The Evolving Long-Term Outcome of Heart Transplantation in Amyloid Patients

Background: Both amyloid light chain (AL) amyloidosis and transthyretin-related (TTR) amyloid are expanding indications for heart transplantation (HTx). In the past, AL amyloid, in particular, had been a contraindication to HTx given its systemic nature and the increased risk for mortality. Modern treatments including proteasome inhibitors have allowed amyloid patients to receive heart transplants at an increasing rate. We sought to assess long-term post-transplant outcome in amyloid patients in the current era. Methods: Between 2010 and 2015, we assessed 27 patients (5 AL, 10 TTR-wildtype (wt), 12 TTR-mutant (m)) underwent heart transplant for cardiac amyloidosis at our single center. A non-amyloid restrictive cardiomyopathy control population was included (n=18). Endpoints included 3-year outcomes including survival, freedom from CAV (as #212121 \u3edefined by stenosis ≥ 30% by angiography), freedom from non-fatal major adverse cardiac events (NF-MACE: myocardial infarction, new congestive heart failure, percutaneous coronary intervention, implantable cardioverter defibrillator/pacemaker implant, stroke), and freedom from any-treated rejection, acute cellular rejection, and antibody-mediated rejection. Results: There was no significant difference between the AL amyloid, TTR-wt, TTR-m, and restrictive non-amyloid patients with respect to 3-year survival and 3-year freedom from CAV, NF-MACE, and rejection (see table). Endomyocardial biopsies post-transplant did not show amyloid. (see Table) Conclusion: In the current era, both AL and TTR amyloid patients have acceptable mid-term outcome after heart transplantation. Larger numbers and longer follow up are needed to confirm these findings

Intermediate Mass Black Hole Induced Quenching of Mass Segregation in Star Clusters

In many theoretical scenarios it is expected that intermediate-mass black holes (IMBHs, with masses M ~ 100-10000 solar masses) reside at the centers of some globular clusters. However, observational evidence for their existence is limited. Several previous numerical investigations have focused on the impact of an IMBH on the cluster dynamics or brightness profile. Here we instead present results from a large set of direct N-body simulations including single and binary stars. These show that there is a potentially more detectable IMBH signature, namely on the variation of the average stellar mass between the center and the half-light radius. We find that the existence of an IMBH quenches mass segregation and causes the average mass to exhibit only modest radial variation in collisionally relaxed star clusters. This differs from when there is no IMBH. To measure this observationally requires high resolution imaging at the level of that already available from the Hubble Space Telescope (HST) for the cores of a large sample of galactic globular clusters. With a modest additional investment of HST time to acquire fields around the half-light radius, it will be possible to identify the best candidate clusters to harbor an IMBH. This test can be applied only to globulars with a half-light relaxation time less than or equal to 1 Gyr, which is required to guarantee efficient energy equipartition due to two-body relaxation.Comment: 15 pages, 3 figures, ApJ, in pres

Decreasing survival benefit from cardiac transplantation for outpatients as the waiting list lengthens

AbstractMany patients are accepted for cardiac transplantation during a period of clinical instability associated with a high risk of death, even though most can be discharged home to await transplantation. As the waiting lists lengthen, priority is awarded solely on the basis of the waiting time of outpatients, who now usually undergo transplantation after they have already survived a major period of jeopardy. To determine the impact of the current waiting times and priority system on the previously expected benefit offered by transplantation, 1-year actuarial survival without transplantation was recalculated after each month without transplantation for 214 potential candidates with an ejection fraction of 0.17 ± 0.05 discharged on tailored medical therapy after evaluation. These data were compared with the 1-year survival data of 88 outpatients who underwent transplantation.Actuarial survival after 1 year was 67% on tailored therapy compared with 88% after transplantation (p = 0.009). Death without transplantation was sudden in 43 of 51 patients, resulting from hemodynamic decompensation in 8. For outpatients already surviving 6 months without transplantation, actuarial survival over the next 12 months was 83% without transplantation. Thus, the expected improvement in survival after transplantation would be only 5% over the subsequent year for patients waiting 6 months, which is the waiting time for many outpatients. Such patients should be reevaluated to determine whether transplantation remains indicated during the next year

