Mario C. Deng

Noninvasive discrimination of rejection in cardiac allograft recipients using gene expression profiling

Rejection diagnosis by endomyocardial biopsy (EMB) is invasive, expensive and variable. We investigated gene expression profiling of peripheral blood mononuclear cells (PBMC) to discriminate ISHLT grade 0 rejection (quiescence) from moderate/severe rejection (ISHLT ≥3A). Patients were followed prospectively with blood sampling at post‐transplant visits. Biopsies were graded by ISHLT criteria locally and by three independent pathologists blinded to clinical data. Known alloimmune pathways and leukocyte microarrays identified 252 candidate genes for which real‐time PCR assays were developed. An 11 gene real‐time PCR test was derived from a training set (n = 145 samples, 107 patients) using linear discriminant analysis (LDA), converted into a score (0–40), and validated prospectively in an independent set (n = 63 samples, 63 patients). The test distinguished biopsy‐defined moderate/severe rejection from quiescence (p = 0.0018) in the validation set, and had agreement of 84% (95% CI 66% C94%) with grade ISHLT ≥3A rejection. Patients >1 year post‐transplant with scores below 30 (approximately 68% of the study population) are very unlikely to have grade ≥3A rejection (NPV = 99.6%). Gene expression testing can detect absence of moderate/severe rejection, thus avoiding biopsy in certain clinical settings. Additional clinical experience is needed to establish the role of molecular testing for clinical event prediction and immunosuppression management.

Mechanical circulatory support device database of the international society for heart and lung transplantation: first annual report—2003

Over the last 2 decades, mechanical circulatory support devices have been developed with the goal of supporting patients with advanced heart failure as a bridge to cardiac transplantation, a bridge to recovery, and an alternative to transplantation (also called chronic or destination therapy). The current generation of devices provides a differentiated spectrum of circulatory support. The major limitations of mechanical circulatory support devices are infection, coagulopathies and device dysfunction. The Scientific Council on Mechanical Circulatory Support of the International Society for Heart and Lung Transplantation has established an international database to generate critical data to advance knowledge about the effectiveness of mechanical circulatory support device therapy for one of the most difficult and costly contemporary medical problems, the malignant syndrome of advanced heart failure.

Gene-Expression Profiling for Rejection Surveillance after Cardiac Transplantation

BACKGROUND Endomyocardial biopsy is the standard method of monitoring for rejection in recipients of a cardiac transplant. However, this procedure is uncomfortable, and there are risks associated with it. Gene-expression profiling of peripheral-blood specimens has been shown to correlate with the results of an endomyocardial biopsy. METHODS We randomly assigned 602 patients who had undergone cardiac transplantation 6 months to 5 years previously to be monitored for rejection with the use of gene-expression profiling or with the use of routine endomyocardial biopsies, in addition to clinical and echocardiographic assessment of graft function. We performed a noninferiority comparison of the two approaches with respect to the composite primary outcome of rejection with hemodynamic compromise, graft dysfunction due to other causes, death, or retransplantation. RESULTS During a median follow-up period of 19 months, patients who were monitored with gene-expression profiling and those who underwent routine biopsies had similar 2-year cumulative rates of the composite primary outcome (14.5% and 15.3%, respectively; hazard ratio with gene-expression profiling, 1.04; 95% confidence interval, 0.67 to 1.68). The 2-year rates of death from any cause were also similar in the two groups (6.3% and 5.5%, respectively; P=0.82). Patients who were monitored with the use of gene-expression profiling underwent fewer biopsies per person-year of follow-up than did patients who were monitored with the use of endomyocardial biopsies (0.5 vs. 3.0, P<0.001). CONCLUSIONS Among selected patients who had received a cardiac transplant more than 6 months previously and who were at a low risk for rejection, a strategy of monitoring for rejection that involved gene-expression profiling, as compared with routine biopsies, was not associated with an increased risk of serious adverse outcomes and resulted in the performance of significantly fewer biopsies. (ClinicalTrials.gov number, NCT00351559.)

