Maintenance of geometric alterations associated with percutaneous mitral valve repair: real-time three-dimensional echocardiographic assessment in an ovine model.

BACKGROUND AND AIM OF THE STUDY: Percutaneous catheter-based mitral annuloplasty (PTMA) exploits the anatomic proximity of the coronary sinus (CS) to the mitral valve apparatus. Acute results of PTMA have been favorable, but the durability of the geometric alterations associated with PTMA has not been reported. The study aim was to assess the three-dimensional (3D) geometry of the mitral annulus (MA) in normal sheep at 20 weeks after PTMA implantation. METHODS: A PTMA device was implanted percutaneously in the CS of 10 normal sheep without mitral regurgitation. All animals were followed for 20 weeks with real-time 3D echocardiography (RT3DE). The MA area, the diagonal diameters in four directions, and the angle alpha, representing the degree of the saddle shape of MA, were determined. RESULTS: No significant hemodynamic, pathologic or mechanical complications were observed during implantation or follow up. Both, the MA area (from 4.8 +/- 0.9 cm2 to 3.7 +/- 0.9 cm2) and anterior-posterior (A-P) diameter (from 21.4 +/- 3.0 mm to 17.6 +/- 2.4 mm) were reduced immediately after the procedure (both p <0.05). The angle alpha decreased after the procedure (from 142.0 +/- 11.5 degrees to 128.3 +/- 15.6 degrees; p <0.05). These changes remained stable over the 20-week follow up period. CONCLUSION: RT3DE demonstrates that PTMA reduces the MA area and A-P diameter and maintains the physiologic curved or saddle shape of the MA. These changes remained stable for 20 weeks after device implantation.

Dynamic change in mitral annular area and motion during percutaneous mitral annuloplasty for ischemic mitral regurgitation: preliminary animal study with real-time 3-dimensional echocardiography.

We used a novel 3-dimensional (3D) echocardiographic technique to evaluate the impact of a coronary sinus-based percutaneous transvenous mitral annuloplasty (PTMA) on dynamic changes in mitral annular geometry and motion during the cardiac cycle in 8 sheep with ischemic mitral regurgitation. Using real-time 3D echocardiographic data before and after PTMA, 10 points along the saddle-shaped annulus were identified. For every 3D volume/frame during a cardiac cycle, we assessed mitral annular area and excursion defined as the traveling distance of the annular center. The PTMA device reduced both minimum and maximal mitral annular area (9.5 +/- 0.9-7.0 +/- 0.6 and 12.8 +/- 1.3-9.8 +/- 1.5 cm(2), P < .001 for both, respectively) with reduction of mitral regurgitation jet area (5.1 +/- 2.3-1.2 +/- 0.8 cm(2), P < .001), whereas it did not significantly impair mitral annular excursion amplitude (8.3 +/- 1.1-7.0 +/- 1.9 mm, P = .13). This 3D echocardiographic method noninvasively enabled dynamic study of mitral annular geometry and motion with quantitative analysis of the impact of PTMA.

Percutaneous mitral valve repair.

Surgical mitral valve repair is the procedure of choice to treat mitral regurgitation of all etiologies. Whereas annuloplasty is the cornerstone of mitral valve repair, a variety of other surgical techniques are utilized to correct dysfunction of the leaflets and subvalvular apparatus; in most cases, surgical repair entails application of multiple repair techniques in each patient. Preclinical studies and early human experience have demonstrated that some of these surgical repair techniques can be performed using percutaneous approaches. Specifically, there has been great progress in the development of novel technology to facilitate percutaneous annuloplasty and percutaneous edge-to-edge repair. The objectives of this report were to (1) discuss the surgical foundations for these percutaneous approaches; (2) review device design and experimental and clinical results of percutaneous valve repair; and (3) address future directions, including the key challenges of patient selection and clinical trial design.

Initial impact of drug-eluting stents on coronary artery bypass graft surgery.

