Right and left ventricular cardiac function in a developed world population with human immunodeficiency virus studied with radionuclide ventriculography

Right and left ventricular cardiac function in a developed world population with human immunodeficiency virus studied with radionuclide ventriculography Anne-Mette Lebech, MD, DMS,a Jan Gerstoft, MD, DMS,a Birger Hesse, MD, DMS,b Claus Leth Petersen, MD,c and Andreas Kjær, MD, DMSb Copenhagen, Denmark

Background Cardiac dysfunction has been reported in a substantial part of patients infected with the human immunodeficiency virus (HIV). However, most studies are from a time before the introduction of highly active antiretroviral treatment (HAART), which has significantly reduced HIV-associated morbidity and mortality rates. Accordingly, the prevalence of HIV-associated cardiac dysfunction may also have changed. The aim of the study was to establish the prevalence of right- and left-sided cardiac dysfunction in a Danish HIV population, most of whom were undergoing HAART, with radionuclide ventriculography. Methods

Ninety-five consecutive patients with HIV infection were included. Mean HIV duration was 104 months, and 84% of the patients received HAART. All patients underwent radionuclide ventriculography, and plasma levels of atrial natriuetic peptide (ANP), brain natriuetic peptide (BNP), and endothelin-1 (ET-1) were measured. Thirty age- and sex-matched healthy volunteer subjects were included to establish reference values of radionuclide measurements of left and right ventricular ejection fraction and of left ventricular volume.

Results Of 95 patients with HIV, 1 (1%) had a reduced left ventricular ejection fraction and 6 (7%) had a reduced right ventricle ejection fraction (0.35– 0.42) compared with reference values from the age- and sex-matched reference population. Patients with HIV and reduced cardiac function did not differ in the duration of HIV, CD4 count, CD4 nadir, or HIV RNA load. No correlations were found between reduced cardiac function and levels of the 3 peptides measured. Conclusions

No major dysfunction of the left ventricle is present in a developed world HIV population. However, a small but significant part of this population has modestly reduced right-sided systolic function. (Am Heart J 2004;147: 482– 8.)

Cardiac involvement in patients infected with the human immunodeficiency virus (HIV) has been described in several studies.1– 4 Dilated cardiomyopathy (DCM) with left ventricular dysfunction has been reported to be 1 of the most common cardiovascular complication of HIV,5,6 and early echocardiographic studies have demonstrated cardiomyopathy to be present in approximately one third of patients in the cohorts studied.7,8 In a prospective follow-up study of From the Departments of aInfectious Diseases and bClinical Physiology and Nuclear Medicine, Rigshospitalet, Copenhagen, and the cDepartment of Clinical Physiology and Nuclear Medicine, Frederiksberg Hospital, Copenhagen, Denmark. Supported by a grant from Danish AIDS Foundation. Submitted June 3, 2003; accepted September 5, 2003. Reprint requests: Anne-Mette Lebech, MD, PhD, DMS, Department of Infectious Diseases, M-5132, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark. E-mail: [email protected] 0002-8703/$ - see front matter © 2004, Elsevier Inc. All rights reserved. doi:10.1016/j.ahj.2003.09.009

952 patients who were HIV-positive with no symptoms, an echocardiographic diagnosis of DCM was made in 8%, with a mean annual incidence of 15.9 per 1000. A significant correlation between development of DCM and therapy with zidovudine was found. This paper was, however, recently retracted by the editors of the journal in which it had been published.9 However, all the aforementioned studies were performed before the introduction of highly active antiretroviral treatment (HAART). The availability of potent combination antiretroviral regimes has resulted in a dramatic reduction in the rates of HIV-associated morbidity and mortality in the developed world.10 However, the optimism generated by such treatment has been tampered by the recognition of an increasing array of adverse effects, including dyslipidemia,11,12 and this recognition has raised concerns about possible cardiovascular risks.13,14 Therefore, the prevalence of cardiac dysfunction may have changed in the current

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Table I. Major previous studies of cardiac function in HIV patients Reference 8 33 7 34 20 21 1 15

