In-Hospital and 1-Year Clinical Results from the French Registry Using Polymer-Free Sirolimus-Eluting Stents in Acute Coronary Syndrome and Stable Coronary Artery Disease.

Objectives: The aim of this postmarket clinical study was to assess the safety and efficacy of the latest generation polymer-free sirolimus-eluting stents (PF-SES) in an all-comers population comparing outcomes in stable coronary artery disease (CAD) versus acute coronary syndrome (ACS) in France. Background: The efficacy and safety of the first-generation PF-SES have already been demonstrated by randomized controlled trials and "all-comers" observational studies. Methods: For this all-comers observational, prospective, multicenter study, 1456 patients were recruited in 22 French centers. The primary endpoint was target lesion revascularization (TLR) rate at 12 months and secondary endpoints included major adverse cardiac events (MACE) and bleeding. Results: 895 patients had stable CAD and 561 had ACS. At 12 months, 2% of patients had a TLR, with similar rates between stable CAD and ACS (1.9% vs 2.2%, p = 0.7). The overall MACE rate was 5.2% with an expected higher rate in patients with ACS as compared to those with stable CAD (7.3% vs 3.9%, p = 0.007). The overall bleeding event rate was 4.5%, with similar rates in stable CAD as compared to ACS patients (3.8% vs 5.6%, p = 0.3). Dual antiplatelet therapy (DAPT) interruptions prior to the recommended duration occurred in 41.7% of patients with no increase in MACE rates as compared to patients who did not prematurely interrupt DAPT (3.9% vs 6.1%, p = 0.073). Conclusions: The latest generation PF-SES is associated with low clinical event rates in these all-comers patients. There was a high rate of prematurely terminated DAPT, without any effect on MACE at 12 months. This trial is registered with NCT03809715.

In Vitro and In Silico Potential Inhibitory Effects of New Biflavonoids from Ochna rhizomatosa on HIV-1 Integrase and Plasmodium falciparum.

The aim of this study was to identify bioactive secondary metabolites from Ochna rhizomatosa with potential inhibitory effects against HIV and Plasmodium falciparum. A phytochemical study of O. rhizomatosa root barks resulted in the identification of three new biflavonoids (1-3), along with four known ones (4-7). Compound 7 (Gerontoisoflavone A) was a single flavonoid present in the rootbark of the plant and was used as a reference. Compound 1 (IC50 = 0.047 µM) was the only one with a noteworthy inhibitory effect against HIV-1 integrase in vitro. Chicoric acid (IC50 = 0.006 µM), a pure competitive inhibitor of HIV-1 integrase, was used as control. Compound 2 exhibited the highest antiplasmodial activity (IC50 = 4.60 µM) against the chloroquine-sensitive strain of Plasmodium falciparum NF54. Computational molecular docking revealed that compounds 1 and 2 had the highest binding score (-121.8 and -131.88 Kcal/mol, respectively) in comparison to chicoric acid and Dolutegravir (-116 and -100 Kcal/mol, respectively), towards integrase receptor (PDB:3LPT). As far as Plasmodium-6 cysteine s48/45 domain inhibition is concerned, compounds 1 and 2 showed the highest binding scores in comparison to chloroquine, urging the analysis of these compounds in vivo for disease treatment. These results confirm the potential inhibitory effect of compounds 1 and 2 for HIV and malaria treatment. Therefore, our future investigation to find inhibitors of these receptors in vivo could be an effective strategy for developing new drugs.

Patent Foramen Ovale and Ischemic Stroke in Patients With Pulmonary Embolism: A Prospective Cohort Study.

