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We describe a clinical grade, "active", monopole antenna-based metallic guidewire that has a continuous shaft-to-tip image profile, a pre-shaped tip-curve, standard 0.89 mm (0.035″) outer diameter, and a detachable connector for catheter exchange during cardiovascular catheterization at 0.55T.Electromagnetic simulations were performed to characterize the magnetic field around the antenna whip for continuous tip visibility. The active guidewire was manufactured using medical grade materials in an ISO Class 7 cleanroom. RF-induced heating of the active guidewire prototype was tested in one gel phantom per ASTM 2182-19a, alone and in tandem with clinical metal-braided catheters. Real-time MRI visibility was tested in one gel phantom and in-vivo in two swine. Mechanical performance was compared with commercial equivalents.The active guidewire provided continuous "profile" shaft and tip visibility in-vitro and in-vivo, analogous to guidewire shaft-and-tip profiles under X-ray. The MRI signal signature matched simulation results. Maximum unscaled RF-induced temperature rise was 5.2°C and 6.5°C (3.47 W/kg local background specific absorption rate), alone and in tandem with a steel-braided catheter, respectively. Mechanical characteristics matched commercial comparator guidewires.The active guidewire was clearly visible via real-time MRI at 0.55T and exhibits a favorable geometric sensitivity profile depicting the guidewire continuously from shaft-to-tip including a unique curved-tip signature. RF-induced heating is clinically acceptable. This design allows safe device navigation through luminal structures and heart chambers. The detachable connector allows delivery and exchange of cardiovascular catheters while maintaining guidewire position. This enhanced guidewire design affords the expected performance of X-ray guidewires during human MRI catheterization.

Background Left ventricular (LV) contractility and compliance are derived from pressure–volume (PV) loops during dynamic preload reduction, but reliable simultaneous measurements of pressure and volume are challenging with current technologies. We have developed a method to quantify contractility and compliance from PV loops during a dynamic preload reduction using simultaneous measurements of volume from real-time cardiovascular magnetic resonance (CMR) and invasive LV pressures with CMR-specific signal conditioning. Methods Dynamic PV loops were derived in 16 swine (n = 7 naïve, n = 6 with aortic banding to increase afterload, n = 3 with ischemic cardiomyopathy) while occluding the inferior vena cava (IVC). Occlusion was performed simultaneously with the acquisition of dynamic LV volume from long-axis real-time CMR at 0.55 T, and recordings of invasive LV and aortic pressures, electrocardiogram, and CMR gradient waveforms. PV loops were derived by synchronizing pressure and volume measurements. Linear regression of end-systolic- and end-diastolic- pressure–volume relationships enabled calculation of contractility. PV loops measurements in the CMR environment were compared to conductance PV loop catheter measurements in 5 animals. Long-axis 2D LV volumes were validated with short-axis-stack images. Results Simultaneous PV acquisition during IVC-occlusion was feasible. The cardiomyopathy model measured lower contractility (0.2 ± 0.1 mmHg/ml vs 0.6 ± 0.2 mmHg/ml) and increased compliance (12.0 ± 2.1 ml/mmHg vs 4.9 ± 1.1 ml/mmHg) compared to naïve animals. The pressure gradient across the aortic band was not clinically significant (10 ± 6 mmHg). Correspondingly, no differences were found between the naïve and banded pigs. Long-axis and short-axis LV volumes agreed well (difference 8.2 ± 14.5 ml at end-diastole, -2.8 ± 6.5 ml at end-systole). Agreement in contractility and compliance derived from conductance PV loop catheters and in the CMR environment was modest (intraclass correlation coefficient 0.56 and 0.44, respectively). Conclusions Dynamic PV loops during a real-time CMR-guided preload reduction can be used to derive quantitative metrics of contractility and compliance, and provided more reliable volumetric measurements than conductance PV loop catheters.

Purpose Low-field (0.55 T) high-performance cardiovascular magnetic resonance (CMR) is an attractive platform for CMR-guided intervention as device heating is reduced around 7.5-fold compared to 1.5 T. This work determines the feasibility of visualizing cardiac radiofrequency (RF) ablation lesions at low field CMR and explores a novel alternative method for targeted tissue destruction: acetic acid chemoablation. Methods N = 10 swine underwent X-ray fluoroscopy-guided RF ablation (6–7 lesions) and acetic acid chemoablation (2–3 lesions) of the left ventricle. Animals were imaged at 0.55 T with native contrast 3D-navigator gated T1-weighted T1w) CMR for lesion visualization, gated single-shot imaging to determine potential for real-time visualization of lesion formation, and T1 mapping to measure change in T1 in response to ablation. Seven animals were euthanized on ablation day and hearts imaged ex vivo. The remaining animals were imaged again in vivo at 21 days post ablation to observe lesion evolution. Results Chemoablation lesions could be visualized and displayed much higher contrast than necrotic RF ablation lesions with T1w imaging. On the day of ablation, in vivo myocardial T1 dropped by 19 ± 7% in RF ablation lesion cores, and by 40 ± 7% in chemoablation lesion cores (p Conclusion The visualization of coagulation necrosis from cardiac ablation is feasible using low-field high-performance CMR. Chemoablation produced a more pronounced change in lesion T1 than RF ablation, increasing SNR and CNR and thereby making it easier to visualize in both 3D navigator-gated and real-time CMR and more suitable for low-field imaging.

Background: Left ventricular outflow tract obstruction complicates hypertrophic cardiomyopathy and transcatheter mitral valve replacement. Septal reduction therapies including surgical myectomy and alcohol septal ablation are limited by surgical morbidity or coronary anatomy and high pacemaker rates, respectively. We developed a novel transcatheter procedure, mimicking surgical myotomy, called Septal Scoring Along the Midline Endocardium (SESAME). Methods: SESAME was performed in 5 naive pigs and 5 pigs with percutaneous aortic banding–induced left ventricular hypertrophy. Fluoroscopy and intracardiac echocardiography guided the procedures. Coronary guiding catheters and guidewires were used to mechanically enter the basal interventricular septum. Imparting a tip bend to the guidewire enabled intramyocardial navigation with multiple df . The guidewire trajectory determined the geometry of SESAME myotomy. The myocardium was lacerated using transcatheter electrosurgery. Cardiac function and tissue characteristics were assessed by cardiac magnetic resonance at baseline, postprocedure, and at 7- or 30-day follow-up. Results: SESAME myotomy along the intended trajectory was achieved in all animals. The myocardium splayed after laceration, increasing left ventricular outflow tract area (753 to 854 mm 2 , P =0.008). Two naive pigs developed ventricular septal defects due to excessively deep lacerations in thin baseline septa. No hypertrophy model pig, with increased septal thickness and left ventricular mass compared with naive pigs, developed ventricular septal defects. One animal developed left axis deviation on ECG but no higher conduction block was seen in any animal. Coronary artery branches were intact on angiography with no infarction on cardiac magnetic resonance late gadolinium imaging. Cardiac magnetic resonance chamber volumes, function, flow, and global strain were preserved. No myocardial edema was evident on cardiac magnetic resonance T1 mapping. Conclusions: This preclinical study demonstrated feasibility of SESAME, a novel transcatheter myotomy to relieve left ventricular outflow tract obstruction. This percutaneous procedure using available devices, with a safe surgical precedent, is readily translatable into patients.

