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Noninvasive detection of impaired pulmonary artery endothelial function in people living with HIV

Goerlich, Erina,∗; Mukherjee, Monicaa,∗; Schar, Michaelb; Brown, Todd T.c; Bonanno, Gabrielea,b; Weiss, Robert G.a,b; Hays, Allison G.a,b

Author Information
doi: 10.1097/QAD.0000000000002671

Abstract

Introduction

As therapies to treat HIV have improved over recent decades, people living with HIV (PLWH) are living longer and faced with chronic diseases, including cardiopulmonary disease and pulmonary hypertension [1,2]. The prevalence of HIV-associated pulmonary hypertension (HIV-PH) is higher than in the general population, confers significant morbidity and is an independent predictor of mortality [2–5]. Furthermore, survival rates are worse for those with HIV-PH compared with those with HIV without pulmonary hypertension [2]. In addition to primary pulmonary arterial hypertension, PLWH more frequently develop secondary pulmonary hypertension due to common comorbidities such as coronary atherosclerosis, heart failure and chronic obstructive lung disease [6]. Although the mechanisms underlying pulmonary hypertension are not well understood in PLWH, several factors have been implicated in the pathogenesis, including viral proteins, coinfection with hepatitis C virus (HCV), inflammation, genetics and social factors such as smoking and IDU [6]. What is needed is the ability to detect pulmonary artery injury at the earliest stages both as a tool to understand the natural history of the disease and to tease out the importance of factors contributing to injury as well as for early clinical detection when therapeutic options may have greater efficacy.

Endothelial dysfunction of the pulmonary vascular bed is an early, central underlying pathophysiologic mechanism in the development of pulmonary hypertension, which is characterized by diminished nitric oxide production and impaired relaxation of the pulmonary artery to specific stressors [7,8]. Moreover, studies in animal models of pulmonary hypertension have shown that viral proteins can induce vascular oxidative stress and direct endothelial cell injury, which may progress to pulmonary vasculature remodelling and vasoconstriction [3,9,10]. Endothelial dysfunction in peripheral and coronary arteries of people with and without HIV is a marker of cardiovascular disease and is associated with adverse outcomes [11–13]. Pulmonary artery endothelial function (PAEF) has historically been assessed with invasive catheter-based measures of changes in pulmonary artery cross-sectional area (CSA) and blood flow in response to an endothelial-dependent stressor [14,15]. Previous studies showed that pulmonary vasoreactivity is impaired in patients with idiopathic pulmonary hypertension [16], and predicts mortality in this population [14,17,18]. The invasive nature of prior techniques to quantify the pulmonary artery vasodilatory and flow responses to endothelial-dependent stressors significantly limited the clinical utility of this technique, particularly in those requiring repeated studies and/or studies in clinically stable or healthy individuals. However, because of these invasive requirements, little is known about PAEF in PLWH. A noninvasive method to identify pulmonary endothelial dysfunction would represent a valuable tool to better understand the pathogenesis of pulmonary vascular disease and pulmonary hypertension in HIV.

Previous work from our group utilizing the novel combination of 3T MRI methods with isometric handgrip exercise (IHE), a well established endothelial-dependent stressor, demonstrated a noninvasive method of measuring coronary endothelial function with high reproducibility including in cohorts of PLWH [19,20]. In the present study, we used MRI techniques to quantify PAEF by measuring stress-induced changes in both pulmonary artery CSA and pulmonary artery blood flow (PBF) [21]. We aimed to assess feasibility of this technique as well as to test the hypothesis that PLWH have impaired PAEF compared with age and sex-matched participants without HIV. Furthermore, in order to determine whether the normal observed pulmonary artery vasoreactive responses to IHE are mediated by nitric oxide and thus reflect PAEF, we studied the pulmonary artery response to IHE before and during infusion of NG-monomethyl-l-arginine (l-NMMA), a nitric oxide-synthase inhibitor, in separate group of healthy volunteers.

