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.
Studies of the clinical prevalence of hypertrophic cardiomyopathy indicate that clinical recognition of disease may occur earlier in men than women.1,5,6 Although no race or nationality is ...overrepresented, variable phenotypes have long been appreciated. Because of a relative prevalence of apical hypertrophic cardiomyopathy among East Asian populations, apical involvement is occasionally referred to as Japanese hypertrophic cardiomyopathy. However, the skew of prevalence of phenotypes is mild, making the use of this term misguided.7-9 Hypertrophic cardiomyopathy has been most extensively studied in white populations with associated genetic subtypes best appreciated in this population. The normal cardiac phenotype may differ among races. Recognition of electrocardiographic abnormalities (Q waves, T-wave inversion) in apparently healthy black athletes may cause diagnostic uncertainty.10 The availability of genetic testing with a reasonable signal-to-noise ratio enables the identification of genotype-positive, phenotype-negative individuals. Although the genes associated with hypertrophic cardiomyopathy are well described, the pathways that lead from gene mutation to hypertrophy, restrictive physiology, and atrial and ventricular arrhythmias remain incompletely understood. Those with a positive genotype, but who do not meet diagnostic criteria, should not be considered to have hypertrophic cardiomyopathy, because clinical issues that are important in phenotypically positive disease (e.g., restriction from competitive sports) are considerably less relevant in this population.16,17 Variable penetrance and expressivity mean that we cannot reliably predict the clinical course for genotypepositive, phenotype-negative individuals based on the clinical histories of members of the same family who have hypertrophic cardiomyopathy. The phenotype of hypertrophic cardiomyopathy overlaps with that of normal individuals who are elite athletes18,19 and with that of some black individuals with mild hypertension.10 Additionally, phenocopies of hypertrophic cardiomyopathy (e.g., Fabry disease,20 Friedrich ataxia,21 Noonan syndrome,22 cardiac specific glycogen storage disease23) can closely mimic the classic phenotypes of this disease. Phenocopy identification is critically important because management strategies may differ and potentially change the disease course (i.e., use of replacement therapy with agalsidase α or β in Fabry disease).24 The unique clinical manifestations of these phenocopies that may aid in the differentiation from classic hypertrophic cardiomyopathy are outlined in Appendix 2 (available at www .cmaj.ca /lookup /suppl /doi :10.1503/cmaj.120138 /- /DC1). Although the presence of such diverse phenotypes in the general population can make the identification of classic hypertrophic cardiomyopathy difficult, genetic testing can help to differentiate this disease from other subtypes of pathologic ventricular hypertrophy.
We explored the changes in gene expression correlating with dysfunction and graft failure in endomyocardial biopsies.
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.
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.
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.
The heart transplantation policy change (PC) has improved outcomes in high‐acuity (Old 1A, New 1–3) patients, but the effect on low‐priority (Old 1B/2, New 4–6) patients is unknown. We sought to ...determine if low‐priority patient outcomes were compromised by benefits to high‐priority patients by evaluating for interaction between PC and priority status (PS). We included adult first‐time heart transplant candidates and recipients from the UNOS registry during a 19‐month period before and after the PC. We compared clinical characteristics and performed competing risks and survival analyses stratified by PC and PS. There was a dependence of PC and PS on waitlist death/deterioration with an interaction sub‐distribution hazard ratio (adjusted sdHR) of 0.59 (0.45–0.78), p‐value < .001. There was a trend toward a benefit of PC on waitlist death/deterioration (adjusted sdHR: 0.86 0.73–1.01; p = .07) and an increase in heart transplantation (adjusted sdHR: 1.08 1.02–1.14, p = .007) for low‐priority patients. There was no difference in 1‐year post‐transplant survival (log‐rank p = .22) when stratifying by PC and PS. PC did not negatively affect waitlisted or transplanted low‐priority patients. High‐priority, post‐PC patients had a targeted reduction in waitlist death/deterioration and did not come at the expense of worse post‐transplant survival.
The updated heart allocation policy is associated with improved waitlist outcomes in high‐acuity patients, no significant difference in waitlist outcomes for low‐acuity patients, and no change in one‐year post‐transplant survival.
