Hospitalization of Symptomatic Patients With Heart Failure and Moderate to Severe Functional Mitral Regurgitation Treated With MitraClip: Insights From RESHAPE-HF2.

BACKGROUND: For patients with functional mitral regurgitation (FMR) and symptomatic heart failure (HF), randomized trials of mitral transcatheter edge-to-edge repair (M-TEER) have produced conflicting results. OBJECTIVES: This study sought to assess the impact of M-TEER on hospitalization rates, and explore the effects of M-TEER on patients who did or did not have a history of recent HF hospitalizations before undergoing M-TEER. METHODS: RESHAPE-HF2 (Randomized Investigation of the MitraClip Device in Heart Failure: 2nd Trial in Patients with Clinically Significant Functional Mitral Regurgitation) included patients with symptomatic HF and moderate to severe FMR (mean effective regurgitant orifice area 0.25 cm2; 14% >0.40 cm2, 23% <0.20 cm2) and showed that M-TEER reduced recurrent HF hospitalizations with and without the addition of cardiovascular (CV) death and improved quality of life. We now report the results of prespecified analyses on hospitalization rates and for the subgroup of patients (n = 333) with a HF hospitalization in the 12 months before randomization. RESULTS: At 24 months, the time to first event of CV death or HF hospitalization (HR: 0.65; 95% CI: 0.49-0.85; P = 0.002), the rate of recurrent CV hospitalizations (rate ratio [RR]: 0.75; 95% CI: 0.57-0.99; P = 0.046), the composite rate of recurrent CV hospitalizations and all-cause mortality (RR: 0.74; 95% CI: 0.57-0.95; P = 0.017), and of recurrent CV death and CV hospitalizations (RR: 0.76; 95% CI: 0.58-0.99; P = 0.040), were all lower in the M-TEER group. The RR of recurrent hospitalizations for any cause was 0.82 (95% CI: 0.63-1.07; P = 0.15) for patients in the M-TEER group vs control group patients. Patients randomized to M-TEER lost fewer days due to death or HF hospitalization (13.9% [95% CI: 13.0%-14.8%] vs 17.4% [95% CI: 16.4%-18.4%] of follow-up time; P < 0.0001, and 1,067 vs 1,776 total days lost; P < 0.0001). Patients randomized to M-TEER also had better NYHA functional class at 30 days and at 6, 12, and 24 months of follow-up (P < 0.0001). A history of HF hospitalizations before randomization was associated with worse outcomes and greater benefit with M-TEER on the rate of the composite of recurrent HF hospitalizations and CV death (Pinteraction = 0.03) and of recurrent HF hospitalizations within 24 months (Pinteraction = 0.06). CONCLUSIONS: These results indicate that a broader application of M-TEER in addition to optimal guideline-directed medical therapy should be considered among patients with symptomatic HF and moderate to severe FMR, particularly in those with a history of a recent hospitalization for HF.

Transcatheter Valve Repair in Heart Failure with Moderate to Severe Mitral Regurgitation.

BACKGROUND: Whether transcatheter mitral-valve repair improves outcomes in patients with heart failure and functional mitral regurgitation is uncertain. METHODS: We conducted a randomized, controlled trial involving patients with heart failure and moderate to severe functional mitral regurgitation from 30 sites in nine countries. The patients were assigned in a 1:1 ratio to either transcatheter mitral-valve repair and guideline-recommended medical therapy (device group) or medical therapy alone (control group). The three primary end points were the rate of the composite of first or recurrent hospitalization for heart failure or cardiovascular death during 24 months; the rate of first or recurrent hospitalization for heart failure during 24 months; and the change from baseline to 12 months in the score on the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS; scores range from 0 to 100, with higher scores indicating better health status). RESULTS: A total of 505 patients underwent randomization: 250 were assigned to the device group and 255 to the control group. At 24 months, the rate of first or recurrent hospitalization for heart failure or cardiovascular death was 37.0 events per 100 patient-years in the device group and 58.9 events per 100 patient-years in the control group (rate ratio, 0.64; 95% confidence interval [CI], 0.48 to 0.85; P = 0.002). The rate of first or recurrent hospitalization for heart failure was 26.9 events per 100 patient-years in the device group and 46.6 events per 100 patient-years in the control group (rate ratio, 0.59; 95% CI, 0.42 to 0.82; P = 0.002). The KCCQ-OS score increased by a mean (±SD) of 21.6±26.9 points in the device group and 8.0±24.5 points in the control group (mean difference, 10.9 points; 95% CI, 6.8 to 15.0; P<0.001). Device-specific safety events occurred in 4 patients (1.6%). CONCLUSIONS: Among patients with heart failure with moderate to severe functional mitral regurgitation who received medical therapy, the addition of transcatheter mitral-valve repair led to a lower rate of first or recurrent hospitalization for heart failure or cardiovascular death and a lower rate of first or recurrent hospitalization for heart failure at 24 months and better health status at 12 months than medical therapy alone. (Funded by Abbott Laboratories; RESHAPE-HF2 ClinicalTrials.gov number, NCT02444338.).