Materials and methods

Study participants

Our study was approved by the Johns Hopkins institutional review board, and all participants provided written informed consent. There are two parts to this study: first, testing whether PLWH have impaired pulmonary artery vasoreactivity with IHE as compared with matched controls and second, whether pulmonary artery vasoreactivity to IHE exercise is predominantly nitric oxide mediated. For the first part, HIV-positive participants were prospectively recruited from outpatient clinics at the Johns Hopkins Hospital and were screened for contraindications to MRI. PLWH were on stable ART for at least 2 months with a CD4+ cell count more than 200 cells/μl. The majority had an undetectable viral load, and there was no self-reported recreational drug use for 2 months or more prior to enrolment. HIV-seronegative individuals served as controls and were healthy adults prospectively recruited with no contraindications to MRI, no known history of cardiovascular disease or diabetes, and with at most one traditional cardiovascular risk factor. Control participants were intentionally matched to HIV patients based on age and sex. For the second part on whether the pulmonary artery response to IHE is nitric oxide mediated, we analysed images previously acquired during nitric oxide-synthase inhibition.

MRI protocol

Each individual underwent noncontrast MRI using a commercial 3.0 Tesla (T) whole-body MR scanner (Achieva; Philips, Best, the Netherlands) with a 32-element cardiac coil for signal reception in a fasting state while in the prone position [21]. On the basis of an acquired field map, localized radiofrequency shimming was performed [22]. Baseline anatomical and velocity-encoded scout images were collected at rest and a high-resolution three-dimensional (3D) volume using a segmented gradient echo sequence was used to localize pulmonary artery segments during free breathing with real-time navigator gating and motion tracking as previously described [21]. Images were then acquired perpendicular to a linear segment of a branch pulmonary artery best identified on scout images (Fig. 1a).

F1
Fig. 1:
Example of a healthy adult coronal image of the pulmonary arterial tree.

To obtain PAEF measurements, the imaging plane was localized perpendicular to a well visualized, linear segment of the descending left and/or right pulmonary artery without branches over a distance of approximately 2 cm. A high-resolution coronal 3D MRI angiogram and its transverse reformat were used to ensure that slice orientation was perpendicular to the pulmonary artery (Fig. 1b). For pulmonary artery measurements, a Cartesian, retrospectively VCG-triggered, segmented gradient echo cine acquisition reconstructed to 40 cardiac phases was used. Following anatomical area images, pulmonary artery blood flow images were acquired with gradient echo cine phase contrast velocity-encoded images that were reconstructed to 25 cardiac phases with velocity encoding set to 100 cm/s. The breath-hold duration was approximately 20–25 s for each anatomical and velocity-encoded sequence. Repeat imaging of the same anatomic location was then completed during 4–7 min of continuous IHE using an MRI-compatible dynamometer (Stoelting, Wood Dale, Illinois, USA) at 30% maximum grip strength as directed by a supervising research nurse. Heart rate and blood pressure were monitored throughout using the scanner's vector electrocardiogram (VCG) and a MRI-compatible blood pressure cuff on the calf (Invivo; Precess, Orlando, Florida, USA). The rate pressure product (RPP) was calculated from the product of SBP x heart rate.

NG-monomethyl-l-arginine study

To determine the contribution of nitric oxide to the pulmonary artery vasoreactive response, we analysed previously acquired images collected before and during infusion of NG-monomethyl-l-arginine l-NMMA (0.3 mg/kg per min), a nitric oxide-synthase inhibitor, in healthy volunteers [19]. The prior study was performed to study nitric oxide mediated coronary endothelial function detected by MRI during IHE, but we reanalysed the data for the responses of the pulmonary arteries. Each participant (n = 7, adults without HIV) underwent a first IHE period during which isotonic saline (placebo) was infused. After postexercise recovery, each individual then received an intravenous infusion of l-NMMA at a dose of 0.3 mg/kg per min, as previously described [19]. A new set of baseline images was obtained after 5 min of l-NMMA infusion. A second IHE period was then initiated while l-NMMA infusion continued, and imaging was repeated at the same location, with the average infusion lasting approximately 15–22 min. Pulmonary artery percentage area change measures were obtained at each time point as shown in Fig. 2.

