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In the face of the Supreme Court’s double-novelty requirement and the negative impact that requirement has had on biotechnology, the time has come for a new paradigm of law.

We performed a retrospective review of 402 consecutive patients who underwent heart transplantation at our institution between January 2009 and March 2017. A retained cardiovascular implantable electronic device (CIED) fragment was identified after transplantation in 49 of the 301 patients (16.2%) with CIED at baseline. Patients with retained fragments had leads with longer dwell times (median 2596 [1982, 3389] vs 1384 [610, 2202] days, P < .001), higher prevalence of previously abandoned leads (14.3% vs 2.8%, P = .003), and dual-coil defibrillator leads (98% vs 81%, P = .001) compared with patients without retained fragments. Five patients (10%) with retained CIED fragments underwent magnetic resonance imaging without adverse events. There was no difference in overall mortality between patients with and without CIED fragments (12% vs 11%, P = .81) Patients with retained fragments located in the superior vena cava had significantly higher fluoroscopic times (3.3 vs 2.9 minutes, P = .024) during subsequent endomyocardial biopsies. In a competing risk analysis, presence of a retained CIED fragment was associated with upper extremity deep venous thrombosis (sub hazard ratio [HR] 2.19, 95% confidence interval [CI] 1.17-4.10, P = .014) but not bloodstream infection after adjusting for potential confounders. In summary, retained CIED fragments are common after heart transplantation, and are associated with longer radiation exposure during biopsy procedures and upper extremity deep venous thrombosis.

BACKGROUND: The pulmonary artery pulsatility index (PAPi) has been studied to predict right ventricular failure (RVF) after left ventricular assist device (LVAD) implantation, but only as a single time point before LVAD implantation. Multiple clinical factors and therapies impact RV function in pre-LVAD patients. Thus, we hypothesized that serial PAPi measurements during cardiac intensive care unit (CICU) optimization before LVAD implantation would provide incremental risk stratification for early RVF after LVAD implantation. METHODS AND RESULTS: Consecutive patients who underwent sequential pulmonary artery catherization with cardiac intensive care optimization before durable LVAD implantation were included. Serial hemodynamics were reviewed retrospectively across the optimization period. The optimal PAPi was defined by the initial PAPi + the PAPi at optimized hemodynamics. RVF was defined as need for a right ventricular assist device or prolonged inotrope use (>14 days postoperatively). Patients with early RVF had significantly lower mean optimal PAPi (3.5 vs 7.5, P < .001) compared with those who did not develop RVF. After adjusting for established risk factors of early RVF after LVAD implantation, the optimal PAPi was independently and incrementally associated with early RVF after LVAD implantation (odds ratio 0.64, 95% confidence interval 0.532−0.765, P < .0001). CONCLUSIONS: Optimal PAPi achieved during medical optimization before LVAD implantation provides independent and incremental risk stratification for early RVF, likely identifying dynamic RV reserve.

Less than a handful of casebooks are truly open source, in the sense of being fully modifiable. Patent Law: An Open-Source Casebook is the first patent law casebook that provides adopting professors, students, and others the ability to fully modify its contents. This chapter of the casebook covers the utility requirement.

Background Lower serum chloride (Cl) is associated with mortality in heart failure patients and may be more prognostically relevant than sodium. However, the association of hemodynamics and Cl levels is unknown. Methods 438 sequential patients with advanced chronic heart failure (ACHF) underwent invasive hemodynamic assessment with measured serum Cl levels during an evaluation for ACHF. Patients were followed for death, heart transplant (HT), or ventricular assist device placement (VAD). A backwards regression model determined hemodynamic predictors of Cl (removal, P Results In this cohort, the median Cl level was 102 [98–104]meq/L (range 86–113meq/L). Chloride was weakly correlated with FCI (rho 0.12, P=0.01) and MAP (rho 0.21, P 0.05 for all). In the multivariable model, FCI (beta 0.73meq/L/L/min/m 2 , P=0.002) but not RAP (P=0.3) or MAP (P=0.2), remained associated with Cl. Lower Cl was associated with increased risk of death, HT, or VAD placement (HR 0.94/meq/L, 95% CI 0.89–0.99, P=0.01). However, this association was attenuated after additional adjustment for BUN (P=0.27) and PCWP and FCI (0.48). Conclusions Lower FCI, not lower MAP or higher cardiac filling pressures, was associated with lower chloride. Although lower chloride was associated with poor long-term outcomes, this risk attenuates with adjustment for more conventional clinical parameters.