Transcatheter electrosurgery refers to a family of procedures using radiofrequency energy to vaporize and traverse or lacerate tissue despite flowing blood. The authors review theory, simulations, and benchtop demonstrations of how guidewires, insulation, adjunctive catheters, and dielectric medium interact. For tissue traversal, all but the tip of traversing guidewires is insulated to concentrate current. For leaflet laceration, the "Flying V" configuration concentrates current at the inner lacerating surface of a kinked guidewire. Flooding the field with non-ionic dextrose eliminates alternative current paths. Clinical applications include traversing occlusions (pulmonary atresia, arterial and venous occlusion, and iatrogenic graft occlusion), traversing tissue planes (atrial and ventricular septal puncture, radiofrequency valve repair, transcaval access, Potts and Glenn shunts), and leaflet laceration (BASILICA, LAMPOON, ELASTA-Clip, and others). Tips are provided for optimizing these techniques. Transcatheter electrosurgery already enables a range of novel therapeutic procedures for structural heart disease, and represents a promising advance toward transcatheter surgery.

Objectives This study sought to test safety and exploratory effectiveness of a dedicated transcaval closure device (TCD). Background Transcaval access enables delivery of large-caliber devices to the aorta in patients ineligible for transfemoral arterial access. Closure of aortocaval fistulae using off-label nitinol cardiac occluders has been shown to be safe, but persistent aortocaval fistulae at exit from the catheterization lab and bleeding complications were common in a prospective study. Methods Preclinical testing of the TCD was performed in 24 Yorkshire swine, including 10 under good laboratory practice conditions. Subsequently, subjects undergoing transcatheter aortic valve replacement for symptomatic severe aortic stenosis, ineligible for transfemoral arterial access, were enrolled in a U.S. Food and Drug Administration–approved early feasibility study of the TCD (Transmural Systems, Andover, Massachusetts). Independently adjudicated endpoints included technical, device, and procedural success, incorporating in-hospital and 30-day clinical and imaging follow-up. Results Transcaval access and closure in swine confirmed that at 30 days, TCDs were almost entirely endothelialized. Subsequently, 12 subjects were enrolled in the early feasibility study. Transcaval access, transcatheter aortic valve replacement, and aortocaval fistula closure was successful in all 12 subjects. The primary endpoint of technical success was met in 100% of subjects. Complete closure of the transcaval access tract was achieved in 75% of subjects at exit from the catheterization lab and in 100% of subjects at 30 days. There were zero modified Valve Academic Research Consortium-2 major vascular complications and zero Valve Academic Research Consortium-2 life-threatening or major bleeding complications related to transcaval access or the TCD. Conclusions The TCD achieved complete closure of the transcaval access tract in most subjects at exit from the catheterization lab and essentially eliminated transcaval-related bleeding. Dedicated devices for transcaval access and closure could enable more widespread adoption of transcaval techniques without fear of bleeding complications. (Transmural Systems Transcaval Closure Device for Transcaval Access Ports During Transcatheter Aortic Valve Replacement; NCT03432494).

Objectives: This study sought to develop a novel technique called bioprosthetic or native aortic scallop intentional laceration to prevent coronary artery obstruction (BASILICA).Background:...

OBJECTIVES: Pledget-assisted suture tricuspid valve annuloplasty (PASTA) is a novel technique using marketed equipment to deliver percutaneous trans-annular sutures to create a double-orifice tricuspid valve. BACKGROUND: Tricuspid regurgitation is a malignant disease with high surgical mortality and no commercially available transcatheter solution in the US. METHODS: Two iterations of PASTA were tested using trans-apical or trans-jugular access in swine. Catheters directed paired coronary guidewires to septal and lateral targets on the tricuspid annulus under fluoroscopic and echocardiographic guidance. Guidewires were electrified to traverse the annular targets and exchanged for pledgeted sutures. The sutures were drawn together and knotted, apposing septal and lateral targets, creating a double orifice tricuspid valve. RESULTS: Twenty-two pigs underwent PASTA. Annular and chamber dimensions were reduced (annular area, 10.1±0.8cm(2) to 3.8±1.5cm(2) (naïve) and 13.1±1.5 cm(2) to 6.2±1.0 cm(2) (diseased); septal-lateral diameter, 3.9±0.3mm to 1.4±0.6mm (naïve) and 4.4±0.4mm to 1.7±1.0mm (diseased); and right ventricular end-diastolic volume, 94±13ml to 85±14ml (naïve) and 157±25ml to 143±20ml (diseased)). MRI derived tricuspid regurgitation fraction fell from 32±12% to 4±5%. Results were sustained at 30 days. Pledget pull-through force was five-fold higher (40.6±11.7N vs 8.0±2.6N, p

BackgroundQuantification of cardiac output and pulmonary vascular resistance (PVR) are critical components of invasive hemodynamic assessment, and can be measured concurrently with pressures using phase contrast CMR flow during real-time CMR guided cardiac catheterization.MethodsOne hundred two consecutive patients underwent CMR fluoroscopy guided right heart catheterization (RHC) with simultaneous measurement of pressure, cardiac output and pulmonary vascular resistance using CMR flow and the Fick principle for comparison. Procedural success, catheterization time and adverse events were prospectively collected.ResultsRHC was successfully completed in 97/102 (95.1%) patients without complication. Catheterization time was 20±11min. In patients with and without pulmonary hypertension, baseline mean pulmonary artery pressure was 39±12mmHg vs. 18±4mmHg (p&nbsp

Transcatheter electrosurgery refers to a family of procedures using radiofrequency energy to vaporize and traverse or lacerate tissue despite flowing blood. The authors review theory, simulations, and benchtop demonstrations of how guidewires, insulation, adjunctive catheters, and dielectric medium interact. For tissue traversal, all but the tip of traversing guidewires is insulated to concentrate current. For leaflet laceration, the "Flying V" configuration concentrates current at the inner lacerating surface of a kinked guidewire. Flooding the field with non-ionic dextrose eliminates alternative current paths. Clinical applications include traversing occlusions (pulmonary atresia, arterial and venous occlusion, and iatrogenic graft occlusion), traversing tissue planes (atrial and ventricular septal puncture, radiofrequency valve repair, transcaval access, Potts and Glenn shunts), and leaflet laceration (BASILICA, LAMPOON, ELASTA-Clip, and others). Tips are provided for optimizing these techniques. Transcatheter electrosurgery already enables a range of novel therapeutic procedures for structural heart disease, and represents a promising advance toward transcatheter surgery.

This study sought to test safety and exploratory effectiveness of a dedicated transcaval closure device (TCD).Transcaval access enables delivery of large-caliber devices to the aorta in patients ineligible for transfemoral arterial access. Closure of aortocaval fistulae using off-label nitinol cardiac occluders has been shown to be safe, but persistent aortocaval fistulae at exit from the catheterization lab and bleeding complications were common in a prospective study.Preclinical testing of the TCD was performed in 24 Yorkshire swine, including 10 under good laboratory practice conditions. Subsequently, subjects undergoing transcatheter aortic valve replacement for symptomatic severe aortic stenosis, ineligible for transfemoral arterial access, were enrolled in a U.S. Food and Drug Administration-approved early feasibility study of the TCD (Transmural Systems, Andover, Massachusetts). Independently adjudicated endpoints included technical, device, and procedural success, incorporating in-hospital and 30-day clinical and imaging follow-up.Transcaval access and closure in swine confirmed that at 30 days, TCDs were almost entirely endothelialized. Subsequently, 12 subjects were enrolled in the early feasibility study. Transcaval access, transcatheter aortic valve replacement, and aortocaval fistula closure was successful in all 12 subjects. The primary endpoint of technical success was met in 100% of subjects. Complete closure of the transcaval access tract was achieved in 75% of subjects at exit from the catheterization lab and in 100% of subjects at 30 days. There were zero modified Valve Academic Research Consortium-2 major vascular complications and zero Valve Academic Research Consortium-2 life-threatening or major bleeding complications related to transcaval access or the TCD.The TCD achieved complete closure of the transcaval access tract in most subjects at exit from the catheterization lab and essentially eliminated transcaval-related bleeding. Dedicated devices for transcaval access and closure could enable more widespread adoption of transcaval techniques without fear of bleeding complications. (Transmural Systems Transcaval Closure Device for Transcaval Access Ports During Transcatheter Aortic Valve Replacement; NCT03432494).

