Diuretic Combination Therapy in Acute Heart Failure: An Updated Review.

Loop diuretics are the cornerstone of decongestive therapy in patients presenting with acute heart failure and have been extensively studied in randomized clinical trials. Therefore, in current guidelines, they are the only drug with a class I recommendation to treat signs and symptoms of congestion when present. However, the percentage of patients achieving successful decongestion is suboptimal, and diuretic resistance frequently develops. Patients with a poor response to loop diuretics and those discharged with residual signs of congestion are characterized by a worse prognosis over time. Recently, a renovated interest in different diuretic classes sprouted among heart failure researchers in order to improve decongestion strategies and ameliorate short- and long-term clinical outcomes. Randomized clinical trials investigating associations among diuretic classes and loop diuretics have been performed but yielded variable results. Therefore, despite initial evidence of a possible benefit from some of these compounds, a definite way to approach diuretic resistance via diuretic combination therapy is still missing. The aim of this review is to summarize current clinical evidence on the use of diuretic combination therapy in patients with acute heart failure and to suggest a possible approach to avoid or counteract diuretic resistance.

Mitral Annulus Disjunction in consecutive patients undergoing Cardiac Magnetic Resonance: where is the boundary between normality and disease?

BACKGROUND: The presence of mitral annulus disjunction (MAD) has been considered a high-risk feature for sudden cardiac death based on selected study populations. We aimed to assess the prevalence of MAD in consecutive patients undergoing clinically-indicated Cardiac Magnetic Resonance (CMR), its association with ventricular arrhythmias, Mitral Valve Prolapse (MVP), and other CMR features. METHODS: This single-center retrospective study included consecutive patients referred to CMR at our Institution between June 2021 and November 2021. The MAD was defined as a ≥1mm displacement between the left atrial wall-mitral valve leaflet junction and the left ventricular wall during end-systole. The MAD extent was defined as the maximum longitudinal displacement. Associates of MAD were evaluated at uni- and multi-variariable regression analysis. A study endpoint including (aborted) sudden cardiac death, unexplained syncope, and sustained ventricular tachycardia was evaluated at 12-month follow-up. RESULTS: Four-hundred-forty-one patients (55±18 years, 61% males) were included, and 29 (7%) had MVP. The prevalence of MAD ≥1mm, 4mm, and 6mm were 214 (49%), 63 (14%), and 15 (3%), respectively. Patients with MVP showed a higher prevalence of MAD greater than 1mm (90% vs. 46%; p<0.001), 4mm (48% vs. 12%; p<0.001), and 6mm (10% vs. 3%; p=0.03), and a greater MAD extent (4.2mm, 3.0-5.7mm vs. 2.8mm, 1.9-4.0mm; p<0.001) than patients without MVP. The MVP was the only morpho-functional abnormality associated with MAD at multivariable analysis (p<0.001). A high burden of ventricular ectopic beats at baseline Holter-ECG was associated with MAD ≥4mm and MAD extent (p<0.05). The presence of MAD ≥1mm (0.9% vs. 1.8%; p=0.46), MAD ≥4mm (1.6% vs. 1.3%; p=0.87), or MVP (3.5% vs. 1.2%; p=0.32) were not associated with the study endpoint, whereas patients with MAD ≥6mm showed a trend towards a higher likelihood of the study endpoint (6.7% vs. 1.2%; p=0.07). CONCLUSIONS: A MAD of limited entity was common in consecutive patients undergoing CMR. Patients with MVP showed higher prevalence and greater extent of MAD. Extended MAD was rarer and showed association with ventricular arrhythmias at baseline. The mid-term prognosis of MAD seems benign, however prospective studies are warranted to search for potential "malignant MAD extents" to improve patients' risk stratification.

Effects of Enzyme Replacement Therapy on Cardiac MRI Findings in Fabry Disease: A Systematic Review and Meta-Analysis.

