Inpatient initiation of sodium-glucose cotransporter-2 inhibitors: the prescribing learning curve.

We aimed to describe the safety and tolerability of initiation of sodium-glucose cotransporter 2 inhibitors (SGLT2i) during hospitalisation with heart failure, and the frequency of, and reasons for, subsequent discontinuation. In total, 934 patients who were not already prescribed a SGLT2i were hospitalised with heart failure, 77 (8%) were initiated on a SGLT2i a median of five (3-8.5) days after admission and two (0.5-5) days prior to discharge. During a median follow-up of 182 (124-250) days, SGLT2i were discontinued for 10 (13%) patients, most frequently due to deteriorating renal function. We observed reductions in body weight (mean difference 2.0 ± 0.48 kg, p<0.001), systolic blood pressure (mean difference 9.5 ± 1.9 kg, p<0.001) and small, non-significant reductions in estimated glomerular filtration rate (eGFR mean difference 2.0 ± 1.5 ml/min/1.73 m2, p=0.19) prior to initiation, with further modest reductions in weight (mean difference 1.2 ± 0.4 kg, p=0.006) but not systolic blood pressure (2.4 ± 1.5 mmHg, p=0.13) or eGFR following initiation of SGLT2i. At discharge the proportion prescribed a beta blocker (44% to 92%), angiotensin-receptor/neprilysin inhibitor (6% to 44%) and mineralocorticoid-receptor antagonist (35% to 85%) had increased. In conclusion, inpatient initiation of SGLT2i was safe and well tolerated in a real-world cohort of patients hospitalised with worsening HF. We observed a 13% frequency of discontinuation or serious side effects.

Echocardiographic screening for heart failure and optimization of the care pathway for individuals with pacemakers: a randomized controlled trial.

Individuals with pacemakers are at increased risk of left ventricular systolic dysfunction (LVSD). Whether screening for and optimizing the medical management of LVSD in these individuals can improve clinical outcomes is unknown. In the present study, in a multicenter controlled trial (OPT-PACE), we randomized 1,201 patients (717 men) with a pacemaker to echocardiography screening or usual care. In the screening arm, LVSD was detected in 201 of 600 (34%) patients, who then received management in either primary care or a specialist heart failure (HF) and devices clinic. The primary outcome of the trial was the difference in a composite of time to first HF hospitalization or death. Over 31 months (interquartile range = 30-40 months), the primary outcome occurred in 106 of 600 (18%) patients receiving echocardiography screening, which was not significantly different compared with the occurrence of the primary outcome in 115 of 601 (19%) patients receiving the usual care (hazard ratio = 0.89; 95% confidence interval = 0.69, 1.17). In a prespecified, nonrandomized, exploratory analysis, patients with LVSD managed by the specialist clinic experienced the primary outcome event less frequently than those managed in primary care. The results of this trial indicate that echocardiography screening commonly identifies LVSD in individuals with pacemakers but alone does not alter outcomes. ClinicalTrials.gov registration: NCT01819662 .

Is conduction system pacing a panacea for pacemaker therapy?

INTRODUCTION: While supported by robust evidence and decades of clinical experience, right ventricular apical pacing for bradycardia is associated with a risk of progressive left ventricular dysfunction. Cardiac resynchronization therapy for heart failure with reduced ejection fraction can result in limited electrical resynchronization due to anatomical constraints and epicardial stimulation. In both settings, directly stimulating the conduction system below the atrio-ventricular node (either the bundle of His or the left bundle branch area) has potential to overcome these limitations. Conduction system pacing has met with considerable enthusiasm in view of the more physiological electrical conduction pattern, is rapidly becoming the preferred option of pacing for bradycardia, and is gaining momentum as an alternative to conventional biventricular pacing. AREAS COVERED: This article provides a review of the current efficacy and safety data for both people requiring treatment for bradycardia and the management of heart failure with conduction delay and discusses the possible future roles for conduction system pacing in routine clinical practice. EXPERT OPINION: Conduction system pacing might be the holy grail of pacemaker therapy without the disadvantages of current approaches. However, hypothesis and enthusiasm are no match for robust data, demonstrating at least equivalent efficacy and safety to standard approaches.