Chronic coronary syndromes without standard modifiable cardiovascular risk factors and outcomes: the CLARIFY registry.

BACKGROUND AND AIMS: It has been reported that patients without standard modifiable cardiovascular (CV) risk factors (SMuRFs-diabetes, dyslipidaemia, hypertension, and smoking) presenting with first myocardial infarction (MI), especially women, have a higher in-hospital mortality than patients with risk factors, and possibly a lower long-term risk provided they survive the post-infarct period. This study aims to explore the long-term outcomes of SMuRF-less patients with stable coronary artery disease (CAD). METHODS: CLARIFY is an observational cohort of 32 703 outpatients with stable CAD enrolled between 2009 and 2010 in 45 countries. The baseline characteristics and clinical outcomes of patients with and without SMuRFs were compared. The primary outcome was a composite of 5-year CV death or non-fatal MI. Secondary outcomes were 5-year all-cause mortality and major adverse cardiovascular events (MACE-CV death, non-fatal MI, or non-fatal stroke). RESULTS: Among 22 132 patients with complete risk factor and outcome information, 977 (4.4%) were SMuRF-less. Age, sex, and time since CAD diagnosis were similar across groups. SMuRF-less patients had a lower 5-year rate of CV death or non-fatal MI (5.43% [95% CI 4.08-7.19] vs. 7.68% [95% CI 7.30-8.08], P = 0.012), all-cause mortality, and MACE. Similar results were found after adjustments. Clinical event rates increased steadily with the number of SMuRFs. The benefit of SMuRF-less status was particularly pronounced in women. CONCLUSIONS: SMuRF-less patients with stable CAD have a substantial but significantly lower 5-year rate of CV death or non-fatal MI than patients with risk factors. The risk of CV outcomes increases steadily with the number of risk factors.

ErbB2-NOTCH1 axis controls autophagy in cardiac cells.

Although the epidermal growth factor receptor 2 (ErbB2) and Notch1 signaling pathways have both significant roles in regulating cardiac biology, their interplay in the heart remains poorly investigated. Here, we present evidence of a crosstalk between ErbB2 and Notch1 in cardiac cells, with effects on autophagy and proliferation. Overexpression of ErbB2 in H9c2 cardiomyoblasts induced Notch1 activation in a post-transcriptional, p38-dependent manner, while ErbB2 inhibition with the specific inhibitor, lapatinib, reduced Notch1 activation. Moreover, incubation of H9c2 cells with lapatinib resulted in stalled autophagic flux and decreased proliferation, consistent with the established cardiotoxicity of this and other ErbB2-targeting drugs. Confirming the findings in H9c2 cells, exposure of primary neonatal mouse cardiomyocytes to exogenous neuregulin-1, which engages ErbB2, stimulated proliferation, and this effect was abrogated by concomitant inhibition of the enzyme responsible for Notch1 activation. Furthermore, the hearts of transgenic mice specifically overexpressing ErbB2 in cardiomyocytes had increased levels of active Notch1 and of Notch-related genes. These data expand the knowledge of ErbB2 and Notch1 functions in the heart and may allow better understanding the mechanisms of the cardiotoxicity of ErbB2-targeting cancer treatments.

Adenovirus small E1A directs activation of Alu transcription at YAP/TEAD- and AP-1-bound enhancers through interactions with the EP400 chromatin remodeler.

