Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of abnormal lymphocyte survival caused by defective Fas-mediated apoptosis, leading to lymphadenopathy, hepatosplenomegaly, and an increased number of doublenegative T cells (DNTs). Treatment options for patients with ALPS are limited. Rapamycin has been shown to induce apoptosis in normal and malignant lymphocytes. Since ALPS is caused by defective lymphocyte apoptosis, we hypothesized that rapamycin would be effective in treating ALPS. We tested this hypothesis using rapamycin in murine models of ALPS. We followed treatment response with serial assessment of DNTs by flow cytometry in blood and lymphoid tissue, by serial monitoring of lymph node and spleen size with ultrasonography, and by enzyme-linked immunosorbent assay (ELISA) for anti-double-stranded DNA (dsDNA) antibodies. Three-dimensional ultrasound measurements in the mice correlated to actual tissue measurements at death (r ‫؍‬ .9648). We found a dramatic and statistically significant decrease in DNTs, lymphadenopathy, splenomegaly, and autoantibodies after only 4 weeks when comparing rapamycin-treated mice with controls. Rapamycin induced apoptosis through the intrinsic mitochondrial pathway. We compared rapamycin to mycophenolate mofetil, a second-line agent used to treat ALPS, and found rapamycin's control of lymphoproliferation was superior. We conclude that rapamycin is an effective treatment for murine ALPS and should be explored as treatment for affected humans. (Blood. 2006;108: 1965-1971

ALPS is a recently described disorder of disrupted lymphocyte homeostasis. Patients with ALPS have mutations in the Fas apoptotic pathway, leading to abnormal lymphocyte survival. Clinical manifestations in patients with ALPS vary but typically include autoimmune cytopenias, organomegaly, lymphadenopathy, and increased risk of development of lymphoma and certain leukemias. A similar constellation of findings can be seen in Evans Syndrome (ES), a hematologic disorder defined by autoimmune destruction of at least two hematologic cell types. We hypothesized that a subset of patients diagnosed with ES may have ALPS. We have designed a study to screen children with the diagnosis of ES syndrome for ALPS with a three tiered approach. First, a retrospective chart review was performed on all patients treated at CHOP in the past five years for ES who are still followed by the Division of Hematology. Next, patients with a clinical diagnosis of ES without another underlying diagnosis were screened for ALPS by flow cytometric analysis for double negative T cells (DNTs) (CD3+, CD4−, CD8−, TCRαβ+). DNTs are elevated in patients with ALPS and may provide the best current screening assay for this disease. DNTs analysis is easy to perform at low cost. Finally, patients were tested for ALPS by the gold standard test, defective in-vitro Fas mediated apoptosis. This test is labor intensive and not clinically available. 21 patients met entry criteria for the study, and, of these, 19 consented to enrollment. 16/19 had immune mediated destruction of all three hematologic cell lines. 2/19 had only had destruction of two cell types and 1 patient had immune thrombocytopenia with a positive DAT but no hemolysis or neutropenia. 14/19 had chronic disease with frequent hematologic exacerbations. The other 5 had occasional flares with illness. 10/19 had significant lymphadenopathy and 11/19 had organomegaly at some point in their history. 14/19 had either lymphadenopathy or organomegaly. 17/19 patients were screened for DNTs and 10 had elevated DNTs. Thus far, 7 patients have been tested for defective Fas mediated apoptosis. Every patient was tested in tandem with a normal control who demonstrated normal Fas mediated apoptosis. Five of the patients, all of whom had elevated DNTs, had defective Fas mediated apoptosis, confirming the diagnosis of ALPS. The other two patients did not have defective Fas mediated apoptosis: one did not have elevated DNTs and the other had a borderline result (2.7%; upper limit normal 2.6%). One of the patients with defective Fas mediated apoptosis and elevated DNTs had no history of lymphadenopathy or organomegaly. The lack of clinically identifiable lymphoproliferation in a patient with defective apoptosis is an unexpected finding, in apparent contradiction of the accepted NIH definition of ALPS which lists lymphoproliferation as a mandatory diagnostic criterion. This patient is three years old and may develop clinically identifiable lymphoproliferation with age. In summary, in the group of 17 ES patients screened to date, 59% had elevated DNTs suggestive of ALPS, with functional confirmation in 5/5 tested. Our data suggest that DNTs may be a sensitive first line-screening test and may serve as a marker that identifies patients who require definitive testing. Our preliminary findings suggest a high prevalence of ALPS among ES patients, a novel finding with important implications.

