Acoustic Activation Imaging With Intravenous Perfluoropropane Nanodroplets Results in Selective Bioactivation of the Risk Area.

BACKGROUND: Acoustically activatable perfluoropropane droplets (PD) can be formulated from commercially available microbubble preparations. Diagnostic transthoracic ultrasound frequencies have resulted in acoustic activation (AA) predominately within myocardial infarct zones (IZ). OBJECTIVE: We hypothesized that the AA area following acute coronary ischemia/reperfusion (I/R) would selectively enhance the developing scar zone, and target bioeffects specifically to this region. METHODS: We administered intravenous PD in 36 rats and 20 pigs at various stages of myocardial scar formation (30 minutes, 1 day, and 7 days post I/R) to determine what effect infarct age had on the AA within the IZ. This was correlated with histology, myeloperoxidase activity, and tissue nitrite activity. RESULTS: The degree of AA within the IZ in rats was not associated with collagen content, neutrophil infiltration, or infarct age. AA within 24 hours of I/R was associated with increased nitric oxide utilization selectively within the IZ (P < .05 compared with remote zone). The spatial extent of AA in pigs correlated with infarct size only when performed before sacrifice at 7 days (r = .74, P < .01). CONCLUSIONS: Acoustic activation of intravenous PD enhances the developing scar zone following I/R, and results in selective tissue nitric oxide utilization.

Endovascular Ultrasound Renal Denervation to Treat Hypertension: The RADIANCE II Randomized Clinical Trial.

Importance: Two initial sham-controlled trials demonstrated that ultrasound renal denervation decreases blood pressure (BP) in patients with mild to moderate hypertension and hypertension that is resistant to treatment. Objective: To study the efficacy and safety of ultrasound renal denervation without the confounding influence of antihypertensive medications in patients with hypertension. Design, Setting, and Participants: Sham-controlled, randomized clinical trial with patients and outcome assessors blinded to treatment assignment that was conducted between January 14, 2019, and March 25, 2022, at 37 centers in the US and 24 centers in Europe, with randomization stratified by center. Patients aged 18 years to 75 years with hypertension (seated office systolic BP [SBP] ≥140 mm Hg and diastolic BP [DBP] ≥90 mm Hg despite taking up to 2 antihypertensive medications) were eligible if they had an ambulatory SBP/DBP of 135/85 mm Hg or greater and an SBP/DBP less than 170/105 mm Hg after a 4-week washout of their medications. Patients with an estimated glomerular filtration rate of 40 mL/min/1.73 m2 or greater and with suitable renal artery anatomy were randomized 2:1 to undergo ultrasound renal denervation or a sham procedure. Patients were to abstain from antihypertensive medications until the 2-month follow-up unless prespecified BP criteria were exceeded and were associated with clinical symptoms. Interventions: Ultrasound renal denervation vs a sham procedure. Main Outcomes and Measures: The primary efficacy outcome was the mean change in daytime ambulatory SBP at 2 months. The primary safety composite outcome of major adverse events included death, kidney failure, and major embolic, vascular, cardiovascular, cerebrovascular, and hypertensive events at 30 days and renal artery stenosis greater than 70% detected at 6 months. The secondary outcomes included mean change in 24-hour ambulatory SBP, home SBP, office SBP, and all DBP parameters at 2 months. Results: Among 1038 eligible patients, 150 were randomized to ultrasound renal denervation and 74 to a sham procedure (mean age, 55 years [SD, 9.3 years]; 28.6% female; and 16.1% self-identified as Black or African American). The reduction in daytime ambulatory SBP was greater with ultrasound renal denervation (mean, -7.9 mm Hg [SD, 11.6 mm Hg]) vs the sham procedure (mean, -1.8 mm Hg [SD, 9.5 mm Hg]) (baseline-adjusted between-group difference, -6.3 mm Hg [95% CI, -9.3 to -3.2 mm Hg], P < .001), with a consistent effect of ultrasound renal denervation throughout the 24-hour circadian cycle. Among 7 secondary BP outcomes, 6 were significantly improved with ultrasound renal denervation vs the sham procedure. No major adverse events were reported in either group. Conclusions and Relevance: In patients with hypertension, ultrasound renal denervation reduced daytime ambulatory SBP at 2 months in the absence of antihypertensive medications vs a sham procedure without postprocedural major adverse events. Trial Registration: ClinicalTrials.gov Identifier: NCT03614260.