F2
Fig. 2:
Protocol diagram illustrating MRI N G-monomethyl-l-arginine study of the pulmonary arteries in seven healthy volunteers (mean age 42 ± 3 years, four women).

Image analysis

The images were analysed at baseline and during IHE stress for pulmonary artery CSA, in mm2 and PBF, in ml/min. The relative percentage stress-induced change was calculated for each segment. The CSA was measured using semi-automated software (Cine Version 3.15.17; General Electric, Milwaukee, Wisconsin, USA), which utilized manual outline of the pulmonary artery branch of interest in cross-section followed by automated adjustment of the vessel border according to full-width-half-maximum-algorithm. The CSA was taken during systole at peak vessel diameter and averaged over three image frames. For PBF measurement, a similar technique with automatic outline of each cross-sectional segment with manual correction was applied on phase contrast images, averaged throughout one cardiac cycle, and then integrated to obtain total flow in ml/min in the corresponding vessel using (QFLOW version 3.0; Medis, the Netherlands). Images with poor quality (due to artefact and/or motion) were excluded from the analysis (n = 2, assessed by consensus of two blinded readers). In cases wherein greater than one pulmonary artery were measured in the same individual, the percentage change in CSA and/or PBF between baseline and IHE stress was averaged to perform per-individual analysis. Intraobserver and interobserver measurements were performed by two independent readers blinded to participant group for pulmonary artery CSA and PBF on a subset of 10 healthy individuals (20 segments total), and analysis was performed blinded in terms of state (rest vs. stress). Data analysis for the main pulmonary artery study and l-NMMA study was performed by two independent investigators blinded to study group (placebo vs. l-NMMA) and stage of the protocol (rest vs. stress).

Laboratory measurements

As part of routine clinical evaluation, the most recent CD4+ cell count and HIV RNA were obtained from the electronic medical record (EMR, within 1 year of study), as were CD4+ cell count nadir, HCV testing and lipid panels. When available, any prior clinically indicated echocardiographic data were obtained from the EMR to document right ventricular systolic pressure (RVSP) as a marker of pulmonary pressures.

Statistical analysis

Statistical analysis was performed with GraphPad Prism version 8.3.1 (GraphPad Software, San Diego, California, USA). The Shapiro–Wilk test was used to test the data for normality. Parametric Welch's t-test was used to compare between-group differences in normally distributed data, and nonparametric testing (Wilcoxon rank sum or Mann–Whitney test) was used to make comparisons between skewed data, as appropriate, for differences in pulmonary artery CSA and PBF in response to IHE. Linear regression analysis was performed to assess correlation between-individual BMI and each PAEF parameter (percentage change CSA and PBF from baseline to stress) as well as correlations in the PLWH group between ART duration, most recent CD4+ cell count, CD4+ cell count nadir (if known) and each PAEF parameter. The Bland–Altman method was used to assess interobserver and intraobserver agreement for pulmonary artery CSA and PBF measurements, with P-values derived from Pitman's test of differences. Intraclass correlation coefficients were also determined for inter and intraobserver results for pulmonary artery CSA and PBF using a two-way mixed effects model wherein people effects are random and measure effects are fixed. Statistical significance was defined as a two-tailed P value of 0.05 or less. Data are expressed as mean ± standard error of the mean (SEM).

Results

Participant characteristics

The characteristics of all individuals are reported in Table 1. There was no statistically significant difference between groups in terms of age or sex due to intentional matching. Conventional cardiovascular risk factors of type II diabetes mellitus, hypertension, hyperlipidaemia and tobacco smoking (combined current and former) tended to be higher in the PLWH group but did not meet statistical significance. BMI was significantly higher in the PLWH group (P = 0.004). Importantly, the PLWH participants were all on stable ART for more than 2 months prior to study enrolment with CD4+ cell count more than 200 cells/μl, and 92% with viral load less than 20 copies/ml (the remaining two individuals had detectable viral loads ≤60 copies/ml). All PLWH individuals were negative for HCV. Measurements of low-density lipoprotein (LDL) cholesterol within the preceding 12 months were clinically available for 23 of the PLWH individuals (mean LDL 102.8 ± 6.4 mg/dl). Of those who had prior clinically indicated transthoracic echocardiograms (n = 15, all from the PLWH group), the mean RVSP was within the normal range at 28.3 ± 1.6 mmHg with only one individual with mildly elevated RVSP of 40 mmHg.

