Faculty Bibliography

OBJECTIVES: We sought to confirm our hypothesis that the human sinoatrial node (SAN) is functionally insulated from the surrounding atrial myocardium except for several exit pathways that electrically bridge the nodal tissue and atrial myocardium. BACKGROUND: The site of origin and pattern of excitation within the human SAN has not been directly mapped. METHODS: The SAN was optically mapped in coronary-perfused preparations from nonfailing human hearts (n = 4, age 54 +/- 15 years) using the dye Di-4-ANBDQBS and blebbistatin. The SAN 3-dimensional structure was reconstructed using histology. RESULTS: Optical recordings from the SAN had diastolic depolarization and multiple upstroke components, which corresponded to the separate excitations of the SAN and atrial layers. Excitation originated in the middle of the SAN (66 +/- 17 beats/min), and then spread slowly (1 to 18 cm/s) and anisotropically. After a 82 +/- 17 ms conduction delay within the SAN, the atrial myocardium was excited via superior, middle, and/or inferior sinoatrial conduction pathways. Atrial excitation was initiated 9.4 +/- 4.2 mm from the leading pacemaker site. The oval 14.3 +/- 1.5 mm x 6.7 +/- 1.6 mm x 1.0 +/- 0.2 mm SAN structure was functionally insulated from the atrium by connective tissue, fat, and coronary arteries, except for these pathways. CONCLUSIONS: These data demonstrated for the first time, to our knowledge, the location of the leading SAN pacemaker site, the pattern of excitation within the human SAN, and the conduction pathways into the right atrium. The existence of these pathways explains why, even during normal sinus rhythm, atrial breakthroughs could arise from a region parallel to the crista terminalis that is significantly larger (26.1 +/- 7.9 mm) than the area of the anatomically defined SAN.

BACKGROUND: Herein we study the role of donor-specific antibodies (DSA) to mismatched human leukocyte antigen (HLA) and antibodies (Abs) to the cardiac self-antigens myosin (MYO) and vimentin (VIM) in the pathogenesis of acute antibody-mediated rejection (AMR) in the early post-transplant period (EP, <12 months) and cardiac allograft vasculopathy (CAV) in the late post-transplant period (LP, >12 months) after heart transplantation (HTx). METHODS: One hundred forty-eight HTx recipients (65 in EP, 83 in LP) were enrolled in the study. Development of DSA was determined by Luminex. Circulating Abs against MYO and VIM in sera were measured using enzyme-linked immunoassay (ELISA). Frequency of CD4+ T-helper cells (CD4+ Th) secreting interferon (IFN)-gamma, interleukin (IL)-17, IL-10 or IL-5 specific to either MYO or VIM were analyzed in vitro using ELISpot assays. RESULTS: AMR patients were more likely DSA positive (AMR-: 15%; AMR+: 70%; p = 0.03) and demonstrated increased Abs to MYO (AMR-: 144 +/- 115 mug/ml; AMR+: 285 +/- 70 mug/ml; p = 0.033) and VIM (AMR-: 37 +/- 19 mug/ml; AMR+: 103 +/- 43 mug/ml; p = 0.014). AMR patients demonstrated increased IL-5 CD4+ Th cells specific to MYO (5.2 +/- 0.9 fold, p = 0.003) and VIM (7.3 +/- 2.9-fold, p = 0.004) and decreased IL-10 CD4+ Th cells specific to MYO (2.2 +/- 0.4-fold, p = 0.009) and VIM (1.7 +/- 0.2-fold, p = 0.03). CAV patients were more likely DSA positive (CAV-): 25%; CAV+: 79%; p = 0.03) and demonstrated increased Abs to MYO (CAV-: 191 +/- 120 mug/ml; CAV+: 550 +/- 98 mug/ml; p = 0.025) and VIM (CAV-: 55 +/- 25 mug/ml; CAV+: 255 +/- 49 mug/ml; p = 0.001). CAV patients demonstrated increased IL-17 CD4+ Th cells specific to MYO (10.5 +/- 7.3-fold, p = 0.002) and VIM (7.0 +/- 3.9-fold, p = 0.003). CONCLUSIONS: The presence of DSA in AMR and CAV is significantly associated with development of Abs to MYO and VIM in post-HTx patients. Induction of high CD4+ Th cells specific to cardiac self-antigens that secrete predominantly IL-5 and IL-17 plays a significant role in the development of Abs to self-antigens leading to AMR and CAV, respectively.

