In this case-control study we found a 3-fold higher prevalence of retrospectively diagnosed MetS components in the HIV-associated cryptogenic stroke patients than in HIV+ controls without strokes. Although the mean values of MetS components appeared to be higher in the 11 HIV-related cryptogenic stroke cases than in the 55 HIV+ controls matched for age, sex, and date of stoke diagnosis, only mean arterial pressure (MAP) and serum uric acid (UA) were statistically different between the two groups.
This study, like earlier analyses, has shown that cerebral infarction and not hemorrhage is the predominant form of stroke in HIV+ patients (Cole et al, 2004
; Engstrom et al, 1989
; Ortiz et al, 2007
; Qureshi et al, 1997
). This finding and the normal platelet counts in our patients suggests that immune-mediated thrombocytopenia, a common HIV-associated complication, does not frequently contribute to HIV-associated cryptogenic strokes (Pinto, 1996
Neither HIV replication rates, as assessed by plasma HIV levels, nor degree of immunosuppression (current or nadir CD4 lymphocyte cell counts) contributed to risk of stroke (Ortiz et al, 2007
). This study does not address the role of HIV-associated immunosuppression in risk of stroke-like symptoms from central nervous system (CNS) opportunistic infections and malignancies, as such cases were excluded by design. Risk of such strokes is likely to be increased with advanced immunosuppression.
Both MAP and UA, a proinflammatory marker, were significantly greater for HIV+ cases with cryptogenic strokes than HIV+ controls. In regards to serum UA, normal elderly adults with higher UA values have a 4- to 5-fold increase in risk of cerebral ischemic disease, as assessed by hyperintensities in white matter by MRI (Schretlen et al, 2007
). Although the mechanism remains unknown, our findings support a link between elevations in serum UA and cerebrovascular disease. UA can damage the vascular endothelium (Reynolds, 2007
) causing accelerated atherosclerosis (Kanellis and Kang, 2005
). UA can also produce superoxide anions and lead to increases in oxidative stress. A similar mechanism has been proposed for vascular damage caused directly by HIV infection (Sacktor et al, 2004
The use of combined antiretroviral therapy (cART), in particular PIs, has been associated with the development of MetS (Wang et al, 2007
). However, we found no correlation between cART and stroke, even after controlling for PI use. Our results are similar to those of a recent study that demonstrated no relationship between PI use and MetS (Mangili et al, 2007
). In addition, the self-reported duration of exposure to cART was similar for both groups, suggesting that the observed increases in MAP and serum UA may act through other mechanisms. There was no significant difference in the frequency of PI-based regimens between HIV+ stroke patients and HIV+ controls (55% versus 33%). A possible contribution of PIs to risk of cryptogenic stroke was assessed by post hoc power calculations (Hoenig and Heisey, 2001
). For example, we have calculated that the calculated differences in PI use between these two groups could in fact be as small as −12% or as large as 43% due to the limited sample size (). Larger powered studies are required.
This study has multiple limitations. First, although over 2000 cases were examined, the sample size was small, reflecting the relatively low rate of cryptogenic strokes. It is possible that our observed values actually underestimate the prevalence of HIV-associated strokes due to the loss of patients who died, who may have dropped out because of disabilities associated with their strokes, or who failed to recall or recognize subtle clinical symptoms (Wright et al, 2008
). Second, only random outpatient blood GLU and TRG levels were available, introducing variation that may have obscured relationships between stroke and both these variables and MetS, of which they are components. However, random and fasting levels have been found to correlate in patients with MetS, suggesting that the former may be used as a surrogate for the latter (Ahmadani et al, 2008
). Third, because only BMI, but not waist - circumference or anterior-posterior waist diameter, was available, we used BMI to assess central obesity. Fortunately, the relationship between BMI and waist circumference is linear for BMI values between 20 and 30 kg/m2
(Booth et al, 2000
). Fourth, we were unable to exclude with certainty HIV complications and endocarditis as mechanisms of strokes because only 73% had carotid imaging to detect large vessel atheromas, 45% had TTE for evaluation of endocarditis, and 27% had other tests for cerebral vasculopathy and hypercoagulation (Ortiz et al, 2007
). Previous studies have demonstrated that these conditions could increase the risk of both ischemic and hemorrhagic stroke with HIV infection (Berger, 2004
). Finally, MetS risk factors were assessed an average of nearly 2 years after diagnosis of stroke, allowing for greater variation compared to the extended period before the stroke when they may have operated to increase risk. Although we were surprised that laboratory values for some MetS risk factors were elevated at these later time points, we believe that the observed effects may be even greater for longitudinal studies that assessed cases earlier after their event. Future larger prospective studies to assess these metabolic risk factors are needed to confirm these findings.
This is first study to examine the relationship of MetS and its components to HIV-related stroke in the cART era and in comparison to matched HIV-infected patients without stroke (Ortiz et al, 2007
). Comparisons in the pre-cART era could not examine stroke risk associated with the antiretroviral protease inhibitors or non-nucleoside reverse transcriptase inhibitors that contribute to MetS. The fact that that the effect sizes were quite robust for hypertension and hyperuricemia (Cohen's d
= 1.46 for MAP and for 0.96 for serum UA) suggests the importance of examining these potential predictors in larger cohorts.
We conclude that detecting elevations in MetS components, especially hypertension and hyperuricemia, and reducing them by lifestyle modifications and/or pharmacological therapy may benefit the increasingly aging HIV+ population of most developed countries by preventing strokes.