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In 2009, the International Society for Heart and Lung Transplantation recognized the importance and challenges surrounding generic drug immunosuppression. As experience with generics has expanded and comfort has increased, substantial issues have arisen since that time with other aspects of immunomodulation that have not been addressed, such as access to medicines, alternative immunosuppression formulations, additional generics, implications on therapeutic drug monitoring, and implications for special populations such as pediatrics and older adults. The aim of this consensus document is to address critically each of these concerns, expand on the challenges and barriers, and provide therapeutic considerations for practitioners who manage patients who need to undergo or have undergone cardiothoracic transplantation.

ISHLT members have recognized the importance of a consensus statement on the evaluation and management of patients with chronic thromboembolic pulmonary hypertension. The creation of this document required multiple steps, including the engagement of the ISHLT councils, approval by the Standards and Guidelines Committee, identification and selection of experts in the field, and the development of 6 working groups. Each working group provided a separate section based on an extensive literature search. These sections were then coalesced into a single document that was circulated to all members of the working groups. Key points were summarized at the end of each section. Due to the limited number of comparative trials in this field, the document was written as a literature review with expert opinion rather than based on level of evidence. (C) 2021 International Society for Heart and Lung Transplantation. All rights reserved.

IntroductionDual antiplatelet therapy (DAPT), primarily the combination of aspirin with a P2Y12 inhibitor, in patients undergoing intravascular stent or flow diverter placement remains the primary strategy to reduce device-related thromboembolic complications. However, selection, timing, and dosing of DAPT is critical and can be challenging given the existing significant inter- and intraindividual response variations to P2Y12 inhibitors.MethodsAssessment of indexed, peer-reviewed literature from 2000 to 2020 in interventional cardiology and neuroendovascular therapeutics with critical, peer-reviewed appraisal and extraction of evidence and strategies to utilize DAPT in cardio- and neurovascular patients with endoluminal devices.ResultsBoth geno- and phenotyping for DAPT are rapidly and conveniently available as point-of-care testing at a favorable cost-benefit ratio. Furthermore, systematic inclusion of a quantifying clinical risk score combined with an operator-linked, technical risk assessment for potential adverse events allows a more precise and individualized approach to new P2Y12 inhibitor therapy.ConclusionsThe latest evidence, primarily obtained from cardiovascular intervention trials, supports that combining patient pharmacogenetics with drug response monitoring, as part of an individually tailored, precision medicine approach, is both predictive and cost-effective in achieving and maintaining individual target platelet inhibition levels. Indirect evidence supports that this gain in optimizing drug responses translates to reducing main adverse events and overall treatment costs in patients undergoing DAPT after intracranial stent or flow diverting treatment.

Heart and lung procurements are multiphased processes often accompanied by an array of complex logistics. Approaches to donor evaluation and management, organ procurement, and organ preservation vary among individual procurement teams. Because early graft failure remains a major cause of mortality in contemporary thoracic organ transplant recipients, we sought to establish some standardization in the procurement process. This paper, in this vein, represents an international consensus statement on donor heart and lung procurement and is designed to serve as a guide for physicians, surgeons, and other providers who manage donors to best optimize the clinical status for the procurement of both heart and lungs for transplantation. Donation after brain death (DBD) and donation after circulatory determination death (referred to as donation after circulatory death [DCD] for the remainder of the paper) for both heart and lung transplantation will be discussed in this paper. Although the data available on DCD heart donation are limited, information regarding the surgical technique for procurement is included within this consensus statement. Furthermore, this paper will focus on adult DBD and DCD heart and lung procurement. Currently, no certification, which is either recognized and/or endorsed by the transplant community at large, exists for the training of a cardiothoracic procurement surgeon. Nevertheless, establishing a training curriculum and credentialing requirements are beyond the scope of this paper.

The advent of therapies for successful treatment of hepatitis C virus has allowed the heart and lung transplant community to re-explore the use of hepatitis C virus-positive donors for organ transplantation, with a benefit for many terminally ill patients. The consensus statements provided herein represent the current state of knowledge and expertise in this area, which we expect will continue to rapidly evolve over the next few years.

Purpose Aspirin (ASA) therapy is recommended in left ventricular assist device (LVAD) patients to prevent thromboembolic complications. Up to 30% of LVAD patients may demonstrate ASA resistance, which has been related to thrombotic complications. However, it is unknown whether individual patients exhibit temporal alterations in ASA sensitivity during LVAD support. This project evaluated changes in ASA platelet inhibition over the first 6 months of LVAD support. We hypothesized that ASA platelet inhibition would wane after the initial post-implant period. Methods Patients who underwent placement of Heartware or Heartmate III LVAD at our institution and had serial ASA platelet sensitivity assays were included for analysis. ASA responsiveness was determined by VerifyNow assay with results expressed in aspirin reactivity units (ARU). ASA platelet resistance was defined by ARU greater than 550. ASA responsiveness was assessed post-implant after 5 days, 3 months, and 6 months. Results Out of 28 patients included for analysis only 7% were ASA-resistant at baseline. However, 32% of patients were ASA-resistant at 3 months and 28% at 6 months. (Figure 1). ASA-resistance was significantly more prevalent at 3-months (OR 6.1, p=0.03) with a trend toward increased prevalence at 6 months (OR 4.1, p=0.1) compared to early post-implant. ASA dose was increased in 4% and 14.3% of ASA-resistant patients at 3 and 6 months, respectively. Conclusion ASA responsiveness not only varies between patients, but can significantly change within individual LVAD patients over time. Over the first 3 months, the odds of ASA-resistance increased 6-fold and remained relatively constant at 6 months despite aspirin dose adjustment. Serial assessment of ASA responsiveness may help better identify LVAD patients at risk for thrombotic or bleeding complications. Further study is required into the both the clinical implications and the mechanism of waning aspirin sensitivity in LVAD patients.

