The Role of Cardiac Resynchronization Therapy for the Management of Functional Mitral Regurgitation.

Valve leaflets and chordae structurally normal characterize functional mitral regurgitation (FMR), which in heart failure (HF) setting results from an imbalance between closing and tethering forces secondary to alterations in the left ventricle (LV) and left atrium geometry. In this context, FMR impacts the quality of life and increases mortality. Despite multiple medical and surgical attempts to treat FMR, to date, there is no univocal treatment for many patients.

Predictors of persistence of functional mitral regurgitation after cardiac resynchronization therapy: Review of literature.

Functional mitral regurgitation is a common finding among heart failure patients with ischemic and non-ischemic dilated cardiomyopathies. The presence of moderate or severe mitral regurgitation is associated with higher morbidity and mortality. Heart failure patients meeting electrocardiogram and left ventricle function criteria are good candidates for cardiac resynchronization therapy, which may reduce the degree of functional mitral regurgitation in the short and long term, specifically targeting myocardial dyssynchrony and inducing left ventricle reverse remodeling.

Rate and Predictors of Permanent Pacemaker Implantation After Transcatheter Aortic Valve Implantation: Current Status.

Transcather aortic valve implantation (TAVI) has become a safe and indispensable treatment option for patients with severe symptomatic aortic stenosis who are at high surgical risk. Recently, outcomes after TAVI have improved significantly and TAVI has emerged as a qualified alternative to surgical aortic valve replacement in the treatment of intermediate risk patients and greater adoption of this procedure is to be expected in a wider patients population, including younger patients and low surgical risk patients. However since the aortic valve has close spatial proximity to the conduction system, conduction anomalies are frequently observed in TAVI.

Anticonvulsive Activity in Audiogenic DBA/2 Mice of 1,4-Benzodiazepines and 1,5-Benzodiazepines with Different Activities at Cerebellar Granule Cell GABA Receptors.

Herein, we tested in a model of generalized reflex epilepsy in mice different 1,4-benzodiazepines and 1,5-benzodiazepines with agonistic activity at the GABA receptor population contributing to the peak component of the chloride current elicited by GABA in cerebellar granule cells (CGCs) in culture. The substances have all higher lipophilia than clobazam, an antiepileptic drug well known and used in human therapy. This ensures that they all can pass relatively easily the blood-brain barrier (BBB).

Transcatheter Simultaneous Double-Transapical Access for Paravalvular Mitral Leak Closure Using the Occlutech PLD.

A 67-year-old patient with rheumatic heart valve disease had undergone two cardiac surgeries at the age of 30 years, then re-do with mitral valve replacement at 50 years. She presented with congestive heart failure and hemolytic anemia. Doppler echocardiography showed moderate-severe mitral regurgitation due to paravalvular mitral valve leak (PVML) and severe pulmonary hypertension.

Pulmonary gas embolism after parotid resection.

Pulmonary gas embolism can have very variable consequences and may become a real challenge for anesthesiologists. We hereby report a case of major pulmonary embolism which took place under unusual circumstances and was documented echocardiographically.

Percutaneous Coronary Sinus Catheterization With the ProPlege Catheter Under Transesophageal Echocardiography and Pressure Guidance.

Objectives: Percutaneous catheterization of the coronary sinus (CS) to enable the administration of retrograde cardioplegia may play an important role in minimally invasive cardiac surgery. A new specially designed device (ProPlege; Edwards Lifesciences, Irvine, CA) is described that can be placed under transesophageal echocardiography (TEE) and pressure guidance with a high rate of success and low rate of complications.

Design: Case series.

Study of the Interaction of 1,4- and 1,5-Benzodiazepines with GABAA Receptors of Rat Cerebellum Granule Cells in Culture.

The effects of a classical 1,4-benzodiazepine agonist, such as diazepam, its catabolite N-desmethyl-diazepam (nordiazepam), and 1,5-benzodiazepines such as clobazam and RL 214 (a triazolobenzodiazepine previously synthesized in our labs) were evaluated on native GABAA receptors of cerebellar granule cells in culture. The parameter studied was the increase of GABA-activated chloride currents caused by these substances. The contributions of α6 β2/3 γ2 and α1 α6 β2/3 γ2 receptor subtypes to the increase of GABA-activated chloride current were investigated by comparing the effects of such substances in the presence vs.

