Experimental TET2 Clonal Hematopoiesis Predisposes to Renal Hypertension Through an Inflammasome-Mediated Mechanism.

BACKGROUND: Hypertension incidence increases with age and represents one of the most prevalent risk factors for cardiovascular disease. Clonal events in the hematopoietic system resulting from somatic mutations in driver genes are prevalent in elderly individuals who lack overt hematologic disorders. This condition is referred to as age-related clonal hematopoiesis (CH), and it is a newly recognized risk factor for cardiovascular disease. It is not known whether CH and hypertension in the elderly are causally related and, if so, what are the mechanistic features. METHODS: A murine model of adoptive bone marrow transplantation was employed to examine the interplay between Tet2 (ten-eleven translocation methylcytosine dioxygenase 2) clonal hematopoiesis and hypertension. RESULTS: In this model, a subpressor dose of Ang II (angiotensin II) resulted in elevated systolic and diastolic blood pressure as early as 1 day after challenge. These conditions led to the expansion of Tet2-deficient proinflammatory monocytes and bone marrow progenitor populations. Tet2 deficiency promoted renal CCL5 (C-C motif ligand 5) chemokine expression and macrophage infiltration into the kidney. Consistent with macrophage involvement, Tet2 deficiency in myeloid cells promoted hypertension when mice were treated with a subpressor dose of Ang II. The hematopoietic Tet2-/- condition led to sodium retention, renal inflammasome activation, and elevated levels of IL (interleukin)-1ß and IL-18. Analysis of the sodium transporters indicated NCC (sodium-chloride symporter) and NKCC2 (Na+-K+-Cl- cotransporter 2) activation at residues Thr53 and Ser105, respectively. Administration of the NLRP3 (NLR family pyrin domain containing 3) inflammasome inhibitor MCC950 reversed the hypertensive state, sodium retention, and renal transporter activation. CONCLUSIONS: Tet2-mediated CH sensitizes mice to a hypertensive stimulus. Mechanistically, the expansion of hematopoietic Tet2-deficient cells promotes hypertension due to elevated renal immune cell infiltration and activation of the NLRP3 inflammasome, with consequences on sodium retention. These data indicate that carriers of TET2 CH could be at elevated risk for the development of hypertension and that immune modulators could be useful in treating hypertension in this patient population.

Severe acute heart failure during or following cytokine release syndrome after CAR T-cell therapy.

Although cardiac dysfunction after chimeric antigen receptor (CAR) T-cell therapy has been increasingly reported, the underlying dynamics and pathogenesis are not well documented. Herein, we describe the clinical presentation and treatment for two patients who developed severe acute heart failure after CAR T-cell therapy. Both cases shared several common characteristics, including the bone marrow involvement at the time of CAR T-cell therapy and early onset of cytokine release syndrome (CRS) with fever developing on the day of CAR T-cell infusion. Patients with early onset and/or severe CRS should be carefully monitored for the possibility of heart failure.

Importance of clonal hematopoiesis in heart failure.

Heart failure is prevalent in the elderly population. Inflammatory processes can contribute to the progression of heart failure by altering the balance of tissue healing and pathological remodeling during the injury response. New findings show that aging can alter immune cell phenotypes through the process of clonal hematopoiesis. This condition results from acquired somatic DNA mutations in specific driver genes that give rise to clonal expansions of mutant hematopoietic cells with overactive inflammatory properties. Recent clinical and experimental studies have shown that clonal hematopoiesis is prevalent in heart failure patients and associated with poor prognosis. In this review, we summarize current evidence that associates clonal hematopoiesis with the progression of heart failure. We further describe the mechanistic links between clonal hematopoiesis and the pro-inflammatory responses that can contribute to pathological outcomes in the heart. Finally, we provide perspectives on future research directions in the area of clonal hematopoiesis and heart failure.

The Cancer Therapy-Related Clonal Hematopoiesis Driver Gene Ppm1d Promotes Inflammation and Non-Ischemic Heart Failure in Mice.

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Estimating the Effectiveness of Non-Pharmaceutical Interventions on COVID-19 Control in Korea.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has posed significant global public health challenges and created a substantial economic burden. Korea has experienced an extensive outbreak, which was linked to a religion-related super-spreading event. However, the implementation of various non-pharmaceutical interventions (NPIs), including social distancing, spring semester postponing, and extensive testing and contact tracing controlled the epidemic. Herein, we estimated the effectiveness of each NPI using a simulation model. METHODS: A compartment model with a susceptible-exposed-infectious-quarantined-hospitalized structure was employed. Using the Monte-Carlo-Markov-Chain algorithm with Gibbs' sampling method, we estimated the time-varying effective contact rate to calibrate the model with the reported daily new confirmed cases from February 12th to March 31st (7 weeks). Moreover, we conducted scenario analyses by adjusting the parameters to estimate the effectiveness of NPI. RESULTS: Relaxed social distancing among adults would have increased the number of cases 27.4-fold until the end of March. Spring semester non-postponement would have increased the number of cases 1.7-fold among individuals aged 0-19, while lower quarantine and detection rates would have increased the number of cases 1.4-fold. CONCLUSION: Among the three NPI measures, social distancing in adults showed the highest effectiveness. The substantial effect of social distancing should be considered when preparing for the 2nd wave of COVID-19.

