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1.  Mitral Valve Repair Using ePTFE Sutures for Ruptured Mitral Chordae Tendineae: A Computational Simulation Study 
Annals of biomedical engineering  2013;42(1):10.1007/s10439-013-0908-1.
Mitral valve repair using expanded polytetrafluoroethylene (ePTFE) sutures is an established and preferred interventional method to resolve the complex pathophysiologic problems associated with chordal rupture. We developed a novel computational evaluation protocol to determine the effect of the artificial sutures on restoring mitral valve function following valve repair. A virtual mitral valve was created using three-dimensional echocardiographic data in a patient with ruptured mitral chordae tendineae. Virtual repairs were designed by adding artificial sutures between the papillary muscles and the posterior leaflet where the native chordae were ruptured. Dynamic finite element simulations were performed to evaluate pre- and post-repair mitral valve function. Abnormal posterior leaflet prolapse and mitral regurgitation was clearly demonstrated in the mitral valve with ruptured chordae. Following virtual repair to reconstruct ruptured chordae, the severity of the posterior leaflet prolapse decreased and stress concentration was markedly reduced both in the leaflet tissue and the intact native chordae. Complete leaflet coaptation was restored when four or six sutures were utilized. Computational simulations provided quantitative information of functional improvement following mitral valve repair. This novel simulation strategy may provide a powerful tool for evaluation and prediction of interventional treatment for ruptured mitral chordae tendineae.
doi:10.1007/s10439-013-0908-1
PMCID: PMC3872503  PMID: 24072489
Mitral valve; Three-dimensional echocardiography; Mitral repair; Chordae tendineae; Simulation; Finite element
2.  Nitric Oxide Improves Molecular Imaging of Inflammatory Atheroma using Targeted Echogenic Immunoliposomes 
Atherosclerosis  2013;231(2):10.1016/j.atherosclerosis.2013.09.026.
Objective:
This study aimed to demonstrate whether pretreatment with nitric oxide (NO) loaded into echogenic immunoliposomes (ELIP) plus ultrasound, applied before injection of molecularly targeted ELIP can promote penetration of the targeted contrast agent and improve visualization of atheroma components.
Methods:
ELIP were prepared using the pressurization-freeze method. Atherosclerosis was induced in Yucatan miniswine by balloon denudation and a hyperlipidemic diet. The animals were randomized to receive anti-intercellular adhesion molecule-1 (ICAM-1) ELIP or immunoglobulin (IgG)-ELIP, and were subdivided to receive pretreatment with standard ELIP plus ultrasound, NO-loaded ELIP, or NO-loaded ELIP plus ultrasound. Intravascular ultrasound (IVUS) data were collected before and after treatment.
Results:
Pretreatment with standard ELIP plus ultrasound or NO-loaded ELIP without ultrasound resulted in 9.2 ± 0.7% and 9.2 ± 0.8% increase in mean gray scale values, respectively, compared to baseline (p<0.001 vs. control). Pretreatment with NO-loaded ELIP plus ultrasound activation resulted in a further increase in highlighting with a change in mean gray scale value to 14.7 ± 1.0% compared to baseline (p<0.001 vs. control). These differences were best appreciated when acoustic backscatter data values (RF signal) were used [22.7 ± 2.0% and 22.4 ± 2.2% increase in RF signals for pretreatment with standard ELIP plus ultrasound and NO-loaded ELIP without ultrasound respectively (p<0.001 vs. control), and 40.0 ± 2.9% increase in RF signal for pretreatment with NO-loaded ELIP plus ultrasound (p<0.001 vs. control)].
Conclusion:
NO-loaded ELIP plus ultrasound activation can facilitate anti-ICAM-1 conjugated ELIP delivery to inflammatory components in the arterial wall. This NO pretreatment strategy has potential to improve targeted molecular imaging of atheroma for eventual true tailored and personalized management of cardiovascular diseases.
doi:10.1016/j.atherosclerosis.2013.09.026
PMCID: PMC3871611  PMID: 24267236
Molecular Imaging; Atherosclerosis; Contrast Agent; Nitric Oxide; Ultrasound
3.  Therapeutic Time Window and Dose Dependence of Xenon Delivered via Echogenic Liposomes for Neuroprotection in Stroke 
CNS neuroscience & therapeutics  2013;19(10):773-784.
Aims
Neurologic impairment following ischemic injury complicates the quality of life for stroke survivors. Xenon (Xe) has favorable neuroprotective properties to modify stroke. Xe delivery is hampered by a lack of suitable administration strategies. We have developed Xe-containing echogenic liposomes (Xe-ELIP) for systemic Xe delivery. We investigated the time window for Xe-ELIP therapeutic effect and the most efficacious dose for neuroprotection. Molecular mechanisms for Xe neuroprotection were investigated.
Methods
Xe-ELIP were created by a previously developed pressurization-freezing method. Following right middle cerebral artery occlusion (2 hours), animals were treated with Xe-ELIP at 2, 3 or 5 hours to determine time window of therapeutic effect. The neuroprotectant dosage for optimal effect was evaluated 3 hours after stroke onset. Expression of brain-derived neurotrophic factor (BDNF), protein kinase B (Akt), and mitogen-activated protein kinases (MAPK) were determined.
Results
Xe-ELIP administration for up to 5 hours after stroke onset reduced infract size. Treatment groups given 7 and 14 mg/kg of Xe-ELIP reduced infarct size. Behavioral outcomes corresponded to changes in infarct volume. Xe-ELIP treatment reduced ischemic neuronal cell death via activation of both MAPK and Akt. Elevated BDNF expression was shown following Xe-ELIP delivery.
