Behavioural immune landscapes of inflammation.

Transcriptional and proteomic profiling of individual cells have revolutionized interpretation of biological phenomena by providing cellular landscapes of healthy and diseased tissues1,2. These approaches, however, do not describe dynamic scenarios in which cells continuously change their biochemical properties and downstream 'behavioural' outputs3-5. Here we used 4D live imaging to record tens to hundreds of morpho-kinetic parameters describing the dynamics of individual leukocytes at sites of active inflammation. By analysing more than 100,000 reconstructions of cell shapes and tracks over time, we obtained behavioural descriptors of individual cells and used these high-dimensional datasets to build behavioural landscapes. These landscapes recognized leukocyte identities in the inflamed skin and trachea, and uncovered a continuum of neutrophil states inside blood vessels, including a large, sessile state that was embraced by the underlying endothelium and associated with pathogenic inflammation. Behavioural screening in 24 mouse mutants identified the kinase Fgr as a driver of this pathogenic state, and interference with Fgr protected mice from inflammatory injury. Thus, behavioural landscapes report distinct properties of dynamic environments at high cellular resolution.

Short-term Changes in Hemoglobin and Changes in Functional Status, Quality of Life and Natriuretic Peptides After Initiation of Dapagliflozin in Heart Failure With Reduced Ejection Fraction.

BACKGROUND: We aimed to evaluate the effect of dapagliflozin on short-term changes in hemoglobin in patients with stable heart failure with reduced ejection fraction (HFrEF) and whether these changes mediated the effect of dapagliflozin on functional capacity, quality of life and NT-proBNP levels. METHODS: This is an exploratory analysis of a randomized, double-blinded clinical trial in which 90 stable patients with HFrEF were randomly allocated to dapagliflozin or placebo to evaluate short-term changes in peak oxygen consumption (peak VO2) (NCT04197635). This substudy evaluated 1- and 3-month changes in hemoglobin levels and whether these changes mediated the effects of dapagliflozin on peak VO2, Minnesota Living-With-Heart-Failure test (MLHFQ) and NT-proBNP levels. RESULTS: At baseline, mean hemoglobin levels were 14.3 ± 1.7 g/dL. Hemoglobin levels significantly increased in those taking dapagliflozin (1 month: + 0.45 g/dL (P = 0.037) and 3 months:+ 0.55 g/dL (P = 0.012)]. Changes in hemoglobin levels positively mediated the changes in peak VO2 at 3 months (59.5%; P < 0.001). Changes in hemoglobin levels significantly mediated the effect of dapagliflozin in the MLHFQ at 3 months (-53.2% and -48.7%; P = 0.017) and NT-proBNP levels at 1 and 3 months (-68.0%; P = 0.048 and -62.7%; P = 0.029, respectively). CONCLUSIONS: In patients with stable HFrEF, dapagliflozin caused a short-term increase in hemoglobin levels, identifying patients with greater improvements in maximal functional capacity, quality of life and reduction of NT-proBNP levels.

Patients With High Cardiovascular Risk as Candidates to Bempedoic Acid, After Treatment With Statins, Ezetimibe and PCSK9 Inhibitors: An Estimation and Cost-Effectiveness Analysis.

