Evaluation of Intracardiac Pressures Using Subharmonic-aided Pressure Estimation with Sonazoid Microbubbles.

Purpose To investigate if the right ventricular (RV) systolic and left ventricular (LV) diastolic pressures can be obtained noninvasively using the subharmonic-aided pressure estimation (SHAPE) technique with Sonazoid microbubbles. Materials and Methods Individuals scheduled for a left and/or right heart catheterization were prospectively enrolled in this institutional review board-approved clinical trial from 2017 to 2020. A standard-of-care catheterization procedure was performed by advancing fluid-filled pressure catheters into the LV and aorta (n = 25) or RV (n = 22), and solid-state high-fidelity pressure catheters into the LV and aorta in a subset of participants (n = 18). Study participants received an infusion of Sonazoid microbubbles (GE HealthCare), and SHAPE data were acquired using a validated interface developed on a SonixTablet (BK Medical) US scanner, synchronously with the pressure catheter data. A conversion factor, derived using cuff-based pressure measurements with a SphygmoCor XCEL PWA (ATCOR) and subharmonic signal from the aorta, was used to convert the subharmonic signal into pressure values. Errors between the pressure measurements obtained using the SHAPE technique and pressure catheter were compared. Results The mean errors in pressure measurements obtained with the SHAPE technique relative to those of the fluid-filled pressure catheter were 1.6 mm Hg ± 1.5 [SD] (P = .85), 8.4 mm Hg ± 6.2 (P = .04), and 7.4 mm Hg ± 5.7 (P = .09) for RV systolic, LV minimum diastolic, and LV end-diastolic pressures, respectively. Relative to the measurements with the solid-state high-fidelity pressure catheter, the mean errors in LV minimum diastolic and LV end-diastolic pressures were 7.2 mm Hg ± 4.5 and 6.8 mm Hg ± 3.3 (P ≥ .44), respectively. Conclusion These results indicate that SHAPE with Sonazoid may have the potential to provide clinically relevant RV systolic and LV diastolic pressures. Keywords: Ultrasound-Contrast, Cardiac, Aorta, Left Ventricle, Right Ventricle ClinicalTrials.gov registration no.: NCT03245255 © RSNA, 2024.

Noninvasive Evaluation of Cardiac Chamber Pressures Using Subharmonic-Aided Pressure Estimation With Definity Microbubbles.

BACKGROUND: Noninvasive and accurate assessment of intracardiac pressures has remained an elusive goal of noninvasive cardiac imaging. OBJECTIVES: The purpose of this study was to investigate if errors in intracardiac pressures obtained noninvasively using contrast microbubbles and the subharmonic-aided pressure estimation (SHAPE) technique are <5 mm Hg. METHODS: In a nonrandomized institutional review board-approved clinical trial (NCT03243942), patients scheduled for a left-sided and/or right-sided heart catheterization procedure and providing written informed consent were included. A standard-of-care catheterization procedure was performed advancing clinically used pressure catheters into the left and/or right ventricles and/or the aorta. After pressure catheter placement, patients received an infusion of Definity microbubbles (n = 56; 2 vials diluted in 50 mL of saline; infusion rate: 4-10 mL/min) (Lantheus Medical Imaging). Then SHAPE data was acquired using a validated interface developed on a SonixTablet scanner (BK Medical Systems) synchronously with the pressure catheter data. A conversion factor (mm Hg/dB) was derived from SHAPE data and measurements with a SphygmoCor XCEL PWA device (ATCOR Medical) and was combined with SHAPE data from the left and/or the right ventricles to obtain clinically relevant systolic and diastolic ventricular pressures. RESULTS: The mean value of absolute errors for left ventricular minimum and end diastolic pressures were 2.9 ± 2.0 and 1.7 ± 1.2 mm Hg (n = 26), respectively, and for right ventricular systolic pressures was 2.2 ± 1.5 mm Hg (n = 11). Two adverse events occurred during Definity infusion; both were resolved. CONCLUSIONS: These results indicate that the SHAPE technique with Definity microbubbles is encouragingly efficacious for obtaining intracardiac pressures noninvasively and accurately. (Noninvasive, Subharmonic Intra-Cardiac Pressure Measurement; NCT03243942).

Comparing Central Aortic Pressures Obtained Using a SphygmoCor Device to Pressures Obtained Using a Pressure Catheter.

BACKGROUND: This study compared aortic pressures estimated using a SphygmoCor XCEL PWA device (ATCOR, Naperville, IL) noninvasively with aortic pressures obtained using pressure catheters during catheterization procedures and analyzed the impact of a linear-fit function on the estimated pressure values. METHODS: One hundred and thirty-six patients scheduled for cardiac catheterization procedure were enrolled in IRB approved studies. Catheterization procedures were performed according to standard-of-care to acquire aortic pressure measurements. Immediately after the catheterization procedure with the pressure catheters removed, while the patients were still in the catheterization laboratory, central aortic pressures were estimated with the SphygmoCor device (using its inbuilt transfer function). The error between measured and estimated aortic pressures was evaluated using Bland-Altman analysis (n = 93). A linear-fit was performed between the measured and estimated pressures, and using the linear equation the error measurements were repeated. A bootstrap analysis was performed to test the generalizability of the linear-fit function. In a subset of cases (n = 13), central aortic pressure values were also obtained using solid-state high-fidelity catheters (Millar, Houston, TX), and the error measurements were repeated. RESULTS: The magnitude of errors between the measured and estimated aortic pressures (mean errors >6.4 mm Hg; mean errors >8.0 mm Hg in the subset) were reduced to less than 1 mm Hg after using the linear-fit function derived in this study. CONCLUSIONS: For the population examined in this study, the SphygmoCor data must be used with the linear-fit function to obtain aortic pressures that are comparable to the measurements obtained using pressure catheters. CLINICAL TRIALS REGISTRATION: Trial Numbers NCT03243942 and NCT03245255.