Cardiogenic shock from biventricular failure that requires acute mechanical circulatory support carries high 30 day mortality. Acute mechanical circulatory support can serve as bridge to orthotopic heart transplant (OHT) in selected patients. We report a patient with biventricular failure secondary to rapidly progressive cardiac sarcoidosis refractory to medical management who was bridged to OHT with Impella 5.0 and Impella RP—temporary left and right ventricular assist devices, respectively. This is the first successful bridge to transplantation using these devices in biventricular heart failure and cardiogenic shock. We discuss considerations for using this strategy over veno‐arterial extracorporeal membrane oxygenation or surgically implanted assist devices in patients with cardiogenic shock and biventricular failure as a bridge to OHT.

Survival beyond 1 year after heart transplantation has remained without significant improvement for the last 2 decades. A more individualized approach to post-transplant care could result in a reduction of long-term mortality. Although recipient age has been associated with an increased incidence of certain post-transplant morbidities, its effect on cause-specific mortality has not been established.We analyzed overall and cause-specific mortality of heart transplant recipients registered in the International Society for Heart and Lung Transplantation Registry between 1995 and 2011. Patients were grouped by recipient age: 18 to 29, 30 to 39, 40 to 49, 50 to 59, 60 to 69, and ≥ 70 years. Multivariable regression models were used to examine the association between recipient age and leading causes of post-transplant mortality. We also compared immunosuppression (IS) use among the different recipient age groups.There were 52,995 recipients (78% male; median age [5th, 95th percentile]: 54 [27, 66] years). Survival through 10 years after transplant was lower in heart transplant recipients in the 2 more advanced age groups: 49% for 60 to 69 years and 36% for ≥ 70 years (p0.01 for pairwise comparisons with remaining groups). The risk of death caused by acute rejection (hazard ratio [HR], 4.11; p0.01), cardiac allograft vasculopathy (HR, 2.85; p0.01), and graft failure (HR, 2.29; p0.01) was highest in the youngest recipients (18-29 years) compared with the reference group (50-59 years). However, the risk of death caused by infection (HR, 2.10; p0.01) and malignancy (HR, 2.23; p0.01) was highest in older recipients (≥ 70 years). Similarly, the risk of death caused by renal failure was lower in younger recipients than in the reference group (HR, 0.53; p0.01 for 18-49 years vs 50-59 years). The use of induction IS was similar among the different recipient age groups, and differences in maintenance IS were not clinically important.Causes of death in this large cohort of heart transplant recipients varied significantly with recipient age at the time of transplant, with cause-specific mortality profiles suggesting a possible effect of inadequate IS in younger recipients and over-IS in older recipients. Thus, a more personalized approach, possibly including different IS strategies according to recipient age, might result in improved post-transplant survival.

Drawing upon my prior research, this written testimony first summarizes the current state of patent eligibility law, explaining how patent eligibility law is in a state of crisis and why legislative reform is needed to eliminate that crisis. It explains why the Supreme Court is unlikely to resolve the current crisis, why alternative avenues to project inventive efforts and investments are insufficient, and why it is appropriate for Congress in particular to take action to change patent eligibility law. Such action would likely withstand a challenge under the Constitution given that eligibility law is a question of policy appropriately directed to Congress. Not only would legislative reform be permissible, there is broad consensus that it is necessary. This testimony then identifies four basic principles that should guide any legislative effort to correct patent eligibility law, before using those principles to evaluate amendments to the patent statute proposed by Senators Coons and Tillis and Representatives Doug Collins, Hank Johnson, and Steve Stivers on May 22, 2019.

Have the Supreme Court’s recent patent eligibility cases changed the behavior of venture capital and private equity investment firms, and if so how? This Article provides empirical data about investors’ answers to those important questions. Analyzing responses to a survey of 475 investors at firms investing in various industries and at various stages of funding, this Article explores how the Court’s recent cases have influenced these firms’ decisions to invest in companies developing technology. The survey results reveal investors’ overwhelming belief that patent eligibility is an important consideration in investment decisionmaking, and that reduced patent eligibility makes it less likely their firms will invest in companies developing technology. According to investors, however, the impact differs between industries. For example, investors predominantly indicated no impact or only slightly decreased investments in the software and Internet industry, but somewhat or strongly decreased investments in the biotechnology, medical device, and pharmaceutical industries. The data and these findings (as well as others described in the Article) provide critical insight, enabling evidence-based evaluation of competing arguments in the ongoing debate about the need for congressional intervention in the law of patent eligibility. And, in particular, they indicate reform is most crucial to ensure continued robust investment in the development of life science technologies.