Alu retrotransposons, which form the largest family of mobile DNA elements in the human genome, have recently come to attention as a potential source of regulatory novelties, most notably by participating in enhancer function. Even though Alu transcription by RNA polymerase III is subjected to tight epigenetic silencing, their expression has long been known to increase in response to various types of stress, including viral infection. Here we show that, in primary human fibroblasts, adenovirus small e1a triggered derepression of hundreds of individual Alus by promoting TFIIIB recruitment by Alu-bound TFIIIC. Epigenome profiling revealed an e1a-induced decrease of H3K27 acetylation and increase of H3K4 monomethylation at derepressed Alus, making them resemble poised enhancers. The enhancer nature of e1a-targeted Alus was confirmed by the enrichment, in their upstream regions, of the EP300/CBP acetyltransferase, EP400 chromatin remodeler and YAP1 and FOS transcription factors. The physical interaction of e1a with EP400 was critical for Alu derepression, which was abrogated upon EP400 ablation. Our data suggest that e1a targets a subset of enhancer Alus whose transcriptional activation, which requires EP400 and is mediated by the e1a-EP400 interaction, may participate in the manipulation of enhancer activity by adenoviruses.

Percutaneous repair of moderate-to-severe or severe functional mitral regurgitation in patients with symptomatic heart failure: Baseline characteristics of patients in the RESHAPE-HF2 trial and comparison to COAPT and MITRA-FR trials.

AIM: The RESHAPE-HF2 trial is designed to assess the efficacy and safety of the MitraClip device system for the treatment of clinically important functional mitral regurgitation (FMR) in patients with heart failure (HF). This report describes the baseline characteristics of patients enrolled in the RESHAPE-HF2 trial compared to those enrolled in the COAPT and MITRA-FR trials. METHODS AND RESULTS: The RESHAPE-HF2 study is an investigator-initiated, prospective, randomized, multicentre trial including patients with symptomatic HF, a left ventricular ejection fraction (LVEF) between 20% and 50% with moderate-to-severe or severe FMR, for whom isolated mitral valve surgery was not recommended. Patients were randomized 1:1 to a strategy of delivering or withholding MitraClip. Of 506 patients randomized, the mean age of the patients was 70 ± 10 years, and 99 of them (20%) were women. The median EuroSCORE II was 5.3 (2.8-9.0) and median plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) was 2745 (1407-5385) pg/ml. Most patients were prescribed beta-blockers (96%), diuretics (96%), angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor-neprilysin inhibitors (82%) and mineralocorticoid receptor antagonists (82%). The use of sodium-glucose cotransporter 2 inhibitors was rare (7%). Cardiac resynchronization therapy (CRT) devices had been previously implanted in 29% of patients. Mean LVEF, left ventricular end-diastolic volume and effective regurgitant orifice area (EROA) were 31 ± 8%, 211 ± 76 ml and 0.25 ± 0.08 cm2, respectively, whereas 44% of patients had mitral regurgitation severity of grade 4+. Compared to patients enrolled in COAPT and MITRA-FR, those enrolled in RESHAPE-HF2 were less likely to have mitral regurgitation grade 4+ and, on average, HAD lower EROA, and plasma NT-proBNP and higher estimated glomerular filtration rate, but otherwise had similar age, comorbidities, CRT therapy and LVEF. CONCLUSION: Patients enrolled in RESHAPE-HF2 represent a third distinct population where MitraClip was tested in, that is one mainly comprising of patients with moderate-to-severe FMR instead of only severe FMR, as enrolled in the COAPT and MITRA-FR trials. The results of RESHAPE-HF2 will provide crucial insights regarding broader application of the transcatheter edge-to-edge repair procedure in clinical practice.

LATS1 controls CTCF chromatin occupancy and hormonal response of 3D-grown breast cancer cells.