ABSTRACT: Low-density lipoprotein cholesterol (LDLc) is the lead effector of atherosclerosis and main treatment target. Bempedoic acid is a novel oral drug in the therapeutic armamentarium which is able to reduce LDLc. The objectives of this study were (1) to select the potential patients for administering bempedoic acid such as those with a very high cardiovascular risk in which objectives of LDLc were not achieved despite conventional treatment with PCSK9 inhibitors (PCSK9i) and/or statins and ezetimibe and (2) to estimate the cost-effectiveness of bempedoic acid in different scenarios. The methods used were a multicenter and retrospective study of 652 patients initiating treatment with any PCSK9 inhibitor in 17 different hospitals. Before and on-treatment LDLc cholesterol levels, medical treatments, clinical indication, and baseline characteristics were recorded. The results obtained from 443 subjects in secondary prevention were analyzed. The mean (±) LDLc level at baseline was 142.5 ± 46.4 mg/dL and 61.5 ± 40.5 mg/dL in the follow-up, with a reduction of 55.9% ( P < 0.0001); 71.6% of the patients reached the target of LDL < 55 mg/dL or >50% reduction. Of those patients treated with medium-intensity and low-intensity statins plus PCSK9 inhibitors (with or without ezetimibe), only 5.7% of them were able to reduce LDL below 55 mg/dL and the main LDLc reduction in this group was the lowest (42.9% on average). Patients with TG values >135 mg/dL represented 41.6% of the sample, of which approximately 10% of them were using fibrates. Assuming only LDLc reduction and the UK price, the incremental cost-effectiveness ratio was 88,359€; 83,117€; 82,378€; and 79,015€ for different discount rates. In conclusion, one-third of the patients could achieve the target LDL proposed in the 2019 ESC/EAS guidelines. Approximately 10% of them could also benefit from treating hypertriglyceridemia as indicated in the 2021 ESC guidelines on cardiovascular disease prevention. Patients with medium-intensity and low-intensity statins plus PCSK9i and ezetimibe would be the most benefited. Bempedoic acid could be a not cost-efficacy therapy in all the scenarios, but we need to wait for the CLEAR OUTCOMES Trial results.

Effect of PCSK9 inhibitors on remnant cholesterol and lipid residual risk: The LIPID-REAL registry.

BACKGROUND: Monoclonal antibodies that inhibit the proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce low-density lipoprotein cholesterol (LDLc) by 55%, regardless of baseline treatments. Nonetheless, the effect of other lipid parameters, such as cholesterol remnants or, the so-called lipid residual risk, is unknown. METHODS: Multicenter and retrospective registry of patients treated with PCSK9 inhibitors from 14 different hospitals in Spain. Before and on-treatment lipid parameters were recorded. Residual lipid risk was estimated by (1) cholesterol remnants, (2) triglycerides/HDLc ratio (TG/HDL), (3) total cholesterol/HDLc (TC/HDL) and (4) the triglycerides-to-glucose index (TGGi). RESULTS: Six hundred fifty-two patients were analysed, mean age of 60.2 (9.63) years, 24.69% women and mean LDLc before treatment 149.24 (49.86) mg/dl. Median time to second blood determination was 187.5 days. On-treatment LDLc was 67.46 (45.78) mg/dl, which represented a 55% reduction. Significant reductions were observed for TG/HDL ratio, cholesterol remnants, TC/HDL ratio and TGGi. As consequence, 34.61% patients had LDLc <55 mg/dl and cholesterol remnants <30 mg/dl; additionally, 31.95% had cholesterol remnants <30 mg/dl but LDLc >55 mg/dl. Patients who had levels of cholesterol remnants >30 mg/dl before initiating the treatment with PCSK9 had higher reductions in cholesterol remnants, TG/HDL ratio, TC/HDL and TGGi. By contrast, no reduction differences were observed according to baseline LDLc (< or > the mean), age, gender or obesity. CONCLUSIONS: This multicenter and retrospective registry of real-world patients treated with PCSK9 inhibitors demonstrates a positive effect on cholesterol remnants and lipid residual risk beyond LDLc reductions.

