Technologies for intrapericardial delivery of therapeutics and cells.

The pericardium, which surrounds the heart, provides a unique enclosed volume and a site for the delivery of agents to the heart and coronary arteries. While strategies for targeting the delivery of therapeutics to the heart are lacking, various technologies and nanodelivery approaches are emerging as promising methods for site specific delivery to increase therapeutic myocardial retention, efficacy, and bioactivity, while decreasing undesired systemic effects. Here, we provide a literature review of various approaches for intrapericardial delivery of agents. Emphasis is given to sustained delivery approaches (pumps and catheters) and localized release (patches, drug eluting stents, and support devices and meshes). Further, minimally invasive access techniques, pericardial access devices, pericardial washout and fluid analysis, as well as therapeutic and cell delivery vehicles are presented. Finally, several promising new therapeutic targets to treat heart diseases are highlighted.

Four-dimensional flow cardiovascular magnetic resonance in aortic dissection: Assessment in an ex vivo model and preliminary clinical experience.

OBJECTIVE: Four-dimensional flow cardiovascular magnetic resonance may improve assessment of hemodynamics in patients with aortic dissection. The purpose of this study was to evaluate the feasibility and accuracy of 4-dimensional flow cardiovascular magnetic resonance assessment of true and false lumens flow. METHODS: Thirteen ex vivo porcine aortic dissection models were mounted to a flow loop. Four-dimensional flow cardiovascular magnetic resonance and 2-dimensional phase-contrast cardiovascular magnetic resonance measurements were performed, assessed for intraobserver and interobserver variability, and compared with a reference standard of sonotransducer flow volume measurements. Intraobserver and interobserver variability of 4-dimensional flow cardiovascular magnetic resonance were also assessed in 14 patients with aortic dissection and compared with 2-dimensional phase-contrast cardiovascular magnetic resonance. RESULTS: In the ex vivo model, the intraobserver and interobserver measurements had Lin's correlation coefficients of 0.98 and 0.96 and mean differences of 0.17 (±3.65) mL/beat and -0.59 (±5.33) mL/beat, respectively; 4-dimensional and sonotransducer measurements had a Lin's concordance correlation coefficient of 0.95 with a mean difference of 0.35 (±4.92) mL/beat, respectively. In patients with aortic dissection, the intraobserver and interobserver measurements had Lin's concordance correlation coefficients of 0.98 and 0.97 and mean differences of -0.95 (±8.24) mL/beat and 0.62 (±10.05) mL/beat, respectively; 4-dimensional and 2-dimensional flow had a Lin's concordance correlation coefficient of 0.91 with a mean difference of -9.27 (±17.79) mL/beat because of consistently higher flow measured with 4-dimensional flow cardiovascular magnetic resonance in the ascending aorta. CONCLUSIONS: Four-dimensional flow cardiovascular magnetic resonance is feasible in patients with aortic dissection and can reliably assess flow in the true and false lumens of the aorta. This promotes potential future work on functional assessment of aortic dissection hemodynamics.

Use of three-dimensional models to assist in the resection of malignant cardiac tumors.

The application of three-dimensional (3D) printing enables the creation of material objects from digital images by depositing layers of plastic material into 3D structures and can be used for training, education, and surgical planning. We report two patients with large complex cardiac tumors where 3D technology was utilized to analyze the tumor size, location, and extension more precisely, allowing better preoperative planning and decision making.

Replicating Patient-Specific Severe Aortic Valve Stenosis With Functional 3D Modeling.