One of the most significant legislative reforms of the U.S. patent system occurred in 1952. Prior to 1952, the patent system found itself languishing, undermined by a confusing non-statutory patentability requirement called the “invention” requirement. In 1952, Congress and the President eliminated it. Today we find ourselves in a situation surprisingly similar to the one prior to 1952. The patent system again finds itself languishing, undermined by a new confusing non-statutory patentability requirement, this one called the “inventive concept” requirement. Today, just like in 1952, there are ongoing calls for Congress and the President to eliminate it. Given the striking parallels between these two eras — and the success of legislative reform efforts in 1952 — I have studied the forces behind the reform of 1952: the problems with the law of the day, the people and groups of people involved in reform efforts, and the circumstances and strategies they used to their advantage to create change. This study has led me to identify various factors that led to the success of those efforts in 1952. In parallel with the study of the history behind the Patent Act of 1952, I highlight the problems with the law today, the people and groups of people involved today in reform efforts, and the circumstances and strategies they might use to their advantage to create change. Moreover, drawing from the factors that led to the success of legislative reform efforts in 1952, I analyze how those same factors may contribute to the success of current legislative reform efforts — or hinder it.

Here I provide answers to written questions received from Senators Tillis, Blumenthal, and Hirono as part of their consideration of proposed amendments to the patent statute to address current problems with patent eligibility law. I explain why patent eligibility law is in a state of crisis, and in particular how my research has demonstrated risks of under investment in research and development as a result of the Supreme Court's changes to patent eligibility law. I analyze the impact of returning patent eligibility law to its historical scope, focusing on the impact on industry, consumers, and prices. I explain why congressional intervention is necessary, but why the proposed "field of technology" test is suboptimal. I highlight the role of Congress in addressing moral and ethical concerns with patenting some technologies. I discuss how the proposed change to the disclosure requirement is unnecessary, over-broad, and problematic. I also discuss the lack of a need to codify the double-patenting doctrine. Finally, I analyze potential due process and takings arguments related to the proposed amendments.

This chapter:(1) describes the current state of, and normative basis for, the law of reasonable royalties among the leading jurisdictions for patent infringement litigation, as well as the principal arguments for and against various practices relating to the calculation of reasonable royalties; and(2) for each of the major issues discussed, provides one or more recommendations.The chapter’s principal recommendation is that, when applying a “bottom-up” approach to estimating reasonable royalties, courts should replace the Georgia-Pacific factors (and analogous factors used outside the United States) with a smaller list of considerations, specifically:(1) calculating the incremental value of the invention and dividing it appropriately between the parties;(2) assessing market evidence, such as comparable licenses; and (3) where feasible and cost-justified, using each of these first two considerations as a “check” on the accuracy of the other.

A 39-year-old white woman with a history of adult-onset asthma, chronic sinusitis, and nasal polyposis presented to the ED with dyspnea and left lower extremity weakness and pain. Three months prior to her presentation she had an uncomplicated delivery of her second child, but during her pregnancy she experienced increasing asthma symptoms and nasal congestion. These symptoms progressed after delivery despite treatment with albuterol inhalers and antibiotics.

Elite endurance athletes expose the cardiovascular system to repeated hemodynamic stress which results in adaptations that permit athletes to achieve and maintain a supranormal cardiac output. The development of heart failure in an athlete may be insidious due to high functional capacity at baseline

Introduction Cardiac surgery is associated with significant acute pain. A proportion of patients will eventually transition to chronic pain, with possible ongoing use of opioids. Prescribers play consequential roles in achieving a balance between effective pain management and a patient's access to prolonged opioids. We developed an opioid-specific standards, an educational tool, and a patient agreement form. Mid-level providers completed a pain management course focused on the use of opioid alternatives. Hypothesis The aim of the present study was to investigate the effect of a multidisciplinary Opioid-Sparing Medical Regimen (OSMR) on pain levels and rate of opioid prescriptions upon discharge in patients undergoing left ventricular assist device (LVAD) implantation. Methods A retrospective chart review of all patients receiving LVAD implant from January 1, 2014 to December 30, 2017 was performed. The study sample was limited to patients ≥18 years of age who underwent LVAD implantation. The intervention group consisted of subjects undergoing LVAD implantation, who received postoperative pain management using an OSMR after June 1, 2016. The comparison group consisted of subjects who received LVAD implant prior to OSMR implementation. The pain intensity was independently reported by patients to nursing staff and documented in the electronic medical record. The 11-point Numeric Rating Scale was utilized. Results A total of 194 patients met inclusion criteria. Comparison and OSMR groups represented 97 patients each. There was a reduction in the number of patients requiring opioid prescriptions at the time of hospital discharge following the implementation of an OSMR. Total opioid prescriptions upon discharge decreased from a quarterly average of 67% to 16%. Additionally, at 18 months following implementation of an OSMR, no opioid prescriptions were required at hospital discharge for the management of acute postoperative pain (Figure 1). There was no overall difference in reported pain scores between the 2 cohorts (Figure 2). No statistically significant difference was found on daily reported scores from the time of transfer out of the ICU to day 15. Conclusions OSMR implementation for acute post-operative pain control in LVAD patients is effective and reproducible, with pain scores comparable to an opioid based medication regimen. OSMR was shown to minimize the need for discharge opioid prescriptions potentially reducing the risk of new persistent opioid use.

