Don't judge a book by its cover: a case report of apolipoprotein A-IV cardiac amyloidosis.

Background: To date, at least 20 different amyloidogenic proteins have been documented. Growing evidence suggests that despite being part of the universal amyloid proteome, apolipoprotein A-IV can be amyloidogenic, accounting for less than 1% of cases. Case summary: A 75-year-old woman was admitted for paroxysmal nocturnal dyspnoea and intermittent exertional shortness of breath and was found to be in acute heart failure. The patient underwent intravenous diuretic therapy and was discharged after decongestion. She then underwent a battery of outpatient tests to determine aetiology of her heart failure. Cardiac magnetic resonance imaging showed severe concentric left ventricular hypertrophy and diffuse late gadolinium enhancement, concerning for amyloidosis, but serologic evaluation for amyloidogenic light chain (AL) amyloidosis was negative. Tc 99m pyrophosphate (PYP) scan showed Grade 2 uptake at 1 h that was only moderately suggestive of transthyretin (TTR) amyloidosis. She ultimately received a right heart catheterization and endomyocardial biopsy, which showed apolipoprotein A-IV amyloid deposition within Congo red-positive areas of the endomyocardial specimen. The patient continues to report dyspnoea on exertion but has avoided additional heart failure admissions with intensification of her diuretic regimen. Discussion: In this case, nuclear PYP scan to evaluate for TTR amyloidosis demonstrated focal PYP uptake, but endomyocardial biopsy demonstrated apolipoprotein A-IV deposition without evidence of TTR amyloidosis. Our case increases knowledge of this rare form of amyloidosis, suggests that it may result in false positive nuclear PYP results, and highlights the importance of its evaluation, particularly in circumstances in which investigations do not reveal definitive evidence of AL or TTR amyloidosis.

Coronary artery disease and revascularization associated with immune checkpoint blocker myocarditis: Report from an international registry.

PURPOSE: Immune checkpoint blocker (ICB) associated myocarditis (ICB-myocarditis) may present similarly and/or overlap with other cardiac pathology including acute coronary syndrome presenting a challenge for prompt clinical diagnosis. METHODS: An international registry was used to retrospectively identify cases of ICB-myocarditis. Presence of coronary artery disease (CAD) was defined as coronary artery stenosis >70% in patients undergoing coronary angiogram. RESULTS: Among 261 patients with clinically suspected ICB-myocarditis who underwent a coronary angiography, CAD was present in 59/261 patients (22.6%). Coronary revascularization was performed during the index hospitalisation in 19/59 (32.2%) patients. Patients undergoing coronary revascularization less frequently received steroids administration within 24 h of admission compared to the other groups (p = 0.029). Myocarditis-related 90-day mortality was 9/17 (52.7%) in the revascularised cohort, compared to 5/31 (16.1%) in those not revascularized and 25/156 (16.0%) in those without CAD (p = 0.001). Immune-related adverse event-related 90-day mortality was 9/17 (52.7%) in the revascularized cohort, compared to 6/31 (19.4%) in those not revascularized and 31/156 (19.9%) in no CAD groups (p = 0.007). All-cause 90-day mortality was 11/17 (64.7%) in the revascularized cohort, compared to 13/31 (41.9%) in no revascularization and 60/158 (38.0%) in no CAD groups (p = 0.10). After adjustment of age and sex, coronary revascularization remained associated with ICB-myocarditis-related death at 90 days (hazard ratio [HR] = 4.03, 95% confidence interval [CI] 1.84-8.84, p < 0.001) and was marginally associated with all-cause death (HR = 1.88, 95% CI, 0.98-3.61, p = 0.057). CONCLUSION: CAD may exist concomitantly with ICB-myocarditis and may portend a poorer outcome when revascularization is performed. This is potentially mediated through delayed diagnosis and treatment or more severe presentation of ICB-myocarditis.

Association of cigarette smoking and adverse events in left ventricular assist device patients.

INTRODUCTION: Adverse events (AEs) associated with left ventricular assist devices (LVADs) cause significant morbidity and mortality. Little is known about patient-specific factors that contribute to rates of AEs. The purpose of this study was to assess the association of cigarette smoking history and AEs following LVAD implantation. METHODS: This study was a single-center, observational examination of 355 consecutive patients who underwent continuous-flow LVAD implantation from May 1, 2008 to July 1, 2018. Based on self-report, 348 patients with available data were categorized as never, former, or current smokers. Pre-LVAD implantation baseline characteristics were obtained, and summary characteristics were calculated. Hospitalizations for gastrointestinal bleeds, driveline infections, strokes, pump thromboses, and acute heart failure were evaluated. The Cox proportional hazard model was used to estimate the association of smoking and AE-related hospital admissions. The cumulative incidence competing risk method was used for survival analysis. RESULTS: Current (8.22%, p 0.006) and former (4.75%, p 0.026) smokers had a greater proportion of admissions for pump thrombosis compared to never smokers (2.22%). Former smoking was associated with admission for driveline infection (HR 2.43, CI 1.08-5.46, p 0.03) on multivariate analysis. There were no significant associations between smoking and the other AEs of interest. There was no difference in survival among the three groups. CONCLUSIONS: Smokers had a higher proportion of admissions for pump thrombosis compared to never smokers, and former smoking was associated with admission for driveline infections in patients with LVADs.