Sodium-glucose Co-transporter 2 Inhibitors in Acute Heart Failure: A Review of the Available Evidence and Practical Guidance on Clinical Use.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors were initially conceived as glucose-lowering agents. However, striking renal and cardiovascular benefits were observed in type 2 diabetes trials. This led to evaluate it in dedicated studies in chronic heart failure (HF) and chronic kidney disease, which also showed remarkable clinical results. Given this findings, and taking into account the multiple mechanisms of action, the use of SGLT2 inhibitors in acute heart failure seemed promising. Sotagliflozin was the first SGLT2 inhibitor to reduce heart failure hospitalizations within the acute setting in the SOLOIST-WHF trial. Only type 2 diabetes patients were included, with a preserved and reduced ejection fraction. In slightly less than half of the cohort, this medication was started when the diuretic therapy was transitioned from intravenous to oral, during the hospital admission. In the rest of the patients, sotagliflozin was started early after discharge. Empagliflozin proved to be safe, well-tolerated, increased diuresis, and reduced a combined clinical endpoint (worsening HF, rehospitalization for HF, or death at 60 days) when administered within the first 24 hours of an acute heart failure hospitalization in the EMPA-RESPONSE-AHF trial. More recently, empagliflozin showed a reduction in a composite primary endpoint of death, heart failure events, and quality of life compared to placebo in the EMPULSE trial. Empagliflozin was started after the initial stabilization phase, but while patients were still admitted and receiving intravenous loop diuretics. Less than half of the patients were diabetic and two-thirds had a left ventricular ejection fraction below 40%. Dapagliflozin is currently being tested in the DAPA ACT HF-TIMI 68 trial, which plans to enroll 2400 patients admitted with acute heart failure and reduced ejection fraction. We envision SGLT2 inhibitors as a useful tool in acute heart failure syndrome given the additive diuretic effect, and minimal impact on blood pressure, kidney function, and electrolytes. Its dosage schedule is simple and can help initiation and tolerance of other medical therapy. However, there is an increased risk of genital infections and euglycaemic ketoacidosis. Notwithstanding, once critically ill and fasting patients are excluded, early administration of SGLT2 inhibitors is safe. This review summarizes the development of SGLT2 inhibitors and the available evidence supporting their use during an acute heart failure admission. We also propose a practical guideline for in-hospital initiation and monitoring.

Sex Differences in Low-Density Lipoprotein Cholesterol Reduction With PCSK9 Inhibitors in Real-world Patients: The LIPID-REAL Registry.

BACKGROUND: Previous evidence supports that monoclonal antibodies that inhibit the proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce low-density lipoprotein cholesterol (LDLc) by 50%-65%, regardless of baseline treatments. We tested possible sex differences in a multicentre registry of real-world patients treated with PCSK9 inhibitors. METHODS: This is a multicentre and retrospective study of 652 patients initiating treatment with any PCSK9 inhibitor in 18 different hospitals. Before-treatment and on-treatment LDLc and medical treatments, clinical indication, and clinical features were recorded. RESULTS: Women represented 24.69% of the cohort. The use of statins was similar in both sexes, but women were receiving most frequently ezetimibe. Before-treatment median LDLc was 135 (interquartile range 115-166) mg, and it was higher in women. The median on-treatment LDLc was 57 (interquartile range 38-84) mg/dL, which represented a mean 54.5% reduction. On-treatment LDLc was higher in women, and the mean LDLc reduction was lower in women (47.4% vs. 56.9%; P = 0.0002) receiving evolocumab or alirocumab. The percentage of patients who achieved ≥50% LDLc reduction was higher in men (71.36% vs. 57.62%; P = 0.002). According to LDLc before-treatment quartiles, LDLc reduction was statistically lower in women in the 2 highest and a significant interaction of women and baseline LDLc >135 mg/dL was observed. Women were negatively associated with lower rates of LDLc treatment target achievement (odds ratio: 0.31). Differences were also observed in women with body mas index >25 kg/m2. Only 14 patients (2.14%) presented side effects. CONCLUSIONS: This multicentre and retrospective registry of real-world patients treated with PCSK9 inhibitors highlights significant gender differences in LDLc reduction.

Safety and Efficacy of the Combination of Sacubitril/Valsartan and SGLT2i in HFrEF Patients (SECSI Registry).