Aims The aim of this study was to assess the haemodynamic response and tolerance to aggressive oral hydralazine/isosorbide dinitrate (HYD/ISDN) up-titration after intravenous vasodilator therapy in advanced decompensated heart failure (ADHF). Methods and results Medical records of 147 consecutive ADHF patients who underwent placement of a pulmonary artery catheter and received intravenous vasodilator therapy were reviewed. Intravenous sodium nitroprusside and sodium nitroglycerin as first-line agent for those with preserved blood pressures were utilized in 143 and 32 patients, respectively. Sixty-one percent of patients were converted to oral HYD/ISDN combination therapy through a standardized conversion protocol. These patients had a significantly higher admission mean pulmonary arterial wedge pressure compared with patients not converted (28 ± 7 vs. 25 ± 8 mmHg, respectively; P-value 0.024). Beneficial haemodynamic response to decongestive therapy, defined as low cardiac filling pressures and cardiac index ≥2.20 L/min/m2 without emergent hypotension, was achieved in 32% and 29% of patients who did or did not receive oral HYD/ISDN, respectively (P-value 0.762). HYD/ISDN dosing was progressively and consistently decreased up to the moment of hospital discharge and during outpatient follow-up, primarily due to incident hypotension. Conclusion The use of a standardized haemodynamically guided up-titration protocol for conversion from intravenous to oral vasodilators may warrant subsequent dose reductions upon stabilization.

Background Cardiac pump function is often quantified by left ventricular ejection fraction (LVEF) by various imaging modalities. Since the heart is commonly conceptualized as a hydraulic pump, cardiac power describes the hydraulic function of the heart. We aim to describe the prognostic value of resting cardiac power index (CPI) in ambulatory patients with advanced heart failure (HF).

INTRODUCTION A 2015 Institute Of Medicine statement "Transforming Health Care Scheduling and Access: Getting to Now", has increased concerns regarding patient wait times. Although waiting times have been widely studied, little attention has been paid to the role of patient arrival times as a component of this phenomenon. To this end, we investigated patterns of patient arrival at scheduled ambulatory heart failure (HF) clinic appointments and studied its predictors. We hypothesized that patients are more likely to arrive later than scheduled, with progressively later arrivals later in the day. METHODS AND RESULTS Using a business intelligence database we identified 6,194 unique patients that visited the Cleveland Clinic Main Campus HF clinic between January, 2015 and January, 2017. This clinic served both as a tertiary referral center and a community HF clinic. Transplant and left ventricular assist device (LVAD) visits were excluded. Punctuality was defined as the difference between 'actual' and 'scheduled' check-in times, whereby negative values (i.e., early punctuality) were patients who checked-in early. Contrary to our hypothesis, we found that patients checked-in late only a minority of the time (38% of visits). Additionally, examining punctuality by appointment hour slot we found that patients scheduled after 8AM had progressively earlier check-in times as the day progressed (P < .001 for trend). In both a Random Forest-Regression framework and linear regression models the most important risk-adjusted predictors of early punctuality were: later in the day appointment hour slot, patient having previously been to the hospital, age in the early 70s, and white race. CONCLUSIONS Patients attending a mixed population ambulatory HF clinic check-in earlier than scheduled times, with progressive discrepant intervals throughout the day. This finding may have significant implications for provider utilization and resource planning in order to maximize clinic efficiency. The impact of elective early arrival on patient's perceived wait times requires further study.

Objectives The aim of this paper was to identify sex differences in survival of patients awaiting orthotopic heart transplantation (OHT). Background Women have a higher mortality rate while awaiting OHT than men, and the reason has not been fully determined. Methods We included all adult patients in the Scientific Registry of Transplant Recipients (SRTR) placed on the OHT waiting list from 2000 to 2010. The primary endpoint was all-cause mortality before receiving OHT, analyzed using time-to-event analysis. Multivariate Cox proportional hazards models were used to evaluate sex differences in survival, with data stratified by United Network for Organ Sharing (UNOS) status at time of listing. Results There were 28,852 patients (24% women) awaiting OHT. This cohort included 6,163 UNOS status 1A (25% women), 9,168 UNOS status 1B (25% women), and 13,521 UNOS status 2 (24% women) patients. During a median follow-up of 3.7 years, 1,290 women and 4,286 men died. Female sex was associated with a significant risk of death among UNOS status 1A (adjusted hazard ratio [HR]: 1.20; 95% confidence interval [CI]: 1.05 to 1.37, p = 0.01) after adjusting for more than 30 baseline variables. In contrast, female sex was significantly protective for time to death among UNOS status 2 patients (adjusted HR: 0.75; 95% CI: 0.67 to 0.84, p Conclusions There are sex differences in survival between women and men awaiting heart transplantation, and the current UNOS transplant criteria do not account for this disparity.