Flt3 agonist enhances immunogenicity of arenavirus vector-based simian immunodeficiency virus vaccine in macaques.

Arenaviral vaccine vectors encoding simian immunodeficiency virus (SIV) immunogens are capable of inducing efficacious humoral and cellular immune responses in nonhuman primates. Several studies have evaluated the use of immune modulators to further enhance vaccine-induced T-cell responses. The hematopoietic growth factor Flt3L drives the expansion of various bone marrow progenitor populations, and administration of Flt3L was shown to promote expansion of dendritic cell populations in spleen and blood, which are targets of arenaviral vectors. Therefore, we evaluated the potential of Flt3 signaling to enhance the immunogenicity of arenaviral vaccines encoding SIV immunogens (SIVSME543 Gag, Env, and Pol) in rhesus macaques, with a rhesus-specific engineered Flt3L-Fc fusion protein. In healthy animals, administration of Flt3L-Fc led to a 10- to 100-fold increase in type 1 dendritic cells 7 days after dosing, with no antidrug antibody (ADA) generation after repeated dosing. We observed that administration of Flt3L-Fc fusion protein 7 days before arenaviral vaccine increased the frequency and activation of innate immune cells and enhanced T-cell activation with no treatment-related adverse events. Flt3L-Fc administration induced early innate immune activation, leading to a significant enhancement in magnitude, breadth, and polyfunctionality of vaccine-induced T-cell responses. The Flt3L-Fc enhancement in vaccine immunogenicity was comparable to a combination with αCTLA-4 and supports the use of safe and effective variants of Flt3L to augment therapeutic vaccine-induced T-cell responses.IMPORTANCEInduction of a robust human immunodeficiency virus (HIV)-specific CD4+ and CD8+ T-cell response through therapeutic vaccination is considered essential for HIV cure. Arenaviral vaccine vectors encoding simian immunodeficiency virus (SIV) immunogens have demonstrated strong immunogenicity and efficacy in nonhuman primates. Here, we demonstrate that the immunogenicity of arenaviral vectors encoding SIV immunogens can be enhanced by administration of Flt3L-Fc fusion protein 7 days before vaccination. Flt3L-Fc-mediated increase in dendritic cells led to robust improvements in vaccine-induced T- and B-cell responses compared with vaccine alone, and Flt3L-Fc dosing was not associated with any treatment-related adverse events. Importantly, immune modulation by either Flt3L-Fc or αCTLA-4 led to comparable enhancement in vaccine response. These results indicate that the addition of Flt3L-Fc fusion protein before vaccine administration can significantly enhance vaccine immunogenicity. Thus, safe and effective Flt3L variants could be utilized as part of a combination therapy for HIV cure.

Diabetes mellitus does not alter mortality or hospitalisation risk in patients with newly diagnosed heart failure with preserved ejection fraction: Time to rethink pathophysiological models of disease progression.

INTRODUCTION: Type 2 diabetes is a common and adverse prognostic co-morbidity for patients with heart failure with reduced ejection fraction (HFrEF). The effect of diabetes on long-term outcomes for heart failure with preserved ejection fraction (HFpEF) is less established. METHODS: Prospective cohort study of patients referred to a regional HF clinic with newly diagnosed with HFrEF and HFpEF according to the 2016 European Society of Cardiology guidelines. The association between diabetes, all-cause mortality and hospitalisation was quantified using Kaplan-Meier or Cox regression analysis. RESULTS: Between 1st May 2012 and 1st May 2013, of 960 unselected consecutive patients referred with suspected HF, 464 and 314 patients met the criteria for HFpEF and HFrEF respectively. Within HFpEF and HFrEF groups, patients with diabetes were more frequently male and in both groups patients with diabetes were more likely to be treated with ß-adrenoceptor antagonists and angiotensin converting enzyme inhibitors. After adjustment for age, sex, medical therapy and co-morbidities, diabetes was associated with increased mortality in individuals with HFrEF (HR 1.46 95% CI: 1.05-2.02; p = .023), but not in those with HFpEF (HR 1.26 95% CI 0.92-1.72; p = .146). CONCLUSION: In unselected patients with newly diagnosed HF, diabetes is not an adverse prognostic marker in patients with HFpEF, but is in HFrEF.