Background: Pulmonary embolism (PE) is associated with increased risk for ischemic stroke, but the underlying mechanism remains unclear. The authors hypothesized that paradoxical embolism through patent foramen ovale (PFO) should be the main mechanism. Objective: To determine the frequency of recent ischemic stroke in patients with symptomatic PE according to whether PFO was detected. Design: Prospective cohort study with masked assessment of stroke outcomes. (ClinicalTrials.gov: NCT01216423). Setting: 4 French hospital centers. Participants: 361 consecutive patients with symptomatic acute PE from 13 November 2009 through 21 December 2015. Intervention: Systematic contrast transthoracic echocardiography (TTE) and cerebral magnetic resonance imaging (MRI) within 7 days after enrollment. Measurements: Recent symptomatic or silent ischemic stroke was diagnosed on the basis of clinical examination and cerebral MRI showing a hypersignal on the trace diffusion-weighted image with reduction or pseudonormalization of apparent diffusion coefficient. Results: Contrast TTE was conclusive in 324 of 361 patients and showed PFO in 43 patients (13%). The median age was 66 years (interquartile range, 54 to 77 years). In total, 51% of patients (145/284) had associated deep venous thrombosis, 91% (279/306) had cardiovascular risk factors, and 10% (16/151) presented with arrhythmia (no difference between PFO and non-PFO groups). Cerebral MRI was conclusive in 315 patients. Recent ischemic stroke was more frequent in the PFO group than in the non-PFO group (9 of 42 patients [21.4%] vs. 15 of 273 patients [5.5%]; difference in proportions, 15.9 percentage points [95% CI, 4.7 to 30.7 percentage points]). Limitation: Because of inconclusive contrast TTE or MRI, 46 patients were excluded from analysis. Conclusion: Frequency of recent ischemic stroke in patients with symptomatic PE was higher in patients with PFO than in those without PFO. This finding supports the hypothesis that paradoxical embolism is an important mechanism of ischemic stroke in patients with PFO. Primary Funding Source: French Ministry of Health.

Indoline alkaloids from Tabernaemontana contorta with cancer chemopreventive activity.

Two bisindoline alkaloids, contortarine A, 16-epi-pleiomutinine and a reaction product of pleiomutinine, namely N4-chloromethyl-pleiomutinine, were isolated from the roots of Tabernaemontana contorta Stapf. together with five known compounds: pleiomutinine, 1-carbomethoxy-ß-carboline, strictosidine lactam, pleiocarpamine, and pleiocarpine. The structures and relative configuration of these alkaloids were determined by extensive 1D and 2D NMR, and MS measurements. The absolute configuration of these compounds was determined by comparison of experimental and calculated ECD spectra. Among the isolated compounds, contortarine A, 1-carbomethoxy-ß-carboline and strictosidine lactam presented cancer chemopreventive properties through either quinone reductase (QR) induction with CD values of 16.0 ± 2.5, 30.2 ± 6.1 and 23.1 ± 4.6 µM, respectively, while pleiomutinine and 16-epi-pleiomutinine displayed the inhibition of TNF-α induced NF-κB activity with IC50 at 11.7 ± 2.6 and 3.4 ± 1.1 µM, respectively.

New flavonoids C-glycosides from Rhabdophyllum arnoldianum.

Two new flavone glycosides, 3″-O-acetyl-7-O-methylvitexin (1) and 6″-α-rhamnopyranosyl-7-O-methylvitexin (2), along with nine known compounds (3-11) were isolated from the leaves of Rhabdophyllum arnoldianum (Ochnaceae). The structures of the new compounds were established by detailed spectroscopic studies and mass spectrometry, while known compounds were characterised by direct comparison of their reported NMR data with those found in the literature. All these compounds were the first reported from Rhabdophyllum genus. The biological assays on crude extracts and compounds of this plant demonstrated that the crude extracts possess significant antimicrobial activity against Gram-positive bacteria.

Comparative statistical mechanics of myosin molecular motors in rat heart, diaphragm and tracheal smooth muscle.

PURPOSE: Statistical mechanics establishes a link between microscopic properties of matter and its bulk properties. A. Huxley's equations (1957) [1] provide the necessary phenomenological formalism to use statistical mechanics. METHODS: We compared statistical mechanics in rat diaphragm in tetanus (tet; n=10) and twitch (tw; n=12) modes, in heart in twitch mode (n=20), and in tracheal smooth muscle in tetanus mode (TSM; n=10). This powerful tool makes it possible to determine: (i) statistical entropy (S) which is related to the dispersal of energy and represents a measure of the degree of disorder in muscular system; (ii) thermodynamic force A/T (chemical affinity A and temperature T); (iii) thermodynamic flow (υ); (iv) entropy production rate (A/T×υ), which quantifies irreversible chemical processes generated by myosin crossbridge (CB) molecular motors. RESULTS: All muscles studied operated near equilibrium, i.e., A<<2500J/mol and in a stationary linear regime, i.e., A/T varied linearly with υ. The heart operated farther from equilibrium than both diaphragm (tet and tw) and TSM, as attested by its high entropy production rate. S was of the same order of magnitude in heart and TSM but lower in diaphragm (tet and tw). CONCLUSION: CB kinetics derived from A. Huxley's equations conferred a characteristic profile in terms of statistical mechanics on each muscle type. All studied muscles differed in terms of statistical entropy, chemical affinity, and entropy production rate. Stimulation mode (tet and tw) modulated CB kinetics and statistical mechanics. All muscle types operated near equilibrium and in a stationary linear regime.