Mechanical Circulatory Support for Advanced Heart Failure

Background—Use of wearable left ventricular assist systems (LVAS) in the treatment of advanced heart failure has steadily increased since 1993, when these devices became generally available in Europe. The aim of this study was to identify in an unselected cohort of LVAS recipients those aspects of patient selection that have an impact on postimplant survival. Methods and Results—Data were obtained from the Novacor European Registry. Between 1993 and 1999, 464 patients were implanted with the Novacor LVAS. The majority had idiopathic (60%) or ischemic (27%) cardiomyopathy; the median age at implant was 49 (16 to 75) years. The median support time was 100 days (4.1 years maximum). Forty-nine percent of the recipients were discharged from the hospital on LVAS; they spent 75% of their time out of the hospital. For a subset of 366 recipients, for whom a complete set of data was available, multivariate analysis revealed that the following preimplant conditions were independent risk factors for survival after LV...

Mechanical circulatory support device database of the International Society for Heart and Lung Transplantation.

Over the last 2 decades, mechanical circulatory support devices have been developed at a rapid pace with the goal of supporting patients with advanced heart failure as a bridge to cardiac transplantation, a bridge to recovery, and an alternative to transplantation, also called chronic or destination therapy. The current generation of devices provides a differentiated spectrum of circulatory support. The major limitations are infection, coagulopathies, and device dysfunction. The Scientific Council on Mechanical Circulatory Support of the International Society for Heart and Lung Transplantation has established an international database (http://www.ishlt.org/regist_mcsd_main.htm) to generate critical data to advance knowledge about effectiveness of mechanical circulatory support device therapy for one of the most difficult and costly contemporary medical problems, the malignant syndrome of advanced heart failure.

Effect of receiving a heart transplant: analysis of a national cohort entered on to a waiting list, stratified by heart failure severity

Abstract Objective: To determine whether there is a survival benefit associated with cardiac transplantation in Germany. Design: Prospective observational cohort study. Setting: All 889 adult patients listed for a first heart transplant in Germany in 1997. Main outcome measure: Mortality, stratified by heart failure severity. Results: Within 1 year after listing, patients with a predicted high risk had the highest global death rate (51% v 32% and 29% for medium and low risk patients respectively; P<0.0001), had the highest risk of dying on the waiting list (32% v 20% and 20%; P=0.0003), and were more likely to receive a transplant (48% v 45% and 41%; P=0.01). Differences between the risk groups in outcome after transplantation did not reach significance (P=0.2). Transplantation was not associated with a reduction in mortality risk for the total cohort, but it did provide a survival benefit for the high risk group. Conclusion: Cardiac transplantation in Germany is currently associated with a survival benefit only in patients with a predicted high risk of dying on the waiting list. Patients with a predicted low or medium risk have no reduction in mortality risk associated with transplantation; they should be managed with organ saving approaches rather than transplantation.

Usefulness of Immunosuppression for Giant Cell Myocarditis

Giant cell myocarditis (GCM) is a rare and highly lethal disorder. The only multicenter case series with treatment data lacked cardiac function assessments and had a retrospective design. We conducted a prospective, multicenter study of immunosuppression including cyclosporine and steroids for acute, microscopically-confirmed GCM. From June 1999 to June 2005 in a standard protocol, 11 subjects received high dose steroids and cyclosporine, and 9 subjects received muromonab-CD3. In these, 7 of 11 were women, the mean age was 60 +/- 15 years, and the mean time from symptom onset to presentation was 27 +/- 33 days. During 1 year of treatment, 1 subject died of respiratory complications on day 178, and 2 subjects received heart transplantations on days 2 and 27, respectively. Serial endomyocardial biopsies revealed that after 4 weeks of treatment the degree of necrosis, cellular inflammation, and giant cells decreased (p = 0.001). One patient who completed the trial subsequently died of a fatal GCM recurrence after withdrawal of immunosuppression. Her case demonstrates for the first time that there is a risk of recurrent, sometimes fatal, GCM after cessation of immunosuppression. In conclusion, this prospective study of immunosuppression for GCM confirms retrospective case reports that such therapy improves long-term survival. Additionally, withdrawal of immunosuppression can be associated with fatal GCM recurrence.