Purpose To perform a systematic review and meta-analysis to assess the effect of enzyme replacement therapy on cardiac MRI parameters in patients with Fabry disease. Materials and Methods A systematic literature search was conducted from January 1, 2000, through January 1, 2024, in PubMed, ClinicalTrials.gov, Embase, and Cochrane Library databases. Study outcomes were changes in the following parameters: (a) left ventricular wall mass (LVM), measured in grams; (b) LVM indexed to body mass index, measured in grams per meters squared; (c) maximum left ventricular wall thickness (MLVWT), measured in millimeters; (d) late gadolinium enhancement (LGE) extent, measured in percentage of LVM; and (e) native T1 mapping, measured in milliseconds. A random-effects meta-analysis of the pooled mean differences between baseline and follow-up parameters was conducted. The study protocol was registered in PROSPERO (CRD42022336223). Results The final analysis included 11 studies of a total of 445 patients with Fabry disease (mean age ± SD, 41 years ± 11; 277 male, 168 female). Between baseline and follow-up cardiac MRI, the following did not change: T1 mapping (mean difference, 6 msec [95% CI: -2, 15]; two studies, 70 patients, I2 = 88%) and LVM indexed (mean difference, -1 g/m2 [95% CI: -6, 3]; four studies, 290 patients, I2 = 81%). The following measures minimally decreased: LVM (mean difference, -18 g [95% CI: -33, -3]; seven studies, 107 patients, I2 = 96%) and MLVWT (mean difference, -1 mm [95% CI: -2, -0.02]; six studies, 151 patients, I2 = 90%). LGE extent increased (mean difference, 1% [95% CI: 1, 1]; three studies, 114 patients, I2 = 85%). Conclusion In patients with Fabry disease, enzyme replacement therapy was associated with stabilization of LVM, MLVWT, and T1 mapping values, whereas LGE extent mildly increased. Keywords: Fabry Disease, Enzyme Replacement Therapy (ERT), Cardiac MRI, Late Gadolinium Enhancement (LGE) Supplemental material is available for this article. © RSNA, 2024.

Application of the Academic Research Consortium High Bleeding Risk criteria in patients treated with coronary bioresorbable polymer everolimus-eluting stents: Insights from the POEM trial.

BACKGROUND: Previous studies have investigated a 1 to 6-month short dual antiplatelet therapy (S-DAPT) after percutaneous coronary intervention (PCI) with modern drug eluting-stents to reduce bleeding events. OBJECTIVES: To investigate cardiovascular outcomes in patients at high bleeding risk (HBR) according to the Academic Research Consortium for High Bleeding Risk (ARC-HBR) criteria after PCI with the Synergy bioresorbable-polymer everolimus-eluting stents (EES). METHODS: We applied ARC-HBR criteria in the population of the prospective, single-arm, multicenter POEM (Performance of Bioresorbable Polymer-Coated Everolimus-Eluting Synergy Stent in Patients at HBR Undergoing Percutaneous Coronary Revascularization Followed by 1-Month Dual Antiplatelet Therapy) trial. The primary endpoint was a composite of cardiac death, myocardial infarction, or definite or probable stent thrombosis at 12 months. RESULTS: The original POEM cohort included 356 patients (80.4 %) fulfilling ARC-HBR criteria. Oral anticoagulant (OAC) usage and age ≥75 years were the most frequent major and minor ARC-HBR criteria, respectively. The ARC-HBR group was mainly represented by men (71.1 %), with 74.4 ± 9.3 years and a high burden of cardiovascular risk factors. DAPT was prescribed in 79.3 %, and single antiplatelet (SAPT) with OAC in 18.7 %. 12-month follow-up was completed in 96.2 %. The primary endpoint occurred in 5.2 % (95 % CI 3.29-8.10) of patients, whereas bleeding Academic Research Consortium type 3-5 occurred in 2.7 % (95 % CI, 1.39 %-5.05 %). CONCLUSION: Previous results of the POEM trial showed positive outcomes regarding ischemic and bleeding events with an S-DAPT regimen after Synergy EES. These results are also confirmed in sub-group analysis when ARC-HBR criteria are applied.

Prognostic value of hypochloremia on mortality in patients with heart failure: a systematic review and meta-analysis.