Phenolic dimers and an indole alkaloid from Campylospermum flavum (Ochnaceae).

From the leaves and stem bark of Campylospermum flavum (Ochnaceae), three compounds, namely 4‴-O-methylagathisflavone, flavumchalcone, and flavumindole have been isolated together with 10 known compounds, including three flavonoids, two biflavonoids, two alkaloids, two nitrile glucosides, and glucopyranosyl-ß-sistosterol. The structures of these compounds and their relative configurations were established by 1D and 2D NMR experiments. The methanolic crude extracts of leaves and stem bark of C. flavum and compounds displayed a significant cytotoxicity towards Artemia salina larvae.

Reliability of echocardiography for hemodynamic assessment of end-stage heart failure.

The management of patients with end-stage heart failure is difficult and may require the monitoring of intracardiac pressures. The aim of this prospective study was to assess the reliability of echocardiography in patients with end-stage HF. Twenty consecutive patients presenting with severe left ventricular dysfunction in end-stage heart failure were prospectively studied. All patients underwent right-sided cardiac catheterization and transthoracic echocardiography. Right atrial pressure, estimated using a new echocardiographic parameter, was significantly improved. There was good agreement between systemic and pulmonary vascular resistance, determined by catheterization and echocardiography. All patients with echocardiographic pulmonary vascular resistance<6 Wood units also had invasive pulmonary vascular resistance<6 Wood units. Only echocardiographic mean right atrial pressure was related to the use of saline infusion or bolus infusion of furosemide. All patients requiring intravenous furosemide had pulmonary capillary wedge pressures persistently>or=15 mm Hg despite adequate medication. In conclusion, this study indicates that echocardiography may be a reliable tool for the management of patients with end-stage heart failure.

Usefulness of contrast echocardiography for assessment of left ventricular thrombus after acute myocardial infarction.

Fifty consecutive patients referred to a coronary care unit for acute anterior myocardial infarction with ST-segment elevation underwent coronary arteriography, left ventricular (LV) angiography, and revascularization. Transthoracic echocardiography was systematically performed using fundamental imaging, second harmonic imaging, and contrast agents to assess the LV chamber. Six patients (12%) presented with a confirmed LV mural thrombus. Thirty-five percent of patients with time to revascularization>3 hours presented with an LV mural thrombus versus 0 patients with time to revascularization3 hours.

Prevalence of tako-tsubo syndrome in a large urban agglomeration.

Among 4,551 patients referred to the investigators' catheterization laboratory, 1,613 presented with acute coronary syndrome, and 12 had confirmed Tako-Tsubo syndrome (prevalence 0.7%). In conclusion, the present study emphasizes the underestimation of this new heart disease.

Assessment of patent foramen ovale in carcinoid heart disease.