Table 1 - Baseline characteristics of individuals with HIV vs. seronegative controls.
Characteristics Controls (n = 19) PLWH (n = 25) P
Age (years), mean ± SEM 46.5 ± 2.9 49.6 ± 1.7 0.36
Women, n (%) 11 (58) 16 (64) 0.68
BMI (kg/m2), mean ± SEM 25 ± 0.8 29 ± 1 0.004
Diabetes, n (%) 0 (0) 2 (8) 0.50
HTN, n (%) 4 (22) 9 (36) 0.49
Smoker, n (%) 3 (17) 5 (20) 0.72
Statin use, n (%) 2 (11) 9 (36) 0.053
Years on ART, mean ± SEM N/A 12.6 ± 1.2
Protease inhibitor, n (%) N/A 5 (20)
NNRTI, n (%) N/A 4 (16)
NRTI, n (%) N/A 22 (88)
Integrase inhibitor, n (%) N/A 21 (84)
CD4+ cell count (cells/μl), mean ± SEM N/A 874 ± 72
CD4+ cell nadir (cells/μl), mean ± SEM N/A 288 ± 43
Viral load <20 copies/ml, n (%) N/A 23 (92)
Prior RVSP (mmHg), mean ± SEM n = 15; 28.3 ± 1.6
ART, antiretroviral therapy; HTN, hypertension; NNRTI, nonnucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; RVSP, right ventricular systolic pressure; SE, standard error of the mean.

Haemodynamic effect of isometric handgrip exercise

There was no significant difference in baseline resting heart rate, SBP or RPP between the two groups (P = 0.25, P = 0.46 and P = 0.22, respectively). There was a similar increase in RPP with IHE for both groups (15.4 ± 3.7% for PLWH and 15.9 ± 3.3% for controls, P = 0.92).

Pulmonary artery vasoreactivity

Representative anatomical and velocity-encoded pulmonary artery images are shown in Fig. 1. Image quality was sufficient for analysis of pulmonary artery CSA in all individuals (total of 30 pulmonary artery segments from the control group and 31 pulmonary artery segments from the PLWH group). The image quality for the PBF analysis was adequate for 29 pulmonary artery segments in each group. Bland–Altman analyses for intraobserver and interobserver variability for PAEF measures are shown in the supplement (Supplemental Fig 1, https://links.lww.com/QAD/B824, showing Bland–Altman analyses).

Baseline pulmonary artery CSA and PBF in controls showed no significant difference from PLWH individuals (pulmonary artery CSA 35.6 ± 2.4 vs. 30.3 ± 2.8 mm2, P = 0.07; PBF 322 ± 47 vs. 236 ± 28 ml/min, P = 0.27). In healthy, seronegative controls, the pulmonary artery responded to IHE with vasodilation and an increase in blood flow. However, those normal responses were significantly attenuated in PLWH: pulmonary artery CSA (7.7 ± 2.2 vs. −1.1 ± 1.2%, P = 0.002) and PBF (13.5 ± 4.8 vs. 0.2 ± 2.3%, P = 0.005, Fig. 3).

F3
Fig. 3:
Percentage change in pulmonary artery cross-sectional area (CSA, a) with isometric handgrip exercise (IHE), and percentage change in PA blood flow (PBF, b) with IHE is demonstrated in 25 individuals with HIV (black bars) and 19 controls (gray bars).