IMPORTANCE Heart failure (HF) is often characterized by an insidious disease course leading to frequent rehospitalizations and a high use of ambulatory care. Remote cardiac monitoring is a promising approach to detect worsening HF early and intervene prior to an overt decompensation.OBSERVATIONS Recently, a multitude of novel technologies for remote cardiac monitoring (RCM) in patients with HF have been developed and are undergoing clinical trials. This development has been accelerated by the COVID-19 pandemic.CONCLUSIONS AND RELEVANCE This review summarizes the major clinical trials on RCM in patients with HF and present the most recent developments in noninvasive and invasive RCM technologies.

The coronavirus disease 2019 (COVID-19) pandemic imposed severe restrictions on traditional methods of patient care. During the pandemic, the heart failure program at New York-Presbyterian Hospital in New York, NY rapidly and comprehensively transitioned its care delivery model and administrative organization to conform to a new healthcare environment while still providing high-quality care to a large cohort of patients with heart failure, heart transplantation, and left ventricular assist device. In addition to the widespread adoption of telehealth, our program restructured outpatient care, initiating a shared clinic model and introducing a comprehensive remote monitoring program to manage patients with heart failure and heart transplant. All conferences, including administrative meetings, support groups, and educational seminars were converted to teleconferencing platforms. Following the peak of COVID-19, many of the new changes have been maintained, and the program structure will be permanently altered as a lasting effect of this pandemic. In this article, we review the details of our program’s transition in the face of COVID-19 and highlight the programmatic changes that will endure.

The ability for statins to reduce major cardiovascular events and mortality has lead to this drug class being the most commonly prescribed in the world. In particular, the benefit of these drugs in type 2 diabetes (T2D) is well established. In February 2012, the Food and Drug Administration released changes to statin safety label to include that statins have been associated with increases in hemoglobin A1C and fasting serum glucose levels. This has stirred much debate in the medical community. Estimate for new onset diabetes from statin treatment is approximately one in 255 patients over four years. The number needed to treat for statin benefit is estimated at one in 40 depending on the population. The mechanism of this link remains unknown. Statins may accelerate progression to diabetes via molecular mechanisms that impact insulin resistance and cellular metabolism of carbohydrates. It remains clear that the benefit of statin therapy outweighs the risk of developing diabetes.

Light‐chain (AL) cardiac amyloidosis (CA) has a worse prognosis than transthyretin (ATTR) CA. In this single‐center study, we compared post‐heart transplant (OHT, orthotopic heart transplantation) survival for AL and ATTR amyloidosis, hypothesizing that these differences would persist post‐OHT. Thirty‐nine patients with CA (AL, n = 18; ATTR, n = 21) and 1023 non‐amyloidosis subjects undergoing OHT were included. Cox proportional hazards modeling was used to evaluate the impact of amyloid subtype and era (early era: from 2001 to 2007; late era: from 2008 to 2018) on survival post‐OHT. Survival for non‐amyloid patients was greater than ATTR (P = .034) and AL (P < .001) patients in the early era. One, 3‐, and 5‐year survival rates were higher for ATTR patients than AL patients in the early era (100% vs 75%, 67% vs 50%, and 67% vs 33%, respectively, for ATTR and AL patients). Survival in the non‐amyloid cohort was 87% at 1 year, 81% at 3 years, and 76% at 5 years post‐OHT. In the late era, AL and ATTR patients had unadjusted 1‐year, 3‐year, and 5‐year survival rates of 100%, which was comparable to non‐amyloid patients (90% vs 84% vs 81%). Overall, these findings demonstrate that in the current era, differences in post‐OHT survival for AL compared to ATTR are diminishing; OHT outcomes for selected patients with CA do not differ from non‐amyloidosis patients.

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