New Nitric Oxide Donor NCX 1443: Therapeutic Effects on Pulmonary Hypertension in the SAD Mouse Model of Sickle Cell Disease.

Nitric oxide (NO) donors may be useful for treating pulmonary hypertension (PH) complicating sickle cell disease (SCD), as endogenous NO is inactivated by hemoglobin released by intravascular hemolysis. Here, we investigated the effects of the new NO donor NCX1443 on PH in transgenic SAD mice, which exhibit mild SCD without severe hemolytic anemia. In SAD and wild-type (WT) mice, the pulmonary pressure response to acute hypoxia was similar and was abolished by 100 mg/kg NCX1443. The level of PH was also similar in SAD and WT mice exposed to chronic hypoxia (9% O2) alone or with SU5416 and was similarly reduced by daily NCX1443 gavage. Compared with WT mice, SAD mice exhibited higher levels of HO-1, endothelial NO synthase, and PDE5 but similar levels of lung cyclic guanosine monophosphate. Cultured pulmonary artery smooth muscle cells from SAD mice grew faster than those from WT mice and had higher PDE5 protein levels. Combining NCX1443 and a PDE5 inhibitor suppressed the growth rate difference between SAD and WT cells and induced a larger reduction in hypoxic PH severity in SAD than in WT mice. By amplifying endogenous protective mechanisms, NCX1443 in combination with PDE5 inhibition may prove useful for treating PH complicating SCD.

Sequential cyclophosphamide-bortezomib-dexamethasone unmasks the harmful cardiac effect of dexamethasone in primary light-chain cardiac amyloidosis.

Chemotherapy combining cyclophosphamide, bortezomib and dexamethasone is widely used in light-chain amyloidosis. The benefit is limited in patients with cardiac amyloidosis mainly because of adverse cardiac events. Retrospective analysis of our cohort showed that 39 patients died with 42% during the first month. A new escalation-sequential regimen was set to improve the outcomes. Nine newly-diagnosed patients were prospectively treated with close monitoring of serum N-terminal pro-brain natriuretic peptide, troponin-T and free light chains. The results show that corticoids may destabilise the heart through fluid retention. Thus, a sequential protocol may be a promising approach to treat these patients.

Mechanical abnormalities associated with first- and second-generation drug-eluting stent thrombosis analyzed by optical coherence tomography in the national PESTO French registry.

BACKGROUND AND OBJECTIVES: DES thrombosis may be triggered by different mechanisms that are difficult to identify by angiography alone. This work aimed to investigate and compare the characteristics of stent thrombosis (ST) between 1st- and 2nd-generation drug-eluting stents (DES) among a large cohort of patients explored by optical coherence tomography (OCT). METHODS AND RESULTS: The PESTO study was a prospective national registry involving 29 French catheterization facilities. Patients with acute coronary syndromes were prospectively screened for presence of definite ST and analyzed by OCT after culprit lesion deocclusion. The analysis involved 71 subjects including 34 patients with 1st-generation DES (DES1G) and 35 patients with 2nd-generation DES (DES2G). Most patients (80%) presented with very late stent thrombosis. The median time between initial PCI and ST was longer in DES1G than DES2G patients (3.8 [2.6-6.5] years vs. 1.1 [0.04-2.3] years, p<0.0001). OCT identified an underlying morphological abnormality in 96% of the cases. Significant malapposition was the main abnormality observed either in DES1G (26%) or DES2G patients (35%). Ruptured neoatherosclerotic lesions were more frequently observed with DES1G than with DES2G (26% vs. 3%, p=0.008). There was no significant difference in percentage of malapposed struts and uncovered struts between groups. CONCLUSIONS: In this registry, DES thrombosis mainly occurred ≥1year after initial PCI. OCT identified a mechanical abnormality in the vast majority of the cases. Similar causes were observed between DES1G and DES2G, but neoatherosclerotic lesions were more common in DES1G.

Prevalence, Severity, and Prognostic Value of Sleep Apnea Syndromes in Cardiac Amyloidosis.

