Many heart transplant biopsies currently diagnosed as no rejection have mild molecular antibody-mediated rejection-related changes

[Abstract] Background: The Molecular Microscope (MMDx) system classifies heart transplant endomyocardial biopsies as No-rejection (NR), Early-injury, T cell-mediated (TCMR), antibody-mediated (ABMR), mixed, and possible rejection (possible TCMR, possible ABMR). Rejection-like gene expression patterns in NR biopsies have not been described. We extended the MMDx methodology, using a larger data set, to define a new "Minor" category characterized by low-level inflammation in non-rejecting biopsies. Methods: Using MMDx criteria from a previous study, molecular rejection was assessed in 1,320 biopsies (645 patients) using microarray expression of rejection-associated transcripts (RATs). Of these biopsies, 819 were NR. A new archetypal analysis model in the 1,320 data set split the NRs into NR-Normal (N = 462) and NR-Minor (N = 359). Results: Compared to NR-Normal, NR-Minor were more often histologic TCMR1R, with a higher prevalence of donor-specific antibody (DSA). DSA positivity increased in a gradient: NR-Normal 24%; NR-Minor 34%; possible ABMR 42%; ABMR 66%. The top 20 transcripts distinguishing NR-Minor from NR-Normal were all ABMR-related and/or IFNG-inducible, and also exhibited a gradient of increasing expression from NR-Normal through ABMR. In random forest analysis, TCMR and Early-injury were associated with reduced LVEF and increased graft loss, but NR-Minor and ABMR scores were not. Surprisingly, hearts with MMDx ABMR showed comparatively little graft loss. Conclusions: Many heart transplants currently diagnosed as NR by histologic or molecular assessment have minor increases in ABMR-related and IFNG-inducible transcripts, associated with DSA positivity and mild histologic inflammation. These results suggest that low-level ABMR-related molecular stress may be operating in many more hearts than previously estimated

Molecular states associated with dysfunction and graft loss in heart transplants

[Abstract] Background: We explored the changes in gene expression correlating with dysfunction and graft failure in endomyocardial biopsies. Methods: Genome-wide microarrays (19,462 genes) were used to define mRNA changes correlating with dysfunction (left ventricular ejection fraction [LVEF] ≤ 55) and risk of graft loss within 3 years postbiopsy. LVEF data was available for 1,013 biopsies and survival data for 779 patients (74 losses). Molecular classifiers were built for predicting dysfunction (LVEF ≤ 55) and postbiopsy 3-year survival. Results: Dysfunction is correlated with dedifferentiation-decreased expression of normal heart transcripts, for example, solute carriers, along with increased expression of inflammation genes. Many genes with reduced expression in dysfunction were matrix genes such as fibulin 1 and decorin. Gene ontology (GO) categories suggested matrix remodeling and inflammation, not rejection. Genes associated with the risk of failure postbiopsy overlapped dysfunction genes but also included genes affecting microcirculation, for example, arginase 2, which reduces NO production, and endothelin 1. GO terms also reflected increased glycolysis and response to hypoxia, but decreased VEGF and angiogenesis pathways. T cell-mediated rejection was associated with reduced survival and antibody-mediated rejection with relatively good survival, but the main determinants of survival were features of parenchymal injury. Both dysfunction and graft loss were correlated with increased biopsy expression of BNP (gene NPPB). Survival probability classifiers divided hearts into risk quintiles, with actuarial 3-year postbiopsy survival >95% for the highest versus 50% for the lowest. Conclusions: Dysfunction in transplanted hearts reflects dedifferentiation, decreased matrix genes, injury, and inflammation. The risk of short-term loss includes these changes but is also associated with microcirculation abnormalities, glycolysis, and response to hypoxia

Redefining the molecular rejection states in 3230 heart transplant biopsies: relationships to parenchymal injury and graft survival