Preclinical evaluation of two phylogenetically distant arenavirus vectors for the development of novel immunotherapeutic combination strategies for cancer treatment.

BACKGROUND: Engineered arenavirus vectors have recently been developed to leverage the body's immune system in the fight against chronic viral infections and cancer. Vectors based on Pichinde virus (artPICV) and lymphocytic choriomeningitis virus (artLCMV) encoding a non-oncogenic fusion protein of human papillomavirus (HPV)16 E6 and E7 are currently being tested in patients with HPV16+ cancer, showing a favorable safety and tolerability profile and unprecedented expansion of tumor-specific CD8+ T cells. Although the strong antigen-specific immune response elicited by artLCMV vectors has been demonstrated in several preclinical models, PICV-based vectors are much less characterized. METHODS: To advance our understanding of the immunobiology of these two vectors, we analyzed and compared their individual properties in preclinical in vivo and in vitro systems. Immunogenicity and antitumor effect of intratumoral or intravenous administration of both vectors, as well as combination with NKG2A blockade, were evaluated in naïve or TC-1 mouse tumor models. Flow cytometry, Nanostring, and histology analysis were performed to characterize the tumor microenvironment (TME) and T-cell infiltrate following treatment. RESULTS: Despite being phylogenetically distant, both vectors shared many properties, including preferential infection and activation of professional antigen-presenting cells, and induction of potent tumor-specific CD8+ T-cell responses. Systemic as well as localized treatment induced a proinflammatory shift in the TME, promoting the infiltration of inducible T cell costimulator (ICOS)+CD8+ T cells capable of mediating tumor regression and prolonging survival in a TC-1 mouse tumor model. Still, there was evidence of immunosuppression built-up over time, and increased expression of H2-T23 (ligand for NKG2A T cell inhibitory receptor) following treatment was identified as a potential contributing factor. NKG2A blockade improved the antitumor efficacy of artARENA vectors, suggesting a promising new combination approach. This demonstrates how detailed characterization of arenavirus vector-induced immune responses and TME modulation can inform novel combination therapies. CONCLUSIONS: The artARENA platform represents a strong therapeutic vaccine approach for the treatment of cancer. The induced antitumor immune response builds the backbone for novel combination therapies, which warrant further investigation.

Efficacy of LCMV-based cancer immunotherapies is unleashed by intratumoral injections of polyI:C.

BACKGROUND: Lymphocytic choriomeningitis virus (LCMV) belongs to the Arenavirus family known for inducing strong cytotoxic T-cell responses in both mice and humans. LCMV has been engineered for the development of cancer immunotherapies, currently undergoing evaluation in phase I/II clinical trials. Initial findings have demonstrated safety and an exceptional ability to activate and expand tumor-specific T lymphocytes. Combination strategies to maximize the antitumor effectiveness of LCMV-based immunotherapies are being explored. METHODS: We assessed the antitumor therapeutic effects of intratumoral administration of polyinosinic:polycytidylic acid (poly(I:C)) and systemic vaccination using an LCMV-vector expressing non-oncogenic versions of the E6 and E7 antigens of human papillomavirus 16 (artLCMV-E7E6) in a bilateral model engrafting TC-1/A9 cells. This cell line, derived from the parental TC-1, exhibits low MHC class I expression and is highly immune-resistant. The mechanisms underlying the combination's efficacy were investigated through bulk RNA-seq, flow cytometry analyses of the tumor microenvironment, selective depletions using antibodies and clodronate liposomes, Batf3 deficient mice, and in vivo bioluminescence experiments. Finally, we assessed the antitumor effectiveness of the combination of artLCMV-E7E6 with BO-112, a GMP-grade poly(I:C) formulated in polyethyleneimine, currently under evaluation in clinical trials. RESULTS: Intratumoral injection of poly(I:C) enhanced the antitumor efficacy of artLCMV-E7E6 in both injected and non-injected tumor lesions. The combined treatment resulted in a significant delay in tumor growth and often complete eradication of several tumor lesions, leading to significantly improved survival compared with monotherapies. While intratumoral administration of poly(I:C) did not impact LCMV vector biodistribution or transgene expression, it significantly modified leucocyte infiltrates within the tumor microenvironment and amplified systemic efficacy through proinflammatory cytokines/chemokines such as CCL3, CCL5, CXCL10, TNF, IFNα, and IL12p70. Upregulation of MHC on tumor cells and a reconfiguration of the gene expression programs related to tumor vasculature, leucocyte migration, and the activation profile of tumor-infiltrating CD8+ T lymphocytes were observed. Indeed, the antitumor effect relied on the functions of CD8+ T lymphocytes and macrophages. The synergistic efficacy of the combination was further confirmed when BO-112 was included. CONCLUSION: Intratumoral injection of poly(I:C) sensitizes MHClow tumors to the antitumor effects of artLCMV-E7E6, resulting in a potent therapeutic synergy.