Humoral immune responses to mismatched donor human leukocyte antigen (HLA) and major histocompatibility complex (MHC) class I-related chain A (MICA) have been reported to contribute to immunopathogenesis of antibody-mediated rejection (AMR) in the early period and cardiac allograft vasculopathy (CAV) in the late period after cardiac transplantation (HTx). The goal of this study is to define the roles of donor-specific antibodies (DSA) and anti-MICA in AMR and CAV. A total of 95 post-HTx recipients were enrolled; 43 patients in the early period (12 months post-HTx). Development of DSA and anti-MICA were serially monitored using Luminex. Development of DSA (AMR+: n = 6/8.75%, AMR-: n = 4/35.11%, p = 0.009) and anti-MICA (AMR+: n = 5/8.63%, AMR-: n = 4/35.11%, p = 0.002) was significantly associated with AMR. AMR+DSA+ patients demonstrated increased anti-MICA levels compared with AMR+DSA- patients (p=0.01). Serial monitoring revealed DSA (2.7 +/- 1.4 months) preceded development of anti-MICA (6.5 +/- 2.1 months) in recipients diagnosed with AMR at 8.3 +/- 2.5 months post-HTx. Development of DSA (CAV+: n = 8/12.67%, CAV-: n = 5/40.13%, p = 0.004) and anti-MICA (CAV+: n = 9/12.75%, CAV-: n = 5/40.13%, p = 0.001) was significantly associated with CAV. CAV+DSA+ patients demonstrated increased anti-MICA levels compared with CAV+DSA- patients (p = 0.01). Antibodies to HLA are associated with and precede development of anti-MICA in AMR and CAV. Therefore, DSA and anti-MICA can be used as noninvasive markers for monitoring AMR and CAV.

BACKGROUND: The purpose of this study was to compare operative mortality and long-term outcome of patients undergoing tricuspid valve replacement versus tricuspid valve repair. METHODS: From February 1986 to July 2006, 315 patients underwent tricuspid valve surgery including 93 replacements (72 biologic, 21 mechanical) and 222 repairs. To control for selection bias and varying comorbidities, a matched cohort of patients undergoing repair versus replacement was selected using propensity score analysis (68 patients in each group). RESULTS: In the propensity-matched cohorts, operative mortality was similar for tricuspid valve replacement (13% +/- 4%) and repair (18% +/- 5%; p = 0.64). Intensive care unit length of stay was similar between cohorts (replacement, 4 days; repair, 3 days; p = 0.45), but the replacements had a significantly longer hospital lengths of stay (9 days versus 6 days; p = 0.01). In the replacement cohort, survival was 85% at 1 year, 79% at 5 years, and 49% at 10 years. In the repair cohort, survival rates were similar with 80% at 1 year, 72% at 5 years, and 66% at 10 years (p = 0.66 versus replacement). CONCLUSIONS: Surgical treatment of tricuspid valve disease, regardless of the operative approach, is associated with significant early and late mortality. However, there is no difference favoring tricuspid valve repair over replacement. Thus, we should not hesitate to consider tricuspid valve replacement for patients in whom we believe there is a reasonable chance for recurrence of regurgitation after repair.