[Abstract] The first-generation Molecular Microscope (MMDx) system for heart transplant endomyocardial biopsies used expression of rejection-associated transcripts (RATs) to diagnose not only T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR) but also acute injury. However, the ideal system should detect rejection without being influenced by injury, to permit analysis of the relationship between rejection and parenchymal injury. To achieve this, we developed a new rejection classification in an expanded cohort of 3230 biopsies: 1641 from INTERHEART (ClinicalTrials.gov NCT02670408), plus 1589 service biopsies added to improve the power of the machine learning algorithms. The new system used 6 rejection classifiers instead of RATs and generated 7 rejection archetypes: No rejection, 48%; Minor, 24%; TCMR1, 2.3%; TCMR2, 2.7%; TCMR/mixed, 2.7%; early-stage ABMR, 3.9%; and fully developed ABMR, 16%. Using rejection classifiers eliminated cross-reactions with acute injury, permitting separate assessment of rejection and injury. TCMR was associated with severe-recent injury and late atrophy-fibrosis and rarely had normal parenchyma. ABMR was better tolerated, seldom producing severe injury, but in later biopsies was often associated with atrophy-fibrosis, indicating long-term risk. Graft survival and left ventricular ejection fraction were reduced not only in hearts with TCMR but also in hearts with severe-recent injury and atrophy-fibrosis, even without rejection

Emerging pharmacologic and structural therapies for hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy is the most common inherited heart disease. Although it was first described over 50 years ago, there has been little in the way of novel disease-specific therapeutic development for these patients. Current treatment practice largely aims at symptomatic control using old drugs made for other diseases and does little to modify the disease course. Septal reduction by surgical myectomy or percutaneous alcohol septal ablation are well-established treatments for pharmacologic-refractory left ventricular outflow tract obstruction in hypertrophic cardiomyopathy patients. In recent years, there has been a relative surge in the development of innovative therapeutics, which aim to target the complex molecular pathophysiology and resulting hemodynamics that underlie hypertrophic cardiomyopathy. Herein, we review the new and emerging therapeutics for hypertrophic cardiomyopathy, which include pharmacologic attenuation of sarcomeric calcium sensitivity, allosteric inhibition of cardiac myosin, myocardial metabolic modulation, and renin-angiotensin-aldosterone system inhibition, as well as structural intervention by percutaneous mitral valve plication and endocardial radiofrequency ablation of septal hypertrophy. In conclusion, while further development of these therapeutic strategies is ongoing, they each mark a significant and promising advancement in treatment for hypertrophic cardiomyopathy patients

Emerging pharmacologic and structural therapies for hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy is the most common inherited heart disease. Although it was first described over 50 years ago, there has been little in the way of novel disease-specific therapeutic development for these patients. Current treatment practice largely aims at symptomatic control using old drugs made for other diseases and does little to modify the disease course. Septal reduction by surgical myectomy or percutaneous alcohol septal ablation are well-established treatments for pharmacologic-refractory left ventricular outflow tract obstruction in hypertrophic cardiomyopathy patients. In recent years, there has been a relative surge in the development of innovative therapeutics, which aim to target the complex molecular pathophysiology and resulting hemodynamics that underlie hypertrophic cardiomyopathy. Herein, we review the new and emerging therapeutics for hypertrophic cardiomyopathy, which include pharmacologic attenuation of sarcomeric calcium sensitivity, allosteric inhibition of cardiac myosin, myocardial metabolic modulation, and renin-angiotensin-aldosterone system inhibition, as well as structural intervention by percutaneous mitral valve plication and endocardial radiofrequency ablation of septal hypertrophy. In conclusion, while further development of these therapeutic strategies is ongoing, they each mark a significant and promising advancement in treatment for hypertrophic cardiomyopathy patients

Algorithm for Treatment of Advanced Heart Failure

Heart failure is a growing epidemic worldwide that confers a substantial medical and economic burden on our society. With the aging population and the improved treatment strategies made available over the last several decades including neurohormonal blockade, cardiac resynchronization, and multidisciplinary psychosocial interventions, the prevalence of advanced heart failure is increasing as patients with heart failure are living longer with parallel progression of their disease state. Judicious risk stratification and cautious patient selection are paramount in guiding appropriate therapies. It is imperative to understand the underlying pathophysiology, decision-making strategies, pharmacologic therapies, and comprehensive options in managing advanced heart failure. For patients who exhaust the widely available medical and surgical therapies, then additional algorithms and multidisciplinary decision teams must be in place for consideration of cardiac transplant or mechanical circulatory support device in this subcohort of advanced, end-stage heart failure

Cardiac Amyloidosis: Diagnosis and Treatment Strategies.