Role of Internal Jugular Venous Ultrasound in suspected or confirmed Heart Failure: A Systematic Review.

BACKGROUND: Few data are available on the use of internal jugular vein (IJV) ultrasound parameters to assess central venous pressure and clinical outcomes among patients with suspected or confirmed heart failure (HF). METHODS: We performed electronic searches on PubMed, The Cochrane Library, EMBASE, EBSCO, Web of Science, and CINAHL databases from the inception through January 9, 2021, to identify studies evaluating the accuracy and reliability of the IJV ultrasound parameters and exploring its correlation with central venous pressure and clinical outcomes in adult patients with suspected or confirmed acutely decompensated HF. The studies' report quality was assessed by Quality Assessment of Diagnostic Accuracy Studies-2 scale. RESULTS: A total of 11 studies were eligible for final analysis (n = 1481 patients with HF). The studies were segregated into 3 groups: (1) the evaluation of patients presenting to the emergency department with dyspnea, (2) the evaluation of patients presenting to the HF clinic for follow-up, and (3) the evaluation of hospitalized patients with acutely decompensated HF or undergoing right heart catheterization. US parameters included IJV height, IJV diameter, IJV diameter ratio, IJV cross-sectional area, respiratory compressibility index, and compression compressibility index. CONCLUSIONS: The findings of this systematic review suggest a significant role for ultrasound interrogation of the IJV in evaluation of patients in the emergency department presenting with dyspnea, in the outpatient clinic for poor clinical outcomes in HF, and in determining the timing of discharge for patients admitted with acutely decompensated HF. Further studies are warranted for testing the reliability of the reported ultrasound indices.

Atherosclerotic renal artery stenosis as a cause for hypertension in an adolescent patient.

BACKGROUND: Atherosclerosis causing renal artery stenosis (RAS) is one of the most common secondary causes of hypertension in adults, but is rare in children. CASE-DIAGNOSIS/TREATMENT: RAS associated with coronary artery stenosis was diagnosed in a teenage patient who presented with intermittent chest pain and elevated blood pressures for 6 years. The diagnosis of RAS was suspected after physical examination revealed an abdominal bruit. Renal ultrasound with Doppler revealed normal appearing kidneys with high velocity in the aorta and renal arteries. Computed tomography angiography (CTA) of the chest and abdomen demonstrated generalized calcified atherosclerotic narrowing of the arteries including the renal, celiac, superior mesenteric and coronary arteries in the setting of hyperlipidemia. The lipid panel revealed hypercholesterolemia with elevated serum plant sterol concentrations, suggesting the diagnosis of sitosterolemia. Cardiac catheterization demonstrated left anterior descending artery and left circumflex artery stenosis, which required bypass of the left anterior descending artery and stenting of the left circumflex artery. Aggressive lipid control was recommended and he was treated medically with a beta-blocker, low-dose angiotensin-converting enzyme inhibitor, aspirin, statin, and clopidogrel. CONCLUSION: Although very rare, generalized atherosclerosis caused by genetic disorders should be considered an underlying cause for severe hypertension in children with hyperlipidemia.

Fibrin-targeted phase shift microbubbles for the treatment of microvascular obstruction.

