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An abstract of the study "Left Ventricular Lead Position Influences Optimal AV/PV Delays Determined By Aortic VTI: Preliminary Results of the RESPONSE HF Trial," R. Weiss and colleagues is presented.

Natural nasal spray formulations were prepared by using Zingiber officinalis (Z. officinalis) extract and citral synergically loaded into specifically designed phospholipid vesicles. Phospholipid vesicles were selected according to their stabilizing effect on the nasal mucosal barrier, and their effectiveness was further potentiated by the co-loading of Z. officinalis extract as antioxidant and anti-inflammatory agent, and citral as antibacterial molecule. Cryo-TEM images confirmed the formation of morphologically homogeneous and small vesicles, sized around 100 nm, negatively charged (-44 mV) and highly biocompatible (viability ≥100%) as detected by using epithelial cells. The analysis of size distribution of sprayed droplets, average velocity module and spray cone angle suggested a good aptitude of the vesicles to be nebulized and their effective deposition in the nasal cavity. Moreover, vesicles were effectively capable of inhibiting some nasal pathogenic bacteria (i.e. Streptococcus pyogenes, Staphylococcus aureus, Escherichia coli) and to protect the epithelial cells against oxidative damage. The formulations are natural and safe, and all of them have shown promising technological and biological properties suggesting their possible application in the nasal cavity for the treatment of congestions and non-allergic rhinitis., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The extract of Cardiospermum halicacabum L. ( C. halicacabum ) obtained from flower, leaf and vine was loaded into modified phospholipid vesicles aiming at obtaining sprayable, biocompatible and effective nasal spray formulations for the treatment of nasopharyngeal diseases. Penetration enhancer-containing vesicles (PEVs) and hyalurosomes were formulated, and stabilized by adding a commercial gelatin from fish (20 mg/mL) or chondroitin sulfate from catshark cartilages ( Scyliorhinus canicula, 20 mg/mL). Cryo-TEM images confirmed the formation of spherical vesicles, while photon correlation spectroscopy analysis disclosed the formation of small and negatively-charged vesicles. PEVs were the smaller vesicles (~100 nm) along with gelatin-hyalurosomes (~120 nm), while chondroitin-PEVs and chondroitin-hyalurosomes were larger (~160 nm). Dispersions prepared with chondroitin sulfate were more homogeneous, as the polydispersity index was ~0.15. The in vitro analysis of the droplet size distribution, average velocity module and spray cone angle suggested a good spray-ability and deposition of formulations in the nasal cavity, as the mean diameter of the droplets was in the range recommended by the Food and Drug Administration for nasal targets. The spray plume analysis confirmed the ability of PEVs, gelatin-PEVs, hyalurosomes and gelatin-hyalurosomes to be atomized in fine droplets homogenously distributed in a full cone plume, with an angle ranging from 25 to 30°. Moreover, vesicles were highly biocompatible and capable of protecting the epithelial cells against oxidative damage, thus preventing the inflammatory state.

A total green nanotechnological nasal spray has been manufactured and proposed as an alternative treatment of rhinitis and rhinosinusitis. It was obtained by combining the strengthening effect of liposomes on barrier function, the hydrating and lubricating properties of sodium hyaluronan and the anti-inflammatory and antioxidant activities of the extract of Zingiber officinalis . To this purpose, the extract was loaded in special phospholipid vesicles immobilized with hyaluronic acid (hyalurosomes), which were further enriched with glycerol in the water phase. Liposomes and glycerosomes were prepared as well and used as reference. Vesicles were oligolamellar and multicompartment, as confirmed by cryogenic transmission electron microscopy (cryo-TEM) observation, small in size (~140 nm) and negatively charged (~-23 mV). Spray characteristics were evaluated by using the Spraytec ® and instant images, from which the plume angle was measured. The range of the droplet size distribution and the narrow spray angle obtained suggest a good nebulization and a possible local deposition in the nasal cavity. In vitro studies performed by using human keratinocytes confirmed the high biocompatibility of vesicles and their ability to effectively counteract oxidative damage on cells induced by hydrogen peroxide. The overall collected data suggest that our vesicles are suitable as nasal spray.

