Pulmonary hypertension and congenital heart disease: An insight from the REHAP National Registry.

BACKGROUND: Pulmonary arterial hypertension (PAH) is common in patients with congenital heart disease (CHD). Although Eisenmenger syndrome may be on decline, other types of PAH-CHD are increasing and little is known on long-term outcome of this population. We report the PAH-CHD population of Spain via a national registry with focus on long-term survival. METHODS AND RESULTS: A total of 240 consecutive patients (age 37.7 ± 14.1 years, 67.9% females) with PAH-CHD included in the REHAP registry were analysed. Patients were classified into 3 groups: 1) Eisenmenger syndrome, 2) postoperative-PAH and 3) PAH associated with small defects. Over a median follow-up time of 4.5[1.6-7.1]years, 50 patients (20.8%) died or underwent lung/heart-lung transplantation. Patients with Eisenmenger syndrome had better survival than postoperative-PAH (HR 0.1 95% CI: 0.2-0.9, p=0.048) but no advantage compared to small defects (HR 4.4, 95% CI 0.6-31.4, p=0.15). In the overall PAH-CHD population, patients in NYHA functional class III-IV had a 3-fold increased risk of death (HR 3.0, 95% CI: 1.5-5.9, p=0.001). Amongst patients with Eisenmenger syndrome, a pre-tricuspid shunt had a 2.6-fold increase risk of death (HR 2.6, 95% CI: 1.2-5.6, p=0.03). There was no significant difference in survival between patients with postoperative-PAH and patients with iPAH (HR 0.99 95% CI: 0.6-1.7, p=0.97). CONCLUSION: PAH-CHD is associated with mid to long-term mortality. Outcome relates closely to functional class, type of PAH-CHD and within the Eisenmenger cohort, with location of the shunt. Adults with postoperative-PAH have the worse prognosis in the PAH-CHD cohort, reinforcing the need for lifelong close follow-up of such patients.

Usefulness of progesterone-only components for contraception in patients with congenital heart disease.

The objective of the study is to report the contraceptive methods used by patients with congenital heart disease (CHD) before referral to a specific preconception clinic and evaluate safety and treatment adherence of the alternative contraception method, progesterone-only component (PC), offered. Contraceptive methods in the CHD population reported included estrogen-progesterone combined contraceptives (EPCC), despite the potential risk for thromboembolism. PC has been suggested as an alternative, but, no information on its use has been reported. Retrospective analysis was performed of all patients (n = 237) referred to the preconception clinic of an adult CHD center. Thirty-three percent of patients had used EPCC in the past; 3.8% had had thromboembolic events during its use. Current contraception consisted of barrier methods in 58% of patients, EPCC in 18%, and PC in 1.3%; 21.7% of patients were not using any contraception. PC was offered as an alternative in 146 patients; 73% of patients agreed to start the treatment. At a median follow-up of 1 year, 73% of patients who started PC maintained the treatment. Gynecologic side effects were reported in 25% of patients, with no cardiovascular effects. In conclusion, a significant proportion of patients with CHD were former users of EPCC, although some had formal contraindications, and the rate of PC use before referral to the preconception clinic was low. After being offered as an alternative treatment, the use of PC in its various forms was extensive, with no thrombogenic side effects and an acceptable rate of gynecologic side effects being reported.

The sphingosine-1-phosphate receptor-1 antagonist, W146, causes early and short-lasting peripheral blood lymphopenia in mice.

Agonists of the sphingosine-1-phosphate (S1P) receptors, like fingolimod (FTY720), are a novel class of immunomodulators. Administration of these compounds prevents the egress of lymphocytes from primary and secondary lymphoid organs causing peripheral blood lymphopenia. Although it is well established that lymphopenia is mediated by S1P receptor type 1 (S1P1), the exact mechanism is still controversial. The most favored hypothesis states that S1P1 agonists cause internalization and loss of the cell surface receptor on lymphocytes, preventing them to respond to S1P. Hence, S1P1 agonists would behave in vivo as functional antagonists of the receptor. For this hypothesis to be valid, a true S1P1 antagonist should also induce lymphopenia. However, it has been reported that S1P1 antagonists fail to show this effect, arguing against the concept. Our study demonstrates that a S1P1 antagonist, W146, induces a significant but transient blood lymphopenia in mice and a parallel increase in CD4+ and CD8+ lymphocytes in lymph nodes. Treatment with W146 also causes the accumulation of mature T cells in the medulla of the thymus and moreover, it induces lung edema. We show that both the S1P1 antagonist and a S1P1 agonist cause lymphopenia in vivo in spite of their different effects on receptor expression in vitro. Although the antagonist purely blocks the receptor and the agonist causes its disappearance from the cell surface, the response to the endogenous ligand is prevented in both cases. Our results support the hypothesis that lymphopenia evoked by S1P1 agonists is due to functional antagonism of S1P1 in lymphocytes.