American Heart Journal
Volume 150, Issue 5 , Pages 933.e1-933.e7, November 2005

Indinavir impairs endothelial function in healthy HIV-negative men

  • Sudha S. Shankar, MD

      Affiliations

    • Division of Endocrinology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Ind
    • Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Ind
    • ,
  • Michael P. Dubé, MD

      Affiliations

    • Division of Infectious Diseases, Department of Medicine, Indiana University School of Medicine, Indianapolis, Ind
    • Corresponding Author InformationReprint requests: Michael P. Dubé, MD, Indiana University School of Medicine, 1000 W 10th St, Wishard OPW 430, Indianapolis, IN 46202.
    • ,
  • J. Christopher Gorski, PhD

      Affiliations

    • Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Ind
    • ,
  • James E. Klaunig, PhD, MD

      Affiliations

    • Division of Pharmacology and Toxicology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Ind
    • ,
  • Helmut O. Steinberg, MD

      Affiliations

    • Division of Endocrinology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Ind

Received 1 February 2005; accepted 5 June 2005.

Article Outline

Background

Potent antiretroviral treatment has drastically reduced mortality in HIV-infected patients but may accelerate atherosclerotic disease, which could be partially mediated via endothelial dysfunction.

Methods

In 8 HIV-negative healthy males, leg blood flow responses to intraartery infusions of methacholine chloride (Mch), sodium nitroprusside, and NG-mono-methyl-l-arginine (l-NMMA) were measured before and after 4 weeks of daily oral indinavir. In the same subjects, we also assessed the effect of indinavir on lipids, insulin sensitivity, markers of inflammation, as well as oxidative stress.

Results

After 4 weeks of indinavir, the endothelium-dependent response to methacholine chloride was impaired (195% ± 38% vs 83% ± 13%, P < .05), the response to NG-mono-methyl-l-arginine (nitric oxide–dependent tone) was nearly abrogated (−30% ± 4% vs −1% ± 11%, P < .05), whereas the endothelium-independent response to sodium nitroprusside remained unchanged. Fasting insulin levels increased from 5.8 ± 1.2 to 7.0 ± 1.4 μU/mL (P < .05), and HOMA-IR scores increased from 1.3 ± 0.3 to 1.6 ± 0.3 U (P < .05). There were no changes in blood pressure, lipids, markers of inflammation, or oxidative stress.

Conclusions

Four weeks of the HIV-1 protease inhibitor indinavir, in the absence of HIV-1 infection, causes vascular dysfunction most likely at the level of endothelial nitric oxide production. The vascular dysfunction may be mediated partially by the concomitant induction of insulin resistance but other mechanisms cannot be ruled out.

 

Antiretroviral therapy has led to a dramatic and sustained decline in HIV-1–associated morbidity and mortality.1 However, concomitant with these beneficial effects, accelerated atherosclerosis2, 3 as well as increased rates of cardiovascular disease has been reported in these treated patients,4 particularly those on protease inhibitors.5, 6 Whether this heightened risk is mediated primarily by the effects of protease inhibitors on traditional risk factors or there are other drug-specific effects is not clear.

It is not known how protease inhibitors may cause vascular disease. Potential mechanisms include induction of insulin resistance or dyslipidemia.7, 8, 9 The protease inhibitor-induced change in lipids may lead to endothelial dysfunction by increasing low-density lipoprotein cholesterol (LDL-C) levels, by increasing the fraction of the dense LDL particles, which are more easily oxidized, or by decreasing high-density lipoprotein cholesterol (HDL-C), and thus, impair reverse cholesterol transport from the tissues. Insulin resistance due to protease inhibitors may cause vascular dysfunction via increasing free fatty acid flux10 or free fatty acid concentrations.11

Another potential mechanism for vascular disease, independent of dyslipidemia or insulin resistance, is endothelial dysfunction. Endothelial dysfunction by itself is known to be an early predictor of future cardiovascular events in patients without12 and with known vascular disease.13, 14 These and other studies12, 13, 14 strongly suggest that impaired endothelial function is a marker of subclinical coronary artery disease as well as a risk factor for cardiovascular events. Thus, indinavir as well as other protease inhibitors could potentially cause cardiovascular disease via impairment of endothelial function. In fact, Stein et al15 have found endothelial dysfunction in protease inhibitor-treated HIV-infected patients with dyslipidemia. However, it is unclear whether the drug, the disease, or the interaction between the 2 was responsible for the observed endothelial dysfunction.