Pomace seed extract loaded vesicles were prepared as promising technological and green solution to exploit agri-food wastes and by-products, and develop high value-added products for human health. An antioxidant extract rich in bioactive compounds (epicatechins, catechin, gallic acid, quercetin and procynidins) was obtained from the seeds isolated from the pomace of Cannonau red grape cultivar. The extract was incorporated into phospholipid vesicles ad hoc formulated for intestinal delivery, by combining them, for the first time, whit a maltodextrin (Glucidex). Glucidex-transfersomes, glucidex-hyalurosomes and glucidex-hyalutransferomes were prepared, characterized and tested. Glucidex-liposomes were used as reference. All vesicles were small in size (~ 150 nm), homogeneously dispersed and negatively charged. Glucidex-transfersomes and especially glucidex-hyalutransfersomes disclosed an unexpected resistance to acidic pH and high ionic strength, as they maintained their physico-chemical properties (size and size distribution) after dilution at pH 1.2 simulating the harsh gastric conditions. Vesicles were highly biocompatible and able to counteract the oxidative damages induced in Caco-2 cells by using hydrogen peroxide. Moreover, they promoted the formation of Lactobacillus reuteri biofilm acting as prebiotic formulation. Overall results suggest the potential of glucidex-hyalutransfersomes as food supplements for the treatment of intestinal disorders.

The purpose of this study was to examine the effectiveness of video-based mathematics instruction for seven middle school students with specific learning disability (SLD), using an augmented reality-based training package. The dependent variable was the percentage of steps students performed correctly to solve each type of mathematics problem. The independent variable was the augmented reality video-based intervention, which used video to model the individual steps for solving four types of multistep mathematics problems: (a) addition and subtraction of integers, (b) multiplication and division of integers, (c) using ratio reasoning to convert measurement units, and (d) using multiplication and division to calculate rate of change. Results indicated a functional relation between the video-based mathematics intervention and the percentage of steps completed correctly for each type of problem. All seven participants showed significant gains immediately after receiving the intervention and maintained improved problem-solving skills in at least three out of the four problem categories.

In the present work curcumin loaded hyalurosomes were proposed as innovative systems for the treatment of rheumatoid arthritis. Vesicles were prepared using a one-step and environmentally friendly method. Aiming at finding the most suitable formulation in terms of size, surface charge and stability on storage, an extensive pre-formulation study was performed using different type and amount of phospholipids. Curcumin loaded vesicles prepared with 180 mg/ml of Phospholipon 90G (P90G) and immobilized with sodium hyaluronate (2 mg/ml) were selected because of their small size (189 nm), homogeneous dispersion (PI 0.24), negative charge (-35 mV), suitable ability to incorporate high amount of curcumin (E% ∼88%) and great stability on storage. The in vitro study using fibroblast-like synovial cells cultured in synovial fluid, demonstrated the ability of these vesicles to downregulate the production of anti-apoptotic proteins IAP1 and IAP2 and stimulate the production of IL-10, while the production of IL-6 and IL-15 and reactive oxygen species was reduced, confirming their suitability in counteracting pathogenesis of rheumatoid arthritis., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Glycerosomes were formulated using 1,2-dimyristoyl-sn-glycero-3-phosphatidycholine (DMPC), diclofenac sodium salt and 10, 20 or 30% glycerol in the water phase, while corresponding liposomes were prepared with the same amount of DMPC and diclofenac, without glycerol. The aim of the present work was to evaluate the effect of the used phospholipid on vesicle features and ability to favour diclofenac skin deposition by comparing these results with those found in previous works performed using hydrogenated soy phosphatidylcholine (P90H) and dipalmitoylphosphatidylcholine (DPPC). Liposomes and glycerosomes were multilamellar, liposomes being smaller (72±6nm). Interactions among glycerol, phospholipids and drug led to the formation of a non-rigid bilayer structure and a variation of the main transition temperature, which shifted to lower temperature. The addition of glycerol led to the formation of more viscous systems (from ∼2.5mPa/s for basic liposomes to ∼5mPa/s for glycerosomes), which improved spread ability of the formulations on the skin.Results obtained in vitro were promising using glycerosomes, irrespective of the amount of glycerol used: the amount of drug, which accumulated into and permeated through the different skin strata, was high and comparable with that obtained using P90H, suggesting that glycerosomes may represent an efficient carrier for both local effect or systemic absorption., (Copyright © 2017 Elsevier B.V. All rights reserved.)