Continuous-flow left ventricular assist device (LVAD) placement has become a standard of care in advanced heart failure treatment. Bleeding is the most frequently reported adverse event after LVAD implantation and may be increased by antithrombotic agents used for prevention of pump thrombosis. This retrospective cohort included 85 adult patients implanted with a Heartmate II LVAD. Major bleeding was defined as occurring >7 days after implant and included intracranial hemorrhage, events requiring 2 units of packed red blood cells within a 24-h period, and death from bleeding. Primary outcome was intensity of anticoagulation between patients with or without at least one incidence of nonsurgical major bleeding. Major bleeding occurred in 35 (41%) patients with 0.48 events per patient year and a median (IQR) time to first bleed of 134.5 (39.3, 368.5) days. The median (IQR) INR at time of bleed was 1.7 (1.4, 2.5). Median INR during follow-up did not differ between groups and patients with major bleeding were not more likely to have a supra-therapeutic INR. Patients who bled were more likely to have received LVAD for destination therapy, to have lower weight, worse renal function, and lower hemoglobin at baseline. Duration of LVAD support and survival were similar between groups with no difference in occurrence of thrombosis. Incidence of nonsurgical major bleeding was not significantly associated with degree of anticoagulation. Certain baseline characteristics may be more important than anticoagulation intensity to identify patients at risk for bleeding after LVAD implant. Modification of anticoagulation alone is not a sufficient management strategy and early intervention may be required to mitigate bleeding impact.

Purpose Guidelines suggest optional use of Cytomegalovirus (CMV) T Cell immunity monitoring (TCell) to guide primary prophylaxis duration or need for secondary prophylaxis after infection. This may help balance the negative implications of CMV (rejection, coronary artery vasculopathy) against those of valganciclovir (expense, leukopenia/neutropenia). We present one year of experience to evaluate the potential utility of this test. Methods CMV TCell was implemented at our center to assess immunity at end of primary prophylaxis (R+ serostatus) and need for secondary prophylaxis after treatment of CMV. Heart transplant recipients with CMV TCell September 2019 to 2020 were retrospectively reviewed. Primary prophylaxis tests were excluded if R- serostatus or within 6 months of rATG. Tests at time of CMV detection prior to treatment were also excluded. Results Table 1 describes requirements for implementation. 24 patients had CMV TCell during study period; 1 never processed. Patients were excluded for: R- serostatus (6), rATG (1), and at time of CMV detection (2). 14 patients were included for analysis; 5 CMV R+ to guide primary prophylaxis discontinuation, 8 for secondary prophylaxis after infection treatment, 1 early for neutropenia. The early test for neutropenia was inconclusive after G-CSF administration. Immunity was noted at first test in 2/5 (40%) of the primary prophylaxis and 4/8 (50%) of the secondary group. Of non-immune in primary prophylaxis group, 2 had inconclusive tests concurrent to non-CMV infection and other in setting of neutropenia. After repeat tests, 9/14 (64%) patients were noted to have immunity. Of those with immunity, 5/9 (55%) had recurrence of low level viremia; 2 treated at detection, 3 self-cleared without treatment. Conclusion Early review of our data suggests CMV TCell may serve a role to identify patients who would benefit from secondary prophylaxis after treatment of CMV infection. Additional data over future years will help better define optimal utilization of this test.

Purpose Antibody to angiotensin-II type 1 receptor (AT1R-Ab) may be implicated in allograft dysfunction in patients who are bridged to heart transplant (BTT) with a continuous flow left ventricular assist device (VAD). We studied AT1R-Ab level following VAD implantation on event-free survival in BTT patients and whether AT1R-Ab elevation is independent from inflammation as measured through C-reactive protein (CRP). Methods Sera of 77 BTT patients from 2009 to 2017 were tested for AT1R-Ab and CRP prior to and after VAD placement. Elevated AT1R-Ab level was defined as greater than 10.0 U/mL. For statistical analysis, the value of 40 U/mL was assigned to AT1R-Ab level greater than 40 U/mL. Events were defined as acute cellular rejection, antibody-mediated rejection, cardiac allograft vasculopathy, reduced EF, and death. Results Median follow-up time after transplant was 3.3 years (range 0.4-9.0 years). After VAD implantation, AT1R-Ab was increased as compared to baseline (Fig 1A). Univariate regression analysis revealed that age, female gender, African-American race, time to transplant, type of VAD, HLA sensitization, and positive donor specific antibodies were not risk factors for AT1R-Ab sensitization. The elevated post-VAD AT1R-Ab cohort had more events than the normal AT1R-Ab group (61% vs 29%, Fig 1B). On Kaplan Meier analysis, there was a statistically decrease in 5-year event-free survival in patients who had elevated AT1R-Ab levels (Fig 1C). Multivariate Cox regression analysis showed increased post-VAD AT1R-Ab as an independent risk factor for developing events. Though CRP was high before and after VAD implantation, CRP had no statistically significant correlation with AT1R-Ab level (Fig 1D). Conclusion Increase in AT1R-Ab was seen in BTT patients after VAD implantation and was associated with adverse outcomes after heart transplant. The AT1R-Ab elevation does not appear to be an epiphenomenon related to CRP, a marker of inflammation.

