology (Drs Matetzky, Kar, Noc, Shah, Kaul, and Cercek and Ms Domingo) and Infectious Diseases (Dr Daar), Cedars-Sinai Medical Center, Los Angeles, Calif.


Arch Intern Med. 2003;163(4):457-460. doi:10.1001/archinte.163.4.457.
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Published online

Background  Patients infected with human immunodeficiency virus (HIV) are at an increased risk for premature coronary artery disease. However, the clinical outcome of HIV-infected patients who have had an acute myocardial infarction (AMI) is unknown.

Methods  We studied 24 consecutive HIV-infected patients admitted because of AMI. During the hospital phase, the patients were examined for recurrent ischemia, congestive heart failure, arrhythmia, and death. Patients were followed up for an average of 15 months after discharge for reinfarction; recurrent angina; the need for any angioplasty, bypass surgery, or target vessel revascularization for restenosis and stent thrombosis; HIV-related complications; and death. For comparison, we included a matched control group of non–HIV-infected patients.

Results  The HIV-infected patients with AMI were predominantly male (21 [88%]), 47 ± 9 years of age. Twenty-two (92%) were receiving antiretroviral treatment; 17 (71%), protease inhibitors; and 13 (54%), lipid-lowering therapy. With aggressive therapy, the lipid profile was similar in HIV-infected patients treated with protease inhibitors and those who were not. Twenty-one (88%) of 24 patients underwent immediate angiography and 20 (83%) had angioplasty or bypass surgery. The HIV-infected patients with AMI had a benign in-hospital course, with no deaths or reinfarction. The admission characteristics, treatment strategy, and in-hospital outcome were similar in the matched uninfected patients with AMI. After discharge, HIV-infected patients had a higher incidence of reinfarction (4/20 [20%] vs 2/45 [4%]; P = .07), and 6 (43%) of 14 HIV-infected patients who had successful percutaneous coronary intervention and were available for follow-up required target vessel revascularization compared with 4 (11%) of 38 uninfected patients who had successful percutaneous coronary intervention and were available for follow-up (P = .02).

Conclusions  Patients infected with HIV sustain AMI at a young age and have a benign in-hospital course. Although HIV-infected patients have a higher incidence of postdischarge ischemic events, restenosis, and stent thrombosis, the intermediate-term mortality is low.

REPORTED SERIES of patients have suggested that patients infected with human immunodeficiency virus (HIV) are at an increased risk of premature coronary artery disease (CAD), linked predominantly to the hyperlipidemia and insulin resistance that are associated with protease-inhibitor therapy.19 However, necropsy studies had demonstrated premature CAD in HIV-infected patients even before the advent of protease inhibitors.10,11 Few data exist regarding the course of acute coronary events in HIV-infected patients. We prospectively followed up a series of consecutive HIV-infected patients hospitalized with an acute myocardial infarction (AMI). For comparison, we describe the clinical course of age- and sex-matched non–HIV-infected patients with AMI hospitalized during the same period.

PATIENT POPULATION

The study population comprised 24 consecutive HIV-infected patients admitted with AMI to a university-affiliated community teaching hospital between 1998 and 2000. A control group included 48 non–HIV-infected patients with AMI admitted during the same period, matched for age, sex, and type of AMI (ST-segment elevation or non–ST-segment elevation) in a 1:2 fashion. None of the patients in either group reported recent use of cocaine or anabolic steroids. Criteria for AMI were chest pain at rest lasting for 30 minutes or more, or at least 2 intermittent episodes lasting for 5 minutes or more, associated with dynamic ST-segment deviation (1 mm in at least 2 contiguous electrocardiogram leads and cardiac troponin I elevation (>0.4 ×10− 6 mg/mL). Infection with HIV was diagnosed with the standard enzyme-linked immunosorbent assay and Western blot techniques. If not measured during the 3 months before the index admission, plasma HIV RNA level was determined by quantitative polymerase chain reaction. CD4 count was determined by flow cytometry. Blood samples for a complete lipid profile of each patient were obtained within the first 24 hours of admission.

The standard treatment for patients admitted within 12 hours of an ST-segment–elevation AMI was primary angioplasty with or without stenting (percutaneous coronary intervention [PCI]). Patients with non–ST-segment–elevation AMI underwent coronary angiography at the discretion of the attending physician. All patients were treated with aspirin and with clopidogrel (75 mg/d) for 4 weeks after stent deployment. Their HIV-related treatment was left unchanged after admission for the acute coronary event.