Tet2-mediated clonal hematopoiesis in nonconditioned mice accelerates age-associated cardiac dysfunction.

Clonal hematopoiesis of indeterminate potential is prevalent in elderly individuals and associated with increased risks of all-cause mortality and cardiovascular disease. However, mouse models to study the dynamics of clonal hematopoiesis and its consequences on the cardiovascular system under homeostatic conditions are lacking. We developed a model of clonal hematopoiesis using adoptive transfer of unfractionated ten-eleven translocation 2-mutant (Tet2-mutant) bone marrow cells into nonirradiated mice. Consistent with age-related clonal hematopoiesis observed in humans, these mice displayed a progressive expansion of Tet2-deficient cells in multiple hematopoietic stem and progenitor cell fractions and blood cell lineages. The expansion of the Tet2-mutant fraction was also observed in bone marrow-derived CCR2+ myeloid cell populations within the heart, but there was a negligible impact on the yolk sac-derived CCR2- cardiac-resident macrophage population. Transcriptome profiling revealed an enhanced inflammatory signature in the donor-derived macrophages isolated from the heart. Mice receiving Tet2-deficient bone marrow cells spontaneously developed age-related cardiac dysfunction characterized by greater hypertrophy and fibrosis. Altogether, we show that Tet2-mediated hematopoiesis contributes to cardiac dysfunction in a nonconditioned setting that faithfully models human clonal hematopoiesis in unperturbed bone marrow. Our data support clinical findings that clonal hematopoiesis per se may contribute to diminished health span.

JAK2 V617F -Mediated Clonal Hematopoiesis Accelerates Pathological Remodeling in Murine Heart Failure.

Janus kinase 2 (valine to phenylalanine at residue 617) (JAK2 V617F ) mutations lead to myeloproliferative neoplasms associated with elevated myeloid, erythroid, and megakaryocytic cells. Alternatively these same mutations can lead to the condition of clonal hematopoiesis with no impact on blood cell counts. Here, a model of myeloid-restricted JAK2 V617F expression from lineage-negative bone marrow cells was developed and evaluated. This model displayed greater cardiac inflammation and dysfunction following permanent left anterior descending artery ligation and transverse aortic constriction. These data suggest that JAK2 V617F mutations arising in myeloid progenitor cells may contribute to cardiovascular disease by promoting the proinflammatory properties of circulating myeloid cells.

Validating a single-question depression measure among older adults.

BACKGROUND: A single-item depression measure may not be adequate in capturing the complex entity of mental health, despite wide use of this indicator in community studies. This study evaluated the accuracy of a single-question depression measure in comparison to two composite indices-the Center for Epidemiologic Studies Depression Scale (CESD) and the Geriatric Depression Scale (GDS). MATERIALS AND METHODS: A total of 800 elderly participants ranging from 60 to 89 years of age and residing in Seoul were recruited using a multistage sampling scheme in 2015. The survey was conducted by trained interviewers with a constructed questionnaire. Reliability and validity measures such as the Kappa index, sensitivity, specificity, PPV, NPV, and AUC were used to evaluate the accuracy of the single question measure. Socio-demographic group differences in accuracy were compared by age, sex, marital status, education, employment, and financial status. RESULTS: The prevalence of depression by a single-question measure was much lower than those of CESD and GDS (5.5%, 12.3%, and 12.1%, respectively). The sensitivity of the single-item measure, based on CESD and GDS, was extremely low at 30.6% and 36.1%. In the subgroup analysis, however, there was a marked educational discrepancy in all accuracy measures; in sensitivity, people with a university degree or higher showed about 2.4 times higher sensitivity than those having only a primary school education. CONCLUSIONS: The results show that a single-question depression measure should be used with caution. In addition, the single-question measure could substantially underestimate depression among the risk group of older adults.

The Use of Chemoprophylaxis after Floods to Reduce the Occurrence and Impact of Leptospirosis Outbreaks.

Record-breaking and devastating rainfall events have occurred in the past decade. Rain and floods are considered the main risk factors for leptospirosis and several outbreaks have been reported following extreme weather events. In such situations, one possible intervention to prevent leptospirosis cases in high-risk groups is the use of chemoprophylaxis. However, not enough evidence of its effect is available. The objectives of this study were to review the literature on the current practices of chemoprophylaxis for leptospirosis and to explore, using a mathematical model, how various chemoprophylaxis scenarios may affect the progression of a leptospirosis outbreak. Twenty-six peer-reviewed publications were selected (10 quantitative studies, two systematic reviews and 14 articles of other types). Oral doxycycline was the most used antibiotic for chemoprophylaxis of leptospirosis. Post-exposure prophylaxis was assessed in four studies following a natural disaster. Although evidence of the effectiveness of post-exposure prophylaxis is inconsistent, the direction of association supported a protective effect for morbidity and mortality. The theoretical model showed how the assumed benefit of chemoprophylaxis was influenced by the time and rate of administration. Future models should consider the heterogeneity of affected communities, improved estimates of the effect of chemoprophylaxis on leptospirosis infection and disease, as well as potential detrimental impacts. Additional research is critical to provide clear evidence-based recommendations for leptospirosis control during an outbreak. The results of this study suggest that chemoprophylaxis may provide some protection in reducing the number of leptospirosis cases after a high-risk exposure; however, the effective benefit may depend on a variety of factors such as the timing and coverage of prophylaxis. The information summarized can be used to support decision-making during a high-risk event.