ABSTRACT: Recent studies have proven benefit of SGLT2i drugs in patients with heart failure with reduced ejection fraction (HFrEF), but their safety when combined with angiotensin-neprilysin inhibitor (ARNI) has not been established. The Safety and Efficacy of the Combination of Sacubitril/Valsartan and SGLT2i in HFrEF Patients registry was conducted to address this issue. SECSI registry is a consecutive, observational, retrospective, multicentre study conducted in 3 Heart Failure Units in Spain. It included 144 HFrEF patients who were treated with ARNI and iSGLT2. Data were collected at baseline, month 2, and month 6. The primary endpoint was the estimated glomerular filtration rate (eGFR), after the initiation of ARNI and sodium-glucose cotransporter-2 inhibitors (SGLT2i). Secondary endpoints included potassium levels and functional class (New York Heart Association class). There were 3 prespecified subgroup analyses: Elderly patients (≥70 years), patients with chronic kidney disease (KDIGO classification G3), and the sequence of drug initiation. Mean age was 69.9 ± 10.1 years, and 110 (76.4%) were men. Left ventricular ejection fraction was 32 ± 7.8%, and most patients were symptomatic [123 (87.2%) New York Heart Association II/III/IV]. eGFR decreased at month 2 and this trend was maintained at month 6 [eGFR baseline 68.5 ± 17.3, month 2 62 ± 19.7 and month 6 64.7 ± 8.6 mL/min/1.73 m2 (P < 0.01 for both)]. In prespecified analysis, elder patients and those who simultaneously initiate both treatments showed the steeper decrease in eGFR. To conclude, co-administration of SGLT2i and ARNI in routine care in HFrEF patients produced a slight decrease in eGFR at 6 months of follow-up. This decrease was especially significant in elder patients and those who initiate both drugs simultaneously.

Cytofluorometric assessment of calreticulin exposure on CD38+ plasma cells from the human bone marrow.

Exposure of the endoplasmic reticulum chaperone calreticulin (CALR) on the surface of stressed and dying cells is paramount for their effective engulfment by professional antigen-presenting cells such as dendritic cells (DCs). Importantly, this is required (but not sufficient) for DCs to initiate an adaptive immune response that culminates with an effector phase as well as with the establishment of immunological memory. Conversely, the early exposure of phosphatidylserine (PS) on the outer layer of the plasma membrane is generally associated with the rapid engulfment of stressed and dying cells by tolerogenic macrophages. Supporting the clinical relevance of the CALR exposure pathway, the spontaneous or therapy-driven translocation of CALR to the surface of malignant cells, as well as intracellular biomarkers thereof, have been associated with improved disease outcome in patients affected by a variety of neoplasms, with the notable exception of multiple myeloma (MM). Here, we describe an optimized protocol for the flow cytometry-assisted quantification of surface-exposed CALR and PS on CD38+ plasma cells from the bone marrow of patients with MM. With some variations, we expect this method to be straightforwardly adaptable to the detection of CALR and PS on the surface of cancer cells isolated from patients with neoplasms other than MM.

A virtually supervised exercise program improved fitness and mental wellness in healthy and comorbidity older adult individuals during the COVID-19 pandemic.

Background: The COVID-19 pandemic affected older adults worldwide. Sedentary older adults experienced more severe adverse health effects due to their shelter-in-place. Physical activity was strongly recommended during periods of social distancing. The present study evaluated the impact of a virtually supervised exercise program on the physical fitness and mental health of Mexican older adults during the pandemic's lockdown. Methods: Participants were 44 older adults who were assigned to one of four physical fitness groups: a healthy control group (Ctrl-H, n = 15), a comorbidity control group (Ctrl-COM, n = 9), an exercise group without comorbidities (Exe-H, n = 11), and an exercise group with comorbidities (Exe-COM, n = 9). The participants engaged in a 60-min, virtually-supervised concurrent exercise session three times/week for 12 weeks. Fitness was measured using the online Senior Fitness Tests and the 4-m Gait Speed Test. Mental health was evaluated through virtual interviews using the Hamilton Depression Rating Scale, the Geriatric Depression Scale, and the Connor-Davidson Resilience Scale. Within-subject pre vs. post-intervention comparisons tested for significant differences, between-groups and over time. Results: Significant interactions were found in the scores of the Geriatric Depression Scale (p ≤ 0.0001; ηp2 = 0.35), the Hamilton Depression Scale (p ≤ 0.0001; ηp2 = 0.35), resilience scores (p ≤ 0.0001; ηp2 = 0.46), lower-body strength (p ≤ 0.0001; ηp2 = 0.32), timed up-and-go test (p = 0.018; ηp2 = 0.18), the 6MWT distance scores (p ≤ 0.0001; ηp2 = 0.39), and the 4-m gait speed test scores (p = 0.011; ηp2 = 0.20). Conclusion: A long-term virtually-supervised exercise program conducted during the COVID-19 lockdown period led to marked improvements in both the fitness and mental health of older Mexican adults. Comorbidities did not diminish these benefits. These findings provide empirical support for online exercise programs in the daily routines of older adults to make clinically meaningful improvements in both physical and mental well-being.

