Endomyocardial Biopsy Samples Research Articles

Primary Aldosteronism With Right-Dominant Heart Failure

A 48 year-old obese male with hypertension was admitted to our department because of severe right-dominant heart failure. His heart rhythm was 2:1 atrial flutter and the left ventricle was diffusely hypertrophic and hypokinetic. Primary aldosteronism was diagnosed based on severe hypokalemia (2.6 mEq/L) and a low renin-high aldosterone state with hypertension despite the use of an angiotensin-II receptor blocker, but its etiology could not be clarified with computed tomography, adrenal scintigraphy, and adrenal vein sampling. Ascites and edema rapidly worsened. Ascites aspiration was performed daily, until serum potassium was normalized by a full dose of an aldosterone receptor blocker (spironolactone 100 mg/day). A diuretic (furosemide) was then added. Rate control of atrial flutter was obtained with a beta-adrenergic blocker, and anticoagulation therapy was started. His heart failure was successfully controlled. Coronary arteries were normal on coronary arteriograms, and an endomyocardial biopsy sample obtained from the left ventricle did not show any specific pathological findings. Blood pressure was well controlled with the full dose of the aldosterone receptor blocker, but he died one year later due to intracerebral hemorrhage. As his heart failure was right dominant, we believe that its etiology may have been hyperaldosteronism-induced cardiomyopathy, and not advanced hypertensive heart disease.

Transcriptional Profiling of Septal Wall of the Right Ventricular Outflow Tract in Patients with Idiopathic Ventricular Arrhythmias

Frequent, monomorphic premature ventricular contractions (PVC) and/or ventricular tachycardia (VT) in patients with structurally normal heart usually arise from the right ventricular outflow tract (RVOT). The underlying arrhythmogenic substrate for the genesis of RVOT tachycardias is largely unknown. The aim of this study was to investigate the genome-wide transcriptional profiling of the septal wall of the RVOT in patients with RVOT tachycardia and control subjects. Transcriptional profiling with Affymetrix 3' IVT microarray analysis (Affymetrix, Santa Clara, CA, USA) was performed on the endomyocardial biopsy samples obtained from the septal wall of the RVOT from three unrelated patients with RVOT tachycardia and three control subjects. All study subjects had normal right and left ventricular size and function. Microarray results were validated by real time polymerase chain reaction (PCR). There were 32 statistically significant up-regulated and 60 down-regulated genes in five biological networks in patient population compared with control subjects. Among those genes, there were eight down-regulated [ATP1A2, CACNA1C, Protein Phosphatase 2, Regulatory Subunit B, Gamma Isoform[PPP2R2C], PLCD3, GNAO1, Solute Carrier Family 6 (Transporter, Norepinephrine), Member 2(SLC6A2), CAMK2B, PIK3R2] and two up-regulated (CAMKK2 and ITPR3) genes related to myocardial intracellular calcium regulation. In addition, there were five down-regulated [T-box 3(TBX3), Bone Morphogenetic Protein 2(BMP2), Bone Morphogenetic Protein Receptor, Type IB(BMPR1B), MYH6, Ankyrin Repeat Domain 23 and 39(ANKRD23-39)] and one up-regulated gene (RGS1) related to cardiovascular functions. The expression of genes responsible for the regulation of myocardial intracellular calcium and the development of RVOT are significantly down-regulated in the septal wall of the RVOT in patients with RVOT tachycardia compared with control subjects.

Severe Hypertrophic Cardiomyopathy in an Infant with a Novel PRKAG2 Gene Mutation: Potential Differences Between Infantile and Adult Onset Presentation

Hypertrophic cardiomyopathy (HCM) is a heterogeneous disorder characterized by thickening of the heart and an increased incidence of sudden death. This study is aimed to determine the genetic cause of severe cardiac hypertrophy in an infant. An infant was assigned a diagnosis of ventricular preexcitation and severe biventricular HCM requiring septal myectomy. Genetic testing showed a novel heterozygous E506Q mutation of the adenosine monophosphate (AMP)-activated protein kinase (PRKAG2) gene. Endomyocardial biopsy samples did not demonstrate significant glycogen accumulation. Hypertrophic cardiomyopathy due to PRKAG2 mutations may have a degree of cardiac hypertrophy exceeding that expected from observed amounts of glycogen deposition.