Conclusion
This study demonstrates the therapeutic efficacy of Xe-ELIP administered within 5 hours after stroke onset with an optimal dosage range of 7–14 mg/kg for maximal neuroprotection.
doi:10.1111/cns.12159
PMCID: PMC3806289  PMID: 23981565
Stroke; Xenon; Neuroprotection; Liposomes; Cerebral ischemia
4.  Relationship between cavitation and loss of echogenicity from ultrasound contrast agents 
Physics in medicine and biology  2013;58(18):6541-6563.
Ultrasound contrast agents (UCAs) have the potential to nucleate cavitation and promote both beneficial and deleterious bioeffects in vivo. Previous studies have elucidated the pulse-duration dependent pressure amplitude threshold for rapid loss of echogenicity due to UCA fragmentation. Previous studies have demonstrated that UCA fragmentation was concomitant with inertial cavitation. The purpose of this study was to evaluate the relationship between stable and inertial cavitation thresholds and loss of echogenicity of UCAs as a function of pulse duration. Determining the relationship between cavitation thresholds and loss of echogenicity of UCAs would enable monitoring of cavitation based upon the on-screen echogenicity in clinical applications. Two lipid-shelled UCAs, echogenic liposomes (ELIP) and Definity®, were insonified by a clinical ultrasound scanner in duplex spectral Doppler mode at four pulse durations (“sample volumes”) in both a static system and a flow system. Cavitation emissions from the UCAs insonified by Doppler pulses were recorded using a passive cavitation detection system and stable and inertial cavitation thresholds ascertained. Loss of echogenicity from ELIP and Definity® was assessed within regions of interest on B-mode images. A numerical model based on UCA rupture predicted the functional form of the loss of echogenicity from ELIP and Definity®. Stable and inertial cavitation thresholds were found to have a weak dependence on pulse duration. Stable cavitation thresholds were lower than inertial cavitation thresholds. The power of cavitation emissions was an exponential function of the loss of echogenicity over the investigated range of acoustic pressures. Both ELIP and Definity® lost more than 80% echogenicity before the onset of stable or inertial cavitation. Once this level of echogenicity loss occurred, both stable and inertial cavitation were detected in the physiologic flow phantom. These results imply that stable and inertial cavitation are necessary in order to trigger complete loss of echogenicity acoustically from UCAs and this finding can be used when planning diagnostic and therapeutic applications.
doi:10.1088/0031-9155/58/18/6541
PMCID: PMC4170692  PMID: 24002637
cavitation thresholds; echogenic liposomes; echogenicity; passive cavitation detection; physiologic flow
6.  The Impact of Bubbles on Measurement of Drug Release from Echogenic Liposomes 
Ultrasonics sonochemistry  2012;20(4):1121-1130.
Echogenic liposomes (ELIP) encapsulate gas bubbles and drugs within lipid vesicles, but the mechanisms of ultrasound-mediated drug release from ELIP are not well understood. The effect of cavitation activity on drug release from ELIP was investigated in flowing solutions using two fluorescent molecules: a lipophilic drug (rosiglitazone) and a hydrophilic drug substitute (calcein). ELIP samples were exposed to pulsed Doppler ultrasound from a clinical diagnostic ultrasound scanner at pressures above and below the inertial and stable cavitation thresholds. Control samples were exposed to a surfactant, Triton X-100 (positive control), or to flow alone (negative control). Fluorescence techniques were used to detect release. Encapsulated microbubbles reduced the measured fluorescence intensity and this effect should be considered when assessing drug release from ELIP. The origin of this effect is not specific to ELIP. Release of rosiglitazone or calcein compared to the negative control was only observed with detergent treatment, but not with ultrasound exposure, despite the presence of stable and inertial cavitation activity. Release of rosiglitazone or calcein from ELIP exposed to diagnostic ultrasound was not observed, even in the presence of cavitation activity. Ultrasound-mediated drug delivery strategies with ELIP will thus rely on passage of the drug-loaded liposomes to target tissues.
doi:10.1016/j.ultsonch.2012.12.005
PMCID: PMC3632413  PMID: 23357288
Echogenic liposomes; pulsed Doppler ultrasound; drug release; cavitation; rosiglitazone; spectrofluorometric techniques
7.  Mitral valve function following ischemic cardiomyopathy: a biomechanical perspective 
Ischemic mitral valve (MV) is a common complication of pathologic remodeling of the left ventricle due to acute and chronic coronary artery diseases. It frequently represents the pathologic consequences of increased tethering forces and reduced coaptation of the MV leaflets. Ischemic MV function has been investigated from a biomechanical perspective using finite element-based computational MV evaluation techniques. A virtual 3D MV model was created utilizing 3D echocardiographic data in a patient with normal MV. Two types of ischemic MVs containing asymmetric medial-dominant or symmetric leaflet tenting were modeled by altering the configuration of the normal papillary muscle (PM) locations. Computational simulations of MV function were performed using dynamic finite element methods, and biomechanical information across the MV apparatus was evaluated. The ischemic MV with medial-dominant leaflet tenting demonstrated distinct large stress distributions in the posteromedial commissural region due to the medial PM displacement toward the apical-medial direction resulting in a lack of leaflet coaptation. In the ischemic MV with balanced leaflet tenting, mitral incompetency with incomplete leaflet coaptation was clearly identified all around the paracommissural regions. This computational MV evaluation strategy has the potential for improving diagnosis of ischemic mitral regurgitation and treatment of ischemic MVs.
doi:10.3233/BME-130777
PMCID: PMC4072029  PMID: 24211876
Mitral valve; ischemic mitral regurgitation; leaflet coaptation; echocardiography; finite element
8.  Telomere length in patients with systemic lupus erythematosus and its associations with carotid plaque 
Rheumatology (Oxford, England)  2013;52(6):1101-1108.