The cancer epigenome has been studied in cells cultured in two-dimensional (2D) monolayers, but recent studies highlight the impact of the extracellular matrix and the three-dimensional (3D) environment on multiple cellular functions. Here, we report the physical, biochemical, and genomic differences between T47D breast cancer cells cultured in 2D and as 3D spheroids. Cells within 3D spheroids exhibit a rounder nucleus with less accessible, more compacted chromatin, as well as altered expression of ~2000 genes, the majority of which become repressed. Hi-C analysis reveals that cells in 3D are enriched for regions belonging to the B compartment, have decreased chromatin-bound CTCF and increased fusion of topologically associating domains (TADs). Upregulation of the Hippo pathway in 3D spheroids results in the activation of the LATS1 kinase, which promotes phosphorylation and displacement of CTCF from DNA, thereby likely causing the observed TAD fusions. 3D cells show higher chromatin binding of progesterone receptor (PR), leading to an increase in the number of hormone-regulated genes. This effect is in part mediated by LATS1 activation, which favors cytoplasmic retention of YAP and CTCF removal.

A COVID-19 specific multiparametric and ECG-based score for the prediction of in-hospital mortality: ELCOVID score.

We aimed to develop and validate a COVID-19 specific scoring system, also including some ECG features, to predict all-cause in-hospital mortality at admission. Patients were retrieved from the ELCOVID study (ClinicalTrials.gov identifier: NCT04367129), a prospective, multicenter Italian study enrolling COVID-19 patients between May to September 2020. For the model validation, we randomly selected two-thirds of participants to create a derivation dataset and we used the remaining one-third of participants as the validation set. Over the study period, 1014 hospitalized COVID-19 patients (mean age 74 years, 61% males) met the inclusion criteria and were included in this analysis. During a median follow-up of 12 (IQR 7-22) days, 359 (35%) patients died. Age (HR 2.25 [95%CI 1.72-2.94], p < 0.001), delirium (HR 2.03 [2.14-3.61], p = 0.012), platelets (HR 0.91 [0.83-0.98], p = 0.018), D-dimer level (HR 1.18 [1.01-1.31], p = 0.002), signs of right ventricular strain (RVS) (HR 1.47 [1.02-2.13], p = 0.039) and ECG signs of previous myocardial necrosis (HR 2.28 [1.23-4.21], p = 0.009) were independently associated to in-hospital all-cause mortality. The derived risk-scoring system, namely EL COVID score, showed a moderate discriminatory capacity and good calibration. A cut-off score of ≥ 4 had a sensitivity of 78.4% and 65.2% specificity in predicting all-cause in-hospital mortality. ELCOVID score represents a valid, reliable, sensitive, and inexpensive scoring system that can be used for the prognostication of COVID-19 patients at admission and may allow the earlier identification of patients having a higher mortality risk who may be benefit from more aggressive treatments and closer monitoring.

A progesterone derivative linked to a stable phospholipid activates breast cancer cell response without leaving the cell membrane.

In hormone-responsive breast cancer cells, progesterone (P4) has been shown to act via its nuclear receptor (nPR), a ligand-activated transcription factor. A small fraction of progesterone receptor is palmitoylated and anchored to the cell membrane (mbPR) forming a complex with estrogen receptor alpha (ERα). Upon hormone exposure, either directly or via interaction with ERα, mbPR activates the SRC/RAS/ERK kinase pathway leading to phosphorylation of nPR by ERK. Kinase activation is essential for P4 gene regulation, as the ERK and MSK1 kinases are recruited by the nPR to its genomic binding sites and trigger chromatin remodeling. An interesting open question is whether activation of mbPR can result in gene regulation in the absence of ligand binding to intracellular progesterone receptor (iPR). This matter has been investigated in the past using P4 attached to serum albumin, but the attachment is leaky and albumin can be endocytosed and degraded, liberating P4. Here, we propose a more stringent approach to address this issue by ensuring attachment of P4 to the cell membrane via covalent binding to a stable phospholipid. This strategy identifies the actions of P4 independent from hormone binding to iPR. We found that a membrane-attached progestin can activate mbPR, the ERK signaling pathway leading to iPR phosphorylation, initial gene regulation and entry into the cell cycle, in the absence of detectable intracellular progestin.

Collinsella aerofaciens as a predictive marker of response to probiotic treatment in non-constipated irritable bowel syndrome.