BACKGROUND: 3D stereolithographic printing can be used to convert high-resolution computed tomography images into life-size physical models. We sought to apply 3D printing technologies to develop patient-specific models of the anatomic and functional characteristics of severe aortic valve stenosis. METHODS AND RESULTS: Eight patient-specific models of severe aortic stenosis (6 tricuspid and 2 bicuspid) were created using dual-material fused 3D printing. Tissue types were identified and segmented from clinical computed tomography image data. A rigid material was used for printing calcific regions, and a rubber-like material was used for soft tissue structures of the outflow tract, aortic root, and noncalcified valve cusps. Each model was evaluated for its geometric valve orifice area, echocardiographic image quality, and aortic stenosis severity by Doppler and Gorlin methods under 7 different in vitro stroke volume conditions. Fused multimaterial 3D printed models replicated the focal calcific structures of aortic stenosis. Doppler-derived measures of peak and mean transvalvular gradient correlated well with reference standard pressure catheters across a range of flow conditions (r=0.988 and r=0.978 respectively, P<0.001). Aortic valve orifice area by Gorlin and Doppler methods correlated well (r=0.985, P<0.001). Calculated aortic valve area increased a small amount for both methods with increasing flow (P=0.002). CONCLUSIONS: By combing the technologies of high-spatial resolution computed tomography, computer-aided design software, and fused dual-material 3D printing, we demonstrate that patient-specific models can replicate both the anatomic and functional properties of severe degenerative aortic valve stenosis.

Quantification of chronic functional mitral regurgitation by automated 3-dimensional peak and integrated proximal isovelocity surface area and stroke volume techniques using real-time 3-dimensional volume color Doppler echocardiography: in vitro and clinical validation.

BACKGROUND: The aim of this study was to test the accuracy of an automated 3-dimensional (3D) proximal isovelocity surface area (PISA) (in vitro and patients) and stroke volume technique (patients) to assess mitral regurgitation (MR) severity using real-time volume color flow Doppler transthoracic echocardiography. METHODS AND RESULTS: Using an in vitro model of MR, the effective regurgitant orifice area and regurgitant volume (RVol) were measured by the PISA technique using 2-dimensional (2D) and 3D (automated true 3D PISA) transthoracic echocardiography. The mean anatomic regurgitant orifice area (0.35±0.10 cm(2)) was underestimated to a greater degree by the 2D (0.12±0.05 cm(2)) than the 3D method (0.25±0.10 cm(2); P<0.001 for both). Compared with the flowmeter (40±14 mL), the RVol by 2D PISA (20±19 mL) was underestimated (P<0.001), but the 3D peak (43±16 mL) and integrated PISA-based (38±14 mL) RVol were comparable (P>0.05 for both). In patients (n=30, functional MR), 3D effective regurgitant orifice area correlated well with cardiac magnetic resonance imaging RVol r=0.84 and regurgitant fraction r=0.80. Compared with cardiac magnetic resonance imaging RVol (33±22 mL), the integrated PISA RVol (34±26 mL; P=0.42) was not significantly different; however, the peak PISA RVol was higher (48±27 mL; P<0.001). In addition, RVol calculated as the difference in automated mitral and aortic stroke volumes by real-time 3D volume color flow Doppler echocardiography was not significantly different from cardiac magnetic resonance imaging (34±21 versus 33±22 mL; P=0.33). CONCLUSIONS: Automated real-time 3D volume color flow Doppler based 3D PISA is more accurate than the 2D PISA method to quantify MR. In patients with functional MR, the 3D RVol by integrated PISA is more accurate than a peak PISA technique. Automated 3D stroke volume measurement can also be used as an adjunctive method to quantify MR severity.

Regurgitation quantification using 3D PISA in volume echocardiography.

We present the first system for measurement of proximal isovelocity surface area (PISA) on a 3D ultrasound acquisition using modified ultrasound hardware, volumetric image segmentation and a simple efficient workflow. Accurate measurement of the PISA in 3D flow through a valve is an emerging method for quantitatively assessing cardiac valve regurgitation and function. Current state of the art protocols for assessing regurgitant flow require laborious and time consuming user interaction with the data, where a precise execution is crucial for an accurate diagnosis. We propose a new improved 3D PISA workflow that is initialized interactively with two points, followed by fully automatic segmentation of the valve annulus and isovelocity surface area computation. Our system is first validated against several in vitro phantoms to verify the calculations of surface area, orifice area and regurgitant flow. Finally, we use our system to compare orifice area calculations obtained from in vivo patient imaging measurements to an independent measurement and then use our system to successfully classify patients into mild-moderate regurgitation and moderate-severe regurgitation categories.