Objective. To evaluate telomere length (TL) between patients with SLE and healthy controls and to test if TL is associated with carotid plaque.
Methods. A pilot study of 154 patients with SLE and 152 controls was performed from the SOLVABLE (Study of Lupus Vascular and Bone Long-Term Endpoints) cohort. Demographic and cardiovascular disease (CVD) factors were collected at baseline. The presence or absence of plaque was evaluated by B-mode US. Genomic DNA was isolated from whole peripheral blood. TL was quantified using real-time quantitative PCR.
Results. SLE women had a short TL compared with healthy controls (4.57 vs 5.44 kb, P = 0.03). SLE women showed shorter TL than controls across all age groups: <35 years (4.38 vs 6.37 kb), 35–44 years (4.52 vs 5.30 kb), 45–54 years (4.77 vs 5.68 kb) and ≥55 years (4.60 vs 4.71 kb). Among patients with SLE and carotid plaque there was a trend towards shorter TL at a younger age and it was significantly lower in the 35- to 44-year age group when compared with controls (P = 0.025). Multiple logistic regression analysis indicated a risk of carotid plaque with older age [odds ratio (OR) 1.09; 95% CI 1.06, 1.12] but not with TL (OR 1.05; 95% CI 0.97, 1.13).
Conclusion. SLE women had significantly shorter TL than controls. SLE women trended towards shorter TL at a younger age. When carotid plaque was identified, the younger SLE women had shorter TL. Only older age but not shorter TL was independently associated with carotid plaque. Additional studies are needed to confirm if TL is a novel biomarker for cardiovascular disease in SLE.
doi:10.1093/rheumatology/kes424
PMCID: PMC3651615  PMID: 23382361
systemic lupus erythematosus; cardiovascular disease; telomere length
9.  Adverse pregnancy outcomes and subsequent risk of cardiovascular disease in women with systemic lupus erythematosus 
Lupus Science & Medicine  2014;1(1):e000024.
Background/objective
Patients with systemic lupus erythematosus (SLE) are at increased risk for adverse pregnancy outcomes and cardiovascular disease (CVD). The objective of this exploratory study was to investigate the association between a history of adverse pregnancy outcomes and subsequent risk of subclinical CVD assessed by imaging studies and verified clinical CVD events in 129 women with SLE.
Methods
The occurrence of adverse pregnancy outcomes, specifically pre-eclampsia, preterm birth and low birth weight was ascertained by questionnaire. Subclinical CVD was assessed by coronary artery calcium (CAC) as measured by electron beam CT and carotid plaque measured by B mode ultrasound. Clinical CVD events were verified by medical record review. Logistic regression was used to estimate the association of pregnancy complications with occurrence of subclinical CVD and clinical CVD with a priori adjustment for age, which is associated with CVD and SLE disease duration as a measure of SLE disease burden.
Results
Fifty-six women reported at least one pregnancy complication while 73 had none. Twenty-six women had at least one pregnancy complicated by pre-eclampsia and were more likely to have a CAC score greater than or equal to 10 (adjusted OR=3.7; 95% CI 1.2 to 11.9), but the presence of plaque was not associated with this pregnancy complication, OR=1.1, (95% CI 0.4 to 2.8). Low birth weight and preterm birth were not associated with CAC or plaque.
Conclusions
Patients with SLE with a history of pre-eclampsia had a higher rate of subclinical CVD as measured by CAC score. Future studies are needed to confirm the relationship between adverse pregnancy outcomes and subsequent subclinical CVD and clinical CVD events.
doi:10.1136/lupus-2014-000024
PMCID: PMC4213826  PMID: 25379191
Cardiovascular Disease; Systemic Lupus Erythematosus; Pregnancy; Pre-eclampsia
10.  BROADBAND ATTENUATION MEASUREMENTS OF PHOSPHOLIPID-SHELLED ULTRASOUND CONTRAST AGENTS 
Ultrasound in medicine & biology  2013;40(2):410-421.
The aim of this study was to characterize the frequency-dependent acoustic attenuation of three phospholipid-shelled ultrasound contrast agents (UCAs): Definity, MicroMarker and echogenic liposomes. A broadband through-transmission technique allowed for measurement over 2 to 25 MHz with a single pair of transducers. Viscoelastic shell parameters of the UCAs were estimated using a linearized model developed by N. de Jong, L. Hoff, T. Skotland and N. Bom (Ultrasonics 1992; 30:95–103). The effect of diluent on the attenuation of these UCA suspensions was evaluated by performing attenuation measurements in 0.5% (w/v) bovine serum albumin and whole blood. Changes in attenuation and shell parameters of the UCAs were investigated at room temperature (25°C) and physiologic temperature (37°C). The attenuation of the UCAs diluted in 0.5% (w/v) bovine serum albumin was found to be identical to the attenuation of UCAs in whole blood. For each UCA, attenuation was higher at 37°C than at 25°C, underscoring the importance of conducting characterization studies at physiologic temperature. Echogenic liposomes exhibited a larger increase in attenuation at 37°C versus 25°C than either Definity or MicroMarker.
doi:10.1016/j.ultrasmedbio.2013.09.018
PMCID: PMC4026002  PMID: 24262056
Ultrasound contrast agents; Microbubbles; Broadband characterization; Size distribution; Polyvinylidene fluoride transducer; Echogenic liposomes; Definity; MicroMarker
11.  The effect of patient-specific annular motion on dynamic simulation of mitral valve function 
Journal of biomechanics  2013;46(6):1104-1112.
