Case report: mRNA-1273 COVID-19 vaccine-associated myopericarditis: Successful treatment and re-exposure with colchicine.

Introduction: Vaccine-induced myocarditis is a rare complication of messenger RNA (mRNA) COVID-19 vaccines. Case presentation: We report a case of acute myopericarditis in a recipient of allogeneic hematopoietic cells following the first dose of the mRNA-1273 vaccine and the successful administration of a second and third dose while on prophylactic treatment with colchicine to successfully complete the vaccination. Conclusion: Treatment and prevention of mRNA-vaccine-induced myopericarditis represent a clinical challenge. The use of colchicine is feasible and safe to potentially reduce the risk of this rare but severe complication and allows re-exposure to an mRNA vaccine.

Treosulfan-based Reduced-intensity Allogeneic Hematopoietic Cell Transplantation in Adults With Primary Immunodeficiency: A Case Series.

BACKGROUND/AIM: We report three adult patients with primary immunodeficiency (PID) treated with reduced-intensity allogenic hematopoietic cell transplantation (HCT) with fludarabine/treosulfan conditioning and graft-versus-host disease (GvHD) prophylaxis with alemtuzumab and a calcineurin inhibitor. CASE REPORT: Patient 1, a 51-year-old male, had common variable immunodeficiency (CVID) with protein-losing enteropathy. Patient 2 was a 29-year-old woman with STAT3 (signal transducer and activator of transcription 3)-dependent hyper-IgE syndrome (HIES). Patient 3 was a 25-year-old male with XIAP (X-linked inhibitor of apoptosis)-deficiency presenting as treatment-refractory granulomatous enteropathy. Engraftment occurred in all three patients, with 100% donor chimerism in blood. Two patients survived, whereas the patient with CVID died due to infection. CONCLUSION: This series highlights issues of transplantation for PID in adults and treosulfan-based conditioning, which is feasible for PID patients; infectious complications are the major issue of concern.

Optimized cyclosporine starting dose may reduce risk of acute GvHD after allogeneic hematopoietic cell transplantation: a single-center cohort study.

Cyclosporine A (CsA) is commonly used for Graft versus Host Disease (GvHD) prophylaxis at a recommended starting dose of 3 mg/kg/d: Evidence for the effect of different CsA starting doses on GvHD risk is limited. We therefore estimated the association of 5 mg/kg/d (CsA5) and 3 mg/kg/d (CsA3) CsA starting doses with GvHD risk in two consecutive cohorts of allogeneic hematopoietic cell transplantation (allo-HCT) patients, exploring potential risk factors for incident acute GvHD, with a focus on CsA starting dose. We analyzed 519 patients within CsA5 (n = 153) and CsA3 (n = 366). The cumulative incidence function of acute GvHD grade ≥2 was higher in the CsA3 compared to the CsA5 group (41% vs. 33%, respectively; p = 0.043), without impacting chronic GvHD. In multivariable analysis, a CsA starting dose of 3 mg/kg/d, no ATG use, unrelated donor and high to very high disease risk index were significantly associated with acute GvHD grade ≥2. A higher CsA starting dose of 5 mg/kg/d was independently associated with lower acute GvHD risk, and higher CsA levels in the early period after allo-HCT were reached.

New-onset Post-transplant Diabetes and Therapy in Long-term Survivors After Allogeneic Hematopoietic Stem Cell Transplantation.

BACKGROUND: Survival after allogeneic hematopoietic stem cell transplantation (allo-HSCT) has increased but so have long-term sequelae. New-onset post-transplant diabetes mellitus (PTDM) occurs frequently following allo-HSCT. PATIENTS AND METHODS: Study endpoints were incidence and risk factors of PDTM. We studied 599 adult patients suffering from either acute myeloid leukemia n=220), acute lymphoblastic leukemia (n=79), chronic myeloid leukemia (n=22), myelodysplastic syndrome/myeloproliferative neoplasm (n=105), chronic lymphocytic leukemia (n=37), lymphoma/myeloma (n=116, or non-malignant disorders (e.g. bone marrow failure, hemoglobinopathies) (n=20) who underwent myeloablative (466; 77.8%) or non-myeloablative (131; 21.9%) allo-HSCT between 2006 and 2016. RESULTS: Altogether, 39 patients (6.5%) developed PTDM. In a competing-risk analysis, time to PTDM was associated with acute grade 2-4 graft-versus-host-disease (p=0.017). Further cardiovascular risk factors were hypertension (n=145; 24.2%), coronary artery disease (n=36, 6%), dyslipidemia (n=139; 23.3%), and stroke (n=12; 2%). CONCLUSION: After allo-HSCT, a significant number of patients developed PTDM and patients with acute graft-versus-host-disease were found to have a higher risk for PTDM. Long-term and continuous follow-up for diabetes and cardiovascular risk factors after HSCT is important in order to be able to provide timely and appropriate treatment.

