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Biomedical subjects

Jonathan R Lindner

Publications and source records attributed to Jonathan R Lindner.

At least 37 records · Page 2Linked to original sources
PubMed2005

Effect of microbubble exposure to ultrasound on quantitation of myocardial perfusion.

BACKGROUND: The purpose of this study was to determine whether acoustic disruption of microbubbles in the left ventricular (LV) cavity prior to entry in the coronary circulation or their gradual destruction in the myocardium during myocardial contrast echocardiography (MCE) affects quantitative parameters of myocardial perfusion. METHODS: MCE was performed in 12 open chest dogs with both intermittent high-power imaging (IHPI) and real-time low-power imaging (RLPI). To assess the affects of microbubble destruction in the LV cavity, MCE parameters of myocardial perfusion were compared for imaging planes that included versus avoided the LV cavity. To assess the effects of gradual disruption of microbubbles in the microcirculation during RLPI, MCE parameters from frames acquired continuously were compared to that from acquiring only end-systolic frames. RESULTS: Destruction of microbubbles in the LV cavity did not alter perfusion data for either form of imaging unless RLPI was performed using long (6-frame) destructive pulse sequences. With RLPI, a gradual decay in microbubble signal occurred during their myocardial transit, the degree of which was related to the acoustic power. Signal decay during microbubble transit resulted in an overestimation of the microvascular blood velocity (beta-value) and an underestimation of the microvascular blood volume (A-value). CONCLUSIONS: MCE parameters of perfusion at low power can be significantly altered by microbubble destruction in the LV cavity and in the myocardial microcirculation during RLPI. Short microbubble destruction pulse sequences and imaging only at end-systole can reduce these effects.

Analysis of Variance↗
PubMed2005

Contrast ultrasound assessment of angiogenesis by perfusion and molecular imaging.

There is great interest in the development of noninvasive methods for imaging angiogenic responses. Strategies for assessing angiogenesis have primarily relied on measuring perfusion-related characteristics, such as total blood flow or microvascular volume, or detecting abnormal vascular permeability. Techniques are now being developed that are capable of imaging the cellular and molecular alterations associated with neovessel growth and development. Contrast-enhanced ultrasound is a noninvasive imaging method that has great promise in terms of its ability to characterize changes in either microvascular perfusion or vascular endothelial phenotype. Techniques for evaluating perfusion by contrast ultrasound rely on the measurement of both microvascular blood volume and velocity. Accordingly, this technique can provide unique information on abnormalities in microvascular density and perfusion associated with adaptive and pathologic angiogenesis. Contrast ultrasound methods for imaging vascular phenotype during angiogenesis have also been developed by surface conjugation of ligands against endothelial cell markers of vascular development such as alpha(v)-integrins and growth factor receptors. Due to the high resolution of the technique and the rapid imaging protocols, there is great enthusiasm for the continued development and testing of these techniques. For perfusion imaging, translation to the clinical setting is already taking place, whereas molecular imaging faces many more hurdles in terms of safety and testing efficacy.

Animals↗
PubMed2004

Binding and detachment dynamics of microbubbles targeted to P-selectin under controlled shear flow.

This study was performed to assess the binding kinetics of a targeted microbubble contrast agent exposed to shear stress. An ultrasound contrast targeted to P-selectin was designed by conjugating monoclonal antibodies against murine P-selectin (RB40.34) to the lipid monolayer shell of the microbubble using poly(ethylene glycol)-biotin-streptavidin. The attachment and detachment of targeted microbubbles to P-selectin immobilized on a culture dish were assessed in a parallel-plate flow chamber. Targeted microbubbles (5 x 10(6) particles/ml) drawn through the flow chamber coated with P-selectin (109 sites/microm(2)) at a shear stress of 0.3 dyn/cm(2) accumulated at a rate of 565 mm(-2) min(-1). Attachment rates increased at higher plate surface densities of P-selectin, and microbubble detachment was reduced. Accumulation rate first increased with shear stress, reached a maximum at approximately 0.6 dyn/cm(2) and then decreased. Control experiments on a plate that lacked P-selectin, or was blocked with mAb RB40.34, resulted in minimal bubble attachment. Microbubble detachment was tested by ramping up shear stress at 30-s intervals. Half-maximal detachment was reached at 34 dyn/cm(2). Overall, accumulation and retention of targeted ultrasound contrast agents is possible under physiologic flow conditions and is strongly influenced by shear stress and surface density of the target receptor.

