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Transvascular cellular cardiomyoplasty
International Journal of
Cardiology ELSEVIER
International Journal of Cardiology 95 Suppl. 1 (2004) $47-$49
II
u
III
IIII
www.elsevier.com/locate/ijcard
Transvascular cellular cardiomyoplasty Craig A. T h o m p s o n M D , M M S c * Dartmouth Hitchcock Medical Center, Assistant Professor of Medicine, Dartmouth Medical School, Angiogenesis Research Center, Lebanon, NH, USA
1. Introduction Myocardial cell transplantation has been proposed as a potential alternative or adjunctive therapy for patients presenting with a wide spectrum of myocardial disorders, including acute myocardial infarction (MI) and ischemic cardiomyopathy. Components of such a system for cellular cardiomyoplasty are the cell source(s), delivery vehicle, and delivery system. Given the positive reported findings with multiple cell sources (e.g. skeletal myoblasts, mesenchymal progenitor cells, smooth muscle cells, bone marrow derived mononuclear cells, and bone marrow/peripheral derived hematopoietic progenitor cells) and the likelihood that higher retained cell number translates to improved functional outcome, it is this author's opinion that delivery methods may play as important a role as the cell source utilized [1,2]. Delivery methods for myocardial biologic substrate delivery can broadly be categorized as (1) peripheral (e.g., peripheral intravenous infusion), (2) surgical (e.g., open chest or minimally invasive), and (3) percutaneous (e.g., intracoronary arterial, coronary venous retroinfusion, or catheter-directed myocardial injection). Absent improvements in technologies to facilitate cell homing, it is unlikely that adequate cells can be delivered intravenously to the myocardium within a reasonable clinical therapeutic window to demonstrate an optimal treatment effect. Surgical injection provides accurate access to anterolateral, posterior, and inferior (but not septal) myocardial territories. However, this approach remains somewhat limited by lack of immediate feedback for the surgeon of cell loss (from microvascular bundles within the myocardium) and may have limited applications (and potential contraindications) in the anticipated clinical targets of patients with acute MI and chronic ischemic cardiomyopathy. Catheter-based coronary artery and coronary venous (retro-)infusion can provide homogenous distribution of cells, but are particularly sensitive to cell loss via venous shunting and sequestration. Current-generation endoventricular myocardial delivery catheter platforms (such as MyostarTM [Biosense-Webster, Inc.], MyoCathT M [Bioheart, Inc.], and *Correspondence address: Dartmouth Hitchcock Medical Center, One MedicalCenterDrive,CardiologySection,Lebanon,NH 03770, USA, Tel.: +1-(603)-650-6319; fax: +1-(603)-650-6164. E-mail address: [email protected] 1389-9457/04/$ - see frontmatter © 2004 ElsevierB.V.All rightsreserved. doi: 10.1016/j.ijcard.2004.04.000
Stiletto [Boston Scientific]) can provide mass cell transfer to the left ventricular myocardium and can provide qualitative immediate feedback of substrate retention based on contrast enhancement evident by fluoroscopy (and potentially MRI). The endoventricular direct injection modalities may be limited by (1) targeting accuracy and stability related to ventricular rotational movements during the cardiac cycle, (2) access interference by the subvalvular mitral apparatus, and (3) cell loss via the short needle tract contiguous with the left ventricle. Acute retention efficiency seems to be reduced, likely due to this ventricular "bleedback" phenomenon or injections into trabeculae rather than heart muscle [3,4]. Furthermore, severely thinned (<5 ram) myocardial walls seen in many infarcted areas are currently felt not to be safely accessible from the endoventricular approach because of concerns about transmyocardial perforation and subsequent cardiac tamponade. In an attempt to harness the strengths of the surgical/direct myocardial injection approaches, but resolve many of the aforementioned limitations, a new method for catheter-based myocardial biologic substrate delivery has been proposed that uses ultrasound-guided needle placement through the coronary veins and directly into the heart muscle (Fig. 1). This "transvascular" needle placement thus provides a stable platform for microinfusion catheter insertion tangentially into the myocardium (similar to surgical injections) for accurate and predictable therapeutic substrate delivery, while provid-
Fig. 1. Trans(coronary) venous direct myocardial injection system a specialized catheter system allows for direct myocardial access for therapeutic substrate delivery. Courtesy Transvascular/Medtronic, Inc., Santa Rosa, CA, USA. [Seep. $72 for color illustration.]