In this work, diclofenac was encapsulated, as sodium salt, in glycerosomes containing 10, 20 or 30% of glycerol in the water phase with the aim to ameliorate its topical efficacy. Taking into account previous findings, glycerosome formulation was modified, in terms of economic suitability, using a cheap and commercially available mixture of hydrogenated soy phosphatidylcholine (P90H). P90H glycerosomes were spherical and multilamellar; photon correlation spectroscopy showed that obtained vesicles were ∼131nm, slightly larger and more polydispersed than those made with dipalmitoylphosphatidylcholine (DPPC) but, surprisingly, they were able to ameliorate the local delivery of diclofenac, which was improved with respect to previous findings, in particular using glycerosomes containing high amount of glycerol (20 and 30%). Finally, this drug delivery system showed a high in vitro biocompatibility toward human keratinocytes., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The components of pompia, a hybrid Citrus species cultivated only in Sardinia (Italy), were extracted using an environmentally-friendly method and food-grade solvents. Taking into account that only few data are available on pompia composition, the phytochemical fingerprint of its rind extract was obtained by accurate component separation and identification, combining HPLC and mass spectrometry. Different flavones such as naringin (23.77μg/mg), neoeriocitrin (46.53μg/mg) and neohesperidin (44.57μg/mg) were identified. Additionally, the antioxidant activity and phenolic content were confirmed by DPPH and Folin-Ciocalteu assays. The whole extract was incorporated in innovative phospholipid vesicles, namely glycerosomes, hyalurosomes and glycerol containing hyalurosomes, which were prepared using a high ratio of extract/phospholipid (1/3.5w/w). The in vitro biocompatibility of the nanoincorporated extract and its ability to potentiate the aptitude of the extract to counteract oxidative stress in skin cells were evaluated. The vesicles, especially glycerol containing hyalurosomes, were able to prevent oxidative damage and death of both keratinocytes and fibroblasts, promoting their viability., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Allantoin is traditionally employed in the treatment of skin ulcers and hypertrophic scars. In the present work, to improve its local deposition in the skin and deeper tissues, allantoin was incorporated in conventional liposomes and in new argan oil enriched liposomes. In both cases, obtained vesicles were unilamellar, as confirmed by cryo-TEM observation, but the addition of argan oil allowed a slight increase of the mean diameter (∼130nm versus ∼85nm). The formulations, especially those containing argan oil, favoured the allantoin accumulation in the skin, in particular in the dermis (∼8.7μg/cm(2)), and its permeation through the skin (∼33μg/cm(2)). The performances of vesicles as skin delivery systems were compared with those obtained by water dispersion of allantoin and the commercial gel, Sameplast(®). Moreover, in this work, for the first time, the elastic and viscous moduli of the skin were measured, underlining the different hydrating/moisturizing effects of the formulations. The application of ARG liposomes seems to provide a softening and relaxing effect on the skin, thus facilitating the drug accumulation and passage into and trough it., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Quercetin was incorporated in glycerosomes, new phospholipid-glycerol vesicles, and their protective effect against oxidative stress skin damages was extensively evaluated. In particular, the concentration-dependent effect of glycerol (from 10 to 50%) on vesicle suitability as cutaneous carriers of quercetin was carefully assessed. All vesicles were unilamellar and small in size (∼80-110 nm), as confirmed by cryo-TEM observation, with a drug incorporation efficiency ranging between 81 and 91%. SAXS studies, performed to investigate the bilayer arrangement, indicated a strong, dose-dependent interaction of glycerol with the polar portions of the phospholipid molecules, while quercetin did not significantly change the bilayer packing. In vitro studies on newborn pig skin underlined the concentration-dependent ability of glycerosomes to promote quercetin accumulation in the different layers, also confirmed by confocal microscopic observation of skin treated with fluorescent vesicles. Quercetin incorporated into liposomal and glycerosomal nanoformulations showed a strong ability to scavenge free radicals (DPPH test) and protect human keratinocytes in vitro against hydrogen peroxide damage. Moreover, quercetin-loaded vesicles were avidly taken up by keratinocytes in vitro. Overall, results indicate 40 and 50% glycerosomes as promising nanosystems for the improvement of cutaneous quercetin delivery and keratinocyte protection against oxidative stress damage., (Copyright © 2014 Elsevier B.V. All rights reserved.)