Objective: Dabigatran etexilate is a direct thrombin inhibitor approved for use in patients with non-valvular atrial fibrillation. There is no currently available pharmacological therapy to reverse this renally cleared anticoagulant. Dabigatran has a low level of plasma protein binding and has been considered dialyzable. We used a pig model with renal artery ligation to exclude intrinsic drug excretion to examine the efficacy of ultrafiltration (UF) during cardiopulmonary bypass (CPB) for dabigatran removal. Method: Dabigatran was intravenously infused (20 mg) in Yorkshire pigs (male, n=7, 70±1 kg) following renal artery ligation. CPB with UF was initiated after heparinization and continued until a total volume of 6 liters of UF effluent was removed. Serial labs, including dabigatran concentration, activated coagulation times (ACT), hematocrit and creatinine were drawn at intervals before the start of CPB and then incrementally during UF (0, 2, 4 and 6 L removed). Hemodialysis (HD) was performed on one animal following UF. Results: Dabigatran concentration (ng/mL) rose from undetectable levels at baseline to 296±70 (pConclusions: UF in conjunction with CPB was ineffective at removing dabigatran. Heparin demonstrated a dabigatran-lowering effect, suggesting a possible drug interaction or assay impairment. Based on these findings, emergent cardiac surgery with UF on cardiopulmonary bypass to remove dabigatran is not advisable. Alternative forms of drug removal or reversal must be identified.

Background Gastrointestinal (GI) bleeding is one of the most common complications after continuous-flow left ventricular assist device implantation. More than one third of patients with incident bleed go on to develop recurrent GI bleeding. Octreotide, a somatostatin analog, is proposed to reduce the risk of recurrent GI bleeding in this population. Methods and Results This multicenter, retrospective analysis evaluated 51 continuous-flow left ventricular assist device patients who received secondary prophylaxis with octreotide after their index GI bleed from 2009 to 2015. All patients had a hospitalization for GI bleed and received octreotide after discharge. Patient demographics, medical and medication history, and clinical characteristics of patients who rebled after receiving octreotide were compared with non–rebleeders. These data were also compared with matched historical control patients previously enrolled in the HMII (HeartMate II) clinical trials, none of whom received octreotide, to provide a context for the bleeding rates. Twelve patients (24%) who received secondary octreotide prophylaxis developed another GI bleed, whereas 39 (76%) did not. There were similar intergroup demographics; however, significantly more bleeders had a previous GI bleeding history before left ventricular assist device placement (33% versus 5%; P =0.02) and greater frequency of angiodysplasia confirmed during endoscopy (58% versus 23%; P =0.03). Fewer patients in this study experienced a recurrent GI bleed compared with a matched historical control group that did not receive octreotide (24% versus 43%; P =0.04). Conclusions Patients with continuous-flow left ventricular assist device receiving secondary prophylaxis with octreotide had a significantly lower GI bleed recurrence compared with historical controls not treated with octreotide. Additional prospective studies are needed to confirm these data.

Variceal hemorrhage is associated with high morbidity and mortality. A balloon tamponade device (BTD), such as the Sengstaken-Blakemore or Minnesota tube, may be used in cases of variceal hemorrhage. While these devices may be effective at controlling acute bleeding, the effect on patient outcomes remains less clear. We sought to describe the number of patients with variceal hemorrhage and a BTD who survive to discharge, survive to one-year, and develop complications related to a BTD.In this retrospective study, we identified patients at a single, tertiary care center who underwent placement of a BTD for upper gastrointestinal hemorrhage between 2003 and 2014. Patient characteristics and outcomes were summarized using descriptive statistics.34 patients with a BTD were identified. Median age was 57.5 (IQR 47-63) and 76% (26/34) were male. Approximately 59% (20/34) of patients survived to discharge, and 41% (13/32) were alive after one year. Two patients were lost to follow-up. Of those surviving to discharge, 95% (19/20) had undergone transjugular intrahepatic portosystemic shunt (TIPS), while 36% (5/14) of patients who did not survive to discharge had TIPS (p0.01). One complication, an esophageal perforation, was identified and managed conservatively.In this cohort of patients undergoing BTD placement for variceal hemorrhage, approximately 59% of patients were alive at discharge and 41% were alive after one year. Placement of a BTD as a temporizing measure in the management of acute variceal hemorrhage may be helpful, particularly when utilized as a bridge to more definitive therapy.