Finerenone: towards a holistic therapeutic approach to patients with diabetic kidney disease.

Despite current treatments, which include renin angiotensin system blockers and SGLT2 inhibitors, the risk of progression of kidney disease among patients with diabetes and chronic kidney disease (CKD) remains unacceptably high. The pathogenesis of CKD in patients with diabetes is complex and includes hemodynamic and metabolic factors, as well as inflammation and fibrosis. Finerenone is a highly selective nonsteroidal mineralocorticoid antagonist that, in contrast to current therapies, may directly reduce inflammation and fibrosis, thus adding value in the management of these patients. In fact, finerenone decreases albuminuria and slows CKD progression in persons with diabetes. We now review the mechanisms of action of finerenone, the results of recent clinical trials, and the integration of the kidney and cardiovascular protection afforded by finerenone in the routine care of patients with diabetes and CKD.

Cardiorenal benefits of finerenone: protecting kidney and heart.

Persons with diabetes and chronic kidney disease (CKD) have a high residual risk of developing cardiovascular (CV) complications despite treatment with renin-angiotensin system blockers and sodium-glucose cotransporter type 2 inhibitors. Overactivation of mineralocorticoid receptors plays a key role in the progression of renal and CV disease, mainly by promoting inflammation and fibrosis. Finerenone is a nonsteroidal selective mineralocorticoid antagonist. Recent clinical trials, such as FIDELIO-DKD and FIGARO-DKD and the combined analysis FIDELITY have demonstrated that finerenone decreases albuminuria, risk of CKD progression, and CV risk in subjects with type 2 diabetes (T2D) and CKD. As a result, finerenone should thus be considered as part of a holistic approach to kidney and CV risk in persons with T2D and CKD. In this narrative review, the impact of finerenone treatment on the CV system in persons with type 2 diabetes and CKD is analyzed from a practical point of view.Key messages:Despite inhibition of renin-angiotensin system and sodium-glucose cotransporter type 2, persons with type 2 diabetes (T2D) and chronic kidney disease (CKD) remain on high cardiovascular (CV) residual risk.Overactivation of mineralocorticoid receptors plays a key role in the progression of renal and CV disease, mainly by promoting inflammation and fibrosis that is not targeted by traditional treatments.Finerenone is a nonsteroidal selective mineralocorticoid antagonist that decreases not only albuminuria, but also the risk of CKD progression, and CV risk in subjects with T2D and CKD.

Vascular protection with rivaroxaban in the comprehensive management of atrial fibrillation.

INTRODUCTION: In addition to an increased risk of thromboembolic complications, patients with atrial fibrillation (AF) are at risk for vascular events. Consequently, complete vascular protection is warranted in these patients. AREAS COVERED: A narrative search was conducted on PubMed (MEDLINE), using the MeSH terms [Rivaroxaban] + [Atrial fibrillation] + [Cardiovascular] + [Vascular] + [Treatment]. Original data from clinical trials, prospective and retrospective studies, useful reviews and experimental studies, were selected. EXPERT OPINION: The ROCKET-AF trial showed that rivaroxaban is effective in reducing the risk of stroke, with a lower risk of fatal and intracranial bleeding compared to warfarin. Remarkably, experimental data have provided a number of pathogenic mechanisms through which rivaroxaban could provide beneficial vascular properties beyond its antithrombotic activity. Moreover, in the AF population, additional to its ability to reduce the risk of thromboembolic complications, rivaroxaban is associated with a lower risk of myocardial infarction, major adverse cardiac and limb events, and vascular mortality in patients with diabetes, also attenuating renal impairment during follow-up. These findings suggest that rivaroxaban may provide a comprehensive vascular protection in patients with AF.