AIMS: Electrolyte imbalances are common in patients with heart failure. Several studies have shown that a low serum chloride level is associated with adverse outcomes in hospitalized patients with acute heart failure and in outpatients with chronic heart failure. We performed a systematic review and meta-analysis to assess the association of hypochloremia with all-cause mortality in patients with heart failure. METHODS: Data search was conducted from inception through 1 February 2023, using the following MeSH terms: ('chloride' OR 'hypochloremia') AND 'heart failure'. Studies evaluating the association between serum chloride and all-cause mortality in patients with heart failure were included. The predefined primary outcome was all-cause mortality. Pooled hazard ratios and 95% confidence intervals (CIs) were used as effect estimates and calculated with a random-effects model; fixed-effects model and leave-one-out sensitivity analyses were also performed. RESULTS: A total of 15 studies, involving 25 848 patients, were included. The prevalence of hypochloremia ranged from 8.6 to 31.5%. Follow-up time ranged from 6 to 67 months. Hypochloremia as a categorical variable was associated with an increased risk of all-cause mortality [hazard ratio 1.56; 95% confidence interval (CI) 1.38-1.75; P  < 0.001]. As a continuous variable, serum chloride was associated with all-cause mortality (hazard ratio per mmol/l decrease in serum chloride: 1.06; 95% CI 1.05-1.07; P  < 0.001). Results were confirmed by using several sensitivity analyses. CONCLUSION: Hypochloremia exhibits a significant prognostic value in patients with heart failure. Serum chloride can be used as an effective tool for risk stratifying in patients with heart failure.

Multiparametric Mapping via Cardiovascular Magnetic Resonance in the Risk Stratification of Ventricular Arrhythmias and Sudden Cardiac Death.

Risk stratification for malignant ventricular arrhythmias and sudden cardiac death is a daunting task for physicians in daily practice. Multiparametric mapping sequences obtained via cardiovascular magnetic resonance imaging can improve the risk stratification for malignant ventricular arrhythmias by unveiling the presence of pathophysiological pro-arrhythmogenic processes. However, their employment in clinical practice is still restricted. The present review explores the current evidence supporting the association between mapping abnormalities and the risk of ventricular arrhythmias in several cardiovascular diseases. The key message is that further clinical studies are needed to test the additional value of mapping techniques beyond conventional cardiovascular magnetic resonance imaging for selecting patients eligible for an implantable cardioverter defibrillator.

Vitamin D and Cardiovascular Diseases: From Physiology to Pathophysiology and Outcomes.

Vitamin D is rightly recognized as an essential key factor in the regulation of calcium and phosphate homeostasis, affecting primary adequate bone mineralization. In the last decades, a more complex and wider role of vitamin D has been postulated and demonstrated. Cardiovascular diseases have been found to be strongly related to vitamin D levels, especially to its deficiency. Pre-clinical studies have suggested a direct role of vitamin D in the regulation of several pathophysiological pathways, such as endothelial dysfunction and platelet aggregation; moreover, observational data have confirmed the relationship with different conditions, including coronary artery disease, heart failure, and hypertension. Despite the significant evidence available so far, most clinical trials have failed to prove any positive impact of vitamin D supplements on cardiovascular outcomes. This discrepancy indicates the need for further information and knowledge about vitamin D metabolism and its effect on the cardiovascular system, in order to identify those patients who would benefit from vitamin D supplementation.

Right Heart Remodeling and Outcomes in Patients With Tricuspid Regurgitation: A Literature Review and Meta-Analysis.

BACKGROUND: Functional tricuspid regurgitation (TR) can develop either because of right ventricular (RV) remodeling (ventricular functional TR) and/or right atrial dilation (atrial functional TR). OBJECTIVES: This meta-analysis aimed to investigate the association between right heart remodeling and long-term (>1 year) all-cause mortality in patients with significant TR (at least moderate, ≥2+). METHODS: MEDLINE, ISI Web of Science, and SCOPUS databases were searched. Studies reporting data on at least 1 RV functional parameter and long-term all-cause mortality in patients with significant TR were included. This study was designed according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) requirements. RESULTS: Out of 8,902 studies, a total of 14 were included, enrolling 4,394 subjects. The duration of follow-up across the studies varied, ranging from a minimum of 15.5 months to a maximum of 73.2 months. Overall, long-term all-cause mortality was 31% (95% CI: 20%-41%; P ≤ 0.001). By means of meta-regression analyses, an inverse relation was found between tricuspid annular plane systolic excursion (11 studies enrolling 3,551 subjects, -6.3% [95% CI: -11.1% to -1.4%]; P = 0.011), RV fractional area change (9 studies, 2,975 subjects, -4.4% [95% CI: -5.9% to -2.9%]; P < 0.001), tricuspid annular dimension (7 studies, 2,986 subjects, -4.1% [95% CI: -7.6% to -0.5%]; P = 0.026), right atrial area (6 studies, 1,920 subjects, -1.9% [95% CI: -2.5% to -1.3%]; P < 0.001) and mortality. CONCLUSIONS: RV dysfunction parameters are associated to worse clinical outcomes in patients with TR, whereas right atrial dilatation is linked to a better prognostic outcome. Further studies are needed to unravel the pathophysiological differences within the functional TR spectrum. (Right heart remodeling and outcomes in patients with tricuspid regurgitation; CRD42023418667).