Durable left ventricular assist devices (LVADs) have not only enhanced longevity but also conferred sustained improvements in quality of life, symptom control, and functional capacity in patients with medically refractory advanced heart failure. Problems with device-related infection, bleeding, neurologic events, right-sided heart failure, and device malfunction have dominated the clinical care of patients living on mechanical support. Even as adoption of durable LVADs accelerated globally, we began to encounter a growing dilemma of pump malfunction caused by thrombosis. In early 2011, clinicians began to notice a spike in the incidence of pump thrombosis with the HeartMate II (Thoratec Corp, Pleasanton, CA) LVAD. By 2012, the problem of thrombosis in LVADs began to consume most of the scientific direction as centers and collaborative groups began to dissect this nascent phenomenon. In this perspective, we describe the magnitude and implications of pump thrombosis, discuss secular and management trends in this unique population, attempt to dissect the problem at its root, offer guidance on surveillance and therapeutic principles, and outline issues that deserve our immediate and collaborative attention.

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

ObjectiveFactors contributing to postoperative complications include blood loss and a heightened inflammatory response. The objective of this study was to test the hypothesis that aprotinin would decrease perioperative blood product use, reduce biomarkers of inflammation, and result in improved clinical outcome parameters in neonates undergoing cardiac operations.MethodsThis was a secondary retrospective analysis of a clinical trial whereby neonates undergoing cardiac surgery received either aprotinin (n = 34; before May 2008) or tranexamic acid (n = 42; after May 2008). Perioperative blood product use, clinical course, and measurements of cytokines were compared.ResultsUse of perioperative red blood cells, cryoprecipitate, and platelets was reduced in neonates receiving aprotinin compared with tranexamic acid (P

Antibody-mediated rejection (AMR) continues to present a challenge for the survival of the cardiac allograft. AMR appears to be on the rise, likely secondary to changing trends in clinical practice, including selection of patients for transplantation on mechanical circulatory support and development of more effective combinations of immunosuppressive drugs against acute cellular rejection. Most current strategies are aimed at treating acute AMR, but the treatment of chronic AMR is still not well defined. Clinically, AMR can often be more severe than cellular rejection and more difficult to treat, often not responding to typical protocols of increased immunosuppression. Complex steps involved in the antibody response allows for several potential targets for therapeutic intervention, including suppression of T and B cells, elimination of circulating antibodies, and inhibition of residual antibodies. Existing evidence suggests a multiregimen approach is the best option. Sustenance of accommodation and induction of tolerance could be viewed as viable options if adequate immune surveillance can be achieved in this setting. This review discusses the challenges in treating AMR and provides a critical analysis of current and possible future therapies.

Obesity is a difficult to treat multi-problematic disease. Bariatric surgery (BS) has been regarded as the most effective therapeutic option, however the outcomes strongly depend on baseline conditions and further behavioural modifications. Our aim was to assess the characteristics of severely obese patients seeking BS in a Public Health Service in Italy. Socio-demographic characteristics, eating habits and the presence of stressful situations associated to weight increase, as well as psychiatric disorders of 111 outpatients attending our BS Program were assessed. Twenty-seven percent of patients have familiar history of obesity (FHO). Differences between patients having or not having a FHO were found for several psychiatric conditions, including lower Bulimic symptoms (p=0.025) and lower use of Alcohol (p=0.045). A total of 28.8% of the participants reported a BED; those patients do not differ in BMI (p=0.437) from non-BED patients but had higher psychological disorders associated to eating disorder, as for example Bulimic symptoms (p=0.000), higher BES scores (p=0.000) and psychological distress, such as Depression (p=0.000). Nearly 50% of patients had any psychiatric disorders and depression was the most common disturbance (32.4%); anxiety disorder was present in 15.3% of patients. Moreover, patients who have disclosed traumatic episodes (11.7%) presented higher distress associated to eating disorder variables, such as BES (p=0.001) and EDI-2 BU scores (p=0.000) and presence of BED (p=0.001), and women are more likely to be in this group (p=0.043). Our report proposes that multiple causative factors play a role in obesity, and we need to take them all into account to plan a comprehensive pre- and post-surgical treatment plan.

The development of cardiac allograft vasculopathy remains the Achilles heel of cardiac transplantation. Unfortunately, the definitions of cardiac allograft vasculopathy are diverse, and there are no uniform international standards for the nomenclature of this entity. This consensus document, commissioned by the International Society of Heart and Lung Transplantation Board, is based on best evidence and clinical consensus derived from critical analysis of available information pertaining to angiography, intravascular ultrasound imaging, microvascular function, cardiac allograft histology, circulating immune markers, non-invasive imaging tests, and gene-based and protein-based biomarkers. This document represents a working formulation for an international nomenclature of cardiac allograft vasculopathy, similar to the development of the system for adjudication of cardiac allograft rejection by histology.

