Robi Goswami

Intracardiac Echocardiography Measurement of Dynamic Myocardial Stiffness with Shear Wave Velocimetry

Acoustic radiation force (ARF)-based methods have been demonstrated to be a viable tool for noninvasively estimating tissue elastic properties, and shear wave velocimetry has been used to measure quantitatively the stiffening and relaxation of myocardial tissue in open-chest experiments. Dynamic stiffness metrics may prove to be indicators for certain cardiac diseases, but a clinically viable means of remotely generating and tracking transverse wave propagation in myocardium is needed. Intracardiac echocardiography (ICE) catheter-tip transducers are demonstrated here as a viable tool for making this measurement. ICE probes achieve favorable proximity to the myocardium, enabling the use of shear wave velocimetry from within the right ventricle throughout the cardiac cycle. This article describes the techniques used to overcome the challenges of using a small probe to perform ARF-driven shear-wave velocimetry and presents in vivo porcine data showing the effectiveness of this method in the interventricular septum.

Regulation of the Platelet-derived Growth Factor Receptor-β by G Protein-coupled Receptor Kinase-5 in Vascular Smooth Muscle Cells Involves the Phosphatase Shp2

Smooth muscle cell (SMC) proliferation and migration are substantially controlled by the platelet-derived growth factor receptor-β (PDGFRβ), which can be regulated by the Ser/Thr kinase G protein-coupled receptor kinase-2 (GRK2). In mouse aortic SMCs, however, we found that prolonged PDGFRβ activation engendered down-regulation of GRK5, but not GRK2; moreover, GRK5 and PDGFRβ were coordinately up-regulated in SMCs from atherosclerotic arteries. With SMCs from GRK5 knock-out and cognate wild type mice (five of each), we found that physiologic expression of GRK5 increased PDGF-promoted PDGFRβ seryl phosphorylation by 3-fold and reduced PDGFRβ-promoted phosphoinositide hydrolysis, thymidine incorporation, and overall PDGFRβ tyrosyl phosphorylation by ∼35%. Physiologic SMC GRK5 activity also increased PDGFRβ association with the phosphatase Shp2 (8-fold), enhanced phosphorylation of PDGFRβ Tyr1009 (the docking site for Shp2), and reduced phosphorylation of PDGFRβ Tyr1021. Consistent with having increased PDGFRβ-associated Shp2 activity, GRK5-expressing SMCs demonstrated greater PDGF-induced Src activation than GRK5-null cells. GRK5-mediated desensitization of PDGFRβ inositol phosphate signaling was diminished by Shp2 knock-down or impairment of PDGFRβ/Shp2 association. In contrast to GRK5, physiologic GRK2 activity did not alter PDGFRβ/Shp2 association. Finally, purified GRK5 effected agonist-dependent seryl phosphorylation of partially purified PDGFRβs. We conclude that GRK5 mediates the preponderance of PDGF-promoted seryl phosphorylation of the PDGFRβ in SMCs, and, through mechanisms involving Shp2, desensitizes PDGFRβ inositol phosphate signaling and enhances PDGFRβ-triggered Src activation.

Short-Lag Spatial Coherence Imaging of Cardiac Ultrasound Data: Initial Clinical Results

Short-lag spatial coherence (SLSC) imaging is a novel beamforming technique that reduces acoustic clutter in ultrasound images. A clinical study was conducted to investigate clutter reduction and endocardial border detection in cardiac SLSC images. Individual channel echo data were acquired from the left ventricle of 14 volunteers, after informed consent and institutional review board approval. Paired B-mode and SLSC images were created from these data. Contrast, contrast-to-noise, and signal-to-noise ratios were measured in paired images, and these metrics were improved with SLSC imaging in most cases. Three cardiology fellows rated the visibility of endocardial segments in randomly ordered B-mode and SLSC cine loops. SLSC imaging offered 22%-33% improvement (p < 0.05) in endocardial border visibility when B-mode image quality was poor (i.e., 80% or more of the endocardial segments could not be visualized by the three reviewers). The percentage of volunteers with poor-quality images was decreased from 21% to 7% with the SLSC beamformer. Results suggest that SLSC imaging has the potential to improve clinical cardiac assessments that are challenged by clutter.