Analyzing 24-Hour Blood Pressure Measurements with a Novel Cuffless Pulse Transit Time Device in Clinical Practice-Does the Software for Heartbeat Detection Matter?

: Background: The Somnotouch-Non-Invasive-Blood-Pressure (NIBP) device delivers raw data consisting of electrocardiography and photoplethysmography for estimating blood pressure (BP) over 24 hours using pulse-transit-time. The study's aim was to analyze the impact on 24-hour BP results when processing raw data by two different software solutions delivered with the device. METHODS: We used data from 234 participants. The Somnotouch-NIBP measurements were analyzed using the Domino-light and Schiller software and compared. BP values differing > 5 mmHg were regarded as relevant and explored for their impact on BP classification (normotension vs. hypertension). RESULTS: Mean (±standard deviation) absolute systolic/diastolic differences for 24-hour mean BP were 1.5 (±1.7)/1.1 (±1.3) mm Hg. Besides awake systolic BP (p = 0.022), there were no statistically significant differences in systolic/diastolic 24-hour mean, awake, and asleep BP. Twenty four-hour mean BP agreement (number (%)) between the software solutions within 5, 10, and 15 mmHg were 222 (94.8%), 231 (98.7%), 234 (100%) for systolic and 228 (97.4%), 232 (99.1%), 233 (99.5%) for diastolic measurements, respectively. A BP difference of >5 mmHg was present in 24 (10.3%) participants leading to discordant classification in 4-17%. CONCLUSION: By comparing the two software solutions, differences in BP are negligible at the population level. However, at the individual level there are, in a minority of cases, differences that lead to different BP classifications, which can influence the therapeutic decision.

Reduced dose of post-transplantation cyclophosphamide compared to ATG for graft-versus-host disease prophylaxis in recipients of mismatched unrelated donor hematopoietic cell transplantation: a single-center study.

Post-transplantation cyclophosphamide (PTCy) demonstrated effectiveness to prevent GVHD after haploidentical hematopoietic cell transplantation (HCT). Reducing toxicities with a maximized efficacy is still challenging in HCT. In this retrospective study, we analyzed the safety and efficacy of transplantation from a 1-antigen HLA-mismatched unrelated donor (9/10 MMUD) in 80 patients with hematological disorders between 2010 and 2018; 22 patients received PTCy with a reduced dose of 40 mg/kg, cyclosporine A, and mycophenolate mofetil (MMF); 58 patients received anti-thymocyte globulin (ATG), cyclosporine A, and either methotrexate or MMF for GVHD prophylaxis. Cumulative incidence (CI) of acute GVHD grades II-IV in the PTCy group was significantly lower (15% vs. 50%, p = 0.006); however, CI of chronic GVHD was (not significantly) lower in the PTCy group (26% vs. 35%, p = 0.137). One-year OS was significantly longer (p = 0.008) in the PTCy group with a similar 1-year PFS (p = 0.114) in both groups. Rates of 1-year relapse and non-relapse mortality were similar. Median time to neutrophil engraftment was comparable in both GVHD prophylaxis groups (14 days vs. 16 days, respectively, p = 0.107). Our results show that a lower dose of PTCy-based prophylaxis is an effective and safe strategy to prevent acute GVHD in HCT with 9/10 MMUD compared to ATG.

[Hematopoietic cell transplantation - essentials on indication, patient referral and long term follow up]. / Blutstammzelltransplantation ­ von der Indikation zur Nachsorge.

Hematopoietic cell transplantation - essentials on indication, patient referral and long term follow up Abstract. Both, autologous and allogeneic hematopoietic cell transplantation (HCT) are established treatment components for a large number of predominantly hemato- and lymphopoietic disorders. Diagnosis and disease status, the timing for referral to a transplant center and comorbidities are crucial factors for the patients' outcome. Survivorship care plans are an important contribution to improve intermediate and long-term outcome. Although these are mainly guided by the transplant center, family and referring physicians play an important role in prevention, early detection and treatment of late effects. This review discusses «HCT-essentials¼ for non-transplant physicians for referral and follow up of transplant patients.

