March 2010 | Vol 7 | N.º 3 | CNIC-18 [PDF (841K)]

HIV and cardiovascular disease: Urgent need for sub-clinical detection

Valentín Fuster^1,2, Luis-Jesús Jiménez-Borreguero^1,3, Ginés Sanz⁴ and Borja Ibáñez^1,5

Correspondence:
Borja Ibáñez, Imaging in Experimental Cardiology Laboratory, Atherothrombosis and Cardiovascular Imaging Department, CNIC, Melchor Fernández Almagro, 3, 28029 Madrid, Spain.
Email sgonzalez@cnic.es

ABSTRACT
Modern cardiology faces novel diseases and modifications of previous ones. The recently acknowledged association of human immunodeficiency virus (HIV) infection with cardiovascular disease is an example of both. There is compelling evidence that HIV itself should be considered an independent risk factor for cardiovascular disease. Established protocols for risk stratification in the general population might not be suitable for HIV subjects. Novel imaging technology capable of detecting cardiovascular disease in the subclinical phase might help in the early detection and treatment of HIV-related cardiovascular conditions. Given the large health and economic burden associated both with HIV and with its cardiovascular complications, the endeavour of such a non-invasive approach is worth pursuing. In the National Centre for Cardiovascular Research CNIC, we are developing imaging protocols devoted to risk stratification in this population. The early detection and treatment in the pre-clinical phase will be eventually tailored by imaging parameters.

Introduction
Human immunodeficiency virus (HIV) represents an increasing health problem worldwide. With the advent of revolutionary antiretroviral therapy (ART) in the mid-1990s, a significant reduction in HIV-related mortality was achieved¹. The increased survival has resulted in an increase of comorbid conditions. In the cardiovascular system, atherothrombosis, myocardial disease, hypertension, diabetes, and pulmonary hypertension have arisen as entities associated with this disease. The cardiovascular pathologies significantly contribute to the huge economic burden associated with HIV-infection². Although the overall rate of cardiovascular disease (CVD) events is low in HIV-infected subjects, available data suggest that the risk of cardiovascular events is higher than in the uninfected population³. The growing epidemic of CVD in the HIV population can only be curbed by its early identification, in the subclinical stage⁴. Early detection of CVD can be achieved by non-invasive imaging technologies⁵. In this review, we will describe the cardiovascular conditions associated with HIV infection, the role of imaging for its early detection and future perspectives in this field.

Association between HIV and cardiovascular disease
Extensive evidence supports the notion that there is an increased incidence of CVD among HIV patients. Given the extremely high number of new HIV infections every year worldwide⁶, the cardiovascular consequences of the disease represent a significant health issue. Various cardiovascular conditions have been shown to be increased in HIV patients. The most widely studied HIV-related CV condition is atherothrombotic disease, but HIV patients also have increased risk of other conditions.

Atherosclerosis in HIV population: There is an increased risk of atherosclerotic events in HIV subjects compared to non-HIV infected persons. Various studies have shown increased risk of AMI in HIV patients⁷ (Figure 1). In fact, HIV has been proposed as a CVD risk factor⁸. In addition to increased risk of AMI, HIV patients have significantly higher rates of subclinical atherosclerosis⁹.

The mechanisms responsible for the increased incidence of CVD in HIV patients are not fully understood. Three factors partially explain the high incidence of atherosclerosis in the HIV population: viral factors (inflammation, change in lipid profile and endothelial dysfunction), ART factors (dyslipedaemia and insulin resistance), and host factors (increased incidence of traditional risk factors).

There is strong evidence linking HIV infection itself with atherothrombotic disease. Even before the approval of ART for HIV treatment, it was already noted that infected patients had low HDL levels and increased visceral fat¹⁰. In early stages of HIV infection, there is an increase in circulating levels of triglycerides along with a reduction of HDL and LDL, with a relative increase in small, dense LDL particles¹¹. HIV infection induces a metabolic syndrome-like condition in infected patients¹².

Some HIV proteins have been shown to directly activate endothelial cells¹³, and viral load has been independently associated with high levels of pro-inflammatory cytokines¹⁴ and with endothelial dysfunction¹⁵. In addition, low CD4+ count has been associated with carotid lesions and with cardiovascular events¹⁶. The independent contribution of HIV infection to the development of atherothrombotic disease is therefore supported by growing knowledge. Expanded information can be found in dedicated review papers¹⁷.
There is a strong perception that ART, especially if treatment involves a protease inhibitor, increases the risk of CVD in general and AMI in particular^18,19. However, this association is difficult to establish because the design of clinical studies does not allow for a formal causal relationship to be established.