Most surgical procedures for patients with mitral regurgitation (MR) focus on optimization of annular dimension and shape utilizing ring annuloplasty to restore normal annular geometry, increase leaflet coaptation, and reduce regurgitation. Computational studies may provide insight on the effect of annular motion on mitral valve (MV) function through the incorporation of patient-specific MV apparatus geometry from clinical imaging modalities such as echocardiography. In the present study, we have developed a novel algorithm for modeling patient-specific annular motion across the cardiac cycle to further improve our virtual MV modeling and simulation strategy. The MV apparatus including the leaflets, annulus, and location of papillary muscle tips was identified using patient 3D echocardiography data at end diastole and peak systole and converted to virtual MV model. Dynamic annular motion was modeled by incorporating the ECG-gated time-varying scaled annular displacement across the cardiac cycle. We performed dynamic finite element (FE) simulation of two sets of patient data with respect to the presence of MR. Annular morphology, stress distribution across the leaflets and annulus, and contact stress distribution were determined to assess the effect of annular motion on MV function and leaflet coaptation. The effect of dynamic annular motion clearly demonstrated reduced regions with large stress values and provided an improved accuracy in determining the location of improper leaflet coaptation. This strategy has the potential to better quantitate the extent of pathologic MV and better evaluate functional restoration following MV repair.
doi:10.1016/j.jbiomech.2013.01.014
PMCID: PMC3629842  PMID: 23433464
Mitral valve; Finite element; Annular motion; Mitral regurgitation; Three-dimensional echocardiography
12.  Effect of leaflet-to-chordae contact interaction on computational mitral valve evaluation 
Background
Computational simulation using numerical analysis methods can help to assess the complex biomechanical and functional characteristics of the mitral valve (MV) apparatus. It is important to correctly determine physical contact interaction between the MV apparatus components during computational MV evaluation. We hypothesize that leaflet-to-chordae contact interaction plays an important role in computational MV evaluation, specifically in quantitating the degree of leaflet coaptation directly related to the severity of mitral regurgitation (MR). In this study, we have performed dynamic finite element simulations of MV function with and without leaflet-to-chordae contact interaction, and determined the effect of leaflet-to-chordae contact interaction on the computational MV evaluation.
Methods
Computational virtual MV models were created using the MV geometric data in a patient with normal MV without MR and another with pathologic MV with MR obtained from 3D echocardiography. Computational MV simulation with full contact interaction was specified to incorporate entire physically available contact interactions between the leaflets and chordae tendineae. Computational MV simulation without leaflet-to-chordae contact interaction was specified by defining the anterior and posterior leaflets as the only contact inclusion.
Results
Without leaflet-to-chordae contact interaction, the computational MV simulations demonstrated physically unrealistic contact interactions between the leaflets and chordae. With leaflet-to-chordae contact interaction, the anterior marginal chordae retained the proper contact with the posterior leaflet during the entire systole. The size of the non-contact region in the simulation with leaflet-to-chordae contact interaction was much larger than for the simulation with only leaflet-to-leaflet contact.
Conclusions
We have successfully demonstrated the effect of leaflet-to-chordae contact interaction on determining leaflet coaptation in computational dynamic MV evaluation. We found that physically realistic contact interactions between the leaflets and chordae should be considered to accurately quantitate leaflet coaptation for MV simulation. Computational evaluation of MV function that allows precise quantitation of leaflet coaptation has great potential to better quantitate the severity of MR.
doi:10.1186/1475-925X-13-31
PMCID: PMC3976553  PMID: 24649999
Mitral valve; Finite element; Contact interaction; Coaptation; Echocardiography
13.  Evaluation of Mitral Valve Dynamics 
JACC. Cardiovascular imaging  2013;6(2):263-268.
doi:10.1016/j.jcmg.2012.10.017
PMCID: PMC3629823  PMID: 23489540
14.  Lipid complex of apolipoprotein A-I mimetic peptide 4F is a novel platform for Paraoxonase-1 binding and enhancing its activity and stability 
High density lipoprotein (HDL) associated paraoxonase-1 (PON1) is crucial for the anti-oxidant, anti-inflammatory, and anti-atherogenic properties of HDL. Discoidal apolipoprotein (apo)A-I:1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) complex has been shown to be the most effective in binding PON1, stabilizing it, and enhancing its lactonase and inhibitory activity of low density lipoprotein oxidation. Based on our earlier study demonstrating that apoA-I mimetic peptide 4F forms discoidal complex with 1,2-dimyristoyl-sn-glycero-3-phosphocholine, we hypothesized that lipid complexes of 4F would be able to bind PON1 and enhance its activity and stability. To test our hypothesis, we have expressed and purified a recombinant PON1 (rPON1) and studied its interaction with 4F:POPC complex. Our studies show significant increase, compared to the control, in the paraoxonase activity and stability of rPON1 in the presence of 4F:POPC complex. We propose that 4F:POPC complex is a novel platform for PON1 binding, increasing its stability, and enhancing its enzyme activity. We propose a structural model for the 4F:POPC:PON1 ternary complex that is consistent with our results and published observations.
doi:10.1016/j.bbrc.2012.11.128
PMCID: PMC3555693  PMID: 23261466
High density lipoprotein; Peptide; Amphipathic helix; Apolipoprotein A-I; Lipid; Paraoxonase-1
15.  HIGH PREVALENCE OF SUBCLINICAL ATHEROSCLEROSIS BY CAROTID ULTRASOUND AMONG MEXICAN AMERICANS: DISCORDANCE WITH 10-YEAR RISK ASSESSMENT USING THE FRAMINGHAM RISK SCORE 
Echocardiography (Mount Kisco, N.Y.)  2012;29(10):1224-1232.