BACKGROUND: Drug-eluting stents (DES) reduce the incidence of restenosis after percutaneous coronary intervention and have been predicted to decrease the number of patients referred for coronary artery bypass grafting (CABG). The purpose of this study was to determine the impact of DES on the number and characteristics of patients referred for CABG. METHODS: Drug-eluting stents were introduced at our hospital in April 2003 and reached maturity by June 2003. We compared our isolated CABG patients from the 12 months before the introduction of DES (year 1) with those from the 12 months after full implementation of DES (year 2). RESULTS: In year 1, of 4,348 cardiac catheterization patients, 2,144 (49.3%) underwent percutaneous coronary intervention, and 432 (9.9%) had CABG. In year 2, of 3,986 cardiac catheterization patients, 2,027 (50.9%) had percutaneous coronary intervention, and 337 (8.5%) had CABG, representing a 14% reduction in proportion of cardiac catheterization patients referred for CABG (p = 0.021). Among CABG patients, there was no change in age, prevalence of diabetes, or prevalence of three-vessel disease; however, patients in year 2 were more likely to have left main coronary artery disease (year 1, 36% versus year 2, 44.5%; p < 0.02) and left ventricular ejection fraction greater than 0.50 (year 1, 45% versus year 2, 52%; p < 0.02). CONCLUSIONS: The clinical introduction of DES was associated with a modest decrease in the percentage of cardiac catheterization patients referred for CABG. Of those referred for surgery, an increasing proportion had left main coronary artery disease and preserved left ventricular systolic function. Defining the role of DES versus CABG for coronary revascularization will require elucidation of the long-term outcomes of DES compared with CABG.

Implementing tight glucose control after coronary artery bypass surgery.

BACKGROUND: The clinical benefit of tight glucose control has been demonstrated in diabetic patients. In adopting an approach of tight glucose control for all cardiac surgery patients at Beth Israel Deaconess Medical Center, we encountered several challenges, including defining good glucose control, meaningfully measuring control, and assessing the impact of variables that may affect control. METHODS: An interdisciplinary team used an insulin protocol to achieve tight glucose control of cardiac surgery patients in the operating room and intensive care unit as part of an effort to reduce sternal wound infections. Good control was defined as glucose less than 130 mg/dL for more than 50% of measured time. RESULTS: Eight hundred eighteen patients underwent coronary artery bypass grafting between November 2002 and August 2004. Seven hundred thirty-seven (90%) received insulin. Fifty-seven percent did not have a preoperative diagnosis of diabetes. The trigger for insulin initiation was decreased sequentially from 150 mg/dL to 110 mg/dL, but the measure of good control remained the same: glucose less than 130 mg/dL. The factor most highly predictive of glucose being well controlled was the protocol with the 110 mg/dL trigger for insulin (p < 0.001). Patient factors such as age, ejection fraction, preoperative angiotensin-converting enzyme inhibitor or beta-blocker use, or time on cardiopulmonary bypass were not significantly associated with glucose control. During the course of the protocols, the rate of mediastinitis decreased from 1.6% to 0%. CONCLUSIONS: Key elements to implementing tight glucose control include having a standard protocol and metrics to track protocol performance. This practice improved control and was associated with a marked reduction in mediastinitis.

Percutaneous mitral valve repair for chronic ischemic mitral regurgitation: a real-time three-dimensional echocardiographic study in an ovine model.

BACKGROUND: Although surgical annuloplasty is the standard repair for ischemic mitral regurgitation (IMR), its application is limited by high morbidity and mortality. Using 2D and real-time 3D echocardiography in an ovine model of chronic IMR, we evaluated the geometric impact and short-term efficacy of a percutaneous transvenous catheter-based approach for mitral valve (MV) repair using a novel annuloplasty device placed in the coronary sinus. METHODS AND RESULTS: Six sheep developed IMR 8 weeks after induced posterior myocardial infarction. An annuloplasty device optimized to reduce anterior-posterior (A-P) mitral annular dimension and MR was placed percutaneously in the coronary sinus. Mitral annular A-P and commissure-commissure dimensions and MV tenting area (MVTa) in 3 parallel A-P planes (medial, central, and lateral) were assessed by real-time 3D echocardiography with 3D software. The annuloplasty device reduced MR jet area from 5.4+/-2.6 to 1.3+/-0.9 cm2 (P<0.01), mitral annular A-P dimension in both systole and diastole (24.3+/-2.5 to 19.7+/-2.4 mm; P<0.03; 31.0+/-3.9 to 24.7+/-2.1 mm; P<0.001), and MVTa at mid systole in all 3 planes (153+/-46 to 93+/-24 mm2, P<0.01; 140+/-47 to 88+/-23 mm2, P<0.03; and 103+/-23 to 87+/-26 mm2, P<0.03). CONCLUSIONS: Percutaneous coronary sinus-based mitral annuloplasty reduces chronic IMR by reducing mitral annular A-P diameter and MVTa. This suggests the potential clinical application of a new nonsurgical therapeutic approach in patients with IMR.