Objectives The authors propose a novel transcatheter transection of the anterior mitral leaflet to prevent iatrogenic left ventricular outflow tract (LVOT) obstruction during transcatheter mitral valve replacement (TMVR). Background LVOT obstruction is a life-threatening complication of TMVR caused by septal displacement of the anterior mitral leaflet. Methods In vivo procedures in swine were guided by biplane x-ray fluoroscopy and intracardiac echocardiography. Retrograde transaortic 6-F guiding catheters straddled the anterior mitral leaflet. A stiff 0.014-inch guidewire with polymer jacket insulation was electrified and advanced from the LVOT, through the A2 leaflet base, into the left atrium. The wire was snared and externalized, forming a loop that was energized and withdrawn to lacerate the anterior mitral leaflet. Results The anterior mitral leaflet was successfully lacerated in 7 live and 1 post-mortem swine under heparinization. Lacerations extended to 89 ± 19% of leaflet length and were located within 0.5 ± 0.4 mm of leaflet centerline. The chordae were preserved and retracted the leaflet halves away from the LVOT. LVOT narrowing after benchtop TMVR was significantly reduced with intentional laceration of the anterior mitral leaflet to prevent LVOT obstruction than without (65 ± 10% vs. 31 ± 18% of pre-implantation diameter, p Conclusions Using simple catheter techniques, the anterior mitral valve leaflet was transected. Cautiously applied in patients, this strategy can prevent anterior mitral leaflet displacement and LVOT obstruction caused by TMVR.

Background Cardiovascular magnetic resonance (CMR) fluoroscopy allows for simultaneous measurement of cardiac function, flow and chamber pressure during diagnostic heart catheterization. To date, commercial metallic guidewires were considered contraindicated during CMR fluoroscopy due to concerns over radiofrequency (RF)-induced heating. The inability to use metallic guidewires hampers catheter navigation in patients with challenging anatomy. Here we use low specific absorption rate (SAR) imaging from gradient echo spiral acquisitions and a commercial nitinol guidewire for CMR fluoroscopy right heart catheterization in patients. Methods The low-SAR imaging protocol used a reduced flip angle gradient echo acquisition (10° vs 45°) and a longer repetition time (TR) spiral readout (10 ms vs 2.98 ms). Temperature was measured in vitro in the ASTM 2182 gel phantom and post-mortem animal experiments to ensure freedom from heating with the selected guidewire (150 cm × 0.035″ angled-tip nitinol Terumo Glidewire). Seven patients underwent CMR fluoroscopy catheterization. Time to enter each chamber (superior vena cava, main pulmonary artery, and each branch pulmonary artery) was recorded and device visibility and confidence in catheter and guidewire position were scored on a Likert-type scale. Results Negligible heating (

ObjectivesThis study sought to demonstrate transcatheter deployment of a circumferential device within the pericardial space to modify tricuspid annular dimensions interactively and to reduce functional tricuspid regurgitation (TR) in swine.BackgroundFunctional TR is common and is associated with increased morbidity and mortality. There are no reported transcatheter tricuspid valve repairs. We describe a transcatheter extracardiac tricuspid annuloplasty device positioned in the pericardial space and delivered by puncture through the right atrial appendage. We demonstrate acute and chronic feasibility in swine.MethodsTransatrial intrapericardial tricuspid annuloplasty (TRAIPTA) was performed in 16 Yorkshire swine, including 4 with functional TR. Invasive hemodynamics and cardiac magnetic resonance imaging (MRI) were performed at baseline, immediately after annuloplasty and at follow-up.ResultsPericardial access via a right atrial appendage puncture was uncomplicated. In 9 naïve animals, tricuspid septal-lateral and anteroposterior dimensions, the annular area and perimeter, were reduced by 49%, 31%, 59%, and 24% (p < 0.001), respectively. Tricuspid leaflet coaptation length was increased by 53% (p < 0.001). Tricuspid geometric changes were maintained after 9.7 days (range, 7 to 14 days). Small effusions (mean, 46 ml) were observed immediately post-procedure but resolved completely at follow-up. In 4 animals with functional TR, severity of regurgitation by intracardiac echocardiography was reduced.ConclusionsTransatrial intrapericardial tricuspid annuloplasty is a transcatheter extracardiac tricuspid valve repair performed by exiting the heart from within via a transatrial puncture. The geometry of the tricuspid annulus can interactively be modified to reduce severity of functional TR in an animal model.

This study sought to develop a novel technique called bioprosthetic or native aortic scallop intentional laceration to prevent coronary artery obstruction (BASILICA).Coronary artery obstruction is a rare but fatal complication of transcatheter aortic valve replacement (TAVR).We lacerated pericardial leaflets in vitro using catheter electrosurgery, and tested leaflet splaying after benchtop TAVR. The procedure was tested in swine. BASILICA was then offered to patients at high risk of coronary obstruction from TAVR and ineligible for surgical aortic valve replacement. BASILICA used marketed devices. Catheters directed an electrified guidewire to traverse and lacerate the aortic leaflet down the center line. TAVR was performed as usual.TAVR splayed lacerated bovine pericardial leaflets. BASILICA was successful in pigs, both to left and right cusps. Necropsy revealed full length lacerations with no collateral thermal injury. Seven patients underwent BASILICA on a compassionate basis. Six had failed bioprosthetic valves, both stented and stent-less. Two had severe aortic stenosis, including 1 patient with native disease, 3 had severe aortic regurgitation, and 2 had mixed aortic valve disease. One patient required laceration of both left and right coronary cusps. There was no hemodynamic compromise in any patient following BASILICA. All patients had successful TAVR, with no coronary obstruction, stroke, or any major complications. All patients survived to 30 days.BASILICA may durably prevent coronary obstruction from TAVR. The procedure was successful across a range of presentations, and requires further evaluation in a prospective trial. Its role in treatment of degenerated TAVR devices remains untested.

Objectives: We test the safety of transatrial pericardial access using small catheters, infusion of carbon dioxide (CO2) or iodinated contrast to facilitate sub-xiphoid access, and catheter withdrawal under full anticoagulation. Background: Sub-xiphoid pericardial access is required for electrophysiological and structural heart interventions. If present, an effusion protects the heart from needle injury by separating the myocardium from the pericardium. However, if the pericardium is ‘dry' then there is a significant risk of right ventricle or coronary artery laceration caused by the heart beating against the needle tip. Intentional right atrial exit is an alternative pericardial access route, through which contrast media could be infused to separate pericardial layers. Methods: Transatrial pericardial access was obtained in a total of 30 Yorkshire swine using 4Fr or 2.8Fr catheters. In 16 animals, transatrial catheters were withdrawn under anticoagulation and MRI was performed to monitor for pericardial hemorrhage. In 14 animals, iodinated contrast or CO2 was infused before sub-xiphoid access was obtained. Results: Small effusions (mean 18.5 ml) were observed after 4Fr (1.3 mm outer-diameter) but not after 2.8Fr (0.9 mm outer-diameter) transatrial catheter withdrawal despite full anticoagulation (mean activated clotting time 383 sec), with no hemodynamic compromise. Pericardial CO2 resorbed spontaneously within 15 min. Conclusions: Intentional transatrial exit into the pericardium using small catheters is safe and permits infusion of CO2 or iodinated contrast to separate pericardial layers and facilitate sub-xiphoid access. This reduces the risk of right ventricular or coronary artery laceration. 2.8Fr transatrial catheter withdrawal does not cause any pericardial hemorrhage, even under full anticoagulation. © 2014 Wiley Periodicals, Inc.