STUDY OBJECTIVES: To assess prevalence, severity, and prognostic value of sleep-disordered breathing (SDB), in the three main cardiac amyloidosis (CA) types, i.e., light-chain (AL), transthyretin-related familial (m-TTR), or senile (WT-TTR). METHODS: Patients consecutively referred for CA diagnosis work-up underwent cardiac assessment and nocturnal polygraphy. SDB was defined as apnea-hypopnea index (AHI) ≥ 5/h. Multivariate analysis was used to identify predictors of a major adverse cardiac event (MACE) defined as death, heart transplantation and acute heart failure. RESULTS: Seventy CA patients were included (31 AL, 22 m-TTR, 17 WT-TTR). The mean ± standard deviation age and left ventricular ejection fraction were 71 ± 12 years and 49% ± 13% and median (interquartile range) N terminal pro brain natriuretic peptide (NT-proBNP) was 3,932 (1,607; 7,028) pg/mL. The prevalence of SDB was 90% without difference between amyloidosis types. SDB was central in 27% and obstructive in 73%. AL had less frequent severe SDB compared to m-TTR and WT-TTR (P = 0.015) but longer time with peripheral capillary oxygen saturation (SpO2) < 90% (P = 0.037). After a median follow-up of 7.5 (2.8; 14.9) months, 49% patients experienced MACE. Time with nocturnal SpO2 < 90% was the only independent predictor of MACE. The best-identified threshold was 30 min. Values > 30 min were associated with bad prognosis (Log-rank χ(2): 8.01, P value = 0.005). Using binomial logistic regression, determinants of time with nocturnal SpO2 < 90% were New York Heart Association class (P = 0.011), and log-NT-proBNP (P = 0.04) but not AHI. CONCLUSIONS: In CA population, prevalence of SDB is high (90%) and dominated by the obstructive pattern. Bad prognosis in this population was driven by nocturnal desaturation, reflecting heart failure severity and respiratory involvement.

Usefulness of (99m)Tc-HMDP scintigraphy for the etiologic diagnosis and prognosis of cardiac amyloidosis.

BACKGROUND: Amyloidosis is characterized by extracellular deposits of insoluble proteins that cause tissue damage. The three main types are monoclonal light chain (AL), wild-type transthyretin (wt-TTR) and mutated transthyretin (m-TTR) amyloidosis. Cardiac amyloidosis (CA) raises diagnostic challenges. OBJECTIVE: To assess the diagnostic accuracy of (99m)Tc-HMDP-scintigraphy for typing CA, differentiating CA from non-amyloid left ventricle hypertrophy (LVH), and predicting outcomes. METHODS: 121 patients with suspected CA underwent (99m)Tc-HMDP-scintigraphy in addition to standard investigations. RESULTS: CA was diagnosed in all AL (n = 14) and wt-TTR (n = 21). Among m-TTR (n = 34), 26 had CA, 4 neuropathy without CA and 4 were asymptomatic carriers. Of the 52 patients with non-amyloid heart disease, 37 had LVH and served as controls. (99m)Tc-HMDP cardiac uptake occurred in all wt-TTR, in m-TTR with CA except two and in one AL. A visual score ≥ 2 was 100% specific for diagnosing TTR-CA. Among TTR-CA, heart-to-skull retention (HR/SR) correlated with CA severity (LVEF and NT-proBNP). Median follow-up was 111 days (50;343). In a multivariate Cox model including clinical, echocardiographic and scintigraphic variables, NYHA III-IV and HR/SR > 1.94 predicted acute heart failure and/or death. CONCLUSIONS: This preliminary study suggests that (99m)Tc-HMDP-scintigraphy may aid differentiation between transthyretin and AL-CA as well as CA from other LVHs. (99m)Tc-HMDP-scintigraphy appears to provide prognostic information in CA.

Carotid-femoral pulse wave velocity is not increased in obesity.

