L. Czer

Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial

BACKGROUND Cardiosphere-derived cells (CDCs) reduce scarring after myocardial infarction, increase viable myocardium, and boost cardiac function in preclinical models. We aimed to assess safety of such an approach in patients with left ventricular dysfunction after myocardial infarction. METHODS In the prospective, randomised CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction (CADUCEUS) trial, we enrolled patients 2-4 weeks after myocardial infarction (with left ventricular ejection fraction of 25-45%) at two medical centres in the USA. An independent data coordinating centre randomly allocated patients in a 2:1 ratio to receive CDCs or standard care. For patients assigned to receive CDCs, autologous cells grown from endomyocardial biopsy specimens were infused into the infarct-related artery 1·5-3 months after myocardial infarction. The primary endpoint was proportion of patients at 6 months who died due to ventricular tachycardia, ventricular fibrillation, or sudden unexpected death, or had myocardial infarction after cell infusion, new cardiac tumour formation on MRI, or a major adverse cardiac event (MACE; composite of death and hospital admission for heart failure or non-fatal recurrent myocardial infarction). We also assessed preliminary efficacy endpoints on MRI by 6 months. Data analysers were masked to group assignment. This study is registered with ClinicalTrials.gov, NCT00893360. FINDINGS Between May 5, 2009, and Dec 16, 2010, we randomly allocated 31 eligible participants of whom 25 were included in a per-protocol analysis (17 to CDC group and eight to standard of care). Mean baseline left ventricular ejection fraction (LVEF) was 39% (SD 12) and scar occupied 24% (10) of left ventricular mass. Biopsy samples yielded prescribed cell doses within 36 days (SD 6). No complications were reported within 24 h of CDC infusion. By 6 months, no patients had died, developed cardiac tumours, or MACE in either group. Four patients (24%) in the CDC group had serious adverse events compared with one control (13%; p=1·00). Compared with controls at 6 months, MRI analysis of patients treated with CDCs showed reductions in scar mass (p=0·001), increases in viable heart mass (p=0·01) and regional contractility (p=0·02), and regional systolic wall thickening (p=0·015). However, changes in end-diastolic volume, end-systolic volume, and LVEF did not differ between groups by 6 months. INTERPRETATION We show intracoronary infusion of autologous CDCs after myocardial infarction is safe, warranting the expansion of such therapy to phase 2 study. The unprecedented increases we noted in viable myocardium, which are consistent with therapeutic regeneration, merit further assessment of clinical outcomes. FUNDING US National Heart, Lung and Blood Institute and Cedars-Sinai Board of Governors Heart Stem Cell Center.

Increased Mortality of Women in Coronary Artery Bypass Surgery: Evidence for Referral Bias

STUDY OBJECTIVE To determine whether differences in referral reasons explain the higher operative mortality of women in coronary artery bypass surgery. DESIGN Case series. SETTING A tertiary care, private teaching hospital. PATIENTS Consecutive patients who had isolated coronary artery bypass surgery between 1982 and 1987 (total, 2297; 79% male and 21% female). MEASUREMENTS AND MAIN RESULTS The inhospital mortality rate was significantly higher for women than for men (4.6% compared with 2.6%; P = 0.036; 95% CI for difference in mortality, 0% to 4.0%). Women were older than men (mean, 68.2 and 64.0 years, respectively; P less than 0.001), and a higher percentage of women were referred with unstable angina (P = 0.007), postmyocardial infarction angina (P = 0.029), congestive heart failure (P less than 0.001), and New York Heart Association class IV symptoms (66% compared with 45%, P less than 0.001). More men were referred with a history of an abnormal exercise test (P less than 0.001), and patients referred because of a positive exercise test had a lower mortality (P less than 0.001). Using multivariate analysis, adjustment for the higher preoperative functional class of women and for age accounted for all of the difference in mortality between men and women (odds ratio, 1.04; CI, 0.60 to 1.79; P = 0.89). After correction for functional class alone, there continued to be no significant difference in mortality between men and women (P = 0.40). CONCLUSIONS Differences in functional class and age account for the higher operative mortality of women in coronary bypass surgery. Women are referred for coronary bypass surgery later in the course of their disease than men, and later referral may increase their changes of operative death.