Objective: To review the guidelines and literature for the treatment of hypertension in renal transplant patients and to provide guidance to practitioners in the selection of appropriate nonpharmacologic and pharmacologic treatment options. Data Sources: A PubMed search (January 1948–March 2010) was performed using the search terms hypertension, antihypertensive agents, blood pressure, and cardiovascular disease, in combination with renal transplant and kidney transplant. The search was limited to articles published in English. All relevant peer-reviewed original studies, meta-analyses, guidelines, consensus statements, and review articles were examined. In addition, reference citations from publications identified were reviewed. Study Selection and Data Extraction: All literature found was evaluated for inclusion. Review articles as well as prospective and retrospective original research articles were reviewed. Data Synthesis: Hypertension after solid organ transplantation is a problem commonly encountered in patients during their posttransplantation clinic visits. Effective management of these patients' hypertension is crucial, as hypertension left untreated may lead to increased morbidity and mortality as well as graft loss. The unique, multifactorial etiology of hypertension in this population makes treatment choices more challenging compared to treatment of a nontransplant patient. Therefore, to guide practitioners in this process, we developed a hypertension management protocol, taking into account the unique considerations faced in the adult renal transplant population. The review guides practitioners from the initial assessment of patients' hypertension through the evaluation and selection of nonpharmacologic and pharmacologic treatment options and provides information about the discontinuation of certain antihypertensive medications. It also provides a concise, but comprehensive review of the major antihypertensive drug classes and economic considerations. Conclusions: The management of hypertension in posttransplantation patients is challenging and complicated, yet necessary to prevent morbidity, mortality, and graft loss for these patients. Therapy should be individualized based on patient assessment, response to previous therapy, and economic considerations.

High-density lipoproteins (HDLs) influence the generation of prostacyclin via cyclooxygenase stimulation. Prostaglandins represent an important compensatory pathway in advanced heart failure (HF). Whether HDL levels discriminate prognosis in HF remains unknown.We prospectively evaluated the prognostic relationship of HDL levels in severe HF by examining 132 consecutive patients listed for heart transplantation (52 +/- 11 years of age, 80% men, 79% white, mean follow-up 18 months). Using population mean HDL levels (HDL33 mg/dl [n = 47] vsor =33 mg/dl [n = 85]), patients were grouped and followed for the primary composite end-points of HF hospitalizations or death, stratified by underlying etiology (non-ischemic, n = 52; ischemic, n = 80).Patients with HDL33 mg/dl had lower serum sodium (135 vs 137 mEq/liter, p = 0.008), higher total bilirubin (1.3 vs 0.7 mg/dl, p0.001) and higher uric acid (7.6 vs 6.7 mg/dl, p = 0.048) levels, but similar serum creatinine compared with theor =33 mg/dl HDL group. Survival analysis, using a Cox proportional hazards model, revealed reduced HDL (33 mg/dl) as the most significant independent predictor of HF hospitalizations or death, independent of underlying etiology. Low-cholesterol and low-density lipoprotein (LDL)-cholesterol alone were not found to be independently predictive of outcome.Lower HDL levels correlate with adverse prognosis independent of etiology and predict clinical worsening or death in advanced HF. Further study is warranted as to whether these findings represent a clinical marker or suggest a potential therapeutic target.

Geometric mitral regurgitation is a phenomenon encountered by an otherwise anatomically normal mitral valve in the setting of advanced adverse left ventricular remodeling that alters the alignment characteristics of the mitral valve apparatus leading to functional production of a leaking valve. In this review, we discuss contemporary directions in the knowledge base for managing geometric mitral regurgitation.Much progress has been encountered in describing the types of geometric mitral regurgitation (nonischemic and ischemic origins), standardization of echocardiographic techniques to allow for a common language in ascertaining the severity of mitral regurgitation, knowledge on dynamic mitral regurgitation during exercise, effectiveness of therapy and appropriate use and timing of surgical repair.Geometric mitral regurgitation develops in tandem with progressive ischemic or nonischemic cardiomyopathy and can improve with antiremodeling pharmacological and device-based therapy. Surgical therapy can be accomplished at experienced centers with low morbidity and mortality, and may improve symptoms and enhance pump function. Whether such therapy saves lives remains uncertain. New percutaneous approaches to tackle geometric mitral regurgitation are developing, and early data is encouraging but remains experimental.

Chagas disease is a major public health problem in Bolivia. In the city of Cochabamba, 58% of the population lives in peripheral urban districts ("popular zones") where the infection prevalence is extremely high. From 1995 to 1999, we studied the demographics of Chagas infections in children from five to 13 years old (n = 2218) from the South zone (SZ) and North zone (NZ) districts, which differ in social, environmental, and agricultural conditions. Information gathered from these districts demonstrates qualitative and quantitative evidence for the active transmission of Trypanosoma cruzi in urban Cochabamba. Seropositivity was high in both zones (25% in SZ and 19% in NZ). We observed a high risk of infection in children from five to nine years old in SZ, but in NZ, a higher risk occurred in children aged 10-13, with odds ratio for infection three times higher in NZ than in SZ. This difference was not due to triatomine density, since more than 1,000 Triatoma infestans were captured in both zones, but was possibly secondary to the vector infection rate (79% in SZ and 37% in NZ). Electrocardiogram abnormalities were found to be prevalent in children and pre-adolescents (SZ = 40%, NZ = 17%), indicating that under continuous exposure to infection and re-infection, a severe form of the disease may develop early in life. This work demonstrates that T. cruzi infection should also be considered an urban health problem and is not restricted to the rural areas and small villages of Bolivia.

