Keith A. Collins

Combined Assessment of Myocardial Perfusion and Regional Left Ventricular Function by Analysis of Contrast-Enhanced Power Modulation Images

Background—Echocardiographic contrast media have been used to assess myocardial perfusion and to enhance endocardial definition for improved assessment of left ventricular (LV) function. These methodologies, however, have been qualitative or have required extensive offline image analysis. Power modulation is a recently developed imaging technique that provides selective enhancement of microbubble-generated reflections. Our goal was to test the feasibility of using power modulation for combined quantitative assessment of myocardial perfusion and regional LV function in an animal model of acute ischemia. Methods and Results—Coronary balloon occlusions were performed in 18 anesthetized pigs. Transthoracic power modulation images (Agilent 5500) were obtained during continuous intravenous infusion of the contrast agent Definity (DuPont) at baseline and during brief coronary occlusion and reperfusion and were analyzed with custom software. At each phase, myocardial perfusion was assessed by calculation, in 6 myocardial regions of interest, of mean pixel intensity and the rate of contrast replenishment after high-power ultrasound impulses. LV function was assessed by calculation of regional fractional area change from semiautomatically detected endocardial borders. All ischemic episodes caused detectable and reversible changes in perfusion and function. Perfusion defects, validated with fluorescent microspheres, were visualized in real time and confirmed by a significant decrease in pixel intensity in the left anterior descending coronary artery territory after balloon inflation and reduced rate of contrast replenishment. Fractional area change decreased significantly in ischemic segments and was restored with reperfusion. Conclusions—Power modulation allows simultaneous online assessment of myocardial perfusion and regional LV wall motion, which may improve the echocardiographic diagnosis of myocardial ischemia.

Hemodynamic Ramp Tests in Patients With Left Ventricular Assist Devices

OBJECTIVES This study tested whether combined invasive hemodynamic and echocardiographic ramp tests can help optimize patient management. BACKGROUND Guidelines for optimizing speed and medications in continuous flow ventricular assist device (cfLVAD) patients are mainly based on expert opinion. METHODS Thirty-five cfLVAD patients (21 HeartMate II [Thoratec, Pleasanton, California] and 14 HVAD [HeartWare International, Framingham, Massachusetts]) underwent ramp tests with right heart catheterization (including central venous pressure [CVP], pulmonary artery pressure, pulmonary capillary wedge pressure [PCWP], and blood pressure) and echocardiography. Data were recorded at up to 9 speed settings. Speed changes were in steps of 400 revolutions per minute (RPM) for HeartMate II (8,000 to 12,000 RPM) and 100 RPM for HVAD (2,300 to 3,200 RPM) patients. RESULTS Only 42.9% of patients had normal CVPs and PCWPs at their original RPM settings. Going from lowest to highest speeds, cardiac output improved by 0.16 ± 0.19 l/min/step (total change 1.28 ± 1.41 l/min) and PCWP decreased by 1.23 ± 0.85 mm Hg/step (total change 9.9 ± 6.5 mm Hg). CVP and systolic blood pressure did not change significantly with RPM. RPM were adjusted based on test results to achieve CVPs and PCWPs as close to normal limits as possible, which was feasible in 56% of patients. For the remainder, results indicated which type of medical management should be pursued. CONCLUSIONS Use of combined hemodynamic and echocardiographic ramp tests in patients provides objective means of optimizing RPM, and has the potential to guide medical management. It remains to be tested whether this strategy has a beneficial impact on quality of life or clinical outcomes.

Secondary Coronary Artery Vasospasm Promotes Cardiomyopathy Progression

Genetic defects in the plasma membrane-associated sarcoglycan complex produce cardiomyopathy characterized by focal degeneration. The infarct-like pattern of cardiac degeneration has led to the hypothesis that coronary artery vasospasm underlies cardiomyopathy in this disorder. We evaluated the coronary vasculature of gamma-sarcoglycan mutant mice and found microvascular filling defects consistent with arterial vasospasm. However, the vascular smooth muscle sarcoglycan complex was intact in the coronary arteries of gamma-sarcoglycan hearts with perturbation of the sarcoglycan complex only within the adjacent myocytes. Thus, in this model, coronary artery vasospasm derives from a vascular smooth muscle-cell extrinsic process. To reduce this secondary vasospasm, we treated gamma-sarcoglycan-deficient mice with the calcium channel antagonist verapamil. Verapamil treatment eliminated evidence of vasospasm and ameliorated histological and functional evidence of cardiomyopathic progression. Echocardiography of verapamil-treated, gamma-sarcoglycan-null mice showed an improvement in left ventricular fractional shortening (44.3 +/- 13.3% treated versus 37.4 +/- 15.3% untreated), maximal velocity at the aortic outflow tract (114.9 +/- 27.9 cm/second versus 92.8 +/- 22.7 cm/second), and cardiac index (1.06 +/- 0.30 ml/minute/g versus 0.67 +/- 0.16 ml/minute/g, P < 0.05). These data indicate that secondary vasospasm contributes to the development of cardiomyopathy and is an important therapeutic target to limit cardiomyopathy progression.