Pre-operative Determination of an Individual's Neutrophil Response: A Potential Predictor of Early Cardiac Transplant Cellular Rejection

Success of heart transplantation is affected by allograft rejection, which is known as a lymphocyte-mediated process. Recent studies suggest that neutrophils contribute to this process. We hypothesized that the severity of cardiac rejection can be predicted by evaluating an individual's neutrophil transendothelial migration potential, which can be assessed through artificial stimulation of neutrophils. Eleven patients were recruited from the active heart transplant list. Pre-operative blood samples were stained with neutrophil adhesion molecule (CD11b, CD62L, and PSGL-1) antibodies before and after in vitro stimulation with phorbol 12-myristate 13-acetate (PMA; 1 ng/ml) and lipopolysaccharide (LPS 1 microg/ml), and assessed using flow cytometry. Stimulated neutrophil responses were correlated with rejection grade of the first endomyocardial biopsy sampled 10 days post-operatively. Neutrophil adhesion molecules are upregulated after artificial stimulation. Pre-operative neutrophil surface CD11b expression after in vitro lipopolysaccharide stimulation correlated with rejection grade detected in the first endomyocardial biopsy sample (R = 0.677; p = 0.022). Pre-operative neutrophil response to in vitro stimuli predicted the rejection grade in the first post-transplant endomyocardial biopsy specimen, suggesting that neutrophils may contribute more to cardiac allograft rejection than previously thought.

Human Cardiac Stem Cell Therapy for Heart Failure

Although human cardiac stem cell transplantation had functional benefits in the recovery in experimental myocardial infarction, the major barrier limiting its clinical application is the death of the most of the transplanted cells and poor cardiac differentiation in the host environment. Using the identical technique as clonally cell isolation from experimental animals, we generated human cardiosphere-derived cell (hCDC) enriched Es-marker genes with mesenchymal features, which were obtained from cardiac endomyocardial biopsy samples.

Effects of Angiotensin-Converting Enzyme Inhibitor Versus Valsartan on Cellular Signaling Events in Heart Transplant

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) provide similar biologic effects in model systems and similar clinical impacts in humans. The changes in the cardiac angiotensin system signaling pathways in the human heart in response to ACE inhibitors versus ARBs have been incompletely studied. To investigate the effects of ACE inhibitors versus valsartan on the angiotensin II signal transduction pathways in the transplanted human heart. Twenty-seven stable cardiac transplant recipients were randomized to remain on ACE inhibitor therapy (n = 8) or to receive valsartan (n = 19). Two additional endomyocardial biopsy samples were obtained at baseline and after 9 months of therapy. The expression of cardiac angiotensin type I and II receptors and atrial natriuretic factor (ANF) was measured by quantitative polymerase chain reaction. The expression and phosphorylation levels of selected signal transduction pathways were analyzed by immunoblotting. The mean dose of valsartan was 114 +/- 41 mg/day. The use of valsartan resulted in a similar impact on blood pressure and biochemistry profile. There were no significant changes in the expression of angiotensin type I and II receptors and ANF with valsartan. Similarly, no significant changes in the expression and phosphorylation of Jun N-terminal kinase, extracellular signal-regulated kinase 1 and 2, and p38 mitogen-activated protein kinases or AKT, and mammalian target of rapamycin was observed in the valsartan-treated group. Valsartan use is associated with similar clinical and molecular cardiac effects as ACE inhibitor therapy in stable long-term cardiac transplant recipients.

Vascular abnormalities and cardiomyocyte lipofuscin deposits in endomyocardial biopsy specimens of heart transplant recipients: Are they related to the development of cardiac allograft vasculopathy?

The aim of this study was to assess the predictive value of microvascular abnormalities and lipofuscin observed in endomyocardial biopsy samples for the development of cardiac allograft vasculopathy. The study group consisted of 68 cardiac allograft recipients (63 men and 5 women, 43 +/- 12 years old). We performed a re-evaluation of 1071 endomyocardial biopsy specimens to search for microvascular diseases and lipofuscin in cardiocytes. Endomyocardial biopsy specimens with an International Society for Heart and Lung Transplantation rejection grade of 2 or more and those without arterioles were excluded. Abnormalities found in the remaining 517 specimens were correlated with the grade of rejection. Biopsy specimens obtained 2 weeks, 12 months, and 36 months after transplantation were compared with coronary angiography results, clinical events of cardiac allograft vasculopathies, and survivals. Kaplan-Meier curves were constructed to compare the time to the development of cardiac allograft vasculopathy or death. Enlarged endothelial cells, lymphocytes inside the arteriolar wall, occluded arteriolar lumen, endothelial vacuolization, and hypertrophy of the vascular muscle were significantly correlated with rejection grade. Although none of the vascular abnormalities predicted cardiac allograft vasculopathy, patients with lipofuscin deposits at the 12-month biopsy specimens were characterized by the rapid development of angiography-confirmed cardiac allograft vasculopathy (P < .08) and events related to cardiac allograft vasculopathy (P < .03, log-rank test). Microvascular abnormalities correlate with mild cellular rejection, but they do not seem to be predictive for development of cardiac allograft vasculopathy detected by angiography. The presence of lipofuscin in 12-month endomyocardial biopsy specimens may be predictive of development of angiographically confirmed cardiac allograft vasculopathy.