BackgroundDiagnostic yield of endomyocardial biopsy is low, particularly in disease that affects the myocardium in a non-uniform distribution. We hypothesized that real-time MRI guidance could improve the yield through targeted biopsy of focal myocardial pathology.MethodsAn animal model of focal myocardial pathology was created by infusing 3mL of fluorescent microspheres (NuFlow Hydrocoat, 15μm diameter, 5 million spheres/mL) followed by 2mL of 100% ethanol to a branch coronary artery. Animals were survived for minimum 14days, before undergoing MRI guided endomyocardial biopsy using a custom 6.5Fr active visualization MRI-conditional bioptome and X-ray guided biopsy using a commercial bioptome. Specimens were analyzed using a dissecting microscope under ultraviolet light to determine the proportion of 'on-target' specimens containing fluorescent microspheres.ResultsA total of 77 specimens were obtained using real-time MRI guidance and 87 using X-ray guidance, in five animals. Specimens obtained with the MRI-conditional bioptome were smaller compared with the commercial X-ray bioptome. Real-time MRI guidance significantly increased the diagnostic yield of endomyocardial biopsy (82% vs. 56% on-target biopsy specimens with real-time MRI vs. X-ray guidance, p

Objectives The aim of this study was to test the hypothesis that real-time magnetic resonance imaging (MRI) would enable closed-chest percutaneous cavopulmonary anastomosis and shunt by facilitating needle guidance along a curvilinear trajectory, around critical structures, and between a superior vena cava “donor” vessel and a pulmonary artery “target.” Background Children with single-ventricle physiology require multiple open heart operations for palliation, including sternotomies and cardiopulmonary bypass. The reduced morbidity of a catheter-based approach would be attractive. Methods Fifteen naive swine underwent transcatheter cavopulmonary anastomosis and shunt creation under 1.5-T MRI guidance. An MRI antenna-needle was advanced from the superior vena cava into the target pulmonary artery bifurcation using real-time MRI guidance. In 10 animals, balloon-expanded off-the-shelf endografts secured a proximal end-to-end caval anastomosis and a distal end-to-side pulmonary anastomosis that preserved blood flow to both branch pulmonary arteries. In 5 animals, this was achieved with a novel, purpose-built, self-expanding device. Results Real-time MRI needle access of target vessels (pulmonary artery), endograft delivery, and superior vena cava shunt to pulmonary arteries were successful in all animals. All survived the procedure without complications. Intraprocedural real-time MRI, post-procedural MRI, x-ray angiography, computed tomography, and necropsy showed patent shunts with bidirectional pulmonary artery blood flow. Conclusions MRI guidance enabled a complex, closed-chest, beating-heart, pediatric, transcatheter structural heart procedure. In this study, MRI guided trajectory planning and reproducible, reliable bidirectional cavopulmonary shunt creation.

Real-time MRI creates images with superb tissue contrast that may enable radiation-free catheterization. Simple procedures are the first step towards novel interventional procedures. We aim to perform comprehensive transfemoral diagnostic right heart catheterization in an unselected cohort of patients entirely using MRI guidance.We performed X-ray and MRI-guided transfemoral right heart catheterization in consecutive patients undergoing clinical cardiac catheterization. We sampled both cavae and both pulmonary arteries. We compared success rate, time to perform key steps, and catheter visibility among X-ray and MRI procedures using air-filled or gadolinium-filled balloon-tipped catheters. Sixteen subjects (four with shunt, nine with coronary artery disease, three with other) underwent paired X-ray and MRI catheterization. Complete guidewire-free catheterization was possible in 15 of 16 under both. MRI using gadolinium-filled balloons was at least as successful as X-ray in all procedure steps, more successful than MRI using air-filled balloons, and better than both in entering the left pulmonary artery. Total catheterization time and individual procedure steps required approximately the same amount of time irrespective of image guidance modality. Catheter conspicuity was best under X-ray and next-best using gadolinium-filled MRI balloons.In this early experience, comprehensive transfemoral right heart catheterization appears feasible using only MRI for imaging guidance. Gadolinium-filled balloon catheters were more conspicuous than air-filled ones. Further workflow and device enhancement are necessary for clinical adoption.

Objectives This study sought to evaluate feasibility of nonsurgical transthoracic catheter-based left ventricular (LV) access and closure. Background Implanting large devices, such as mitral or aortic valve prostheses, into the heart requires surgical exposure and repair. Reliable percutaneous direct transthoracic LV access and closure would allow new nonsurgical therapeutic procedures. Methods Percutaneous direct LV access was performed in 19 swine using real-time magnetic resonance imaging (MRI) and an “active” MRI needle antenna to deliver an 18-F introducer sheath. The LV access ports were closed percutaneously using a commercial ventricular septal defect occluder and an “active” MRI delivery cable for enhanced visibility. We used “permissive pericardial tamponade” (temporary fluid instillation to separate the 2 pericardial layers) to avoid pericardial entrapment by the epicardial disk. Techniques were developed in 8 animals, and 11 more were followed up to 3 months by MRI and histopathology. Results Imaging guidance allowed 18-F sheath access and closure with appropriate positioning of the occluder inside the transmyocardial tunnel. Of the survival cohort, immediate hemostasis was achieved in 8 of 11 patients. Failure modes included pericardial entrapment by the epicardial occluder disk (n = 2) and a true-apex entry site that prevented hemostatic apposition of the endocardial disk (n = 1). Reactive pericardial effusion (192 ± 118 ml) accumulated 5 ± 1 days after the procedure, requiring 1-time drainage. At 3 months, LV function was preserved, and the device was endothelialized. Conclusions Direct percutaneous LV access and closure is feasible using real-time MRI. A commercial occluder achieved hemostasis without evident deleterious effects on the LV. Having established the concept, further clinical development of this approach appears realistic.

Objectives The aim of this study was to close ventricular septal defects (VSDs) directly through the chest wall using magnetic resonance imaging (MRI) guidance, without cardiopulmonary bypass, sternotomy, or radiation exposure. Background Surgical, percutaneous, and hybrid management of VSD each have limitations and known morbidity. Methods Percutaneous muscular VSDs were created in 10 naive Yorkshire swine using a transjugular laser catheter. Under real-time MRI guidance, a direct transthoracic vascular access sheath was introduced through the chest into the heart along a trajectory suitable for VSD access and closure. Through this transthoracic sheath, muscular VSDs were occluded using a commercial nitinol device. Finally, the right ventricular free wall was closed using a commercial collagen plug intended for arterial closure. Results Anterior, posterior, and mid-muscular VSDs (6.8 ± 1.8 mm) were created. VSDs were closed successfully in all animals. The transthoracic access sheath was displaced in 2, both fatal. Thereafter, we tested an intracameral retention sheath to prevent this complication. Right ventricular access ports were closed successfully in all, and after as many as 30 days, healed successfully. Conclusions Real-time MRI guidance allowed closed-chest transthoracic perventricular muscular VSD closure in a clinically meaningful animal model. Once applied to patients, this approach may avoid traditional surgical, percutaneous, or open-chest transcatheter (“hybrid”) risks.