Rationale: Microvascular obstruction (MVO) following percutaneous coronary intervention (PCI) is a common problem associated with adverse clinical outcomes. We are developing a novel treatment, termed sonoreperfusion (SRP), to restore microvascular patency. This entails using ultrasound-targeted microbubble cavitation (UTMC) of intravenously administered gas-filled lipid microbubbles (MBs) to dissolve obstructive microthrombi in the microvasculature. In our prior work, we used standard-sized lipid MBs. In the present study, to improve upon the efficiency and efficacy of SRP, we sought to determine the therapeutic efficacy of fibrin-targeted phase shift microbubbles (FTPSMBs) in achieving successful reperfusion of MVO. We hypothesized that owing to their much smaller size and affinity for thrombus, FTPSMBs would provide more effective dissolution of microthrombi when compared to that of the corresponding standard-sized lipid MBs. Methods: MVO in the rat hindlimb was created by direct injection of microthrombi into the left femoral artery. Definity MBs (Lantheus Medical Imaging) were infused through the jugular vein for contrast-enhanced ultrasound imaging (CEUS). A transducer was positioned vertically above the hindlimb for therapeutic US delivery during the concomitant administration of various therapeutic formulations, including (1) un-targeted MBs; (2) un-targeted phase shift microbubbles (PSMBs); (3) fibrin-targeted MB (FTMBs); and (4) fibrin-targeted PSMBs (FTPSMBs). CEUS cine loops with burst replenishment were obtained at baseline (BL), 10 min post-MVO, and after each of two successive 10-minute SRP treatment sessions (TX1, TX2) and analyzed (MATLAB). Results: In-vitro binding affinity assay showed increased fibrin binding peptide (FBP) affinity for the fibrin clots compared with the untargeted peptide (DK12). Similarly, in our in-vitro model of MVO, we observed a higher binding affinity of fluorescently labeled FTPSMBs with the porcine microthrombi compared to FTMBs, PSMBs, and MBs. Finally, in our hindlimb model, we found that UTMC with FTPSMBs yielded the greatest recovery of blood volume (dB) and flow rate (dB/sec) following MVO, compared to all other treatment groups. Conclusions: SRP with FTPSMBs achieves more rapid and complete reperfusion of MVO compared to FTMBs, PSMBs, and MBs. Studies to explore the underlying physical and molecular mechanisms are underway.

Effect of Ambient Conditions on Acoustic Activation of the Perfluoropropane Droplets Within the Infarct Zone.

BACKGROUND: Acoustically activated perfluoropropane droplets (PD) formulated from lipid encapsulated microbubble preparations produce a delayed myocardial contrast enhancement that preferentially highlights the infarct zones (IZ). Since activation of PDs may be temperature sensitive, it is unclear what effect body temperature (BT) has on acoustic activation (AA). OBJECTIVE: We sought to determine whether the microvascular retention and degree of myocardial contrast intensity (MCI) would be affected by BT at the time of intravenous injection. METHODS: We administered intravenous (IV) PD in nine rats following 60 min of ischemia followed by reperfusion. Injections in these rats were given at temperatures above and below 36.5°C, with high MI activation in both groups at 3 or 6 min following IV injection (IVI). In six additional rats (three in each group), IV PDs were given only at one temperature (<36.5°C or ≥36.5°C), permitting a total of 12 comparisons of different BT. Differences in background subtracted MCI at 3-6 min post-injection were compared in the infarct zone (IZ) and remote zone (RZ). Post-mortem lung hematoxylin and eosin (H&E) staining was performed to assess the effect potential thermal activation on lung tissue. RESULTS: Selective MCI within the IZ was observed in 8 of 12 rats who received IVI of PDs at <36.5°C, but none of the 12 rats who had IVI at the higher temperature (p < 0.0001). Absolute MCI following droplet activation was significantly higher in both the IZ and RZ when given at the lower BT. H&E indicated significant red blood extravasation in 5/7 rats who had had IV injections at higher BT, and 0/7 rats who had IV PDs at <36.5°C. CONCLUSIONS: Selective IZ enhancement with AA of intravenous PDs is possible, but temperature sensitive. Thermal activation appears to occur when PDs are given at higher temperatures, preventing AA, and increasing unwanted bioeffects.

Dynamic Behavior of Polymer Microbubbles During Long Ultrasound Tone-Burst Excitation and Its Application for Sonoreperfusion Therapy.