Cardiac amyloidosis in the United States is most often due to myocardial infiltration by immunoglobulin protein, such as in AL amyloidosis, or by the protein transthyretin, such as in hereditary and senile amyloidosis. Cardiac amyloidosis often portends a poor prognosis especially in patients with systemic AL amyloidosis. Despite better understanding of the pathophysiology of amyloid, many patients are still diagnosed late in the disease course. This review investigates the current understanding and new research on the diagnosis and treatment strategies in patients with cardiac amyloidosis. Myocardial amyloid infiltration distribution occurs in a variety of patterns. Structural and functional changes on echocardiography can suggest presence of amyloid, but CMR and nuclear imaging provide important complementary information on amyloid burden and the amyloid subtype, respectively. While for AL amyloid, treatment success largely depends on early diagnosis, for ATTR amyloid, new investigational agents that reduce production of transthyretin protein may have significant impact on clinical outcomes. Advancements in the non-invasive diagnostic detection and improvements in early disease recognition will undoubtedly facilitate a larger proportion of patients to receive early therapy when it is most effective

Cardiac Amyloidosis: Diagnosis and Treatment Strategies.

Cardiac amyloidosis in the United States is most often due to myocardial infiltration by immunoglobulin protein, such as in AL amyloidosis, or by the protein transthyretin, such as in hereditary and senile amyloidosis. Cardiac amyloidosis often portends a poor prognosis especially in patients with systemic AL amyloidosis. Despite better understanding of the pathophysiology of amyloid, many patients are still diagnosed late in the disease course. This review investigates the current understanding and new research on the diagnosis and treatment strategies in patients with cardiac amyloidosis. Myocardial amyloid infiltration distribution occurs in a variety of patterns. Structural and functional changes on echocardiography can suggest presence of amyloid, but CMR and nuclear imaging provide important complementary information on amyloid burden and the amyloid subtype, respectively. While for AL amyloid, treatment success largely depends on early diagnosis, for ATTR amyloid, new investigational agents that reduce production of transthyretin protein may have significant impact on clinical outcomes. Advancements in the non-invasive diagnostic detection and improvements in early disease recognition will undoubtedly facilitate a larger proportion of patients to receive early therapy when it is most effective

Heart Failure Therapies for End-Stage Chemotherapy-Induced Cardiomyopathy.

With ongoing advancements in cancer-related treatments, the number of cancer survivors continues to grow globally, with numbers in the United States predicted to reach 18 million by 2020. As a result, it is expected that a greater number of patients will present with chemotherapy-related side effects. One entity in particular, chemotherapy-related cardiomyopathy (CCMP), is a known cardiotoxic manifestation associated with agents such as anthracyclines, trastuzumab, and tyrosine kinase inhibitors. Although such effects have been described in the medical literature for decades, concrete strategies for screening, prevention, and management of CCMP continue to be elusive owing to limited studies. Late recognition of CCMP is associated with a poorer prognosis, including a lack of clinical response to pharmacologic therapy, and end-stage heart failure. A number of advanced cardiac therapies, including cardiac resynchronization therapy, ventricular assist devices, and orthotopic cardiac transplantation, are available to for end-stage heart failure; however, the role of these therapies in CCMP is unclear. In this review, management of end-stage CCMP with the use of advanced therapies and their respective effectiveness are discussed, as well as clinical characteristics of patients undergoing these treatments. The relative paucity of data in this field highlights the importance and need for larger-scale longitudinal studies and long-term registries tracking the outcomes of cancer survivors who have received cardiotoxic cancer therapy to determine the overall incidence of end-stage CCMP, as well as prognostic factors that will ultimately guide such patients toward receiving appropriate end-stage care