Direct measurement of proximal isovelocity surface area by real-time three-dimensional color Doppler for quantitation of aortic regurgitant volume: an in vitro validation.

OBJECTIVE: The proximal isovelocity surface area (PISA) method is useful in the quantitation of aortic regurgitation (AR). We hypothesized that actual measurement of PISA provided with real-time 3-dimensional (3D) color Doppler yields more accurate regurgitant volumes than those estimated by 2-dimensional (2D) color Doppler PISA. METHODS: We developed a pulsatile flow model for AR with an imaging chamber in which interchangeable regurgitant orifices with defined shapes and areas were incorporated. An ultrasonic flow meter was used to calculate the reference regurgitant volumes. A total of 29 different flow conditions for 5 orifices with different shapes were tested at a rate of 72 beats/min. 2D PISA was calculated as 2pi r(2), and 3D PISA was measured from 8 equidistant radial planes of the 3D PISA. Regurgitant volume was derived as PISA x aliasing velocity x time velocity integral of AR/peak AR velocity. RESULTS: Regurgitant volumes by flow meter ranged between 12.6 and 30.6 mL/beat (mean 21.4 +/- 5.5 mL/beat). Regurgitant volumes estimated by 2D PISA correlated well with volumes measured by flow meter (r = 0.69); however, a significant underestimation was observed (y = 0.5x + 0.6). Correlation with flow meter volumes was stronger for 3D PISA-derived regurgitant volumes (r = 0.83); significantly less underestimation of regurgitant volumes was seen, with a regression line close to identity (y = 0.9x + 3.9). CONCLUSION: Direct measurement of PISA is feasible, without geometric assumptions, using real-time 3D color Doppler. Calculation of aortic regurgitant volumes with 3D color Doppler using this methodology is more accurate than conventional 2D method with hemispheric PISA assumption.

Three-dimensional ultrasound imaging model of mitral valve regurgitation: design and evaluation.

We describe the development of a cardiac flow model and imaging chamber to permit Doppler assessment of complex and dynamic flow events. The model development included the creation of a circulatory loop with variable compliance and resistance; the creation of a secondary regurgitant circuit; and incorporation of an ultrasound imaging chamber to allow two-dimensional (2D) and three-dimensional (3D) Doppler characterization of both simple and complex models of valvular regurgitation. In all, we assessed eight different pulsatile regurgitant volumes through each of four rigid orifices differing in size and shape: 0.15 cm(2) circle, 0.4 cm(2) circle, 0.35 cm(2) slot and 0.4 cm(2) arc. The achieved mean (and range) hemodynamic measures were: peak trans-orifice pressure gradient 117 mm Hg (40 to 245 mm Hg), trans-orifice peak Doppler velocity 560 cm/s (307 to 793 cm/s), Doppler time-velocity integral 237 cm (111 to 362 cm), regurgitant volume 43 mL (11 to 84 mL) and orifice area 0.32 cm(2) (0.15 to 0.4 cm(2)). The model was designed to optimize Doppler signal quality while reflecting anatomic structural relationships and flow events. The 2D color Doppler, 3D color Doppler and continuous wave Doppler quality was excellent whether the data were acquired from the imaging window parallel or perpendicular to the long-axis of flow. This model can be easily adapted to mimic other intracardiac flow pathology or assess future Doppler applications.

Three-dimensional color Doppler echocardiography for direct measurement of vena contracta area in mitral regurgitation: in vitro validation and clinical experience.