Studying Adipose Endothelial Cell/Adipocyte Cross-Talk in Human Subcutaneous Adipose Tissue.

Microvascular endothelial cells (MVECs) have many critical roles, including control of vascular tone, regulation of thrombosis, and angiogenesis. Significant heterogeneity in endothelial cell (EC) genotype and phenotype depends on their vascular bed and host disease state. The ability to isolate MVECs from tissue-specific vascular beds and individual patient groups offers the opportunity to directly compare MVEC function in different disease states. Here, using subcutaneous adipose tissue (SAT) taken at the time of insertion of cardiac implantable electronic devices (CIED), we describe a method for the isolation of a pure population of functional human subcutaneous adipose tissue MVEC (hSATMVEC) and an experimental model of hSATMVEC-adipocyte cross-talk. hSATMVEC were isolated following enzymatic digestion of SAT by incubation with anti-CD31 antibody-coated magnetic beads and passage through magnetic columns. hSATMVEC were grown and passaged on gelatin-coated plates. Experiments used cells at passages 2-4. Cells maintained classic features of EC morphology until at least passage 5. Flow cytometric assessment showed 99.5% purity of isolated hSATMVEC, defined as CD31+/CD144+/CD45-. Isolated hSATMVEC from controls had a population doubling time of approximately 57 h, and active proliferation was confirmed using a cell proliferation imaging kit. Isolated hSATMVEC function was assessed using their response to insulin stimulation and angiogenic tube-forming potential. We then established an hSATMVEC-subcutaneous adipocyte co-culture model to study cellular cross-talk and demonstrated a downstream effect of hSATMVEC on adipocyte function. hSATMVEC can be isolated from SAT taken at the time of CIED insertion and are of sufficient purity to both experimentally phenotype and study hSATMVEC-adipocyte cross-talk.

Sodium-glucose cotransporter 2 inhibitors influence skeletal muscle pathology in patients with heart failure and reduced ejection fraction.

AIMS: Patients with heart failure and reduced ejection fraction (HFrEF) exhibit skeletal muscle pathology, which contributes to symptoms and decreased quality of life. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve clinical outcomes in HFrEF but their mechanism of action remains poorly understood. We aimed, therefore, to determine whether SGLT2i influence skeletal muscle pathology in patients with HFrEF. METHODS AND RESULTS: Muscle biopsies from 28 male patients with HFrEF (New York Heart association class I-III) treated with SGLT2i (>12 months) or without SGLT2i were compared. Comprehensive analyses of muscle structure (immunohistochemistry), transcriptome (RNA sequencing), and metabolome (liquid chromatography-mass spectrometry) were performed, and serum inflammatory profiling (ELISA). Experiments in mice (n = 16) treated with SGLT2i were also performed. Myofiber atrophy was ~20% less in patients taking SGLT2i (p = 0.07). Transcriptomics and follow-up measures identified a unique signature in patients taking SGLT2i related to beneficial effects on atrophy, metabolism, and inflammation. Metabolomics identified influenced tryptophan metabolism in patients taking SGLT2i: kynurenic acid was 24% higher and kynurenine was 32% lower (p < 0.001). Serum profiling identified that SGLT2i treatment was associated with lower (p < 0.05) pro-inflammatory cytokines by 26-64% alongside downstream muscle interleukin (IL)-6-JAK/STAT3 signalling (p = 008 and 0.09). Serum IL-6 and muscle kynurenine were correlated (R = 0.65; p < 0.05). Muscle pathology was lower in mice treated with SGLT2i indicative of a conserved mammalian response to treatment. CONCLUSIONS: Treatment with SGLT2i influenced skeletal muscle pathology in patients with HFrEF and was associated with anti-atrophic, anti-inflammatory, and pro-metabolic effects. These changes may be regulated via IL-6-kynurenine signalling. Together, clinical improvements following SGLT2i treatment in patients with HFrEF may be partly explained by their positive effects on skeletal muscle pathology.

