Faculty Bibliography

An increasing number of patients are implanted with continuous-flow left ventricular assist devices (LVAD) for the treatment of severe congestive heart failure. In parallel with this growing experience has been an increase in knowledge of how these devices alter cardiac physiology and the important implications this has for cardiac function. Echocardiography offers the ability to provide serial noninvasive evaluation before and after LVAD implantation to document these changes, guide management decisions, and identify LVAD dysfunction. The authors detail a comprehensive assessment of LVAD function by transthoracic echocardiography.

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: 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.

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.

Lysosome-associated membrane protein (LAMP2) cardiomyopathy is an X-linked and highly progressive myocardial storage disorder associated with diminished survival, which clinically resembles sarcomeric hypertrophic cardiomyopathy. As shown here in a young woman, the natural history of LAMP2 may demonstrate an extreme profile of left ventricular remodeling with regression of hypertrophy (i.e. marked wall thinning), chamber dilatation, and severe systolic dysfunction, all of which are associated with widespread transmural scarring.

BACKGROUND: Continuous-flow left ventricular assist devices (LVAD) are increasingly being used in patients with end-stage heart failure and have largely replaced older generation pulsatile devices. While significant rates of infection have been reported in patients with pulsatile device support, incidence and outcomes of this complication for the continuous-flow device patients remain unknown. METHODS: Between June 2005 and August 2009, 81 patients were implanted with continuous-flow LVADs at Washington University School of Medicine either as bridge to transplantation or as destination therapy. Outcomes of this study included incidence of postimplantation infection, types of infection, microbiologic profile, and association of postimplantation infections with clinical endpoints. RESULTS: Forty-two patients (51.9%) had at least one type of infection on continuous-flow LVAD support with a mean follow-up period of 9.2 +/- 9.2 months. Patients who had an infection on LVAD support had a significantly prolonged hospital stay (37.9 +/- 32.0 versus 20.7 +/- 23.0 days, p = 0.008) and a trend toward increased mortality (33.1% versus 18.7% at 2 years, respectively, log rank p = 0.102) compared with patients who did not. Subgroup analysis revealed that postimplantation sepsis was significantly associated with increased mortality in the continuous-flow LVAD cohort (61.9% versus 18.0% at 2 years, respectively, in septic and nonseptic patients, log rank p = 0.001). The majority of the sepsis cases occurred before hospital discharge, whereas most of the device related infections occurred after discharge. Resistant Staphylococcus and Pseudomonas species were the most common pathogens leading to device- and nondevice-related local infections. Development of driveline or pocket infection had no effect on survival in patients with continuous-flow assist device support (p = 0.193). CONCLUSIONS: Even though better clinical outcomes have been achieved with the newer generation continuous-flow devices, infection complications-in particular sepsis-are still a major risk for patients with continuous-flow LVAD implantation. Prevention strategies with aggressive medical and surgical management of infections may increase survival and decrease morbidity among continuous-flow LVAD patients.