OBJECTIVES: Our goal was to prospectively compare the accuracy of real-time three-dimensional (3D) color Doppler vena contracta (VC) area and two-dimensional (2D) VC diameter in an in vitro model and in the clinical assessment of mitral regurgitation (MR) severity. BACKGROUND: Real-time 3D color Doppler allows direct measurement of VC area and may be more accurate for assessment of MR than the conventional VC diameter measurement by 2D color Doppler. METHODS: Using a circulatory loop with an incorporated imaging chamber, various pulsatile flow rates of MR were driven through 4 differently sized orifices. In a clinical study of patients with at least mild MR, regurgitation severity was assessed quantitatively using Doppler-derived effective regurgitant orifice area (EROA), and semiquantitatively as recommended by the American Society of Echocardiography. We describe a step-by-step process to accurately identify the 3D-VC area and compare that measure against known orifice areas (in vitro study) and EROA (clinical study). RESULTS: In vitro, 3D-VC area demonstrated the strongest correlation with known orifice area (r = 0.92, p < 0.001), whereas 2D-VC diameter had a weak correlation with orifice area (r = 0.56, p = 0.01). In a clinical study of 61 patients, 3D-VC area correlated with Doppler-derived EROA (r = 0.85, p < 0.001); the relation was stronger than for 2D-VC diameter (r = 0.67, p < 0.001). The advantage of 3D-VC area over 2D-VC diameter was more pronounced in eccentric jets (r = 0.87, p < 0.001 vs. r = 0.6, p < 0.001, respectively) and in moderate-to-severe or severe MR (r = 0.80, p < 0.001 vs. r = 0.18, p = 0.4, respectively). CONCLUSIONS: Measurement of VC area is feasible with real-time 3D color Doppler and provides a simple parameter that accurately reflects MR severity, particularly in eccentric and clinically significant MR where geometric assumptions may be challenging.

In vitro validation of real-time three-dimensional color Doppler echocardiography for direct measurement of proximal isovelocity surface area in mitral regurgitation.

The 2-dimensional (2D) color Doppler (2D-CD) proximal isovelocity surface area (PISA) method assumes a hemispheric flow convergence zone to estimate transvalvular flow. Recently developed 3-dimensional (3D)-CD can directly visualize PISA shape and surface area without geometric assumptions. To validate a novel method to directly measure PISA using real-time 3D-CD echocardiography, a circulatory loop with an ultrasound imaging chamber was created to model mitral regurgitation (MR). Thirty-two different regurgitant flow conditions were tested using symmetric and asymmetric flow orifices. Three-dimensional-PISA was reconstructed from a hand-held real-time 3D-CD data set. Regurgitant volume was derived using both 2D-CD and 3D-CD PISA methods, and each was compared against a flow-meter standard. The circulatory loop achieved regurgitant volume within the clinical range of MR (11 to 84 ml). Three-dimensional-PISA geometry reflected the 2D geometry of the regurgitant orifice. Correlation between the 2D-PISA method regurgitant volume and actual regurgitant volume was significant (r(2) = 0.47, p <0.001). Mean 2D-PISA regurgitant volume underestimate was 19.1 +/- 25 ml (2 SDs). For the 3D-PISA method, correlation with actual regurgitant volume was significant (r(2) = 0.92, p <0.001), with a mean regurgitant volume underestimate of 2.7 +/- 10 ml (2 SDs). The 3D-PISA method showed less regurgitant volume underestimation for all orifice shapes and regurgitant volumes tested. In conclusion, in an in vitro model of MR, 3D-CD was used to directly measure PISA without geometric assumption. Compared with conventional 2D-PISA, regurgitant volume was more accurate when derived from 3D-PISA across symmetric and asymmetric orifices within a broad range of hemodynamic flow conditions.

Indirect flow rate estimation of the NEDO PI Gyro pump for chronic BVAD experiments.