Linear regression analysis revealed no significant correlation between BMI in all participants and each PAEF parameter (P = 0.19 for CSA, P = 0.17 for PBF). A separate analysis of PAEF in a subset of individuals matched for BMI [PLWH (n = 23 for CSA, n = 25 for PBF) vs. controls (n = 14 for CSA, n = 13 for PBF)] revealed a consistently significant difference in pulmonary artery CSA and PBF change with IHE between groups (7.6 ± 2.3 vs. −1.1 ± 1.2%, P = 0.004 and 12.2 ± 5.5 vs. 0.2 ± 2.3%, P = 0.02, respectively). Linear regression was performed in the PLWH group to evaluate the association between CD4+ cell count (n = 21) and PAEF and revealed a positive association between CD4+ cell count and IHE-induced PBF change (r2 = 0.32, P = 0.0096); however, this was no longer significant after removing an outlier (r2 = 0.007, P = 0.73). Similarly, there was no significant relationship between CD4+ cell count and CSA change (r2 = 0.11, P = 0.14, Fig. 4). Additional linear regression analysis on ART duration, nadir CD4+ cell count and LDL cholesterol vs. each PAEF parameter in the PLWH cohort revealed no significant correlations.

F4
Fig. 4:
Intravenous infusion of N G-monomethyl-l-arginine blocks isometric handgrip exercise induced pulmonary artery vasodilation in seven healthy volunteers measured by MRI.

Pulmonary artery area changes with NG-monomethyl-l-arginine

For the pulmonary artery analysis of previously acquired l-NMMA images in seven healthy adults (age 42 ± 3 years, four women), there was significant pulmonary artery dilation in response to the first IHE, consistent with the observations above (Fig. 4). There was no difference in resting CSA of the pulmonary artery before the first IHE episode (during placebo infusion) and before the second IHE episode (during l-NMMA infusion, P = 0.4). However, in contrast to the vasodilatory pulmonary artery response to IHE during placebo, there was no significant increase in pulmonary artery area when IHE was repeated during l-NMMA infusion (Fig. 4, P = 0.3 vs. baseline). When comparing the IHE response between placebo and l-NMMA conditions, the normal pulmonary artery area increase with IHE (as % baseline) was completely blocked by l-NMMA infusion (12.4 ± 5.8 vs. 1.6 ± 3%, placebo vs. l-NMMA; P = 0.001, Fig. 4).

Discussion

In this study, we demonstrate that noninvasive, noncontrast 3T MRI measures of pulmonary artery cross-sectional area and blood flow are feasible with high temporal and spatial resolution as well as reproducible with good intraobserver and interobserver agreement for vasoreactivity. Moreover, the normal response to IHE of pulmonary artery vasodilatation and increased flow are primarily nitric oxide dependent and that normal response is nearly completely lost in otherwise healthy, virally suppressed PLWH. This new ability to noninvasively characterize nitric oxide dependent PAEF provides an opportunity to expand our understanding of the dynamic pathophysiologic factors contributing to pulmonary endothelial dysfunction in PLWH who are at risk for pulmonary hypertension and, in the clinical setting, to potentially assess the response to interventions with noninvasive serial studies.

Pulmonary endothelial dysfunction is a proposed common mechanism underlying the development of pulmonary hypertension due to attenuated nitric oxide release and the resulting impaired relaxation of the pulmonary arteries [9,10]. Studies have directly demonstrated reduced endothelial nitric oxide production and decreased responsiveness of pulmonary vascular smooth muscle to vasodilators in animal models of severe pulmonary hypertension [9,23]. One study showed that intrapulmonary nitric oxide levels were significantly lower in patients with pulmonary hypertension (due to pulmonary arterial hypertension) than healthy controls, and nitric oxide reaction product levels were inversely correlated with pulmonary artery pressures [24]. Moreover, one of the mainstay treatment categories for pulmonary hypertension targets the nitric oxide pathway to soluble guanylate cyclase. Taken together with several biochemical studies investigating the expression of factors and cofactors for nitric oxide in patients with pulmonary hypertension, it has been concluded that impaired synthesis and/or activation of nitric oxide may contribute to the development and progression of pulmonary hypertension [25]. Thus, our findings of impaired nitric oxide mediated vasodilation are particularly compelling in a patient population known to be at an increased risk of developing pulmonary hypertension.

