Faculty Bibliography

The cardiac transplantation program at Cleveland Clinic has performed 1,627 adult orthotopic heart transplants, with a current 1-year survival of 96% and a 3-year survival of 82%. The change in the heart allocation system in 2006 has affected our Center by both reducing the number of transplants we perform annually and increasing the percentage of recipients on MCS at the time of transplant. Despite the increased utilization of left ventricular assist devices (LVADs) as a bridge to transplant, we continue to maintain excellent outcomes. The major clinical advances in LVAD technology have allowed us to expand this therapy to ineligible transplant patients, with outcomes that are continually improving. Nevertheless, the field of MCS as permanent therapy is still in its infancy. The number of patients who can benefit from this technology in the U.S. alone is in the thousands, but refinements in patient selection and management are needed to further advance this lifesaving therapy.

Over the years, policies adopted by United Network of Organ Sharing (UNOS) have directed allocation of donor hearts in the USA. These policies have been based on algorithms that allocate a higher priority status to those patients who are the most infirm, and would thereby benefit patients in the most dire of circumstances. Over the last 2 decades, the increased use of LVADs as a bridge to transplantation has had a major impact on lowering the mortality among those on the heart transplant waiting list. Given the constant risk of potential complications related to these devices, early UNOS policies were implemented to specifically allocate higher priority status to patients on LVADs. However, recent advances in LVAD technology coupled with refinements in patient selection and management have dramatically improved patient survival and led to a reduction in complications. It is inevitable that favorable experiences with the current generation of LVADs coupled with continued improvements in technology will lead to increased use of these devices as a bridge to transplantation or to candidacy.

This study compared the effects of ATP-regulated potassium channel (K(ATP)) openers, diazoxide and pinacidil, on diseased and normal human atria and ventricles. We optically mapped the endocardium of coronary-perfused right (n=11) or left (n=2) posterior atrial-ventricular free wall preparations from human hearts with congestive heart failure (CHF, n=8) and non-failing human hearts without (NF, n=3) or with (INF, n=2) infarction. We also analyzed the mRNA expression of the K(ATP) targets K(ir)6.1, K(ir)6.2, SUR1, and SUR2 in the left atria and ventricles of NF (n=8) and CHF (n=4) hearts. In both CHF and INF hearts, diazoxide significantly decreased action potential durations (APDs) in atria (by -21+/-3% and -27+/-13%, p<0.01) and ventricles (by -28+/-7% and -28+/-4%, p<0.01). Diazoxide did not change APD (0+/-5%) in NF atria. Pinacidil significantly decreased APDs in both atria (-46 to -80%, p<0.01) and ventricles (-65 to -93%, p<0.01) in all hearts studied. The effect of pinacidil on APD was significantly higher than that of diazoxide in both atria and ventricles of all groups (p<0.05). During pinacidil perfusion, burst pacing induced flutter/fibrillation in all atrial and ventricular preparations with dominant frequencies of 14.4+/-6.1 Hz and 17.5+/-5.1 Hz, respectively. Glibenclamide (10 muM) terminated these arrhythmias and restored APDs to control values. Relative mRNA expression levels of K(ATP) targets were correlated to functional observations. Remodeling in response to CHF and/or previous infarct potentiated diazoxide-induced APD shortening. The activation of atrial and ventricular K(ATP) channels enhances arrhythmogenicity, suggesting that such activation may contribute to reentrant arrhythmias in ischemic hearts.

BACKGROUND: The structure-function relationship in the atrioventricular junction (AVJ) of various animal species has been investigated in detail; however, less is known about the human AVJ. In this study, we performed high-resolution optical mapping of the human AVJ (n = 6) to define its pacemaker properties and response to autonomic stimulation. METHODS AND RESULTS: Isolated, coronary-perfused AVJ preparations from failing human hearts (n = 6, 53 +/- 6 years) were optically mapped using the near-infrared, voltage-sensitive dye, di-4-ANBDQBS, with isoproterenol (1 mumol/L) and acetylcholine (1 mumol/L). An algorithm detecting multiple components of optical action potentials was used to reconstruct multilayered intramural AVJ activation and to identify specialized slow and fast conduction pathways (SP and FP). The anatomic origin and propagation of pacemaker activity was verified by histology. Spontaneous AVJ rhythms of 29 +/- 11 bpm (n = 6) originated in the nodal-His region (n = 3) and/or the proximal His bundle (n = 4). Isoproterenol accelerated the AVJ rhythm to 69 +/- 12 bpm (n = 5); shifted the leading pacemaker to the transitional cell regions near the FP and SP (n = 4) and/or coronary sinus (n = 2); and triggered reentrant arrhythmias (n = 2). Acetylcholine (n = 4) decreased the AVJ rhythm to 18 +/- 4 bpm; slowed FP/SP conduction leading to block between the AVJ and atrium; and shifted the pacemaker to either the transitional cell region or the nodal-His region (bifocal activation). CONCLUSIONS: We have demonstrated that the AVJ pacemaker in failing human hearts is located in the nodal-His region or His bundle regions and can be modified with autonomic stimulation. Moreover, we found that both the FP and SP are involved in anterograde and retrograde conduction.

BACKGROUND: We determined the role of donor-specific antibodies (DSA) and antibodies (Abs) to self-antigens, collagen-V (Col-V), and K-alpha1-Tubulin (KAT) in pathogenesis of acute antibody-mediated rejection (AMR) and cardiac allograft vasculopathy (CAV) after human heart transplantation (HTx). METHODS: One hundred thirty-seven HTx recipients, with 60 early period (12 months), were enrolled in this study. Circulating DSA was determined using LUMINEX. Abs against Col-I, II, IV, V, and KAT were measured using ELISA. Frequency of CD4+T helper cells (CD4+Th) secreting interferon (IFN)-gamma, interleukin (IL)-5, -10, or -17 specific to self-antigens were determined using Enzyme Linked Immunosorbent Spot assay. RESULTS: A significant association between AMR and DSA was demonstrated. Development of DSA in AMR patients correlated well with the development of auto-Abs to Col-V (AMR[+]: 383 +/- 72 mug/mL, AMR[-]: 172 +/- 49 mug/mL, P=0.033) and KAT (AMR[+]: 252 +/- 49 mug/mL, AMR[-]: 61 +/- 21 mug/mL, P=0.014). Patients who developed AMR demonstrated increased frequencies of CD4+Th secreting IFN-gamma and IL-5 with reduction in IL-10 specific for Col-V/KAT. Patients diagnosed with CAV also developed DSA and auto-Abs to Col-V (CAV[+]: 835 +/- 142 mug/mL, CAV[-]: 242 +/- 68 mug/mL, P=0.025) and KAT (CAV[+]: 768 +/- 206 mug/mL, CAV[-]: 196 +/- 72 mug/mL, P=0.001) with increased frequencies of CD4+Th secreting IL-17 with reduction in IL-10 specific for Col-V/KAT. CONCLUSIONS.: Development of Abs to human leukocyte antigens and self-antigens are associated with increases in CD4+Th secreting IFN-gamma and IL-5 in AMR and IL-17 in CAV, with reduction in CD4+Th secreting IL-10 in both AMR and CAV.