Higher levels of certain high-density lipoproteins (HDLs) improve the survival of pulmonary arterial hypertension (PAH) patients, according to a recent evaluation of two PAH patient cohorts. Targeting certain HDL subclasses may improve future PAH treatment.
The study, “Reduced plasma levels of small HDL particles transporting fibrinolytic proteins in pulmonary arterial hypertension” was published in the journal Thorax.
HDLs are one of five groups of protein complexes that transport fat molecules (e.g. cholesterol) in the body. HDLs transport cholesterol out of tissues, which can result in vasodilation, anti-inflammatory effects, and protection of the endothelium (cells that line the interior surface of blood vessels).
Previous studies found that experimental manipulation of certain HDLs reduced pulmonary hypertension.
Now, researchers investigated the effects of HDL on PAH prognosis by analyzing clinical outcomes in PAH patients. The team also examined HDL-related protein interactions, and their potential use as future therapeutic targets in PAH.
The team enrolled PAH patients from the National Pulmonary Hypertension Service at Hammersmith Hospital in London, England.
Blood samples and clinical features of two different PAH cohorts, a discovery cohort with 127 patients (mean age 54) and a validation cohort with 77 patients (mean age 57), were analyzed. Both cohorts included patients with idiopathic or heritable PAH, and the median follow-up time was 4.9 and 3.4 years, respectively.
In total, 43 patients (34%) from the discovery cohort, and 45 (58%) from the validation cohort died during the follow-up period.
Blood analyses identified three of 105 plasma-circulating lipoproteins that were associated with survival in both cohorts. The three lipoproteins were part of a subclass of HDL called HDL-4, which is the smallest and most dense subclass among HDLs. Higher levels of HDL-4 were significantly associated with improved survival compared with other HDL subclasses.
The team further found that one of these proteins, HDL-4-Apo A-2 — an HDL-4 protein and the second-most abundant lipoprotein in HDL — showed the most significant association with patient survival. When researchers grouped patient data according to HDL-4-Apo A-2 plasma levels, they found a concentration-dependent effect of HDL-4-Apo A-2 on survival.
None of the other lipoprotein classes had prognostic value.
Results also showed that, while PAH patients treated with lipid-lowering statin medications showed reduced low-density lipoprotein (LDL) levels, HDL levels were unaffected. These findings are consistent with earlier studies, showing no effect of statins on PAH-related exercise capacity, cardiac output, or survival.
Among proteins known to be associated with HDL-4-Apo A-2, researchers found three that are linked to the regulation of fibrinolysis (a process that prevents blood clotting and is sometimes impaired in pulmonary hypertension), and the kallikrein–kinin pathway (a pathway involved in inflammation, vasodilation, and coagulation). The proteins are called alpha-2-antiplasmin, coagulation factor XI, and prekallikrein.
“Our data suggest that HDL subclasses differ in their contribution to the pathology of PAH; only plasma small HDL-4 levels were independently prognostic in patients with PAH,” the researchers said, emphasizing that reduced plasma levels of HDL-4-Apo A-2, in particular, “are independently linked with higher mortality in PAH, supporting a biologically important role in the natural history of this disorder.”
The team suggests that “apolipoproteins and other HDL-4-associated proteins, including prekallikrein and alpha-2-antiplasmin, regulate biological mechanisms relevant to PAH, such as fibrinolysis and vasodilation.” Therefore, “further investigation into the potential therapeutic benefit of increasing the levels of small HDL and its associated proteins in PAH” is needed, the researchers concluded.