Objectives The aim of this study was to investigate the use of durable mechanical circulatory support (MCS) in patients with chemotherapy-induced cardiomyopathy (CCMP) and determine their outcomes and survival in comparison to that of other patients with end-stage heart failure treated similarly. Background Patients with end-stage heart failure as a result of CCMP from anthracyclines are often precluded from heart transplantation because of a history of cancer. In such patients, durable MCS may offer an important chance for life prolongation. Yet, there are no data to support the use of MCS in this increasingly prevalent group of patients. Methods We searched 3,812 MCS patients from June 2006 through March 2011 in the INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) database for the diagnosis of CCMP. We compared characteristics, outcomes, and survival between CCMP patients and patients with nonischemic cardiomyopathy and ischemic cardiomyopathy. Results Compared with patients with nonischemic cardiomyopathy and ischemic cardiomyopathy, patients with CCMP were overwhelmingly female (72% vs. 24% vs. 13%, p = 0.001), had MCS more often implanted as destination therapy (33% vs. 14% vs. 22%, p = 0.03), required more right ventricular assist device support (19% vs. 11% vs. 6%, p = 0.006), and had a higher risk of bleeding (p = 0001). Survival of CCMP patients was similar to that of other groups. Conclusions CCMP patients treated with MCS have survival similar to other MCS patients despite more frequent need for right ventricular assist device support and increased bleeding risk.

Ventricular assist devices (VADs) are increasingly being used as a bridge to transplantation and have been implicated as a risk factor for allosensitization to human leukocyte antigens (HLA). We investigate the association between VAD and allosensitization to human leukocyte antigens (HLA) and major-histocompatibility-complex (MHC) class I-related Chain A (MICA) antigens.We considered all patients who received a VAD at our institution between 2000 and 2009; 89 of them had pre-VAD and post-VAD (≤6 months after implant) HLA antibody screening. A control group of non-VAD heart transplant candidates was constructed with at least 2 pre-transplant panel-reactive antibody (PRA) tests within 8 months. Two controls were randomly selected/VAD patient matched for year (n = 178). Patients and controls with available sera from these time-points were tested by Luminex/flow PRA single-antigen beads and by MICA antibody Luminex single-antigen beads. Medical records were reviewed for comparison of pre-transplant immunologic risk factors and post-transplant outcomes between the 2 groups.Compared with controls, VAD patients had greater Class I differences between peak and initial PRA (18% vs. 0%, p0.0001) and higher peak PRA (24% vs. 6%, p0.0001). The differences between the 2 groups in Class II were less pronounced than in Class I. Of patients who had single-antigen testing, VAD implantation was significantly associated with development of new HLA antibody specificities (Class I and/or Class II) post-VAD with an increase in calculated PRA (cPRA) post-VAD compared with controls (16% vs. 0%, p0.0001). This risk was still present after adjusting for age, gender, pre-VAD PRA, transfusion and duration of follow-up in a multivariate analysis (p0.0001 and 0.02, respectively). There were no differences in development of MICA antibodies between the 2 groups (14% in both). There was no significant difference in the incidence of pre-transplant positive T-cell crossmatch, pre-transplant donor-specific HLA antibodies, rejection episodes or graft survival between the 2 groups.Our results suggest that VAD is associated with significant HLA allosensitization independent of common risk factors.

We report the case of a male heart transplant recipient who developed acute antibody-mediated rejection and was treated with 5 weeks of a rituximab-containing regimen. Two months later he presented with progressive motor and cognitive impairments and was diagnosed with progressive multifocal leukoencephalopathy (PML). He was treated with reduction of his immunosuppressive medications, mirtazapine, IVIG and plasmapheresis. He died within weeks. We reviewed the current literature on PML and its association with immunosuppression, highlighting its impact in the setting of solid organ transplantation and considering the potential effect of newer biologic drugs on the incidence of this devastating disease in the transplant population.