Two experienced observers, blinded to the patients' HIV status, evaluated the angiograms for the number of diseased arteries, identity of the infarct-related artery, and procedural success. Successful PCI was defined as achievement of normal (TIMI III) coronary flow with residual stenosis of less than 20%.

During hospitalization, patients were followed up for the following adverse events: recurrent ischemia, congestive heart failure, arrhythmia, and death. After discharge, patients were followed up by telephone interview and by review of the hospital records for reinfarction, recurrent angina, PCI or bypass operation, the need for target vessel revascularization after initial successful PCI, HIV-related complications, and death.

STATISTICAL ANALYSIS

Parametric variables are presented as percentages and were compared by χ2 with Yates correction or with 2-tailed Fisher exact test. Normally distributed continuous variables are presented as mean ± SD and compared with t test. If not normally distributed, the variables are presented as median and interquartile range and compared with Wilcoxon test.

ADMISSION CHARACTERISTICS

Of the 24 HIV-infected patients, 21 (88%) were male, and the average age was 47 ± 9 years (Table 1). At the time of the index event, time from diagnosis of HIV infection was 10 ± 4 years, CD4 cell count was 318 ± 210 ×10− 3/µL, and 4 patients (17%) had acquired immunodeficiency syndrome. Three (12%) of the HIV-infected patients had had a neoplastic disease before the coronary event. Twenty-two HIV-infected patients (92%) were receiving an antiretroviral drug and 17 (71%) at least 1 protease inhibitor. Eleven HIV-infected patients (46%) were treated with statins and 2 (8%) with fibrates. The qualifying coronary event was ST-segment–elevation AMI in 14 (58%) and non–ST-segment–elevation AMI in 10 (42%) of the patients. Of the ST-segment–elevation AMIs, 8 (57%) were anterior.

EFFECT OF TREATMENT WITH PROTEASE INHIBITORS

The HIV-infected patients treated with protease inhibitors (n = 17), compared with those who were not so treated (n = 7), were similar with respect to age (47 ± 10 vs 47 ± 6 years; P = .90) and sex (88% [15] vs 86% [6] male; P = .90). The mean duration of the infection was 10.7 ± 4.4 years in patients with and 8.4 ± 4.2 years in patients without protease inhibitor treatment (P = .33). CD4 cell count in the 2 groups was 268 ± 159 and 426 ± 277 ×10− 3/µL, respectively (P = .15).

The HIV-infected patients treated with protease inhibitors were more likely to be treated with lipid-lowering therapy (10/17 [59%] vs 3/7 [43%]; P = .06) and had levels of cholesterol (180 ± 48 vs 164 ± 55 mg/dL [4.66 ± 1.24 vs 4.24 ± 1.42 mmol/L]; P = .55), low-density lipoprotein cholesterol (108 ± 41 vs 94 ± 39 mg/dL [2.79 ± 1.06 vs 2.43 ± 1.01 mmol/L]; P = .51), and triglyceride (213 ± 101 vs 190 ± 86 mg/dL [2.40 ± 1.14 vs 2.14 ± 0.97 mmol/L]; P = .63) similar to those of patients not treated with protease inhibitors. High-density lipoprotein cholesterol level was low in both groups of HIV-infected patients, irrespective of treatment with protease inhibitors (32 ± 9 vs 32 ± 12 mg/dL [0.82 ± 0.23 vs 0.82 ± 0.31 mmol/L]; P = .96).

ANGIOGRAPHIC CHARACTERISTICS AND CORONARY REVASCULARIZATION

Of the 14 HIV-infected patients with ST-segment–elevation AMI, 12 (86%) underwent immediate PCI. Two of the 14 HIV-infected patients had patent infarct-related artery with evidence of thrombus but with only mild residual stenosis, and no PCI was performed. Otherwise, all other urgently catheterized patients underwent primary PCI. Altogether, 21 (88%) of 24 HIV-infected patients with AMI had coronary angiography while in the hospital. Prevalence of multivessel CAD was high in 16 (76%) of these 21 patients, and 20 (83%) underwent revascularization (17 patients had PCI and 3 had coronary artery bypass grafting).

IN-HOSPITAL CLINICAL COURSE

The HIV-infected patients had a relatively benign in-hospital course (Table 2). There were no deaths or reinfarctions. The peak troponin I level was on average mildly elevated (8 ×10− 6 mg/mL), mean left ventricular ejection fraction was mildly depressed (46% ± 11%), and 9 patients (37.5%) developed new Q waves.