This work describes glycerosomes, vesicles composed of phospholipids, glycerol, and water, as novel vesicular carriers for (trans)dermal drug delivery. In this work, glycerosomes were prepared by hydrating dipalmitoylglycerophosphatidylcholine-cholesterol films with glycerol aqueous solutions (10-30%, v/v). The model drug was diclofenac sodium salt and conventional liposomes were used as control. Prepared formulations were characterized in terms of size distribution, morphology, zeta potential, and vesicle deformability. Glycerosomes and liposomes were oligo/multilamellar vesicles, spherical in shape with a mean diameter ranging between 81 and 97 nm and a fairly narrow distribution (P.I.=0.14-0.19), negative zeta potential values (from -35 to -48) and drug loading capacity between 64 and 73%. Deformability index of both conventional liposomes and glycerosomes showed that glycerol is able to act as edge activator for dipalmitoylglycerophosphatidylcholine bilayers when used in concentration higher than 10%. DSC studies suggested that glycerosomes are in a more fluid state than conventional liposomes. In vitro transdermal delivery experiments showed an improved skin deposition and permeation of diclofenac when 20 and 30% glycerosomes were used. MTT test demonstrated that glycerosomes were able to reduce the in vitro drug toxicity versus keratinocytes., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The preparation of Chitosan (CHT)-coated liposomes and their applicability as a carrier for delivery of drugs to the lungs by nebulisation was investigated. Empty SUV (small unilamellar) liposomes were initially prepared (with different lipid compositions) and coated with CHT by dropwise addition of CHT solution in the liposome dispersion. CHT-coating efficiency was calculated after separation of coated/non-coated liposomes by centrifugation, and measurement of lipid in each fraction. After establishing the best conditions for CHT-coating (concentration of CHT in the solution), RIF-loaded CHT-coated liposomes, with different lipid compositions (negatively charged and non-charged) were constructed, and their encapsulation efficiency (EE) and nebulisation efficiency (NE%)/stability (NER%) were evaluated. Charged liposomes (containing phosphatidylglycerol [PG]) can be coated with CHT better compared to non-charged ones. The EE of CHT-coated liposomes (that contain PG) is slightly increased while their stability after nebulisation is significantly increased (NER%). Mucoadhesive properties of CHT-coated liposomes were substantially better (compared to non-coated ones) while the toxicity of liposomal RIF towards A549 epithelial cells was lower compared to free drug for all the types of vesicles evaluated, and especially the CHT-coated ones. Thereby, it is concluded that CHT-coated liposomes have advantages (compared to non-coated) when the delivery of drugs to the lungs by nebulisation is considered.

Mycobacterium avium complex (MAC), the most frequent cause of opportunistic nontuberculous pulmonary infection, is made up of a group of intracellular pathogens that are able to survive and multiply inside lung alveolar macrophages. As nebulized liposomes are reported to be effective to target antibacterial agents to macrophages, in this work we have prepared and characterized re-dispersible freeze-dried rifampicin (RFP)-loaded vesicles by using soy lecithin (SL) and a commercial, enriched mixture of soy phosphatidylcholine (Phospholipon 90, P90) with or without cholesterol. The obtained results showed that RFP could be loaded stably in SL vesicles only when cholesterol was not present in the film preparation, whereas with P90 vesicles, the highest stability was obtained with formulations prepared with P90/cholesterol 7:1 or 4:1 molar ratios. RFP-liposome aerosols were generated using an efficient high-output continuous-flow nebulizer, driven by a compressor. After the experiments, nebulization efficiency (NE%) and nebulization efficiency of the encapsulated drug (NEED%) were evaluated. The results of our study indicated that nebulization properties and viscosity of formulations prepared with the low-transition-temperature phospholipids, SL and P90, are affected by vesicle composition. However, all formulations showed a good stability during nebulization and they were able to retain more than 65% of the incorporated drug. The effect of liposome encapsulation on lung levels of RFP following aerosol inhalation was determined in rats. The in vitro intracellular activity of RFP-loaded liposomes against MAC residing in macrophage-like J774 cells was also evaluated. Results indicated that liposomes are able to inhibit the growth of MAC in infected macrophages and to reach the lower airways in rats.