Objectives The aim of this study was to identify differences in survival on the basis of type of heart disease while awaiting orthotopic heart transplantation (OHT). Background Patients with restrictive cardiomyopathy (RCM), congenital heart disease (CHD), or hypertrophic cardiomyopathy (HCM) may be at a disadvantage while awaiting OHT because they often are poor candidates for mechanical circulatory support and/or inotropes. Methods The study included all adults in the Scientific Registry of Transplant Recipients database awaiting OHT from 2004 to 2014, and outcomes were evaluated on the basis of type of heart disease. The primary endpoint was time to all-cause mortality, censored at last patient follow-up and time of transplantation. Multivariate Cox proportional hazards modeling was performed to evaluate survival by type of cardiomyopathy. Results There were 14,447 patients with DCM, 823 with RCM, 11,799 with ischemic cardiomyopathy (ICM), 602 with HCM, 964 with CHD, 584 with valvular disease, and 1,528 in the “other” category (including 1,216 for retransplantation). During median follow-up of 3.7 months, 4,943 patients died (1,253 women, 3,690 men). After adjusting for possible confounding variables including age, renal function, inotropes, mechanical ventilation, and mechanical circulatory support, the adjusted hazard ratios by diagnoses relative to DCM were 1.70 for RCM (95% confidence interval [CI]: 1.43 to 2.02), 1.10 for ICM (95% CI: 1.03 to 1.18), 1.23 for HCM (95% CI: 0.98 to 1.54), 1.30 for valvular disease (95% CI: 1.07 to 1.57), 1.37 for CHD (95% CI: 1.17 to 1.61), and 1.51 for “other” diagnoses (95% CI: 1.34 to 1.69). Sex was a significant modifier of mortality for ICM, RCM, and “other” diagnoses (p Conclusions In the United States, patients with RCM, CHD, or prior heart transplantation had a higher risk for death while awaiting OHT than patients with DCM, ICM, HCM, or valvular heart disease.

Background— Although various studies revealed the beneficial effects of statins in post–cardiac transplant patients, these were relatively small and low-powered studies. We performed a meta-analysis of published studies to evaluate the role of statins in post–cardiac transplant patients, specifically examining the effects on hemodynamically significant/fatal graft rejection, coronary vasculopathy, terminal cancer, and overall survival. Methods and Results— We searched PubMed, Cochran CENTRAL, and Web of Science databases using the search terms “cardiac transplant” or “heart transplant,” and “statin” for a literature search. A random-effects model with Mantel–Haenszel method was used to pool the data. We identified 10 studies, 4 randomized controlled trials, and 6 nonrandomized studies, which compared outcomes in heart transplant recipients undergoing statin therapy to statin-naive patients. A pooled analysis of 9 studies reporting mortality revealed that the use of statins was associated with significant reduction in all-cause mortality (odds ratio, 0.26; 95% confidence interval, 0.20–0.35; P P =0.0005), incidence of coronary vasculopathy (odds ratio, 0.33; 95% confidence interval, 0.16–0.68; P =0.003), and terminal cancer (odds ratio, 0.30; 95% confidence interval, 0.15–0.63; P =0.002). Conclusions— The evidence from a pooled analysis suggests that statins improve survival in heart transplant recipients. Statins may prevent fatal rejection episodes, decrease terminal cancer risk, and reduce the incidence of coronary vasculopathy. Additional prospective studies are needed to further investigate and explain this association.

OBJECTIVE: The objective was to study whether the temporal pattern of transient hyponatremia development in acute heart failure might provide insight into its pathophysiology and prognostic relevance. METHODS: A post hoc analysis of the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) and Diuretic Optimization Strategies Evaluation in Acute Heart Failure (DOSE AHF) studies was performed (n = 716). Patients were stratified according to the temporal pattern of hyponatremia development: (1) no hyponatremia, (2) persistent hyponatremia, (3) decompensation hyponatremia disappearing with decongestive treatment, and (4) treatment-induced hyponatremia. RESULTS: Transient decompensation versus no hyponatremia was associated with significantly elevated blood urea nitrogen/creatinine ratio (P < .001), plasma renin activity (P < .001), and plasma aldosterone levels (P < .001) at baseline. Disease severity characteristics of such patients were intermediate between no and persistent hyponatremia. In contrast, patients with treatment-induced versus no hyponatremia had similar baseline characteristics and comparable natriuretic peptide levels, and both groups had little neurohumoral activation at baseline. Diuretic efficacy, defined as net fluid balance (milliliters) per 40 mg furosemide-equivalent dose administered, was lower in patients with persistent or treatment-induced hyponatremia versus decompensation hyponatremia or no hyponatremia, respectively. The former versus latter groups also had more pronounced neurohumoral activation with decongestive treatment. The risk for all-cause mortality (hazard ratio, 2.50; 95% confidence interval, 1.50-4.19; P < .001) and death or heart failure readmission (hazard ratio, 2.18; 95% confidence interval, 1.60-2.97; P < .001) was significantly elevated in patients with persistent versus no hyponatremia, with the risk of decompensation and treatment hyponatremia situated in between. CONCLUSIONS: Transient hyponatremia is prognostically relevant, but it has a heterogeneous cause according to its temporal pattern of development. (C) 2016 Elsevier Inc. All rights reserved. FHV is supported by a PhD fellowship of the Research Foundation-Flanders (FWO, 11L8214N). FHV and WM are researchers for the Limburg Clinical Research Program UHasselt-ZOL-Jessa, supported by the foundation Limburg Sterk Merk, Hasselt University, Ziekenhuis Oost-Limburg, and Jessa Hospital. WHWT is supported by the National Institutes of Health grant R01HL103931.