OBJECTIVE: Ultrasound (US)-targeted microbubble (MB) cavitation (UTMC)-mediated therapies have been found to restore perfusion and enhance drug/gene delivery. Because of the potentially longer circulation time and relative ease of storage and reconstitution of polymer-shelled MBs compared with lipid MBs, we investigated the dynamic behavior of polymer microbubbles and their therapeutic potential for sonoreperfusion (SRP) therapy. METHODS: The fate of polymer MBs during a single long tone-burst exposure (1 MHz, 5 ms) at various acoustic pressures and MB concentrations was recorded via high-speed microscopy and passive cavitation detection (PCD). SRP efficacy of the polymer MBs was investigated in an in vitro flow system and compared with that of lipid MBs. DISCUSSION: Microscopy videos indicated that polymer MBs formed gas-filled clusters that continued to oscillate, fragment and form new gas-filled clusters during the single US burst. PCD confirmed continued acoustic activity throughout the 5-ms US excitation. SRP efficacy with polymer MBs increased with pulse duration and acoustic pressure similarly to that with lipid MBs but no significant differences were found between polymer and lipid MBs. CONCLUSION: These data suggest that persistent cavitation activity from polymer MBs during long tone-burst US excitation confers excellent reperfusion efficacy.

Effect of Ultrasound Pulse Length on Sonoreperfusion Therapy.

In recent years, long- and short-pulse ultrasound (US)-targeted microbubble cavitation (UTMC) has been found to increase perfusion in healthy and ischemic skeletal muscle, in pre-clinical animal models of microvascular obstruction and in the myocardium of patients presenting with acute myocardial infarction. There is evidence that the observed microvascular vasodilation is driven by the nitric oxide pathway and purinergic signaling, but the time course of the response and the dependency on US pulse length are not well elucidated. Because our prior data supported that sonoreperfusion efficacy is enhanced by long-pulse US versus short-pulse US, in this study, we sought to compare long-pulse (5000 cycles) and short-pulse (500 × 10 cycles) US at a pressure of 1.5 MPa with an equivalent total number of acoustical cycles, hence constant acoustic energy, and at the same frequency (1 MHz), in a rodent hind limb model with and without microvascular obstruction (MVO). In quantifying perfusion using burst replenishment contrast-enhanced US imaging, we made three findings: (i) Long and short pulses result in different vasodilation kinetics in an intact hind limb model. The long pulse causes an initial spasmic reduction in flow that spontaneously resolved at 4 min, followed by sustained higher flow rates (approximately twofold) compared with baseline, starting 10 min after therapy (p < 0.05). The short pulse caused a short-lived approximately twofold increase in flow rate that peaked at 4 min (p < 0.05), but without the initial spasm. (ii) The sustained increased response with the long pulse is not simply reactive hyperemia. (iii) Both pulses are effective in reperfusion of MVO in our hindlimb model by restoring blood volume, but only the long pulse caused an increase in flow rate after treatment ii, compared with MVO (p < 0.05). Histological analysis of hind limb muscle post-UTMC with either pulse configuration indicates no evidence of tissue damage or hemorrhage. Our findings indicate that the microbubble oscillation induces vasodilation, and therapeutic efficacy for the treatment of MVO can be tuned by varying pulse length; relative to short-pulse US, longer pulses drive greater microbubble cavitation and more rapid microvascular flow rate restoration after MVO, warranting further optimization of the pulse length for sonoreperfusion therapy.

Ultrasound-Targeted Microbubble Cavitation During Machine Perfusion Reduces Microvascular Thrombi and Graft Injury in a Rat Liver Model of Donation After Circulatory Death.

BACKGROUND: Ischemic cholangiopathy is a process of bile duct injury that might result from peribiliary vascular plexus (PBP) thrombosis and remains a dreaded complication in liver transplantation from donors after circulatory death (DCD). The aim of this study was to propose a mechanical method of clot destruction to clear microvascular thrombi in DCD livers before transplantation. METHODS: Sonothrombolysis (STL) is a process by which inertial cavitation of circulating microbubbles entering an ultrasound field create a high-energy shockwave at a microbubble-thrombus interface, causing mechanical clot destruction. The effectiveness of STL in DCD liver treatment remains unclear. We carried out STL treatment during normothermic, oxygenated, ex vivo machine perfusion (NMP), introducing microbubbles into the perfusate with the liver enveloped in an ultrasound field. RESULTS: The STL livers showed reduction in hepatic arterial and PBP thrombus and decreases in hepatic arterial and portal venous flow resistance, reduced parenchymal injury as measured by aspartate transaminase release and oxygen consumption, and improved cholangiocyte function. Light and electron microscopy showed reduction of hepatic arterial and PBP thrombus in STL livers compared with controls and preserved hepatocyte structure, sinusoid endothelial morphology, and biliary epithelial microvilli. CONCLUSION: In this model, STL improved flow and functional measures in DCD livers undergoing NMP. These data suggest a novel therapeutic approach to treat PBP injury in DCD livers, which may ultimately increase the pool of grafts available to patients awaiting liver transplantation.

