M. Kittleson

Complications of Extracorporeal Membrane Oxygenation for Treatment of Cardiogenic Shock and Cardiac Arrest: A Meta-Analysis of 1,866 Adult Patients

BACKGROUND Venoarterial extracorporeal membrane oxygenation (ECMO) has been used successfully for treatment of cardiogenic shock or cardiac arrest. The exact complication rate is not well understood, in part because of small study sizes. In the absence of large clinical trials, performance of pooled analysis represents the best method for ascertaining complication rates for ECMO. METHODS A systematic PubMed search was conducted on ECMO for treatment of cardiogenic shock or cardiac arrest in adult patients only, updated to November 2012. Studies with more than 10 patients published in the year 2000 or later that reported complication rates for ECMO were included. Specific complications analyzed included lower extremity ischemia, fasciotomy or compartment syndrome, amputation, stroke, neurologic complications, acute kidney injury, renal replacement therapy, major or significant bleeding, rethoracotomy for bleeding or tamponade, and significant infection. For studies that included overlapping patients, the largest study was included and the others excluded. Cochrans Q and I-squared were calculated. A more conservative random-effects model was chosen for all analyses. RESULTS Twenty studies were included in the analyses encompassing 1,866 patients. Seventeen studies reported survival to hospital discharge, with a cumulative survival rate of 534 of 1,529, and a range of 20.8% to 65.4%. Analyses encompassed 192 to 1,452 patients depending on the specific complication analyzed. The pooled estimate rates of complications with 95% confidence intervals were as follows: lower extremity ischemia, 16.9% (12.5% to 22.6%); fasciotomy or compartment syndrome, 10.3% (7.3% to 14.5%); lower extremity amputation, 4.7% (2.3% to 9.3%); stroke, 5.9% (4.2% to 8.3%); neurologic complications, 13.3% (9.9% to 17.7%); acute kidney injury, 55.6% (35.5% to 74.0%); renal replacement therapy, 46.0% (36.7% to 55.5%); major or significant bleeding, 40.8% (26.8% to 56.6%); rethoracotomy for bleeding or tamponade in postcardiotomy patients, 41.9% (24.3% to 61.8%); and significant infection, 30.4% (19.5% to 44.0%). CONCLUSIONS Although ECMO can improve survival of patients with advanced heart disease, there is significant associated morbidity with performance of this intervention. These findings should be incorporated in the risk-benefit analysis when initiation of ECMO for cardiogenic shock is being considered.

Asymptomatic Antibody-mediated Rejection After Heart Transplantation Predicts Poor Outcomes

BACKGROUND Antibody-mediated rejection (AMR) has been associated with poor outcome after heart transplantation. The diagnosis of AMR usually includes endomyocardial biopsy findings of endothelial cell swelling, intravascular macrophages, C4d+ staining, and associated left ventricular dysfunction. The significance of AMR findings in biopsy specimens of asymptomatic heart transplant patients (normal cardiac function and no symptoms of heart failure) is unclear. METHODS Between July 1997 and September 2001, AMR was found in the biopsy specimens of 43 patients. Patients were divided into 2 groups: asymptomatic AMR (AsAMR, n = 21) and treated AMR (TxAMR with associated left ventricular dysfunction, n = 22). For comparison, a control group of 86 contemporaneous patients, without AMR, was matched for age, gender, and time from transplant. Outcomes included 5-year actuarial survival and development of cardiac allograft vasculopathy (CAV). Patients were considered to have AMR if they had > or = 1 endomyocardial biopsy specimen positive for AMR. RESULTS The 5-year actuarial survival for the AsAMR (86%), TxAMR (68%), and control groups (79%) was not significantly different (p = 0.41). Five-year freedom from CAV (> or = 30% stenosis in any vessel) was AsAMR, 52%; TxAMR, 68%; and control, 79%. Individually, freedom from CAV was significantly lower in the AsAMR group compared with the control group (p = 0.02). There was no significant difference between AsAMR vs TxAMR and TxAMR vs control for CAV. CONCLUSIONS Despite comparable 5-year survival with controls after heart transplantation, AsAMR rejection is associated with a greater risk of CAV. Trials to treat AsAMR to alter outcome are warranted.