Probiotics are exploited for adjuvant treatment in IBS, but reliable guidance for selecting the appropriate probiotic to adopt for different forms of IBS is lacking. We aimed to identify markers for recognizing non-constipated (NC) IBS patients that may show significant clinical improvements upon treatment with the probiotic strain Lacticaseibacillus paracasei DG (LDG). To this purpose, we performed a post-hoc analysis of samples collected during a multicenter, double-blind, parallel-group, placebo-controlled trial in which NC-IBS patients were randomized to receive at least 24 billion CFU LDG or placebo capsules b.i.d. for 12 weeks. The primary clinical endpoint was the composite response based on improved abdominal pain and fecal type. The fecal microbiome and serum markers of intestinal (PV1 and zonulin), liver, and kidney functions were investigated. We found that responders (R) in the probiotic arm (25%) differed from non-responders (NR) based on the abundance of 18 bacterial taxa, including the families Coriobacteriaceae, Dorea spp. and Collinsella aerofaciens, which were overrepresented in R patients. These taxa also distinguished R (but not NR) patients from healthy controls. Probiotic intervention significantly reduced the abundance of these bacteria in R, but not in NR. Analogous results emerged for C. aerofaciens from the analysis of data from a previous trial on IBS with the same probiotic. Finally, C. aerofaciens was positively correlated with the plasmalemmal vesicle associated protein-1 (PV-1) and the markers of liver function. In conclusion, LDG is effective on NC-IBS patients with NC-IBS with a greater abundance of potential pathobionts. Among these, C. aerofaciens has emerged as a potential predictor of probiotic efficacy.

Trends in atrial fibrillation-related mortality in Europe, 2008-2019.

AIMS: Update data regarding the atrial fibrillation (AF)-related mortality trend in Europe remain scant. We assess the age- and sex-specific trends in AF-related mortality in the European states between the years 2008 and 2019. METHODS AND RESULTS: Data on cause-specific deaths and population numbers by sex for European countries were retrieved through the publicly available World Health Organization mortality dataset for the years 2008-2019. Atrial fibrillation-related deaths were ascertained when the International Classification of Diseases, 10th Revision code I48 was listed as the underlying cause of death in the medical death certificate. To calculate annual trends, we assessed the average annual % change (AAPC) with relative 95% confidence intervals (CIs) using Joinpoint regression. During the study period, 773 750 AF-related deaths (202 552 males and 571 198 females) occurred in Europe. The age-adjusted mortality rate (AAMR) linearly increased from 12.3 (95% CI: 11.2-12.9) per 100 000 population in 2008 to 15.3 (95% CI: 14.7-15.7) per 100 000 population in 2019 [AAPC: +2.0% (95% CI: 1.6-3.5), P < 0.001] with a more pronounced increase among men [AAPC: +2.7% (95% CI: 1.9-3.5), P < 0.001] compared with women [AAPC: +1.7% (95% CI: 1.1-2.3), P < 0.001] (P for parallelism 0.01). Higher AAMR increases were observed in some Eastern European countries such as Latvia, Lithuania, and Poland, while the lower increases were mainly clustered in Central Europe. CONCLUSION: Over the last decade, the age-adjusted AF-related mortality has increased in Europe, especially among males. Disparities still exist between Western and Eastern European countries.

New-onset atrial fibrillation and chronic coronary syndrome in the CLARIFY registry.

BACKGROUND AND AIMS: Data on new-onset atrial fibrillation (NOAF) in patients with chronic coronary syndromes (CCS) are scarce. This study aims to describe the incidence, predictors, and impact on cardiovascular (CV) outcomes of NOAF in CCS patients. METHODS: Data from the international (45 countries) CLARIFY registry (prospeCtive observational LongitudinAl RegIstry oF patients with stable coronary arterY disease) were used. Among 29 001 CCS outpatients without previously reported AF at baseline, patients with at least one episode of AF/flutter diagnosed during 5-year follow-up were compared with patients in sinus rhythm throughout the study. RESULTS: The incidence rate of NOAF was 1.12 [95% confidence interval (CI) 1.06-1.18] per 100 patient-years (cumulative incidence at 5 years: 5.0%). Independent predictors of NOAF were increasing age, increasing body mass index, low estimated glomerular filtration rate, Caucasian ethnicity, alcohol intake, and low left ventricular ejection fraction, while high triglycerides were associated with lower incidence. New-onset atrial fibrillation was associated with a substantial increase in the risk of adverse outcomes, with adjusted hazard ratios of 2.01 (95% CI 1.61-2.52) for the composite of CV death, non-fatal myocardial infarction, or non-fatal stroke, 2.61 (95% CI 2.04-3.34) for CV death, 1.64 (95% CI 1.07-2.50) for non-fatal myocardial infarction, 2.27 (95% CI 1.85-2.78) for all-cause death, 8.44 (95% CI 7.05-10.10) for hospitalization for heart failure, and 4.46 (95% CI 2.85-6.99) for major bleeding. CONCLUSIONS: Among CCS patients, NOAF is common and is strongly associated with worse outcomes. Whether more intensive preventive measures and more systematic screening for AF would improve prognosis in this population deserves further investigation.