GLP-1-ra and heart failure-related outcomes in patients with and without history of heart failure: an updated systematic review and meta-analysis.

AIMS: Glucagon-like peptide-1 receptor agonists (GLP1-ra) have shown to reduce cardiovascular (CV) events in patients with diabetes, including heart failure (HF) hospitalizations. However, whether such benefit consistently occurs in patients with history of HF remains uncertain. We performed a systematic review and meta-analysis to assess the impact of GLP1-ra on CV outcomes in patients with and without HF history. METHODS AND RESULTS: All randomized, placebo-controlled trials evaluating GLP1-ra and reporting CV outcomes stratified by HF history were searched in Pubmed from inception to November 12th, 2023. The primary outcome was HF hospitalizations. Secondary outcomes included CV death, the composite of CV death and hospitalizations for HF, and major adverse cardiovascular events (MACE). Hazard ratio (HR) and 95% confidence interval (CIs) were used as effect estimates and calculated with a random-effects model. 68,653 patients (GLP1-ra = 34,301, placebo = 34,352) from 10 trials were included. GLP1-ra reduced HF hospitalization (no HF: HR = 0.79, 95% CI 0.63-0.98; HF: HR = 1.00, 95% CI 0.82-1.24, pinteraction = 0.12), CV death (no HF: HR = 0.81, 95% CI 0.71-0.92; HF: HR = 0.97, 95% CI 0.81-1.15, pinteraction = 0.11), and the composite of HF hospitalizations and CV death (no HF: HR = 0.80, 95% CI 0.72-0.89; HF: HR = 1.00 95% CI 0.88-1.15, pinteraction = 0.010) only in patients without history of HF, despite a significant interaction between HF history and treatment effect was detected only for the latter. MACE were reduced in both subgroups without significant interaction between HF history and treatment effect (no HF: HR = 0.86, 95% CI 0.78-0.96; HF: HR = 0.83, 95% CI 0.72-0.95, pinteraction = 0.69). CONCLUSION: GLP1-ra do not decrease HF-hospitalization risk, despite a potential benefit in patients without history of HF, but are effective in reducing ischemic events irrespective of the presence of HF. PROSPERO-registered (CRD42022371264).

The Smokers Health Multiple ACtions (SMAC-1) Trial: Study Design and Results of the Baseline Round.