Mandeep R. Mehra, MD (Chair), Charles E. Canter, MD, Margaret M. Hannan, MD, Marc J. Semigran, MD, Patricia A. Uber, PharmD, David A. Baran, MD, Lara Danziger-Isakov, MD, MPH, James K. Kirklin, MD, Richard Kirk, MD, Sudhir S. Kushwaha, MD, Lars H. Lund, MD, PhD, Luciano Potena, MD, PhD, Heather J. Ross, MD, David O. Taylor, MD, Erik A.M. Verschuuren, MD, PhD, Andreas Zuckermann, MD and on behalf of the International Society for Heart Lung Transplantation (ISHLT) Infectious Diseases, Pediatric and Heart Failure and Transplantation Councils

Background New anti-neoplastic drugs have improved survival of cancer patients but have also been associated with chemotherapy-induced cardiomyopathy (CCMP), ultimately requiring orthotopic heart transplantation (OHT). We conducted this study to describe the clinical characteristics and outcomes of patients with CCMP treated with OHT and compare them with outcomes of patients with other forms of non-ischemic cardiomyopathy (NICMP). Methods We retrospectively identified 232 CCMP patients and 8,890 NICMP patients from the International Society of Heart and Lung Transplantation Registry who underwent OHT between January 2000 and December 2008. Survival rates were calculated using the Kaplan-Meier method. Categoric characteristics and outcomes groups were compared using the χ 2 and Fisher exact test. Comparisons for continuous variables were made using Wilcoxon–Mann-Whitney test. Multivariable analyses of predictors of survival were performed using Cox proportional hazard regression analysis. Results Short-term and long-term post-transplant survival of the 232 CCMP patients was similar to the 8,890 NICMP patients ( p = 0.19). Survival (95% confidence interval) at 1, 3, and 5 years was, respectively, 86% (0.81–0.91), 79% (0.76–0.87), and 71% 0.73–0.85) in the CCMP patients and 87% (0.86–0.88), 81% (0.82–0.84), and 74% (0.80–0.81) in the NICMP patients ( p = 0.19). Compared with NICMP patients, CCMP patients had higher rates of post-OHT infection (22% vs 14%, p = 004) and malignancies (5% vs 2%, p = 0.006), but neither affected survival. There was only 1 malignancy recurrence in the CCMP patients and no differences in post-OHT death due to malignancies between the groups. Importantly, CCMP patients were twice as likely as NICMP patients to require right ventricular assist devices before OHT (5.6% vs 2.3%, p = 0.0021). Conclusions Patients with CCMP selected for OHT are younger, have less comorbidity, and are more likely to require biventricular mechanical support pre-OHT than other NICMP patients who receive allografts. Despite the higher incidence of malignancy and infection in CCMP patients who have received a heart transplant, their survival is comparable to those who receive allografts for other cardiomyopathies.

Background— Racial differences in long-term survival after heart transplant (HT) are well known. We sought to assess racial/ethnic differences in wait-list outcomes among patients listed for HT in the United States in the current era. Methods and Results— We compared wait-list and posttransplant in-hospital mortality among white, black, and Hispanic patients ≥18 years of age listed for their primary HT in the United States between July 2006 and September 2010. Of 10 377 patients analyzed, 71% were white, 21% were black, and 8% were Hispanic. Black and Hispanic patients were more likely to be listed with higher urgency (listing status 1A/1B) in comparison with white patients ( P Conclusions— Hispanic patients listed for HT in the United States appear to be at higher risk of dying on the wait-list or becoming too sick for a transplant in comparison with white patients. Black patients are not at higher risk of wait-list mortality, but they have higher early posttransplant mortality.