Serum from COVID-19 patients promotes endothelial cell dysfunction through protease-activated receptor 2.

BACKGROUND: Endothelial dysfunction plays a central role in the pathophysiology of COVID-19 and is closely linked to the severity and mortality of the disease. The inflammatory response to SARS-CoV-2 infection can alter the capacity of the endothelium to regulate vascular tone, immune responses, and the balance between anti-thrombotic and pro-thrombotic properties. However, the specific endothelial pathways altered during COVID-19 still need to be fully understood. OBJECTIVE: In this study, we sought to identify molecular changes in endothelial cells induced by circulating factors characteristic of COVID-19. METHODS AND RESULTS: To this aim, we cultured endothelial cells with sera from patients with COVID-19 or non-COVID-19 pneumonia. Through transcriptomic analysis, we were able to identify a distinctive endothelial phenotype that is induced by sera from COVID-19 patients. We confirmed and expanded this observation in vitro by showing that COVID-19 serum alters functional properties of endothelial cells leading to increased apoptosis, loss of barrier integrity, and hypercoagulability. Furthermore, we demonstrated that these endothelial dysfunctions are mediated by protease-activated receptor 2 (PAR-2), as predicted by transcriptome network analysis validated by in vitro functional assays. CONCLUSION: Our findings provide the rationale for further studies to evaluate whether targeting PAR-2 may be a clinically effective strategy to counteract endothelial dysfunction in COVID-19.

[Critical reading of cardiovascular trials with neutral or negative findings]. / Approccio critico all'interpretazione dei trial cardiovascolari con risultati neutri o negativi.

Randomized controlled trials showing a significant benefit are met with enthusiasm because they may change the standard of care for patients who share the clinical and pathophysiologic characteristics of trial participants. Nonetheless, a well-designed and fully executed trial with neutral or negative findings also represents a critically important investigation deserving careful scientific scrutiny. In this paper we propose a 10-step approach to the interpretation of neutral or negative trials to exclude important methodological issues before concluding that the treatment really does not work. We will discuss this approach using the most classic trials of the past and some notable examples among superiority trials (mostly phase 3 trials) published over the last years.

Combinatorial Treatment with PARP and MAPK Inhibitors Overcomes Phenotype Switch-Driven Drug Resistance in Advanced Melanoma.

Metastatic melanoma is either intrinsically resistant or rapidly acquires resistance to targeted therapy treatments, such as MAPK inhibitors (MAPKi). A leading cause of resistance to targeted therapy is a dynamic transition of melanoma cells from a proliferative to a highly invasive state, a phenomenon called phenotype switching. Mechanisms regulating phenotype switching represent potential targets for improving treatment of patients with melanoma. Using a drug screen targeting chromatin regulators in patient-derived three-dimensional MAPKi-resistant melanoma cell cultures, we discovered that PARP inhibitors (PARPi) restore sensitivity to MAPKis, independent of DNA damage repair pathways. Integrated transcriptomic, proteomic, and epigenomic analyses demonstrated that PARPis induce lysosomal autophagic cell death, accompanied by enhanced mitochondrial lipid metabolism that ultimately increases antigen presentation and sensitivity to T-cell cytotoxicity. Moreover, transcriptomic and epigenetic rearrangements induced by PARP inhibition reversed epithelial-mesenchymal transition-like phenotype switching, which redirected melanoma cells toward a proliferative and MAPKi-sensitive state. The combination of PARP and MAPKis synergistically induced cancer cell death both in vitro and in vivo in patient-derived xenograft models. Therefore, this study provides a scientific rationale for treating patients with melanoma with PARPis in combination with MAPKis to abrogate acquired therapy resistance. SIGNIFICANCE: PARP inhibitors can overcome resistance to MAPK inhibitors by activating autophagic cell death and reversing phenotype switching, suggesting that this synergistic combination could help improve the prognosis of patients with melanoma.