BACKGROUND: Lung cancer screening with low-dose helical computed tomography (LDCT) reduces mortality in high-risk subjects. Cigarette smoking is linked to up to 90% of lung cancer deaths. Even more so, it is a key risk factor for many other cancers and cardiovascular and pulmonary diseases. The Smokers health Multiple ACtions (SMAC-1) trial aimed to demonstrate the feasibility and effectiveness of an integrated program based on the early detection of smoking-related thoraco-cardiovascular diseases in high-risk subjects, combined with primary prevention. A new multi-component screening design was utilized to strengthen the framework on conventional lung cancer screening programs. We report here the study design and the results from our baseline round, focusing on oncological findings. METHODS: High-risk subjects were defined as being >55 years of age and active smokers or formers who had quit within 15 years (>30 pack/y). A PLCOm2012 threshold >2% was chosen. Subject outreach was streamlined through media campaign and general practitioners' engagement. Eligible subjects, upon written informed consent, underwent a psychology consultation, blood sample collection, self-evaluation questionnaire, spirometry, and LDCT scan. Blood samples were analyzed for pentraxin-3 protein levels, interleukins, microRNA, and circulating tumor cells. Cardiovascular risk assessment and coronary artery calcium (CAC) scoring were performed. Direct and indirect costs were analyzed focusing on the incremental cost-effectiveness ratio per quality-adjusted life years gained in different scenarios. Personalized screening time-intervals were determined using the "Maisonneuve risk re-calculation model", and a threshold <0.6% was chosen for the biennial round. RESULTS: In total, 3228 subjects were willing to be enrolled. Out of 1654 eligible subjects, 1112 participated. The mean age was 64 years (M/F 62/38%), with a mean PLCOm2012 of 5.6%. Former and active smokers represented 23% and 77% of the subjects, respectively. At least one nodule was identified in 348 subjects. LDCTs showed no clinically significant findings in 762 subjects (69%); thus, they were referred for annual/biennial LDCTs based on the Maisonneuve risk (mean value = 0.44%). Lung nodule active surveillance was indicated for 122 subjects (11%). Forty-four subjects with baseline suspicious nodules underwent a PET-FDG and twenty-seven a CT-guided lung biopsy. Finally, a total of 32 cancers were diagnosed, of which 30 were lung cancers (2.7%) and 2 were extrapulmonary cancers (malignant pleural mesothelioma and thymoma). Finally, 25 subjects underwent lung surgery (2.25%). Importantly, there were zero false positives and two false negatives with CT-guided biopsy, of which the patients were operated on with no stage shift. The final pathology included lung adenocarcinomas (69%), squamous cell carcinomas (10%), and others (21%). Pathological staging showed 14 stage I (47%) and 16 stage II-IV (53%) cancers. CONCLUSIONS: LDCTs continue to confirm their efficacy in safely detecting early-stage lung cancer in high-risk subjects, with a negligible risk of false-positive results. Re-calculating the risk of developing lung cancer after baseline LDCTs with the Maisonneuve model allows us to optimize time intervals to subsequent screening. The Smokers health Multiple ACtions (SMAC-1) trial offers solid support for policy assessments by policymakers. We trust that this will help in developing guidelines for the large-scale implementation of lung cancer screening, paving the way for better outcomes for lung cancer patients.

Update on long-term cardiovascular risk after pre-eclampsia: a systematic review and meta-analysis.

BACKGROUND/INTRODUCTION: There is a need for further studies on the cardiovascular risk of women experiencing pre-eclampsia (PE). PURPOSE: To update the literature regarding the association between a history of PE and subsequent cardiovascular diseases, including cardiovascular death, coronary heart diseases, heart failure, and stroke, focusing on the trend in the effect size (ES) estimates over time. METHODS AND RESULTS: Following PRISMA guidelines, from inception to May 2023, we performed a systematic review of PubMed, MEDLINE, Scopus, and EMBASE. Randomized, cohort, or case-control studies in English were included if fulfiling the following criteria:(i) The association between PE and subsequent cardiovascular disease was adjusted for clinically relevant variables, (ii) the presence of a control group, and (iii) at least 1 year of follow-up. Pooled adjusted ESs and 95% confidence intervals (CIs) were used as effect estimates and calculated with a random-effect model. Twenty-two studies met the inclusion criteria. PE was associated with a higher risk of cardiovascular death (ES 2.08, 95% CI 1.70-2.54, I2 56%, P < 0.00001), coronary artery diseases (ES 2.04, 95% CI 1.76-2.38, I2 87%, P < 0.00001), heart failure (ES 2.47, 95% CI 1.89-3.22, I2 83%, P < 0.00001), and stroke (ES 1.75, 95% CI 1.52-2.02, I2 72%, P < 0.00001) after adjusting for potential confounders. This risk is evident in the first 1-to-3 years of follow-up and remains significant until 39 years of follow-up. CONCLUSIONS: Compared to women who experienced a normal pregnancy, those suffering from PE have about double the risk of lifetime cardiovascular disease.

Single-Cell RNA Sequencing Reveals Metabolic Stress-Dependent Activation of Cardiac Macrophages in a Model of Dyslipidemia-Induced Diastolic Dysfunction.