Relationship between circulating levels of monocyte chemoattractant protein-1 and systolic dysfunction in patients with hypertrophic cardiomyopathy

Progression of hypertrophic cardiomyopathy (HCM) to left ventricular dilatation and systolic dysfunction sometimes occurs. However, the mechanism of the transition from hypertrophy to dysfunction has not been elucidated. It has been reported that circulating levels of monocyte chemoattractant protein-1 (MCP-1), which is a major factor promoting the accumulation of macrophages, are increased in patients with congestive heart failure. We measured circulating levels of MCP-1 in patients with HCM and examined whether MCP-1 was expressed in the myocardium of HCM patients. We also examined whether circulating levels of MCP-1 were correlated with left ventricular dysfunction. Circulating levels of MCP-1 were measured by an enzyme immunoassay in 26 patients with HCM (60+/-2 years old) and 20 control subjects (57+/-2 years old). Cardiac function was evaluated by two-dimensional echocardiography and cardiac catheterization. HCM patients had significantly elevated levels of MCP-1 (HCM: 309+/-30 vs. control: 178+/-8 pg/ml, P<.001). MCP-1 levels in patients with systolic dysfunction were significantly higher than those in patients without systolic dysfunction (P<.05) and were also significantly higher than those in patients with outflow obstruction (P<.05). Immunohistochemical analysis revealed that MCP-1 was expressed in endomyocardial biopsy samples obtained from HCM patients with systolic dysfunction. Furthermore, MCP-1 levels were inversely correlated with fractional shortening (r=-.401, P<.05) and correlated with left ventricular end-diastolic pressure (r=-.579, P<.01). These results show that MCP-1 is associated with, and might be involved in the pathogenesis of, left ventricular systolic dysfunction in patients with HCM.

A 32‐year‐old woman with arthralgias and severe hypotension

A 32‐year‐old woman with arthralgias and severe hypotension

Superoxide-Dependent Cathepsin Activation Is Associated with Hypertensive Myocardial Remodeling and Represents a Target for Angiotensin II Type 1 Receptor Blocker Treatment

The elastolytic activity of cathepsins in the myocardium is implicated in hypertensive heart failure (HF). Given that reactive oxygen species are also implicated in protease activation associated with cardiac remodeling, we examined the role of the reactive oxygen species-induced cathepsin activation system in cardiac remodeling during the development of hypertensive HF. Dahl salt-sensitive hypertensive rats maintained on a high-salt diet were treated with vehicle, the cathepsin inhibitor E64d, or the angiotensin receptor blocker olmesartan from 12 to 19 weeks of age. Cathepsin expression and activity were increased in the left ventricle of HF rats; olmesartan inhibited these effects, restored the balance between elastin and collagen in the left ventricle, and suppressed degradation of the elastic lamina of coronary arteries of HF rats. Furthermore, olmesartan inhibited up-regulation of NADPH oxidase subunits and activity as well as superoxide generation. These effects of olmesartan were mimicked by E64d and were accompanied by amelioration of cardiac fibrosis. Finally, olmesartan and apocynin reduced angiotensin II-induced increases in cathepsin mRNA and protein levels in cultured rat neonatal cardiac myocytes. These data suggest that cathepsins likely trigger and promote cardiac remodeling and that blocking the angiotensin II type 1 receptor attenuates cathepsin expression and activity by inhibiting the production of superoxide by NADPH oxidase, thereby attenuating cardiac remodeling and dysfunction.