Intracardiac acoustic radiation force impulse (ARFI) and shear wave imaging in pigs with focal infarctions

Four pigs, three with focal infarctions in the apical intraventricular septum (IVS) and/or left ventricular free wall (LVFW), were imaged with an intracardiac echocardiography (ICE) transducer. Custom beam sequences were used to excite the myocardium with focused acoustic radiation force (ARF) impulses and image the subsequent tissue response. Tissue displacement in response to the ARF excitation was calculated with a phase-based estimator, and transverse wave magnitude and velocity were each estimated at every depth. The excitation sequence was repeated rapidly, either in the same location to generate 40 Hz M-modes at a single steering angle, or with a modulated steering angle to synthesize 2-D displacement magnitude and shear wave velocity images at 17 points in the cardiac cycle. Both types of images were acquired from various views in the right and left ventricles, in and out of infarcted regions. In all animals, acoustic radiation force impulse (ARFI) and shear wave elasticity imaging (SWEI) estimates indicated diastolic relaxation and systolic contraction in noninfarcted tissues. The M-mode sequences showed high beat-to-beat spatio-temporal repeatability of the measurements for each imaging plane. In views of noninfarcted tissue in the diseased animals, no significant elastic remodeling was indicated when compared with the control. Where available, views of infarcted tissue were compared with similar views from the control animal. In views of the LVFW, the infarcted tissue presented as stiff and non-contractile compared with the control. In a view of the IVS, no significant difference was seen between infarcted and healthy tissue, whereas in another view, a heterogeneous infarction was seen to be presenting itself as non-contractile in systole.

Clutter reduction in echocardiography with short-lag spatial coherence (SLSC) imaging

Clutter, a problematic noise artifact in echocardiography, appears as a diffuse haze that obscures endocardial borders and inhibits accurate diagnoses. Several approaches are available to reduce clutter in cardiac images, yet difficult-to-image patients still exist. We have recently developed a novel imaging method, termed short-lag spatial coherence (SLSC) imaging, that has demonstrated potential to reduce clutter in simulated and experimental data. With this technique, images are created from the same individual channel signals used to form B-mode images, but instead of applying a conventional delay-and-sum beamformer, the data are cross-correlated to measure and display differences in spatial coherence. This technique was applied to in vivo cardiac images. Individual channel signals were acquired to form matched B-mode and SLSC images of the left ventricle in fourteen human volunteers. The contrast and contrast-to-noise ratio (CNR) of the ventricle and the signal-to-noise ratio (SNR) of the endocardium were measured in the same locations in matched B-mode and SLSC images. In SLSC images created with a short-lag value equivalent to 16% of the transmit aperture, contrast and CNR was improved by 9±7 dB and 0.4±0.2, respectively, in the SLSC images. The average SNR of the endocardium was 1.7±0.4 in the SLSC images and 1.8±0.4 in the B-mode images. The presented approach demonstrates a new method for reducing clutter in cardiac images.

Improved visualization of endocardial borders with Short-Lag Spatial Coherence imaging of fundamental and harmonic ultrasound data

Endocardial border visualization, a common task in echochardiography, is typically challenged by the presence of acoustic clutter. This study investigates endocardial border visibility in co-registered fundamental and harmonic data when utilizing the Short-Lag Spatial Coherence (SLSC) beamformer, a clutter reduction approach that we developed. Individual channel echo data were acquired from the left ventricle of 12 volunteers, after informed consent and IRB approval, to create matched image quadruplets of fundamental and harmonic B-mode and SLSC images. Contrast-to-noise ratios (CNR) were measured, and three cardiologists rated the visibility of endocardial segments in randomly ordered cine loops. The statistical significance of visibility ratings was determined with a Holm-Bonferroni correction at a significance level, α = 0.05. CNR increased approximately twofold in fundamental and harmonic SLSC images compared to fundamental and harmonic B-mode images. Fundamental and Harmonic SLSC imaging offered the greatest benefits when fundamental B-mode image quality was poor. Improvements in endocardial segment visibility in short-axis views ranged from 1628% (α = 0.05) compared to fundamental B-mode images, while improvements in the apical four chamber views ranged from 2235% (α = 0.05) compared to fundamental and harmonic B-mode images. Results suggest that SLSC and HSCI have the potential to increase endocardial border visualization and thereby improve cardiac assessments of poor-quality B-mode images.

Ranolazine-related dyspnea on exertion

BACKGROUND Ranolazine is increasingly being prescribed for the treatment of chronic stable angina. This report describes an adverse effect that may be related to ranolazine. CASE SUMMARY A 77-year-old white man with chronic renal insufficiency was evaluated for moderate dyspnea on exertion (DOE). Cardiac and pulmonary workup revealed nonobstructive coronary artery disease and mild obstructive lung disease. The patient had been taking ranolazine 500 mg daily for possible angina for the past 2 months. Given the temporal association of his symptoms with drug initiation, ranolazine was discontinued during the hospitalization. One month after discontinuing ranolazine, the patients DOE had completely resolved; the only intervention had been discontinuation of ranolazine. The patients Naranjo algorithm score was 3, indicating a possible adverse drug reaction. CONCLUSIONS No previous cases of ranolazine-related DOE requiring drug cessation have been published. Ranolazine may be associated with DOE in this elderly man.