BACKGROUND: Metabolic distress is often associated with heart failure with preserved ejection fraction (HFpEF) and represents a therapeutic challenge. Metabolism-induced systemic inflammation links comorbidities with HFpEF. How metabolic changes affect myocardial inflammation in the context of HFpEF is not known. METHODS: We found that ApoE knockout mice fed a Western diet recapitulate many features of HFpEF. Single-cell RNA sequencing was used for expression analysis of CD45+ cardiac cells to evaluate the involvement of inflammation in diastolic dysfunction. We focused bioinformatics analysis on macrophages, obtaining high-resolution identification of subsets of these cells in the heart, enabling us to study the outcomes of metabolic distress on the cardiac macrophage infiltrate and to identify a macrophage-to-cardiomyocyte regulatory axis. To test whether a clinically relevant sodium glucose cotransporter-2 inhibitor could ameliorate the cardiac immune infiltrate profile in our model, mice were randomized to receive the sodium glucose cotransporter-2 inhibitor dapagliflozin or vehicle for 8 weeks. RESULTS: ApoE knockout mice fed a Western diet presented with reduced diastolic function, reduced exercise tolerance, and increased pulmonary congestion associated with cardiac lipid overload and reduced polyunsaturated fatty acids. The main immune cell types infiltrating the heart included 4 subpopulations of resident and monocyte-derived macrophages, determining a proinflammatory profile exclusively in ApoE knockout- Western diet mice. Lipid overload had a direct effect on inflammatory gene activation in macrophages, mediated through endoplasmic reticulum stress pathways. Investigation of the macrophage-to-cardiomyocyte regulatory axis revealed the potential effects on cardiomyocytes of multiple inflammatory cytokines secreted by macrophages, affecting pathways such as hypertrophy, fibrosis, and autophagy. Finally, we describe an anti-inflammatory effect of sodium glucose cotransporter-2 inhibitor in this model. CONCLUSIONS: Using single-cell RNA sequencing , in a model of diastolic dysfunction driven by hyperlipidemia, we have determined the effects of metabolic distress on cardiac inflammatory cells, in particular on macrophages, and suggest sodium glucose cotransporter-2 inhibitors as potential therapeutic agents for the targeting of a specific phenotype of HFpEF.

Clinical and procedural outcomes of percutaneous coronary intervention for de novo lesions involving the ostial left circumflex coronary artery.

BACKGROUND: Percutaneous treatment for ostial left circumflex artery (LCx) lesions is known to be associated with suboptimal results. AIMS: The present study aims to assess the procedural and long-term clinical outcomes of percutaneous coronary intervention (PCI) for de novo ostial LCx lesions overall and according to the coronary revascularization strategy. METHODS: Consecutive patients undergoing PCI with second generation drug eluting stents or drug coated balloons for de novo ostial LCx lesions in three high-volume Italian centers between 2012 and 2021 were retrospectively evaluated. The primary endpoint was target-vessel revascularization (TVR) at 2 years. Secondary endpoints included major adverse cardiovascular and cerebrovascular events (MACCE), target lesion revascularization, myocardial infarction, stroke, all-cause death, and repeat revascularization. RESULTS: A total of 366 patients were included in the analysis with a median follow-up of 901 (IQR: 450-1728) days. 79.5% of the patients were male, 33.6% were diabetic, 49.7% had a previous PCI, and 23.1% a prior surgical revascularization. Very ostial LCx stenting was performed in 34.1%, crossover from left main to LCx in 17.3%, and a two-stent strategy in 48.6% of cases, respectively. In the overall population, the incidence of TVR at 2 years was 19.0% while MACCE rate was 25.7%. No major differences in clinical outcomes were found according to the stenting strategy. Use of intracoronary imaging was associated with fewer MACCE (HR: 0.47, 95% CI: 0.25-1.13, p = 0.01), while the diameter of the stent implanted in the ostial LCx was associated with less TVR (HR: 0.43, 95% CI: 0.25-0.75, p = 0.002). CONCLUSIONS: Percutaneous revascularization of the ostial LCx is associated with a high rate of TVR, regardless of the stenting strategy. Intracoronary imaging and proper stent sizing may reduce the failure rates.

Drug-Coated Balloon Angioplasty for De Novo Lesions on the Left Anterior Descending Artery.