BACKGROUND AND OBJECTIVE: Carcinoid syndrome may involve right carcinoid heart disease (CHD), secondary to the release of vasoactive substances. Left CHD is rare, as the inactivation of serotonin by the lung protects the left heart. We attempted to evaluate the prevalence of CHD and patent foramen ovale (PFO) with serial contrast transthoracic echocardiographic studies and to determine the markers of right and left CHD progression. METHODS: Forty-one consecutive patients with proved digestive endocrine tumor and carcinoid syndrome were prospectively enrolled. All patients underwent serial conventional and contrast transthoracic echocardiographic studies. Right and left CHD, PFO, radiological examinations, and biological carcinoid markers were systematically assessed. RESULTS: Left CHD was present in 5 patients at baseline and in 13 patients (32%) during follow-up (P = .03). The 13 patients with left CHD also had PFO, and no left CHD occurred without PFO (P < .0001). Right CHD was present in 16 patients (39%) at baseline and in 25 patients (61%) at the end of follow-up (P = .04). The prevalence of right and left CHD was significantly higher in patients with PFO (88% and 76%, respectively; P < .04). A progression of right and left CHD was present, respectively, in 19 and 9 patients but was mainly found in patients with PFO (15 and 9 patients; P < .0001). The main marker of CHD progression was the presence of PFO (odds ratio 44.2, 95% confidence interval 4.4-447.7; P = .001). CONCLUSIONS: PFO is a new marker of CHD progression and should be systematically assessed with routine contrast transthoracic echocardiography in patients with carcinoid syndrome to determine patients at high risk of CHD progression.

Echocardiographic automated cardiac output measurement of pulmonary output and quantification of intracardiac shunt.

BACKGROUND: The quantification of intracardiac shunt (ICS) with echocardiographic pulsed-wave Doppler (PWD) method using pulmonary-to-systemic flow ratio (QP/QS ratio) remains difficult and may induce false quantification of pulmonary output. We sought to validate the recent echocardiographic automated cardiac output measurement (ACM) for the calculation of pulmonary output and the quantification of ICS in adults. METHODS: One hundred and twenty consecutive patients were divided in 1) 40 patients who underwent echocardiographic and invasive explorations (group I) with groups IA (quantification of ICS using ACM, PWD and invasive oximetric methods in 20 patients) and IB (calculation of pulmonary output with ACM, PWD and thermodilution methods in 20 patients); 2) 80 patients underwent calculation of aortic and pulmonary outputs using echocardiographic ACM and PWD methods (group II). RESULTS: The feasibility of ACM and conventional PWD methods for the calculation of pulmonary output was respectively 93.3% and 90%. Correlations between ACM and invasive pulmonary output were strong (r2=0.92 vs. r2=0.80 for PWD). The best correlation and agreement between invasive and echocardiographic QP/QS ratio were observed with ACM (r=0.96 vs. r=0.82 for PWD). Intracardiac shunts were best-classified with ACM, as compared to PWD (respectively 94% and 72%); sensitivities and specificities for evaluation of significant ICS were 92.3% and 100% with ACM (85% and 40% with PWD). CONCLUSIONS: This study shows that ACM is a reliable and accurate echocardiographic method for calculating pulmonary output and quantifying ICS in adults and may be routinely performed in clinical practice.

Diagnosis of right ventricular dysfunction in acute pulmonary embolism using helical computed tomography.

Forty-six consecutive patients with pulmonary embolism (PE) who underwent pulmonary angiography, helical computed tomography (CT), and echocardiography in the investigators' emergency department were studied. It was determined that the CT right ventricular (RV)/left ventricular (LV) end-diastolic area ratio was correlated with PE obstruction and echocardiography. A CT RV/LV area ratio >1 had a sensitivity of 88% and a specificity of 88% in diagnosing significant PE. The present study suggests that helical CT may be used as a triage tool in acute PE for selecting high-risk patients, using calculation of the RV/LV area ratio to detect RV dysfunction.

Changes in crossbridge mechanical properties in diabetic rat cardiomyopathy.

Diabetes mellitus is associated with an increased risk of heart failure, resulting from a specific cardiomyopathy independent of coronary atherosclerosis. It is not yet established whether altered myocardial function is related to changes in molecular mechanics of myosin. Accordingly, we investigated the total number, single force and kinetics of myosin crossbridges (CB) in a rat model of streptozotocin-induced diabetic cardiomyopathy. Experiments were conducted on left ventricular papillary muscles from male diabetic (D) Wistar (n = 16) and age-matched control (C) rats (n = 15). Mechanical indices including the maximum unloaded shortening velocity V(max) and the maximum total isometric tension normalized per cross-sectional area TF(max) were determined. Using A. F. Huxley's equations, we calculated the total cycling CB number per mm(2) Psi, the elementary force per single CB Pi, the maximum values of the rate constant for CB attachment f(1) and detachment g(1) and g(2), and the turnover rate of myosin ATPase per site k(cat). The D rats exhibited a 25% decrease in TF(max) and a 34% decrease in V(max) as compared to C. This contractile dysfunction was associated with a significant reduction in Psi (9.0 +/- 1.6 in D versus 11.4 +/- 1.9 10(9)mm(-2) in C, P < 0.001) without significant change in Pi (6.1 +/- 0.8 in D versus 6.3 +/- 0.9 pN in C, NS). In the 2 groups, TF(max) correlated positively with Psi (r = 0.76, P < 0.001 and r = 0.64, P < 0.01, in D and C respectively) but no relationship was found between TF(max) and Pi. As compared to C, D showed lower values of f(1), g(1) and g(2), and a slower turnover rate of myosin ATPase. Thus, present data suggested that the cardiac contractile impairment observed in streptozotocin-induced diabetic rat cardiomyopathy was mainly related to a decrease in active CB total number and CB kinetics alterations without significant change in CB single force.