981-46 Impact of a Comprehensive Management Program on the Hospitalization Rate for Patients with Advanced Heart Failure

Patients with advanced heart failure have a course that is often characterized by frequent hospitalizations and progressive deterioration. These patients are commonly referred to specialized centers for consideration of heart transplantation (Tx). To assess the impact of the changes in therapy made in conjunction with heart transplantation evaluation on patient outcomes, we assessed the hospitalization rate and patient's functional status in the 6 months prior to referral compared to the 6 months after referral. Since 1/91, 214 patients were evaluated, accepted for Tx, and discharged having undergone adjustments in medical therapy and a comprehensive patient education program. At time of referral patients had mean LVEF 0.21, NYHA class 3.3, VO2 max 11.0ml/kg, and had undergone a total of 429 hospitalizations in the previous 6 months. During evaluation patients had their ACE inhibitor dose increased by a mean 91.5mg/day of captopril or the equivalent, were diuresed a mean 4.2 liters, were placed on a flexible regimen of loop diuretics, and were counseled on dietary management and home based progressive aerobic exercise. After 6 months of follow-up there were only 63 hospitalizations required (mean hospitalization rate per patient over the 6 months pre-evaluation 2.00±1.45 vs post-evaluation 0.29±0.53 p<0.00001). Patient's NYHA class improved to 2.4 (p<0.0001) and VO2 max increased to 15.2 (p<0.001). Excluding the 12 elective status Tx, 14 urgent status Tx, and 9 deaths within 6 months yielded similar results (344 pre vs 34 post-evaluation hospitalizations). 64 patients (30%) improved their functional status to the point that transplantation was deferred in favor of sustained medical therapy.Referral to a heart failure specialty program is associated with a dramatic occurred between day 10±1 and 3 month. 4 patients died after hospital discharge (no death directly related to thromboembolic disease). Thus no higher risk of PE can be seen in patients with free floating prox-DVT and anticoagulant therapy should be efficient to prevent recurrent PE in such patient

Improving survival for patients with advanced heart failure: A study of 737 consecutive patients

Objectives.This study sought to determine whether survival and risk of sudden death have improved for patients with advanced heart failure referred for consideration for heart transplantation as advances in medical therapy were systematically implemented over an 8-year period.Background.Recent survival trials in patients with mild to moderate heart failure and patients after a myocardial infarction have shown that angiotensin-converting enzyme inhibitors are beneficial, type I antiarrhythmic drugs can be detrimental, and amiodarone may be beneficial in some groups. The impact of advances in therapy may be enhanced or blunted when applied to severe heart failure.Methods.One-year mortality and sudden death were determined in relation to time, baseline variables and therapeutics for 737 consecutive patients referred for heart transplantation and discharged home on medical therapy from 1986 to 1988, 1989 to 1990 and 1991 to 1993. Medical care was directed by a single team of physicians with policies established by consensus. From 1986 to 1990, the hydralazine/isosorbide dinitrate combination or angiotensin-converting enzyme inhibitors were the initial vasodilators, and class I antiarrhythmic drugs were allowed. After 1990, captopril was the initial vasodilator, given to 86% of patients compared with 46% of patients before 1989. After mid-1989, class I agents were routinely withdrawn, and amiodarone was used for frequent ventricular ectopic beats or atrial fibrillation (53% of patients after 1990 vs. 10% before 1989).Results.The total 1-year mortality rate decreased from 33% before 1989 to 16% after 1990 (p = 0.0001), and sudden death decreased from 20% to 8% (p = 0.0006). Adjusted for clinical and hemodynamic variables in multivariate proportional hazards models, total mortality and sudden death were lower after 1990.Conclusions.The large reduction in mortality, particularly in sudden death, from advanced heart failure since 1990 may reflect an enhanced impact of therapeutic advances shown in large randomized trials when they are incorporated into a comprehensive approach in this population. This improved survival supports the growing practice of maintaining potential heart transplant candidates on optimal medical therapy until clinical decompensation mandates transplantation