Dyslipidemia and lipid-lowering treatment in a hematopoietic stem cell transplant cohort: 25 years of follow-up data.

BACKGROUND: Dyslipidemia is common after hematopoietic stem cell transplantation (HSCT). Few data regarding the time course of lipid profiles after HSCT, the effect of multiple transplantations, and efficacy and safety of lipid-lowering treatments are available. OBJECTIVE: The objective of the study was to determine the prevalence and treatment of dyslipidemia over a 25-year period in a large, single-center cohort. METHODS: One thousand one hundred ninety-six adult patients (≥16 years) who underwent HSCT during 1973 to 2013 and who survived ≥100 days were studied retrospectively. RESULTS: The prevalence of dyslipidemia before transplantation was 36% and 28% in the autologous and allogeneic groups, respectively (P < .001). Three months after HSCT, the prevalence rose to 62% and 74% (P < .001), and at 25 years, it was 67% and 89%. Lipid profiles were similar after first and subsequent transplants. Baseline dyslipidemia (odds ratio [OR] = 2.72), allogeneic transplant (OR = 2.44), and age ≥ 35 years (OR = 2.33) were independent risk factors for dyslipidemia at 1 year. Lipid-lowering treatment was given to 223 (19%) patients, primarily in the form of statins (86%) and was associated with a decrease in total cholesterol from 246 to 192 mg/dL (P < .01) and from 244 to 195 mg/dL (P < .001) in the autologous and allogeneic groups, respectively. There were 10 cases (4%) of muscle symptoms prompting cessation of lipid-lowering therapy, including 1 case of rhabdomyolysis. The OR for dyslipidemia among patients who suffered a cardiovascular event (conditional logistic regression) was 3.5 (95% confidence interval = 1.6-7.7, P = .002). CONCLUSION: This study confirms that dyslipidemia is a common and long-lasting phenomenon among both allogeneic and autologous HSCT patients. Statins are effective, generally well-tolerated and should be highly recommended for the management of post-HSCT dyslipidemia.

Late Na(+) current and protracted electrical recovery are critical determinants of the aging myopathy.

The aging myopathy manifests itself with diastolic dysfunction and preserved ejection fraction. We raised the possibility that, in a mouse model of physiological aging, defects in electromechanical properties of cardiomyocytes are important determinants of the diastolic characteristics of the myocardium, independently from changes in structural composition of the muscle and collagen framework. Here we show that an increase in the late Na(+) current (INaL) in aging cardiomyocytes prolongs the action potential (AP) and influences temporal kinetics of Ca(2+) cycling and contractility. These alterations increase force development and passive tension. Inhibition of INaL shortens the AP and corrects dynamics of Ca(2+) transient, cell contraction and relaxation. Similarly, repolarization and diastolic tension of the senescent myocardium are partly restored. Thus, INaL offers inotropic support, but negatively interferes with cellular and ventricular compliance, providing a new perspective of the biology of myocardial aging and the aetiology of the defective cardiac performance in the elderly.

Inositol 1, 4, 5-trisphosphate receptors and human left ventricular myocytes.

BACKGROUND: Little is known about the function of inositol 1,4,5-trisphosphate receptors (IP3Rs) in the adult heart experimentally. Moreover, whether these Ca(2+) release channels are present and play a critical role in human cardiomyocytes remains to be defined. IP3Rs may be activated after Gαq-protein-coupled receptor stimulation, affecting Ca(2+) cycling, enhancing myocyte performance, and potentially favoring an increase in the incidence of arrhythmias. METHODS AND RESULTS: IP3R function was determined in human left ventricular myocytes, and this analysis was integrated with assays in mouse myocytes to identify the mechanisms by which IP3Rs influence the electric and mechanical properties of the myocardium. We report that IP3Rs are expressed and operative in human left ventricular myocytes. After Gαq-protein-coupled receptor activation, Ca(2+) mobilized from the sarcoplasmic reticulum via IP3Rs contributes to the decrease in resting membrane potential, prolongation of the action potential, and occurrence of early afterdepolarizations. Ca(2+) transient amplitude and cell shortening are enhanced, and extrasystolic and dysregulated Ca(2+) elevations and contractions become apparent. These alterations in the electromechanical behavior of human cardiomyocytes are coupled with increased isometric twitch of the myocardium and arrhythmic events, suggesting that Gαq-protein-coupled receptor activation provides inotropic reserve, which is hampered by electric instability and contractile abnormalities. Additionally, our findings support the notion that increases in Ca(2+) load by IP3Rs promote Ca(2+) extrusion by forward-mode Na(+)/Ca(2+) exchange, an important mechanism of arrhythmic events. CONCLUSIONS: The Gαq-protein/coupled receptor/IP3R axis modulates the electromechanical properties of the human myocardium and its propensity to develop arrhythmias.