Purpose To develop a catheter-based model of large pulmonary embolism (PE) in swine based on in situ venous thrombus formation. Materials and Methods Ten Yorkshire swine underwent transjugular implantation of a retrievable inferior vena cava (IVC) filter. A thrombin and collagen mixture was injected into a confined space created by two balloons inflated proximal and distal to the IVC filter. Animals were left to survive for 7 days ± 3 to allow thrombus to organize in situ. The caval thrombus was released on transcatheter retrieval of the IVC filter and embolized into the main and branch pulmonary arteries. The severity of PE was scored based on digital subtraction angiography with the Miller index. At necropsy, thrombi were recovered and analyzed histopathologically. Results Large PE was induced in all animals (Miller index score of 15 ± 5). Two animals developed saddle embolus with bilateral pulmonary artery occlusion, and five developed proximal occlusion of the left or right pulmonary artery. Nevertheless, no animal exhibited significant hemodynamic compromise. Large tubular thrombi were explanted in the size range of 5–10 cm long and 0.5–1 cm wide. Histologic analysis indicated an organized thrombus with infiltration of white blood cells and fibrin deposition. Conclusions Large caval thrombi can be formed in vivo and released at a predetermined time to induce large PE in a large animal model. This may help in the development and testing of new therapeutic approaches for PE.

INTRODUCTION—Closed-chest access and closure of direct cardiac punctures may enable a range of therapeutic procedures. We evaluate the safety and feasibility of closing percutaneous direct ventricular access sites using a commercial collagen-based femoral artery closure device. METHODS—Yorkshire swine underwent percutaneous transthoracic left ventricular access (n=13). The access port was closed using a commercial collagen-based vascular closure device (Angio-Seal, St Jude Medical) with or without prior separation of the pericardial layers by instillation of fluid into the pericardial space (“permissive pericardial tamponade”). After initial nonsurvival feasibility experiments (n=6); animals underwent one-week (n=3) or six-week follow up (n=4). RESULTS—In naive animals, the collagen plug tended to deploy outside the parietal pericardium, where it failed to accomplish hemostasis. “Permissive pericardial tamponade” was created under MRI, and accomplished early hemostasis by allowing the collagen sponge to seat on the epicardial surface inside the pericardium. After successful closure, six of seven animals accumulated a large pericardial effusion 5±1 days after closure. Despite percutaneous drainage during 6-week follow-up, the large pericardial effusion recurred in half, and was lethal in one. CONCLUSIONS—A commercial collagen based vascular closure device may achieve temporary but not durable hemostasis when closing a direct left ventricular puncture port, but only after intentional pericardial separation. These insights may contribute to development of a superior device solution. Elective clinical application of this device to close apical access ports should be avoided.

Objectives We developed and tested a novel transcatheter circumferential annuloplasty technique to reduce mitral regurgitation in porcine ischemic cardiomyopathy. Background Catheter-based annuloplasty for secondary mitral regurgitation exploits the proximity of the coronary sinus to the mitral annulus, but is limited by anatomic variants and coronary artery entrapment. Methods The procedure, “cerclage annuloplasty,” is guided by magnetic resonance imaging (MRI) roadmaps fused with live X-ray. A coronary sinus guidewire traverses a short segment of the basal septal myocardium to re-enter the right heart where it is exchanged for a suture. Tension is applied interactively during imaging and secured with a locking device. Results We found 2 feasible suture pathways from the great cardiac vein across the interventricular septum to create cerclage. Right ventricular septal re-entry required shorter fluoroscopy times than right atrial re-entry, which entailed a longer intramyocardial traversal but did not cross the tricuspid valve. Graded tension progressively reduced septal-lateral annular diameter, but not end-systolic elastance or regional myocardial function. A simple arch-like device protected entrapped coronary arteries from compression even during supratherapeutic tension. Cerclage reduced mitral regurgitation fraction (from 22.8 ± 12.7% to 7.2 ± 4.4%, p = 0.04) by slice tracking velocity-encoded MRI. Flexible cerclage reduced annular size but preserved annular motion. Cerclage also displaced the posterior annulus toward the papillary muscles. Cerclage introduced reciprocal constraint to the left ventricular outflow tract and mitral annulus that enhanced leaflet coaptation. A sample of human coronary venograms and computed tomography angiograms suggested that most have suitable venous anatomy for cerclage. Conclusions Transcatheter mitral cerclage annuloplasty acutely reduces mitral regurgitation in porcine ischemic cardiomyopathy. Entrapped coronary arteries can be protected. MRI provided insight into the mechanism of cerclage action.

A sedentary workforce may be at increased risk for future cardiovascular disease. Exercise at the work site has been advocated, but effects on endothelium as a biomarker of risk and relation to weight loss, lipid changes, or circulating endothelial progenitor cells (EPCs) have not been reported. Seventy-two office and laboratory employees (58 women; average age 45 years, range 22 to 62; 26 with body mass index values30 kg/m(2)) completed 3 months of participation in the National Heart, Lung, and Blood Institute's Keep the Beat program, with the determination of vital signs, laboratory data, and peak oxygen consumption (VO(2)) during treadmill exercise. Brachial artery endothelium was tested by flow-mediated dilation (FMD), which at baseline was inversely associated with Framingham risk score (r = -0.3689, p0.0001). EPCs were quantified by colony assay. With exercise averaging 98 +/- 47 minutes each workweek, there was improvement in FMD (from 7.8 +/- 3.4% to 8.5 +/- 3.0%, p = 0.0096) and peak VO(2) (+1.2 +/- 3.1 ml O(2)/kg/min, p = 0.0028), with reductions in diastolic blood pressure (-2 +/- 8 mm Hg, p = 0.0478), total cholesterol (-8 +/- 25 mg/dl, p = 0.0131), and low-density lipoprotein cholesterol (-7 +/- 19 mg/dl, p = 0.0044) but with a marginal reduction in weight (-0.5 +/- 2.1 kg, p = 0.0565). By multiple regression modeling, lower baseline FMD, greater age, reductions in total and low-density lipoprotein cholesterol and diastolic blood pressure, and increases in EPC colonies and peak VO(2) were jointly statistically significant predictors of change in FMD and accounted for 47% of the variability in FMD improvement with program participation. Results were similar when modeling was performed for women only. In contrast, neither adiposity at baseline nor change in weight was a predictor of improved endothelial function. In conclusion, daily exercise achievable at their work sites by employees with sedentary occupations improves endothelial function, even with the absence of weight loss, which may decrease cardiovascular risk, if sustained.

Purpose The authors performed this study to report their initial preclinical experience with real-time magnetic resonance (MR) imaging–guided atrial septal puncture by using a MR imaging–conspicuous blunt laser catheter that perforates only when energized. Materials and Methods The authors customized a 0.9-mm clinical excimer laser catheter with a receiver coil to impart MR imaging visibility at 1.5 T. Seven swine underwent laser transseptal puncture under real-time MR imaging. MR imaging signal-to-noise ratio profiles of the device were obtained in vitro. Tissue traversal force was tested with a calibrated meter. Position was corroborated with pressure measurements, oximetry, angiography, and necropsy. Intentional non-target perforation simulated serious complication. Results Embedded MR imaging antennae accurately reflected the position of the laser catheter tip and profile in vitro and in vivo. Despite having an increased profile from the microcoil, the 0.9-mm laser catheter traversed in vitro targets with similar force (0.22 N ± 0.03) compared with the unmodified laser. Laser puncture of the atrial septum was successful and accurate in all animals. The laser was activated an average of 3.8 seconds ± 0.4 before traversal. There were no sequelae after 6 hours of observation. Necropsy revealed 0.9-mm holes in the fossa ovalis in all animals. Intentional perforation of the aorta and atrial free wall was evident immediately. Conclusions MR imaging–guided laser puncture of the interatrial septum is feasible in swine and offers controlled delivery of perforation energy by using an otherwise blunt catheter. Instantaneous soft tissue imaging provides immediate feedback on safety.