948-46 Preserved Cardiac Baroreflex Control of Renal Cortical Blood Flow in Advanced Heart Failure Patients: A Positron Emission Tomography Study

Cardiac baroreflex (CBR) control of forearm blood flow (FBF) is blunted or reversed in humans with heart failure (HF). but little is known about CBR control of renal cortical blood flow (RCBF) in HF due to technical limitations. Positron emission tomography (PET) 0–15 water is a new, precise method to measure RCBF quantitatively. We compared CBR control of RCBF and FBF (venous plethysmography) in 8 patients with HF (mean age, 47±3 y, ejection fraction 0.25±0.02) and 10 normal humans (mean age 35±5 y) during CBR unloading with phlebotomy (450ml). In 5 normals, cold pressor test was used as a strong, non-baroreflex mediated stimulus to vasoconstriction.ResultsPhlebotomy decreased central venous pressure (p <0.001), but did not change mean arterial pressure or heart rate in HF patients or controls. The major findings of the study are: 1) At rest, RCBF is markedly diminished in HF vs normals (2.4±0.1 vs 4.3±0.2ml/min/g, p < 0.001). 2) In normal humans during phlebotomy, FBF decreased substantially (basal vs phlebotomy: 3.3±0.4 vs 2.6±0.3 ml/min/100 ml, p=0.021, and RCBF decreased slightly, but significantly (basal vs phlebotomy: 4.3±0.2 vs 4.0±0.3 ml/min/g, p=0.01). 3) The small magnitude of reflex renal vasoconstriction is not explained by the inability of the renal circulation to vasoconstrict since the cold pressor stimulus induced substantial decreases in RCBF in normals (basal vs cold pressor: 4.4±0.1 vs 3.7±0.1 ml/min/g, p=0.003). 4) In humans with heart failure during phlebotomy, FBF did not change (basal vs phlebotomy: 2.6±0.3 vs 2.7±0.2 ml/min/100 ml, p=NS), but RCBF decreased slightly but significantly (basal vs phlebotomy: 2.4±0.1 vs 2.1±0.1 ml/min/g, p=0.01). Thus, in patients with heart failure, there is an abnormality in cardiopulmonary baroreflex control of the forearm circulation, but not the renal circulationConclusionThis study 1) shows the power of PET to study physiologic and pathophysiologic reflex control of the renal circulation in humans, and 2) describes the novel finding of selective dysfunction of cardiac baroreflex control of the forearm circulation, but its preservation of the renal circulation, in patients with heart failur

Combination of electroweak and QCD corrections to single W production at the Fermilab Tevatron and the CERN LHC

Precision studies of the production of a high-transverse momentum lepton in association with missing energy at hadron colliders require that electroweak and QCD higher-order contributions are simultaneously taken into account in theoretical predictions and data analysis. Here we present a detailed phenomenological study of the impact of electroweak and strong contributions, as well as of their combination, to all the observables relevant for the various facets of the p\smartpap \to {\rm lepton} + X physics programme at hadron colliders, including luminosity monitoring and Parton Distribution Functions constraint, $W$ precision physics and search for new physics signals. We provide a theoretical recipe to carefully combine electroweak and strong corrections, that are mandatory in view of the challenging experimental accuracy already reached at the Fermilab Tevatron and aimed at the CERN LHC, and discuss the uncertainty inherent the combination. We conclude that the theoretical accuracy of our calculation can be conservatively estimated to be about 2% for standard event selections at the Tevatron and the LHC, and about 5% in the very high $W$ transverse mass/lepton transverse momentum tails. We also provide arguments for a more aggressive error estimate (about 1% and 3%, respectively) and conclude that in order to attain a one per cent accuracy: 1) exact mixed ${\cal O}(\alpha \alpha_s)$ corrections should be computed in addition to the already available NNLO QCD contributions and two-loop electroweak Sudakov logarithms; 2) QCD and electroweak corrections should be coherently included into a single event generator.Comment: One reference added. Final version to appear in JHE