Gene expression profile after cardiopulmonary bypass and cardioplegic arrest.

OBJECTIVE: This study examines the cardiac and peripheral gene expression responses to cardiopulmonary bypass and cardioplegic arrest. METHODS: Atrial myocardium and skeletal muscle were harvested from 16 patients who underwent coronary artery bypass grafting before and after cardiopulmonary bypass and cardioplegic arrest. Ten sample pairs were selected for patient similarity, and oligonucleotide microarray analyses of 12,625 genes were performed using matched precardiopulmonary bypass tissues as controls. Array results were validated with Northern blotting, real-time polymerase chain reaction, in situ hybridization, and immunoblotting. Statistical analyses were nonparametric. RESULTS: Median durations of cardiopulmonary bypass and cardioplegic arrest were 74 and 60 minutes, respectively. Compared with precardiopulmonary bypass, postcardiopulmonary bypass myocardial tissues revealed 480 up-regulated and 626 down-regulated genes with a threshold P value of.025 or less (signal-to-noise ratio: 3.46); skeletal muscle tissues showed 560 and 348 such genes, respectively (signal-to-noise ratio: 3.04). Up-regulated genes in cardiac tissues included inflammatory and transcription activators FOS; jun B proto-oncogene; nuclear receptor subfamily 4, group A, member 3; MYC; transcription factor-8; endothelial leukocyte adhesion molecule-1; and cysteine-rich 61; apoptotic genes nuclear receptor subfamily 4, group A, member 1 and cyclin-dependent kinase inhibitor 1A; and stress genes dual-specificity phosphatase-1, dual-specificity phosphatase-5, and B-cell translocation gene 2. Up-regulated skeletal muscle genes included interleukin 6; interleukin 8; tumor necrosis factor receptor superfamily, member 11B; nuclear receptor subfamily 4, group A, member 3; transcription factor-8; interleukin 13; jun B proto-oncogene; interleukin 1B; glycoprotein Ib, platelet, alpha polypeptide; and Ras-associated protein RAB27A. Down-regulated genes included haptoglobin and numerous immunoglobulins in the heart, and factor H-related gene 2, protein phosphatase 1, regulatory subunit 3A, and growth differentiation factor-8 in skeletal muscle. CONCLUSIONS: By establishing a profile of the gene-expression responses to cardiopulmonary bypass and cardioplegia, this study allows a better understanding of their effects and provides a framework for the evaluation of new cardiac surgical modalities directly at the genome level.

Percutaneous mitral valve repair: a feasibility study in an ovine model of acute ischemic mitral regurgitation.

Annuloplasty is the cornerstone of surgical mitral valve repair. A percutaneous transvenous catheter-based approach for mitral valve repair was tested by placing a novel annuloplasty device in the coronary sinus of sheep with acute ischemic mitral regurgitation. Mitral regurgitation was reduced from 3-4+ to 0-1+ in all animals (P < 0.03). The annuloplasty functioned by reducing septal-lateral mitral annular diameter (30 +/- 2.1 mm preinsertion vs. 24 +/- 1.7 mm postinsertion; P < 0.03). These preliminary experiments demonstrate that percutaneous mitral annuloplasty is feasible. Further study is necessary to demonstrate long-term safety and efficacy of this novel approach.

Mitogen-activated protein kinase inhibition and cardioplegia-cardiopulmonary bypass reduce coronary myogenic tone.

