The levels of survivin protein in the blood may help determine if surgery to treat pulmonary arterial hypertension (PAH) will be successful in people with congenital heart disease (CHD), according to new research.
Findings in a rat model of PAH also suggest that the amount of survivin may help predict the extent of lung lesions in these patients.
The study, “The expression of survivin in irreversible pulmonary arterial hypertension rats and its value in evaluating the reversibility of pulmonary arterial hypertension secondary to congenital heart disease,” was published in the journal Pulmonary Circulation.
PAH is a common complication of CHDs that are characterized by impaired oxygenated-venous blood separation. Whether or not PAH is reversible determines the success of surgery to close the shunts, or holes in the heart that allow the blood from the heart’s left and the right sides to get mixed. However, no existing methods or biomarkers are widely established to predict PAH progress in people with congenital heart defects.
Previous studies have demonstrated that resistance to apoptosis — “programmed” cell death, as opposed to death caused by injury — is a key mechanism of both vascular endothelial cells (those that line the interior of blood vessels) and smooth muscle cells that contributes to the irreversibility of PAH.
Apoptosis-related markers have been suggested as potential tools for improving diagnostic accuracy and providing information on the prognosis of cancer. Experiments also have demonstrated that using the chemotherapy daunorubicin could reduce pulmonary arterial wall thickness by boosting apoptosis.
Supporting this hypothesis, levels of survivin — a member of inhibitor of apoptosis proteins family — are markedly increased and help determine prognosis in diverse cancer types. Yet, whether this protein may be useful in PAH remains unclear.
Researchers from Capital Medical University, in Beijing, and University of Iowa Carver College of Medicine addressed this knowledge gap in a rat model of irreversible PAH induced by injecting a natural plant toxin called monocrotaline following left lung removal. Survivin’s potential as a biomarker of PAH reversibility also was investigated in 60 patients with CHD.
Animals with irreversible PAH showed prominent obstructive lesions due to proliferation of cells from the inner layer of small lung arteries. This was associated with reduced apoptosis and with marked increased in both the number of cells containing survivin, and the circulating blood levels of this protein.
In turn, rats with reversible PAH showed a less accentuated increase in mean pulmonary arterial pressure (mPAP), and no changes in an index of right ventricular enlargement relative to the CHD animals without PAH. In addition, unlike those with irreversible disease, these animals showed no decrease in cardiac index — which takes into account cardiac output and body surface area. They also exhibited enlargement of the arterial medial layer, resulting in mild vessel blockage, with increased apoptosis, and unaltered survivin levels compared with the controls.
In all rats, the higher the blood levels of survivin, the greater the amount of this protein in the lungs.
Supported by these findings, the team believes that high levels of “survivin may be correlated with the extent of pulmonary [disease-associated] lesions, as in tumors.”
Among the patients, the classification of irreversible or reversible PAH was based on whether mPAP remained high or was normalized after surgery. Those with irreversible PAH (22 patients with a mean age of 29 years, of whom 13 were females) showed higher blood levels of survivin before surgery than those with reversible PAH (38 patients; mean age 22.5 years, 21 women), and CHD patients without PAH (control group).
Survivin blood levels were found to be correlated with pre-surgery pulmonary vascular resistance and both post-surgery mPAP, and change in mPAP. Subsequent analysis showed that survivin levels above or below 27.5 pg/mL could help define the outcome of surgery in CHD patients with a sensitivity of 89.5% and a specificity of 68.2%.
Both reversible and irreversible PAH patients showed increased levels of the cardiac disease biomarker brain natriuretic peptide (BNP). However, this increase was more pronounced in participants with irreversible changes. Higher blood levels of survivin correlated with greater amounts of BNP.
“In conclusion, the increased survivin level is a feature of irreversible PAH and the serum survivin represents a candidate biomarker reflecting the operability of CHD-PAH patients,” researchers said.
Studies with longer follow-up and a larger number of patients are needed to validate these findings, the team cautioned.
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