Impaired exercise tolerance and skeletal muscle myopathy in sulfonylurea receptor-2 mutant mice

By sensing intracellular energy levels, ATP-sensitive potassium (K(ATP)) channels help regulate vascular tone, glucose metabolism, and cardioprotection. SUR2 mutant mice lack full-length K(ATP) channels in striated and smooth muscle and display a complex phenotype of hypertension and coronary vasospasm. SUR2 mutant mice also display baseline cardioprotection and can withstand acute sympathetic stress better than normal mice. We now studied response to a form of chronic stress, namely that induced by 4 wk of daily exercise on SUR2 mutant mice. Control mice increased exercise capacity by 400% over the training period, while SUR2 mutant mice showed little increase in exercise capacity. Unexercised SUR2 mutant showed necrotic and regenerating fibers in multiple muscle skeletal muscles, including quadriceps, tibialis anterior, and diaphragm muscles. Unlike exercised control animals, SUR2 mutant mice did not lose weight, presumably due to less overall exertion. Unexercised SUR2 mutant mice showed a trend of mildly reduced cardiac function, measured by fractional shortening, (46 +/- 4% vs. 57 +/- 7% for SUR2 mutant and control, respectively), and this decrease was not exacerbated by chronic exercise exposure. Despite an improved response to acute sympathetic stress and baseline cardioprotection, exercise intolerance results from lack of SUR2 K(ATP) channels in mice.

Semi-automated analysis of dynamic changes in myocardial contrast from real-time three-dimensional echocardiographic images as a basis for volumetric quantification of myocardial perfusion

AIMS Despite the potential of real-time three-dimensional (3D) echocardiography (RT3DE) to assess myocardial perfusion, there is no quantification method available for perfusion analysis from RT3DE images. Such method would require 3D regions of interest (ROI) to be defined and adjusted frame-by-frame to compensate for cardiac translation and deformation. Our aims were to develop and test a technique for automated identification of 3D myocardial ROI suitable for translation-free quantification of myocardial videointensity over time, MVI(t), from contrast-enhanced RT3DE images. METHODS AND RESULTS Twelve transthoracic RT3DE (Philips) data sets obtained in pigs during transition from no contrast to steady-state enhancement (Definity) were analysed using custom software. Analysis included: (i) semi-automated detection of left ventricular endo- and epicardial surfaces using level-set techniques in one frame to define a 3D myocardial ROI, (ii) rigid 3D registration to reduce translation and rotation, (iii) elastic 3D registration to compensate for deformation, and (iv) quantification of MVI(t) in the 3D ROI from the registered and non-registered data sets to assess the effectiveness of registration. For each MVI(t) curve we computed % variability during steady-state enhancement (100 x SD/mean) and goodness of fit (r2) to the indicator dilution equation MVI(t) = A[1-exp(-betat)]. Analysis of myocardial contrast throughout contrast inflow was feasible in all data sets. Three-dimensional registration improved MVI(t) curves in terms of both % variability (2.8 +/- 1.8 to 1.5 +/- 0.9%; P < 0.05) and goodness of fit (r2 from 0.79 +/- 0.2 to 0.90 +/- 0.1; P < 0.05). CONCLUSION This is the first study to describe a new technique for semi-automated volumetric quantification of myocardial contrast from RT3DE images that includes registration and thus provides the basis for 3D measurement of myocardial perfusion.

Screening for Outflow Cannula Malfunction of Left Ventricular Assist Devices (LVADs) With the Use of Doppler Echocardiography: New LVAD-Specific Reference Values for Contemporary Devices

BACKGROUND Echocardiographic assessment of left ventricular assist devices (LVADs) is used as a screening tool to evaluate the integrity and mechanics of the pump and circuit. We aimed to 1) establish the normal range and upper reference limit of peak velocity of the outflow cannula for the modern era of LVADs and 2) assess the clinical performance of the currently cited and newly proposed reference limits in patients with continuous-flow LVADs as a screening tool for cannula malfunction. METHODS LVAD outflow peak CW velocities were measured with the use of Doppler transthoracic echocardiography (TTE) in 57 patients with LVADs (44 with Heartmate II (HM2), 13 with Heartware (HW)). The average velocity and the upper and lower normal reference limits (defined as ±2 standard deviations from the mean) for each LVAD type was calculated. The upper reference limit was then used as a screening threshold for cannula malfunction. RESULTS The average outflow cannula peak velocity for the normal HM2 cohort was 1.86 ± 0.44 m/s with upper and lower reference limits of 2.73 m/s and 0.98 m/s, respectively. The average outflow cannula peak velocity for the normal HW cohort was 2.36 ± 0.53 m/s with upper and lower reference limits of 3.42 m/s and 1.3 m/s, respectively, which was significantly higher than the HM2 cohort (P = .004). CONCLUSIONS In both HM2 and HW LVADs, the average peak outflow velocity and reference limit for the normal population, as measured by Doppler TTE, was markedly higher than the currently used LVAD reference limits of 2 m/s and are significantly different between devices. Patients with peak outflow velocities above our upper reference limits should be evaluated for LVAD outflow cannula malfunction.