Background
Framingham Risk Scores (FRS) were validated in a mostly Caucasian population. Evaluation of subclinical atherosclerosis by carotid ultrasound may improve ascertainment of risk in non-White populations. This study aimed to evaluate carotid intima-media thickness (cIMT) and carotid plaquing among Mexican Americans, and to correlate these markers with coronary risk factors and the FRS.
Methods/Results
Participants (n=141) were drawn from the Cameron County Hispanic Cohort. Carotid artery ultrasound was performed and cIMT measured. Carotid plaque was defined as areas of thickening >50% of the thickness of the surrounding walls. Mean age was 53.1±11.7 years (73.8% female). Most were overweight or obese (88.7%) and more than half (53.2%) had the metabolic syndrome. One third (34.8%) had abnormal carotid ultrasound findings (either cIMT ≥75th percentile for gender and age or presence of plaque). Among those with abnormal carotid ultrasound, the majority were classified as being at low 10-year risk for cardiovascular events. Carotid ultrasound reclassified nearly a third of the cohort as being at high risk. This discordance between 10-year FRS and carotid ultrasound was noted whether risk was assessed for hard coronary events or global risk. Concordance between FRS and carotid ultrasound findings was best when long-term (30-year) risk was assessed and no subject with an abnormal carotid ultrasound was categorized as low risk by the 30-year FRS algorithm.
Conclusions
Integration of carotid ultrasound findings to coronary risk assessments and use of longer term prediction models may provide better risk assessment in this minority population, with earlier initiation of appropriate therapies.
doi:10.1111/j.1540-8175.2012.01774.x
PMCID: PMC3687003  PMID: 22747630
Carotid ultrasound; Subclinical atherosclerosis; Framingham risk score; Minority population; Risk assessment
16.  Nitric oxide-loaded echogenic liposomes for treatment of vasospasm following subarachnoid hemorrhage 
Delayed cerebral vasospasm following subarachnoid hemorrhage causes severe ischemic neurologic deficits leading to permanent neurologic dysfunction or death. Reduced intravascular and perivascular nitric oxide (NO) availability is a primary pathophysiology of cerebral vasospasm. In this study, we evaluated NO-loaded echogenic liposomes (NO-ELIP) for ultrasound-facilitated NO delivery to produce vasodilation for treatment of vasospasm following subarachnoid hemorrhage. We investigated the vasodilative effects of NO released from NO-ELIP both ex vivo and in vivo. Liposomes containing phospholipids and cholesterol were prepared, and NO was encapsulated. The encapsulation and release of NO from NO-ELIP were determined by the syringe/vacuum method and ultrasound imaging. The ex vivo vasodilative effect of NO-ELIP was investigated using rabbit carotid arteries. Arterial vasodilation was clearly observed with NO-ELIP exposed to Doppler ultrasound whereas there was little vasodilative effect without exposure to Doppler ultrasound in the presence of red blood cells. Penetration of NO into the arterial wall was determined by fluorescent microscopy. The vasodilative effects of intravenously administered NO-ELIP in vivo were determined in a rat subarachnoid hemorrhage model. NO-ELIP with ultrasound activation over the carotid artery demonstrated effective arterial vasodilation in vivo resulting in improved neurologic function. This novel methodology for ultrasound-controlled delivery of NO has the potential for therapeutic treatment of vasospasm following subarachnoid hemorrhage. This ultrasound-controlled release strategy provides a new avenue for targeted bioactive gas and therapeutic delivery for improved stroke treatment.
doi:10.2147/IJN.S48856
PMCID: PMC3873237  PMID: 24379666
vasospasm; vasodilation; subarachnoid hemorrhage; nitric oxide; liposomes; ultrasound
17.  A Method to Co-encapsulate Gas and Drugs in Liposomes for Ultrasound-Controlled Drug Delivery 
Ultrasound in medicine & biology  2008;34(8):10.1016/j.ultrasmedbio.2008.01.005.
A novel method for the facile production of gas-containing liposomes with simultaneous drug encapsulation is described. Liposomes of phospholipid and cholesterol were prepared by conventional procedures of hydrating the lipid film, sonicating, freezing and thawing. A single, but critical modification of this procedure generates liposomes that contain gas (air, perfluorocarbon, argon); after sonication, the lipid is placed under pressure with the gas of interest. After equilibration, the sample is frozen. The pressure is then reduced to atmospheric and the suspension thawed. This procedure leads to entrapment of air in amounts up to 10% by volume by lipid dispersions at moderate (10mg/ml) concentrations of lipids. The amount of gas encapsulated increases with gas pressure and lipid concentration. Utilizing 0.32 M mannitol to provide an aqueous phase with physiological osmolarity, 1, 3, 6 or 9 atm of pressure was applied to 4 mg of lipid. This led to encapsulation of 10, 15, 20, and 30 μl of gas in a total of 400 μl of liposome dispersion (10mg lipids/ml), respectively. The mechanism for gas encapsulation presumably depends upon the fact that air (predominantly nitrogen and oxygen), like most solutes, dissolves poorly in ice and is excluded from the ice that forms during freezing. The excluded air then comes out of solution as air pockets that are stabilized in some form by a lipid coating. The presence of air in these preparations sensitizes them to ultrasound (1MHz, 8 W/cm2,10 second) such that up to half of their aqueous contents (which could be a water soluble drug) can be released by short (10 s) applications of ultrasound. Both diagnostic and therapeutic applications of the method are conceivable.
doi:10.1016/j.ultrasmedbio.2008.01.005
PMCID: PMC3809124  PMID: 18407399
Phospholipid freeze-thawing; controlled release; drug encapsulation; ultrasound
18.  THROMBOLYTIC EFFICACY OF TISSUE PLASMINOGEN ACTIVATOR-LOADED ECHOGENIC LIPOSOMES IN A RABBIT THROMBUS MODEL 
Thrombosis research  2011;130(4):629-635.