This MRI method of vasomotor testing has previously shown that PLWH have profound abnormalities in coronary endothelial function despite being on typical ART regimens with low viral loads and adequate CD4+ cell counts, which is consistent with the findings in PAEF in low-risk PLWH in this study [26]. Importantly, prior studies have shown that the reported prevalence of HIV-PH did not change significantly after the introduction of ART in PLWH [6,27,28]. This is supported by our observation that there was no significant relationship between either CD4+ cell count or ART duration and PAEF.

The prevalence of pulmonary hypertension in PLWH is higher than in the general population [2,4,5,28], and the development of pulmonary hypertension is considered to be an independent predictor of mortality [2,3]. The degree of pulmonary artery endothelial dysfunction observed in PLWH may explain in part why this population is at greater risk for pulmonary hypertension. Prior studies have suggested that early diagnosis and treatment of pulmonary hypertension may lead to improved long-term outcomes; therefore, the earlier detection of pulmonary artery endothelial dysfunction that contributes to pulmonary hypertension is important [29–31]. Thus, our noninvasive method of assessing PAEF may provide additional information for evaluating PLWH who are at a higher risk for developing pulmonary hypertension. Importantly, as the MRI-IHE technique is well tolerated and reproducible, this method may be used to follow patient response to therapy over time and therefore warrants further study.

Limitations

The main limitation of the study is the relatively modest sample size. However, the sample size was adequate to test our hypotheses, and importantly, we detected a significant difference in PAEF between PLWH and the control group with 44 participants total. It is difficult to determine from this cross-sectional study whether the mechanistic abnormalities in PAEF in the PLWH are due to the HIV infection itself, ART or another confounding factor. However, the groups were well matched in terms of age, sex and cardiovascular comorbidities such as hypertension and diabetes. Although the BMI was significantly higher in the PLWH group, regression analysis showed no significant correlation between BMI and PAEF suggesting that the abnormal endothelial response in the PLWH group cannot be explained by the higher BMI alone. This study was not conducted with patients who have known HIV-PH, which could provide further insight into the pathophysiology underlying the disease. Further studies are needed with such cohorts. Another limitation of the study is that the MRI measurements of PAEF were not compared with invasive methods of pulmonary artery vasomotor testing, as this was not clinically indicated in relatively healthy individuals. However, given our goal of measuring CSA and blood flow, MRI has been previously validated for these measures (with the gold standard of invasive angiography) in other vascular beds [32,33].

Conclusion

The present study demonstrates that high-resolution MRI combined with IHE provides an innovative reproducible noninvasive approach to the assessment of nitric oxide mediated endothelial-dependent vasoreactivity of the pulmonary vascular bed and that PLWH who have no known pulmonary vascular disease have significantly impaired PAEF compared with matched controls without HIV. Importantly, we demonstrated that the degree of pulmonary artery endothelial dysfunction was not related to duration of ART and present despite well controlled HIV infection. Our findings suggest that this noninvasive approach to measure PAEF may complement the risk assessment, be used to test new therapies for pulmonary vascular health, and to follow progression for PLWH who are at risk for pulmonary hypertension.

Acknowledgements

R.G.W. and A.G.H. conceived the study and obtained regulatory approval. A.G.H., M.S. and G.B. collected data. A.G.H., E.G. and M.M. analysed data. E.G. and M.M. both drafted the first manuscript in close collaboration with R.G.W. and A.G.H. All of the authors reviewed the manuscript.

This work was supported by the Ruth L. Kirschstein Institutional National Research Service Award; T32HL007227-Pathophysiology of Myocardial Disease. This work was supported by the National Institute of Health (1R01HL147660, HL007227, HL125059).

Conflicts of interest

There are no conflicts of interest.

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Both Erin Goerlich and Monica Mukherjee contributed equally to this article.

Keywords:

endothelial function; HIV; MRI; pulmonary hypertension; pulmonary vascular disease

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