BACKGROUND: There are conflicting results in the literature concerning the relationship between obesity and arterial stiffness, assessed by carotid-femoral pulse wave velocity (PWV). The discrepancies could be due to differences in carotid-femoral distance measurement and/or to the presence of pathologies frequently associated with obesity and which increase arterial stiffness. In this study, we examine the relationship between PWV and weight, without and with associated cardiovascular risk factors (diabetes and/or dyslipidemia). METHODS: PWV was assessed with a Complior SP device (Alam Medical, France) in 2,034 patients referred for ambulatory blood pressure monitoring. The carotid-femoral distance used to calculate PWV was measured with a flexible tape and from the estimated straight carotid-femoral distance obtained with a published equation. RESULTS: In the whole cohort, PWV did not differ significantly according to weight (9.6±2.1, 9.8±2.2 and 9.7±1.9 m/s in normal weight, overweight and obese subjects, respectively, with the distance measured with a tape). PWV was significantly higher in the four groups of patients with cardiovascular risk factors (e.g., 11.1±2.4, 11.0±2.7 and 10.4±2.0 m/s in normal weight, overweight, and obese subjects, respectively, in the group treated for diabetes and dyslipidemia) than in the group of patients without cardiovascular risk factors (8.5±1.6, 8.8±1.7 and 8.5±1.2 in normal weight, overweight, and obese subjects, respectively). There was no relationship between PWV value and weight status, whether or not there were cardiovascular risk factors, and whatever the distance used to calculate PWV. CONCLUSIONS: In our cohort, obesity per se was not associated with increased arterial stiffness.

[Senile systemic amyloidosis: definition, diagnosis, why thinking about?]. / Amylose systémique sénile : définition, diagnostic, pourquoi y penser ?

Senile systemic amyloidosis (SSA) is characterized by infiltration of amyloid transthyretin fibrils in the myocardium. SSA occurs mainly (but not always) in elderly men. SSA leads to hypertrophic and/or restrictive cardiomyopathy complicated by conduction disturbances, atrial arrhythmia and systemic embolization (stroke…). That is why SSA needs a special care and to be diagnosed. Cardiac SSA diagnosis needs to exclude two other forms of cardiac amyloidosis: AL amyloidosis (light chain) and hereditary transthyretin amyloidosis (genetic testing). Scintigraphic 99mTc-DPD heart retention is observed in cardiac amyloidosis. DPD heart retention is more frequent in cardiac transthyretin amyloidosis than in cardiac AL amyloidosis. Specific treatments of cardiac TTR amyloidosis are in development.

Rapamycin reverses pulmonary artery smooth muscle cell proliferation in pulmonary hypertension.

Pulmonary artery (PA) smooth muscle cell (SMC) proliferation in pulmonary hypertension (PH) may be linked to dysregulated mammalian target of rapamycin (mTOR) signaling. The mTOR pathway involves two independent complexes, mTORC1 and mTORC2, which phosphorylate S6 kinase (S6K) and serine/threonine kinase (Akt), respectively, and differ in their sensitivity to rapamycin. Here, we evaluated rapamycin-sensitive mTOR substrates and PA-SMC proliferation in rats with monocrotaline (MCT)-induced PH (MCT-PH). Compared with cells from control rats, cultured PA-SMCs from MCT-PH rats exhibited increased growth responses to platelet-derived growth factor, serotonin (5-hydroxytryptophan), IL-1ß, insulin-like growth factor-1, or fetal calf serum (FCS), with increases in phosphorylated (Ser-473)Akt, (Thr-308)Akt, glycogen synthase kinase (GSK)3, and S6K reflecting activated mTORC1 and mTORC2 signaling. Treatment with rapamycin (0.5 µM) or the Akt inhibitor, A-443654 (0.5 µM), reduced FCS-stimulated growth of PA-SMCs from MCT-PH rats to the level in control rats while inhibiting Akt, GSK3, and S6K activation. Neither the tyrosine kinase inhibitor, imatinib (0.1 µM), nor the 5-hydroxytryptophan transporter inhibitor, fluoxetine (5 µM), normalized the increased PA-SMC growth response to FCS. Rapamycin treatment (5 mg/kg/d) of MCT-PH rats from Day 21 to Day 28 markedly reduced phoshop (p)-Aky, p-GSK3, and p-S6K in PAs, and normalized growth of derived PA-SMCs. This effect was not observed after 1 week of imatinib (100 mg/kg/d) or fluoxetine (20 mg/kg/d). Rapamycin given preventively (Days 1-21) or curatively (Days 21-42) inhibited MCT-PH to a greater extent than did imatinib or fluoxetine. Experimental PH in rats is associated with a sustained proliferative PA-SMC phenotype linked to activation of both mTORC1 and mTORC2 signaling and is suppressed by rapamycin treatment.