Complex cardiovascular surgery often results in postoperative hemorrhage. Excessive blood product use may cause systemic thrombosis, end-organ dysfunction, and edema preventing chest closure. Recombinant activated factor VII (rFVIIa) concentrate may decrease hemorrhage where other treatment measures failed. We reviewed our experience with rFVIIa after complex cardiovascular surgery.A retrospective review evaluating 846 complex cardiovascular surgery patients of whom 36 received rFVIIa between January 1, 2001, and December 31, 2006, was performed. Efficacy and safety data were collected for the entire cohort in addition to delayed sternal closure requirements, reoperation, and operative mortality in the patient cohort temporally separated into two groups (pre-rFVIIa era, 2001 to 2003, 1 patient received rFVIIa; rFVIIa era, 2004 to 2006, 35 patients received rFVIIa).A total of 36 patients received 41 rFVIIa doses with an in-hospital survival of 91.7%. Hemorrhage was controlled in 83.3% of patients, with 1 dose sufficient in 75.0%. There was a significant decrease (p0.005) in all blood product requirements post-rFVIIa compared with pre-rFVIIa administration. In the intensive care unit (n = 6), rFVIIa significantly reduced chest tube output (p = 0.028) and prevented reexploration for bleeding in 5 patients. The requirement for delayed sternal closure was significantly higher in the pre-rFVIIa era versus the rFVIIa era (p = 0.011). The incidence of thrombosis in all patients receiving rFVIIa was 11.1%. In the rFVIIa era, a higher incidence of postoperative renal failure (p = 0.005) and pneumonia (p0.002) was detected in patients receiving rFVIIa.Recombinant activated factor VII appears to be effective in patients with refractory coagulopathy undergoing high-risk cardiovascular surgery.

Background We have previously demonstrated that a peripheral blood transcriptional profile using 11 distinct genes predicts onset of cardiac allograft rejection weeks to months prior to the actual event. Methods In this analysis, we ascertained the performance of this transcriptional algorithm in a Bayesian representative population: 28 cardiac transplant recipients who progressed to moderate to severe rejection; 53 who progressed to mild rejection; and 46 who remained rejection-free. Furthermore, we characterized longitudinal alterations in the transcriptional gene expression profile before, during and after recovery from rejection. Results In this patient cohort, we found that a gene expression score (range 0 to 40) of ≤20 represents very low risk of rejection in the subsequent 12 weeks: 0 progressed to treatable (ISHLT Grade ≥3A) rejection; 16 of 53 (30%) from the intermediate group (those who progressed to ISHLT Grade 1B or 2) and 13 of 46 (28%) controls (who remained Grade 0 or 1A) had scores ≤20. A gene score of ≥30 was associated with progression to moderate to severe rejection in 58% of cases. These two extreme scores (≤20 or ≥30) represented 44% of the cardiac transplant population within 6 months post-transplant. In addition, longitudinal gene expression analysis demonstrated that baseline scores were significantly higher for those who went on to reject, remained high during an episode of rejection, and dropped post-treatment for rejection ( p Conclusions The use of gene expression profiling early after transplantation allows for separation into low-, intermediate- or high-risk categories for future rejection, permitting development of discrete surveillance strategies.

Left ventricular hypertrophy (LVH) is a known predictor of morbidity and mortality in patients with essential hypertension. The prevalence and significance of LVH in heart transplant recipients is unknown.Transthoracic echocardiograms were performed as part of a routine protocol 1 year after heart transplantation in 141 consecutive patients. Demographic and echocardiographic data were collected using patients' records and center-specific data from the Cardiac Transplant Research Database and analyzed to determine the prevalence and predictors of LVH at 1 year post-transplantation. Patients were divided into three groups based on left ventricular mass (LVM): normal (LVM150 g); mild-moderate LVH (LVM 150 to 250 g); and severe LVH (LVM250 g).LVH was common at 1 year after heart transplantation, present in 83% of heart transplant recipients. Univariate predictors of severe LVH were increased body mass index (p0.01), pre-transplant diabetes mellitus (p = 0.02) and pre-transplant hypertension (p = 0.01). By multivariate analysis, pre-transplant hypertension was the only independent predictor of severe LVH (hazard ratio [HR] 2.3, 95% confidence interval [CI] 1.1 to 5.4, p = 0.05). Heart transplant recipients with severe LVH had significantly decreased survival, as compared to patients with normal LVM and mild-moderate LVH (p = 0.03). After multivariate analysis adjusting for age, race, gender, pre-transplant hypertension and diabetes, severe LVH remained a strong, independent predictor of mortality (HR 3.6, 95% CI 1.0 to 12.1, p = 0.04).LVH is common at 1 year after heart transplantation and is a strong, independent predictor of increased mortality. Hypertension before transplantation is an independent predictor of the presence of severe LVH at 1 year after heart transplantation.