Integration of implantable device therapy in patients with heart failure. A clinical consensus statement from the Heart Failure Association (HFA) and European Heart Rhythm Association (EHRA) of the European Society of Cardiology (ESC).

Implantable devices form an integral part of the management of patients with heart failure (HF) and provide adjunctive therapies in addition to cornerstone drug treatment. Although the number of these devices is growing, only few are supported by robust evidence. Current devices aim to improve haemodynamics, improve reverse remodelling, or provide electrical therapy. A number of these devices have guideline recommendations and some have been shown to improve outcomes such as cardiac resynchronization therapy, implantable cardioverter-defibrillators and long-term mechanical support. For others, more evidence is still needed before large-scale implementation can be strongly advised. Of note, devices and drugs can work synergistically in HF as improved disease control with devices can allow for further optimization of drug therapy. Therefore, some devices might already be considered early in the disease trajectory of HF patients, while others might only be reserved for advanced HF. As such, device therapy should be integrated into HF care programmes. Unfortunately, implementation of devices, including those with the greatest evidence, in clinical care pathways is still suboptimal. This clinical consensus document of the Heart Failure Association (HFA) and European Heart Rhythm Association (EHRA) of the European Society of Cardiology (ESC) describes the physiological rationale behind device-provided therapy and also device-guided management, offers an overview of current implantable device options recommended by the guidelines and proposes a new integrated model of device therapy as a part of HF care.

A replicating LCMV-based vaccine for the treatment of solid tumors.

Harnessing the immune system to eradicate tumors requires identification and targeting of tumor antigens, including tumor-specific neoantigens and tumor-associated self-antigens. Tumor-associated antigens are subject to existing immune tolerance, which must be overcome by immunotherapies. Despite many novel immunotherapies reaching clinical trials, inducing self-antigen-specific immune responses remains challenging. Here, we systematically investigate viral-vector-based cancer vaccines encoding a tumor-associated self-antigen (TRP2) for the treatment of established melanomas in preclinical mouse models, alone or in combination with adoptive T cell therapy. We reveal that, unlike foreign antigens, tumor-associated antigens require replication of lymphocytic choriomeningitis virus (LCMV)-based vectors to break tolerance and induce effective antigen-specific CD8+ T cell responses. Immunization with a replicating LCMV vector leads to complete tumor rejection when combined with adoptive TRP2-specific T cell transfer. Importantly, immunization with replicating vectors leads to extended antigen persistence in secondary lymphoid organs, resulting in efficient T cell priming, which renders previously "cold" tumors open to immune infiltration and reprograms the tumor microenvironment to "hot." Our findings have important implications for the design of next-generation immunotherapies targeting solid cancers utilizing viral vectors and adoptive cell transfer.

Outcomes following cardiac resynchronisation therapy in older people.

INTRODUCTION: Older patients may be less likely to receive cardiac resynchronisation therapy (CRT) for the management of heart failure. We aimed to describe the differences in clinical response, complications, and subsequent outcomes following CRT implantation compared to younger patients. METHODS: We conducted a retrospective cohort study of unselected, consecutive patients implanted with CRT devices between March 2008 and July 2017. We recorded complications, symptomatic and echocardiographic response, hospitalisation for heart failure, and all-cause mortality comparing patients aged <70, 70-79 and ≥ 80 years. RESULTS: Five hundred and seventy-four patients (median age 76 years [interquartile range 68-81], 73.3% male) received CRT. At baseline, patients aged ≥80 years had worse symptoms, were more likely to have co-morbidities, and less likely to be receiving comprehensive medical therapy, although left ventricular function was similar. Older patients were less likely to receive CRT-defibrillators compared to CRT-pacemakers. Complications were infrequent and not more common in older patients. Age was not a predictor of symptomatic or echocardiographic response to CRT (67.2%, 71.2% and 62.6% responders in patients aged <70, 70-79 and ≥ 80 years, respectively; P = 0.43), and time to first heart failure hospitalisation was similar across age groups (P = 0.28). Ten-year survival was lower for older patients (49.9%, 23.9% and 6.8% in patients aged <70, 70-79 and ≥ 80 years, respectively; P < 0.001). CONCLUSIONS: The benefits of CRT on symptoms and left ventricular function were not different in older patients despite a greater burden of co-morbidities and less optimal medical therapy. These findings support the use of CRT in an ageing population.