OBJECTIVE: The purpose of this investigation was to examine the impact of prosthesis-patient mismatch after bioprosthetic aortic valve replacement on long-term survival in patients greater than 70 years of age compared with those less than or equal to 70 years of age. METHODS: Between 1992 and 2007, 1399 patients underwent bioprosthetic aortic valve replacement, including 881 (63%) patients older than 70 years of age. Prosthesis-patient mismatch was defined as severe (prosthetic effective orifice area/body surface area < 0.65 cm(2)/m(2)), moderate (0.65-0.85 cm(2)/m(2)), or absent (>0.85 cm(2)/m(2)). For patients less than or equal to 70 years of age, mismatch was severe in 62 (12%), moderate in 251 (48%), and absent in 205 (40%). For patients greater than 70 years of age, mismatch was severe in 109 (12%), moderate in 451 (51%), and absent in 321 (37%). There was no difference in the distribution of prosthesis-patient mismatch between age groups (P = .50). RESULTS: For patients less than or equal to 70 years, prosthesis-patient mismatch was associated with impaired long-term survival (P = .02). Survival at 5 and 10 years was 61% +/- 7% and 28% +/- 12% for severe mismatch, 65% +/- 3% and 40% +/- 5% for moderate mismatch, and 73% +/- 5% and 46% +/- 9% for no mismatch. For patients greater than 70 years, prosthesis-patient mismatch did not affect long-term survival (P = .25). Survival at 5 and 10 years was 62% +/- 5% and 42% +/- 6% for severe mismatch, 62% +/- 2% and 30% +/- 5% for moderate mismatch, and 53% +/- 4% and 29% +/- 5% for absent mismatch. CONCLUSIONS: After bioprosthetic aortic valve replacement, prosthesis-patient mismatch had a negative impact on late survival for patients less than or equal to 70 years of age, but for patients greater than 70 years of age, prosthesis-patient mismatch did not influence late survival.

BACKGROUND: Myocardial systolic strain patterns in dilated cardiomyopathy are considered non-homogeneous but have not been investigated with magnetic resonance imaging (MRI)-based multiparametric systolic strain analysis. Left ventricular (LV) 3-dimensional (3D) multiparametric systolic strain analysis is sensitive to regional contractility and is generated from sequential MRI of tissue-tagging gridline-point displacements. METHODS: Sixty normal human volunteers underwent MRI-based 3D systolic strain analysis to supply normal average and standard deviation values for each of three strain parameters at each of 15,300 individual LV grid-points. Patient-specific multiparametric systolic strain data from each dilated cardiomyopathy patient (n = 10) were then subjected to a point-by-point comparison (n = 15,300 LV points) to the normal strain database for three individual strain components (45,900 database comparisons per patient). The resulting composite multiparametric Z-score values (standard deviation from normal average) were color contour mapped over patient-specific 3D LV geometry to detect the normalized regional contractile patterns associated with dilated cardiomyopathy. RESULTS: Average multiparametric strain Z-score values varied significantly according to ventricular level (p = 0.001) and region (p = 0.003). Apical Z-scores were significantly less than those in both the base (p = 0.037) and mid-ventricle (p = 0.002), whereas anterolateral wall Z-scores were less than those in the anteroseptal (p = 0.023) and posteroseptal walls (p = 0.028). CONCLUSIONS: MRI-based multiparametric systolic strain analysis suggests that myocardial systolic strain in patients with dilated cardiomyopathy has a heterogeneous regional distribution and, on average, falls almost 2 standard deviations from normal.

OBJECTIVES: This study sought to evaluate the use of a continuous-flow rotary left ventricular assist device (LVAD) as a bridge to heart transplantation. BACKGROUND: LVAD therapy is an established treatment modality for patients with advanced heart failure. Pulsatile LVADs have limitations in design precluding their use for extended support. Continuous-flow rotary LVADs represent an innovative design with potential for small size and greater reliability by simplification of the pumping mechanism. METHODS: In a prospective, multicenter study, 281 patients urgently listed (United Network of Organ Sharing status 1A or 1B) for heart transplantation underwent implantation of a continuous-flow LVAD. Survival and transplantation rates were assessed at 18 months. Patients were assessed for adverse events throughout the study and for quality of life, functional status, and organ function for 6 months. RESULTS: Of 281 patients, 222 (79%) underwent transplantation, LVAD removal for cardiac recovery, or had ongoing LVAD support at 18-month follow-up. Actuarial survival on support was 72% (95% confidence interval: 65% to 79%) at 18 months. At 6 months, there were significant improvements in functional status and 6-min walk test (from 0% to 83% of patients in New York Heart Association functional class I or II and from 13% to 89% of patients completing a 6-min walk test) and in quality of life (mean values improved 41% with Minnesota Living With Heart Failure and 75% with Kansas City Cardiomyopathy questionnaires). Major adverse events included bleeding, stroke, right heart failure, and percutaneous lead infection. Pump thrombosis occurred in 4 patients. CONCLUSIONS: A continuous-flow LVAD provides effective hemodynamic support for at least 18 months in patients awaiting transplantation, with improved functional status and quality of life. (Thoratec HeartMate II Left Ventricular Assist System [LVAS] for Bridge to Cardiac Transplantation; NCT00121472).