Relationship Between Regional Cardiac Hyperinnervation and Ventricular Arrhythmia

BACKGROUND Sympathetic nerve activity is known to be important in ventricular arrhythmogenesis, but there is little information on the relation between the distribution of cardiac sympathetic nerves and the occurrence of spontaneous ventricular arrhythmias in humans. METHODS AND RESULTS We studied 53 native hearts of transplant recipients, 5 hearts obtained at autopsy of patients who died of noncardiac causes, and 7 ventricular tissues that had been surgically resected from the origin of ventricular tachycardia. The history was reviewed to determine the presence (group 1A) or absence (group 1B) of spontaneous ventricular arrhythmias. Immunocytochemical staining for S100 protein, neurofilament protein, tyrosine hydroxylase, and protein gene product 9.5 was performed to study the distribution and the density of sympathetic nerves. The average left ventricular ejection fraction was 0.22+/-0.07. A total of 30 patients had documented ventricular arrhythmias, including ventricular tachycardia and sudden cardiac death. A regional increase in sympathetic nerves was observed around the diseased myocardium and blood vessels in all 30 hearts. The density of nerve fibers as determined morphometrically was significantly higher in group 1A patients (total nerve number 19.6+/-11.2/mm(2), total nerve length 3.3+/-3.0 mm/mm(2)) than in group 1B patients (total nerve number 13.5+/-6.1/mm(2), total nerve length 2.0+/-1.1 mm/mm(2), P<0. 05 and P<0.01, respectively). CONCLUSIONS There is an association between a history of spontaneous ventricular arrhythmia and an increased density of sympathetic nerves in patients with severe heart failure. These findings suggest that abnormally increased postinjury sympathetic nerve density may be in part responsible for the occurrence of ventricular arrhythmia and sudden cardiac death in these patients.

Posttransplant therapy using high-dose human immunoglobulin (intravenous gammaglobulin) to control acute humoral rejection in renal and cardiac allograft recipients and potential mechanism of action.

BACKGROUND Intravenous gammaglobulin (i.v.IG) contains anti-idiotypic antibodies that are potent inhibitors of HLA-specific alloantibodies in vitro and in vivo. In addition, highly HLA-allosensitized patients awaiting transplantation can have HLA alloantibody levels reduced dramatically by i.v.IG infusions, and subsequent transplantation can be accomplished successfully with a crossmatch-negative, histoincompatible organ. METHODS In this study, we investigated the possible use of i.v.IG to reduce donor-specific anti-HLA alloantibodies arising after transplantation and its efficacy in treating antibody-mediated allograft rejection (AR) episodes. We present data on 10 patients with severe allograft rejection, four of whom developed AR episodes associated with high levels of donor-specific anti-HLA alloantibodies. RESULTS Most patients showed rapid improvements in AR episodes, with resolution noted within 2-5 days after i.v.IG infusions in all patients. i.v.IG treatment also rapidly reduced donor-specific anti-HLA alloantibody levels after i.v.IG infusion. All AR episodes were reversed. Freedom from recurrent rejection episodes was seen in 9 of 10 patients, some with up to 5 years of follow-up. Results of protein G column fractionation studies from two patients suggest that the potential mechanism by which i.v.IG induces in vivo suppression is a sequence of events leading from initial inhibition due to passive transfer of IgG to eventual active induction of an IgM or IgG blocking antibody in the recipient. CONCLUSION I.v.IG appears to be an effective therapy to control posttransplant AR episodes in heart and kidney transplant recipients, including patients who have had no success with conventional therapies. Vascular rejection episodes associated with development of donor-specific cytotoxic antibodies appears to be particularly responsive to i.v.IG therapy.

INTRAVENOUS IMMUNOGLOBULIN SUPPRESSION OF HLA ALLOANTIBODY IN HIGHLY SENSITIZED TRANSPLANT CANDIDATES AND TRANSPLANTATION WITH A HISTOINCOMPATIBLE ORGAN

Patients awaiting solid organ transplantation who are highly sensitized to HLA antigens remain problematic in terms of finding compatible (crossmatch-negative) donors. We have used intravenous gammaglobulin (IVIG; 10% Gamimune N) to determine both its efficacy in reducing panel-reactive antibodies in vitro and the prognostic value of the in vitro testing for in vivo efficacy. In 18 patients with PRAs ranging from 40 to 100% (mean: 77%) we found a reduction in absolute PRA of 4-70% (mean decrease: 35%; percent inhibition: 4-100%; residual PRA 0-96%). In 7 cases, the residual antibody specificity could be easily determined and often appeared to include a short HLA-A2. This was independent of A2 subtype as determined by PCR-SSOP. Testing the IVIG on a panel of 21 HLA reagent alloantisera resulted in heterogeneous inhibitory patterns (7 complete, 3 partial, 8 differential, 3 none) independent of titer or specificity. In vivo administration to a 13-year-old kidney patient awaiting retransplant resulted in a PRA drop from 95% to 15% and successful retransplantation (now 11 months post-transplant). More impressively, successive in vivo administration of IVIG to a sensitized (anti-HLA-A2, A68, A69; B57, B58) heart transplant candidate resulted in successful transplantation with an A2+ histoincompatible heart. The patient experienced only one subclinical humoral rejection in the first 5 months posttransplant. Biochemical studies to determine the effective component of IVIG show that it is the IgG fraction and not soluble antigen or the minor IgM or IgA contaminants that is responsible. This suggests an antiidiotypic modulation of anti-HLA antibodies in vitro and in vivo.