Temporal trends in evidence supporting therapeutic interventions in heart failure and other European Society of Cardiology guidelines.

AIMS: This study aimed to determine whether any change occurred over time in level of evidence (LoE) of therapeutic interventions supporting heart failure (HF) and other European Society of Cardiology guideline recommendations. METHODS AND RESULTS: We selected topics with at least three documents released between 2008 and April 2022. Classes of recommendations (CoR) and supporting LoE related to therapeutic interventions within each document were collected and compared over time. A total of 1822 recommendations from 18 documents on 6 topics [median number per document = 112, 867 (48%) CoR I] were included in the analysis. There was a trend towards a reduction over time in the percentage of CoR I in HF (46-36-34%), non-ST elevation myocardial infarction (NSTEMI; 78-58-54%), and pulmonary embolism (PE; 65-50-39%) guidelines, with a decrease in the total number of recommendations for HF only. Percentage of CoR I was stable over time around 40% for valvular heart disease (VHD) and atrial fibrillation (AF), and around 60% for cardiovascular prevention (CVP), with an increase in the total number of recommendations for VHD and CVP and a decrease for AF. Among CoR I, 319 (37%) were supported by LoE A, with a decrease over time for HF (56-46-42%), an increase for NSTEMI (29-38-48%) and AF (28-31-36%), a bimodal distribution for PE and CVP, and a lack for VHD. CONCLUSIONS: LoE supporting therapeutic recommendations in contemporary European guidelines is generally low. Physicians should be aware of these limitations, and scientific societies promote a greater understanding of their significance and drive future research directions.

Association between coffee or tea consumption and cardiovascular outcomes in patients with stable coronary artery disease: Analysis from the CLARIFY registry.

BACKGROUND: Conflicting data exist on the association between consumption of coffee or tea and cardiovascular outcomes, and few focus on patients with established coronary artery disease. AIM: To describe the association between coffee or tea consumption and cardiovascular outcomes in patients with stable coronary artery disease, using an extensive contemporary international registry, allowing the identification of multiple potential confounders. METHODS: The Prospective Observational Longitudinal Registry of Patients With Stable Coronary Artery Disease (CLARIFY) registry enrolled in 2009 and 2010 in 45 countries, with a 5-year follow-up. Patients were categorized according to daily consumption of coffee or tea, and were compared with those declaring neither. The primary composite outcome of myocardial infarction, stroke or cardiovascular death was analysed at 5years, as well as all-cause mortality. Sensitivity analyses were performed with a multivariable model. RESULTS: A total of 15,459 and 10,029 patients declared coffee or tea consumption, respectively. At 5years, after full adjustment, no association was found between coffee consumption and the primary outcome: hazard ratio 1.04 (95% confidence interval 0.89-1.21) for 1 cup; 0.94 (0.82-1.08) for 2-3 cups; and 1.04 (0.86-1.27) for ≥4 cups (P=0.51). Drinking tea was not associated with a different incidence of the primary outcome before or after adjustment, with fully adjusted hazard ratios of 1.08 (95% confidence interval 0.84-1.38) for 1 cup, 1.12 (0.96-1.31) for 2-3 cups and 0.95 (0.79-1.14) for ≥4 cups (P=0.30). After full adjustment, neither coffee nor tea drinking was associated with all-cause mortality. CONCLUSIONS: In outpatients with stable coronary artery disease, there was no association between coffee or tea consumption and ischaemic outcomes or all-cause mortality.

Comprehensive characterization of non-cardiac comorbidities in acute heart failure: an analysis of ESC-HFA EURObservational Research Programme Heart Failure Long-Term Registry.