$48
C.A. Thompson~International Journal of Cardiology 95 Suppl. 1 (2004) $47-$49
ing immediate qualitative feedback of substrate retention with contrast as a surrogate [5].
2. Transvascular cell delivery technique After prepping and draping in standard fashion, six French arterial (Cordis Corp., Miami, FL) and 14 French venous (Transvascular/Medtronic Inc., Santa Rosa, CA) femoral sheaths are placed percutaneously. Coronary angiography is performed with emphasis on venous follow-through phase to assess coronary venous patency and anomalies. The coronary sinus (CS) is accessed by placing a porcine 3 catheter (TransVascular, Inc., Menlo Park, CA/Medtronic, Inc) into the right ventricle, withdrawing with clockwise torque across the tricuspid valve. Using this technique, the catheter tends to fall into, or near, the CS. An exchange length, 0.035 hydrophilic guidewire (Terumo Corporation, Tokyo, Japan) with J-tip is then advanced into the CS, through the great cardiac vein (GCV), and into the anterior interventricular coronary vein (AIV). The diagnostic catheter is withdrawn, with the guidewire in place, and a 10 French CS guiding catheter (Transvascular, Inc., Menlo Park, CA/ Medtronic, Inc.) and introducer are placed with conventional over-the-wire technique. The hydrophilic guidewire can then be exchanged for a 0.014 H 300cm Balance Middleweight (BMW) gnidewire (Guidant Corp., Santa Clara, CA), and the guide catheter introducer sheath subsequently removed. The TransAccess ® catheter is a 6 French, monorail, composite catheter system combining a phased array intravascular ultrasound (IVUS, compatible with Volcano Therapeutics system) and a pre-shaped, sheathed, extendable 24 gauge nitinol needle (Fig. 2a). This TransAccess® catheter is advanced over the 0.014 guidewire and into the AIV in preparation for myocardial access. The catheter positioning with respect to the infarcted area is accomplished with angiographic landmarks (ventriculography, fluoroscopy, epicardial vascular branchpoints). Intravascular orientation is performed using the corresponding artery, pericardium, and ventricular chamber as landmarks with IVUS imaging (Fig. 2b). After confirmation of position within the coronary vein and with respect to
(a)
(b)
(c)
Fig. 2. (a) The TransAccessT M catheteris a compositesystemthat combines a sheathed, extendablenitinol needle with (b) a phased array intravascular ultrasound (compatible with Volcano therapeutics system) for guidance for transvascularmyocardialaccess. (c) Once the needle is deployedinto the myocardium, a microinfusioncatheter can be advanced into remote myocardiumfor biologic substrate delivery(arrows). [Seep. $72 for color illustration.]
surrounding structures, the nitinol needle is extended into the myocardium (~5-7 mm depth) to access the infarct and peri-infarct regions. A 0.015" microinfusion (MicrolumeTM) catheter is advanced through the needle, and into the myocardial tissue. Because the myocardial tissue is a potential space, and without room for prolapse, all of the force for the otherwise floppy Microlume TM catheter is forward, essentially allowing this catheter tip to become a drill capable of tunneling through remote myocardium (~40-50 mm and beyond) in plane with the needle puncture. Injections of cell suspension can be performed in a manner to lay an injection latticework pattern in the infarct and peri-infarct regions (Fig. 2c). The current generation of this catheter system is highly flexible and can track over a 0.014" coronary guidewire for selective access into the middle and lateral cardiac veins, as well as the AIV (without need for subselective guiding catheter placement). Changes in the length and angulation of the nitinol needle allow for broad myocardial access from a single location, obviating the need to reposition the catheter as frequently to access different myocardial zones. This versatility provides the operator with multiple options to address anatomic variability.