Modulation of pre-capillary arteriolar pressure with drag-reducing polymers: a novel method for enhancing microvascular perfusion.

OBJECTIVE: We have shown that drag-reducing polymers (DRP) enhance capillary perfusion during severe coronary stenosis and increase red blood cell velocity in capillaries, through uncertain mechanisms. We hypothesize that DRP decreases pressure loss from the aorta to the arteriolar compartment. METHODS: Intravital microscopy of the rat cremaster muscle and measurement of pressure in arterioles (diameters 20-132 µm) was performed in 24 rats. DRP (polyethylene oxide, 1 ppm) was infused i.v. and measurements were made at baseline and 20 minutes after completion of DRP infusion. In a 10-rat subset, additional measurements were made three minutes after the start, and one to five and 10 minutes after completion of DRP. RESULTS: Twenty minutes after the completion of DRP, mean arteriolar pressure was 22% higher than baseline (from 42 ± 3 to 49 ± 3 mmHg, p < 0.005, n = 24). DRP decreased the pressure loss from the aorta to the arterioles by 24% (from 35 ± 6 to 27 ± 5 mmHg, p = 0.001, n = 10). In addition, there was a strong trend toward an increase in pressure at 10 minutes after the completion of DRP (n = 10). CONCLUSIONS: Drag-reducing polymers diminish pressure loss between the aorta and the arterioles. This results in a higher pre-capillary pressure and probably explains the observed DRP enhancement in capillary perfusion.

Bedside ultrasound to assess acute central venous pressure change during treatment of decompensated heart failure.

Background: Accurate volume status assessment is crucial for the treatment of acute decompensated heart failure (ADHF). Volume status assessment by physical exam is often inaccurate, necessitating invasive measurement with right heart catheterization (RHC), which carries safety, pragmatic (scheduling, holding anticoagulants, etc.), and financial burdens. Therefore, a reliable, non-invasive, cost-effective alternative is desired. Previously, we developed an ultrasound (US) based technique to measure internal jugular vein (IJV) compliance during RHC which was used for single time point central venous pressure (CVP) predictions. We now aim to apply this technique to track acute changes in CVP during diuresis for ADHF in patients with an in-dwelling pulmonary artery catheter (PAC). Methods: We used an observational, prospective study design and recruited 15 patients from the cardiac critical unit (CCU) being treated for ADHF (systolic or diastolic) with intravenous (IV) diuretics with/without inotropic agents who underwent Swan- Ganz catheter/PAC insertion for continuous CVP monitoring. 13 of 15 patients received milrinone infusions. US images of the IJV were obtained at end-expiration and during the strain phase of Valsalva at multiple 2-3 hours intervals. Change in IJV cross-sectional area (CSA) (ImageJ) was used as a measure of IJV compliance. Patients unable to perform the Valsalva maneuver were excluded. Results: Calculated percentage change (%Δ) in CSA of IJV was plotted against CVP. An inverse relationship was observed between CVP and %Δ in CSA of IJV. The data was fit with a polynomial regression curve (R2 = 0.36, root mean square error = 3.19). Fivefold cross-validation showed a stable model for predicting CVP based on CSA (R2 = 0.31, root mean square error = 3.18). Conclusion: Serial portable US assessment of IJV compliance can act as a surrogate measure of CVP and, therefore, can provide reliable information on acute hemodynamic changes in ADHF.

Lipid nitroalkene nanoparticles for the focal treatment of ischemia reperfusion.