In silico design of novel 2H-chromen-2-one derivatives as potent and selective MAO-B inhibitors.

Inhibition data on rat monoamine oxidase B isoform of a large number of 7-metahalobenzyloxy-2H-chromen-2-one derivatives (67 compounds) carrying at position 4 a variety of substituents differing in steric, electrostatic, lipophilic and H-bonding properties, were modeled by Gaussian field-based 3D-QSAR and docking simulations carried out on rat MAO-B homology model. The computational study combining two different approaches provided easily interpretable binding modes, highlighting the dominant role of the steric effects at position 4, and guided the design of new, potent and selective MAO-B inhibitors. The 4-hydroxyethyl-, 4-chloroethyl-, 4-carboxamidoethyl-coumarin derivatives 70, 71, and 76, respectively, were endowed with high MAO-B inhibitory potency (pIC50 = 8.

Treatment of cardiogenic shock in severe aortic stenosis with the Edwards INTUITY valve.

We report the first known cases of successful implantation of the Edwards INTUITY (Edwards Lifesciences LLC, Irvine, CA) rapid-deployment valve in 3 patients with aortic stenosis presenting under emergency cardiogenic shock. At the 6-month follow-up, the 3 patients showed improved left ventricular function and improved functional capacity.

1,8-Naphthyridines IX. Potent anti-inflammatory and/or analgesic activity of a new group of substituted 5-amino[1,2,4]triazolo[4,3-a][1,8]naphthyridine-6-carboxamides, of some their Mannich base derivatives and of one novel substituted 5-amino-10-oxo-10H-pyrimido[1,2-a][1,8]naphthyridine-6-carboxamide derivative.

A new group of 5-(alkylamino)-9-isopropyl[1,2,4]triazolo[4,3-a][1,8]naphthyridine derivatives bearing a CONHR group at the 6-position (1c-g), designed to obtain new effective analgesic and/or anti-inflammatory agents, were synthesized and tested along with three new 9-alkyl-5-(4-alkyl-1-piperazinyl)-N,N-diethyl [1,2,4]triazolo[4,3-a][1,8]naphthyridine-6-carboxamides (2b-d). Besides, a new class of analogues of compounds 1 and 2, bearing a Mannich base moiety at the 9-position (12a-d), as well as the novel N,N-diethyl-5-(isobutylamino)-8-methyl-10-oxo-10H-pyrimido[1,2-a][1,8]naphthyridine-6-carboxamide (15) were prepared and tested. Compounds 1c-g exhibited very interesting anti-inflammatory properties in rats, whereas compounds 2b-d and 15 proved to be endowed with prevalent analgesic activity frequently associated with sedative effects in mice.

Multibranched Frozen Elephant Trunk with Left Subclavian Artery Cannulation.

Patients with aortic pathology involving the ascending aorta, the arch, and the descending aorta present a complex surgical challenge. A one-step hybrid procedure with ascending aorta repair, arch debranching, and frozen elephant trunk is reported in five patients. Left subclavian artery side graft cannulation is used to perfuse the spinal cord during circulatory arrest time.

Fine molecular tuning at position 4 of 2H-chromen-2-one derivatives in the search of potent and selective monoamine oxidase B inhibitors.

The effects on the inhibition potencies of monoamine oxidase isoforms A (MAO-A) and B (MAO-B) depending upon changes in the physicochemical properties (size, shape, H-bonding, lipophilicity, etc.) of substituents at the C4 position of 2H-chromen-2-one derivatives were extensively investigated, and the results significantly added to our knowledge on this class of MAO inhibitors. All the 67 examined compounds showed high MAO-B selectivity, some of them achieving potency in the low nanomolar range.

GABA Receptors of Cerebellar Granule Cells in Culture: Interaction with Benzodiazepines.

GABA receptor mediated inhibition plays an important role in modulating the input/output dynamics of cerebellum. A characteristic of cerebellar GABA receptors is the presence in cerebellar granule cells of subunits such as α6 and δ which give insensitivity to classical benzodiazepines. In fact, cerebellar GABA receptors have generally been considered a poor model for testing drugs which potentially are active at the benzodiazepine site.