3. Experience to date Our experience is that this method of percutaneous cell transplantation is highly accurate (100% in the seminal feasibility study in swine with normal hearts) for targeting specific myocardial zones. The needle and infusion catheter are seated deeply within the heart muscle, and therefore rotate with the heart. Conceptually, backbleeding and cell/substrate loss is minimal through the needle tract and multiple injections can be performed within seconds. Immediate "on-line" angiographic feedback for identification of troublesome microvascular bundles (and potential cell loss) is possible with contrast enhancement of the cell suspension. The microcatheter may then be adjusted (by millimeters) to secure a more quiescent zone to facilitate substrate retention. We demonstrated the labeled cells in all transplanted animals ranging from acute sacrifice to one month post injection. Brasselet and colleagues [6] subsequently demonstrated similar safety and feasibility using a myoblast cell source. Smits et al. [3,4] demonstrated that the transvascular method of delivering biologic substrate to the myocardium provided superior efficiency and retention compared to two separate endoventricular catheter systems using a radiolabelled VEGF substrate. The TransAccess injection system had a one minute retention efficiency of 63.5%(-t-26%), comparing favorably with 26%(+23%) and 25%(4-18%) seen with the Biosense and Bioheart endoventricular systems, respectively. Thinned, scarred myocardial tissue has not presented a prohibitive challenge at this point. Our pilot study of the functional effect of autologous bone marrow derived
C.A. Thompson~International Journal of Cardiology 95 Suppl. 1 (2004)$47-$49
$49
4. Conclusions The chosen method of cell transfer may be an important component to augment therapeutic yield in cell transplantation for myocardial diseases. Catheter-based, IVUS guided, direct myocardial cell transplantation through the coronary veins provides a robust, stable, accurate, and relatively efficient platform for cell and biologic substrate delivery. This method and its supporting enabling technologies may contribute to the armamentarium needed to make cardiovascular regenerative medicine a clinical reality.
References Fig. 3. (left) Ex vivo MRI of porcine heart demonstrating thinned area of myocardial scar (yellow box) that received pre-labeled, bone marrow derived transvascular cell transplantation. H&E (top right) and direct fluorescence (bottom right) demonstrate cell grafts expressing cell membrane label two months post transplantation. Subsequent DAPI labeling confirmed cellular viability [not shown]. Magnification x200. [See p. $73 for color illustration.]
cell transplantation in a porcine model of chronic myocardial infarction-induced heart failure (currently in peer review) suggests that this delivery method is feasible, safe, and may have promising biologic effect in this anatomic environment (Fig. 3). The percutaneous transvenous transplantation of autologous myoblasts in the treatment of postinfarction heart failure (POZNAN) phase I clinical trial was presented recently by Dr. Tomasz Siminiak at the American College of Cardiology scientific sessions 2004. The transvascular method was used to transplant autologous skeletal myoblasts in patients with post-infarction heart failure. Nine of ten patients attempted were successful. Approximately l0 s myoblasts were delivered in 2 to 4 channels ranging from 1.5 to 4.5 cm depth from the coronary venous system. The single failure was due to inability to cannulate the coronary sinus with a guidewire. No procedure- (catheter-) related complications occurred.
[1] Thompson CA, Oesterle SN. Biointerventional cardiology: the future interface of interventional cardiovascular medicine and bioengineering. Vasc Med 20027:135-140. [2] Vacanti JP, Langer R. Tissue engineering: the design and fabrication of living replacement devices for surgical reconstruction and transplantation. Lancet 1999;354:SI32-4. [3] Smits PC, van der Giessen WJ. Reys AE, Bakker W, Verdouw P, Serruys PW. Comparison in efficiency between a NOGA and fluoroscopy guided transendomyocardial injection catheter. AHA Abstract: Scientific Conference on Therapeutic Angiogenesis & Myocardial Laser Revascularization, January 2001. [4] Smits PC, van der Giessen WJ, Reys AE, Bakker W, Gabriel G, Verdouw P, Serruys PW. Efficiency and retention of percutaneons transendomyocardial injection of VEGF 165 by a fluoroscopy guided injection catheter: a radionuclide study. AHA Abstract: Scientific Conference on Therapeutic Angiogenesis & Myocardial Laser Revascutarization, January 2001. [5] Thompson CA, Nasseri BA, Makower J, Houser S, McGarry M, Lamson T, Pomerantseva I, Chang JY, Gold HK, Vacanti JR Oesterle SN. Percutaneous transvenous cellular cardiomyoplasty. A novel nonsurgical approach for myocardial cell transplantation. J Am Coll Cardiol 2003 ;41:1964-71. [6] Brasselet C, et al. The coronary sinus: A safe and effective route for percutaneous myoblast transplantation. ACC Abstract: American College of Cardiology Conference, April 2003.