Feasibility and safety of transthoracic cardiac acoustic radiation force impulse imaging methods

This work examines clinical feasibility of using noninvasive transthoracic echocardiography techniques to visualize temporal variations of stiffness through the cardiac cycle using acoustic radiation force impulse (ARFI) imaging. Custom M-mode ARFI sequences were implemented on a Verasonics Research Platform using a Philips/ATL P4-2 phased-array echocardiography transducer. The research systems robust power supply, full parallel-receive capability, and programmable interface enabled sustained excitations, rapid data acquisition, and real-time processing and display of images in the clinic. An extended radiation force pulse length of 480 μs was used to produce tissue displacements up to 12μm around a region of excitation focused at 3 cm. Quadratic motion filters were used to separate ARFI excitation-induced displacements from intrinsic cardiac and respiratory physiological motion artifacts. Acoustic intensity and face heating measurements, as well as finite element method tissue focal heating simulations, were completed. These measurements and simulations calibrated the sequences with respect to the FDA acoustic exposure limits for intensity, mechanical index (MI) and tissue heating. Tests were conducted in phantom and animal models in preparation for the clinical trial. A series of 7 healthy volunteers were scanned in accordance with an approved Duke University Medical Center Institutional Review Board (IRB) protocol. Measurements were acquired from the apical 4 chamber view of the apex, at power levels with MIs ranging from 1.9-3.0. During each M-mode ARFI acquisition, the matched ECG signal was acquired, enabling registration with cardiac cycle. The M-mode ARFI displacement images reflect the expected myocardial stiffness changes through the cardiac cycle, with greatest displacements in diastole and lowest in systole. In the 7 volunteers, the mean displacements throughout the cardiac cycle rose with increasing transmit power level. The ratio of diastolic-to-systolic displacement was examined as a possible indicator of myocardial health. In this study, the measured ratios were in range up to 3.1:1 for the 7 patients, showing agreement with previous ratios reported by an animal studies using transthoracic, intracardiac and epicardial imaging methods. These preliminary clinical results support the feasibility of real-time imaging of cardiac stiffness in vivo using transthoracic ARFI imaging.

Cardiac Phase Space Tomography: A novel method of assessing coronary artery disease utilizing machine learning

Background Artificial intelligence (AI) techniques are increasingly applied to cardiovascular (CV) medicine in arenas ranging from genomics to cardiac imaging analysis. Cardiac Phase Space Tomography Analysis (cPSTA), employing machine-learned linear models from an elastic net method optimized by a genetic algorithm, analyzes thoracic phase signals to identify unique mathematical and tomographic features associated with the presence of flow-limiting coronary artery disease (CAD). This novel approach does not require radiation, contrast media, exercise, or pharmacological stress. The objective of this trial was to determine the diagnostic performance of cPSTA in assessing CAD in patients presenting with chest pain who had been referred by their physician for coronary angiography. Methods This prospective, multicenter, non-significant risk study was designed to: 1) develop machine-learned algorithms to assess the presence of CAD (defined as one or more ≥ 70% stenosis, or fractional flow reserve ≤ 0.80) and 2) test the accuracy of these algorithms prospectively in a naïve verification cohort. This report is an analysis of phase signals acquired from 606 subjects at rest just prior to angiography. From the collective phase signal data, features were extracted and paired with the known angiographic results. A development set, consisting of signals from 512 subjects, was used for machine learning to determine an algorithm that correlated with significant CAD. Verification testing of the algorithm was performed utilizing previously untested phase signals from 94 subjects. Results The machine-learned algorithm had a sensitivity of 92% (95% CI: 74%-100%) and specificity of 62% (95% CI: 51%-74%) on blind testing in the verification cohort. The negative predictive value (NPV) was 96% (95% CI: 85%-100%). Conclusions These initial multicenter results suggest that resting cPSTA may have comparable diagnostic utility to functional tests currently used to assess CAD without requiring cardiac stress (exercise or pharmacological) or exposure of the patient to radioactivity.

CORONARY ARTERY DISEASE LEARNING AND ALGORITHM DEVELOPMENT STUDY: EARLY ANALYSIS OF EJECTION FRACTION EVALUATION

Background: Heart failure is a progressive disease affecting approximately 6 million people in the United States. Left ventricular ejection fraction (LVEF) is used to guide therapy and determine cardiac risks. Methods used to determine LVEF include ventriculography, multigated acquisition scan,