Year of study

No. of patients

Methods used

Findings

1989 1991 1992 1992 1994 1996 1998 2000

70 50 114 173 296 13 440 1042

Echocardiography Echocardiography Echocardiography Echocardiography Echocardiography Cine-MRI Autopsy Echocardiography

11% With dilated cardiomyopathy 16% Had reduced LVEF 16.6% With dilated cardiomyopathy 7.5 With dilated cardiomyopathy 8.4% With reduced RVEF, 10.8% with reduced LVEF 38% Had reduced RVEF 2.7% With dilated cardiomyopathy Dilated cardiomyopathy in 8.1% of patients treated with only NRTI* and in 1.8% of patients treated with HAART†

*Patients treated with nucleoside reverse transcriptase inhibitors (NRTI) during the period 1989 –1995. †Patients in HAART during the period 1996 –1998.

treatment era. In support of this view, a retrospective clinical study found a significant decrease in the prevalence, from 8.1% to 1.8%, of DCM in patients undergoing HAART on the basis of echocardiography.15 Major previous studies are summarized in Table I. Pulmonary hypertension is another known serious complication of HIV,16 which has been recognized recently with increasing frequency.17,18 Although 1000 times more prevalent in patients infected with HIV, this condition is, however, still only present in 1 of 200 patients.19 Isolated impaired right ventricular (RV) function has been reported to occur in as many as 12 of 296 patients infected with HIV when determined with echocardiography.20 Evaluation of RV function with echocardiography, however, is technically challenging and not very accurate. In a small study using magnetic resonance imaging (MRI), reduced RV ejection fraction (RVEF) was found in one third of the patients when using standard cutoff values.21 However, cutoff values reported in the literature vary considerably, and locally established reference values are preferable.22 The natriuretic peptides are now recognized as valuable markers of cardiac function.23 It has been shown that an increase in plasma concentrations of atrial natriuretic peptide (ANP) and especially brain natriuretic peptide (BNP) correlates well with reductions in left ventricular ejection fraction (LVEF) and increased left ventricular end diastolic volume index (LVEDVI).23,24 Therefore, DCM, if present in patients infected with HIV, should be detectable by measurement of natriuretic peptides, a very simple and inexpensive screening method for left ventricular (LV) dysfunction. Endothelin-1 (ET-1), which previously has been shown to correlate strongly with pulmonary pressure,23,25,26 could in the same way offer a simple technique for screening for pulmonary hypertension. The aim of this study was to establish the prevalence of right- and left-sided cardiac dysfunction in a devel-

oped world population with HIV, in which most patients received HAART. To do so, we used radionuclide ventriculography (RNV; first-pass and gated blood-pool imaging) as the method for determination of cardiac function. An age- and sex-matched control group of healthy volunteer subjects was included to establish the limits of normalcy. In addition, we studied whether measurement of ANP, BNP, or ET-1 could be used for the detection of cardiac dysfunction in patients with HIV.

Methods Study subjects Between April 2001 and July 2002, patients and control subjects were enrolled. The Danish Ethical Committee approved the study, and written informed consent was obtained from all the participants.

Patients A total of 95 consecutive patients with HIV infection were included. The patients were recruited from the outpatient clinic at the Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark. Inclusion criteria were age from 18 to 60 years and proven HIV infection. Exclusion criteria were known alcohol abuse and pregnancy or lactation. The basic characteristics of the patients are summarized in Table II. Most patients (84%) received HAART. The antiviral drugs used are listed in Table III. Of the 80 patients receiving HAART, HIV RNA was fully suppressed in 68 patients (85%) and was between 32 and 26,000 copies/mL in the remaining patients. In the patients with HIV who were not receiving anti-viral treatment, the HIV virus load was between 21 and 114,000 copies/mL. None of the patients had documented valvular heart disease, coronary artery disease, or previous myocardial infarction.