Inhibition of gut- and lung-derived serotonin attenuates pulmonary hypertension in mice.

Decreasing the bioavailability of serotonin (5-HT) by inhibiting its biosynthesis may represent a useful adjunctive treatment of pulmonary hypertension (PH). We assessed this hypothesis using LP533401, which inhibits the rate-limiting enzyme tryptophan hydroxylase 1 (Tph1) expressed in the gut and lung, without inhibiting Tph2 expressed in neurons. Mice treated repeatedly with LP533401 (30-250 mg/kg per day) exhibited marked 5-HT content reductions in the gut, lungs, and blood, but not in the brain. After a single LP533401 dose (250 mg/kg), lung and gut 5-HT contents decreased by 50%, whereas blood 5-HT levels remained unchanged, suggesting gut and lung 5-HT synthesis. Treatment with the 5-HT transporter (5-HTT) inhibitor citalopram decreased 5-HT contents in the blood and lungs but not in the gut. In transgenic SM22-5-HTT+ mice, which overexpress 5-HTT in smooth muscle cells and spontaneously develop PH, 250 mg/kg per day LP533401 or 10 mg/kg per day citalopram for 21 days markedly reduced lung and blood 5-HT levels, right ventricular (RV) systolic pressure, RV hypertrophy, distal pulmonary artery muscularization, and vascular Ki67-positive cells (P < 0.001). Combined treatment with both drugs was more effective in improving PH-related hemodynamic parameters than either drug alone. LP533401 or citalopram treatment partially prevented PH development in wild-type mice exposed to chronic hypoxia. Lung and blood 5-HT levels were lower in hypoxic than in normoxic mice and decreased further after LP533401 or citalopram treatment. These results provide proof of concept that inhibiting Tph1 may represent a new therapeutic strategy for human PH.

Reappraisal of percutaneous aortic balloon valvuloplasty as a preliminary treatment strategy in the transcatheter aortic valve implantation era.

AIMS: To assess the results of percutaneous aortic balloon valvuloplasty (PABV) as a potential bridge to further intervention in patients referred for transcatheter aortic valve implantation (TAVI). METHODS AND RESULTS: Two hundred and fifty-three patients referred for TAVI were studied: 41 (16%) were considered transiently unsuitable for either aortic valve replacement (AVR) or TAVI and underwent PABV as a bridge to intervention. In the others, primary TAVI or AVR was performed in 140 cases, and medical therapy alone in 72.The overall population was at high risk: 82 ± 8 years, logistic EuroSCORE: 28 ± 16%, STS score: 16 ± 10%. There was no PABV-related death. Twenty-three patients underwent secondary TAVI (n=19) or AVR (n=4), 18 did not undergo further intervention. One and two year survival rates were respectively 94 ± 5% and 85 ± 10% after bridge PABV, and 33 ± 11 and 6 ± 5% after PABV alone. There was no difference in survival between the primary TAVI / AVR and bridge PABV (p=0.08), and between medical treatment and PABV alone (p=0.36). CONCLUSION: In high-risk patients with aortic stenosis and temporary contraindications to AVR or TAVI, PABV may be used as a bridge to intervention with good mid-term outcomes. In others, PABV can be safely used but is associated with a poor outcome.