Clinical predictors and impact of ambulatory blood pressure monitoring in pediatric hypertension referrals.

Elevated blood pressure (BP) is rising in children. Significant proportions of children have reactive hypertension or masked hypertension, making ambulatory BP monitoring (ABPM) a valuable tool, although with potential economic implications. In youth referred for elevated BP, we sought clinic BP combinations that obviated the need for ABPM and to specify the economic role of ABPM. In a retrospective pediatric referral cohort (N = 170), we examine clinic systolic BP (SBP) predictors of components of ABPM hypertension and their combination. In economic analyses, we compared effectiveness and charges of three diagnostic pathways: (1) clinic BP alone; (2) abnormal clinic BP prompting ABPM; or (3) universal ABPM. ABPM hypertension occurred in 55 (32.4%) and reactive hypertension in 37 (21.8%), average automated (ß = 0.208; 95% confidence interval, 0.027, 0.389; P = .03) and maximum auscultatory clinic SBP (ß = 0.160; 95% confidence interval 0.022, 0.299; P = .02) were associated with ABPM SBP mean, but none predicted SBP load. No clinic SBP combination was associated with ABPM hypertension. Universal ABPM accrued the lowest average charge per hypertensive youth identified ($10,948). We did not identify a clinic SBP combination that predicted ABPM hypertension in youth referred for elevated BP. Universal ABPM, in this context, may be the most economically and clinically efficient diagnostic strategy.

BH3-triggered structural reorganization drives the activation of proapoptotic BAX.

BAX is a proapoptotic BCL-2 family member that lies dormant in the cytosol until converted into a killer protein in response to cellular stress. Having recently identified the elusive trigger site for direct BAX activation, we now delineate by NMR and biochemical methods the essential allosteric conformational changes that transform ligand-triggered BAX into a fully activated monomer capable of propagating its own activation. Upon BAX engagement by a triggering BH3 helix, the unstructured loop between α helices 1 and 2 is displaced, the carboxy-terminal helix 9 is mobilized for membrane translocation, and the exposed BAX BH3 domain propagates the death signal through an autoactivating interaction with the trigger site of inactive BAX monomers. Our structure-activity analysis of this seminal apoptotic process reveals pharmacologic opportunities to modulate cell death by interceding at key steps of the BAX activation pathway.

Inhibition of human DNA polymerase beta activity by the anticancer prodrug Cloretazine.

The antineoplastic prodrug Cloretazine exerts its cytotoxicity via a synergism between 2-chloroethylating and carbamoylating activities that are cogenerated upon activation in situ. Cloretazine is reported here to inhibit the nucleotidyl-transferase activity of purified human DNA polymerase beta (Pol beta), a principal enzyme of DNA base excision repair (BER). The 2-chloroethylating activity of Cloretazine alkylates DNA at the O(6) position of guanine bases resulting in 2-chloroethoxyguanine monoadducts, which further react to form cytotoxic interstrand DNA crosslinks. Alkylated DNA is often repaired via BER in vivo. Inhibition of the polymerase activity of Pol beta may account for some of the synergism between Cloretazine's two reactive subspecies in cytotoxicity assays. This inhibition was only observed using agents with carbamoylating activity. Furthermore, while therapeutically relevant concentrations of Cloretazine inhibited the polymerase activity of Pol beta, the enzyme's lyase activity, which may also participate in BER, was not significantly inhibited.

BAX activation is initiated at a novel interaction site.

BAX is a pro-apoptotic protein of the BCL-2 family that is stationed in the cytosol until activated by a diversity of stress stimuli to induce cell death. Anti-apoptotic proteins such as BCL-2 counteract BAX-mediated cell death. Although an interaction site that confers survival functionality has been defined for anti-apoptotic proteins, an activation site has not been identified for BAX, rendering its explicit trigger mechanism unknown. We previously developed stabilized alpha-helix of BCL-2 domains (SAHBs) that directly initiate BAX-mediated mitochondrial apoptosis. Here we demonstrate by NMR analysis that BIM SAHB binds BAX at an interaction site that is distinct from the canonical binding groove characterized for anti-apoptotic proteins. The specificity of the human BIM-SAHB-BAX interaction is highlighted by point mutagenesis that disrupts functional activity, confirming that BAX activation is initiated at this novel structural location. Thus, we have now defined a BAX interaction site for direct activation, establishing a new target for therapeutic modulation of apoptosis.