Iron deficiency and supplementation in heart failure and chronic kidney disease.

Iron is a key element for normal cellular function and plays a role in many cellular processes including mitochondrial respiration. The role of iron deficiency (ID) in heart failure (HF) has been a subject of debate amid increasing advocacy for intravenous (IV) supplementation. Both the definition and the approach to treatment of ID in HF have been adapted from the experience in patients with chronic kidney disease (CKD). In this review, we highlight the differences in regulatory mechanisms as well as pathophysiology of ID in CKD and HF population both at the systemic and cellular levels. We will review the major clinical trials in HF patients that have shown symptomatic benefit from IV iron supplementation but without effect on clinical outcomes. Intravenous iron loading bypasses the mechanisms that tightly regulate iron uptake and can potentially cause myocardial and endothelial damage by releasing reactive oxygen species. By contrast, newer oral iron preparations do not have similar toxicity concerns and might have a role in heart failure.

Iron and Heart Failure: Diagnosis, Therapies, and Future Directions.

To date, 3 clinical trials have shown symptomatic benefit from the use of intravenous (IV) iron in patients with heart failure (HF) with low serum iron. This has led to recommendations in support of the use of IV iron in this population. However, the systemic and cellular mechanisms of iron homeostasis in cardiomyocyte health and disease are distinct, complex, and poorly understood. Iron metabolism in HF appears dysregulated, but it is still unclear whether the changes are maladaptive and pathologic or compensatory and protective for the cardiomyocytes. The serum markers of iron deficiency in HF do not accurately reflect cellular and mitochondrial iron levels, and the current definition based on the ferritin and transferrin saturation values is broad and inclusive of patients who do not need IV iron. This is particularly relevant in view of the potential risks that are associated with the use of IV iron. Reliable markers of cellular iron status may differentiate subgroups of HF patients who would benefit from cellular and mitochondrial iron chelation rather than IV iron.

Evaluating Biventricular Myocardial Velocity and Interventricular Dyssynchrony in Adult Patients During the First Year After Heart Transplantation.

BACKGROUND: Magnetic resonance tissue phase mapping (TPM) measures three-directional myocardial velocities of the left and right ventricle (LV, RV). This noninvasive technique may supplement endomyocardial biopsy (EMB) in monitoring grafts post-heart transplantation (HTx). PURPOSE: To assess biventricular myocardial velocity alterations in grafts and investigate the relationship between velocities and acute cellular rejection (ACR) episodes. STUDY TYPE: Prospective. SUBJECTS: Twenty-seven patients within 1 year post-HTx (49 ± 13 years, 19 M) and 18 age-matched controls (49 ± 15 years, 12 M). FIELD STRENGTH/SEQUENCE: 1.5T, 2D balanced steady-state free precession, and TPM. ASSESSMENT: Ventricular function: end-diastolic and end-systolic volumes, stroke volumes, ejection fraction (EF), and myocardial mass. TPM velocities: peak-systolic and peak-diastolic velocities, cardiac twist, and interventricular dyssynchrony. ACR rejection episodes: International Society for Heart and Lung Transplantation grading of EMB specimens. STATISTICAL TESTS: The Lilliefors test for normality, unpaired t-tests, and Wilcoxon rank-sum tests for normally and nonnormally distributed data, respectively, were used, as well as multivariate regression for confounding variables and Pearson's correlation for associations between TPM velocities and global function. RESULTS: Compared to controls, HTx patients demonstrated reduced biventricular systolic longitudinal velocities (LV: 5.2 ± 2.1 vs. 4.0 ± 1.5 cm/s, P < 0.05; RV: 4.2 ± 1.3 vs. 3.1 ± 1.2 cm/s, P < 0.01). Correlation analysis revealed significant positive relationships for biventricular EF with radial peak velocities of the same ventricle in both systole and diastole (LV systole: r = 0.48, P < 0.01; LV diastole: r = 0.28, P < 0.05; RV systole: r = 0.35, P < 0.01; RV diastole: r = 0.36, P < 0.01). Segmentally, longitudinal velocities were impaired in 7/16 LV segments and 5/10 RV segments in systole and 7/10 RV segments in diastole. TPM analysis in studies with >4 preceding ACR episodes showed globally reduced RV and LV systolic radial velocity, and segmentally reduced radial and longitudinal systolic velocities. DATA CONCLUSION: Biventricular global and segmental velocities were reduced in HTx patients. Patients with >4 rejection episodes showed reduced myocardial velocities. The TPM sequence may add functional information for monitoring graft dysfunction. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 2 J. Magn. Reson. Imaging 2020;52:920-929.