Antibodies, Monoclonal↗
PubMed2004

Contrast echocardiography: clinical utility for the evaluation of left ventricular systolic function.

Despite continued improvements in imaging technology, transthoracic echocardiography does not reliably provide images adequate for interpretation in all patients. In these patients, the administration of ultrasound contrast agents can markedly enhance the diagnostic utility of the test. Contrast echocardiography relies on the ultrasound detection of contrast agents composed of encapsulated microbubbles that are generally smaller than red blood cells. Intravenous administration of microbubble contrast agents results in left ventricular opacification and facilitates delineation of the endocardial border. This procedure has been shown to consistently increase the number of myocardial segments that can be interpreted, to improve accuracy of assessing regional and global left ventricular function, to decrease interinterpreter variability, to increase interpreter confidence, and to be a cost-effective strategy. Accordingly, patient selection for contrast echocardiography should be based not only on adequacy of the baseline images, but also on the clinical question being asked.

Chemistry, Pharmaceutical↗
PubMed2004

Increased prevalence of regurgitant valvular heart disease in acromegaly.

Cardiac involvement is common in acromegaly, but the prevalence of valvular abnormalities in patients with acromegaly has not been documented and is the topic of this study. In a prospective study design, 40 consecutive patients with acromegaly and 120 control subjects (matched for age, sex, hypertension, and left ventricular systolic function) were studied. All patients and controls were evaluated using conventional two-dimensional and Doppler echocardiography. Significant valve disease was more prevalent in acromegalics compared with controls (22% vs. 6.7%, respectively; P = 0.005). Aortic valve regurgitation (>/=>trace severity) was present in 30% of patients vs. 7% of controls (P < 0.001), and mitral regurgitation (>/=moderate severity) was absent in controls but present in 5% of acromegalics (P = 0.014 vs. controls). Binary logistic regression analysis showed a significant impact only for disease duration on valvular disease, with an odds ratio of 1.19 (95% confidence interval, 1.028-1.376; P = 0.019). Acromegaly is associated with an increased prevalence of regurgitant valvular heart disease. This is dependent on the duration of exposure to increased GH concentrations, with a 19% increase in odds per year. This increased prevalence of occult valvular disease indicates that these patients require appropriate follow-up care and monitoring, especially patients with inadequate control of GH overproduction.

Acromegaly↗
PubMed2004

Microvascular recruitment is an early insulin effect that regulates skeletal muscle glucose uptake in vivo.

Insulin increases glucose disposal into muscle. In addition, in vivo insulin elicits distinct nitric oxide synthase-dependent vascular responses to increase total skeletal muscle blood flow and to recruit muscle capillaries (by relaxing resistance and terminal arterioles, respectively). In the current study, we compared the temporal sequence of vascular and metabolic responses to a 30-min physiological infusion of insulin (3 mU. min(-1). kg(-1), euglycemic clamp) or saline in rat skeletal muscle in vivo. We used contrast-enhanced ultrasound to continuously quantify microvascular volume. Insulin recruited microvasculature within 5-10 min (P < 0.05), and this preceded both activation of insulin-signaling pathways and increases in glucose disposal in muscle, as well as changes in total leg blood flow. Moreover, l-NAME (N(omega)-nitro-l-arginine-methyl ester), a specific inhibitor of nitric oxide synthase, blocked this early microvascular recruitment (P < 0.05) and at least partially inhibited early increases in muscle glucose uptake (P < 0.05). We conclude that insulin rapidly recruits skeletal muscle capillaries in vivo by a nitric oxide-dependent action, and the increase in capillary recruitment may contribute to the subsequent glucose uptake.

Animals↗
PubMed2003

Imaging tumor angiogenesis with contrast ultrasound and microbubbles targeted to alpha(v)beta3.