Transcriptomic Biomarkers for Individual Risk Assessment in New-Onset Heart Failure

Prediction of prognosis remains a major unmet need in new-onset heart failure (HF). Although several clinical tests are in use, none accurately distinguish between patients with poor versus excellent survival. We hypothesized that a transcriptomic signature, generated from a single endomyocardial biopsy, could serve as a novel prognostic biomarker in HF. Endomyocardial biopsy samples and clinical data were collected from all patients presenting with new-onset HF from 1997 to 2006. Among a total of 350 endomyocardial biopsy samples, 180 were identified as idiopathic dilated cardiomyopathy. Patients with phenotypic extremes in survival were selected: good prognosis (event-free survival for at least 5 years; n=25) and poor prognosis (events [death, requirement for left ventricular assist device, or cardiac transplant] within the first 2 years of presentation with HF symptoms; n=18). We used human U133 Plus 2.0 microarrays (Affymetrix) and analyzed the data with significance analysis of microarrays and prediction analysis of microarrays. We identified 46 overexpressed genes in patients with good versus poor prognosis, of which 45 genes were selected by prediction analysis of microarrays for prediction of prognosis in a train set (n=29) with subsequent validation in test sets (n=14 each). The biomarker performed with 74% sensitivity (95% CI 69% to 79%) and 90% specificity (95% CI 87% to 93%) after 50 random partitions. These findings suggest the potential of transcriptomic biomarkers to predict prognosis in patients with new-onset HF from a single endomyocardial biopsy sample. In addition, our findings offer potential novel therapeutic targets for HF and cardiomyopathy.

Association of device surface and biomaterials with immunologic sensitization after mechanical support

Biomaterials and textured surfaces in early pulsatile left ventricular assist devices (HeartMate I; Thoratec Corporation, Pleasanton, Calif) may increase immunologic risk through allosensitization. We hypothesized that axial-flow devices without biologic membranes or textured surfaces (HeartMate II; Thoratec; and DeBakey; MicroMed Cardiovascular, Inc, Houston, Tex) would cause less allosensitization than devices with such membranes and surfaces. HeartMate II and DeBakey (n = 24) and HeartMate I (n = 36) devices were implanted from 1999 to 2006 in patients with severe heart failure cohort-matched for age, etiology, and support duration. Serum samples reacting with more than 10% of the HLA reference panel were considered positive for anti-HLA antibodies. Endomyocardial biopsy samples were collected after transplant. There were no significant cohort differences in age, etiology, sex, blood transfusion, or support duration. Anti-HLA antibodies were not detected at implantation of either HeartMate II and DeBakey or HeartMate I devices; however, significant increases in anti-HLA antibodies were present within 1 and 3 months of support with HeartMate I but not HeartMate II and DeBakey devices. Overall, fewer patients with HeartMate II and DeBakey devices demonstrated positive anti-HLA antibodies during support (8% vs 28%, P = .02), and fewer episodes of acute rejection per patient were seen within the first 9 posttransplant months(0.31 vs 0.69, P = .052). Long-term posttransplant survival was not different between groups. Hemodynamic support with HeartMate II and DeBakey devices produced less allosensitization than did HeartMate I devices. Device selection may improve clinical outcomes for high-risk patients.

Myofilament Degradation and Dysfunction of Human Cardiomyocytes in Fabry Disease

Early detection of myocardial dysfunction in Fabry disease (FD) cardiomyopathy suggests the contribution of myofilament structural alterations. Six males with untreated FD cardiomyopathy submitted to cardiac studies, including tissue Doppler imaging and left ventricular endomyocardial biopsy. Active and resting tensions before and after treatment with protein kinase A (PKA) were determined in isolated Triton-permeabilized cardiomyocytes. Cardiomyocyte cross-sectional area, glycosphingolipid vacuole area, myofibrillolysis, and extent of fibrosis were also determined. Biopsies of mitral stenosis in patients with normal left ventricles served as controls. Active tension was four times lower in FD cardiomyocytes and correlated with extent of myofibrillolysis. Resting tension was six times higher in FD cardiomyocytes than in controls. PKA treatment decreased resting tension but did not affect active force. Protein analysis revealed troponin I and desmin degradation products. FD cardiomyocytes were significantly larger and filled with glycosphingolipids. Fibrosis was mildly increased compared with controls. Tissue Doppler imaging lengthening and shortening velocities were reduced in FD cardiomyocytes compared with controls, correlating with resting and active tensions, respectively, but not with cardiomyocyte area, percentage of glycosphingolipids, or extent of fibrosis. In conclusion, myofilament degradation and dysfunction contribute to FD cardiomyopathy. Partial reversal of high resting tension after pharmacological PKA treatment of cardiomyocytes suggests potential benefits from enzyme replacement therapy and/or energy-releasing agents.