References values of radionuclide ventriculography Thirty age- and sex- matched healthy volunteer subjects (female/male, 23%/77%; age, 45 ⫾ 10 years; age range,

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Table II. Characteristics of the patients with HIV and the healthy controls

Age (y) Sex (female/male) (%) BMI (kg/m2) Duration of HIV (months) CD4 (cells/mm3) CD4 nadir (cells/mm3) HAART (%) Fully suppressed HIV RNA* in HAART patients (%) P-cholesterol (mmol/L) P-triglyceride (mmol/L) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg)

Patients with HIV (n ⴝ 95)

Controls (n ⴝ 30)

43 ⫾ 9 (25–60) 13/87 24 ⫾ 3 (17–32) 104 ⫾ 60 (11–204) 540 ⫾ 243 (75–1,300) 219 ⫾ 176 (10–880) 84 (CI 75–91) 85 (CI 75–92) 6.0 ⫾ 1.6 (2.8–13.4)† 2.7 ⫾ 2.5 (0.4–14.7)‡ 131 ⫾ 19 (90–183) 82 ⫾ 12 (59–119)

45 ⫾ 10 (25–60) 23/77 25 ⫾ 3 (19–32) – – – – – NA NA 135 ⫾ 15 (107–170) 79 ⫾ 12 (55–103)

Values are mean ⫾ SD with range in parenthesis unless otherwise indicated. *HIV RNA ⱕ 20 copies/mL. NA, Not available. †12% Above upper reference limit of 7.8 mmol/L. ‡42% Above upper reference limit of 2.2 mmol/L.

Table III. Anti-viral drugs used at time of study in the 80 patients in HAART Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs) Zidovudin (64%) Lamivudin (88%) Abacavir (16%) Stavudin (26%) ddl (8%) Non-nucleoside reverse transcriptase inhibitors (NNRTIs) Efavirenz (34%) Nevirapin (4%) Protease inhibitors (Pls) Amprenavir (1%) Indinavir/ritonavir (36%) Saquinavir/ritonavir (24%) Lopinavir/ritonavir (9%) Nelfinavir (6%) All patients received at least 3 drugs simultaneously; 6% received 3 NRTIs, 16% received 2 NRTIs and 1 NNRTI, 59% received 2 NRTIs and 1 PI, and 19% received ⬎3 drugs (“mega HAART”).

25– 60 years; body mass index, 25 ⫾ 3 kg/m2; body mass range, 19 –32 kg/m2) were included to exactly establish the reference values of the RNV measures. The control subjects were included from individuals participating in a Danish prospective population study (Copenhagen Centre of Prospective Population Studies at the Institute of Preventive Medicine, Bispebjerg Hospital, University of Copenhagen, Denmark).

RNV With a small field-of-view gamma camera positioned in a right anterior oblique 30° view and a bolus of 700 to 900 MBq of 99mTc-labeled human serum albumin, RVEF was measured with a first-pass radionuclide study in 91 of the patients with HIV. LVEF was mea-

sured in all 95 of the patients with HIV by using a multiple electrocardiogram-gated equilibrium study in which the gamma camera was positioned in a left anterior oblique view 30° view, with a caudal tilt of 5° to 10° and adjusted for optimal separation of the ventricles. LV end-diastolic volume (LVED) was calculated according to a previously described method27 and was normalized to body surface area. RVEF and LVEF were calculated with GE software programs (eNTEGRA version 1.5, General Electric, Milwaukee, Wis). The 95% confidence limits are ⫾ 0.03 on a single measurement for LVEF and ⫾ 0.06 for RVEF.

Blood sample analysis Blood was drawn into tubes containing ethylenediamine tetraacetic acid plus aprotinin and immediately transferred to ice-cold water. The samples were centrifuged at 10,000 g for 10 minutes; then the plasma was transferred to polyethylene tubes and immediately frozen and kept at ⫺20°C until analyzed. ANP was measured with a radioimmunoassay (RIA) of plasma extracted by means of C18 Sep-Pak cartridges according to a previously described procedure.28 The sensitivity of the assay was 3.1 pg/mL, and the intra-assay and interassay coefficients of variation were 4% and 5%, respectively. BNP was measured with a RIA of plasma extracted by means of C18 Sep-Pak cartridges according to a previously described procedure.29 The sensitivity of the assay was 5 pg/mL, and the intra-assay and interassay coefficients of variation were 9% and 10%, respectively. ET-1 was measured with an enzyme-linked immunosorbent assay (Peninsula Laboratories, Belmont, Calif) of plasma extracted by means of C18 Sep-Pak

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cartridges according to a previously described procedure.29 The minimum sensitivity of the assay was 0.78 pg/mL and the intra-assay and interassay coefficients of variation were 6% and 9%, respectively.