BACKGROUND: Angiogenesis is a critical determinant of tumor growth and metastasis. We hypothesized that contrast-enhanced ultrasound (CEU) with microbubbles targeted to alpha(v)-integrins expressed on the neovascular endothelium could be used to image angiogenesis. METHODS AND RESULTS: Malignant gliomas were produced in 14 athymic rats by intracerebral implantation of U87MG human glioma cells. On day 14 or day 28 after implantation, CEU was performed with microbubbles targeted to alpha(v)beta3 by surface conjugation of echistatin. CEU perfusion imaging with nontargeted microbubbles was used to derive tumor microvascular blood volume and blood velocity. Vascular alpha(v)-integrin expression was assessed by immunohistochemistry, and microbubble adhesion was characterized by confocal microscopy. Mean tumor size increased markedly from 14 to 28 days (2+/-1 versus 35+/-14 mm2, P<0.001). Tumor blood volume increased by approximately 35% from day 14 to day 28, whereas microvascular blood velocity decreased, especially at the central portions of the tumors. On confocal microscopy, alpha(v)beta3-targeted but not control microbubbles were retained preferentially within the tumor microcirculation. CEU signal from alpha(v)beta3-targeted microbubbles in tumors increased significantly from 14 to 28 days (1.7+/-0.4 versus 3.3+/-1.0 relative units, P<0.05). CEU signal from alpha(v)beta3-targeted microbubbles was greatest at the periphery of tumors, where alpha(v)-integrin expression was most prominent, and correlated well with tumor microvascular blood volume (r=0.86). CONCLUSIONS: CEU with microbubbles targeted to alpha(v)beta3 can noninvasively detect early tumor angiogenesis. This technique, when coupled with changes in blood volume and velocity, may provide insights into the biology of tumor angiogenesis and be used for diagnostic applications.

Animals↗
PubMed2003

Detection of myocardial viability by contrast echocardiography in acute infarction predicts recovery of resting function and contractile reserve.

OBJECTIVES: We sought to determine whether myocardial contrast echocardiography (MCE) performed before and early after primary coronary stenting (PCS) in patients with acute myocardial infarction (AMI) could predict recovery of resting left ventricular systolic function and contractile reserve. BACKGROUND: Myocardial contrast echocardiography can be used to assess perfusion within the risk area before PCS and the extent of necrosis soon after PCS. METHODS: In 30 patients with AMI, MCE and two-dimensional echocardiography were performed before PCS and 3 to 5 days and 4 weeks after PCS. Contractile reserve was assessed by dobutamine echocardiography at four weeks in patients with persistent severe wall-motion abnormalities. RESULTS: Of segments without perfusion at 3 to 5 days, 95% had severe hypokinesis to akinesis at 4 weeks. Of segments with normal perfusion at 3 to 5 days, 90% had normal wall motion or mild hypokinesis at 4 weeks, whereas those with partial perfusion at 3 to 5 days were evenly divided between normal wall motion, hypokinesis, and akinesis. In segments with persistent severe wall-motion abnormalities at four weeks, contractile reserve was found in >80% of segments with perfusion, compared with only 10% of segments without detectable perfusion (p < 0.01). The presence of myocardial perfusion by MCE before PCS was associated with maintained or improved perfusion at 3 to 5 days and eventual recovery of resting wall motion. CONCLUSIONS: Myocardial contrast echocardiography performed early after PCS provides information on the extent of infarction, and hence the likelihood for recovery of resting systolic function or contractile reserve. The presence of perfusion before PCS, from either collateral or antegrade flow, predicts the maintenance of perfusion and recovery of systolic function.

Aged↗
PubMed2003

Noninvasive assessment of angiogenesis by ultrasound and microbubbles targeted to alpha(v)-integrins.