BACKGROUND: The HeartMate II (Thoratec, Pleasanton, CA) is an effective bridge to transplantation (BTT) but requires anti-coagulation with warfarin and aspirin. We evaluated the risk of thromboembolism and hemorrhage related to the degree of anti-coagulation as reflected by the international normalized ratio (INR). METHODS: INRs were measured monthly for 6 months in all discharged HeartMate II BTT patients and at an event. Each INR was assigned to ranges of INRs. Adverse events analyzed were ischemic and hemorrhagic stroke, pump thrombosis, and bleeding requiring surgery or transfusion. Events were correlated to the INR during the event and at the start of the month. RESULTS: In 331 patients discharged on support, 10 had thrombotic events (9 ischemic strokes, 3 pump thromboses), and 58 had hemorrhagic events (7 strokes, 4 hemorrhages requiring surgery, and 102 requiring transfusions). The median INR was 2.1 at discharge and 1.90 at 6 months. Although the incidence of stroke was low, 40% of ischemic strokes occurred in patients with INRs < 1.5 and 33% of hemorrhagic strokes were in patients with INRs > 3.0. The highest incidence of bleeding was at INRs > 2.5. CONCLUSIONS: The rate of thromboembolism during long-term outpatient support with the HeartMate II is low. The low number of thrombotic events appears to be offset by a greater number of hemorrhagic events. An appropriate target INR is 1.5 to 2.5 in addition to aspirin therapy. In patients having recurrent episodes of bleeding, the risk of lowering the target INR appears to be small.

BACKGROUND: Recent data suggest that octogenarians' long-term survival after complete coronary artery bypass graft revascularization is superior to incomplete revascularization. Discriminating between variable definitions of "complete" complicates interpretation of survival data. We aimed to clarify octogenarian long-term survival rates by stratifying revascularization subtypes. METHODS AND RESULTS: From 1986 to 2007, 580 patients 80 to 94 years of age underwent coronary artery bypass graft. Functional complete revascularization was defined as at least 1 graft to all diseased coronary vessels with >50% stenosis. Traditional complete revascularization was defined as 1 graft to each major arterial system with at least 50% stenosis. Incomplete revascularization was defined as leaving diseased, ungrafted regions. Revascularization was functional in 279 (48%), traditional in 181 (31%), and incomplete in 120 (21%). Long-term survival was evaluated by Kaplan-Meier analysis. Of 537 operative survivors, there were 402 late deaths. Cumulative long-term survival totaled 2890 patient-years. Late survival (Kaplan-Meier) was similar between functional (mean, 6.8 years) and traditional (6.7 years) groups (P=0.51), but diminished with incomplete (4.2 years) revascularization (P=0.007). Survival by group at 5 years was: 59+/-3% functional, 57+/-4% traditional, and 45+/-5% incomplete. Survival at 8 years was: 40+/-3% functional, 37+/-4% traditional, and 26+/-5% incomplete. To minimize selection bias in patients with limited life expectancy, Kaplan-Meier analysis was repeated including only patients with survival >12 months. Survival was again impaired with incomplete revascularization (P=0.04), and there was no difference between functional and traditional complete revascularization (P=0.73). CONCLUSIONS: Bypassing all diseased arterial vessels after revascularization does not afford significant long-term survival advantage compared to a traditional approach. Incomplete revascularization, related to more extensive disease, is associated with an 18% decline in survival. These data suggest that it is important to avoid incomplete revascularization in octogenarians, but the supplementary endeavor required to perform functional complete revascularization does not improve survival.