AIMS: To evaluate the prevalence and associations of non-cardiac comorbidities (NCCs) with in-hospital and post-discharge outcomes in acute heart failure (AHF) across the ejection fraction (EF) spectrum. METHODS AND RESULTS: The 9326 AHF patients from European Society of Cardiology (ESC)-Heart Failure Association (HFA)-EURObservational Research Programme Heart Failure Long-Term Registry had complete information for the following 12 NCCs: anaemia, chronic obstructive pulmonary disease (COPD), diabetes, depression, hepatic dysfunction, renal dysfunction, malignancy, Parkinson's disease, peripheral vascular disease (PVD), rheumatoid arthritis, sleep apnoea, and stroke/transient ischaemic attack (TIA). Patients were classified by number of NCCs (0, 1, 2, 3, and ≥4). Of the AHF patients, 20.5% had no NCC, 28.5% had 1 NCC, 23.1% had 2 NCC, 15.4% had 3 NCC, and 12.5% had ≥4 NCC. In-hospital and post-discharge mortality increased with number of NCCs from 3.0% and 18.5% for 1 NCC to 12.5% and 36% for ≥4 NCCs.Anaemia, COPD, PVD, sleep apnoea, rheumatoid arthritis, stroke/TIA, Parkinson, and depression were more prevalent in HF with preserved EF (HFpEF). The hazard ratio (95% confidence interval) for post-discharge death for each NCC was for anaemia 1.6 (1.4-1.8), diabetes 1.2 (1.1-1.4), kidney dysfunction 1.7 (1.5-1.9), COPD 1.4 (1.2-1.5), PVD 1.2 (1.1-1.4), stroke/TIA 1.3 (1.1-1.5), depression 1.2 (1.0-1.5), hepatic dysfunction 2.1 (1.8-2.5), malignancy 1.5 (1.2-1.8), sleep apnoea 1.2 (0.9-1.7), rheumatoid arthritis 1.5 (1.1-2.1), and Parkinson 1.4 (0.9-2.1). Anaemia, kidney dysfunction, COPD, and diabetes were associated with post-discharge mortality in all EF categories, PVD, stroke/TIA, and depression only in HF with reduced EF, and sleep apnoea and malignancy only in HFpEF. CONCLUSION: Multiple NCCs conferred poor in-hospital and post-discharge outcomes. Ejection fraction categories had different prevalence and risk profile associated with individual NCCs.

The current analysis from ESC-Heart Failure Long-Term Registry represents the largest and most comprehensive study in an acute heart failure (AHF) population with HF with reduced ejection fraction (HFrEF), HF with mildly reduced EF (HFmrEF), and HF with preserved EF (HFpEF), on prevalence and association with in-hospital and post-discharge outcomes of a large number of non-cardiac comorbidities.A greater number of non-cardiac comorbidities (CNNs) were associated at admission with older age, preserved EF, more severe NYHA class, and longer duration of HF. In-hospital and post-discharge mortality gradually increased with number of CNNs.The association between each individual comorbidity and post-discharge outcomes varied substantially in AHF patients with HFrEF, HFmrEF, and HFpEF, suggesting that an 'EF-specific' multidisciplinary approach with distinct comorbidity management programs should be applied in post-discharge phase.

Cardiovascular prevention: sometimes dreams can come true.

Cardiovascular disease (CVD) is a chronic condition driven by the complex interaction of different risk factors including genetics, lifestyle, environment, etc. which, differently from other pathologies, can be prevented. Treatment of CVD has been inconceivably successful but now it seems that it has reached a plateau suggesting that prevention is the way forward. However, the COVID-19 pandemic has spotted all the limits of the actual health system regarding territorial and, particularly, of preventive medicine. To this end, recently, the SCORE2 risk prediction algorithms, a contemporary model to estimate 10 years risk of CVD in Europe and the new guidelines on prevention have been released. The present review article describes a dream: how prevention of CVD should be addressed in the future. New concepts and paradigms like early genetically personalized and imaging driven risk factors, cardiac risk cartography, measurements of the exposome, estimation of costs of a delayed outcome vs. healthy lifespan, are all addressed. We highlight the importance of technologies and the concept of being engaged in a 'healthy' and not just 'sick' system as it is today. The concept of 'clearing house' with a 'care health team' instead of a 'heart team' is described. Finally, we articulate the four points necessary for the dream to come true.