BACKGROUND: Noninvasive methods for characterizing neovessel formation during angiogenesis are currently lacking. We hypothesized that angiogenesis could be imaged with the use of contrast-enhanced ultrasound (CEU) with microbubbles targeted to alpha(v)-integrins. METHODS AND RESULTS: Microbubbles targeted to alpha(v)-integrins were prepared by conjugating echistatin (MB(E)) or monoclonal antibody against murine alpha(v) (MB(alpha)) to their surface. Control microbubbles (MB(c)) were also prepared. The microvascular behavior of these microbubbles was assessed by intravital microscopy of the cremaster muscle in mice treated for 4 days with sustained-release FGF-2. Microvascular retention was much greater (P<0.01) for MB(E) (11+/-6 mm(-3)) and MB(alpha) (10+/-7 mm(-3)) than that for MB(c) (1+/-1 mm(-3)). Retained MB(E) and MB(alpha) attached directly to the microvascular endothelial surface. Microbubble retention in 4 control mice was minimal. Subcutaneous matrigel plugs enriched with FGF-2 were created in 12 mice and studied 10 days later. Neovessels within the matrigel stained positive for alpha(v)-integrins. CEU demonstrated greater (P<0.01) acoustic intensity for MB(E) (16.0+/-5.9 U) and MB(alpha) (17.0+/-5.5 U) compared with MB(c) (5.8+/-2.6 U). The signal from targeted microbubbles (MB(E) and MB(alpha)) correlated well (r=0.90) with the matrigel blood volume determined by CEU perfusion imaging. CONCLUSIONS: CEU with microbubbles targeted for alpha(v)-integrins may provide a noninvasive method for assessing therapeutic angiogenesis.

Animals↗
PubMed2003

Targeted tissue transfection with ultrasound destruction of plasmid-bearing cationic microbubbles.

The aim of this study was to assess the relative efficacy and mechanism of gene transfection by ultrasound (US) destruction of plasmid-bearing microbubbles. Luciferase reporter plasmid was charge-coupled to cationic lipid microbubbles. Rat hindlimb skeletal muscle was exposed to intermittent high-power US during dose-adjusted intra-arterial (IA) or IV administration of plasmid-bearing microbubbles via the carotid artery or jugular vein, respectively. At 4 days, luciferase activity in US-exposed skeletal muscle was 200-fold greater with IA than with IV administration of plasmid-bearing microbubbles, and was similar to transfection achieved by IM injection of plasmid (positive control). No transfection occurred with US and IA injection of plasmid alone. Intravital microscopy of the cremaster muscle in mice following administration of microbubbles and US exposure demonstrated perivascular deposition of fluorescent plasmid, the extent of which was twofold greater for IA compared to IV injection. Electron microscopy demonstrated a greater extent of myocellular microporations in US-exposed muscle after IA injection of microbubbles. We conclude that muscle transfection by US destruction of plasmid-bearing cationic microbubbles is amplified by IA, rather than IV, injection of microbubbles due to greater extravascular deposition of plasmid and to greater extent of myocellular microporation.

Animals↗
PubMed2002

Detection of inflamed plaques with contrast ultrasound.

Inflammatory cell infiltration is an important factor in the progression and instability of atherosclerotic plaques. There has been great interest in the development of noninvasive methods that can assess these inflammatory processes to detect vulnerable plaques or patients, and to assess novel therapies. This review focuses on some recent advances in contrast-enhanced ultrasound (CEU), which can potentially be used for imaging plaque inflammation. These methods rely on ultrasound detection of microbubble contrast agents that are targeted to inflamed tissue. For this purpose, novel microbubbles have been formulated that are targeted either to activated leukocytes adherent to inflamed endothelium, or to endothelial cell adhesion molecules (p-selectin, intercellular adhesion molecule-1, alpha(v)beta(3)) expressed on the plaque surface or within plaque neovessels. Microbubble targeting has been achieved by modifications of shell components or conjugation of specific ligands to the shell surface. Although application of targeted CEU for imaging inflamed plaques is at the early stages of development, it is potentially easily translatable to routine clinical practice because the technique is relatively inexpensive, portable, and uses technology that already is used widely to evaluate vascular disease.

Animals↗
PubMed2002

Evolving applications for contrast ultrasound.

Future clinical applications for contrast-enhanced ultrasound will likely expand beyond perfusion imaging. There has been considerable progress in the past few years in the development of site-targeted microbubbles, such that instead of passing unimpeded through the circulation, they attach to specific markers of disease. Accumulation of targeted microbubbles in diseased tissue can allow noninvasive ultrasound imaging of molecular and cellular processes. In this review, the strategies for designing site-targeted microbubbles and the early experience with molecular imaging will be discussed. The use of microbubbles and ultrasound for therapeutic purposes is also just now being realized. A promising development is the ability to package either drugs or genes into or onto microbubble contrast agents. Conceptually, ultrasound-mediated destruction of microbubble vehicles will provide focal release in a tissue of interest and may facilitate extravascular sojourn of the therapeutic agent. Preliminary experience using microbubbles as vectors for gene delivery is also reviewed.