Recently three groups of rifampicin (RIF)-loaded microparticles (MPs), consisting of chitosan (CHT), PLGA and PLGA/CHT mixtures, were assessed in terms of RIF-loading and retention during nebulisation. The CHT-coated PLGA MPs were found to exhibit high RIF-loading ability together with nebulisation ability, stability, and mucoadhesive properties. All MP types had comparable toxicity towards alveolar cells which was significantly lower than that of the free drug. Herein, we study the release of RIF from all MP-types, during incubation in buffer with pH values: 4.40 and 7.40. Results show that CHT particles exhibit a higher burst release compared to PLGA MPs; at pH 4.40, which is explained by the higher solubility of CHT in acidic media. At pH 7.40 burst release from CHT MP's is significantly lower when CHT is crosslinked with glutaraldehyde, which is consistent with their - previously observed - increased stability during nebulization. From PLGA MPs, RIF release was pH independent under the conditions applied, while the amount of PVA (stabilizer) considerably affected drug release. When PLGA MP's were coated with CHT, at pH 7.40 the retention of RIF increased further (compared to non-coated MPs), while at pH 4.40 the release was faster from the CHT-coated particles. Concluding, it is proven that when PLGA MPs are coated with CHT, in addition to increased particle mucoadhesive properties, the release kinetics of RIF are modified.

Preparation of drug-loaded freeze-dried (FD) liposomes, designed for delivery to lungs after rehydration/nebulization was investigated. Rifampicin (RIF) incorporating multilamelar (MLV) and dried rehydrated vesicles (DRV); composed of phosphatidylcholine (PC), dipalmitoyloglycero-PC (DPPC) or distearoyloglycero-PC (DSPC), containing or not Cholesterol (Chol), were prepared. Vesicles were characterized for encapsulation efficiency (EE%), size distribution, zeta-potential, stability during freeze drying (FD) and nebulization (nebulization efficiency (NE%) and retention of RIF after nebulization (NER%)). Mucoadhesion and toxicity in A549 cells was measured. RIF EE% was not affected by liposome type but lipid composition was important; Synthetic lipid vesicles (DPPC and DSPC) had higher EE% compared to PC. As Chol increased EE% decreased. Freeze drying (FD) had no effect on EE%, however trehalose decreased EE% possibly due to RIF displacement. NER% was highly affected by lipid composition. Results of NE% and NER% for RIF-loaded liposomes show that DSPC/Chol (2:1) is the best composition for RIF delivery in vesicular form to lungs, by nebulization. Mucoadhesion and A549 cell toxicity studies were in line with this conclusion, however if mucoadhesion is required, improvement may be needed.

The effect of SLN incorporation on transdermal delivery and in vitro antiherpetic activity of Artemisia arborescens essential oil was investigated. Two different SLN formulations were prepared using the hot-pressure homogenization technique, Compritol 888 ATO as lipid, and Poloxamer 188 and Miranol Ultra C32 as surfactants. Formulations were examined for their stability for two years by monitoring average size distribution and zeta potential values. The antiviral activity of free and SLN incorporated essential oil was tested in vitro against Herpes Simplex Virus-1 (HSV-1) by a quantitative tetrazolium-based colorimetric method (MTT), while the effects of essential oil incorporation into SLN on both the permeation through and the accumulation into the skin strata was investigated by using in vitro diffusion experiments through newborn pig skin and an almond oil Artemisia essential oil solution as a control. Results showed that both SLN formulations were able to entrap the essential oil in high yields and that the mean particle size increased only slightly after two years of storage, indicating a high physical stability. In vitro antiviral assays showed that SLN incorporation did not affect the essential oil antiherpetic activity. The in vitro skin permeation experiments demonstrated the capability of SLN of greatly improving the oil accumulation into the skin, while oil permeation occurred only when the oil was delivered from the control solution.