To better define the effect of protease inhibitors alone on vascular function, in the absence of confounding factors such as HIV infection, we tested the hypothesis that administration of the protease inhibitor indinavir results in impaired endothelial function. To this end, we measured endothelium-dependent vasodilation (EDV), endothelium-independent vasodilation (EIV), as well as nitric oxide (NO)–dependent vascular tone before and after 4 weeks of daily oral indinavir administration in healthy normal HIV-negative nonobese volunteers. Because the chronic effect of the drug on endothelial function was determined ∼2 hours after the last dose of indinavir, we also measured the acute effects of indinavir on vascular function in a subgroup to define the time course of the indinavir effect on vascular function (acute vs 4 weeks). Finally, we also measured endothelial function in a subgroup ∼4 weeks after cessation of the drug to determine whether the effect of the drug on vascular function was reversible.

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Methods 

Subjects 

Demographic characteristics of the subject groups are shown in Table I. All subjects were HIV negative, healthy, nonobese (BMI ≤ 27 kg/m2), normotensive by cuff measurements per JNC VI criteria,16 had normal 75 g of oral glucose tolerance tests per ADA criteria17 and lipid profiles per NCEP III criteria,18 and were not taking any medications. Studies were approved by the Indiana University Human Subjects Institutional Review Board, and all volunteers gave written informed consent. Subjects were instructed to maintain their usual dietary and physical activity habits during study. Smokers did not change the amount of tobacco consumed over the 4-week period and abstained from smoking for 12 hours before each assessment of metabolic and vascular function.

Table I. Clinical and metabolic characteristics of the volunteer group before and after 4 weeks of daily oral indinavir 800 mg TID
Pre-indinavirPost-indinavirP
Weight (kg)71.2 ± 3.370.6 ± 3.1.3
BMI (kg/m2)23.8 ± 0.923.6 ± 0.9.5
Heart rate (beat/min)56 ± 358 ± 3.5
Systolic blood pressure (mm Hg)116 ± 6114 ± 4.5.7
Diastolic blood pressure (mm Hg)66 ± 464 ± 4.7
Basal LBF (L/min)0.226 ± 0.010.212 ± 0.01.32
MAP (mm Hg)83 ± 581 ± 4.7
Total cholesterol (mmol/L)4.09 ± 0.254.29 ± 0.11.5
LDL-C (mmol/L)2.43 ± 0.252.64 ± 0.11.28
HDL-C (mmol/L)1.09 ± 0.131.01 ± 0.05.5
Triglycerides (mg/dL)104 ± 15.7109 ± 21.7.7
Fasting glucose (mmol/L)5.1 ± 0.15.1 ± 0.1.8
Fasting insulin (μU/mL)5.8 ± 1.157.0 ± 1.44.023
HOMA-IR1.33 ± 0.291.59 ± 0.34.035
C-reactive protein (ng/mL)4.75 ± 1.275.53 ± 1.22.5
MDA (nmol/L)10.3 ± 2.812.4 ± 1.9.5

HOMA-IR homeostasis model for the assessment of insulin resistance.

Study drugs 

All vascular drugs were diluted in normal saline achieving concentrations of 25 μg/mL of methacholine chloride (Mch; Clinalfa, CH-4448 Läufelfingen, Switzerland), 7 μg/mL of sodium nitroprusside (SNP; Roche Laboratories, Division of Hoffman-La Roche, Nutley, NJ), and 8 mg/mL of NG-mono-methyl-l-arginine (l-NMMA; Calbiochem Corp, San Diego, Calif). Indinavir (Merck, West Point, NJ) was administered as two 400-mg capsules orally thrice daily (every 8 hours) on an empty stomach.