Cardiomyogenesis in the aging and failing human heart.

BACKGROUND: Two opposite views of cardiac growth are currently held; one views the heart as a static organ characterized by a large number of cardiomyocytes that are present at birth and live as long as the organism, and the other views the heart a highly plastic organ in which the myocyte compartment is restored several times during the course of life. METHODS AND RESULTS: The average age of cardiomyocytes, vascular endothelial cells (ECs), and fibroblasts and their turnover rates were measured by retrospective (14)C birth dating of cells in 19 normal hearts 2 to 78 years of age and in 17 explanted failing hearts 22 to 70 years of age. We report that the human heart is characterized by a significant turnover of ventricular myocytes, ECs, and fibroblasts, physiologically and pathologically. Myocyte, EC, and fibroblast renewal is very high shortly after birth, decreases during postnatal maturation, remains relatively constant in the adult organ, and increases dramatically with age. From 20 to 78 years of age, the adult human heart entirely replaces its myocyte, EC, and fibroblast compartment ≈8, ≈6, and ≈8 times, respectively. Myocyte, EC, and fibroblast regeneration is further enhanced with chronic heart failure. CONCLUSIONS: The human heart is a highly dynamic organ that retains a remarkable degree of plasticity throughout life and in the presence of chronic heart failure. However, the ability to regenerate cardiomyocytes, vascular ECs, and fibroblasts cannot prevent the manifestations of myocardial aging or oppose the negative effects of ischemic and idiopathic dilated cardiomyopathy.

Tracking chromatid segregation to identify human cardiac stem cells that regenerate extensively the infarcted myocardium.

RATIONALE: According to the immortal DNA strand hypothesis, dividing stem cells selectively segregate chromosomes carrying the old template DNA, opposing accumulation of mutations resulting from nonrepaired replication errors and attenuating telomere shortening. OBJECTIVE: Based on the premise of the immortal DNA strand hypothesis, we propose that stem cells retaining the old DNA would represent the most powerful cells for myocardial regeneration. METHODS AND RESULTS: Division of human cardiac stem cells (hCSCs) by nonrandom and random segregation of chromatids was documented by clonal assay of bromodeoxyuridine-tagged hCSCs. Additionally, their growth properties were determined by a series of in vitro and in vivo studies. We report that a small class of hCSCs retain during replication the mother DNA and generate 2 daughter cells, which carry the old and new DNA, respectively. hCSCs with immortal DNA form a pool of nonsenescent cells with longer telomeres and higher proliferative capacity. The self-renewal and long-term repopulating ability of these cells was shown in serial-transplantation assays in the infarcted heart; these cells created a chimeric organ, composed of spared rat and regenerated human cardiomyocytes and coronary vessels, leading to a remarkable restoration of cardiac structure and function. The documentation that hCSCs divide by asymmetrical and symmetrical chromatid segregation supports the view that the human heart is a self-renewing organ regulated by a compartment of resident hCSCs. CONCLUSIONS: The impressive recovery in ventricular hemodynamics and anatomy mediated by clonal hCSCs carrying the "mother" DNA underscores the clinical relevance of this stem cell class for the management of heart failure in humans.

Evidence for human lung stem cells.

BACKGROUND: Although progenitor cells have been described in distinct anatomical regions of the lung, description of resident stem cells has remained elusive. METHODS: Surgical lung-tissue specimens were studied in situ to identify and characterize human lung stem cells. We defined their phenotype and functional properties in vitro and in vivo. RESULTS: Human lungs contain undifferentiated human lung stem cells nested in niches in the distal airways. These cells are self-renewing, clonogenic, and multipotent in vitro. After injection into damaged mouse lung in vivo, human lung stem cells form human bronchioles, alveoli, and pulmonary vessels integrated structurally and functionally with the damaged organ. The formation of a chimeric lung was confirmed by detection of human transcripts for epithelial and vascular genes. In addition, the self-renewal and long-term proliferation of human lung stem cells was shown in serial-transplantation assays. CONCLUSIONS: Human lungs contain identifiable stem cells. In animal models, these cells participate in tissue homeostasis and regeneration. They have the undemonstrated potential to promote tissue restoration in patients with lung disease. (Funded by the National Institutes of Health.).