Anatomy of the Heart: Difference between revisions

However, the relative contribution of each traditional risk factor for CVD risk within a patient is comparable in HIV-infected and uninfected populations, irrespective of HIV-infection status.<cite>3</cite> As such, although the risk factor prevalence is increased in HIV-infected populations, it likely does not at itself explain the increased risk of CVD in this population, and, therefore, several HIV-related factors need to be taken into consideration.

Contemporary ART treatment strategies adhere to a combination of antiretroviral drugs (as such called combined ART (cART)), usually consisting of 2 nucleoside reverse transcriptase inhibitors (NRTIs) in combination with a protease inhibitor (PI), or a non-nucleoside reverse transcriptase inhibitor (NNRTI) in combination with an integrase inhibitor. Several reports have indicated an association between ART treatment and CVD. In particular early studies have reported an increased risk for early acute myocardial infarction (AMI) in patients treated with PIs, which was associated with concomitantly raised cholesterol levels, a known side-effect of PI treatment.<cite>3</cite><cite>11</cite> The associated risk was related to the duration of PI exposure. Nonetheless, the increased risk persisted after statistical correction for lipid concentrations, which implicates an independent direct effect of PI treatment on early occurrence of AMI. Importantly, such increased risk has not been as clearly established for all PIs, and conclusive data remains absent for several ART agents from the PI group. Nonetheless, even in the presence of an increased risk for early AMI, the risk-benefit ratio remains positive towards PI use, due to the unequivocal benefits of cART on survival that outweigh the PI-use associated risk for AMI. For the NRTI group of ART, in particular for abacavir and didanosine, such an association between drugs and CVD is less clearly established, as large cohort studies have yielded conflicting results.<cite>3</cite><cite>11</cite> Nonetheless, there seems to be a consistent reporting of increased AMI risk in HIV-positive populations treated with (c)ART. The complex interrelation of HIV-infection, antiretroviral drugs and concomitant co-morbidities in the presence of traditional CVD risk factors makes it difficult to extract the actual origin of an increased risk for AMI. Nevertheless, an association between ART drugs and AMI must be assumed for all subclasses of ART drugs, although PI use is most consistently found a determinant of early AMI risk.

Besides the CVD risk conferred by the use of aggressive cART, the HIV-infection itself may add to the accumulated CVD risk in HIV-positive patients. HIV-infection related factors include the persistent inflammatory status and immune dysfunction associated with high viral loads, as well as viral load independent factors.

In general populations, persistent inflammation is associated with an increased risk for CVD.<cite>29</cite><cite>30</cite> Markers of inflammation are persistently elevated in HIV-positive patients<cite>31</cite>, which was shown to be directly associated with (increases in) levels of viral loads.<cite>32</cite><cite>33</cite> Different components of HIV are independently associated with increased markers of endothelial cell activation (sVCAM), systemic inflammation (CCL2, IL-10), and adipose tissue activation (adiponectin), which may actively advance atherosclerosis.<cite>34</cite> Moreover, persistent inflammation in HIV-infected patients is directly associated with mortality in this patient population.<cite>35</cite><cite>36</cite> These findings suggest that inflammation itself may explain (part of) the CVD risk in HIV-positive populations additive to traditional risk factors.  

Several studies have indicated that immune dysfunction is associated with CVD risk among HIV-infected patients. CD4+ T-cell counts of <500/IL have been associated with an increase in cardiovascular events, independent of traditional CVD risk factors or ART, carrying an additive risk comparable with that of smoking or sub-optimally treated LDL cholesterol levels.<cite>37</cite> CD4+ T-cell counts of <200/IL were associated with an increased risk of AMI, which was comparable in magnitude to the risk imposed by traditional CVD risk factors.<cite>38</cite> Consistently, episodic CD4+ cell count-guided ART is associated with a substantial increase in risk for AMI compared with continuous ART, indicating an important role of viral load and immune dysfunction for the extent of CVD risk.<cite>39</cite> Moreover, several studies have shown a decrease in non-AIDS related events following the start of ART, and a notable increase in CVD events in patients with incomplete immune recovery following start of ART.<cite>40</cite><cite>41</cite> In addition, the risk of AMI was recently shown to be significantly increased in patients with a recent episode of immune dysfunction defined as CD4 count <200 or HIV-RNA count of >500 copies.<cite>58</cite> It can therefore be acknowledged that (residual) compromise of immune function is an important determinant of risk for CVD as well.

The associations discussed in the previous sections may implicate that suppression of HIV replication, and normalization of inflammation and immune function by (c)ART mitigates the associated CVD risk. However, even viral replication suppression with (c)ART does not fully normalize these processes, and even residual levels may result in adverse cardiovascular outcome. Concordantly, it was shown that carotid intima media thickness is increased in all HIV-infected subgroups compared with controls, including HIV-infected patients that maintain an undetectable HIV viral load without the use of (c)ART.<cite>15</cite><cite>42</cite> This finding was independent of prior ART exposure duration, viremia, or advanced immunodeficiency. Moreover, a recent large cohort study of HIV-infected patients compared with age and CVD-risk matched non-infected controls including more than 80.000 subjects indicated that, although mitigated by virologic suppression, the risk for CVD, and AMI in particular, remains present despite virologic suppression.<cite>26</cite>