Introduction
Ultrasound (US)-enhanced thrombolytic treatment protocols currently in clinical trials for stroke applications involve systemic administration of tissue plasminogen activator (tPA; Alteplase), which carries a risk of adverse bleeding events. The present study aimed to compare the thrombolytic efficacy of a tPA-loaded echogenic liposome (ELIP) formulation with insonification protocols causing rapid fragmentation or acoustically-driven diffusion.
Materials and Methods
Thrombi were induced in the abdominal aortas of male New Zealand white rabbits (2–3 kg) using thrombin and a sclerosing agent (sodium ricinoleate) after aortic denudation with a balloon catheter. Thrombolytic and cavitation nucleation agents (200 μg of tPA alone, tPA mixed with 50 μg of a microbubble contrast agent, or tPA-loaded ELIP) were bolus-injected proximal to the clot through a catheter introduced into the abdominal aorta from the carotid artery. Clots were exposed to transabdominal color Doppler US (6 MHz) for 30 minutes at a low mechanical index (MI = 0.2) to induce sustained bubble activity (acoustically-driven diffusion), or for 2 minutes at an MI of 0.4 to cause ELIP fragmentation. Degree of recanalization was determined by Doppler flow measurements distal to the clots.
Results
All treatments showed thrombolysis, but tPA-loaded ELIP was the most efficacious regimen. Both US treatment strategies enhanced thrombolytic activity over control conditions.
Conclusions
The thrombolytic efficacy of tPA-loaded ELIP is comparable to other clinically described effective treatment protocols, while offering the advantages of US monitoring and enhanced thrombolysis from a site-specific delivery agent.
doi:10.1016/j.thromres.2011.11.010
PMCID: PMC3305817  PMID: 22133272
thrombolysis; ultrasound; plasminogen activators; thrombus
19.  Volumetric three-dimensional intravascular ultrasound visualization using shape-based nonlinear interpolation 
Background
Intravascular ultrasound (IVUS) is a standard imaging modality for identification of plaque formation in the coronary and peripheral arteries. Volumetric three-dimensional (3D) IVUS visualization provides a powerful tool to overcome the limited comprehensive information of 2D IVUS in terms of complex spatial distribution of arterial morphology and acoustic backscatter information. Conventional 3D IVUS techniques provide sub-optimal visualization of arterial morphology or lack acoustic information concerning arterial structure due in part to low quality of image data and the use of pixel-based IVUS image reconstruction algorithms. In the present study, we describe a novel volumetric 3D IVUS reconstruction algorithm to utilize IVUS signal data and a shape-based nonlinear interpolation.
Methods
We developed an algorithm to convert a series of IVUS signal data into a fully volumetric 3D visualization. Intermediary slices between original 2D IVUS slices were generated utilizing the natural cubic spline interpolation to consider the nonlinearity of both vascular structure geometry and acoustic backscatter in the arterial wall. We evaluated differences in image quality between the conventional pixel-based interpolation and the shape-based nonlinear interpolation methods using both virtual vascular phantom data and in vivo IVUS data of a porcine femoral artery. Volumetric 3D IVUS images of the arterial segment reconstructed using the two interpolation methods were compared.
Results
In vitro validation and in vivo comparative studies with the conventional pixel-based interpolation method demonstrated more robustness of the shape-based nonlinear interpolation algorithm in determining intermediary 2D IVUS slices. Our shape-based nonlinear interpolation demonstrated improved volumetric 3D visualization of the in vivo arterial structure and more realistic acoustic backscatter distribution compared to the conventional pixel-based interpolation method.
Conclusions
This novel 3D IVUS visualization strategy has the potential to improve ultrasound imaging of vascular structure information, particularly atheroma determination. Improved volumetric 3D visualization with accurate acoustic backscatter information can help with ultrasound molecular imaging of atheroma component distribution.
doi:10.1186/1475-925X-12-39
PMCID: PMC3651297  PMID: 23651569
Intravascular ultrasound; Shape-based interpolation; Three-dimensional reconstruction
20.  ELECTROCARDIOGRAPHIC ABNORMALITIES AMONG MEXICAN AMERICANS: CORRELATIONS WITH DIABETES, OBESITY, AND THE METABOLIC SYNDROME 
SUMMARY
BACKGROUND
Resting ischemic electrocardiographic abnormalities have been associated with cardiovascular mortality. Simple markers of abnormal autonomic tone have also been associated with diabetes, obesity, and the metabolic syndrome in some populations. Data on these electrocardiographic abnormalities and correlations with coronary risk factors are lacking among Mexican Americans wherein these conditions are prevalent.
OBJECTIVE
This study aimed to evaluate the prevalent resting electrocardiographic abnormalities among community-dwelling Mexican Americans, and correlate these findings with coronary risk factors, particularly diabetes, obesity, and the metabolic syndrome.