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Figure 1

Statistical analysis Data are presented as means plus or minus SD. Proportions are presented with 95% CIs. Comparisons between groups were performed with a 2-sample t test and with the Fisher exact test (2 ⫻ 2 contingency tables). Correlations between hormones and cardiac parameters were tested with a linear regression model. A P ⬍.05 was considered to be significant.

Results LV function With a reference interval defined as mean ⫾ 2 SD, the lower normal value of LVEF in the age- and sexmatched reference group was 0.49. With this cutoff point, 1 of 95 patients with HIV (1%; 95% CI, 0 – 6%) had a reduced LVEF (0.47; Figure 1). The patient with reduced LVEF also had reduced RVEF. With a reference interval defined as mean ⫾ 2 SD, the upper normal limit of LVEDVI was 117 mL/m2. With this cutoff point, only 1 of 95 patients (1%; 95% CI, 0 – 6%) patients had an increased LVEDVI.

RV function With a reference interval defined as mean ⫾ 2 SD, the lower normal value of RVEF in the age- and sexmatched control group was 0.44. With this cutoff point, 6 of 91 patients with HIV (7%; 95% CI, 3%–14%) had a reduced RVEF (0.35– 0.42; Figure 1). The patients with HIV and a reduced RVEF did not differ from the other patients with HIV (data summarized in Table IV) in history of pulmonary disease, duration of HIV, CD4 count, CD4 nadir, alcohol/tobacco consumption, triglyceride level, or proportion with fully suppressed HIV RNA (P ⬎.05). None of the patients were intravenous drug abusers. Plasma cholesterol level was higher than the upper normal limit in 3 of 6 patients with reduced RVEF, but only in 8 of 85 patients with normal RVEF (P ⬍.05, Fisher exact test).

Peptide levels The natriuretic peptides ANP and BNP and ET-1 were similar in patients with HIV who had normal RVEF and patients with HIV who had a reduced RVEF when compared with the t test (Table V, P ⬎.05). For ANP, in the group with reduced RVEF, 2 of 6 patients had an ANP higher than the upper normal limit, whereas in the group with normal RVEF, only 3 of 85 patients had an ANP higher than the upper normal limit (P ⬍.05, Fisher exact test).

Distribution of LVEF (A) and RVEF values (B) in the HIV population studied. Vertical dashed lines indicate lower normal limits as established by the age- and sex-matched control group. Intervals are chosen so the cutoff value is between intervals.

Discussion In a Danish population with HIV, in which most of the patients receive anti-viral treatment, we found that left-sided cardiac dysfunction was rare (1%). This contrasts with most previous studies, in which reduced systolic function of the LV and dilatation were reported to be present in a significant proportion.5– 8 Also, dilatation of the left ventricle was rare, because only 1 patient had a marginally increased LVEDVI. Therefore, it seems that our patients with HIV had normal LV function and geometry when taking into account how our normal limits are defined. One explanation for this discrepancy with previous studies could be that most of those studies were performed before the introduction of HAART. If, as previously suggested, the cardiac dysfunction could be caused by myocarditis (eg, caused by HIV itself30,31) or by other infectious organisms,32 HAART would be expected to reduce this cause. Indeed, HIV was suppressed in most of our pa-

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Table IV. Characteristics of patients with HIV and reduced and normal RVEF, respectively

Age (y) Sex (female/male) (%) BMI (kg/m2) Duration of HIV (months) CD4 (cells/mm3) CD4 nadir (cells/mm3) HAART (%) Fully suppressed HIV RNA* in HAART patients (%) P-cholesterol (mmol/L) P-triglyceride (mmol/L) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg)