Rationale: The treatment of microvascular obstruction (MVO) using ultrasound-targeted LNP cavitation (UTC) therapy mechanically relieves the physical obstruction in the microcirculation but does not specifically target the associated inflammatory milieu. Electrophilic fatty acid nitroalkene derivatives (nitro-fatty acids), that display pleiotropic anti-inflammatory signaling and transcriptional regulatory actions, offer strong therapeutic potential but lack a means of rapid targeted delivery. The objective of this study was to develop nitro-fatty acid-containing lipid nanoparticles (LNP) that retain the mechanical efficacy of standard LNP and can rapidly target delivery of a tissue-protective payload that reduces inflammation and improves vascular function following ischemia-reperfusion. Methods: The stability and acoustic behavior of nitro-fatty acid LNP (NO2-FA-LNP) were characterized by HPLC-MS/MS and ultra-high-speed microscopy. The LNP were then used in a rat hindlimb model of ischemia-reperfusion injury with ultrasound-targeted cavitation. Results: Intravenous administration of NO2-FA-LNP followed by ultrasound-targeted LNP cavitation (UTC) in both healthy rat hindlimb and following ischemia-reperfusion injury showed enhanced NO2-FA tissue delivery and microvascular perfusion. In addition, vascular inflammatory mediator expression and lipid peroxidation were decreased in tissues following ischemia-reperfusion revealed NO2-FA-LNP protected against inflammatory injury. Conclusions: Vascular targeting of NO2-FA-LNP with UTC offers a rapid method of focal anti-inflammatory therapy at sites of ischemia-reperfusion injury.

Sex-related differences in clinical outcomes among patients with myocardial infarction with nonobstructive coronary artery disease: A systematic review and meta-analysis.

BACKGROUND: Among patients who present with acute myocardial infarction (MI), 2-6% are found to have non-obstructive coronary arteries (NOCA). Patients with MINOCA are more commonly women and present at a younger age (51-59 years). The influence of sex on adverse event rates remains unclear. METHODS: PubMed, MEDLINE, CENTRAL (Cochrane Central Register of Controlled Trials), EMBASE, EBSCO, Web of Science and CINAHL databases were searched for trials comparing gender differences in clinical outcomes among patients with MINOCA from inception through April 10, 2022. The primary endpoint of the study was composite major adverse clinical events (MACE) including all-cause mortality, non-fatal MI, stroke, and cardiovascular readmissions, and secondary endpoints were the individual components of the MACE. RESULTS: Seven studies with a total of 28,671 MINOCA patients were included (n = 11,249 men and n = 17,422 women) over a mean follow-up of 2 years. Women had more MACE than men (10.1% vs. 9.1%, OR 1.15, 1.04-1.23, I2 = 44.7%). Among secondary endpoints, only the incidence of stroke was higher in women (3.5% vs. 2.2%, OR 1.3, 1.01-1.68, I2 = 0%). All-cause mortality, non-fatal MI, and cardiovascular readmissions were not significantly different between the two groups. CONCLUSIONS: We hypothesize that small vessel disease associated with MINOCA drives MACE in women and the diminishing influence of estrogen, hypercoagulability and underprescribing could contribute to the differences sex-related outcomes.

Acoustic Detection of Retained Perfluoropropane Droplets Within the Developing Myocardial Infarct Zone.

Perfluoropropane droplets (PDs) cross endothelial barriers and can be acoustically activated for selective myocardial extravascular enhancement following intravenous injection (IVI). Our objective was to determine how to optimally activate extravascular PDs for transthoracic ultrasound-enhanced delineation of a developing scar zone (DSZ). Ultrafast-frame-rate microscopy was conducted to determine the effect of pulse sequence on the threshold of bubble formation from PDs. In vitro studies were subsequently performed at different flow rates to determine acoustic activation and inertial cavitation thresholds for a PD infusion using multipulse fundamental non-linear or single-pulse harmonic imaging. IVIs of PDs were given in 9 rats and 10 pigs following prolonged left anterior descending ischemia to detect and quantify PD kinetics within the DSZ. A multipulse sequence had a lower myocardial index threshold for acoustic activation by ultrafast-frame-rate microscopy. Acoustic activation was observed at a myocardial index ≥0.4 below the inertial cavitation threshold for both pulse sequences. In rats, confocal microscopy and serial acoustic activation imaging detected higher droplet presence (relative to remote regions) within the DSZ at 3 min post-IVI. Transthoracic high-mechanical-index impulses with fundamental non-linear imaging in pigs at this time post-IVI resulted in selective contrast enhancement within the DSZ.