LONG-TERM CLINICAL COURSE

Duration of follow-up was 14.7 ± 8.0 months for HIV-infected patients (Table 2). The HIV-infected patients had a high incidence of reinfarction (4 [20%]) and rehospitalization for recurrent coronary event (9 [45%]). One HIV-infected patient underwent urgent aortofemoral bypass surgery for leg ischemia, and 1 had acute arterial thrombotic occlusion of the upper extremity. In aggregate, HIV-infected patients were likely to have a recurrent acute atherothrombotic event; this occurred in 6 (30%) of 20 patients with follow-up. Three (15%) of 20 HIV-infected patients with follow-up had deep vein thrombosis with pulmonary embolism or arterial thromboembolism. Two HIV-infected patients developed HIV-related dementia. In one of them the dementia was associated with development of wasting syndrome. Two additional HIV-infected patients each had an episode of acute pancreatitis, another had persistent thrombocytopenia (platelet count ≤60 ×103/µL), and a fourth patient developed severe chronic diarrhea.

TARGET VESSEL REVASCULARIZATION

Of the 14 HIV-infected patients who were followed up after successful PCI, 6 (43%) required target vessel revascularization for recurrent ischemia and restenosis. Two of the HIV-infected patients with target vessel revascularization had more than 1 repeated intervention for recurrent restenosis.

The 6 HIV-infected patients who underwent target vessel revascularization, as compared with the 8 HIV patients who did not, had a higher incidence of detectable HIV RNA load (5/6 [83%] vs 3/8 [38%]; P = .14) and lower CD4 count (280 ± 45 vs 388 ± 185 × 10− 3/µL; P = .4), although the differences were not statistically significant.

COMPARISON WITH MATCHED CONTROL PATIENTS WITH AMI

In accord with the study design, sex distribution and mean age of control HIV-negative patients were similar to those of HIV-infected patients (Table 1). The HIV-infected patients had lower low-density lipoprotein cholesterol and lower high-density lipoprotein cholesterol values than HIV-negative patients. Otherwise, there were no significant differences in risk factors for CAD (Table 1), ST-segment–elevation AMI, and AMI localization between HIV-infected patients and control patients. The HIV-infected patients were more likely than the control patients to have had a PCI before the index event (10 [42%] vs 8 [17%]; P = .04).

Angiographic characteristics of control patients were similar to the characteristics of HIV-infected patients, as were the prevalence of multivessel disease (16/21 [76%] and 25/46 [54%]; P = .15) and the prevalence of revascularization, PCI, or coronary artery bypass grafting (45 [94%] and 20 [83%]; P>.99) in the 2 groups of patients, respectively.

In-hospital course of matched control patients was benign, as in HIV-infected patients (Table 2). During the postdischarge follow-up, HIV-infected patients had a higher incidence of reinfarction (4 [20%] vs 2 [4%]; P = .07) and rehospitalization for recurrent coronary event (9 [45%] vs 5 [11%]; P = .007) than uninfected control patients (Table 2).

Several recent reports suggest an increased risk of premature CAD in HIV-infected patients.18 Most of the described patients had severe dyslipidemia associated with the use of protease inhibitors.15,8 Accordingly, the need for aggressive lipid-lowering therapy was emphasized. There is little information regarding the clinical course and outcome of acute coronary syndrome in these patients.

In the present study, we report the clinical and angiographic characteristics and clinical course of 24 consecutive HIV-infected patients admitted with AMI. We found that AMI in HIV-infected patients is associated with a favorable in-hospital outcome, not unlike the outcome in the matched control patients. The favorable outcome is likely due to the young age of the patients and the absence of significant hemodynamic compromise. The HIV-infected patients, however, had a high incidence of recurrent coronary and atherothrombotic events in a follow-up of approximately 15 months. Nevertheless, our data suggest that prognosis in HIV-infected patients with manifest CAD will likely be determined by the complications related to HIV infection and not to coronary events. We also observed that PCI in HIV-infected patients was associated with a high incidence of restenosis and in-stent thrombosis.