Cardiology ELSEVIER
International Journal of Cardiology 95 Suppl. 1 (2004) $47-$49
II
u
III
IIII
www.elsevier.com/locate/ijcard
Transvascular cellular cardiomyoplasty Craig A. T h o m p s o n M D , M M S c * Dartmouth Hitchcock Medical Center, Assistant Professor of Medicine, Dartmouth Medical School, Angiogenesis Research Center, Lebanon, NH, USA
1. Introduction Myocardial cell transplantation has been proposed as a potential alternative or adjunctive therapy for patients presenting with a wide spectrum of myocardial disorders, including acute myocardial infarction (MI) and ischemic cardiomyopathy. Components of such a system for cellular cardiomyoplasty are the cell source(s), delivery vehicle, and delivery system. Given the positive reported findings with multiple cell sources (e.g. skeletal myoblasts, mesenchymal progenitor cells, smooth muscle cells, bone marrow derived mononuclear cells, and bone marrow/peripheral derived hematopoietic progenitor cells) and the likelihood that higher retained cell number translates to improved functional outcome, it is this author's opinion that delivery methods may play as important a role as the cell source utilized [1,2]. Delivery methods for myocardial biologic substrate delivery can broadly be categorized as (1) peripheral (e.g., peripheral intravenous infusion), (2) surgical (e.g., open chest or minimally invasive), and (3) percutaneous (e.g., intracoronary arterial, coronary venous retroinfusion, or catheter-directed myocardial injection). Absent improvements in technologies to facilitate cell homing, it is unlikely that adequate cells can be delivered intravenously to the myocardium within a reasonable clinical therapeutic window to demonstrate an optimal treatment effect. Surgical injection provides accurate access to anterolateral, posterior, and inferior (but not septal) myocardial territories. However, this approach remains somewhat limited by lack of immediate feedback for the surgeon of cell loss (from microvascular bundles within the myocardium) and may have limited applications (and potential contraindications) in the anticipated clinical targets of patients with acute MI and chronic ischemic cardiomyopathy. Catheter-based coronary artery and coronary venous (retro-)infusion can provide homogenous distribution of cells, but are particularly sensitive to cell loss via venous shunting and sequestration. Current-generation endoventricular myocardial delivery catheter platforms (such as MyostarTM [Biosense-Webster, Inc.], MyoCathT M [Bioheart, Inc.], and *Correspondence address: Dartmouth Hitchcock Medical Center, One MedicalCenterDrive,CardiologySection,Lebanon,NH 03770, USA, Tel.: +1-(603)-650-6319; fax: +1-(603)-650-6164. E-mail address: [email protected] 1389-9457/04/$ - see frontmatter © 2004 ElsevierB.V.All rightsreserved. doi: 10.1016/j.ijcard.2004.04.000
Stiletto [Boston Scientific]) can provide mass cell transfer to the left ventricular myocardium and can provide qualitative immediate feedback of substrate retention based on contrast enhancement evident by fluoroscopy (and potentially MRI). The endoventricular direct injection modalities may be limited by (1) targeting accuracy and stability related to ventricular rotational movements during the cardiac cycle, (2) access interference by the subvalvular mitral apparatus, and (3) cell loss via the short needle tract contiguous with the left ventricle. Acute retention efficiency seems to be reduced, likely due to this ventricular "bleedback" phenomenon or injections into trabeculae rather than heart muscle [3,4]. Furthermore, severely thinned (<5 ram) myocardial walls seen in many infarcted areas are currently felt not to be safely accessible from the endoventricular approach because of concerns about transmyocardial perforation and subsequent cardiac tamponade. In an attempt to harness the strengths of the surgical/direct myocardial injection approaches, but resolve many of the aforementioned limitations, a new method for catheter-based myocardial biologic substrate delivery has been proposed that uses ultrasound-guided needle placement through the coronary veins and directly into the heart muscle (Fig. 1). This "transvascular" needle placement thus provides a stable platform for microinfusion catheter insertion tangentially into the myocardium (similar to surgical injections) for accurate and predictable therapeutic substrate delivery, while provid-
Fig. 1. Trans(coronary) venous direct myocardial injection system a specialized catheter system allows for direct myocardial access for therapeutic substrate delivery. Courtesy Transvascular/Medtronic, Inc., Santa Rosa, CA, USA. [Seep. $72 for color illustration.]
