Congenital heart disease and pulmonary arterial hypertension in South America (2013 Grover Conference series).

South America is a territory of 17,819,100 km(2), where ∼388 million people live in 13 countries. In the region, access to medical assistance (e.g., for treatment of cardiovascular disorders) is relatively easy in metropolitan areas but difficult in remote places such as the Andes and the Amazon. Altitudes up to ∼6,700 m influence the prevalence of congenital heart disease (CHD) and pulmonary arterial hypertension (PAH). In tertiary centers, CHD is now treated earlier in life but remains an important etiology of PAH. In adolescents and adults with PAH assisted at institutions devoted to treatment of cardiovascular disorders, the relative frequency of PAH-CHD (∼50%-60%) is even higher than that of idiopathic PAH. In one big tertiary center in São Paulo, Brazil, the prevalence of advanced PAH in children and adults with CHD is 1.2% and 4.2%, respectively. In young patients with cardiac septal defects (aged up to 2 years), pulmonary vascular abnormalities are a matter of concern in the decision about operability in 4.9% of cases. Access to specific PAH drugs is not uniform in South America, being unrealistic in remote places. In big cities, there are real possibilities for management of complex CHD, neonatal disorders, and even cardiac transplantation. Research activities have been implemented at clinical, translational, and basic levels. However, because of social and economic inequalities and political issues, access to best standards of medical care remains a problem in the region as a whole.

Platelet protease-activated receptor 1 and membrane expression of P-selectin in pulmonary arterial hypertension.

INTRODUCTION: Pulmonary arterial hypertension (PAH) is frequently associated with thrombotic events, particularly involving the pulmonary microcirculation at sites of vascular injury. We therefore decided to analyse protease-activated receptor 1 (PAR1), a key element in the activation of human platelets by thrombin, in PAH patients in stable clinical condition. METHODS: Using flow cytometry, we analyzed platelet PAR1 density, PAR1-mediated exposure of P-selectin and the formation of platelet-leukocyte aggregates in 30 PAH patients aged 11 to 78 years (median 50.5 years). The control group consisted of 25 healthy subjects with the same age range as patients. RESULTS: In patients, total platelet PAR1 density and uncleaved PAR1 density correlated negatively with platelet count (r(2)=0.33 and r(2)=0.34 respectively, p<0.0015). In patients with a low platelet count (<150x10(9) platelets/L), both densities were increased relative to controls (82% and 33% respectively, p<0.05). Thrombin peptide-induced platelet exposure of P-selectin was directly related to total and uncleaved PAR1 density (respectively, r(2)=0.33 and r(2)=0.29, p<0.0025) and increased in subjects with low platelet count (46% versus those with normal platelet count, p<0.05). Patients with low platelet count had decreased in vitro thrombin-induced formation of platelet-leukocyte aggregates (57% decrease versus controls, p<0.05). CONCLUSIONS: There seems to be a subpopulation of PAH patients with increased propensity to thrombotic events as suggested by increased platelet PAR1 expression and PAR-mediated surface exposure of P-selectin associated with decreased platelet count.

ALDH1A2 (RALDH2) genetic variation in human congenital heart disease.

BACKGROUND: Signaling by the vitamin A-derived morphogen retinoic acid (RA) is required at multiple steps of cardiac development. Since conversion of retinaldehyde to RA by retinaldehyde dehydrogenase type II (ALDH1A2, a.k.a RALDH2) is critical for cardiac development, we screened patients with congenital heart disease (CHDs) for genetic variation at the ALDH1A2 locus. METHODS: One-hundred and thirty-three CHD patients were screened for genetic variation at the ALDH1A2 locus through bi-directional sequencing. In addition, six SNPs (rs2704188, rs1441815, rs3784259, rs1530293, rs1899430) at the same locus were studied using a TDT-based association approach in 101 CHD trios. Observed mutations were modeled through molecular mechanics (MM) simulations using the AMBER 9 package, Sander and Pmemd programs. Sequence conservation of observed mutations was evaluated through phylogenetic tree construction from ungapped alignments containing ALDH8 s, ALDH1Ls, ALDH1 s and ALDH2 s. Trees were generated by the Neighbor Joining method. Variations potentially affecting splicing mechanisms were cloned and functional assays were designed to test splicing alterations using the pSPL3 splicing assay. RESULTS: We describe in Tetralogy of Fallot (TOF) the mutations Ala151Ser and Ile157Thr that change non-polar to polar residues at exon 4. Exon 4 encodes part of the highly-conserved tetramerization domain, a structural motif required for ALDH oligomerization. Molecular mechanics simulation studies of the two mutations indicate that they hinder tetramerization. We determined that the SNP rs16939660, previously associated with spina bifida and observed in patients with TOF, does not affect splicing. Moreover, association studies performed with classical models and with the transmission disequilibrium test (TDT) design using single marker genotype, or haplotype information do not show differences between cases and controls. CONCLUSION: In summary, our screen indicates that ALDH1A2 genetic variation is present in TOF patients, suggesting a possible causal role for this gene in rare cases of human CHD, but does not support the hypothesis that variation at the ALDH1A2 locus is a significant modifier of the risk for CHD in humans.

Likelihood of left main coronary artery compression based on pulmonary trunk diameter in patients with pulmonary hypertension.

PURPOSE: In patients with pulmonary hypertension, extrinsic compression of the left main coronary artery by a dilated pulmonary trunk may cause angina, left ventricular ischemia, and sudden death. We assessed coronary artery compression in relation to pulmonary trunk diameter and other demographic, echocardiographic, hemodynamic, and scintigraphic variables. METHODS: Thirty-six patients (aged 15 to 86 years) with pulmonary hypertension, either idiopathic or associated with congenital heart disease, were enrolled. Left main coronary artery compression was defined angiographically as > or =50% obstruction associated with downward displacement of the vessel. Pulmonary trunk and aortic diameters were measured by transthoracic echocardiography. RESULTS: Twenty-six patients had angina, of whom 7 had left coronary artery compression. Compression was related to pulmonary trunk diameter (P = 0.002) and to the ratio of pulmonary trunk diameter to aortic diameter (P = 0.02). Compression was not seen at pulmonary artery diameters <40 mm; among 19 patients with values > or =40 mm, the rate was 37%. Similarly, compression did not occur at pulmonary trunk to aortic diameter ratios <1.21; among 27 patients with ratios > or =1.21, the rate was 26%. CONCLUSION: In pulmonary hypertension, noninvasive measurement of pulmonary trunk diameter may be helpful in determining the likelihood of left coronary artery compression and in selecting patients for diagnostic coronary angiography.

Hipertensão arterial por coarctação de aorta em adultos / Arterial hypertension due to coarctation of the aorta in adults

A hipertensão arterial secundária à coarctação da aorta constitui-se em uma situação preocupante pela sua alta prevalência, até mesmo entre os pacientes operados com sucesso. Ainda não existe um consenso que estabeleça a razão pela qual esse evento ocorre. Tanto os pacientes que seguem a história natural quanto aqueles que representam a evolução pós-operatória tardia da malformação estão expostos a riscos de morbidade e mortalidade cardiovascular decorrentes das complicações da hipertensão arterial. Neste artigo, são abordados os fatores relacionados à hipertensão arterial em portadores de coarctação de aorta, com ênfase nos aspectos anatômicos da malformação, da história natural e da evolução pós-operatória tardia. Também são discutidos os resultados da cirurgia sobre o comportamento da pressão arterial e sobre a morbidade e mortalidade cardiovascular em pacientes adultos, e as principais complicações da coarctação de aorta não tratada.