Dyslipidemia associated with protease inhibitor therapy was proposed as a significant factor for premature CAD in HIV-infected patients.15,8 In our series, 17 patients (71%) received protease inhibitors and 10 of them (59%) were treated with lipid-lowering therapy. The lipid profile of these patients was similar to the profile of HIV-infected patients not treated with protease inhibitors and control patients. Although the hyperlipidemia and insulin resistance associated with the use of protease inhibitors may contribute to the development of premature CAD, results of our study and others1012 suggest that HIV infection is associated with CAD independent of the metabolic effects of antiretroviral therapy. This is supported by necropsy findings of premature atherosclerosis in a high percentage of HIV-positive patients not treated with protease inhibitors10 and in children who have died of acquired immunodeficiency syndrome.11

Coronary atherosclerosis was very widespread in the HIV-infected patients; 76% had 3-vessel disease, compared with only 30% in the noninfected patients. These patients also had frequent complications of peripheral vascular disease and venous thrombosis. Increased risk of premature atherosclerosis and vascular events in HIV-infected patients may be related to the several detrimental effects of the infection. Infection with HIV has a direct toxic effect to endothelium7 and increases interleukin 6 production in mononuclear cells.13,14 Elevated levels of interleukin 6 have been implicated in the pathogenesis of acute coronary syndrome15,16 and a higher incidence of reinfarction and refractory angina in patients with unstable angina.17 Infection with HIV also confers a hypercoagulable state, reflected by increased prothrombin fragment levels, F 1,2. The prothrombotic tendency is increased with an increase in viral load and reduced CD4 cell count.7 This prothrombotic state may account in part for a higher incidence of thromboembolic events and in-stent thrombosis in our HIV-infected patients.

The present study suggests that HIV infection is associated with an increased rate of restenosis after PCI. This association is particularly evident in patients with increased viral load, irrespective of protease inhibitor therapy. These findings are supported by results of experimental studies from our laboratory18 and others,19 which demonstrate that immunodeficiency is associated with increased intimal thickening in response to acute arterial wall injury.

STUDY LIMITATIONS

Although, to the best of our knowledge, this is the largest reported series of HIV-infected patients with acute coronary syndrome, the number of patients included is still relatively small. This warrants caution in data interpretation and generalization.

CLINICAL IMPLICATIONS

We conclude that HIV-infected patients admitted with AMI, when compared with non–HIV-infected patients, have more postdischarge adverse cardiac events. Nevertheless, the major determinants of prognosis likely remain complications associated with HIV infection.

Corresponding author and reprints: Bojan Cercek, MD, PhD, Division of Cardiology, Room 5314, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048 (e-mail: cercek@cshs.org).

Accepted for publication June 14, 2002.

This study was presented at the American College of Cardiology Scientific Sessions, Atlanta, Ga, March 18, 2002.

Henry  KMelroe  HHuebsch  J  et al.  Severe premature coronary artery disease with protease inhibitors [letter]. Lancet. 1998;3511328
Behrens  GSchmidt  HMeyer  DStoll  MSchmidt  E Vascular complications associated with use of HIV protease inhibitors [letter]. Lancet. 1998;3511958
Gallet  BPulik  MGenet  PChedin  PHiltgen  M Vascular complications associated with use of HIV protease inhibitors [letter]. Lancet. 1998;3511958- 1959
Vittecoq  DEscaut  LMonsuez  JJ Vascular complications associated with use of HIV protease inhibitors [letter]. Lancet. 1998;3511959
Eriksson  UOpravil  MAmann  FWSchaffner  A Is treatment with ritonavir a risk factor for myocardial infarction in HIV-infected patients [letter]? AIDS. 1998;122079- 2080
Sullivan  AKNelson  MRMoyle  GJNewell  AMFeher  MDGazzard  BG Coronary artery disease occurring with protease inhibitor therapy. Int J STD AIDS. 1998;9711- 712
Karmochkine  MAnkri  ACalvez  VBonmarchant  MCoutellier  AHerson  S Plasma hypercoagulability is correlated to plasma HIV load [letter]. Thromb Haemost. 1998;80208- 209
Flynn  TEBricker  LA Myocardial infarction in HIV-infected men receiving protease inhibitors [letter]. Ann Intern Med. 1999;131548
Carr  ASamaras  KThorisdottir  AKaufmann  GRChisholm  DJCooper  DA Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor–associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study. Lancet. 1999;3532093- 2099
Tabib  AGreenland  TMercier  ILoire  RMornex  JF Coronary lesions in young HIV-positive subjects at necropsy [letter]. Lancet. 1992;340730
Bharati  SJoshi  VVConnor  EMOleske  JMLev  M Conduction system in children with acquired immunodeficiency syndrome. Chest. 1989;96406- 413
Constans  JMarchand  JMConri  C  et al.  Asymptomatic atherosclerosis in HIV-positive patients: a case-control ultrasound study. Ann Med. 1995;27683- 685
Birx  DLRedfield  RRTencer  KFowler  ABurke  DSTosato  G Induction of interleukin-6 during human immunodeficiency virus infection. Blood. 1990;762303- 2310
Boue  FWallon  CGoujard  CBarre-Sinoussi  FGalanaud  PDelfraissy  JF HIV induces IL-6 production by human B lymphocytes: role of IL-4. J Immunol. 1992;1483761- 3767
Biasucci  LMVitelli  ALiuzzo  G  et al.  Elevated levels of interleukin-6 in unstable angina. Circulation. 1996;94874- 877
Neumann  FJOtt  IGawaz  M  et al.  Cardiac release of cytokines and inflammatory responses in acute myocardial infarction. Circulation. 1995;92748- 755
Mazzone  ADe Servi  SMazzucchelli  I  et al.  Increased concentration of inflammatory mediators in unstable angina: correlation with troponin T. Heart. 2001;85571- 575
Remskar  MLi  HChyu  K-YShah  PKCercek  B Absence of CD40 signaling is associated with an increase in intimal thickening after arterial injury. Circ Res. 2001;88390- 394
Hansson  GKHolm  JHolm  SFotev  ZHedrich  HJFingerle  J T lymphocytes inhibit the vascular response to injury. Proc Natl Acad Sci U S A. 1991;8810530- 10534