Percutaneous mitral annuloplasty with the Carillon device: Outcomes in proportionate and disproportionate functional mitral regurgitation.

BACKGROUND: It has been suggested that the disparity of outcomes between the studies of transcutaneous edge-to-edge repair (TEER) for functional mitral regurgitation (FMR) in heart failure with reduced ejection fraction (HFrEF) could be due to systematic differences in the populations studied. One proposal is that there are 2 broad groups: those with proportional FMR who respond less favorably, and those in whom the FMR is greater than expected (disproportionate) FMR where edge-to-edge TEER seems to be more effective. Whether this grouping is relevant for other percutaneous interventions for FMR is unknown. OBJECTIVES: We sought to compare clinical and echocardiographic outcomes of patients with HFrEF and proportionate and disproportionate FMR treated with indirect annuloplasty using the Carillon device. METHODS: This is a pooled analysis from 3 trials of patients with FMR. Key patient eligibility in these trials specified persistent grade 2+ to 4+ FMR with >5.5 cm left ventricular (LV) end-diastolic diameter (LVEDD) and reduced ejection fraction. Patients with an effective regurgitant orifice area/LV end-diastolic volume (EROA/LVEDV) ratio under 0.15 were assigned to the proportionate FMR group (n = 74;65%) and those with a ratio above 0.15 were classed as having disproportionate FMR (n = 39;35%). RESULTS: At 12 months following treatment, both groups showed improvements in all MR variables including regurgitation volume, EROA and vena contracta. Moreover, in patients with proportionate MR there were clinically relevant and statistically significant improvements in LV volumes and diameters. There was no independent relationship between the degree of proportionality as a continuous variable and the remodeling response to Carillon therapy (change in LVEDV r = 0.17; change in LVESV r = 0.14). CONCLUSION: Percutaneous mitral annuloplasty with the Carillon device reduces MR in patients with both proportionate and disproportionate FMR, and also results in LV reverse remodeling in those with proportionate FMR. The effect on remodeling remains to be verified in a large-scale trial.

Atrial secondary mitral regurgitation: prevalence, characteristics, management, and long-term outcomes.

BACKGROUND: The prevalence, clinical characteristics, management and long-term outcomes of patients with atrial secondary mitral regurgitation (ASMR) are not well described. METHODS: We performed a retrospective, observational study of consecutive patients with grade III/IV MR determined by transthoracic echocardiography. The aetiology of MR was grouped as being either primary (due to degenerative mitral valve disease), ventricular SMR (VSMR: due to left ventricular dilatation/dysfunction), ASMR (due to LA dilatation), or other. RESULTS: A total of 388 individuals were identified who had grade III/IV MR; of whom 37 (9.5%) had ASMR, 113 (29.1%) had VSMR, 193 had primary MR (49.7%), and 45 (11.6%) were classified as having other causes. Compared to MR of other subtypes, patients with ASMR were on average older (median age 82 [74-87] years, p < 0.001), were more likely to be female (67.6%, p = 0.004) and usually had atrial fibrillation (83.8%, p = 0.001). All-cause mortality was highest in patients with ASMR (p < 0.001), but similar to that in patients with VSMR once adjusted for age and sex (hazard ratio [HR] 0.81, 95% confidence interval [CI] 0.52-1.25). Hospitalisation for worsening heart failure was more commonly observed in those with ASMR or VSMR (p < 0.001) although was similar between these groups when age and sex were accounted for (HR 0.74, 95% CI 0.34-1.58). For patients with ASMR, the only variables associated with outcomes were age and co-morbidities. CONCLUSIONS: ASMR is a prevalent and distinct disease process associated with a poor prognosis, with much of this related to older age and co-morbidities.