The 2018 United Network for Organ Sharing (UNOS) heart transplant policy change (PC) sought to improve waitlist risk stratification to decrease waitlist mortality and promote geographically broader ...sharing for high-acuity patients awaiting heart transplantation. Our analysis sought to determine the effect of the UNOS PC on outcomes in patients waiting for, or who have received, a heart-kidney transplantation.
We analyzed adult (≥18 years old), first-time, heart-only and heart-kidney transplant candidates and recipients from the UNOS Registry. Patients were divided into pre-PC (PRE: October 18, 2016-May 30, 2018) and post-PC (POST: October 18, 2018-May 30, 2020) groups for comparison. Competing risks analysis (subdistribution and cause-specific hazards analyses) was performed to assess for differences in waitlist death/deterioration or heart transplantation. One-year post-transplant survival was assessed with Kaplan-Meier and Cox analyses. We included an interaction term (policy era × heart ± kidney) in our analyses to evaluate the effect of PC on outcomes in heart-kidney patients.
One-year post-transplant survival was similar (p = 0.83) for PRE heart-kidney and heart-only recipients, but worse (p < 0.001) for POST heart-kidney vs heart-only recipients. There was a policy-era interaction between heart-kidney and heart-only recipients (HR 1.921.04,3.55, p = 0.038) indicating a detrimental effect of policy on 1-year survival in POST vs PRE heart-kidney recipients. No added beneficial effect of PC on waitlist outcomes in heart-kidney vs heart-only candidates was observed.
There was no added policy-era benefit on waitlist outcomes for heart-kidney candidates when compared to heart-only candidates. POST heart-kidney recipients experienced worse 1-year survival compared to PRE heart-kidney recipients with no policy effect on heart-only recipients.
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.
Highlights • The incidence of chemotherapy induced cardiomyopathy (CCMP) will rise with an increasing cancer survivor population. • Limited studies of beta blockers and angiotensin converting enzyme ...inhibitor agents have suggested benefit in CCMP. • Small studies have shown benefit of cardiac resynchronization therapy in CCMP who meet guideline based indications. • CCMP patients requiring left ventricular assist device therapy have a higher incidence of right ventricular dysfunction. • CCMP patients undergoing orthotopic heart transplantation have similar survival outcomes compared to other nonischemic controls.
Background
As the population of patients with a Fontan palliation grows so does, the number of patients with cardiac failure necessitating orthotopic heart transplant (OHT) and combined heart–liver ...transplant (CHLT). There is recent evidence that current era cardiac transplant in Fontan patients has improved outcomes, but most studies have a preponderance of pediatrics patients in their cohorts. We examine our institutional experience with adult OHT and CHLT transplantation for failed Fontan physiology.
Methods and Results
Retrospective analysis of patients at the Ahmanson/UCLA Adult Congenital Heart Disease Center who underwent OHT or CHLT for failing Fontan physiology from January 1, 2002 to May 31, 2017. We identified 20 patients with single‐ventricle physiology and Fontan palliation who underwent OHT or CHLT. The median age was 29.5 years (range 19‐44). Five patients underwent CHLT because of biopsy proven hepatic cirrhosis. The median length of hospital stay was 23 days (range 8‐76) post‐OHT and 51 days (range 26‐77) post‐CHLT. During a median follow‐up of 56 months (range 2‐178), there was one mortality occurring at 34 months post‐OHT due to coronary vasculopathy. Most frequent early postoperative complications included bleeding and infection (55% and 20%, respectively) and surgical reintervention for bleeding complications (n = 8, 40%). One CHLT patient experienced clinically significant hepatic rejection requiring admission and steroid treatment.
Conclusions
Despite inherent risks and complexities of OHT or CHLT in patients with a failed Fontan, transplant is a reasonable therapy. Peri‐ and postoperative complications are common and may require surgical reintervention. Continued observation of practices and unifying themes may help improve patient selection, pre‐ and postoperative treatment and ultimately outcomes.
Important developments have occurred during the past 2 years in the field of heart transplantation. These include refinements in donor management, preservation, and allocation, and evaluation of ...immunosuppression strategies for rejection and for allograft vascular disease. Finally, long-term outcomes addressing areas of significant morbidity for patients, including renal dysfunction and cancer, have seen important advances. This contemporary review will highlight the key articles for 2012 to 2013.
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