A New Cell-penetrating Peptide That Blocks the Autoinhibitory XIP Domain of NCX1 and Enhances Antiporter Activity

The plasma membrane Na⁺/Ca²⁺ exchanger (NCX) is a high-capacity ionic transporter that exchanges 3Na⁺ ions for 1Ca²⁺ ion. The first 20 amino acids of the f-loop, named exchanger inhibitory peptide (XIP_NCX1), represent an autoinhibitory region involved in the Na⁺-dependent inactivation of the exchanger. Previous research has shown that an exogenous peptide having the same amino acid sequence as the XIP_NCX1 region exerts an inhibitory effect on NCX activity. In this study, we identified another regulatory peptide, named P1, which corresponds to the 562–688aa region of the exchanger. Patch-clamp analysis revealed that P1 increased the activity of the exchanger, whereas the XIP inhibited it. Furthermore, P1 colocalized with NCX1 thus suggesting a direct binding interaction. In addition, site-directed mutagenesis experiments revealed that the binding and the stimulatory effect of P1 requires a functional XIP_NCX1 domain on NCX1 thereby suggesting that P1 increases the exchanger activity by counteracting the action of this autoinhibitory sequence. Taken together, these results open a new strategy for developing peptidomimetic compounds that, by mimicking the functional pharmacophore of P1, might increase NCX1 activity and thus exert a therapeutic action in those diseases in which an increase in NCX1 activity might be helpful.     

Transcatheter pulmonary valve implantation in native pulmonary outflow tract using the Edwards SAPIEN? transcatheter heart valve

Percutaneous pulmonary valve implantation (PPVI) is now an accepted alternative option to conventional surgery for patients with dysfunctional conduits between the right ventricle and pulmonary artery. PPVI will reduce the total number of repeat operations in such patients. However, surgery remains the primary option in postoperative tetralogy of Fallot patients with severe pulmonary regurgitation who underwent transannular patch reconstruction of their right ventricular outflow tract (RVOT). Traditionally, an RVOT patch is considered a relative contraindication to PPVI, however, in selected patients PPVI was successfully performed. We report the case of a 12-year-old patient after neonatal repair of tetralogy of Fallot and pulmonary atresia, who developed advanced liver disease and severe pulmonary regurgitation. In this patient, the risk for surgical valve replacement was considered too high and he was treated with percutaneous implantation of the Edwards SAPIEN? transcatheter heart valve.     

Lung anabolic activity in patients with chronic heart failure: Potential implications for clinical practice

ObjectiveThe proteins in the lungs are in constant flux, undergoing degradation and resynthesis. We investigated pulmonary protein and amino acid metabolism, the biochemical basis of the remodeling process, in individuals with chronic heart failure receiving or not receiving β-blocker therapy with bisoprolol (BIS).MethodsClinically stable rehabilitative patients with chronic heart failure, without metabolic diseases or liver/renal failure, and with a stable weight over the preceding 3 mo underwent right heart catheterization, and radial artery cannulation. Mixed central venous and arterial blood samples were drawn simultaneously to calculate the venous-arterial difference of amino acids (pulmonary uptake and release).ResultsTwenty-two patients on BIS therapy and eight not receiving BIS were analyzed. The two groups showed a net pulmonary protein synthesis (i.e., a positive value of phenylalanine [venous-arterial difference] × cardiac index product) and amino acid extraction, the rates of which were significantly lower in patients on BIS therapy. The two groups had pulmonary hypertension (mean pulmonary artery pressure >19 mmHg). Pulmonary vascular resistance was 57% higher in patients not receiving BIS than in those on BIS therapy (6.65 ± 2.90 versus 4.23 ± 1.49 mmHg/L · min^?1 · m^?2, P < 0.05). Pulmonary vascular resistance correlated positively with the pulmonary extraction of total essential amino acids (r = +0.4576, P = 0.01) and leucine (r = +0.5083, P = 0.004), the most important amino acid for protein synthesis.ConclusionPatients with chronic heart failure have increased rates of amino acid extraction and pulmonary protein synthesis, suggesting, at least in part, an increased rate of lung remodeling. Therapy with BIS attenuates lung metabolic abnormalities.     