Protocol 

In an open-label study, 8 healthy men (aged 41 ± 1 years) were studied before and after 4 weeks of daily oral indinavir. All subjects were admitted to the Indiana University General Clinical Research Center 2 days before study and were fed a weight-maintaining diet. After an overnight fast, hemodynamic measurements were obtained with the subject in the supine position as previously described.19 Vascular function was studied in all subjects at baseline and after 4 weeks of therapeutic doses of indinavir by constructing dose-response curves for leg blood flow (LBF) in response to graded intrafemoral artery infusions of 5, 10, and 15 μg/min of the endothelium-dependent vasodilator Mch and 1.75, 3.5, and 7 μg/min of the endothelium-independent vasodilator SNP. Vascular function was also studied 1 hour after the first dose of indinavir (n = 3). We also assessed vascular function as early as 4 weeks after discontinuation of indinavir (n = 4). To study the effect of indinavir on NO-dependent vascular tone, we assessed the LBF responses to intrafemoral artery infusion of the NO synthase inhibitor l-NMMA at a dose of 16 mg/min. Vascular studies at 4 weeks were performed ∼2 hours after the last dose of indinavir, at a point where peak serum indinavir levels would be expected.

Measurements 

Subjects had body weight, height, basal heart rates, systolic and diastolic blood pressure, and fasting lipid profile measurements done before and 4 weeks after indinavir therapy. Dual energy x-ray absorptiometry scans (DXA, Lunar DPX-L; Lunar Corp, Madison, Wis, system software 4.6 b) for body fat measurement were performed at baseline.

Analytical methods 

Total cholesterol and triglyceride levels were measured on a Kodak Ektachem 702 Analyzer with an enzymatic method (Eastman Kodak Co, Rochester, NY). High-density lipoprotein cholesterol was measured with the Magnetic HDL kit (Reference Diagnostics, Inc, Arlington, Mass) and LDL-C was calculated according to the Friedewald formula.20 Plasma malondialdehyde (MDA) levels were determined as previously described.21 Tumor necrosis factor alpha (TNF-α), interleukin 1 (IL-1), and interleukin 6 (IL-6) were determined using multiplex panels with the Luminex system (LINCO Research Inc, St Charles, Mo). High-sensitivity C-reactive protein (hsCRP) was measured using the high-sensitivity assay from Diagnostic Systems Laboratories (Webster, Tex). Plasma peak (60 minutes postdose) and trough (predose) indinavir levels were measured at 2- and 4-week points by high performance liquid chromatography, with ultraviolet detection as previously described with slight modification.22 The coefficient of variation of quality control samples was less than 10%.

Statistical analysis 

Results are shown as the mean ± SEM. HOMA-IR was calculated according to the homeostasis model (HOMA-IR = {insulin in microunits per milliliter × glucose in millimoles per liter}/22.5).23 Mean arterial pressure (MAP) is expressed in millimeter mercury and LBF is expressed in liters per minute. Changes in LBF are expressed as absolute (Δ) and percent change (%Δ) to adjust for differences at baseline. Leg vascular resistance (LVR) was calculated as MAP/LBF (mm Hg/[L/min]) and is given in arbitrary units (U). Repeated-measures ANOVA (RMANOVA) was used to compare the changes in LBF and LVR in response to the graded drug infusions, before and after 4 weeks of indinavir administration. After RMANOVA showed a significant difference between pre- and postdrug dose-response curves, paired t tests were performed to assess differences in LBF within and between treatment groups at each Mch infusion rate. The maximal response to Mch and SNP was defined as the highest LBF achieved. Significance was accepted at a level of P < .05. Paired 2-tailed t test was used to compare differences in demographic, metabolic and other hemodynamic parameters, including heart rate, blood pressure, and maximal change in LVR before and after indinavir. Statistical significance was accepted at a level of P < .05. Statistics were performed with Stat View IV (Abacus Concepts, Inc, Berkeley, Calif).

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Results 

Metabolic and hemodynamic effects of indinavir 

Indinavir had no effect on BMI, fasting plasma glucose, total cholesterol, LDL-C, and HDL-C, or triglyceride levels (Table I). Fasting insulin levels (P < .05) and HOMA-IR values rose in response to indinavir (P < .05). TNF-α, IL-1, and IL-6 were below the detection limits before and after indinavir. CRP and MDA levels did not change significantly (Table I).

Resting heart rate, systolic pressure, diastolic pressure, and MAP, and resting LBF did not change in response to indinavir treatment. Subjects had mean peak plasma indinavir levels of 7.6 ± 1.0 μM/L (range 4.8-10.6 μM/L) and mean trough levels of 1.6 ± 0.4 μM/L (range 0.3-2.6 μM/L).