Development of circulatory-renal limitations to angiotensin-converting enzyme inhibitors identifies patients with severe heart failure and early mortality ☆

OBJECTIVES This study examined the hypothesis that patients who develop angiotensin-converting enzyme inhibitor intolerance attributable to circulatory-renal limitations (CRLimit) have more severe underlying disease and worse outcome. BACKGROUND Although the renin-angiotensin system contributes to the progression of heart failure (HF), it also supports the failing circulation. Patients with the most severe disease may not tolerate inhibition of this system. METHODS Consecutive inpatient admissions to the cardiomyopathy service of the Brigham and Womens Hospital between 2000 and 2002 were reviewed retrospectively for initial profiles, discharge medications, and documented reasons for discontinuation of angiotensin-converting enzyme inhibitors. Outcomes of death and transplantation were determined. RESULTS Of the 259 patients, 86 were not on an angiotensin-converting enzyme inhibitor at discharge. Circulatory-renal limitations of symptomatic hypotension, progressive renal dysfunction, or hyperkalemia were documented in 60 patients (23%); other adverse effects, including cough, in 24 patients; and absent reasons in 2 patients. Compared with patients on angiotensin-converting enzyme inhibitors, patients with CRLimit were older (60 vs. 55 years; p = 0.006), with longer history of HF (5 vs. 2 years; p = 0.009), lower systolic blood pressure (104 vs. 110 mm Hg; p = 0.05), lower sodium (135 vs. 138 mEql/l; p = 0.002), and higher initial creatinine (2.5 vs. 1.2 mg/dl; p = 0.0001). Mortality was 57% in patients with CRLimit and 22% in the patients on angiotensin-converting enzyme inhibitors during a median 8.5-month follow-up (p = 0.0001). CONCLUSIONS Development of CRLimit to angiotensin-converting enzyme inhibitor intolerance identifies patients with severe disease who are likely to die during the next year. New treatment strategies should be targeted to this population.

Identification of a Gene Expression Profile That Differentiates Between Ischemic and Nonischemic Cardiomyopathy

Background—Gene expression profiling refines diagnostic and prognostic assessment in oncology but has not yet been applied to myocardial diseases. We hypothesized that gene expression differentiates ischemic and nonischemic cardiomyopathy, demonstrating that gene expression profiling by clinical parameters is feasible in cardiology. Methods and Results—Affymetrix U133A microarrays of 48 myocardial samples from Johns Hopkins Hospital (JHH) and the University of Minnesota (UM) obtained (1) at transplantation or left ventricular assist device (LVAD) placement (end-stage; n=25), (2) after LVAD support (post-LVAD; n=16), and (3) from newly diagnosed patients (biopsy; n=7) were analyzed with prediction analysis of microarrays. A training set was used to develop the profile and test sets to validate the accuracy of the profile. An etiology prediction profile developed in end-stage JHH samples was tested in independent samples from both JHH and UM with 100% sensitivity and 100% specificity in end-stage samples and 33% sensitivity and 100% specificity in both post-LVAD and biopsy samples. The overall sensitivity was 89% (95% CI 75% to 100%), and specificity was 89% (95% CI 60% to 100%) over 210 random partitions of end-stage samples into training and test sets. Age, gender, and hemodynamic differences did not affect the profile’s accuracy in stratified analyses. Select gene expression was confirmed with quantitative polymerase chain reaction. Conclusions—Gene expression profiling accurately predicts cardiomyopathy etiology, is generalizable to samples from separate institutions, is specific to disease stage, and is unaffected by differences in clinical characteristics. This strongly supports ongoing efforts to incorporate expression profiling–based biomarkers in determining prognosis and response to therapy in heart failure.