Patients with HIV and reduced RVEF (n ⴝ 6)

Patients with HIV and normal RVEF (n ⴝ 85)

46 ⫾ 11 (32–59) 0/100 27 ⫾ 4 (22–31) 75 ⫾ 27 (39–156) 455 ⫾ 201 (88–680) 219 ⫾ 172 (71–540) 83 (Cl 36–100) 80 (Cl 28–99) 7.9 ⫾ 3.2 (4.9–13.4)† 4.9 ⫾ 5.2 (1.0–14.7)† 131 ⫾ 24 (104–160) 79 ⫾ 6 (68–85)

43 ⫾ 9 (25–60) 14/86 23 ⫾ 2 (17–32) 105 ⫾ 62 (11–204) 550 ⫾ 251 (75–1,300) 214 ⫾ 181 (10–880) 87 (Cl 78–93) 84 (Cl 73–91) 5.8 ⫾ 1.4 (2.8–10.7)‡§ 2.6 ⫾ 2.2 (0.4–14.1)㛳 130 ⫾ 18 (90–183) 82 ⫾ 13 (59–119)

Values are mean ⫾ SD with range in parenthesis unless otherwise indicated. *HIV RNA ⱕ20 copies/mL. †50% Above upper reference limit. ‡9% Above upper reference limit. §P ⬍ .05 when comparing number above upper normal limit by Fisher’s exact test. 㛳40% Above upper reference limit.

Table V. Plasma levels of atrial natriuretic peptide (ANP), brain natiuretic peptide (BNP) and endothelin-1 (ET-1) in HIV infected patients with reduced and normal RVEF Patients with Patients with HIV and reduced HIV and normal Normal RVEF (n ⴝ 6) RVEF (n ⴝ 85) values23 ANP (pmol/L)* 23 ⫾ 16 (7–44)§¶ 19 ⫾ 9 (6–56)㛳 BNP (pmol/L)† 1.4 ⫾ 0.8 (0.4–2.4) 1.5 ⫾ 0.8 (0.1–3.6) ET-1 (pmol/L)‡ 4.9 ⫾ 2.1 (1.1–7.3) 4.2 ⫾ 1.4 (1.0–8.3)

ⱕ39 ⱕ6.1 ⱕ8.3

Values are mean ⫾ SD with range in parenthesis. *Conversion from pmol/L to pg/mL by multiplying by 3.08. †Conversion from pmol/L to pg/mL by multiplying by 3.464. ‡Conversion from pmol/L to pg/mL by multiplying by 2.491. §Two of 6 above upper normal limit. 㛳Three of 85 above upper normal limit. ¶P ⬍ .05 when comparing number above upper normal limit by Fisher’s exact test.

tients effectively with HAART, as indicated by the HIV RNA values. Nearly 50% of our patients had duration of HIV ⬎7 years (ie, from the pre-HAART era). The possibility that the cardiac dysfunction might have been reversible in those patients seems less likely. In our opinion, another more likely explanation may be an overestimation of the frequency of left cardiac dysfunction in previous studies. An important difference may be our age- and sex-matched reference values for this study and the use of RNV, which has a much lower variability in LVEF than echocardiography. In contrast, we found right-sided cardiac dysfunction as measured by RVEF in a small, but significant proportion (7%) of the patients with HIV. The reduction in RVEF was very modest. Previous studies have found a

highly variable prevalence of reduced RVEF, ranging from 4% to 38%.21,33,34 All these studies were performed before the introduction of the current anti-viral treatment, and most of them were based on echocardiography as the only method for detection of RV dysfunction. However, echocardiography, being observerdependent, is not an accurate method for the detection of modestly reduced RV systolic function. In a small population, 1 previous study used cardiac magnetic resonance imaging, which is considered by many to be a gold standard for the right ventricle. The authors found a prevalence of reduced RVEF in 38% of patients, using a standard cutoff level.21 In comparison with our data, it seems that the prevalence of RV dysfunction may have decreased after the introduction of HAART. However, if we had relied on standard cutoff levels rather than on those from our carefully matched control group, we would have reported a more than twice as high, but overestimated, prevalence of reduced RVEF. What is the mechanism behind the reduction in RVEF? No correlation with CD4, CD4 nadir, or duration of HIV infection was found. It is possible that it is related to the increased incidence of lung infections or the increased prevalence of pulmonary hypertension found in patients with HIV.3 However, none of the 6 patients with reduced RVEF had reported serious episodes of lung infections (eg, Pneumocystis carinii pneumonia). With an additional lung function test including measurement of pulmonary diffusion capacity, slightly reduced lung diffusion capacity in 2 of the patients but otherwise normal lung function was revealed.