Multiparametric Cardiac Magnetic Resonance Imaging Can Detect Acute Cardiac Allograft Rejection After Heart Transplantation.

OBJECTIVES: The purpose of this study was to evaluate the sensitivity of multiparametric cardiac magnetic resonance imaging (CMR) for the detection of acute cardiac allograft rejection (ACAR). BACKGROUND: ACAR is currently diagnosed by endomyocardial biopsy, but CMR may be a noninvasive alternative because of its capacity for regional myocardial structure and function characterization. METHODS: Fifty-eight transplant recipients (mean age 47.0 ± 14.7 years) and 14 control subjects (mean age 47.7 ± 16.7 years) were prospectively recruited from August 2014 to May 2017 and underwent 97 CMR studies (83 transplant recipients, 14 control subjects) for assessment of global left ventricular function and myocardial T2, T1, and extracellular volume fraction (ECV). CMR studies were divided into 4 groups on the basis of biopsy grade: control subjects (n = 14), patients with no ACAR (no history of ACAR; n = 36), patients with past ACAR (history of ACAR; n = 24), and ACAR+ patients (active grade ≥1R ACAR; n = 23). RESULTS: Myocardial T2 was significantly higher in patients with past ACAR compared with those with no ACAR (51.0 ± 3.8 ms vs. 49.2 ± 4.0 ms; p = 0.02) and in patients with no ACAR compared with control subjects (49.2 ± 4.0 ms vs. 45.2 ± 2.3 ms; p < 0.01). ACAR+ patients demonstrated increased T2 compared with the no ACAR group (52.4 ± 4.7 ms vs. 49.2 ± 4.0 ms, p < 0.01) but not compared with the past ACAR group. In contrast, ECV was significantly elevated in ACAR+ patients compared with transplant recipients without ACAR regardless of history of ACAR (no ACAR: 31.5 ± 3.9% vs. 26.8 ± 3.3% [p < 0.01]; past ACAR: 31.5 ± 3.9% vs. 26.8 ± 4.0% [p < 0.01]). Receiver operating characteristic curve analysis revealed that a combined model of age at CMR, global T2, and global ECV was predictive of ACAR (area under the curve = 0.84). CONCLUSIONS: The combination of CMR-derived myocardial T2 and ECV has potential as a noninvasive tissue biomarker for ACAR. Larger studies during acute ACAR are needed for continued development of multiparametric CMR for transplant recipient surveillance.

Cardiac Structure-Function MRI in Patients After Heart Transplantation.

BACKGROUND: Following heart transplantation (Tx), recipients are closely monitored using endomyocardial biopsy, which is limited by cost and invasiveness, and echocardiography, which is limited regarding detailed structural and functional evaluation. PURPOSE: To test the feasibility of comprehensive structure-function cardiac MRI as a noninvasive modality to assess changes in myocardial structure and function. STUDY TYPE: Prospective. SUBJECTS: MR was performed in 61 heart transplant recipients (age 47.9 ± 16.3 years, 39% female) and 14 age-matched healthy controls (age 47.7 ± 16.7 years, 36% female). FIELD STRENGTH/SEQUENCE: 1.5T; 2D CINE steady state free precession (SSF)P imaging, T2 -mapping, pre- and postgadolinium contrast T1 -mapping, and tissue-phase mapping (TPM). ASSESSMENT: Quantification of myocardial T2 (as a measure of edema), pre- and post-Gd T1 (allowing calculation of extracellular volume (ECV) to estimate interstitial expansion), and TPM-based assessment of peak regional left ventricular (LV) velocities, dyssynchrony, and twist. STATISTICAL TESTS: Comparisons between transplant recipients and controls were performed using independent samples t-tests. Relationships between structural (T2 , T1 , ECV) and functional measures (myocardial velocities, dyssynchrony, twist) were assessed using Pearson correlation analysis. RESULTS: T2 and T1 were significantly elevated in transplant recipients compared to controls (global T2 : 50.5 ± 3.4 msec vs. 45.2 ± 2.3 msec, P < 0.01; global T1 : 1037.8 ± 48.0 msec vs. 993.8 ± 34.1 msec, P < 0.01). Systolic longitudinal function was impaired in transplant recipients compared to controls (reduced peak systolic longitudinal velocities, 2.9 ± 1.1 cm/s vs. 5.1 ± 1.2 cm/s, P < 0.01; elevated systolic longitudinal dyssynchrony, 60.2 ± 30.2 msec vs. 32.1 ± 25.1 msec, P < 0.01). Correlation analysis revealed a significant positive relationship between T2 and ECV (r = 0.45,P < 0.01). In addition, peak systolic longitudinal velocities demonstrated a significant inverse relationship with T2 (global r = -0.29, P = 0.02), and systolic radial dyssynchrony was positively associated with peak T2 and peak T1 (r = 0.26,P = 0.04; r = 0.27,P = 0.03). DATA CONCLUSION: MR techniques are sensitive to structural and functional differences in transplant recipients compared to controls. Structural (T2 , T1 ) and functional (peak myocardial velocities, dyssynchrony) measures were significantly associated, suggesting a structure-function relationship of cardiac abnormalities following heart transplant. LEVEL OF EVIDENCE: 2 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2019;49:678-687.