Because of the complexities associated with anticoagulation in temporary percutaneous ventricular assist device (pVAD) recipients, a lack of standardization exists in their management. This retrospective analysis evaluates current anticoagulation practices at a single center with the aim of identifying an optimal anticoagulation strategy and protocol. Patients were divided into two cohorts based on pVAD implanted (CentriMag (Thoratec; Pleasanton, CA) / TandemHeart (CardiacAssist; Pittsburgh, PA) or Impella (Abiomed, Danvers, MA)), with each group individually analyzed for bleeding and thrombotic complications. Patients in the CentriMag/TandemHeart cohort were subdivided based on the anticoagulation monitoring strategy (activated partial thromboplastin time (aPTT) or antifactor Xa unfractionated heparin (anti-Xa) values). In the CentriMag/TandemHeart cohort, there were five patients with anticoagulation titrated based on anti-Xa values; one patient developed a device thrombosis and a major bleed, whereas another patient experienced major bleeding. Eight patients received an Impella pVAD. Seven total major bleeds in three patients and no thrombotic events were detected. Based on distinct differences between the devices, anti-Xa values, and outcomes, two protocols were created to guide anticoagulation adjustments. However, anticoagulation in patients who require pVAD support is complex with constantly evolving anticoagulation goals. The ideal level of anticoagulation should be individually determined using several coagulation laboratory parameters in concert with hemodynamic changes in the patient's clinical status, the device, and the device cannulation.

Twelve heart transplant recipients selected for conversion from cyclosporine to tacrolimus because of adverse effects of cyclosporine therapy underwent echocardiography at baseline and 6 months after conversion. Left ventricular mass decreased by 24% and left ventricular geometry returned toward normal at 6 months after conversion, without significant changes in blood pressure.

Background: Cardiac allograft vasculopathy continues to represent the major limitation to long-term cardiac allograft survival. Routine angiography and intravascular ultrasound fall short in their ability to detect microcirculatory aberrations. Thrombolysis in myocardial infarction (TIMI) myocardial perfusion grades (TMPG) have been used as a measure of microvascular circulation in patients treated for acute myocardial infarction. We studied the correlation of epicardial coronary anatomy with microvascular flow as determined by TMPG and correlated it with patient outcome. Methods: We enrolled 66 consecutive cardiac transplant recipients (49 men; mean age 52 ± 13 years; range 15-70 years) undergoing surveillance coronary angiogram during a 9-month period. All angiograms were interpreted for epicardial coronary anatomy by an independent investigator. Another investigator, blinded for clinical data and angiogram interpretation, interpreted TMPGs. TMPG 0 was defined as no apparent tissue-level perfusion; TMPG 1 indicated presence of myocardial blush but no clearance from the microvasculature; TMPG 2 blush cleared slowly; and TMPG 3 indicated that blush began to clear during washout (blush is minimally persistent after 3 cardiac cycles of washout). Cardiac deaths served as the primary outcome variable. Results: Fifty-eight of 66 patients had an abnormal TMPG. Mean TMPG in all these patients was 4.2 ± 3 (normal is 9). Forty-four patients (Group A) with no angiographic coronary narrowing had TMPG 4.81 ± 3.1, and 22 patients (Group B) with epicardial coronary narrowing 40% of lumen diameter had TMPG 3.0 ± 2.5 (p = 0.007). There was no difference in TMPG related to the coronary territory involved. At a mean follow-up of 30 ± 2.5 months, 6 (13.6%) of 44 patients in Group A had died, and 7 (31.8%) of 22 in Group B had died (p < 0.03). Conclusions: Microcirculatory aberrations as assessed by tissue TMPG is abnormal across all coronary territories in cardiac transplant recipients and associated with poor survival, suggesting a generalized microvascular involvement even in the presence of a normal angiogram. Patients with focal epicardial coronary narrowing have significantly greater decline in tissue perfusion, independent of the coronary territory involved, and exhibit poor survival compared with patients without epicardial coronary disease.

Background Compared with cyclosporine, tacrolimus-based immunosuppression yields improved metabolic outcomes in heart transplantation. Whether corticosteroid freedom provides incremental metabolic benefits in tacrolimus and mycophenolate mofetil immunoprophylaxis remains uncertain. Methods In a prospective trial, 41 heart transplant patients treated with tacrolimus and mycophenolate mofetil underwent steroid weaning immediately after transplantation until weaning was complete. Weaning was interrupted only for treated rejection with or without hemodynamic compromise. Benefits of steroid weaning assessed following the first year included B-type natriuretic peptide (BNP), late infections, lipids, blood pressure, hyperglycemia, and body mass index (BMI). Results Of this 41 patient cohort (age 53 ± 9 years, 50% black American, 35% women) followed for a total of 47 ± 5 months, 25 had corticosteroids discontinued (62%) by an average of 20 ± 11 months. No differences between the two groups were noted in baseline characteristics. Significant predictors of failure to wean steroids included higher rejection, BNP, and lower dose of mycophenolate mofetil. No significant benefits of steroid weaning were noted on lipids, blood pressure, hyperglycemia, and BMI. However, late infections (after 1 year) requiring hospitalizations were more frequent in the failure to wean group (0.60.4 vs 0 infections/patient/y, P Inferences Unlike known metabolic benefits of steroid withdrawal with cyclosporine, heart transplant recipients treated with tacrolimus and mycophenolate mofetil demonstrate no incremental metabolic benefits, but instead experience benefits of decreased serious late infections. Furthermore, failure to discontinue corticosteroids in this series is predicted by early allograft rejection, use of lower doses of mycophenolate mofetil, and higher BNP levels suggesting poor cardiac adaptation.