Use of transthoracic echocardiography combined with venous ultrasonography in patients with pulmonary embolism.

BACKGROUND: The diagnosis of pulmonary embolism (PE) remains difficult. Ultrasounds allow for the exploration of the venous system to great extent and for the detection of indirect signs of PE. The aim of this study was to determine the incidence of acute cor pulmonale (ACP) and deep venous thrombosis (DVT) found by ultrasonographic techniques in a population of patients with PE. METHODS: One hundred and seventy-three consecutive patients with acute PE (diagnosed either by spiral computed tomography or selective pulmonary angiography) had subsequently both transthoracic echocardiography (TTE) and venous ultrasonography. The diagnostic criterion used for defining ACP by echocardiography was the right to left ventricular end-diastolic area ratio over (or equal to) 0.6 with paradoxical septal wall motion. The diagnosis of DVT rested on vein incompressibility. RESULTS: ACP was found in 56% of our patients while 75% were found to have DVT and 89% of the patients had either ACP or DVT or both. All of the patients with proximal PE had ACP and/or DVT. The presence of ACP using echocardiography was significantly different according to the localization of PE (P<0.0001) and the clinical presentation (P=0.0001). The incidence of ACP and/or DVT was significantly different according to the localization of PE (P=0.001). Echocardiography combined with venous ultrasonography had improved the diagnosis value of venous ultrasonography in only 4% of patients with distal PE (P=0.65). CONCLUSION: A combined strategy using echocardiography with venous ultrasonography improves significantly the diagnostic value of venous ultrasonography in proximal and lobar PE and fails in distal PE.

Value of tissue Doppler imaging to predict left ventricular filling pressure in patients with coronary artery disease.

Assessment of left ventricular (LV) diastolic filling pressure provides important information on the hemodynamic status in the general population. The aim of our study was to investigate the reliability of tissue Doppler imaging (TDI) in estimating left ventricular filling pressure in patients with coronary artery disease (CAD). We prospectively studied 32 consecutive CAD-patients, mean age 64 +/- 12 years, in sinus rhythm. All patients underwent cardiac catheterization and echocardiography within the same hour. Catheterization investigated pre-A-wave pressure (preA) and LV ejection fraction (LVEF). Echocardiographic LVEF was calculated using wall motion indexes (WMI) with segmental division of LV wall. The following Doppler parameters were assessed: (1) PW Doppler signals from the mitral inflow (E), (2) PW TDI of the mitral annulus (E'), thus allowing to obtain the mitral inflow to annulus ratio (E/E'). The best correlation between invasive and echocardiographic LVEF was observed using WMI (r = 0.91). The correlations between preA and E, E', and E/E' were significant (r = 0.36, r = 0.38, and r = 0.60, respectively). In patients with LVEF >50%, no correlation between E/E' and preA was found (r = 0.18, P = 0.44), whereas with LVEF <50%, this correlation was strong (r = 0.76, P < 0.001). In patients with myocardial infarction, the correlation between E/E' and preA was significant whatever the localization of myocardial infarction (r > 0.71, P < 0.05). ROC curve analysis identified an E/E'>9 to be the best cut-off value related to preA > 15 mmHg. We conclude that the mitral inflow-to-annulus ratio is a reliable method in CAD patients and allows determination of LV filling pressure when LVEF <50%.