Our purpose was to determine predictors of endothelial function and potential association with cardiovascular risk in women with sedentary occupations, in whom obesity-associated risk factors may contribute to excess morbidity and mortality. Ninety consecutive women (age range 22 to 63 years, 22 overweight (body mass index [BMI]or =25 to 29.9 kg/m(2)) and 42 obese (BMIor = 30 kg/m(2)), had vital signs, lipids, insulin, glucose, high-sensitivity C-reactive protein, and sex hormones measured. Endothelial function was determined using brachial artery flow-mediated dilation after 5 minutes of forearm ischemia. Treadmill stress testing was performed with gas exchange analysis at peak exercise (peak oxygen consumption [Vo(2)]) to assess cardiorespiratory fitness. Brachial artery reactivity was negatively associated with Framingham risk score (r = -0.3542, p = 0.0007). Univariate predictors of endothelial function included peak Vo(2) (r = 0.4483, p0.0001), age (r = -0.3420, p = 0.0010), BMI (r = -0.3065, p = 0.0035), and high-sensitivity C-reactive protein (r = -0.2220, p = 0.0400). Using multiple linear regression analysis with stepwise modeling, peak Vo(2) (p = 0.0003) was the best independent predictor of brachial artery reactivity, with age as the only other variable reaching statistical significance (p = 0.0436) in this model. In conclusion, endothelial function was significantly associated with cardiovascular risk in women with sedentary occupations, who were commonly overweight or obese. Even in the absence of routine exercise, cardiorespiratory fitness, rather than conventional risk factors or body mass, is the dominant predictor of endothelial function and suggests a modifiable approach to risk.

Background In current practice, the diagnostic yield of endomyocardial biopsy is low because the procedure is performed ‘blind’ using X-ray fluoroscopy guidance and because many pathologies affect the myocardium in a patchy distribution. We hypothesized that biopsy performed under direct realtime MRI guidance would have superior diagnostic yield, in an animal model of focal myocardium pathology.

Background Conventional guidewires are not suitable for use during cardiovascular magnetic resonance (CMR) catheterization. They employ metallic shafts for mechanical performance, but which are conductors subject to radiofrequency (RF) induced heating. To date, non-metallic CMR guidewire designs have provided inadequate mechanical support, trackability, and torquability. We propose a metallic guidewire for CMR that is by design intrinsically safe and that retains mechanical performance of commercial guidewires. Methods The NHLBI passive guidewire is a 0.035” CMR-safe, segmented-core nitinol device constructed using short nitinol rod segments. The electrical length of each segment is less than one-quarter wavelength at 1.5 Tesla, which eliminates standing wave formation, and which therefore eliminates RF heating along the shaft. Each of the electrically insulated segments is connected with nitinol tubes for stiffness matching to assure uniform flexion. Iron oxide markers on the distal shaft impart conspicuity. Mechanical integrity was tested according to International Organization for Standardization (ISO) standards. CMR RF heating safety was tested in vitro in a phantom according to American Society for Testing and Materials (ASTM) F-2182 standard, and in vivo in seven swine. Results were compared with a high-performance commercial nitinol guidewire. Results The NHLBI passive guidewire exhibited similar mechanical behavior to the commercial comparator. RF heating was reduced from 13 °C in the commercial guidewire to 1.2 °C in the NHLBI passive guidewire in vitro, using a flip angle of 75°. The maximum temperature increase was 1.1 ± 0.3 °C in vivo, using a flip angle of 45°. The guidewire was conspicuous during left heart catheterization in swine. Conclusions We describe a simple and intrinsically safe design of a metallic guidewire for CMR cardiovascular catheterization. The guidewire exhibits negligible heating at high flip angles in conformance with regulatory guidelines, yet mechanically resembles a high-performance commercial guidewire. Iron oxide markers along the length of the guidewire impart passive visibility during real-time CMR. Clinical translation is imminent.

Background— Percutaneous access for mitral interventions is currently limited to transapical and transseptal routes, both of which have shortcomings. We hypothesized that the left atrium could be accessed directly through the posterior chest wall under imaging guidance. Methods and Results— We tested percutaneous transthoracic left atrial access in 12 animals (10 pigs and 2 sheep) under real-time magnetic resonance imaging or x-ray fluoroscopy plus C-arm computed tomographic guidance. The pleural space was insufflated with CO 2 to displace the lung, an 18F sheath was delivered to the left atrium, and the left atrial port was closed using an off-the-shelf nitinol cardiac occluder. Animals were survived for a minimum of 7 days. The left atrial was accessed, and the port was closed successfully in 12/12 animals. There was no procedural mortality and only 1 hemodynamically insignificant pericardial effusion was observed at follow-up. We also successfully performed the procedure on 3 human cadavers. A simulated trajectory to the left atrium was present in all of 10 human cardiac computed tomographic angiograms analyzed. Conclusions— Percutaneous transthoracic left atrial access is feasible without instrumenting the left ventricular myocardium. In our experience, magnetic resonance imaging offers superb visualization of anatomic structures with the ability to monitor and address complications in real-time, although x-ray guidance seems feasible. Clinical translation seems realistic based on human cardiac computed tomographic analysis and cadaver testing. This technique could provide a direct nonsurgical access route for future transcatheter mitral implantation.

Background—Cardiac perforation during atrial septal puncture (ASP) might be avoided by improved image guidance. X-ray fluoroscopy (XRF), which guides ASP, visualizes tissue poorly and does not convey depth information. Ultrasound is limited by device shadows and constrained imaging windows. Alternatively, real-time MRI (rtMRI) provides excellent tissue contrast in any orientation and may enable ASP and balloon atrial septostomy (BAS) in swine. Materials and Methods—Custom MRI catheters incorporated “active” (receiver antenna) and “passive” (iron or gadolinium) elements. Wholly rtMRI-guided transfemoral ASP and BAS were performed in 10 swine in a 1.5T interventional suite. Hemodynamic results were measured with catheters and velocity encoded MRI. Results—Successful ASP was performed in all 10 animals. Necropsy confirmed septostomy confined within the fossa ovalis in all. BAS was successful in 9/10 animals. Antenna failure in a reused needle led to inadvertent vena cava tear prior to BAS in one animal. ASP in the same animal was easily performed using a new needle. rtMRI illustrated clear device-tissue-lumen relationships in multiple orientations, and facilitated simple ASP and BAS. The mean procedure time was 19 ± 10 minutes. Septostomy achieved a mean left to right shunt ratio of 1.3:1 in these healthy animals. Conclusion—Interactive rtMRI permits rapid transcatheter ASP and BAS in swine. Further technical development may enable novel applications.