Obliteration of cardiomyocyte nuclear architecture in a patient with LMNA gene mutation

The aim of our study was to perform an immunohistochemical and ultrastructural analysis of the nuclear architecture of cardiomyocytes from an end-stage DCM patient with a missense point mutation in the exon 3 of the LMNA gene which is predicted to result in a D192G substitution. We studied endomyocardial biopsy samples taken from the right ventricle by immunostaining using antibodies against the lamins A and C and by electron microscopy. The cardiomyocyte ultrastructure was analysed, with particular attention to the nuclear architecture. Thirty percent of cardiomyocyte nuclei from the D192G carrier showed chromatin disorganization and a changed nuclear shape. The most surprising finding was the appearance of sarcoplasmic organelles within the nuclear matrix of well enveloped nuclei. To our knowledge, this intriguing phenomenon was observed for the first time in cardiomyocytes. The study documents that D192G mutation in LMNA gene may lead to the disruption of the nuclear wall in cardiomyocytes, thus supporting the mechanical hypothesis of dilated cardiomyopathy development in humans, which might be mutation-specific.

Characterization of C4d Immunostaining Utilizing Paraffin-Embedded Tissue of Nonpresensitized Pediatric Heart Transplant Patients

Immunoperoxidase techniques for demonstration of complement split product C4d on paraffin-embedded endomyocardial biopsy samples have been used for the evaluation of humoral rejection mainly in adult heart transplantation. Interpretation of suspected humoral rejection in children requires knowledge of the pattern and frequency of C4d deposition in nonpresensitized pediatric heart transplantation patients. Paraffin-embedded endomyocardial biopsy samples of 65 patients with no rejection, acute cellular rejection (ACR), or early ischemic/reperfusion injury were studied. Six biopsies within each grade of ACR both early (<6 months) and late (>6 months) after heart transplantation were reviewed, as were 5 biopsies of ischemic/reperfusion injury. None of the subjects was sensitized prior to transplant. All slides were blindly evaluated for histologic features traditionally associated with humoral rejection. C4d staining was quantified by counting the number of positive capillaries in 10 random high-power fields (hpf). C4d positivity (C4d+) was defined as >10 capillaries/10 hpf. C4d+ was observed in 6 (9%) endomyocardial biopsy samples; 2 in the early and 4 in the late ACR groups. Four had ACR grades 1A/B, and 2 had grade 3B/4. Thirteen (20%) endomyocardial biopsy samples had histologic features suggestive of humoral rejection. Of these, only 2 were C4d+ and both had ACR grade 3B/4. No C4d+ staining was found in the ischemic/reperfusion injury group. C4d immunostaining was negative in endomyocardial biopsy samples of the majority of our patients (91%). Endomyocardial biopsy samples with C4d+ did not show consistent ACR grade or time specificity. Contrary to previously reported data, none of the ischemic/reperfusion injury endomyocardial biopsy samples was C4d+, and histologic features alone were poor predictors of C4d+.

Mechanical dyssynchrony: another mechanism of left ventricular dysfunction in hypertension?

Mechanical dyssynchrony: another mechanism of left ventricular dysfunction in hypertension?

Clinical Summaries

Clinical Summaries

Diastolic Stiffness of the Failing Diabetic Heart

Excessive diastolic left ventricular stiffness is an important contributor to heart failure in patients with diabetes mellitus. Diabetes is presumed to increase stiffness through myocardial deposition of collagen and advanced glycation end products (AGEs). Cardiomyocyte resting tension also elevates stiffness, especially in heart failure with normal left ventricular ejection fraction (LVEF). The contribution to diastolic stiffness of fibrosis, AGEs, and cardiomyocyte resting tension was assessed in diabetic heart failure patients with normal or reduced LVEF. Left ventricular endomyocardial biopsy samples were procured in 28 patients with normal LVEF and 36 patients with reduced LVEF, all without coronary artery disease. Sixteen patients with normal LVEF and 10 with reduced LVEF had diabetes mellitus. Biopsy samples were used for quantification of collagen and AGEs and for isolation of cardiomyocytes to measure resting tension. Diabetic heart failure patients had higher diastolic left ventricular stiffness irrespective of LVEF. Diabetes mellitus increased the myocardial collagen volume fraction only in patients with reduced LVEF (from 14.6+/-1.0% to 22.4+/-2.2%, P<0.001) and increased cardiomyocyte resting tension only in patients with normal LVEF (from 5.1+/-0.7 to 8.5+/-0.9 kN/m2, P=0.006). Diabetes increased myocardial AGE deposition in patients with reduced LVEF (from 8.8+/-2.5 to 24.1+/-3.8 score/mm2; P=0.005) and less so in patients with normal LVEF (from 8.2+/-2.5 to 15.7+/-2.7 score/mm2, P=NS). Mechanisms responsible for the increased diastolic stiffness of the diabetic heart differ in heart failure with reduced and normal LVEF: Fibrosis and AGEs are more important when LVEF is reduced, whereas cardiomyocyte resting tension is more important when LVEF is normal.