$48
C.A. Thompson~International Journal of Cardiology 95 Suppl. 1 (2004) $47-$49
ing immediate qualitative feedback of substrate retention with contrast as a surrogate [5].
2. Transvascular cell delivery technique After prepping and draping in standard fashion, six French arterial (Cordis Corp., Miami, FL) and 14 French venous (Transvascular/Medtronic Inc., Santa Rosa, CA) femoral sheaths are placed percutaneously. Coronary angiography is performed with emphasis on venous follow-through phase to assess coronary venous patency and anomalies. The coronary sinus (CS) is accessed by placing a porcine 3 catheter (TransVascular, Inc., Menlo Park, CA/Medtronic, Inc) into the right ventricle, withdrawing with clockwise torque across the tricuspid valve. Using this technique, the catheter tends to fall into, or near, the CS. An exchange length, 0.035 hydrophilic guidewire (Terumo Corporation, Tokyo, Japan) with J-tip is then advanced into the CS, through the great cardiac vein (GCV), and into the anterior interventricular coronary vein (AIV). The diagnostic catheter is withdrawn, with the guidewire in place, and a 10 French CS guiding catheter (Transvascular, Inc., Menlo Park, CA/ Medtronic, Inc.) and introducer are placed with conventional over-the-wire technique. The hydrophilic guidewire can then be exchanged for a 0.014 H 300cm Balance Middleweight (BMW) gnidewire (Guidant Corp., Santa Clara, CA), and the guide catheter introducer sheath subsequently removed. The TransAccess ® catheter is a 6 French, monorail, composite catheter system combining a phased array intravascular ultrasound (IVUS, compatible with Volcano Therapeutics system) and a pre-shaped, sheathed, extendable 24 gauge nitinol needle (Fig. 2a). This TransAccess® catheter is advanced over the 0.014 guidewire and into the AIV in preparation for myocardial access. The catheter positioning with respect to the infarcted area is accomplished with angiographic landmarks (ventriculography, fluoroscopy, epicardial vascular branchpoints). Intravascular orientation is performed using the corresponding artery, pericardium, and ventricular chamber as landmarks with IVUS imaging (Fig. 2b). After confirmation of position within the coronary vein and with respect to
(a)
(b)
(c)
Fig. 2. (a) The TransAccessT M catheteris a compositesystemthat combines a sheathed, extendablenitinol needle with (b) a phased array intravascular ultrasound (compatible with Volcano therapeutics system) for guidance for transvascularmyocardialaccess. (c) Once the needle is deployedinto the myocardium, a microinfusioncatheter can be advanced into remote myocardiumfor biologic substrate delivery(arrows). [Seep. $72 for color illustration.]
surrounding structures, the nitinol needle is extended into the myocardium (~5-7 mm depth) to access the infarct and peri-infarct regions. A 0.015" microinfusion (MicrolumeTM) catheter is advanced through the needle, and into the myocardial tissue. Because the myocardial tissue is a potential space, and without room for prolapse, all of the force for the otherwise floppy Microlume TM catheter is forward, essentially allowing this catheter tip to become a drill capable of tunneling through remote myocardium (~40-50 mm and beyond) in plane with the needle puncture. Injections of cell suspension can be performed in a manner to lay an injection latticework pattern in the infarct and peri-infarct regions (Fig. 2c). The current generation of this catheter system is highly flexible and can track over a 0.014" coronary guidewire for selective access into the middle and lateral cardiac veins, as well as the AIV (without need for subselective guiding catheter placement). Changes in the length and angulation of the nitinol needle allow for broad myocardial access from a single location, obviating the need to reposition the catheter as frequently to access different myocardial zones. This versatility provides the operator with multiple options to address anatomic variability.