Identification of the Mtus1 Splice Variant as a Novel Inhibitory Factor Against Cardiac Hypertrophy.

BACKGROUND: In cardiac hypertrophy and failure, there is a widespread alteration in mRNA splicing, but the role of splice variants in cardiac hypertrophy has not yet been fully elucidated. In this study, we used an exon array to identify novel splice variants associated with cardiac hypertrophy. METHODS AND RESULTS: We performed genome-wide exon array analysis and developed a splicing profile in murine hearts with hypertrophy induced by transverse aortic constriction for 8 weeks. Following global analysis of splice variants using the Mouse Exon 1.0 ST Array, we identified 46 spliced genes and narrowed our focus to 1 gene, mitochondrial tumor suppressor 1 (Mtus1), whose splice variants were registered in the NCBI RefSeq database. Notably, one of the splice variants Mtus1A was specifically upregulated, although the total expression of the Mtus1 gene remained unchanged. We showed that Mtus1A was localized in the mitochondria, and its expression level increased with the degree of cardiac hypertrophy. In cultured cardiomyocytes, Mtus1A overexpression reduced phenylephrine-induced reactive oxygen species production and consequent ERK phosphorylation, resulting in a decrease in both cell size and protein synthesis. In vivo, cardiac-specific Mtus1A transgenic mice showed left ventricle wall thinning and a reduced hypertrophic response to pressure overload and phenylephrine treatment. CONCLUSIONS: We found that Mtus1 is specifically spliced in hypertrophic hearts and that the Mtus1A variant has an inhibitory effect on cardiac hypertrophy. Mtus1A is, therefore, a possible diagnostic and therapeutic target for cardiac hypertrophy and failure.

AMPK controls the speed of microtubule polymerization and directional cell migration through CLIP-170 phosphorylation.

AMP-activated protein kinase (AMPK) is an energy-sensing Ser/Thr protein kinase originally shown to be regulated by AMP. AMPK is activated by various cellular stresses that inhibit ATP production or stimulate ATP consumption. In addition to its role in metabolism, AMPK has recently been reported to reshape cells by regulating cell polarity and division. However, the downstream targets of AMPK that participate in these functions have not been fully identified. Here, we show that phosphorylation of the microtubule plus end protein CLIP-170 by AMPK is required for microtubule dynamics and the regulation of directional cell migration. Both inhibition of AMPK and expression of a non-phosphorylatable CLIP-170 mutant resulted in prolonged and enhanced accumulation of CLIP-170 at microtubule tips, and slower tubulin polymerization. Furthermore, inhibition of AMPK impaired microtubule stabilization and perturbed directional cell migration. All of these phenotypes were rescued by expression of a phosphomimetic CLIP-170 mutant. Our results demonstrate, therefore, that AMPK controls basic cellular functions by regulating microtubule dynamics through CLIP-170 phosphorylation.

Identification of genes related to heart failure using global gene expression profiling of human failing myocardium.

Although various management methods have been developed for heart failure, it is necessary to investigate the diagnostic or therapeutic targets of heart failure. Accordingly, we have developed different approaches for managing heart failure by using conventional microarray analyses. We analyzed gene expression profiles of myocardial samples from 12 patients with heart failure and constructed datasets of heart failure-associated genes using clinical parameters such as pulmonary artery pressure (PAP) and ejection fraction (EF). From these 12 genes, we selected four genes with high expression levels in the heart, and examined their novelty by performing a literature-based search. In addition, we included four G-protein-coupled receptor (GPCR)-encoding genes, three enzyme-encoding genes, and one ion-channel protein-encoding gene to identify a drug target for heart failure using in silico microarray database. After the in vitro functional screening using adenovirus transfections of 12 genes into rat cardiomyocytes, we generated gene-targeting mice of five candidate genes, namely, MYLK3, GPR37L1, GPR35, MMP23, and NBC1. The results revealed that systolic blood pressure differed significantly between GPR35-KO and GPR35-WT mice as well as between GPR37L1-Tg and GPR37L1-KO mice. Further, the heart weight/body weight ratio between MYLK3-Tg and MYLK3-WT mice and between GPR37L1-Tg and GPR37L1-KO mice differed significantly. Hence, microarray analysis combined with clinical parameters can be an effective method to identify novel therapeutic targets for the prevention or management of heart failure.