In this study, we found that treatment-naïve HIV(+) individuals present greater arterial stiffness compared to age- and sex-matched controls. This difference remained significant after adjusting for HR, MAP, and current smoking. Despite a greater cfPWV, we paradoxically also found a tendency for lower brachial and central pulse pressure in the HIV(+) group. The results of this study replicate previous findings on the harmful effect on HIV infection itself on the arterial vasculature. Furthermore, this is the first study assessing arterial stiffness in HIV infected Mexican individuals. It is important to establish the effect of chronic infectious diseases in different populations such as HIV, given that the immune activation has been reported -in some studies- to vary between ethnicities. For example, compared to Caucasians, Hispanic individuals have been reported to present a greater prevalence of diabetes and insulin resistance and greater average years of life lost after HIV infection. Currently, it unknown whether Latin-American individuals with HIV infection could develop, to a greater degree, metabolic abnormalities secondary to inflammation and accelerated arteriosclerosis.
4.1 Arterial stiffness
In our study, cfPWV was significantly greater in HIV treatment-naïve individuals, which agree with the findings reported by other groups in non-treated HIV infection[31-34], while others have reported similar cfPWV in non-treated HIV individuals versus controls[21, 35, 36]. Schillaci et al. found a lower BMI, HDL-c, and a higher TG and cfPWV in HIV(+) individuals without ART. A greater aortic stiffness in the setting of recently diagnosed HIV infection could be a combination of functional and structural changes in the arterial wall. The development of arterial stiffness is a complex phenomenon where different factors intervene, such as endothelial dysfunction, smooth muscle vascular tone, and structural changes. For example, one of the mechanisms that regulate endothelial function is nitric oxide (NO). NO produces vasodilation, inhibits inflammation, and prevents thrombosis. Chronic inflammation and greater oxidative stress impair NO by reducing its bioavailability; both processes present during HIV infection[39, 40]. For instance, Clapp et al. reported that after the administration of the typhoid vaccine, inflammatory cytokines increase, and anti-oxidant capacity decreases, resulting in endothelial dysfunction. Furthermore, Zhou et al. conducted a study in antioxidant (superoxide dismutase) knock-out mice where they found that the mice lacking the antioxidant exhibited progressively greater PWV over time compared to the wild type mice. In individuals with HIV, it has been reported a reduction of the antioxidant glutathione in the early stages of infection, total antioxidant capacity, and increased peroxidation potential. Furthermore, in a previous study from our laboratory, we had similar findings as Schillaci et al., where serum gamma-glutamyl transpeptidase, a serum enzyme associated with insulin resistance, liver disease, and oxidative stress, was positively correlated with arterial stiffness.
One of the mechanisms by which non-treated HIV infection may cause arterial structural changes is through the dysregulation of matrix metalloproteinases (MMPs). MMPs are a group of endopeptidases that degrade components of the extracellular matrix, including the arterial wall’s collagen, elastin, laminin, and fibrillin. Specifically, MMP-9 (gelatinase B) and MMP-2 have been associated with vascular remodeling . Both endopeptidases can break down the elastic component of the arterial wall (i.e., elastin) and have been positively associated with aortic PWV in individuals with isolated systolic hypertension. One in vitro study reported that HIV-infected macrophages upregulate the secretion of MMP-9 by 3.1-fold compared to non-infected macrophages. More specifically, the HIV-derived proteins, envelope glycoprotein 120 (gp120), and Tat protein have been reported to stimulate MMP-9 expression[47, 48]. Although these endopeptidases were not assessed in our study, this mechanism could partially explain our findings regarding greater cfPWV.
The degree of immunosuppression has been linked to the development of atherosclerosis, due to impairment of cholesterol efflux in HIV infected macrophages and arterial stiffness. In our HIV cohort, we observed that 63.6% of individuals had a lymphocyte T CD4+ count <500 cell/mm3, which may indirectly indicate a long-standing HIV infection before diagnosis; thus, a chronic and more detrimental effect on the vasculature.
4.2 Central hemodynamics
Regarding central hemodynamics, we found a significantly lower cPP but only a tendency in pPP in HIV(+) compared to the uninfected group. These results are likely caused by a combination of a slightly reduced cSBP and pSBP and higher pDBP in HIV(+). A slight decrease in cSBP, despite greater PWV, may be explained by peripheral vasodilation (small and medium-sized arteries), possibly due to the vasodilating effect of prostaglandins[50, 51] through a NO-independent mechanism and inflammatory cytokines (i.e., interleukin 1beta) which are increased after HIV infection. This vasodilation effect on peripheral reflection sites (e.g., arterial bifurcations) might cause a decreased reflection of the backward wave and reduced contribution to cSBP. However, Maloberti et al. found no difference in cPP between controls and HIV(+) receiving ART or treatment naïve. Only HIV individuals who received ART and presented chronic kidney disease had significantly greater cPP compared to HIV(-). The lack of difference in their study might be due to underpowered sample size to detect differences in cPP, as their HIV subgroup comparison was relatively small. Likewise, Vlachopoulos et al. reported similar cPP and cfPWV; however, they observed a reduced cSBP compared to uninfected individuals.
4.3 Lipid metabolism
Abnormal lipid metabolism after HIV infection can be caused by the HIV infection itself, chronic inflammation, and ART. The greater arterial stiffness could be explained by dyslipidaemia observed in the HIV(+) naïve group. Alterations in lipid metabolism have been mainly associated with ART, specifically protease inhibitors[56, 57]. However, lipid abnormalities have also been reported in HIV treatment-naïve individuals, identified as low HDL-c and TC, and increased TG. In this study, we found a tendency for lower TC and significantly lower HDL-c compared to uninfected controls. The majority of HIV(+) individuals in our study presented low HDL-c (<1.04 mmol/L) (78.2% vs. 21.8%) and TC below 5.2 mmol/L (60.8% vs. 39.2%) compared to the HIV(-) group, respectively. From the traditional risk factor point of view, HDL-c plays an essential role in the development of CVD in HIV. HDL-c provides atherogenic protection, defends the vasculature against inflammation and oxidative stress, and helps to preserve endothelial function[60, 61]. A large cohort study in the U.S. found that HDL-c levels <1.04 mmol/L were associated with greater carotid stiffness compared to patients with normal or >1.04 mmol/L HDL-c levels.
Previous findings of the effect of HIV on arterial stiffness have not been consistent. This can be due to several causes, including a pooled comparison of individuals receiving and not receiving ART and different methodologies to assess arterial stiffness such as ultrasound-based carotid-brachial PWV53 and one point PWV[62, 63]. By exploring treatment-naïve HIV infected individuals, this study allowed us to exclude the negative effect of ART on the arterial system and evaluate the impact of HIV infection itself and traditional risk factors as potential etiologies. However, our study has several limitations. Due to its cross-sectional design, we were unable to establish a causal relationship. The smoking history was statistically adjusted, and we were not able to assess biomarkers of inflammation or vascular disease, which have been associated with future CV events, like highly-sensitive C-reactive protein[64, 65]. Additionally, waist measurements were not available to establish the presence of metabolic syndrome. Prospective studies are needed to further clarify the molecular mechanisms involved in CVD after HIV infection and the effect of different ART combinations to reduce cardiovascular mortality in this population.