Background: Cardiovascular risk factors contribute to atherogenesis by inducing endothelial-cell injury and dysfunction. We hypothesized that endothelial progenitor cells derived from bone marrow have a role in ongoing endothelial repair and that impaired mobilization or depletion of these cells contributes to endothelial dysfunction and cardiovascular disease progression. Methods: We measured the number of colony-forming units of endothelial progenitor cells in peripheral-blood samples from 45 men (mean [+/-SE] age, 50+/-2 years). The subjects had various degrees of cardiovascular risk but no history of cardiovascular disease. Endothelium-dependent and endothelium-independent function was assessed by high-resolution ultrasonography of the brachial artery. Results: We observed a strong correlation between the number of circulating endothelial progenitor cells and the subjects' combined Framingham risk factor score (r=-0.47, P=0.001). Measurement of flow-mediated brachial-artery reactivity also revealed a significant relation between endothelial function and the number of progenitor cells (r=0.59, P

Background— Although reduced endothelial nitric oxide (NO) bioavailability has been demonstrated in arteriosclerotic vascular disease, the integrity of this system in sickle cell disease remains uncertain. Methods and Results— We measured forearm blood flow in 21 patients with sickle cell disease (hemoglobin SS genotype) and 18 black control subjects before and after intra-arterial infusions of acetylcholine, nitroprusside, and the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA). Endothelium-dependent vasodilation, measured by the percent increase in flow induced by acetylcholine infusion, was significantly greater than in controls (252±37% for patients versus 134±24% for controls; P P =0.035). Similarly, basal NO bioactivity, as measured by the percent decrease in flow induced by L-NMMA, was depressed in male compared with female patients (−17±5% versus −34±4%; P =0.01), as was the response to nitroprusside (86±21% versus 171±22%; P =0.008). L-NMMA reduced the blood flow response to acetylcholine in women, but not in men. Sex differences in vascular cell adhesion molecule-1 were appreciated, with significant correlations between levels of soluble vascular cell adhesion molecule-1 and blood flow responses to L-NMMA and nitroprusside ( r =0.53, P =0.004 and r =−0.66, P Conclusions— NO bioavailability and NO responsiveness are greater in women than in men with sickle cell disease and determines adhesion molecule expression. Endothelium-dependent blood flows are largely non-NO mediated in male patients. These results provide a possible mechanism for reported sex differences in sickle cell disease morbidity and mortality and provide a basis for novel pharmacological interventions.

Background Realtime MR enables radiation free guidance for right heart catheterization (RHC). In addition to catheter navigation for sampling of invasive pressures and blood oxygen saturations, MR permits concomitant assessment of cardiac chamber volumes and cardiac output with phase contrast flow measurements. By performing repeat measurements under different physiological provocations (e.g. saline volume challenge, inhaled nitric oxide, or exercise), diagnostic yield increases by revealing symptoms and pathologic findings not apparent at rest. Herein we present the NIH experience of MR RHC to date.

Tricuspid regurgitation is a malignant disease with high surgical mortality and no commercially available transcatheter solution in the US. We propose a percutaneous pledget-assisted suture tricuspid valve annuloplasty (PASTA) using marketed equipment. X-ray fluoroscopy and intracardiac

We test the safety of transatrial pericardial access using small catheters, infusion of carbon dioxide (CO2 ) or iodinated contrast to facilitate sub-xiphoid access, and catheter withdrawal under full anticoagulation.Sub-xiphoid pericardial access is required for electrophysiological and structural heart interventions. If present, an effusion protects the heart from needle injury by separating the myocardium from the pericardium. However, if the pericardium is 'dry' then there is a significant risk of right ventricle or coronary artery laceration caused by the heart beating against the needle tip. Intentional right atrial exit is an alternative pericardial access route, through which contrast media could be infused to separate pericardial layers.Transatrial pericardial access was obtained in a total of 30 Yorkshire swine using 4Fr or 2.8Fr catheters. In 16 animals, transatrial catheters were withdrawn under anticoagulation and MRI was performed to monitor for pericardial hemorrhage. In 14 animals, iodinated contrast or CO2 was infused before sub-xiphoid access was obtained.Small effusions (mean 18.5 ml) were observed after 4Fr (1.3 mm outer-diameter) but not after 2.8Fr (0.9 mm outer-diameter) transatrial catheter withdrawal despite full anticoagulation (mean activated clotting time 383 sec), with no hemodynamic compromise. Pericardial CO2 resorbed spontaneously within 15 min.Intentional transatrial exit into the pericardium using small catheters is safe and permits infusion of CO2 or iodinated contrast to separate pericardial layers and facilitate sub-xiphoid access. This reduces the risk of right ventricular or coronary artery laceration. 2.8Fr transatrial catheter withdrawal does not cause any pericardial hemorrhage, even under full anticoagulation.

Fractalkine, a chemokine expressed by inflamed endothelium, induces leukocyte adhesion and migration via the receptor CX3CR1, and the CX3CR1 polymorphism V249I affects receptor expression and function. Here we show that this polymorphism is an independent risk factor for atherosclerotic coronary artery disease (CAD). Genotyping of the CX3CR1-V249I polymorphism was performed in a cohort of 339 white individuals who underwent cardiac catheterization (n=197 with and n=142 without CAD, respectively). In 203 patients, intracoronary acetylcholine 15 μg/min) and sodium nitroprusside (20 μg/min) were administered to test endothelium-dependent and -independent coronary vascular function, respectively. Change in coronary vascular resistance (ΔCVR) was measured as an index of microvascular dilation. An association was observed between presence of the CX3CR1 I249 allele and reduced prevalence of CAD, independent of established CAD risk factors (odds ratio=0.54 [95% confidence interval, 0.30 to 0.96], P =0.03). Angiographic severity of CAD was also lower in these subjects ( P =0.01). Furthermore, endothelium-dependent vasodilation was greater in these individuals compared with individuals homozygous for the CX3CR1-V249 allele (ΔCVR during acetylcholine = −46±3% versus −36±3%, respectively, P =0.02), whereas ΔCVR with sodium nitroprusside was similar in both groups (−55±2% versus −53±2%, P =0.45). The association between CX3CR1 genotype and endothelial function was independent of established risk factors and presence of CAD by multivariate analysis ( P =0.02). Thus, the CX3CR1 I249 allele is associated with decreased risk of CAD and improved endothelium-dependent vasodilation. This suggests that CX3CR1 may be involved in the pathogenesis of CAD.

OBJECTIVES The aim of our study was to investigate coronary vascular kinin receptor function in patients with atherosclerosis or its risk factors. BACKGROUND Although acetylcholine (ACH) is used as a probe for testing vascular function in vivo, endogenous bradykinin (BK) regulates resting and flow-mediated epicardial tone. METHODS In 53 patients with mild atherosclerosis or its risk factors and 9 control subjects, endothelium-dependent vasomotion was tested with intracoronary ACH (30 μg/min) and BK (62.5 ng/min and 4 μg/min), and endothelium-independent function with sodium nitroprusside. Metabolic vasodilation was assessed during cardiac pacing (n = 19). Correlation with serum angiotensin-converting enzyme (ACE) levels and the ACE insertion/deletion genotype was performed. RESULTS There was progressive impairment in ACH-mediated microvascular dilation with increasing numbers of risk factors (p = 0.025, analysis of variance). By contrast, BK- and sodium nitroprusside-mediated microvascular dilation was similar in all groups. Similarly, there was no correlation between epicardial coronary responses to ACH and BK; segments that constricted or dilated with ACH had similar dilator responses with BK. Bradykinin, but not ACH-mediated vasomotion, was depressed in epicardial segments that constricted with pacing. Finally, epicardial BK responses were depressed in patients with high ACE levels and in those with the ACE DD genotype. CONCLUSIONS Endothelial dysfunction in atherosclerosis appears to be receptor-specific, involving the muscarinic receptor with relative sparing of the kinin receptor pathways. Abnormal reactivity of epicardial coronary arteries during physiologic stress is better represented by BK and not by ACH responses. Bradykinin activity and, hence, physiologic coronary vasomotion appears to be influenced by serum ACE levels and the ACE insertion/deletion genotype.