Evidence of activity of Irinotecan in patients with advanced AIDS-related Kaposi's sarcoma

Fourteen HIV-infected patients with advanced Kaposi's sarcoma (KS) received Irinotecan 150 mg/m intravenously on days 1 and 10. All patients were relapsed/progressed during highly active antiretroviral therapy, administered as primary antineoplastic therapy. An objective response, all partial remissions, occurred in 75% of patients. Irinotecan was well tolerated, severe leukopenia occurred in only 33% of patients. In HIV-infected patients with advanced KS, irinotecan is active and well tolerated.     

Noninvasive etiologic diagnosis of cardiac amyloidosis using 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy.

OBJECTIVES: We investigated the diagnostic accuracy of 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) scintigraphy for differentiation of monoclonal immunoglobulin light-chain (AL) and transthyretin (TTR)-related cardiac amyloidosis. BACKGROUND: Differential diagnosis between TTR-related and AL amyloidosis is often complex and time-consuming. METHODS: Patients under routine observation with TTR-related/AL systemic amyloidosis and echocardiographic evidence of cardiac involvement were studied with 99mTc-DPD scintigraphy. RESULTS: Patients with cardiac involvement of TTR-related (group A; n = 15) and AL (group B; n = 10) etiology were comparable for left ventricular mass and renal function. Heart and heart/whole-body tracer retention were significantly higher (p < 0.05) in group A as compared with group B and with 10 unaffected controls. At visual scoring, cardiac 99mTc-DPD uptake was present in all group A patients and absent in all group B patients; thus, using genotyping/immunohistochemistry as the reference technique, the accuracy of 99mTc-DPD scintigraphy for distinction of TTR-related and AL etiology was 100%. Cardiac 99mTc-DPD uptake was also absent among unaffected controls. Using echocardiography as the reference standard for recognition of cardiac involvement, sensitivity and specificity of scintigraphy were both 100% for group A patients; in group B, sensitivity was 0% and specificity was 100% (accuracy, 50%). Eleven patients with myocardial 99mTc-DPD uptake underwent 99mTc-methylene diphosphonate (99mTc-MDP) scintigraphy; all patients showed a 99mTc-MDP myocardial visual score of 0. CONCLUSIONS: Etiology is a third major cause--in addition to type of organ-involved (soft-tissue/heart) and tracer type--of scintigraphic variability in cardiac amyloidosis. This is a highly relevant consideration for future studies. We conclude that 99mTc-DPD scintigraphy is a useful step in the workup of the differential diagnosis of TTR versus AL etiology in patients with documented cardiac amyloidosis.     

Phosphoinositide 3-kinase gamma-deficient hearts are protected from the PAF-dependent depression of cardiac contractility

OBJECTIVES: Following an ischemic insult, cardiac contractile recovery might be perturbed by the release of autacoids, like platelet-activating factor (PAF), that depress heart function by acting through G protein-coupled receptors (GPCRs). The signaling events downstream the PAF receptor that lead to the negative inotropic effect are still obscure. We thus investigated whether the GPCR-activated phosphoisositide 3-kinase gamma (PI3Kgamma) could play a role in the cardiac response to PAF. METHODS: The negative inotropic effect of PAF was studied ex vivo, in isolated electrically driven atria and in Langendorff-perfused whole hearts derived from wild-type and PI3Kgamma-null mice. Postischemic recovery of contractility was analyzed in normal and mutant whole hearts subjected to 30 min of ischemia and 40 min of reperfusion in the presence or absence of a PAF receptor antagonist. RESULTS: While wild-type hearts stimulated with PAF showed increased nitric oxide (NO) production and a consequent decreased cardiac contractility, PI3Kgamma-null hearts displayed reduced phosphorylation of nitric oxide synthase 3 (NOS3), blunted nitric oxide production and a complete protection from the PAF-induced negative inotropism. In addition, Langendorff-perfused PI3Kgamma-null hearts showed a better contractile recovery after ischemia/reperfusion, a condition where PAF is known to be an important player in depressing contractility. In agreement with a role of PI3Kgamma in this PAF-mediated signaling, postischemic contractile recovery in PI3Kgamma-null mice appeared overlapping with that of normal hearts treated with the PAF receptor antagonist WEB 2170. CONCLUSION: These data indicate a novel PAF-dependent signaling pathway that, involving PI3Kgamma and NOS3, contributes to postischemic contractile depression.