Patients who underwent orthotopic heart transplant (OHT) can develop vasoplegia, which is associated with high mortality and morbidity. Herein we examine the pre-operative risk in OHT recipients at our institution.We reviewed peri-operative data from 311 consecutive adult patients who underwent OHT between January 2003 and June 2008. Vasoplegia was defined as persistent low systemic vascular resistance, despite multiple intravenous pressor drugs at high dose, between 6 and 48 hours after surgery.In our cohort of 311 patients, 35 (11%) patients developed vasoplegia syndrome; these patients were more likely to be UNOS Status 1A, with a higher body surface area (1.8 ± 0.25 vs 1.63 ± 0.36, p = 0.0007), greater history of thyroid disease (38.2% vs 18.5%, p = 0.0075) and a higher rate of previous cardiothoracic surgery (79% vs 48%, p = 0.0006). Pre-operatively, they were more frequently treated with aspirin (73% vs 48%, p = 0.005) and mechanical assist devices (ventricular assist devices [VADs]: 45% vs 17%, p0.0001; total artificial hearts: 8.6% vs 0%, p0.0001), and less treated with milrinone (14.7% vs 45.8%, p = 0.0005). Bypass time (118 ± 37 vs 142 ± 39 minutes, p = 0.0002) and donor heart ischemic time (191 ± 46 vs 219 ± 51 minutes, p = 0.002) were longer, with higher mortality (3.2% vs 17.1%, p = 0.0003) and morbidity in the first 30 days after transplant. In the multivariate analysis, history of thyroid disease (odds ratio [OR] = 2.7, 95% CI 1.0 to 7.0, p = 0.04) and VAD prior to transplant (OR = 2.8, 95% CI 1.07 to 7.4, p = 0.03) were independent risk factors for development of vasoplegia syndrome.High body mass index, long cardiopulmonary bypass time, prior cardiothoracic surgery, mechanical support, use of aspirin, and thyroid disease are risk factors associated with development of vasoplegia syndrome.

Compared with conventional diuretic (CD) therapy, ultrafiltration (UF) is associated with greater weight loss and fewer re-hospitalizations in patients admitted with decompensated heart failure (HF). Concerns have been raised regarding its safety and efficacy in patients with more advanced heart failure. The authors conducted a single-center, prospective, randomized controlled trial in patients with advanced HF admitted to an intensive care unit for hemodynamically guided therapy, comparing UF (n=17) with CD (n=19) at admission. The primary end point was the time required for pulmonary capillary wedge pressure (PCWP) to be maintained at a value of ≤18 mm Hg for at least 4 consecutive hours. Secondary end points included levels of cytokines and neurohormones, as well as several clinical outcomes. In our study cohort, the time to achieve the primary end point was lower in the UF group but did not reach statistical significance (P = .08). UF resulted in greater weight reduction, higher total volume removed, and shorter hospital length of stay. There were no differences in kidney function, biomarkers, or adverse events. In patients with advanced HF under hemodynamically tailored therapy, UF can be safely performed to achieve higher average volume removed than CD therapy without leading to adverse outcomes. Congest Heart Fail. 2012;18:54–63. ©2011 Wiley Periodicals, Inc.

Heart transplant recipients sensitized to human leukocyte antigens comprise a challenging subgroup of patients. Sensitization has been associated with a variety of effects that determine short-term and long-term outcomes. These include a higher rate of acute rejection and graft loss, and a heightened risk for developing cardiac allograft vasculopathy. Because of improvements in both tissue typing and immunomodulatory therapies coupled with the growing population receiving mechanical circulatory support/LVAD, the percent of sensitized patients listed for heart transplantation has increased, inflicting a greater burden to the already scarce donor pool. Despite these potentially adverse developments, pre-transplant immunologic management has resulted in decreased waiting times and outcomes that were not possible over 10 yr ago. The following review will focus on the contemporary management of the sensitized heart transplant candidate and highlight therapies that have allowed the successful transplantation of this growing and challenging patient population, including several approaches in development.

Purpose of review There is continued interest in defining viable noninvasive alternatives to endomyocardial biopsy (EMB) for monitoring recipients of orthotopic heart transplantation for episodes of rejection. This review summarizes the evidence of clinical utility for both available and emerging surrogate markers of rejection. Recent findings A variety of imaging modalities and peripheral biomarkers has been evaluated for this purpose and to date have had inadequate accuracy to replace EMB. Gene expression profile analysis is the most promising complementary technology to emerge, but there is insufficient clinical trial evidence at this time to allow gene expression profile as a substitution for EMB in all but a select group of patients. Summary The gold standard at this time for routine surveillance of orthotopic heart transplantation rejection remains EMB. However, on the basis of recent clinical trial results, gene expression profile analysis appears to be a useful adjunctive tool in monitoring for rejection and may permit a significant reduction in the frequency of EMB in low-risk patients.