The aim of this work was to study the influence of beta-cyclodextrin (beta-CD) on the biopharmaceutic properties of diclofenac (DCF). To this purpose the physicochemical characterization of diclofenac-beta-cyclodextrin binary systems was performed both in solution and solid state. Solid phase characterization was performed using differential scanning calorimetry (DSC), powder x-ray diffractometry (XRD), and Fourier transform infrared spectroscopy (FTIR). Phase solubility analyses, and in vitro permeation experiments through a synthetic membrane were performed in solution. Moreover, DCF/beta-CD interactions were studied in DMSO by 1H nuclear magnetic resonance (NMR) spectroscopy. The effects of different preparation methods and drug-to-beta-CD molar ratios were also evaluated. Phase solubility studies revealed 1:1 M complexation of DCF when the freeze-drying method was used for the preparation of the binary system. The true inclusion for the freeze-dried binary system was confirmed by 1H NMR spectroscopy, DSC, powder XRD, and IR studies. The dissolution study revealed that the drug dissolution rate was improved by the presence of CDs and the highest and promptest release was obtained with the freeze-dried binary system. Diffusion experiments through a silicone membrane showed that DCF diffusion was higher from the saturated drug solution (control) than the freeze-dried inclusion complexes, prepared using different DCF-beta-CD molar ratios. However, the presence of the inclusion complex was able to stabilize the system giving rise to a more regular diffusion profile.

Objectives: We examined the effect of mechanical unloading with ventricular assist device (VAD) therapy on myocardial inducible nitric oxide synthase (iNOS) expression and cardiomyocyte apoptosis in patients with end-stage heart failure (HF)., Background: Despite advances in medical therapy, HF continues to be a progressive and ultimately fatal disorder. High levels of iNOS expression are present in the myocardium of failing hearts, suggesting a potential role for iNOS in HF progression., Methods: Inducible NOS protein expression was analyzed by Western blotting and cardiomyocyte apoptosis by terminal deoxynucleotidyltransferase dUTP nick end-labeling (TUNEL) in myocardial samples from failing hearts. Included in these analyses were tissues from 9 patients at the time of transplantation (HF-transplant group), 10 patients at the time of VAD insertion (pre-VAD group), and 11 patients undergoing transplant after VAD support (post-VAD group). Seven control samples were obtained at autopsy., Results: Low or undetectable levels of iNOS were present in controls (0.005 +/- 0.002). The HF-transplant and pre-VAD myocardial specimens exhibited a marked increase in iNOS expression (1.48 +/- 0.34 and 1.29 +/- 0.26, respectively; p < 0.01 for both vs. controls). The increase in iNOS expression was reversed in the post-VAD group (0.36 +/- 0.16; p < 0.01 vs. HF-transplant and pre-VAD groups). The rate of TUNEL-positive cardiomyocytes was high in the pre-VAD group and significantly lower in the post-VAD group (0.64 +/- 0.15% in pre-VAD group and 0.16 +/- 0.07% in post-VAD group; p < 0.01). The iNOS levels correlated significantly with cardiomyocyte apoptosis (r = 0.66, p < 0.01)., Conclusions: Therapy with VAD normalizes iNOS expression in association with diminished cardiomyocyte apoptosis in the failing heart. Further work is required to define whether a causal relationship exists between iNOS and cardiomyocyte apoptosis.