Modulation of native GABA(A) receptor activity by triazolo 1,5-benzodiazepines.

In previous work our group described the synthesis and the activity on rat cerebellum granule cell GABAA receptors of new 1,5-benzodiazepine compounds. Here we are describing the synthesis of new triazolobenzodiazepines (mainly 1,5-benzodiazepine derivatives) and the evaluation of their biological activity in terms of effects on those GABAA receptors. Their effects were compared to those of 1,4-benzodiazepine agonists and some known 1,5-benzodiazepines.

Synthesis, in vitro antiplatelet activity and molecular modelling studies of 10-substituted 2-(1-piperazinyl)pyrimido[1,2-a]benzimidazol-4(10H)-ones.

The multistep preparation of the new 10-substituted 2-(1-piperazinyl)pyrimido[1,2-a]benzimidazol-4(10H)-ones 6a-o, and of the two isomers 10-ethyl-2-(diethylamino)pyrimido[1,2-a]benzimidazol-4(10H)-one 6p and 10-ethyl-4-(diethylamino)pyrimido[1,2-a]benzimidazol-2(10H)-one 13, as well as the in vitro evaluation of their inhibitory activity on human platelet aggregation induced in platelet-rich plasma by ADP, collagen or the Ca(2+) ionophore A23187 were here described. Nine out of fifteen 2-(1-piperazinyl)derivatives (6g-o) showed good inhibitory properties towards all the platelet aggregation agonists used. Moreover, a molecular modelling study has been performed on two of the best compounds of this series (6i and 6o) to confirm in silico their interactions with the catalytic site of human platelet PDE3, using the X-ray data of the PDE3B isoform in complex with an inhibitor.

Efficacy and safety of very low-dose self-management of oral anticoagulation in patients with mechanical heart valve replacement.

Background: Self-management improves oral anticoagulation control. Here we provide data of a preplanned interim analysis of very low-dose early self-controlled anticoagulation.

Methods: In a prospective, randomized, multicenter trial, 1,137 patients performed low-dose international normalized ratio (INR) self-management with a target INR range of 1.

New 1,5-benzodiazepine compounds: activity at native GABA(A) receptors.

Various new 1,5-benzodiazepine compounds were synthesized and tested for their biological activity in terms of effects on GABA(A) receptors of rat cerebellar granules in culture. Their effects were compared to those of a 1,4-benzodiazepine agonist, flunitrazepam and the already known 1,5-benzodiazepine antiepileptic clobazam. The effects were evaluated for the two different GABA(A) receptor populations present in these neurons, one mediating phasic inhibition and the other one mediating tonic inhibition.

1,8-Naphthyridines VIII. Novel 5-aminoimidazo[1,2-a] [1,8]naphthyridine-6-carboxamide and 5-amino[1,2,4]triazolo[4,3-a] [1,8]naphthyridine-6-carboxamide derivatives showing potent analgesic or anti-inflammatory activity, respectively, and completely devoid of acute gastrolesivity.

On the basis of the very interesting pharmacological properties shown by the 5-amino[1,2,4]triazolo[4,3-a][1,8]naphthyridine-6-carboxamide derivatives 1, previously described by us, we have now prepared the 5-aminoimidazo[1,2-a][1,8]naphthyridine-6-carboxamide derivatives 2a-o (a new structural class) whose tricyclic system is isosteric to that of compounds 1. Both compounds 2 and some new properly substituted compounds 1 (1f-k) now synthesized were tested in vivo for their analgesic and anti-inflammatory activities: on the whole, compounds 2 showed notable analgesic properties, whereas many compounds 1 exhibited a very potent anti-inflammatory activity, coupled to scarce analgesic activity. All the effective compounds proved to be completely devoid of acute gastrolesivity (gastric damage) in rats (at the 200 mg kg(-1) oral dose).

1,8-Naphthyridines VII. New substituted 5-amino[1,2,4]triazolo[4,3-a][1,8]naphthyridine-6-carboxamides and their isosteric analogues, exhibiting notable anti-inflammatory and/or analgesic activities, but no acute gastrolesivity.