Report from a consensus conference on antibody-mediated rejection in heart transplantation

BACKGROUND The problem of AMR remains unsolved because standardized schemes for diagnosis and treatment remains contentious. Therefore, a consensus conference was organized to discuss the current status of antibody-mediated rejection (AMR) in heart transplantation. METHODS The conference included 83 participants (transplant cardiologists, surgeons, immunologists and pathologists) representing 67 heart transplant centers from North America, Europe, and Asia who all participated in smaller break-out sessions to discuss the various topics of AMR and attempt to achieve consensus. RESULTS A tentative pathology diagnosis of AMR was established, however, the pathologist felt that further discussion was needed prior to a formal recommendation for AMR diagnosis. One of the most important outcomes of this conference was that a clinical definition for AMR (cardiac dysfunction and/or circulating donor-specific antibody) was no longer believed to be required due to recent publications demonstrating that asymptomatic (no cardiac dysfunction) biopsy-proven AMR is associated with subsequent greater mortality and greater development of cardiac allograft vasculopathy. It was also noted that donor-specific antibody is not always detected during AMR episodes as the antibody may be adhered to the donor heart. Finally, recommendations were made for the timing for specific staining of endomyocardial biopsy specimens and the frequency by which circulating antibodies should be assessed. Recommendations for management and future clinical trials were also provided. CONCLUSIONS The AMR Consensus Conference brought together clinicians, pathologists and immunologists to further the understanding of AMR. Progress was made toward a pathology AMR grading scale and consensus was accomplished regarding several clinical issues.

Discrepancies between Doppler and catheter gradients in aortic prosthetic valves in vitro. A manifestation of localized gradients and pressure recovery.

To evaluate possible causes of discrepancy between Doppler and catheter gradients across prosthetic valves, five sizes (19-27 mm) of St. Jude and Hancock valves were studied in an aortic pulsatile flow model. Catheter gradients at multiple sites distal to the valve were compared with simultaneously obtained Doppler gradients. In the St. Jude valve, significant differences between Doppler and catheter gradients measured 30 mm downstream from the valve were found: Doppler gradients exceeded peak catheter gradients of 10 mm Hg or more by 81 +/- 35% (15 +/- 3.6 mm Hg), and mean catheter gradients by 71 +/- 11% (10.3 +/- 2.5 mm Hg). When the catheter was pulled back through the tunnel-like central orifice of the valve, high localized gradients at the valve plane and significant early pressure recovery were found. When the catheter was pulled back through the large side orifices, gradients at the same level were only 46 +/- 6% of the central orifice gradients (mean difference, 7.6 +/- 4.5 mm Hg). Doppler peak and mean gradients showed excellent agreement with the highest central orifice catheter gradients (mean difference, 1.0 +/- 3.1 and 0.9 +/- 1.5 mm Hg, respectively). A significantly better agreement between Doppler and catheter gradients at 30 mm was found for the Hancock valve, although Doppler peak and mean gradients were still slightly greater than catheter gradients. Doppler gradients exceeded catheter gradients by 18 +/- 10% (3.4 +/- 1.9 mm Hg) and 13 +/- 11% (2.1 +/- 0.9 mm Hg), respectively. When the catheter was pulled back through the valve, the highest gradients were found approximately 20 mm distal to the valve ring.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical Profile and Predictors of Complications in Peripartum Cardiomyopathy