Diagnosis and treatment of myocarditis: The role of endomyocardial biopsy

Viral infections often affect the heart. In the majority of cases, the course of the disease is benign and patients recover spontaneously. However, viral infection may persist and lead to acute cardiac failure or progress to dilated cardiomyopathy. Viral infections are considered to be the most common causes of myocarditis. There is evidence that intramyocardial viral persistence is associated with progressive ventricular dysfunction, even when the infiltrate is sparse or missing. The diagnosis of viral myocarditis necessitates the detection of viral genome by molecular biology techniques and the evaluation of myocardial inflammation by the immunohistochemistry on endomyocardial biopsy samples. Autoreactive myocarditis can also only be diagnosed by endomyocardial biopsy. Infiltration of leukocytes and a negative polymerase chain reaction on microbial agents are their hallmarks. Apart from symptomatic or supportive therapy, etiologic treatment strategies have to address the underlying causative virus or the autoimmune process. In symptomatic or deteriorating patients, targeted antiviral therapy is a reasonable algorithm to eradicate the virus, which will contribute to resolving inflammation or apoptosis, thus confining myocardial damage. The Marburg registry favors intravenous immunoglobulin treatment in biopsy-proven adenovirus and parvovirus B19 myocarditis combined with optimal conventional therapy to achieve virus clearance. In fulminant myocarditis, biopsy is mandatory to identify giant cell myocarditis and cardiac sarcoidosis to be treated by immunosuppression. In cardiogenic shock, the use of mechanical circulatory support by means of a ventricular assist device as a bridge to recovery may be a lifesaving approach. In perimyocarditis with dominant pericardial affection, colchicine over a period of 1 to 6 months can dissolve the pericardial effusion effectively in more than 80% of cases.

Abstract 1753: Transcriptomic based Biomarkers Contain Diagnostic and Prognostic Information about Patients with new onset Heart Failure

INTRODUCTION: One of the clinical dilemmas in cardiology is to accurately diagnose the etiology of patients with new onset heart failure such as to differentiate between potentially reversible myocarditis from idiopathic dilated cardiomyopathy (IDCM). Furthermore, it is difficult to predict the clinical trajectory of patients with IDCM. We hypothesized that the transcriptomic signatures generated from endomyocardial biopsies, obtained from patients at first presentation of heart failure, could serve as novel biomarkers to distinguish between myocarditis and IDCM as well as to predict the prognosis of patients classified as having IDCM. METHODS AND RESULTS: Endomyocardial biopsy samples were collected from 68 patients with new onset heart failure due to IDCM (n=49) and myocarditis (n=19). The average follow-up was 5 years and included information on mortality, need for left ventricular assist device (LVAD), or heart transplant. We used the U133 Plus 2.0 microarray (Affymetrix) and data analysis was performed with Significance Analysis of Microarrays (SAM) and Prediction Analysis of Microarrays (PAM). First, we identified a molecular signature of 39 genes in our training cohort (n=25 IDCM and n=8 myocarditis). When tested in independent patients (myocarditis: n=11; IDCM: n=11), this signature performed with 97% accuracy. Next, we identified a transcriptomic signature of 45 genes in a group of patients with IDCM that delineated between patients classified as having a good prognosis (event free survival &gt; 5 years; n=18) vs a bad prognosis (death or requirement for insertion of LVAD or tx within 2 years of presentation; n=12). We tested this biomarker in independent samples and were able to predict prognosis with 87% accuracy. The transcriptomic biomarker was substantially more accurate in assigning prognosis than the Seattle Heart Failure Score (p=0.011). CONCLUSION: Together these findings illustrate the potential utility of using transcriptomic biomarkers generated from a single endomyocardial biopsy to improve the accuracy of diagnosis and prognosis in patients with new onset heart failure. This creates novel modalities to enhance management and identification of patients at highest risk for complications of heart failure in the short term.