The [1,2,4]triazolo[4,3-a][1,8]naphthyridine-6-carboxamide derivatives 5-amino (2) or 5-alkoxy (3) substituted and the 5-amino[1,2,4]triazolo[4,3-a]quinoline-4-carboxamide derivatives (4), designed to obtain new effective analgesic and/or anti-inflammatory agents were synthesized. Ten compounds 2 and 4 showed an interesting analgesic activity: the most potent ones are 2j (36% inhibition, P<0.05) and 4b (77% inhibition, P<0.

1,8-Naphthyridines VI. Synthesis and anti-inflammatory activity of 5-(alkylamino)-N,N-diethyl[1,2,4]triazolo[4,3-a][1,8]naphthyridine-6-carboxamides with a new substitution pattern on the triazole ring.

On the basis of the good anti-inflammatory properties shown by the 9-alkyl-N,N-dialkyl-5-(alkylamino)[1,2,4]triazolo[4,3-a][1,8]naphthyridine-6-carboxamides 1, a series of analogues of such compounds, in which the 9-alkyl substituent was replaced by an ester or amide group (compounds 3a-i), was prepared and tested (inhibition of carrageenan-induced paw edema in the rat). Also two 5-(N-alkyl,N-acylamino) derivatives (compounds 4a,b) were synthesized and evaluated for the same purpose. Even though the general trend for these new [1,2,4]triazolo[4,3-a][1,8]naphthyridine derivatives was a decrease in activity compared with compounds 1, some of the new synthesized compounds exhibited still good anti-inflammatory properties.

Synthesis and in vitro antiplatelet activity of new 4-(1-piperazinyl)coumarin derivatives. Human platelet phosphodiesterase 3 inhibitory properties of the two most effective compounds described and molecular modeling study on their interactions with phosphodiesterase 3A catalytic site.

The synthesis and in vitro antiplatelet activity significant data of coumarin derivatives 5i-x and quinolin-2(1H)-one derivatives 22a,b, as well as the corresponding structure-activity relationships are described. The recently reported 8-methyl-4-(1-piperazinyl)-7-(3-pyridylmethoxy)coumarin 5f and its potent 7-(2-morpholinoethoxy)-substituted new analogue 5u were notably more effective inhibitors of pure human platelet PDE3 than milrinone and cilostazol: these data were related, through a molecular modeling study, with the molecular interactions of the four compounds with the human PDE3A catalytic site.

Topical cooling for myocardial protection: the results of a prospective randomized study of the "shallow technique".

Introduction And Background: Respiratory distress following cardiac surgery is a troublesome complication. In several cases it is associated to cool-related phrenic nerve injury (PNI) after adoption of iced slush or hypothermic cardiopulmonary bypass. We compare two different strategies for myocardial protection: the "shallow technique" (ST) (dripping and prompt removal of cold saline solution from the epicardial surface) plus normothermic cardiopulmonary bypass, versus mild hypothermic cardiopulmonary bypass plus iced slush.

Effects of anti-inflammatory [1, 2, 4]triazolo[4, 3-a] [1, 8]naphthyridine derivatives on human stimulated PMN and endothelial cells: an in vitro study.

Background: 124 triazolo [4, 3-a]18naphthyridine derivatives (including NF161 and NF177) were tested for anti-inflammatory, analgesic and antipyretic properties and for their effects on spontaneous locomotor activity in mice and acute gastrolesivity in rats. Both NF161 and NF177 appeared to be anti-inflammatory and analgesic agents without toxic effects or acute gastrolesivity, but NF161 showed stronger anti-inflammatory activity, whereas NF177 was more active as analgesic.

Methods: An EIA kit was used to investigate the ability of NF161 and NF177 to affect prostaglandin E2 (PGE2) and prostacyclin (PGI2) production by human umbilical vascular endothelial cells (HUVEC).

1,5-Benzodiazepines XIV. Synthesis of new substituted 9H-bis-[1,2,4]triazolo[4,3-a:3',4'-d] [1,5]benzodiazepines and relate compounds endowed with in vitro cytotoxic properties.

A series of 11 new 9H-bis-[1,2,4]triazolo[4,3-a:3',4'-d] [1,5]benzodiazepine derivatives 8e-o was synthesized. Ten of these compounds (8e-m,o), along with four analogues (8a-d) (previously synthesized by us) were tested in vitro in order to evaluate their cytotoxic and anti-HIV-1 properties. In this connection other six original compounds, i.