3. Experience to date Our experience is that this method of percutaneous cell transplantation is highly accurate (100% in the seminal feasibility study in swine with normal hearts) for targeting specific myocardial zones. The needle and infusion catheter are seated deeply within the heart muscle, and therefore rotate with the heart. Conceptually, backbleeding and cell/substrate loss is minimal through the needle tract and multiple injections can be performed within seconds. Immediate "on-line" angiographic feedback for identification of troublesome microvascular bundles (and potential cell loss) is possible with contrast enhancement of the cell suspension. The microcatheter may then be adjusted (by millimeters) to secure a more quiescent zone to facilitate substrate retention. We demonstrated the labeled cells in all transplanted animals ranging from acute sacrifice to one month post injection. Brasselet and colleagues [6] subsequently demonstrated similar safety and feasibility using a myoblast cell source. Smits et al. [3,4] demonstrated that the transvascular method of delivering biologic substrate to the myocardium provided superior efficiency and retention compared to two separate endoventricular catheter systems using a radiolabelled VEGF substrate. The TransAccess injection system had a one minute retention efficiency of 63.5%(-t-26%), comparing favorably with 26%(+23%) and 25%(4-18%) seen with the Biosense and Bioheart endoventricular systems, respectively. Thinned, scarred myocardial tissue has not presented a prohibitive challenge at this point. Our pilot study of the functional effect of autologous bone marrow derived
C.A. Thompson~International Journal of Cardiology 95 Suppl. 1 (2004)$47-$49
$49
4. Conclusions The chosen method of cell transfer may be an important component to augment therapeutic yield in cell transplantation for myocardial diseases. Catheter-based, IVUS guided, direct myocardial cell transplantation through the coronary veins provides a robust, stable, accurate, and relatively efficient platform for cell and biologic substrate delivery. This method and its supporting enabling technologies may contribute to the armamentarium needed to make cardiovascular regenerative medicine a clinical reality.
References Fig. 3. (left) Ex vivo MRI of porcine heart demonstrating thinned area of myocardial scar (yellow box) that received pre-labeled, bone marrow derived transvascular cell transplantation. H&E (top right) and direct fluorescence (bottom right) demonstrate cell grafts expressing cell membrane label two months post transplantation. Subsequent DAPI labeling confirmed cellular viability [not shown]. Magnification x200. [See p. $73 for color illustration.]
cell transplantation in a porcine model of chronic myocardial infarction-induced heart failure (currently in peer review) suggests that this delivery method is feasible, safe, and may have promising biologic effect in this anatomic environment (Fig. 3). The percutaneous transvenous transplantation of autologous myoblasts in the treatment of postinfarction heart failure (POZNAN) phase I clinical trial was presented recently by Dr. Tomasz Siminiak at the American College of Cardiology scientific sessions 2004. The transvascular method was used to transplant autologous skeletal myoblasts in patients with post-infarction heart failure. Nine of ten patients attempted were successful. Approximately l0 s myoblasts were delivered in 2 to 4 channels ranging from 1.5 to 4.5 cm depth from the coronary venous system. The single failure was due to inability to cannulate the coronary sinus with a guidewire. No procedure- (catheter-) related complications occurred.
[1] Thompson CA, Oesterle SN. Biointerventional cardiology: the future interface of interventional cardiovascular medicine and bioengineering. Vasc Med 20027:135-140. [2] Vacanti JP, Langer R. Tissue engineering: the design and fabrication of living replacement devices for surgical reconstruction and transplantation. Lancet 1999;354:SI32-4. [3] Smits PC, van der Giessen WJ. Reys AE, Bakker W, Verdouw P, Serruys PW. Comparison in efficiency between a NOGA and fluoroscopy guided transendomyocardial injection catheter. AHA Abstract: Scientific Conference on Therapeutic Angiogenesis & Myocardial Laser Revascularization, January 2001. [4] Smits PC, van der Giessen WJ, Reys AE, Bakker W, Gabriel G, Verdouw P, Serruys PW. Efficiency and retention of percutaneons transendomyocardial injection of VEGF 165 by a fluoroscopy guided injection catheter: a radionuclide study. AHA Abstract: Scientific Conference on Therapeutic Angiogenesis & Myocardial Laser Revascutarization, January 2001. [5] Thompson CA, Nasseri BA, Makower J, Houser S, McGarry M, Lamson T, Pomerantseva I, Chang JY, Gold HK, Vacanti JR Oesterle SN. Percutaneous transvenous cellular cardiomyoplasty. A novel nonsurgical approach for myocardial cell transplantation. J Am Coll Cardiol 2003 ;41:1964-71. [6] Brasselet C, et al. The coronary sinus: A safe and effective route for percutaneous myoblast transplantation. ACC Abstract: American College of Cardiology Conference, April 2003.