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The incidence of HIV-associated pulmonary hypertension is 1 in 200, compared with 1 in 200,000 in the general population.19 The exact mechanism for this condition is unknown, but it is believed that HIV indirectly causes vasoconstriction and plexiform pulmonary arteriopathy. Possible mechanisms involved include increased vascular endothelial growth factor-A, increased intrapulmonary platelet-derived growth factor, HIV gp120-mediated stimulation of ET-1 and tumor necrosis factor-␣, or HIV tat-mediated activation of endothelial cells.3 The phenomenon of reduced RVEF may well relate to the same mechanism and may be a more sensitive marker than invasive measurements of pulmonary pressure. However, overt pulmonary hypertension was probably not the cause in our patients, because we performed an additional echocardiography in 3 of the 6 patients with reduced RVEF and found the pulmonary pressure to be normal, as estimated with the tricuspid gradient. As previously mentioned, myocarditis in patients with HIV has been suggested to play a role in the development of ventricular dysfunction.30 –32 However, we find this an unlikely cause of right-sided dysfunction because nearly all of our cases with reduced RVEF had normal LV function. In recent years, plasma levels of a range of neurohormones have been suggested as diagnostic markers in heart failure.23,24 The goal has been to achieve an inexpensive, noninvasive technique as a sensitive method for diagnosing congestive heart failure. Plasma concentrations of ANP35 and, in particular, BNP have proven promising as markers in the clinical diagnosis of heart failure.36,37 BNP has been found to be a powerful marker of impaired systolic function, LV volumes, and myocardial mass,24 and ANP has also been shown to be a marker of impaired systolic function, especially associated with increased LV end-diastolic dimensions and pressure.38 Considering our findings of virtually normal left-sided function, it is not surprising that plasma levels of BNP and ANP were not increased in our patients. Dilation of the right side of the heart, especially the atrium, can also lead to increased ANP levels. In agreement with this, we found a higher proportion with ANP higher than the upper normal reference value in patients with reduced RVEF than in patients with normal RVEF. In several studies, plasma levels of circulating ET-1 have been shown to be increased in patients with pulmonary hypertension, and ET-1 may become a prognostic marker for this condition.25,26,39 However, in our study, the plasma level of ET-1 did not differ between the patients with reduced RVEF and patients with normal RVEF, in agreement with the echocardiographical data indicating that overt pulmonary hypertension was not present in our patients with reduced RVEF.

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In conclusion, using RNV and age- and sex-matched reference values, we found no major dysfunction or dilation of the left ventricle, but that a limited, but significant part of this population with HIV from the developed part of the world had modestly reduced RV systolic function. The mechanism behind the isolated RV dysfunction and the clinical significance remain to be established.

Study limitations The study is a cross-sectional study, and prospective studies with sequential measurements of cardiac function are warranted. Furthermore, we only looked at cardiac function at rest. Studies during exercise could have detected latent dysfunction, and such studies would therefore be of interest. We thank Bente Baadegaard and Lene Pors Jensen and laboratory technicians at the AIDS Laboratory, Rigshospitalet, for their assistance during the course of this study; laboratory technicians Elsa Larsen and Jytte Oxbøl, Department of Medical Physiology, the Panum Institute, for their skillful technical assistance with the hormone analyses; and Merete Appelyard, PhD, Copenhagen Centre of Prospective Population Studies at the Institute of Preventive Medicine, Bispebjerg Hospital, for the referral of control subjects to the study.

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