BACKGROUND: Drug-coated balloons (DCB) are an emerging tool for modern percutaneous coronary intervention (PCI), but evidence on their use for de novo lesions on large vessels is limited. METHODS: Consecutive patients undergoing DCB-based PCI on the left anterior descending artery in 2 Italian centers from 2018 to 2022 were retrospectively enrolled and compared with patients who received left anterior descending PCI with contemporary drug-eluting stents (DES). In-stent restenosis was excluded. The DCB group included both patients undergoing DCB-only PCI and those receiving hybrid PCI with DCB and DES combined. The primary end point was target lesion failure at 2 years, defined as the composite of target lesion revascularization, cardiac death, and target vessel myocardial infarction. RESULTS: We included 147 consecutive patients undergoing DCB-based treatment on the left anterior descending artery and compared them to 701 patients who received conventional PCI with DES. In the DCB group, 43 patients (29.2%) were treated with DCB only and 104 (70.8%) with a hybrid approach; DCB length was greater than stent length in 55.1% of cases. Total treated length was higher in the DCB group (65 [40-82] versus 56 [46-66] mm; P=0.002), while longer DESs were implanted (38 [24-62] versus 56 [46-66] mm; P<0.001) and a higher rate of large vessels were treated (76.2% versus 83.5%; P=0.036) in the DES cohort. The cumulative 2-year target lesion failure incidence was not significantly different between the 2 groups (DCB, 4.1% versus DES, 9.8%; hazard ratio, 0.51 [95% CI, 0.20-1.27]; P=0.15). After a 1:1 propensity score matching resulting in 139 matched pairs, the DCB-based treatment was associated with a lower risk for target lesion failure at 2 years compared with DES-only PCI (hazard ratio, 0.2 [95% CI, 0.07-0.58]; P=0.003), mainly driven by less target lesion revascularization. CONCLUSIONS: A DCB-based treatment approach for left anterior descending revascularization allows a significantly reduced stent burden, thereby potentially limiting target lesion failure risk at midterm follow-up.

One-Month Dual Antiplatelet Therapy in Patients With Chronic and Acute Coronary Syndromes Treated With Bioresorbable Polymer Everolimus-Eluting Stents.

There is a paucity of data regarding the safety of a 1-month dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) in patients at high bleeding risk (HBR) presenting with acute coronary syndromes (ACS). We aimed to compare the clinical outcomes of patients at HBR with chronic coronary syndrome (CCS) or ACS treated with PCI using bioresorbable polymer everolimus-eluting stent (BP-EES) followed by 1-month DAPT. Patients at HBR who underwent PCI with BP-EES were prospectively enrolled in 10 Italian centers. All patients were treated with 1-month DAPT. In case of need for anticoagulation, patients received an oral anticoagulant in addition to a P2Y12 inhibitor for 1 month, followed by oral anticoagulation only after that. The primary end point was a composite of cardiac death, myocardial infarction, or definite/probable stent thrombosis at 12 months. Overall, 263 patients (59.4%) with CCS and 180 patients (40.6%) with ACS were enrolled. No significant difference was evident between patients with CCS and ACS for the primary end point (4.3% vs 5.6%, respectively, p = 0.497) and for each isolated component. The risk for Bleeding Academic Research Consortium (BARC) type 1 to 5 or type 3 to 5 bleedings was also similar between patients with CCS and ACS (4.3% vs 5.2%, p = 0.677, and 1.6% vs 2.9%, p = 0.351, respectively). In conclusion, among HBR patients with ACS who underwent PCI with BP-EES, a 1-month DAPT strategy is associated with a similar risk of ischemic and bleeding events compared with those with CCS.

Cardiac Aging Is Promoted by Pseudohypoxia Increasing p300-Induced Glycolysis.

BACKGROUND: Heart failure is typical in the elderly. Metabolic remodeling of cardiomyocytes underlies inexorable deterioration of cardiac function with aging: glycolysis increases at the expense of oxidative phosphorylation, causing an energy deficit contributing to impaired contractility. Better understanding of the mechanisms of this metabolic switching could be critical for reversing the condition. METHODS: To investigate the role of 3 histone modifications (H3K27ac, H3K27me3, and H3K4me1) in the metabolic remodeling occurring in the aging heart, we cross-compared epigenomic, transcriptomic, and metabolomic data from mice of different ages. In addition, the role of the transcriptional coactivator p300 (E1A-associated binding protein p300)/CBP (CREB binding protein) in cardiac aging was investigated using a specific inhibitor of this histone acetyltransferase enzyme. RESULTS: We report a set of species-conserved enhancers associated with transcriptional changes underlying age-related metabolic remodeling in cardiomyocytes. Activation of the enhancer region of Hk2-a key glycolysis pathway gene-was fostered in old age-onset mouse heart by pseudohypoxia, wherein hypoxia-related genes are expressed under normal O2 levels, via increased activity of P300/CBP. Pharmacological inhibition of this transcriptional coactivator before the onset of cardiac aging led to a more aerobic, less glycolytic, metabolic state, improved heart contractility, and overall blunting of cardiac decline. CONCLUSIONS: Taken together, our results suggest how epigenetic dysregulation of glycolysis pathway enhancers could potentially be targeted to treat heart failure in the elderly.