Background B-natriuretic peptide (BNP) is effective in the treatment of decompensated heart failure, but has not specifically been evaluated in the immediate postoperative cardiac transplant population. Objective To determine if BNP can favorably alter hemodynamics in the perioperative setting after heart transplantation. Methods and results We administered human BNP ( h BNP, Nesiritide) to 10 consecutive patients with preexisting renal insufficiency and elevated filling pressures. All patients had failed to respond to inotropes and escalating doses of diuretics. BNP was started 48 hours after transplantation, and continued for 48 to 72 hours. Intravascular hemodynamics were measured. With h BNP therapy, the pulmonary capillary wedge pressure, central venous pressure, and mean pulmonary artery pressure were all attenuated, whereas the cardiac output was significantly increased. The mean urine output increased significantly in the first 24 hours of therapy with no increase in diuretics. Implementation of BNP therapy allowed for a reduction of patients' inotropes and diuretics, while decreasing serum BNP levels. Conclusion An improvement in cardiac hemodynamics and renal function was observed with administration of h BNP in these postsurgical patients with elevated filling pressures and acute on chronic renal insufficiency. This study demonstrates that posttransplant patients retain the capacity to respond to exogenous BNP immediately after surgery.

Background Black American heart transplant recipients receiving cyclosporine-based primary immunoprophylaxis suffer higher rates of allograft rejection with hemodynamic compromise, infections, and posttransplant coronary artery disease. We examined the hypothesis that a combination of tacrolimus and mycophenolate mofetil resurrects clinical outcome of black Americans to those seen in white heart transplant recipients. Methods. Sixty-three adult primary heart transplant recipients were included in this study. Twenty black American and 21 white patients who received tacrolimus-based primary immunoprophylaxis were enrolled in this prospective, observational parallel cohort investigation. A separate group of 22 black American patients were randomly allocated to receive cyclosporine-microemulsion-based primary prophylaxis and served as the control population for assessing outcomes in the black American group. Adjunctive immunosuppression included mycophenolate mofetil and corticosteroids. The primary end-point was the freedom from allograft rejection requiring treatment at 1 year. Secondary end-points included rejection with hemodynamic compromise, and patient or graft survival. Adverse events evaluated included development of infections requiring hospitalization and nonimmunological outcomes including hyperlipidemia, hypertension, and diabetes mellitus (new onset or worsened). Results. Tacrolimus-treated black American patients had greater freedom from allograft rejection requiring treatment at 1 year than those treated with cyclosporine (64% vs. 37%, P=0.01). No differences were noted between tacrolimus-treated black Americans and whites in the primary end point (64% and 67% respectively, P=nonsignificant [NS]). Tacrolimus-based immunosuppression was associated with better 1-year survival in black Americans compared with cyclosporine (95% vs. 73%, P=0.04), and this end point was similar to that achieved in tacrolimus-treated white heart transplant recipients (95%). No differences in infection rates were noted among either group. Cyclosporine-treated black Americans suffered more hyperlipidemia and worse hypertension than tacrolimus-treated patients. Conclusions. Compared with cyclosporine, an immunosuppressive strategy using tacrolimus in black Americans achieves superior efficacy with regard to allograft rejection, higher allograft survival, and similar safety. Furthermore, tacrolimus-based immunosuppression is similar in immunological efficacy and safety in black Americans and in white heart transplant recipients.

A large number of chronic heart failure patients escape from the benefits of neurohormonal blockade only to transit into a discouragingly miserable state of what the physician often refers to as “end-stage heart failure.” Conceptually, the designation of “end-stage” as a description of a clinical scenario implies pessimism concerning recourse to a therapeutic avenue. A variety of surgical therapeutic techniques that take advantage of the law of Laplace, designed to effectively restore the cardiac shape from a spherical, mechanically inefficient pump to a more elliptical, structurally sound organ are now being employed. Additionally, the field of mechanical device implantation is surging ahead at a rapid pace. The weight of evidence regarding mechanical unloading using assist devices suggests that hemodynamic restoration is accompanied by regression of cellular hypertrophy, normalization of the neuroendocrine axis, improved expression of contractile proteins, enhanced cellular respiratory control, and decreases in markers of apoptosis and cellular stress. Thus, these lines of data point toward discarding the notion of “end-stage” heart failure. We are at a new crossroad in our quest to tackle chronic heart failure. It is our contention that the use of antiremodeling strategies, including device approaches, will soon signal the end of “end-stage” heart failure.