Dapagliflozin and short-term changes on circulating antigen carbohydrate 125 in heart failure with reduced ejection fraction.

Circulating antigen carbohydrate 125 (CA125) has emerged as a proxy of fluid overload in heart failure. This study aimed to evaluate the effect of dapagliflozin on short-term CA125 levels in patients with stable heart failure with reduced ejection fraction (HFrEF) and whether these changes mediated the effects on peak oxygen consumption (peakVO2). This study is a post-hoc sub-analysis of a randomized, double-blinded clinical trial in which 90 stable patients with HFrEF were randomly assigned to receive either dapagliflozin or placebo to evaluate change in peakVO2 (NCT04197635). We used linear mixed regression analysis to compare changes in the natural logarithm of CA125 (logCA125) and percent changes from baseline (Δ%CA125). We used the "rwrmed" package to perform mediation analyses. CA125 was available in 87 patients (96.7%). LogCA125 significantly decreased in patients on treatment with dapagliflozin [1-month: Δ - 0.18, (CI 95% = - 0.33 to - 0.22) and 3-month: Δ - 0.23, (CI 95% = - 0.38 to - 0.07); omnibus p-value = 0.012]. Δ%CA125 decreased by 18.4% and 31.4% at 1 and 3-month, respectively (omnibus p-value = 0.026). Changes in logCA125 mediated the effect on peakVO2 by 20.4% at 1 month (p < 0.001). We did not find significant changes for natural logarithm of NTproBNP (logNT-proBNP) [1-month: Δ - 0.03, (CI 95% = - 0.23 to 0.17; p = 0.794), and 3-month: Δ 0.73, (CI 95% = - 0.13 to 0.28; p-value 0.489), omnibus p-value = 0.567]. In conclusion, in patients with stable HFrEF, dapagliflozin resulted in a significant reduction in CA125. Dapagliflozin was not associated with short-term changes in natriuretic peptides. These changes mediated the effects on peakVO2.

Should atrial fibrillation be considered a vascular disease? The need for a comprehensive vascular approach.

INTRODUCTION: Atrial fibrillation (AF) cannot be considered an isolated disease. Patients with AF should be managed using a comprehensive approach that is not limited to stroke prevention. AREAS COVERED: In this manuscript, the potential role of AF as a vascular disease that is managed as part of a holistic approach was reviewed. EXPERT OPINION: The residual risk of stroke in patients with AF reaches 1-2% annually, despite appropriate anticoagulation therapy. Additionally, patients with AF may develop cognitive impairment through stroke-independent pathways. Furthermore, patients with AF may have a higher risk of developing atherosclerotic vascular disease in various vascular beds and chronic kidney disease; conversely, patients with atherosclerotic disease may have an increased risk of developing AF. AF should be considered a truly systemic vascular disease, since it brings together several hemodynamic and systemic changes, including inflammation, oxidative stress, activation of the renin-angiotensin-aldosterone and sympathetic systems, as well as a prothrombotic state and endothelial dysfunction. In this regard, patients with AF should be treated based on a holistic approach that is not limited to oral anticoagulation but includes complete vascular protection.

Early glomerular filtration rate decline is associated with hemoglobin rise following dapagliflozin initiation in heart failure with reduced ejection fraction.