Effect of indinavir on EDV 

Chronic effect of indinavir on vascular function 
Endothelium-dependent vasodilation 

Under basal conditions, LBF rose in a dose-dependent manner in response to the graded intrafemoral artery infusions of Mch (P < .01, RMANOVA).

After 4 weeks of daily indinavir, LBF still increased in response to Mch, but maximal increments in LBF above baseline (ΔLBF) in response to Mch were significantly reduced, with ΔLBF of 0.421 ± 0.077 versus 0.174 ± 0.027 L/min before and after 4 weeks of indinavir, respectively (P < .01). Leg blood flow changes expressed relative to baseline (%Δ) were significantly lower (P < .05) after 4 weeks of indinavir (Figure 1).

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  • Figure 1. 

    Leg blood flow increments relative to baseline (Δ%LBF) in response to graded intrafemoral artery infusions of Mch before and after 4 weeks of indinavir (800 mg PO TID). White circles, before indinavir; black circles, after 4 weeks of indinavir. *P < .05 (paired t test) before versus after indinavir, †P < .05 versus baseline (no Mch infusion).

To adjust for small changes in blood pressure, basal LVR and the LVR response to Mch were calculated before and after indinavir. Changes in LVR mirrored the changes in LBF. Leg vascular resistance decreased in a dose-dependent manner in response to the graded Mch infusions (P < .01). After 4 weeks of indinavir, maximal decrements in LVR below baseline (ΔLVR) in response to Mch tended to be blunted, with ΔLVR of 256 ± 35 versus 190 ± 16 U (P = .08, baseline vs 4 weeks of indinavir). Maximum LVR changes expressed relative to baseline (%Δ) were significantly reduced after 4 weeks of indinavir (64% ± 5% and 44% ± 4% baseline vs 4 weeks of indinavir, respectively, P < .01).

Endothelium-independent vasodilation 

Leg blood flow rose in a dose-dependent manner in response to the graded intrafemoral artery infusions of SNP, both before and after indinavir (P < .01). Maximal increments in LBF above baseline (ΔLBF) in response to SNP were 0.12 ± 0.03 versus 0.13 ± 0.06 L/min before and after indinavir, respectively (P = .9). Expressing the LBF changes in response to SNP relative to baseline (%Δ) revealed no differences before and after indinavir (Figure 2). Maximal percent increments in LBF were 47% ± 11% and 68% ± 30% before and after indinavir, respectively (P = .5). These data indicate that indinavir does not impair EIV.

  • View full-size image.
  • Figure 2. 

    Leg blood flow increments relative to baseline (Δ%LBF) in response to graded intrafemoral artery infusions of SNP before and after 4 weeks of indinavir (800 mg PO TID). White circles, before indinavir; black circles, after 4 weeks of indinavir. †P < .05 (paired t test) Mch infusion versus baseline (no Mch infusion).

Nitric oxide–dependent vascular tone 

Leg blood flow fell in response to the intrafemoral artery infusions of l-NMMA, before indinavir (P < .05). This effect of l-NMMA to reduce LBF was abolished by indinavir. Decrements in LBF below baseline (ΔLBF) in response to l-NMMA were 0.068 ± 0.01 versus 0.005 ± 0.02 L/min before and after indinavir, respectively (P < .05). Expressing the LBF changes in response to l-NMMA as a percentage to adjust for differences in baseline values revealed loss of the effect of l-NMMA to decrease LBF after 4 weeks of oral indinavir (Figure 3). Maximal percent changes (decrements) in LBF were −30% ± 4% and −1% ± 11% before and after 4 weeks of oral indinavir, respectively (P < .05). Maximal percent increments in LVR in response to l-NMMA were significantly blunted after 4 weeks of IDV (57.8% ± 12.1% vs 19.9% ± 8.5%, P < .05). These data indicate that indinavir, administered for 4 weeks, impairs basal NO-dependent endothelial tone.

  • View full-size image.
  • Figure 3. 

    Leg blood flow decrements (%Δ) in response to intrafemoral artery infusion of l-NMMA (16 mg/min), an inhibitor of NO synthase, before and after 4 weeks of indinavir (800 mg PO TID).