Background —Vascular nitric oxide (NO) bioavailability is reduced in patients with coronary artery disease (CAD). We investigated whether oral l -arginine, the substrate for NO synthesis, improves homeostatic functions of the vascular endothelium in patients maintained on appropriate medical therapy and thus might be useful as adjunctive therapy. Methods and Results —Thirty CAD patients (29 men; age, 67±8 years) on appropriate medical management were randomly assigned to l -arginine (9 g) or placebo daily for 1 month, with crossover to the alternate therapy after 1 month off therapy, in a double-blind study. Nitrogen oxides in serum (as an index of endothelial NO release), flow-mediated brachial artery dilation (as an index of vascular NO bioactivity), and serum cell adhesion molecules (as an index of NO-regulated markers of inflammation) were measured at the end of each treatment period. l -Arginine significantly increased arginine levels in plasma (130±53 versus 70±17 μmol/L, P l -arginine on nitrogen oxides (19.3±7.9 versus 18.6±6.7 μmol/L, P =0.546), on flow-mediated dilation of the brachial artery (11.9±6.3% versus 11.4±7.9%, P =0.742), or on the cell adhesion molecules E-selectin (47.8±15.2 versus 47.2±14.4 ng/mL, P =0.601), intercellular adhesion molecule-1 (250±57 versus 249±57 ng/mL, P =0.862), and vascular cell adhesion molecule-1 (567±124 versus 574±135 ng/mL, P =0.473). Conclusions —Oral l -arginine therapy does not improve NO bioavailability in CAD patients on appropriate medical management and thus may not benefit this group of patients.

As a substrate for nitric oxide synthesis, L-arginine may give the same protection as estrogen, but its other biologic effects may adversely affect atherogenesis. Therefore, possible endocrine and lipid effects of L-arginine were investigated in a double-blind, placebo-controlled, single crossover study. After randomization, oral L-arginine (9 g) or placebo was given daily for 1 month, with crossover to the alternate therapy after a 1-month washout period, to 10 postmenopausal women receiving no estrogen. Compared with placebo, L-arginine increased growth hormone (1.5+/-1.8 mg/L vs. 0.6+/-0.6 mg/L, P = .04) but had no effect on insulin and catecholamines. Total cholesterol, triglyceride, apolipoprotein E, and low-, very-low-, and high-density lipoprotein cholesterol levels were also unaffected. Lipoprotein(a) measured by an immunoturbidimetric method was increased by L-arginine in 9 of 10 women relative to placebo (0.46+/-0.35 g/L vs. 0.38+/-0.30 g/L, P = .053), and the changes in lipoprotein(a) levels significantly correlated with the relative increase in growth hormone (r = 0.85, P = .03). However, lipoprotein(a) measured by an enzyme-linked immunosorbent assay failed to demonstrate significant changes. Lack of an increase by L-arginine in lipoprotein(a) with a verifiable apolipoprotein(a) isoform-independent method, despite an increase in growth hormone, questions the validity of previous observations for growth hormone-induced increases in lipoprotein(a). The observed lack of effect on major endocrine hormones and lipid profile support the safety of oral L-arginine administration.

OBJECTIVES We examined whether oral administration of L-arginine, the substrate for nitric oxide (NO) synthesis, increases NO bioactivity in healthy postmenopausal women. BACKGROUND Nitric oxide may protect arteries against atherosclerosis, as suggested by experimental studies in animals. Estrogen therapy, which has been shown to increase NO bioactivity in the vasculature of healthy postmenopausal women, is not acceptable for long-term use by many women. METHODS In a randomized, double-blind, crossover study, 10 postmenopausal women without additional risk factors for atherosclerosis received L-arginine 9 g or placebo daily for one month, with treatment periods separated by one month. Nitric oxide levels in serum (as an index of endothelial NO release), brachial artery endothelium-dependent dilator responses to hyperemia by ultrasonography (as an index of vascular NO bioactivity) and markers of inflammation in blood that are inhibited by NO in cell culture experiments were measured at the end of each treatment period. RESULTS L-arginine levels in plasma were increased in all women during L-arginine treatment compared with placebo (136.8 ± 63.1 vs. 75.2 ± 16.2 μmol/liter, p = 0.009). However, there was no change in serum nitrogen oxide levels (42.1 ± 24.5 vs. 39.1 ± 16.6 μmol/liter, p = 0.61), nor was there an effect of L-arginine on flow-mediated dilation during hyperemia (3.8 ± 3.0% vs. 4.9 ± 4.8%, p = 0.53) compared with placebo. Our study had sufficient power (β = 0.80) to detect a true absolute treatment difference in flow-mediated brachial artery dilation of 1.7% or larger as statistically significant at alpha = 0.05. There was no effect of L-arginine on serum levels of soluble cell adhesion molecules compared with placebo: E-selectin (50.6 ± 14.8 vs. 52.1 ± 17.0 ng/ml, p = 0.45), intercellular adhesion molecule-1 (230 ± 51 vs. 230 ± 52 ng/ml, p = 0.97) and vascular cell adhesion molecule-1 (456 ± 62 vs. 469 ± 91 ng/ml, p = 0.53). CONCLUSIONS Oral administration of L-arginine may not augment endothelial NO synthesis and release in postmenopausal women and is thus unlikely to be of general benefit to healthy postmenopausal women in protection from the development of atherosclerosis.

Background Invasive right heart catheterization plays a central role in the investigation of patients with cardiac and pulmonary vascular disease. Physiological provocations during invasive heart catheterization augment the diagnostic yield and can provide useful prognostic information. MRI catheterization combines invasive hemodynamic measurements with MRI structural and functional evaluations thus providing superior diagnostic information than either test alone. An additional benefit to both patient and operator is no ionizing radiation, which is of particular value in pediatric patients.

Background We have begun to perform routine and research MRI right heart catheterization in adults and research MRI catheterization in children. We report our technologist workflow. Methods Scanner preparation: The scanner facade and bore are covered with adhesive clear sterile drapes and surface coils enveloped in sterile plastic bags. A MR catheterization pack contains only non-ferromagnetic supplies. Sterile

Objectives. This study sought to compare the circadian variations in transient ischemic activity, mean heart rate and ischemic threshold between women and men with coronary artery disease.Background. There is a circadian variation in ischemic activity, onset of myocardial infarction and sudden cardiac death in patients with coronary artery disease, but studies assessing ischemia have incorporated predominantly male subjects.Methods. Thirty-one women and 45 men underwent at least 48 h of ambulatory ST segment monitoring.Results. There was a similar and significant circadian variation in ischemic activity in both women and men (p < 0.001 and p < 0.0001, respectively), with a trough at night, a surge in the morning and a peak between 1 and 2 pm, corresponding to a similar circadian variation in mean hourly heart rate (p < 0.0001) that was not different between men and women (p = 0.28, power to detect a shift 99.9%). Mean heart rate at onset of ischemia (ischemia threshold) had similar variability in women and men (p = 0.96), and harmonic regression analysis confirmed a significant circadian variation (p < 0.0001), with a trough at night and a peak during activity hours. Heart rate increased significantly in the 5 min before ischemia throughout the 24 h (p < 0.0001), with no gender differences in the pattern of preonset to onset heart rate changes over time (p = 0.52); the smallest differences were recorded in the middle of the night. The majority of ischemic episodes (80%) had a heart rate increase >5 beats/min in the 5 min before ischemia, but there were no gender differences.Conclusions. Women with coronary artery disease have a pattern of ischemic activity and underlying pathophysiologic mechanisms very similar to men. The importance of increase in myocardial oxygen demand in the genesis of ischemia in both men and women is reflected by similar magnitude of heart rate increases before ischemia. The lower ischemic threshold during the nocturnal hours, when blood pressure is also lower, is consistent with a circadian variation is underlying coronary vascular tone.

LAMPOON is a technique we developed directing radiofrequency (RF) energy through a coronary guidewire to lacerate the anterior mitral leaflet to prevent outflow obstruction during transcatheter mitral valve replacement. Tissue laceration requires concentration of RF energy at the guidewire-tissue