INTRODUCTION AND OBJECTIVES: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) induce short-term changes in renal function and hemoglobin. Their pathophysiology is incompletely understood. We aimed to evaluate the relationship between 1- and 3-month estimated glomerular filtration rate (eGFR) and hemoglobin changes following initiation of dapagliflozin in patients with stable heart failure with reduced ejection fraction (HFrEF). METHODS: This is a post hoc analysis of a randomized clinical trial that evaluated the effect of dapagliflozin on 1- and 3-month peak oxygen consumption in outpatients with stable HFrEF (DAPA-VO2 trial, NCT04197635). We used linear mixed regression analysis to assess the relationship between eGFR and hemoglobin changes across treatment arms. RESULTS: A total of 87 patients were evaluated in this substudy. The mean age was 67.0± 10.5 years, and 21 (24.1%) were women. The mean baseline eGFR and hemoglobin were 66.9±20.7mL/min/1.73m2 and 14.3±1.7g/dL, respectively. Compared with placebo, eGFR did not significantly change at either time points in the dapagliflozin group, but hemoglobin significantly increased at 1 and 3 months. At 1 month, the hemoglobin increase was related to decreases in eGFR only in the dapagliflozin arm (P <.001). At 3 months, there was no significant association in either treatment arms (P=.123). Changes in eGFR were not associated with changes in peak oxygen consumption, quality of life, or natriuretic peptides. CONCLUSIONS: In patients with stable HFrEF, 1-month changes in eGFR induced by dapagliflozin are inversely related to changes in hemoglobin. This association was no longer significant at 3 months.

Dinaciclib synergizes with BH3 mimetics targeting BCL-2 and BCL-XL in multiple myeloma cell lines partially dependent on MCL-1 and in plasma cells from patients.

A better understanding of multiple myeloma (MM) biology has led to the development of novel therapies. However, MM is still an incurable disease and new pharmacological strategies are needed. Dinaciclib, a multiple cyclin-dependent kinase (CDK) inhibitor, which inhibits CDK1, 2, 5 and 9, displays significant antimyeloma activity as found in phase II clinical trials. In this study, we have explored the mechanism of dinaciclib-induced death and evaluated its enhancement by different BH3 mimetics in MM cell lines as well as in plasma cells from MM patients. Our results indicate a synergistic effect of dinaciclib-based combinations with B-cell lymphoma 2 or B-cell lymphoma extra-large inhibitors, especially in MM cell lines with partial dependence on myeloid cell leukemia sequence 1 (MCL-1). Simultaneous treatment with dinaciclib and BH3 mimetics ABT-199 or A-1155463 additionally showed a synergistic effect in plasma cells from MM patients, ex vivo. Altered MM cytogenetics did not affect dinaciclib response ex vivo, alone or in combined treatment, suggesting that these combinations could be a suitable therapeutic option for patients bearing cytogenetic alterations and poor prognosis. This work also opens the possibility to explore cyclin-dependent kinase 9 inhibition as a targeted therapy in MM patients overexpressing or with high dependence on MCL-1.

Ecto-calreticulin expression in multiple myeloma correlates with a failed anti-tumoral immune response and bad prognosis.

Immunogenic cell death (ICD) has been proposed to be a crucial process for antitumor immunosurveillance. ICD is characterized by the exposure and emission of Damage Associated Molecular Patterns (DAMP), including calreticulin (CRT). A positive correlation between CRT exposure or total expression and improved anticancer immunosurveillance has been found in certain cancers, usually accompanied by favorable patient prognosis. In the present study, we sought to evaluate CRT levels in the plasma membrane of CD38+ bone marrow mononuclear cells (BMMCs) isolated from 71 patients with varying degrees of multiple myeloma (MM) disease and examine the possible relationship between basal CRT exposure and the bone marrow immune microenvironment, as well as its connection with different clinical markers. Data show that increased levels of cell surface-CRT were associated with more aggressive clinical features and with worse clinical prognosis in MM. High CRT expression in MM cells was associated with increased infiltration of NK cells, CD8+ T lymphocytes and dendritic cells (DC), indicative of an active anti-tumoral immune response, but also with a significantly higher presence of immunosuppressive Treg cells and increased expression of PD-L1 in myeloma cells.

Bending oxygen saturation index and risk of worsening heart failure events in chronic heart failure.