Platelets and the Atherosclerotic Process: An Overview of New Markers of Platelet Activation and Reactivity, and Their Implications in Primary and Secondary Prevention.

The key role played by platelets in the atherosclerosis physiopathology, especially in the acute setting, is ascertained: they are the main actors during thrombus formation and, thus, one of the major investigated elements related to atherothrombotic process involving coronary arteries. Platelets have been studied from different points of view, according with the technology advances and the improvement in the hemostasis knowledge achieved in the last years. Morphology and reactivity constitute the first aspects investigated related to platelets with a significant body of evidence published linking a number of their values and markers to coronary artery disease and cardiovascular events. Recently, the impact of genetics on platelet activation has been explored with promising findings as additional instrument for patient risk stratification; however, this deserves further confirmations. Moreover, the interplay between immune system and platelets has been partially elucidated in the last years, providing intriguing elements that will be basic components for future research to better understand platelet regulation and improve cardiovascular outcome of patients.

Coronary Vascular (DYS) Function and Invasive Physiology Assessment: Insights into Bolus and Continuous Thermodilution Methods.

A considerable number of patients with angina or myocardial ischemia have no significant coronary artery disease on invasive angiography. In recent years, several steps towards a better comprehension of the pathophysiology of these conditions, angina or ischemia with non-obstructive coronary arteries (ANOCA/INOCA), have been made. Nevertheless, several gaps in knowledge still remain. This review is intended to provide a comprehensive overview of ANOCA and INOCA, with a particular focus on pathophysiology, recent diagnostic innovations, gaps in knowledge and treatment modalities.

Rationale and design of the CV-PREVITAL study: an Italian multiple cohort randomised controlled trial investigating innovative digital strategies in primary cardiovascular prevention.

INTRODUCTION: Prevention of cardiovascular disease (CVD) is of key importance in reducing morbidity, disability and mortality worldwide. Observational studies suggest that digital health interventions can be an effective strategy to reduce cardiovascular (CV) risk. However, evidence from large randomised clinical trials is lacking. METHODS AND ANALYSIS: The CV-PREVITAL study is a multicentre, prospective, randomised, controlled, open-label interventional trial designed to compare the effectiveness of an educational and motivational mobile health (mHealth) intervention versus usual care in reducing CV risk. The intervention aims at improving diet, physical activity, sleep quality, psycho-behavioural aspects, as well as promoting smoking cessation and adherence to pharmacological treatment for CV risk factors. The trial aims to enrol approximately 80 000 subjects without overt CVDs referring to general practitioners' offices, community pharmacies or clinics of Scientific Institute for Research, Hospitalization and Health Care (Italian acronym IRCCS) affiliated with the Italian Cardiology Network. All participants are evaluated at baseline and after 12 months to assess the effectiveness of the intervention on short-term endpoints, namely improvement in CV risk score and reduction of major CV risk factors. Beyond the funded life of the study, a long-term (7 years) follow-up is also planned to assess the effectiveness of the intervention on the incidence of major adverse CV events. A series of ancillary studies designed to evaluate the effect of the mHealth intervention on additional risk biomarkers are also performed. ETHICS AND DISSEMINATION: This study received ethics approval from the ethics committee of the coordinating centre (Monzino Cardiology Center; R1256/20-CCM 1319) and from all other relevant IRBs and ethics committees. Findings are disseminated through scientific meetings and peer-reviewed journals and via social media. Partners are informed about the study's course and findings through regular meetings. TRIAL REGISTRATION NUMBER: NCT05339841.