Takotsubo cardiomyopathy with LVOT obstruction in a case of STEMI: a rare cause of peri-PCI hypotension.

Takotsubo cardiomyopathy (TCM) associated with left ventricular outflow tract (LVOT) obstruction in the event of an ST-elevation myocardial infarction (STEMI) is a rare cause of hypotension during percutaneous coronary intervention (PCI). Herein, we describe a 57-year-old woman who presented with STEMI and underwent PCI. She developed hypotension which worsened during inotropic therapy. Echocardiography revealed evidence of LVOT obstruction in the setting of TCM. Therefore, inotropic support was promptly discontinued. Beta blockers and phenylephrine were rapidly administrated, resulting in improved blood pressure and stabilisation of the patient.

Detection of elevated right atrial pressure using a simple bedside ultrasound measure.

AIMS: Accurate assessment of right atrial pressure (RAP) often requires invasive measurement. With normal RAP, Valsalva increases right internal jugular vein (RIJV) cross sectional area (CSA) 20% to 30%. With high RAP, when venous compliance is low, we hypothesized that the increase in CSA would be blunted and could be detected non-invasively with bedside ultrasound. METHODS AND RESULTS: RIJV ultrasound images were obtained in 67 patients undergoing right heart catheterization. The median RAP at end-expiration was 7 mm Hg (interquartile range [IQR] 5-9 mm Hg) in patients with normal RAP (n = 47) versus 15 mm Hg (IQR 12-22 mm Hg) in patients with elevated RAP (n = 20). With Valsalva, the median percent change in RIJV CSA was 35% (IQR 19%-79%) versus 5% (IQR 3%-14%) for normal and high RAP, respectively. By receiver operating curve analysis, a <17% increase in RIJV CSA with Valsalva predicted elevated RAP (> or =12 mmHg) with 90% sensitivity, 74% specificity, 94% negative predictive value, and 60% positive predictive value (area under the curve 0.86, P < .001). CONCLUSIONS: An increase in RIJV CSA >17% during Valsalva effectively rules out elevated RAP. This simple bedside technique may be useful to assess central venous pressure and reduce the need for invasive pressure measurement.

Noninvasive sublingual microvascular imaging reveals sex-specific reduction in glycocalyx barrier properties in patients with coronary artery disease.

BACKGROUND: Risk factors for coronary artery disease (CAD) have been associated with endothelial dysfunction and degradation of the endothelial glycocalyx. This study was designed to compare sublingual microvascular perfusion and glycocalyx barrier properties in CAD patients and controls using noninvasive side stream darkfield imaging. METHODS: Imaging of the sublingual microvasculature was performed in 52 case subjects (CAD confirmed by left heart catheterization) and 63 controls (low Framingham risk score). Red blood cell (RBC) filling percentage and functional microvascular density, measures of microvascular perfusion, and perfused boundary region (PBR), an index of glycocalyx barrier function, were measured in microvessels with a diameter ranging from 5-25 µm. RESULTS: RBC filling percentage was lower in patients with CAD compared to controls (p < .001). Functional microvascular density did not differ between groups. The overall PBR was marginally greater in the CAD group compared to the control group (p = .08). PBR did not differ between male CAD cases and controls (p = .17). However, PBR was greater in females with CAD compared with female controls (p = .04), indicating reduced glycocalyx barrier function. This difference became more pronounced after adjusting for potential confounders. CONCLUSIONS: Our data suggest that patients with CAD are characterized by a reduction in percentage of time microvessels are occupied by RBCs. In addition, CAD is significantly associated with impaired sublingual microvascular glycocalyx barrier function in women but not men. More research is needed to determine the significance of peripheral microvascular dysfunction in the pathophysiology of CAD, and how this may differ by sex.

Sonoreperfusion therapy for microvascular obstruction: A step toward clinical translation.