Antibodies, Monoclonal↗
PubMed2002

Influence of microbubble surface charge on capillary transit and myocardial contrast enhancement.

OBJECTIVE: The goal of the study was to determine whether microbubble charge influences the microvascular retention of microbubble contrast agents. BACKGROUND: Interactions between serum proteins and lipid membranes are greater with anionic compared with neutral membranes. These interactions may influence the microvascular behavior of anionic lipid microbubbles. METHODS: Intravital microscopy of the cremaster muscle was performed in six wild-type mice and three C3-deficient mice during intravenous injection of lipid-shelled microbubbles with either a neutral or a negative charge. Both agents were prepared with and without a protective surface layer of polyethyleneglycol (PEG). Complement attachment to microbubbles was assessed by flow cytometry with flourescein isothiocyanate-conjugated anti-C3b monoclonal antibody. Myocardial contrast echocardiography was performed in six dogs to assess pulmonary and myocardial retention of microbubbles. RESULTS: Size-independent capillary retention of microbubbles, occurring for a few seconds to >10 min, was frequently observed with anionic, but rarely with neutral, microbubbles (4.3 +/- 0.3 vs. 0.4 +/- 0.1 mm(-3), p < 0.01). Anionic microbubble retention was reduced by 70% by surface PEG and was also markedly reduced in C3-deficient mice (1.4 +/- 0.1 mm(-3), p < 0.05 vs. wild-type). Flow cytometry demonstrated complement attachment to only anionic microbubbles. Contrast echocardiography indicated both pulmonary and myocardial retention of only anionic microbubbles, the latter evidenced by persistent opacification >10 min after bolus intravenous injection. CONCLUSIONS: Lipid microbubbles with a net negative charge can be retained within capillaries via complement-mediated attachment to endothelium. This property may be useful for the development of ultrasound contrast agents that can be imaged late after venous injection.

Animals↗
PubMed2002

Assessment of myocardial inflammation produced by experimental coronary occlusion and reperfusion with 99mTc-RP517, a new leukotriene B4 receptor antagonist that preferentially labels neutrophils in vivo.

BACKGROUND: 99mTc-RP517 is a new leukotriene B4 (LTB4) receptor antagonist developed for imaging acute inflammation or infection. A unique property of 99mTc-RP517 is its ability to label white blood cells in vivo after intravenous injection. The goals of this study were to determine relative 99mTc-RP517 binding to human leukocyte subtypes and the 99mTc-RP517 uptake pattern in canine myocardium where inflammation was induced by either coronary occlusion and reperfusion or tumor necrosis factor alpha (TNFalpha) injection. METHODS AND RESULTS: Fluorescence-activated cell sorter analysis was performed on whole human blood (n=2) and isolated neutrophils (n= 4) with a fluorescent analog of 99mTc-RP517, [F]-RP517. In whole blood, [F]-RP517 (500 nmol/L) preferentially labeled neutrophils. On isolated neutrophils, [F]-RP517 (10 nmol/L) binding was inhibited by 44% when LTB4 (400 nmol/L) was added. 99mTc-RP517 was injected intravenously in anesthetized, open-chest dogs before coronary occlusion (90 minutes) and reperfusion (120 minutes) (n=9) or before intramyocardial TNFalpha injection (n=3). Ex vivo images of heart slices were acquired. The left ventricle was divided into 72 segments for flow and 99mTc-RP517 uptake analysis. There was an inverse exponential relationship between 99mTc-RP517 uptake and occlusion flow (r=0.73). In the same 15 segments, 99mTc-RP517 uptake was highly correlated with the neutrophil enzyme myeloperoxidase (r=0.91). Ex vivo images revealed tracer uptake in the reperfused area (ischemic to normal count ratio=2.7+/-0.2). CONCLUSIONS: RP517 binds to the neutrophil LTB4 receptor after intravenous injection. After reperfusion, 99mTc-RP517 uptake correlated with myeloperoxidase and was observed on ex vivo images, indicating that this tracer may have potential as an inflammation-imaging agent.

Animals↗