METHODS
Study subjects (n=1280) were drawn from the Cameron County Hispanic Cohort comprised of community-dwelling Mexican Americans living in Brownsville, Texas at the United States-Mexico border. Ischemic electrocardiographic abnormalities were defined as presence of ST/T wave abnormalities suggestive of ischemia, abnormal Q waves, and left bundle branch block. Parameters that reflect autonomic tone, such as heart rate-corrected QT interval and resting heart rate, were also measured.
RESULTS
Ischemic electrocardiographic abnormalities were more prevalent among older persons and those with hypertension, diabetes, obesity, and the metabolic syndrome. Subjects in the highest quartiles of QTc interval and resting heart rate were also more likely to be diabetic, hypertensive, obese, or have the metabolic syndrome.
CONCLUSIONS
Among Mexican Americans, persons with diabetes, obesity, and the metabolic syndrome were more likely to have ischemic electrocardiographic abnormalities, longer QTc intervals, and higher resting heart rates. A resting electrocardiogram can play a complementary role in the comprehensive evaluation of cardiovascular risk in this minority population.
doi:10.4236/wjcd.2012.22009
PMCID: PMC3600844  PMID: 23515880
Electrocardiogram; Coronary Risk Factors; Minority; Health Disparity
21.  Structural Insight into the Role of the Human Melanocortin 3 Receptor Cysteine Residues on Receptor Function 
Peptides  2011;32(12):2377-2383.
Melanocortin-3 receptor (MC3R), expressed in the hypothalamus and limbic systems of the brain, as well as by peripheral sites, plays an important role in the regulation of energy homeostasis and other physiological functions. Past work shows that MC3R-deficiency resulted in fat mass increase, feeding efficiency increase, hyperleptinemia and mild hyperinsulinemia in mice and human. MC3R belongs to G-protein coupled receptor (GPCR) family and many studies indicate that some cysteine residues in GPCR play key roles in maintaining receptor tertiary structure and function. In this study, we examined the role of cysteine residues in MC3R on receptor function. Human MC3R (hMC3R) has eighteen cysteine residues where they are located in the extracellular loops (ELs), the transmembrane domains (TMs) and the intracellular loops (ILs). We replaced these cysteines with serine and expressed these receptors in HEK-293 cells which lack endogenous MC3R. Our results indicate that five cysteines in eighteen of the hMC3R are important for hMC3R function. Mutations, C305S, C311S, and C313S in EL3, resulted in significant decrease in receptor expression and receptor function while two other mutations C115S and C162S in TM3 significantly decreased NDP-MSH binding affinity and potency. These results suggest that extracellular cysteine residue 305, 311 and 313 are crucial for receptor expression and the transmembrane cysteine residue, C115 and 162 are important for ligand binding and signaling. These findings provide important insights into the importance of cysteine residues of hMC3R on receptor tertiary structure and function.
doi:10.1016/j.peptides.2011.09.024
PMCID: PMC3242444  PMID: 22079958
MSH; MC3R; cysteine; MCR; GPCR
22.  Clinical Status and Cardiovascular Risk Profile of Adults with a History of Juvenile Dermatomyositis 
The Journal of pediatrics  2011;159(5):795-801.
Objective
A pilot study of adults who had onset of juvenile dermatomyositis (JDM) in childhood, before current therapeutic approaches, to characterize JDM symptoms and subclinical cardiovascular disease.
Study design
Eight adults who had JDM assessed for disease activity and 8 healthy adults (cardiovascular disease controls) were tested for carotid intima media thickness and brachial arterial reactivity. Adults who had JDM and 16 age-, sex-, and body mass index-matched healthy metabolic controls were evaluated for body composition, blood pressure, fasting glucose, lipids, insulin resistance, leptin, adiponectin, proinflammatory oxidized high-density lipoprotein (HDL), and nail-fold capillary end row loops.
Results
Adults with a history of JDM, median age 38 years (24–44 years) enrolled a median 29 years (9–38 years) after disease onset, had elevated disease activity scores, skin (7/8), muscle (4/8), and creatine phosphokinase (2/8). Compared with cardiovascular disease controls, adults who had JDM were younger, had lower body mass index and HDL cholesterol (P = .002), and increased intima media thickness (P = .015) and their brachial arterial reactivity suggested impairment of endothelial cell function. Compared with metabolic controls, adults who had JDM had higher systolic and diastolic blood pressure, P = .048, P = .002, respectively; lower adiponectin (P = .03); less upper arm fat (P = .008); HDL associated with end row loops loss (r = −0.838, P = .009); and increased proinflammatory oxidized HDL (P = .0037).
Conclusion
Adults who had JDM, 29 years after disease onset, had progressive disease and increased cardiovascular risk factors.
doi:10.1016/j.jpeds.2011.05.015
PMCID: PMC3193560  PMID: 21784434
23.  Ultrasound-Enhanced Thrombolytic Effect of Tissue Plasminogen Activator–Loaded Echogenic Liposomes in an In Vivo Rabbit Aorta Thrombus Model—Brief Report 
Objective
Ultrasound enhances thrombolysis when combined with a thrombolytic and a contrast agent. This study aimed to evaluate the thrombolytic effect of our tissue plasminogen activator (tPA)–loaded echogenic liposomes (ELIP) in an in vivo clot model, with and without ultrasound treatment.