Sonoreperfusion therapy is being developed as an intervention for the treatment of microvascular obstruction. We investigated the reperfusion efficacy of two clinical ultrasound systems (a modified Philips EPIQ and a Philips Sonos 7500) in a rat hindlimb microvascular obstruction model. Four ultrasound conditions were tested using 20 min treatments: Sonos single frame, Sonos multi-frame, EPIQ low pressure and EPIQ high pressure. Contrast-enhanced perfusion imaging of the microvasculature was conducted at baseline and after treatment to calculate microvascular blood volume (MBV). EPIQ high pressure treatment resulted in significant recovery of MBV from microvascular obstruction, returning to baseline levels after treatment. EPIQ low pressure and Sonos multi-frame treatment resulted in significantly improved MBV after treatment but below baseline levels. Sonos single-frame and control groups showed no improvement post-treatment. This study demonstrates that the most effective sonoreperfusion therapy occurs at high acoustic pressure coupled with high acoustic intensity. Moreover, a clinically available ultrasound system is readily capable of delivering these effective therapeutic pulses.

Ultrasound-Targeted Microbubble Cavitation with Sodium Nitrite Synergistically Enhances Nitric Oxide Production and Microvascular Perfusion.

Microvascular obstruction is a common repercussion of percutaneous coronary intervention for distal microembolization, ischemia-reperfusion injury and inflammation, which increases post-myocardial infarction heart failure and mortality. Ultrasound-targeted microbubble cavitation (UTMC) may resolve microvascular obstruction while activating endothelial nitric oxide synthase (eNOS) and increasing endothelium-derived nitric oxide (NO) bioavailability. Nitrite, a cardioprotective agent, offers an additional source of NO and potential synergy with UTMC. UTMC and nitrite co-therapy increased microvascular perfusion and NO concentration in a rat hindlimb model. Using N-nitro-L-arginine methyl ester for eNOS blockade, we found a three-way interaction effect between nitrite, UTMC and eNOS on microvascular perfusion and NO production. Modulating ultrasound peak negative acoustic pressure (0.33-1.5 MPa) significantly affected outcomes, while microbubble dosage (2 × 108 bubbles/mL, 1.5 mL/h to 1 × 109 bubbles/mL, 3 mL/h) did not. Nitrite co-therapy also protected against oxidative stress. Comparison of nitrite to sodium nitroprusside with UTMC revealed synergistic effects were specific to nitrite. Synergy between UTMC and nitrite holds therapeutic potential for cardiovascular disease.

Myocardial ischemic memory imaging with molecular echocardiography.

BACKGROUND: Diagnosing acute coronary syndrome in patients presenting with chest discomfort is a challenge. Because acute myocardial ischemia/reperfusion is associated with endothelial upregulation of leukocyte adhesion molecules, which persist even after ischemia has resolved, we hypothesized that microbubbles designed to adhere to endothelial selectins would permit echocardiographic identification of recently ischemic myocardium. METHODS AND RESULTS: Lipid microbubbles (diameter, 3.3+/-1.7 microm) were synthesized. The selectin ligand sialyl Lewis(x) was conjugated to the microbubble surface (MB(sLex)). Control bubbles (MB(CTL)) bore surface Lewis(x) or sialyl Lewis(c). Intravital microscopy of mouse cremaster muscle was performed after intravenous injection of MB(sLex) (n=11) or MB(CTL) (n=9) with or without prior intrascrotal tumor necrosis factor-alpha. There was greater adhesion of MB(sLex) to inflamed versus noninflamed endothelium (P = 0.0081). Rats (n=12) underwent 15 minutes of anterior descending coronary artery occlusion. After 30 minutes and 1 hour of reperfusion, high-mechanical-index nonlinear echocardiographic imaging was performed in which single frames were acquired at 3.5 and 4 minutes after intravenous injection of MB(sLex) or MB(CTL). Video intensity at 4 minutes was subtracted from that at 3.5 minutes to derive target-specific acoustic signal. MB(sLex) caused greater opacification in postischemic versus nonischemic myocardium at both time points (P < or = 0.002). Immunostaining confirmed endothelial P-selectin expression in the ischemic bed. CONCLUSIONS: Echocardiographic identification of recently ischemic myocardium is possible using ultrasound contrast agents targeted to selectins. This may offer a new approach to the more timely and precise diagnosis of acute coronary syndrome in patients presenting with chest pain of uncertain cardiac origin.