In totally implantable ventricular assist device systems, measuring flow rate of the pump is necessary to ensure proper operation of the pump in response to the recipient's condition or pump malfunction. To avoid problems associated with the use of flow probes, several methods for estimating flow rate of a rotary blood pump used as a ventricular assist device have been studied. In the present study, we have performed a chronic animal experiment with two NEDO PI gyro pumps as the biventricular assist device for 63 days to evaluate our estimation method by comparing the estimated flow rate with the measured one every 2 days. Up to 15 days after identification of the parameters, our estimations were accurate. Errors increased during postoperation days 20 to 30. Meanwhile, their correlation coefficient r was higher than 0.9 in all the acquired data, and estimated flow rate could simulate the profile of the measured one.

PREFABRICATION DESIGN CONSIDERATIONS FOR A LONG-TERM ELECTRICALLY-ACTUATED ABDOMINAL LEFT VENTRICULAR ASSIST DEVICE (E-TYPE ALVAD).

The conceptual design and development of a long-term, low-profile intracorporeal left ventricular assist device is a multifaceted project involving a series of technical, anatomic and physiologic considerations. Patients with severe left ventricular failure refractory to all other forms of therapy could benefit from such a device. Prior to fabrication of such a blood pump, consideration must be given to physiologic parameters of the projected patient population. The pump must be designed to meet physiologic demands and yet conform to the anatomic constraints posed by the patient population. We measured the body surface area (BSA) of a group of patients (n=50) and found the mean BSA for this group to be 1.804 +/- 0.161 m(2). Using 25 ml/m(2) as a stroke volume index indicative of left ventricular failure and a stroke volume index of 45 ml/m(2) as normal, distributions of stroke volumes (normal and in left ventricular failure) were plotted for a potential population and demonstrated that 63% of the projected population can be returned to normal by a pump with a stroke volume >/= 83 ml. Cadaver fitting studies established that 73% of the potential population can accommodate an ALVAD 10.8 cm in diameter. In-vitro tests demonstrated that a pump stroke volume >/= 83 ml could be achieved by the proposed pump with a 15 mmHg filling pressure at rates up to 125 B/min. A pusher-plate stroke of 0.56 inches would be necessary to provide a stroke volume >/= 83 ml. The percent of the patient population that could be served was determined by excluding those in whom the pump would not fit or in whom it would provide less than a normal resting stroke volume. Approximately 73% of the projected patient population would accommodate this pump and be returned to normal circulatory dynamics.

UTILIZATION OF HAND-HELD PROGRAMMABLE CALCULATORS FOR RAPID BEDSIDE COMPUTATION OF PHYSIOLOGIC-PHARMACOLOGIC VARIABLES AND PROGNOSTIC INDICES DURING MECHANICAL CIRCULATORY SUPPORT.

This study describes five programs that may be used on compact, low-cost programmable calculators with adequate memory and sufficient numbers of program steps to compute cardiorespiratory variables. These short programs are especially useful in the operating room and at the bedside.

THEORETICAL DESIGN CONSIDERATIONS AND PHYSIOLOGIC PERFORMANCE CRITERIA FOR AN IMPROVED INTRACORPOREAL (ABDOMINAL) ELECTRICALLY ACTUATED LONG-TERM LEFT VENTRICULAR ASSIST DEVICE ("E-TYPE" ALVAD) OR PARTIAL ARTIFICIAL HEART.

Our laboratories are engaged in the design of a clinically-oriented electrically actuated long-term intracorporeal (abdominal) left ventricular assist device ("E-type" ALVAD) or partial artificial heart. This infradiaphragmatic blood pump is designed to be powered by implantable electrical to mechanical energy converter systems. THE FOLLOWING ANALYSES WERE UNDERTAKEN TO: [List: see text] The proposed "E-type" ALVAD should be capable of pumping 4-7 liters per minute at heart rates of 75-100 beats per minute during rest, and 10 liters per minute at rates of 120 beats per minute during moderate exercise. These performance levels should be exceeded with a maximum device stroke volume of 85-90 ml and a mean pump inflow (filling) impedance of