BACKGROUND: Cardioplegia-cardiopulmonary bypass (C/CPB) is associated with coronary microcirculatory dysfunction. Regulation of the microcirculation includes myogenic tone. Mitogen-activated protein kinases (MAPK) have been implicated in coronary vasomotor function. We hypothesized that vasomotor dysfunction of the coronary microcirculation is mediated in part by alterations in extracellular signal regulated kinase 1/2 (ERK1/2) activity following C/CPB in humans. METHODS AND RESULTS: Atrial myocardium was harvested from patients (n=15) before and after blood cardioplegia and short-term reperfusion under conditions of CPB. Myogenic tone of coronary arterioles was measured by videomicroscopy. Microvessel tone was determined post-C/CPB and after PD98059, a MAPK/ERK kinase 1/2 (MEK1/2) inhibitor. MAPK phosphatase-1 (MKP-1) and activated ERK1/2 were measured by Western blot. MKP-1 gene expression was determined by Northern blot. In situ hybridization and immunohistochemistry were used to localize myocardial MKP-1 and activated ERK1/2, respectively. Myogenic tone was reduced in coronary arterioles post-C/CPB (-10.5+/-0.9%, P<0.01 versus control/pre-C/CPB, n=5). Myogenic tone was decreased in coronary microvessels after 30 micromol/L (n=5) and 50 micromol/L (n=5) PD98059 treatment (-11.0+/-0.8% and -14.6+/-2.0%, respectively, both P<0.01 versus control/pre-C/CPB). Myocardial levels of activated ERK1/2 were reduced post-C/CPB (0.6+/-0.1, post/pre-C/CPB ratio, P<0.05, n=5) while MKP-1 levels increased (4.2+/-0.6, post/pre-C/CPB ratio, P<0.05, n=5). Myocardial MKP-1 gene expression increased post-C/CPB (3.0+/-0.8, post/pre-C/CPB ratio, P<0.05, n=5). MKP-1 and activated ERK1/2 localized to coronary arterioles in myocardial sections. CONCLUSIONS: Coronary myogenic tone is dependent on ERK1/2 and decreased after C/CPB. C/CPB reduces levels of activated ERK1/2, potentially by increased levels of MKP-1. The ERK1/2 signal transduction pathway in part mediates coronary microvascular dysfunction after C/CPB in humans.

Cardiopulmonary bypass reduces peripheral microvascular contractile function by inhibition of mitogen-activated protein kinase activity.

BACKGROUND: Mitogen-activated protein kinases (MAPK) have been implicated in pathophysiologic responses to cardiopulmonary bypass (CPB). MAPK are deactivated by phosphatases, such as MAPK phosphatase-1 (MKP-1). We hypothesized that MAPK mediate peripheral microvascular contractile dysfunction caused by CPB in humans. METHODS: Skeletal muscle was harvested before and after CPB. Protein levels of MKP-1 and activated extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 were measured. MKP-1 gene expression was measured. Peripheral microvessel responses to vasopressors were studied by videomicroscopy. Contractile function also was measured after MAPK inhibition with PD98059 (ERK1/2) and SB203580 (p38). ERK1/2, p38, and MKP-1 were localized by immunohistochemistry and in situ hybridization. RESULTS: ERK1/2 and p38 activity was decreased in peripheral tissue after CPB. MKP-1 was increased after CPB. Contractile responses of peripheral arterioles to phenylephrine and vasopressin were decreased after CPB. Microvessel reactivity also was reduced after treatment with PD98059 and SB203580. ERK1/2, p38, and MKP-1 localized to peripheral arterioles in tissue sections. CONCLUSIONS: CPB reduces ERK1/2 and p38 activity in peripheral tissue, potentially by MKP-1. Contractile responses of peripheral arterioles to phenylephrine and vasopressin are dependent on ERK1/2 and p38 and are decreased after CPB. These results suggest that alterations in MAPK pathways in part regulate peripheral microvascular dysfunction after CPB in humans.

Intracardiac ultrasonic suture welding for knotless mitral valve replacement.

OBJECTIVE: The difficulty in tying multiple knots with endoscopic instruments constitutes a technical obstacle to the development of closed-chest valve surgery. The following set of experiments was undertaken to ascertain the in-vivo feasibility of using an intracardiac ultrasonic welding device for knotless suture fixation during mitral valve replacement (MVR). METHODS: Five adult sheep weighing 48-52 kg underwent MVR with a commercially available mechanical prosthesis, using pledgetted interrupted polypropylene sutures. An ultrasonic suture welder designed for intracardiac use was used to adjust suture tension and fuse strands together without knots. Echocardiographic assessment of the mitral prosthesis was carried out at baseline and after maintenance of supraphysiologic arterial pressures for 60 min. Subsequently, the animals' explanted hearts were assessed under sustained left ventricular (LV) pressurization to 180 mmHg in an ex-vivo pressure-loop system. RESULTS: MVR was successfully performed in all animals and welds reliably completed in less than 1 s. One sheep could not successfully be weaned off cardiopulmonary bypass; however, a normal prosthetic valve implant was confirmed at post-mortem examination. Echocardiographic assessment prior to and during LV pressurization revealed normal seating and function of the prosthesis in all cases. At post-mortem examination all valves were adequately implanted, suture tails laid flat on the surface of the prosthesis' sewing ring, welded suture strands were intact and accurately point-fused together, and no evidence of perivalvular leak was found around any of the prostheses despite sustained LV pressurization. CONCLUSIONS: This new modality proved reliable in an acute sheep model of MVR and could constitute a promising avenue towards facilitation of total endoscopic valve procedures in humans.