AIMS: Bendopnea is a clinical symptom of advanced heart failure with uncertain prognostic value. We aimed to evaluate whether bendopnea and the change in oxygen saturation when bending forward (bending oxygen saturation index [BOSI]) are associated with adverse outcomes in ambulatory chronic heart failure (CHF) patients. METHODS AND RESULTS: We prospectively evaluated 440 subjects with symptomatic CHF. BOSI was defined as the difference between sitting and bending oxygen saturation (SpO2 ). The endpoint was the total number of worsening heart failure (WHF) events (heart failure hospitalization or urgent heart failure visit requiring parenteral diuretic therapy). The mean age was 74 ± 10 years, 257 (58.6%) were male, and 226 (51.4%) had a left ventricular ejection fraction <50%. Bendopnea was present in 94 (21.4%) patients, and 120 (27.3%) patients had a BOSI ≥-3%. The agreement between BOSI ≥-3% and bendopnea was moderate (Gwet's AC 0.482, p < 0.001). At a median (p25%-p75%) follow-up of 2.17 years (0.88-3.16), we registered 441 WHF events in 148 patients. After multivariable adjustment, BOSI was independently associated with the risk for total WHF episodes (overall, p < 0.001). Compared to improvement/no change in SpO2 when bending (BOSI 0%), those with BOSI ≥-3% showed an increased risk of WHF events (incidence rate ratio [IRR] 2.16, 95% confidence interval [CI] 1.67-2.79; p < 0.001). In contrast, bendopnea was not associated with the risk of total WHF episodes (IRR 1.04, 95% CI 0.83-1.31; p = 0.705). CONCLUSIONS: In ambulatory and stable CHF patients, BOSI ≥-3% and not bendopnea was independently associated with an increased risk of total (first and recurrent) WHF episodes. Awareness of SpO2 while assessing bendopnea may be a useful tool for predicting heart failure decompensations.

Short-term effects of dapagliflozin on maximal functional capacity in heart failure with reduced ejection fraction (DAPA-VO2 ): a randomized clinical trial.

AIMS: This study aimed to evaluate the effect of dapagliflozin on 1 and 3-month maximal functional capacity in patients with stable heart failure with reduced ejection fraction (HFrEF). METHODS AND RESULTS: In this multicentre, randomized, double-blind clinical trial, 90 stable patients with HFrEF were randomly assigned to receive either dapagliflozin (n = 45) or placebo (n = 45). The primary outcome was a change in peak oxygen consumption (peakVO2 ) at 1 and 3 months. Secondary endpoints were changes at 1 and 3 months in 6-min walk test (6MWT) distance, quality of life (Minnesota Living with Heart Failure Questionnaire [MLHFQ]), and echocardiographic parameters (diastolic function, left chamber volumes, and left ventricular ejection fraction). We used linear mixed regression analysis to compare endpoint changes. Estimates were adjusted for multiple comparisons. The mean age was 67.1 ± 10.7 years, 69 (76.7%) were men, 29 (32.2%) had type 2 diabetes, and 80 (88.9%) were in New York Heart Association class II. Baseline means of peakVO2 , 6MWT and MLHFQ were 13.2 ± 3.5 ml/kg/min, 363 ± 110 m, and 23.1 ± 16.2, respectively. The median (25th-75th percentile) of N-terminal pro-brain natriuretic peptide was 1221 pg/ml (889-2100). Most patients were on treatment with sacubitril/valsartan (88.9%), beta-blockers (91.1%), and mineralocorticoid receptor antagonists (74.4%). PeakVO2 significantly increased in patients on treatment with dapagliflozin (1 month: +Δ 1.09 ml/kg/min, 95% confidence interval [CI] 0.14-2.04; p = 0.021, and 3 months: +Δ 1.06 ml/kg/min, 95% CI 0.07-2.04; p = 0.032). Similar positive findings were found when evaluating changes from baseline. No significant differences were observed in secondary endpoints. CONCLUSIONS: Among patients with stable HFrEF, dapagliflozin resulted in a significant improvement in peakVO2 at 1 and 3 months. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04197635.