ART drugs are the cornerstone of HIV treatment, but they are associated with dyslipidaemia and insulin resistance. After ART initiation, there is a significant increase in LDL levels, with HDL remaining low. These lipid changes are particularly marked when a protease inhibitor is used²⁰. ART therapy further increases the systemic triglyceride levels and exacerbates the metabolic syndrome associated with the disease²¹. Overall, HIV patients under state-of-the-art ART therapy have a proatherogenic lipid profile, thus contributing to increased CVD incidence.
The third factor potentially accounting for the increased atherothrombotic incidence in the HIV population is the higher prevalence of traditional risk factors compared to matched populations. Beyond the already explained effects of the disease and ART on the lipid profile and metabolic status, HIV patients tend to have more traditional risk factors than matched controls. Smoking is highly prevalent among HIV-infected patients^22-24. Cocaine consumption is also slightly higher in HIV patients than in matched non-HIV populations, further contributing to the clinical consequences of atherothrombotic disease. Limited additional data also suggest that HIV patients might have diets high in saturated fat compared with community control groups²⁵.

From the above details, it seems that the increased risk of atherothrombotic disease results from different factors. The interplay among viral infection, ART therapy and traditional risk factors might be the cause for this increased risk.

Non-atherosclerotic cardiovascular problems in the HIV population: HIV patients under ART are at higher risk of developing left ventricular (LV) dysfunction with clinical manifestations in terms of heart failure. HIV affects the heart structurally and functionally. Most of the information on the effects of HIV infection in the heart was obtained before the era of novel ART; therefore, the beneficial effects of ART on the heart are not fully known²⁶. Before the introduction of antiretroviral drugs, myocarditis and pericarditis were the most frequent cardiovascular complications in HIV-infected subjects²⁷. Indeed, myo/pericarditis was found in ≈60% of biopsy specimens from HIV patients with heart disease^28,29. Pericardial effusion, arrhythmias, pericarditis, and electrical conduction system abnormalities are usually associated with HIV-related myocarditis.
Pulmonary hypertension (PH) is significantly increased in the HIV population. Indeed, one of every 200 HIV adult patients develops PH3. The anatomopathologic findings of HIV-related PH are identical to those of primary HP. However, opposite to primary PH, the incidence of this disease is much higher in male patients, and the prognosis is worse than that of primary PH. The 1-year mortality rate in HIV-associated PH is ≈50%, compared with ≈30% in non-HIV patients with the primary form of PH³⁰. Early diagnosis and treatment of PH in HIV patients is critical, given that the prognosis of HIV patients with PH is much worse than that of HIV patients without PH. The median survival of HIV patients with PH is ~6 months irrespective of ART26.

2. Imaging in the HIV population
HIV-infected subjects are at high risk for atherosclerosis-related diseases. Here, we present the available evidence of subclinical atherosclerosis in the HIV population arising from non-invasive imaging evaluation5,³¹.

Carotid thickening (intima-media thickening, IMT) is a validated surrogate marker of systemic involvement of atherosclerotic disease³². The HIV population tends to have a higher incidence of subclinical atherosclerosis than the general matched population, as evaluated by carotid ultrasound. HIV has been proposed as an independent predictor of the degree of carotid IMT; in addition, IMT of the carotids progresses faster in HIV-positive individuals than in matched non-infected subjects³³. However, the relationship between ART and IMT degree remains unclear, as conflicting results exist^34,35.

Non-invasive imaging of coronary arteries can be achieved with the use of multislice computed tomography (MSCT)³⁶. MSCT is able to quantify coronary artery calcification. In addition, coronary calcium scoring by MSCT correlates with the risk of future events³⁷. MSCT has been used to detect and quantify atherosclerotic plaques^38,39 and to monitor changes in plaque size⁴⁰. Even though there is no precedence for coronary imaging by MDCT in the asymptomatic population, it has been recently shown that young HIV subjects have a significantly higher incidence of obstructive coronary artery lesions than matched non-HIV subjects, as evaluated by MSCT angiography⁴¹. This evidence suggests that HIV subjects of the same traditional risk factor profile could be at higher risk for CVD, which might warrant an independent stratification of CVD in this population. More studies on the role of MSCT in the HIV population are needed to determine the additional impact of coronary (calcium) imaging in the risk stratification of this population.