BACKGROUND Clinical profile and predictors of major adverse events (MAE) associated with peripartum cardiomyopathy (PPCM) have not been characterized. METHODS AND RESULTS A retrospective review and analysis of clinical data of 182 patients with PPCM. Forty-six patients had >or=1 MAE, including death (13), heart transplantation (11), temporary circulatory support (4), cardiopulmonary arrest (6), fulminant pulmonary edema (17), thromboembolic complications (4), and defibrillator or pacemaker implantation (10). Diagnosis of PPCM was delayed >or=1 week in 48% of patients with MAE that preceded the diagnosis in 50% of these patients. Seven (32%) of the surviving patients who had MAE and did not undergo heart transplantation had residual brain damage. Significant predictors of MAE were: left ventricular ejection fraction <or=25% (HR 4.20, CI 2.04-8.64) and non-Caucasian background(HR 2.16, CI 1.17- 3.97). These predictors in addition to diagnosis delay (HR 5.51, CI 1.21-25.04) were also associated with death or heart transplantation. CONCLUSIONS 1. PPCM may be associated with mortality or severe and lasting morbidity. 2. Incidence of MAE is higher in non-Caucasians and in women with left ventricular ejection fraction <or=25%. 3. Diagnosis of PPCM is often delayed and preceded by MAE. 4. Increased awareness of PPCM is required for early diagnosis and aggressive therapy in an attempt to prevent complications.

Treatment of severe platelet dysfunction and hemorrhage after cardiopulmonary bypass: reduction in blood product usage with desmopressin.

Impairment of platelet function commonly occurs after cardiopulmonary bypass, and may result in substantial bleeding. Because desmopressin acetate (a synthetic analogue of vasopressin) shortens bleeding time in a variety of platelet disorders, a controlled clinical trial of intravenous desmopressin was performed in 39 patients with excessive mediastinal bleeding (greater than 100 ml/h) and a prolonged template bleeding time (greater than 10 minutes) more than 2 hours after termination of cardiopulmonary bypass. Twenty-three desmopressin recipients and 16 control patients (no desmopressin) were similar in surgical procedure, pump time, platelet count, template bleeding time and amount of bleeding before therapy (p = NS). Compared with the control group, the patients receiving desmopressin (20 micrograms; mean 0.3 micrograms/kg) utilized fewer blood products (29 +/- 19 versus 15 +/- 13 units/patient; p less than 0.05), especially platelets (12 +/- 9 versus 4 +/- 7 units/patient; p = 0.004), while achieving a similarly effective reduction in mediastinal bleeding (4.8- and 4.3-fold, p = 0.001 for both). Severe platelet dysfunction was partially corrected within 1 hour after desmopressin infusion, during which interval no blood products were administered: the template bleeding time shortened (from 17 to 12.5 minutes, p less than 0.05), whereas the platelet count remained unchanged (at 96 +/- 35 and 105 +/- 31 X 10(3)/mm3, p = NS). The plasma levels of two factor VIII components increased: procoagulant activity (VIII:C) from 0.97 +/- 0.43 to 1.52 +/- 0.74 units/ml (p less than 0.05) and von Willebrand factor (VIII:vWF) from 1.28 to 1.78 units/ml (p less than 0.05); these increases correlated with the shortening of the bleeding time (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

The clinical significance of antibodies to human vascular endothelial cells after cardiac transplantation.

BACKGROUND Vascular endothelial cells are primary targets for injury during both cellular and humoral allograft rejection (AR). In cardiac transplantation, the role of humoral immunity in mediating AR has not been extensively characterized. METHODS Antibodies against human vascular endothelial cells (AECA) were measured using a cellular ELISA developed from human umbilical vein endothelial cells in 80 consecutive patients after cardiac transplantation. The aim was to determine the incidence of AECA formation after transplantation and their association with different types of AR, graft survival, and development of cardiac allograft vasculopathy (CAV). At least eight serum samples obtained from each patient were examined for AECA and an endomyocardial biopsy was performed at regular intervals during the first year after transplantation. RESULTS Of the 80 patients examined, 31 were AECA (+) and 49 patients were AECA (-). There were no significant differences between the AECA (+) and (-) groups when examined for age, sex, and pretransplantation ischemia time. A significant correlation was found between the presence of AECA and humoral AR (P<0.015). AECA positivity did not correlate with the presence of cellular AR or the number of rejection episodes. In addition, allograft survival at 2 years after transplantation was significantly better in the AECA (-) group compared with that in the AECA (+) group (89.8% vs. 71.0%, P<0.0004). The persistence of AECA positivity during the first year after transplantation was also associated with a significantly greater incidence of CAV when compared with the patients who were AECA (-) (25.8% vs. 14.3%, P<0.004). CONCLUSIONS AECA may be important in the mediation of humoral AR, may decrease allograft survival, and may identify a high-risk group for CAV.