Figures

References

Henry  KMelroe  HHuebsch  J  et al.  Severe premature coronary artery disease with protease inhibitors [letter]. Lancet. 1998;3511328
Behrens  GSchmidt  HMeyer  DStoll  MSchmidt  E Vascular complications associated with use of HIV protease inhibitors [letter]. Lancet. 1998;3511958
Gallet  BPulik  MGenet  PChedin  PHiltgen  M Vascular complications associated with use of HIV protease inhibitors [letter]. Lancet. 1998;3511958- 1959
Vittecoq  DEscaut  LMonsuez  JJ Vascular complications associated with use of HIV protease inhibitors [letter]. Lancet. 1998;3511959
Eriksson  UOpravil  MAmann  FWSchaffner  A Is treatment with ritonavir a risk factor for myocardial infarction in HIV-infected patients [letter]? AIDS. 1998;122079- 2080
Sullivan  AKNelson  MRMoyle  GJNewell  AMFeher  MDGazzard  BG Coronary artery disease occurring with protease inhibitor therapy. Int J STD AIDS. 1998;9711- 712
Karmochkine  MAnkri  ACalvez  VBonmarchant  MCoutellier  AHerson  S Plasma hypercoagulability is correlated to plasma HIV load [letter]. Thromb Haemost. 1998;80208- 209
Flynn  TEBricker  LA Myocardial infarction in HIV-infected men receiving protease inhibitors [letter]. Ann Intern Med. 1999;131548
Carr  ASamaras  KThorisdottir  AKaufmann  GRChisholm  DJCooper  DA Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor–associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study. Lancet. 1999;3532093- 2099
Tabib  AGreenland  TMercier  ILoire  RMornex  JF Coronary lesions in young HIV-positive subjects at necropsy [letter]. Lancet. 1992;340730
Bharati  SJoshi  VVConnor  EMOleske  JMLev  M Conduction system in children with acquired immunodeficiency syndrome. Chest. 1989;96406- 413
Constans  JMarchand  JMConri  C  et al.  Asymptomatic atherosclerosis in HIV-positive patients: a case-control ultrasound study. Ann Med. 1995;27683- 685
Birx  DLRedfield  RRTencer  KFowler  ABurke  DSTosato  G Induction of interleukin-6 during human immunodeficiency virus infection. Blood. 1990;762303- 2310
Boue  FWallon  CGoujard  CBarre-Sinoussi  FGalanaud  PDelfraissy  JF HIV induces IL-6 production by human B lymphocytes: role of IL-4. J Immunol. 1992;1483761- 3767
Biasucci  LMVitelli  ALiuzzo  G  et al.  Elevated levels of interleukin-6 in unstable angina. Circulation. 1996;94874- 877
Neumann  FJOtt  IGawaz  M  et al.  Cardiac release of cytokines and inflammatory responses in acute myocardial infarction. Circulation. 1995;92748- 755
Mazzone  ADe Servi  SMazzucchelli  I  et al.  Increased concentration of inflammatory mediators in unstable angina: correlation with troponin T. Heart. 2001;85571- 575
Remskar  MLi  HChyu  K-YShah  PKCercek  B Absence of CD40 signaling is associated with an increase in intimal thickening after arterial injury. Circ Res. 2001;88390- 394
Hansson  GKHolm  JHolm  SFotev  ZHedrich  HJFingerle  J T lymphocytes inhibit the vascular response to injury. Proc Natl Acad Sci U S A. 1991;8810530- 10534

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