Our study shows that plasma HDL-C is low in PAH, and that this is associated with higher mortality and increased clinical worsening. This association does not appear to be explained by underlying cardiovascular risk factors, insulin resistance, or the severity of PAH.
We demonstrate significantly depressed circulating levels of HDL-C in subjects with PAH, even when compared with a population that was older and had a higher frequency of males, coronary artery disease, systemic hypertension, and diabetes, all conditions associated with lower HDL-C concentrations. Although it is known that HDL-C is low in chronic inflammatory conditions, such as scleroderma (28
), we show intermediate HDL-C levels in subjects with CTD but without pulmonary hypertension. HDL-C in this group was higher than in subjects with PAH but lower than in control subjects.
There is no consensus on how to diagnose insulin resistance, and “gold standard” tests such as the euglycemic hyperinsulinemic clamp and insulin suppression tests are laborious and expensive. Proposed surrogate markers are elevated TG/HDL-C (sensitivity, 64%; specificity, 68%) (29
) and high HOMA-IR (correlation coefficient between −0.69 and −0.88) (25
). Our PAH cohort was insulin resistant by the former, but HOMA-IR was similar to apparently healthy control subjects. These could suggest that the observed low HDL-C levels are not related to insulin resistance. However, as we did not use the gold standard for the diagnosis of insulin resistance, our data do not exclude its role in PAH.
Zamanian and colleagues have reported similarly low HDL-C levels in 81 females with PAH (43.3 ± 1.58 mg/dl), compared with age- and sex-matched National Health and Nutrition Examination Surveys control subjects (60.5 ± 0.54 mg/dl) (18
). Whereas our findings confirm their observation that the TG/HDL-C ratio is associated with event-free survival (18
), another index of insulin resistance, HOMA-IR, had no association with clinical outcomes. HDL-C had a much stronger association with mortality and clinical worsening than either index, and remained significant when adjusted for both HOMA-IR and TG/HDL-C ratio. Many studies have shown that insulin resistance and the metabolic syndrome carry a higher risk of systemic cardiovascular events (30
), but this is not universal (35
). In one study (32
) cardiovascular events were more closely dependent on insulin resistance than HDL-C levels, whereas another study suggested that HDL-C was the better predictor (37
). Certainly, more clinical research is needed to clarify these issues regarding pulmonary vascular disease. Our data do not rule out a role for insulin resistance, but they do suggest that HDL-C may have prognostic significance in pulmonary vascular disease above and beyond insulin resistance. Possible explanations include the fact that HDL-C has antioxidant and antiinflammatory properties (6
), attenuates endothelial dysfunction (8
), has anticoagulant effects (10
), and enhances the half-life of prostacyclin (12
). The antiinflammatory properties of HDL-C may be particularly relevant here, because we observed systemic inflammation and endothelial activation in patients with PAH with low HDL-C levels ().
Patients with lower HDL-C were not older or more obese than subjects with higher HDL-C, suggesting that the association between HDL-C and mortality was not driven by obesity or older age. Furthermore, HDL-C remained associated with mortality when adjusting individually for established cardiovascular risk factors, the presence of coronary artery disease, statin use, and CRP levels. Elevated CRP levels are associated with the metabolic syndrome and cardiovascular mortality (40
), and have been reported to be predictive of outcomes in PAH (41
). We confirmed the latter finding, but HDL-C predicted mortality independently of CRP levels. Patients with PAH with low HDL-C had more severe functional limitation, higher BNP levels, and more elevated right atrial pressures, suggesting more severe pulmonary vascular disease. Nevertheless, the association between HDL-C and mortality does not appear to be explained by the severity of PAH. Importantly, PCWP was identical in patients with high and low HDL-C, arguing against the presence of more diastolic dysfunction in subjects with lower levels.
As this is an observational study, we cannot establish a cause-and-effect relationship between HDL-C and clinical outcomes in PAH. It is possible that patients with more severe PAH are more functionally limited, hence more sedentary and obese, and thus lower HDL-C is simply a consequence of this and is not related to mortality. However, our data show that patients with lower HDL-C were not more obese or older. Strikingly, patients with PAH had lower HDL-C levels compared with a large population with more cardiovascular risk factors. Furthermore, HDL-C remained predictive of important clinical outcomes when adjusted for age and BMI, several cardiovascular risk factors, functional class, and the 6MWD. Another potential limitation is the lack of data on low-density lipoprotein cholesterol (LDL-C), as it is an important predictor of death and cardiovascular risk. However, the Framingham Study (4
) and more recent studies (5
) have also shown that HDL-C is a protective factor for cardiovascular events, independent of the levels of LDL-C.
In summary, we report low plasma levels of HDL-C in patients with PAH, which were associated with worse clinical outcomes. This association seems to be independent of other cardiovascular risk factors, insulin resistance, and the severity of PAH. Our novel findings of the association between HDL-C and clinical outcomes in PAH suggest that HDL-C may play an important role in the initiation and/or progression of pulmonary vascular disease.