Cardiac Myocyte Apoptosis Is Associated With Increased DNA Damage and Decreased Survival in Murine Models of Obesity

Disruption of leptin signaling is associated with obesity, heart failure, and cardiac hypertrophy, but the role of leptin in cardiac myocyte apoptosis is unknown. We tested the hypothesis that apoptosis increases in leptin-deficient ob/ob and leptin-resistant db/db mice and is associated with aging and left ventricular hypertrophy, increased DNA damage, and decreased survival. We studied young (2- to 3-month-old) and old (12- to 14-month-old) ob/ob and db/db mice and wild-type (WT) controls (n=2 to 4 per group). As expected, ventricular wall thickness and heart weights were similar among young ob/ob, db/db, and WT mice, but higher in old ob/ob and db/db versus old WT. Young ob/ob and db/db showed markedly elevated apoptosis by TUNEL staining and caspase 3 levels compared with WT. Differences in apoptosis were further accentuated with age. Leptin treatment significantly reduced apoptosis in ob/ob mice both in intact hearts and isolated myocytes. Tissue triglycerides were increased in ob/ob hearts, returning to WT levels after leptin repletion. Furthermore, the DNA damage marker, 8oxoG (8-oxo-7,8-dihydroguanidine), was increased, whereas the DNA repair marker, MYH glycosylase, was decreased in old ob/ob and db/db compared with old WT mice. Both ob/ob and db/db mice had decreased survival compared with WT mice. We conclude that leptin-deficient and leptin-resistant mice demonstrate increased apoptosis, DNA damage, and mortality compared with WT mice, suggesting that normal leptin signaling is necessary to prevent excess age-associated DNA damage and premature mortality. These data offer novel insights into potential mechanisms of myocardial dysfunction and early mortality in obesity.

Reduction of alloantibodies via proteosome inhibition in cardiac transplantation

BACKGROUND The presence of alloantibodies in patients awaiting heart transplantation is associated with increased waiting time to transplant, increased risk of rejection after transplant, an increased risk of cardiac allograft vasculopathy, and decreased survival. So far, treatments to reduce circulating antibodies to allow transplantation have been limited. We report the first clinical experience using a plasma-cell-depleting strategy with bortezomib to reduce anti-HLA antibodies in the heart transplant population. METHODS Six patients awaiting cardiac transplantation demonstrated persistently elevated anti-HLA antibodies, despite receiving a course of treatment with intravenous immunoglobulin (IVIg) and rituximab. These patients then underwent supplemental therapy with bortezomib in conjunction with plasmapheresis. One additional patient awaiting cardiac transplantation with elevated anti-HLA antibodies required bortezomib treatment for amyloidosis. Antibody strength was monitored after completion of treatment by solid-phase (single-antigen-bead) assay. RESULTS The mean calculated panel-reactive antibody (cPRA) was reduced from 62% to 35% following a course of bortezomib (p = 0.01). Six of 7 patients demonstrated a significant decline in antibody levels. One patient remained refractory to desensitization therapy and died from sepsis while awaiting heart transplantation. Four patients successfully underwent cardiac transplantation without evidence of rejection or graft dysfunction. One patient developed early post-transplant graft dysfunction and died at 1 month from sepsis. Infection was the most common adverse effect associated with desensitization. CONCLUSIONS In this pilot study, use of plasmapheresis and bortezomib appeared to decrease cPRA, even in patients refractory to desensitization with IVIg/rituximab, thus increasing the chances that an acceptable donor heart will be available for the sensitized patient awaiting heart transplantation. However, desensitization is associated with an increased risk of infection. Further studies are warranted to determine whether the benefits of desensitization using this strategy outweigh the risks.

Cardiac allograft rejection

Success in cardiac transplantation has been achieved by the development of improved immunosuppressive therapies, which have led to a concomitant decrease in cardiac allograft rejection and infection. Rejection however continues to be the cause of significant morbidity and mortality particularly in the first year after cardiac transplantation. The endomyocardial biopsy remains an essential tool for its diagnosis. Acute cellular rejection has been a well recognized phenomenon although more recently, the diagnosis of antibody-mediated rejection has gained acceptance, a condition associated with greater graft dysfunction, subsequent development of cardiac allograft vasculopathy and mortality. In this article we review the current status of the diagnosis of cardiac allograft rejection as determined by the traditional endomyocardial biopsy, the more recent advances in the non-invasive evaluation of rejection, detection of circulating antibodies and the treatment of rejection.