Beyond MSCT, magnetic resonance imaging (MRI) is able to detect, quantify, characterise, and monitor changes in atherosclerotic plaques. However, it is fair to say that MRI evaluation of atherosclerosis has not been fully introduced to clinical practise, even though it is an accurate and reproducible method⁴² for assessing and characterising⁴³ atheroma plaques in the HIV-free population. This novel technology might be useful for visualising subclinical atherosclerosis in HIV infected patients. Positron emission tomography (PET) with 18FDG can also serve as a tool to detect inflammation in atheroma plaques. 18FDG-PET is very reproducible for plaque-inflammation imaging⁴⁴ and can also be useful for characterising atheroma plaques in HIV infected persons. 18FDG imaging has also been fused with MRI for a better anatomical and functional vessel evaluation (Figure 2).

HIV can affect the myocardium either directly (cardiomyocyte virus infection and/or myocarditis) or indirectly (CAD). The anatomical and functional evaluation of the myocardium can reveal asymptomatic involvement of the myocardium. The evaluation of the myocardium can be achieved by different modalities, such as electrocardiogram, biomarkers and different imaging modalities. Even before the era of ART, echocardiographic examinations revealed signs of dilated cardiomyopathy in 8% of infected patients, with a mean annual incidence rate of 15.9%27. In a cross-sectional study of asymptomatic HIV-infected subjects, most of them on ART, Nayak et al. observed an unexpectedly high prevalence (37%) of mild or moderate diastolic dysfunction. Most patients did not have traditional risk factors associated with diastolic relaxation abnormalities, such as diabetes or hypertension, and CAD risk scores were low⁴⁵. Even though there is no clear recommendation for imaging screening in this population, upon confirmation of these data, screening guidelines might be revisited for HIV subjects. Dilated cardiomyopathy as a consequence of LV systolic dysfunction is also relatively common in HIV positive subjects, conferring a poor prognosis. Given that symptoms related to LV dysfunction may be similar to those of pulmonary disease, imaging examinations in HIV patients with pulmonary symptoms not clearly related to lung pathology should be performed.

Cardiac MRI may also provide accurate information about ventricular ejection fraction and volume in patients with dilated cardiomyopathy. More importantly, from the etiologic point of view, contrast enhanced MRI has proven to be an efficient technique to characterise the myocardium. Hyper-enhancement suggests fibrosis, necrosis, or inflammation. In the clinical context and the special distribution in the myocardial wall may suggest different pathology. Subendocardial enhancement is typical of myocardial infarction in both acute and chronic stages (Figure 3), whereas a patched or subepiciardial pattern suggests an inflammatory process, for example, myocarditis^46-48. Furthermore, contrast enhanced MRI enables the evaluation and monitoring of inflammatory heart disease. There is good correlation between contrast enhancement of the myocardium in suspected myocarditis and active inflammation defined by histopathology⁴⁹. This technique has not yet been fully evaluated in asymptomatic HIV-infected subjects to establish the prevalence of unrecognised myocarditis.

Finally, PH evaluation can be achieved by echocardiographic examinations and by MRI^50-52. MRI has recently received special interest because it represents a promising new approach to the investigation of not only the anatomical, but also the functional and molecular features of PH.

3. Future directions
HIV infection is associated with a wide range of cardiovascular pathologies. From the pathophysiological point of view, it seems that both HIV infection itself and ART are involved in the cardiovascular abnormalities observed. Notably, HIV infection and ART are associated with a metabolic syndrome-like condition, especially with a pro-atherogenic lipid profile and enhanced inflammatory status. The identification of cardiovascular abnormalities in HIV-positive subjects before symptoms arise might be extremely useful to overcome the huge health and economic burden associated with them. Non-invasive imaging modalities will certainly arise as tools not only to detect vascular pathology in HIV asymptomatic patients, but also to monitor the effect of treatments targeting CVD53.

In our centre, we are developing specific imaging algorithms to be validated in the HIV population. These imaging studies will be performed in pre-clinical stages of the disease and will improve our understanding of the association between HIV and cardiovascular disease, as well as help monitor the effect of novel therapies in this population.