Quantitative analysis of myocardial perfusion and regional left ventricular function from contrast-enhanced power modulation images

Our goal was to test the feasibility of using power modulation, a new echocardiographic imaging technique, for combined quantitative assessment of myocardial perfusion and regional LV function. Coronary balloon occlusions were performed in 18 anesthetized pigs. Images were obtained during iv contrast infusion at baseline, during coronary occlusion and reperfusion, and analyzed using custom software. At each phase, regional myocardial perfusion was assessed by calculating mean pixel intensity and the rate of contrast replenishment following high-power ultrasound impulses. LV function was assessed by calculating regional fractional area change. All ischemic episodes caused delectable and reversible changes in perfusion and function. Perfusion defects were visualized in real time and confirmed by a significant decrease in pixel intensity in the LAD territory following balloon inflation and reduced rate of contrast replenishment. Fractional area change significantly decreased in ischemic segments, and was restored with reperfusion. Power modulation allows simultaneous on-line assessment of myocardial perfusion and regional LV wall motion.

Quantitative assessment of myocardial perfusion using real-time three-dimensional echocardiographic imaging

The new real-time three-dimensional (RT3D) echocardiographic technology offers an opportunity for myocardial perfusion imaging in the entire heart without the need for reconstruction from multiple slices and repeated contrast maneuvers. Our aims were to develop and validate a technique for quantitative volumetric assessment of myocardial perfusion. Studies were conducted in 5 isolated rabbit hearts and in 5 patients with ischemic heart disease. In rabbits, RT3D datasets were acquired over 30 sec, during which infusion of contrast agent definity was initiated and reached steady-state myocardial enhancement. Data were obtained at 3 different levels of coronary flow. At each level, myocardial videointensity (MVI) was measured over time in 3 LV short-axis slices of fixed thickness and peak contrast inflow rate (PCIR) was calculated. Administration of contrast resulted in clearly visible and measurable dynamic changes in MVI. PCIR followed the changes in coronary flow (p<0.0I). Feasibility in humans was tested by imaging the interventricular septum during initiation of infusion of definity at rest and during adenosine infusion. Dynamic changes in MVI were visible and suitable for quantitative analysis. In 2 patients, adenosine resulted in dark regions, reflecting lack of myocardial filling in stenosis-related territories. RT3D imaging and quantification of myocardial perfusion using our algorithm are feasible. This approach can potentially allow more accurate assessment of the extent of perfusion defects than 2D myocardial contrast echocardiography.

Simultaneous quantitative assessment of myocardial perfusion and function using analysis of color-encoded contrast-enhanced images

We hypothesized that analysis of color-encoded, contrast-enhanced, power modulation images could allow simultaneous quantification of myocardial perfusion and regional LV wall motion. We studied 12 anesthetized pigs at baseline, during acute ischemia and subsequent reperfusion, as well as 8 patients post acute myocardial infarction. Color kinesis was used to color-encode endocardial motion during real-time perfusion imaging with high-energy ultrasound pulses. Wall motion was assessed by calculating regional fractional area changes. Translation-free perfusion analysis was performed in automatically identified myocardial regions of interest. Steady-state intensity and initial rate of contrast replenishment were calculated. In all animals, ischemia caused reversible changes in the images and the calculated perfusion and function indices. A significant decrease in pixel intensity (14%) and contrast replenishment rate (66%) in LAD-related segments coincided with a decrease in fractional area change (34%). In patients, respective perfusion and function indices were 61%, 51% and 58% lower in segments where perfusion defects and/or regional wall motion abnormalities were noted in grey-scale images. Color-encoded, contrast-enhanced power modulation allows simultaneous real-time quantification of myocardial perfusion and regional LV function.

Semi-automated segmentation and registration of triggered three-dimensional echocardiographic images as a basis for volumetric analysis of myocardial perfusion

We developed a technique for automated identification of 3D myocardial ROI suitable for translation-free quantification of myocardial videointensity over time, MVI(t), from RT3DE images. Our software was tested on 12 ECG-triggered RT3DE datasets obtained in pigs during transient contrast inflow. Analysis included: (1) semi-automated detection of endo- and epicardial surfaces using level-set techniques to define a 3D myocardial ROI, (2) rigid 3D registration to reduce translation and rotation, (3) elastic 3D registration to compensate for deformation, and (4) quantification of MVI(t) with and without registration to assess its effectiveness. Analysis of myocardial contrast throughout contrast inflow was feasible in all datasets. 3D registration improved MVI(t) curves in terms of both % variability during steady-state enhancement: 2.8plusmn1.8% to 1.5plusmn0.9%, and goodness of fit to the indicator dilution equation MVI(t)=Aldr(1-exp(-betat)): r2 from 0.79plusmn0.2 to 0.90plusmn0.1. This is the first study to describe a new technique for semi-automated volumetric quantification of myocardial contrast from RT3DE images that includes registration and thus provides the basis for 3D measurement of myocardial perfusion.