Left ventricular pressure and volume unloading during pulsatile versus nonpulsatile left ventricular assist device support

BACKGROUND Nonpulsatile axial or centrifugal pumps are the latest generation of left ventricular assist devices (LVAD). Whether left ventricular (LV) unloading and outcome in these devices is similar to pulsatile LVADs during long-term support has not been investigated. We compared LV unloading and mortality between different types of LVAD support (pulsatile versus nonpulsatile). METHODS In 31 patients undergoing long-term LVAD implantation (nonpulsatile = 10, pulsatile = 21) preoperative and postoperative echocardiographic and hemodynamic assessment with right heart catheterization had been obtained. RESULTS All patients had similar echocardiographic, hemodynamic, and clinical heart failure characteristics at baseline. The degree of LV pressure unloading was the same in both device types, caused by similar reduction of mean pulmonary pressure (18.6 +/- 5.1 versus 18.3 +/- 7.5 mm Hg) and pulmonary capillary wedge pressure (8.9 +/- 4.4 versus 8.0 +/- 7.0 mm Hg). Left ventricular volume unloading was pronounced with a pulsatile device owing to a statistically significant higher pump output (5.1 +/- 1.0 L/min) in comparison with nonpulsatile LVADs (3.6 +/- 0.9 L/min, p < 0.001). Echocardiographic-determined end-systolic indicators confirm this augmentation in pulsatile LVADs. Etiology or the time interval of hemodynamic reassessment had no impact in left ventricular pressure unloading, but LV volume unloading decreased between day 60 and 120 in patients with nonpulsatile LVADs. The preoperative and postoperative transplant mortality was comparable in both groups. CONCLUSIONS Left ventricular pressure unloading is similar in patients with nonpulsatile as compared with pulsatile implantable long-term assist devices. Left ventricular volume unloading is pronounced in pulsatile LVADs.

Impact of left ventricular dysfunction on cytokines, hemodynamics, and outcome in bypass grafting

BACKGROUND Although patients with reduced left ventricular ejection fraction undergoing cardiac operation experience a higher rate of perioperative complications, the contribution of proinflammatory cytokines released during extracorporeal circulation is not well defined. METHODS We compared arterial and mixed venous levels of interleukin-6, tumor necrosis factor-alpha, soluble interleukin-2 receptor, and interleukin-2 at 10 points in time (24 hours before until 48 hours after extracorporeal circulation) in 21 patients with an ejection fraction of less than 0.45 (study group) to 15 patients with an ejection fraction of more than 0.55 (control group) undergoing elective coronary artery bypass grafting. The study and control group differed with regard to left ventricular ejection fraction (0.37 +/- 0.05 versus 0.66 +/- 0.11, p < 0.05) and reperfusion time (35 +/- 42 minutes versus 18 +/- 4 minutes, p = 0.07), but not age, sex, vessel involvement, number of grafts performed, cross-clamp time, extracorporeal circulation time, core temperature, and duration of ventilation. RESULTS Six patients in the study group required mechanical support and 1 died. There were no complications in the control group. In the study group, there were higher preoperative interleukin-2 and tumor necrosis factor-alpha levels and a higher maximum cytokine response to extracorporeal circulation for interleukin-2, soluble interleukin-2 receptor, interleukin-6, and tumor necrosis factor-alpha (all p < 0.05). Interleukin-6 correlated with duration of extracorporeal circulation, dose of norepinephrine and epinephrine support, pulmonary capillary wedge pressure, mean pulmonary arterial pressure, right atrial pressure, heart rate, cardiac index, and inversely with systemic vascular resistance. Interleukin-6 was highest in patients with complications. Arterial and venous cytokine levels correlated closely. CONCLUSIONS Preoperative left ventricular dysfunction is associated with a higher degree of proinflammatory cytokine release during elective coronary artery bypass grafting. This response is associated with impaired hemodynamics and a higher incidence of perioperative complications.

Vascular collagens: spotlight on the role of type VIII collagen in atherogenesis

Collagens play a central role in maintaining the integrity and stability of the undiseased as well as of the atherosclerotic vessel wall. An imbalanced metabolism may lead to uncontrolled collagen accumulation reducing vessel wall velocity, frequently resulting in arterial occlusion or thrombosis. A reduced production of collagen and its uncontrolled degradation may affect the stability of the vessel wall and especially of the atherosclerotic plaques by making them prone to rupture and aneurysm. This review presents an overview on the four groups of vascular collagens and on their role in atherogenesis. The major focus was to highlight the extraordinary role and importance of the short chain network forming type VIII collagen in the extracellular matrix of undiseased arteries and of atherosclerotic plaques. The molecular structure of type VIII collagen, its cellular origin, its implication in atherogenesis, its temporal and spatial expression patterns in human and experimental models of atherogenesis, the factors modulating its expression, and--not at least--its potential function is discussed.