Background: The contribution of the sarcomere's thin filament to the contractile dysfunction of human cardiomyopathy is not well understood., Methods and Results: We have developed techniques to isolate and functionally characterize intact (native) thin filaments obtained from failing and nonfailing human ventricular tissue. By use of in vitro motility and force assays, native thin filaments from failing ventricular tissue exhibited a 19% increase in maximal velocity but a 27% decrease in maximal contractile force compared with nonfailing myocardium. Native thin filaments isolated from human myocardium after left ventricular assist device support demonstrated a 37% increase in contractile force. Dephosphorylation of failing native thin filaments resulted in a near-normalization of thin-filament function, implying a phosphorylation-mediated mechanism. Tissue expression of the protein kinase C isoforms alpha, beta1, and beta2 was increased in failing human myocardium and reduced after left ventricular assist device support., Conclusions: These novel findings demonstrate that (1) the thin filament is a key modulator of contractile performance in the failing human heart, (2) thin-filament function is restored to near normal levels after LVAD support, and (3) the alteration of thin-filament function in failing human myocardium is mediated through phosphorylation, most likely through activation of protein kinase C.

Despite recent advances in medical therapy, mortality remains high following the diagnosis of heart failure (HF). Cardiac transplantation is still the standard surgical treatment option for highly selected patients with severe end-stage HF; however, it is only available to a small percentage of patients. The small number of available donor hearts is an inherent limitation on the ability of cardiac transplantation to greatly impact the management of advanced HF. The increased incidence and prevalence of HF in an ever aging and medically complex population has paved the way for alternative surgical and device treatment strategies. Some of these treatment options include ventricular reduction/remodeling surgery, mitral valve repair, mechanical ventricular assist device implantation, implantable cardioverter-defibrillators, and cardiac resynchronization therapy. Several recent trials have demonstrated the effectiveness of these therapies with regard to improvement in primary cardiac end points, HF symptoms, and survival. Surgical and device techniques are usually combined with optimal medical management of HF. The total cost and actual cost-effectiveness of employing these new therapeutic modalities in a growing population of HF patients remains to be determined.

Despite recent advances in medical therapy, mortality remains high following the diagnosis of heart failure (HF). Cardiac transplantation is still the standard surgical treatment option for highly selected patients with severe end-stage HF; however, it is available only to a small percentage of patients. The small number of available donor hearts is an inherent limitation on the ability of cardiac transplantation to greatly impact the management of advanced HF. The increased incidence and prevalence of HF in an ever aging and medically complex population has paved the way for alternative surgical and device treatment strategies. Some of these treatment options include ventricular reduction and remodeling surgery, mitral valve repair, mechanical ventricular assist device implantation, implantable cardioverter defibrillators, and cardiac resynchronization therapy. Several recent trials have demonstrated effectiveness of these therapies with regard to improvement in physiologic end points, HF symptoms, and survival. Surgical and device techniques are usually combined with optimal medical management of HF. The total cost and actual cost-effectiveness of employing these new therapeutic modalities in a growing population of HF patients remain to be determined.

The alpha(1)-subunit of the cardiac/vascular Ca(2+) channel, which is the dihydropyridine (DHP)-binding site (the DHP receptor), provides the pore structure for Ca(2+) entry. It contains the binding sites for multiple classes of drugs collectively known as Ca(2+) antagonists. As an initial step toward understanding the mechanisms controlling transcription of the rat cardiac alpha(1C)-subunit gene, we have cloned a 2.3-kb fragment containing the 5'-flanking sequences and identified the alpha(1C)-subunit gene transcription start site. The rat alpha(1C)-subunit gene promoter belongs to the TATA-less class of such basal elements. Using deletion analysis of alpha(1C)-subunit promoter-luciferase reporter gene constructs, we have characterized the transcriptional modulating activity of the 5'-flanking region and conducted transient transfections in cultured neonatal rat cardiac ventricular myocytes and vascular smooth muscle cells. Sequence scanning identified several potential regulatory elements, including five consensus sequences for the cardiac-specific transcription factor Nkx2.5, an AP-1 site, a cAMP response element, and a hormone response element. Transient transfection experiments with the promoter-luciferase reporter fusion gene demonstrate that the 2-kb 5'-flanking region confers tissue specificity and hormone responsiveness to expression of the Ca(2+) channel alpha(1C)-subunit gene. Electrophoretic mobility shift assays identified a region of the alpha(1C)-subunit gene promoter that can bind transcription factors and appears to be important for gene expression.