Acute effect of indinavir on vascular function 

Because the profound vascular dysfunction after 4 weeks of indinavir was found ∼ 2 hours after the last dose of the drug, we examined whether this result could be explained by an acute effect. Therefore, 1 hour after a single oral dose of 800 mg of indinavir, when peak plasma drug levels are achieved, the LBF response to Mch was determined in 3 subjects. One hour after the first dose of indinavir, the LBF response to graded doses of Mch, as well as the maximal increments in LBF above baseline (ΔLBF), was unchanged (0.488 ± 0.125 vs 0.567 ± 0.269 L/min) as compared to basal conditions. No change in the LVR response to indinavir was observed 1 hour after a single dose of oral indinavir (data not shown) when peak plasma concentrations were achieved. Furthermore, EIV, the LBF response to SNP, as well as NO-dependent vascular tone, the LBF response to l-NMMA, was unchanged 1 to 2 hours after one dose of indinavir.

Effect of drug washout on vascular function 

Given the profound vascular dysfunction induced by 4 weeks of indinavir, we assessed whether this indinavir-induced dysfunction was reversible in 4 of the 8 study subjects. As early as 4 weeks after discontinuation of indinavir, LBF responses to Mch returned to normal (pre-indinavir studies). In these 4 subjects, maximal LBF changes above baseline (%Δ LBF) in response to Mch were 314% ± 156% and 323% ± 124% before drug administration and after drug discontinuation, respectively. (In these 4 subjects, %Δ LBF was only 78% ± 57% after 4 weeks of indinavir.) These results indicate that the impairment in EDV caused by 4 weeks of indinavir is reversible. Similarly, LVR decrements in response to Mch returned to normal as early as 4 weeks after discontinuation of indinavir (data not shown).

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Discussion 

In the current open-label study, we determined the effect of indinavir on endothelial function in HIV-1 negative, nonobese, and insulin-sensitive subjects. The results of our study show that 4 weeks of oral indinavir treatment (1) impairs EDV, (2) nearly abrogates basal NO-dependent vascular tone, and (3) has no effect on EIV. Taken together, these data indicate that indinavir causes vascular dysfunction at the level of the endothelial cell by reducing NO production/release or NO bioavailability.

Indinavir is an HIV-1 protease inhibitor used as a component of antiretroviral regimens. Besides its potent antiviral effects, it has also been reported to induce acute and chronic insulin resistance.24, 25, 26, 27, 28 We have shown previously that insulin resistance is associated with impaired endothelial vascular function.29, 30, 31 Endothelial dysfunction is a key event in atherosclerosis and enhances cardiovascular risk.12, 14, 32 There have been reports suggesting that antiretroviral therapy, including protease inhibitor-based regimens, appears to augment cardiovascular risk.2, 3, 4, 5, 6 We, therefore, tested the hypothesis that indinavir induces endothelial dysfunction, which in turn could potentially explain, at least in part, the increased cardiovascular risk.

We studied the effects of 4 weeks of indinavir on endothelial function in the absence of HIV infection. We found that in just 4 weeks, indinavir induced a striking 60% blunting of EDV, as measured by the vasodilatory response to methacholine. The magnitude of this effect on EDV is comparable to what we have reported among obese type 2 diabetics, as compared to lean healthy subjects.30, 31 Thus, by virtue of the effect size, we believe that these observations related to indinavir are likely to have significant clinical impact for patients receiving indinavir, and possibly, other protease inhibitors. It is important to point out that these effects were seen at pharmacologically relevant plasma indinavir levels, are not due to toxicity, and could, thus, potentially affect any or all patients on this agent.

The impaired vasodilatory response to methacholine could be due to reduced NO production/release by the endothelial cell, reduced NO bioavailability, or reduced NO action at the level of the vascular smooth muscle cell. Our observation showing intact vasodilatory response to SNP clearly indicates that indinavir spares vascular smooth muscle function.

Most of the EDV that occurs in response to methacholine is NO dependent.33 Given the effect of indinavir on the response to methacholine, we investigated if this was a result of the effect of indinavir on NO-dependent tone. Indeed, we found that 4 weeks of indinavir nearly abolishes basal NO-dependent tone, as measured by the blood flow response to the endothelial nitric oxide synthase inhibitor l-NMMA. Taken together, our data strongly indicate that chronic indinavir administration leads to impaired NO production at the level of the endothelium whereas leaving NO action intact. The notion that indinavir impairs NO production is supported by observations in cell culture studies.34 However, our results cannot completely rule out the possibility that NO production/release might be intact with decreased NO bioavailability due to scavenging of NO before it can act on cyclic guanosine monophosphate in the vascular smooth muscle cell.