Donor and Recipient Characteristics in Heart Transplantation Are Associated with Altered Myocardial Tissue Structure and Cardiac Function.

PURPOSE: To use structure-function cardiac MRI in the evaluation of relationships between donor and heart transplantation (HTx) recipient characteristics and changes in cardiac tissue structure and function. HTx candidates and donor hearts are evaluated for donor-recipient matches to improve survival, but the impact of donor and recipient characteristics on changes in myocardial tissue and function in the transplanted heart is not fully understood. MATERIALS AND METHODS: Cardiac MRI at 1.5 T was performed from August 2014 to June 2017 in 58 HTx recipients (mean age, 51.1 years ± 12.6 [standard deviation], 26 female patients) and included T2 mapping (to evaluate edematous and/or inflammatory changes), precontrast and postcontrast T1 mapping (allowing the calculation of extracellular volume fraction [ECV] to estimate interstitial expansion), and tissue phase mapping (allowing the calculation of myocardial velocities and twist). Donor and recipient demographics (age, sex, height, weight, and body mass index [BMI]) and comorbidities (hypertension, diabetes, and smoking history) were evaluated for relationships with cardiac MRI measures. RESULTS: Sex-influenced cardiac MRI measures of myocardial tissue and function are as follows: Female HTx recipients demonstrated increased precontrast T1 (P = .002) and reduced systolic peak long-axis velocities (P = .015). Increased age of the donor heart was associated with elevated T2 (r = 0.32; P < .05) and ECV (r = 0.47; P < .01), indicating increased edema and interstitial expansion, as well as impaired diastolic peak long-axis velocities (r = 0.41; P < .01). Recipient-donor differences in age, weight, and BMI were significantly associated with elevated ECV (r = 0.36-0.48; P < .05). Hypertension in donors resulted in increased ECV (31.0% ± 4.2 vs 26.0% ± 3.3; P = .001). CONCLUSION: Donor and HTx recipient characteristics were significantly associated with cardiac MRI-derived measures of myocardial tissue structure and function.© RSNA, 2019.

Phase I trial of a new schedule of romidepsin in patients with advanced cancers.

PURPOSE: Romidepsin is a potent histone deacetylase inhibitor (HDI) with activity in T-cell lymphoma. Given preclinical data showing greater induction of gene expression with longer exposures to HDIs, a phase I study of a day 1, 3, and 5 romidepsin schedule was evaluated. A secondary objective was to assess the effect of romidepsin on radioactive iodine (RAI) uptake in thyroid cancers. EXPERIMENTAL DESIGN: Open-label, single-arm, phase I, 3 + 3 dose escalation study. Romidepsin was administered as a 4-hour infusion on days 1, 3, and 5 of a 21-day cycle. Pharmacokinetics (PK) and pharmacodynamics (PD) were assessed, including histone acetylation in peripheral blood mononuclear cells (PBMC), RAI uptake in refractory thyroid cancer, and HDI-related ECG changes. RESULTS: Twenty-eight patients with solid tumors, including 11 patients with thyroid cancer were enrolled. Six dose levels were explored, and 7 mg/m(2) on days 1, 3, and 5 was identified as tolerable. No Response Evaluation Criteria In Solid Tumors-defined objective responses were recorded although 9 patients had stable disease a median 30 weeks (range, 21-112) including 6 with thyroid cancer a median of 33 weeks. PD studies detected acetylated histones in PBMCs and ECG changes beginning at low dose levels. Follow-up RAI scans in patients with RAI refractory thyroid cancer did not detect meaningful increases. CONCLUSIONS: A romidepsin dose of 7 mg/m(2) administered on days 1, 3, and 5 was found tolerable and resulted in histone acetylation in PBMCs. Although there were no objective responses with romidepsin alone, this schedule may be useful for developing combination studies in solid tumors.