Benefit of immune monitoring in heart transplant patients using ATP production in activated lymphocytes.

BACKGROUND Balancing immunosuppression to prevent rejection while minimizing infection or drug toxicity risk is a major challenge in heart transplantation. Therapeutic drug monitoring alone is inadequate to measure the immune response. An immune monitoring (IM) assay (ImmuKnow; Cylex, Columbia, MD) performed on peripheral blood measures adenosine triphosphatase (ATP) release from activated lymphocytes and may predict the immune state. Therefore, we sought to determine the utility of IM in heart transplant recipients. METHODS Between November 2005 and July 2008, 296 heart transplant recipients had a total of 864 IM assays performed at 2 weeks to 10 years post-transplant and were correlated with infection and rejection events that occurred within 1 month after IM testing. All patients received standard triple-drug immunosuppressive therapy with tacrolimus, mycophenolate mofetil and corticosteroids, without induction therapy. RESULTS There were 38 infectious episodes and 8 rejection episodes. The average IM score was significantly lower during infection than steady state (187 vs 280 ng ATP/ml, p < 0.001). The average IM score was not significantly different during rejection when compared with steady state (327 vs 280 ng ATP/ml, p = 0.35). Interestingly, 3 of 8 rejection episodes were antibody-mediated rejections and had hemodynamic compromise and, for these, the mean IM score was significantly higher than for steady-state patients (491 vs 280 ng ATP/ml, p < 0.001). CONCLUSIONS The non-invasive IM test appears to predict infectious risk in heart transplant patients. The association between high IM scores and rejection risk is inconclusive due to the small number of rejection episodes. Further studies with larger sample sizes for rejection episodes are required.

The gene expression profile of patients with new-onset heart failure reveals important gender-specific differences

AIMS We sought to test the hypothesis that inherent biological factors contribute to gender differences in disease pathophysiology of new-onset heart failure (HF), which can be detected from the transcriptome of a single endomyocardial biopsy (EMB). METHODS AND RESULTS We analysed samples from male (n = 29) and female patients (n = 14) with idiopathic dilated cardiomyopathy (IDCM) and new-onset HF with U133 Plus 2.0 microarrays (Affymetrix) and significance analysis of microarrays (SAM). There were 35 overexpressed and 16 downregulated transcripts in men vs. women [q < 5%, fold change (FC) > 1.2]. In addition to overexpression of Y-chromosome-related transcripts (n = 18), such as USP9Y (FC > 13.1), DDX3Y (FC > 11.3), RPS4Y1 (FC > 9.9), and EIF1AY (FC > 11.8) in males, there was overexpression of CD24 (FC > 5.6) and KCNK1 (FC > 1.5). In females, XIST was highly overexpressed (FC > 28.9), together with X-linked zinc finger proteins (FC > 1.9) and autosomal genes GATAD1 (FC > 1.6), SLC2A12 (FC > 2.9), and PDE6B (FC > 1.5). Analysis of a public data set of end-stage IDCM (n = 15) resulted in approximately 85% overlap with our findings. CONCLUSION This is the first study that identified gender-specific transcriptomic differences in new-onset HF. Our findings may offer novel insights into fundamental biological differences in the pathophysiology of HF between sexes and provide a platform for personalized medicine.

The long‐term outcome of treated sensitized patients who undergo heart transplantation

Kobashigawa JA, Patel JK, Kittleson MM, Kawano MA, Kiyosaki KK, Davis SN, Moriguchi JD, Reed EF, Ardehali AA. The long‐term outcome of treated sensitized patients who undergo heart transplantation.
Clin Transplant 2011: 25: E61–E67.