Indinavir has been reported to exhibit acute effects on glucose metabolism with a time course ranging from 6 minutes to 2 hours.24, 25, 26, 27 Having demonstrated a chronic effect of indinavir on endothelial function, we attempted to define the time course of this effect of indinavir. We assessed the acute effect of indinavir on endothelial as well as vascular smooth muscle function after a single dose of indinavir. At peak therapeutic levels, 1 to 2 hours after a single dose, indinavir had no effect on EDV, NO-dependent tone, or EIV. This indicates that the effect of indinavir on endothelial function is cumulative and time dependent with no acute component. These findings also suggest that the mechanism(s) responsible for the vascular effects of indinavir may be distinct from those underlying its acute effect on glucose metabolism.

Because treatment (a pharmacological challenge) with indinavir caused endothelial dysfunction, we tested if withdrawal of indinavir would result in reversal of the endothelial dysfunction. In all retested subjects (n = 4), we found that endothelial function was restored to normal. Restoration of endothelial function was observed as early as 4 weeks after discontinuation of indinavir. This indicates that the observed impairment in endothelial function is attributable to indinavir, and further, that the impairment is due to a reversible functional defect, most likely at the level of eNOS, rather than irreversible structural damage.

The mechanism for the indinavir-induced loss of EDV is unknown. Factors known to impair EDV, such as age, blood pressure, cholesterol levels, and smoking habits, remained unchanged throughout the study. Fasting insulin levels and HOMA-IR increased significantly after 4 weeks of indinavir, consistent with induction of insulin resistance, as has been reported by others.28 Because insulin sensitivity is known to correlate positively with NO-dependent endothelial function,35 our findings suggest that the indinavir-induced insulin resistance may be responsible, at least in part, for the decrease in NO production and endothelial function. However, the magnitude of the change in insulin levels was quite small, and insulin levels remained well within the normal range making it unlikely that significant insulin resistance was induced by indinavir. Further, the changes in methacholine-induced blood flow did not correlate significantly with changes in insulin levels. Taken together, these observations suggest that insulin resistance alone is unlikely to solely account for the marked impairment of endothelial function seen after 4 weeks of indinavir.

Alternatively, indinavir-induced endothelial dysfunction could be mediated by changes in other nonclassic cardiovascular risk factors. One of these nonclassic risk factors includes increased production of free oxygen radicals that could quench NO and render it ineffective.36, 37 We found that plasma MDA levels, a measure of oxidative stress,38 did not change after 4 weeks of indinavir, thus, making increased oxidative stress an unlikely cause. Similarly, 4 weeks of indinavir did not increase levels of TNF-α, IL-1, IL-6, or CRP, arguing against indinavir-induced inflammation as a cause of the vascular dysfunction. However, because of the small number of subjects studied, we cannot completely rule out that 4 weeks of indinavir led to an increase in oxidative stress or cytokines. Thus, we found no evidence to suggest that weight gain, dyslipidemia, hypertension, and smoking status are mediators for the effect of indinavir to induce endothelial dysfunction. Further, it is unlikely that either insulin resistance alone or oxidative stress are primarily responsible. A direct drug-induced effect of indinavir on the endothelium is a highly plausible explanation for these observed findings. Further studies are needed to define this more clearly.

In summary, these studies demonstrate that the protease inhibitor indinavir in HIV-1 negative nonobese subjects causes endothelial dysfunction largely through reduced NO release. Although the overall risk-benefit of therapy for HIV with protease inhibitors must be taken into account, it is important to recognize the increased risk of vascular disease potentially presented by indinavir, and possibly, other protease inhibitors. More research is necessary to clarify the mechanism(s) by which indinavir causes endothelial dysfunction to better develop therapies that counteract or prevent this detrimental effect.

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We are indebted to the subjects who volunteered for this study and all of the staff of the Indiana University General Clinical Research Center.

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 This work was supported by an Indiana University Biomedical Research grant, General Clinical Research Center grant M01-RR00750, HL72711, and AI052852, and an unrestricted research grant from Merck and Co.

PII: S0002-8703(05)00584-3

doi:10.1016/j.ahj.2005.06.005

American Heart Journal
Volume 150, Issue 5 , Pages 933.e1-933.e7, November 2005

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