Methods and Results
The femoral arteries of New Zealand White rabbits (n=4 per group) were cannulated. The abdominal aortas were denuded, and thrombi were created using a solution of sodium ricinoleate plus thrombin. Rabbits were then randomly selected to receive tPA-loaded ELIP (200 μg of tPA/5 mg of lipid) or empty ELIP with or without pulsed (color) Doppler ultrasound (5.7 MHz) for 2 minutes. Thrombus was imaged and echogenicity analyzed before and after ELIP injection. Blood flow velocities were measured at baseline, after clot formation, and serially after treatment up to 15 minutes. tPA-loaded ELIP highlighted thrombus in the abdominal aorta more effectively than empty ELIP (P<0.05). Ultrasound enhanced the thrombolytic effect of tPA-loaded ELIP, resulting in earlier and more complete recanalization rates (P<0.001).
Conclusion
This study demonstrates effective highlighting of clots and thrombolytic effect of tPA-loaded ELIP in an in vivo rabbit aorta clot model. Doppler ultrasound treatment enhances this thrombolytic effect, resulting in earlier and more complete recanalization rates.
doi:10.1161/ATVBAHA.111.225938
PMCID: PMC3287366  PMID: 21441137
arterial thrombosis; contrast echo; Doppler ultrasound; echocardiography; thrombolysis
24.  TREADMILL EXERCISE AND RESISTANCE TRAINING IN PATIENTS WITH PERIPHERAL ARTERIAL DISEASE WITH AND WITHOUT INTERMITTENT CLAUDICATION: A RANDOMIZED CONTROLLED TRIAL 
Jama  2009;301(2):165-174.
Background
The role of strength training in peripheral arterial disease (PAD) is unclear. Benefits of supervised treadmill exercise in PAD patients without intermittent claudication (IC) are not established.
Objective
To determine whether supervised treadmill exercise and lower extremity resistance training, respectively, improve functional performance compared to a control group in PAD persons with and without IC.
Design
Randomized controlled clinical trial performed between 4/1/04 and 8/19/08.
Participants
156 people with PAD (ankle brachial index ≤ 0.95), including 81.4% without IC.
Measurements
Primary outcomes were six-minute walk performance and the short physical performance battery (SPPB). Additional outcomes were brachial artery flow-mediated dilation (FMD), treadmill walking performance, the Walking Impairment Questionnaire (WIQ), and the Short-Form 36 Physical Functioning score (SF-36 PF).
Interventions
Three parallel arms: supervised treadmill exercise, supervised lower extremity resistance training, and a control group.
Results
Compared to control, the treadmill exercise group increased six-minute walk distance (+35.9 meters, 95% confidence interval (CI), +15.3 to +56.5; P <0.001), while the resistance trained group did not improve (+12.4 meters, 95% CI, −8.42 to +33.3; P=0.24). Neither exercise group improved the SPPB. Compared to control, treadmill exercise improved brachial artery FMD (+1.53%, 95% CI, +0.35 to +2.70, P=0.018), time on treadmill (+3.44 minutes, 95% CI, +2.05 to +4.84; P<0.001), the WIQ distance score P=0.015), and the SF-36 PF score (P=0.02). Compared to control, resistance training improved time on treadmill (+1.98 minutes, 95% CI, +0.56 to +3.39; P=0.007), the WIQ distance score (P=0.02), the WIQ stair climbing score (P=0.02), and the SF-36 PF score (P=0.04).
Conclusion
Supervised treadmill exercise improved six-minute walk distance, treadmill walking performance, brachial artery FMD, and quality of life, but not the SPPB, in PAD participants with and without classic IC symptoms. Resistance training improved treadmill walking performance, quality of life, and stair climbing ability in patients with PAD.
doi:10.1001/jama.2008.962
PMCID: PMC3268032  PMID: 19141764
25.  Key amino acid residues in the Melanocortin-4 Receptor for nonpeptide THIQ Specific Binding and Signaling 
Regulatory peptides  2009;155(1-3):46-54.
Melanocortin 4 receptor (MC4R) plays an important role in the regulation of food intake and glucose homeostasis. Synthetic nonpeptide compound N- (3R)-1 4-tetrahydroisoquinolinium-3-ylcarbonyl -(1R)-1-(4-chlorobenzyl)-2- 4-cyclohexyl-4-(1H-1,2,4-triazol-1-ylmethyl)piperidin-1-yl -2-oxoethylamine (THIQ) is a potent agonist at MC4R but not at hMC2R. In this study, we utilized two approaches (chimeric receptor and site-directed mutagenesis) to narrow down the key amino acid residues of MC4R responsible for THIQ binding and signaling. Cassette substitutions of the second, third, fourth, fifth, and sixth transmembrane regions (TMs) of the human MC4R (hMC4R) with the homologous regions of hMC2R were constructed. Our results indicate that the cassette substitutions of these TMs of the hMC4R with homologous regions of the hMC2R did not significantly alter THIQ binding affinity and potency except the substitution of the hMC4R TM3, suggesting that the conserved amino acid residues in these TMs of the hMC4R are main potential candidates for THIQ binding and signaling while non conserved residues in TM3 of MC4R may also be involved. Nineteen MC4R mutants were then created, including 13 conserved amino acid residues and 6 non-conserved amino acid residues. Our results indicate that seven conserved residue [E100 (TM2), D122 (TM3), D126 (TM3), F254 (TM6), W258 (TM6), F261 (TM6), H264 (TM6)] are important for THIQ binding and three non-conserved residues [N123 (TM3), I129 (TM3) and S131 (TM3)] are involved in THIQ selectivity. In conclusion, our results suggest that THIQ utilize both conserved and non-conserved amino acid residues for binding and signaling at hMC4R and non conserved residues may be responsible for MC4R selectivity.
doi:10.1016/j.regpep.2009.03.006
PMCID: PMC3216638  PMID: 19303903

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