Derivation and Validation of the PRECISE-HBR Score to Predict Bleeding After Percutaneous Coronary Intervention.

BACKGROUND: Accurate bleeding risk stratification after percutaneous coronary intervention (PCI) is important for treatment individualization. However, there is still an unmet need for a more precise and standardized identification of high bleeding risk patients. We derived and validated a novel bleeding risk score by augmenting the PRECISE-DAPT score with the Academic Research Consortium for High Bleeding Risk (ARC-HBR) criteria. METHODS: The derivation cohort comprised 29,188 patients undergoing PCI, of whom 1136 (3.9%) had a Bleeding Academic Research Consortium (BARC) 3 or 5 bleeding at 1 year, from four contemporary real-world registries and the XIENCE V USA trial. The PRECISE-DAPT score was refitted with a Fine-Gray model in the derivation cohort and extended with the ARC-HBR criteria. The primary outcome was BARC 3 or 5 bleeding within 1 year. Independent predictors of BARC 3 or 5 bleeding were selected at multivariable analysis (p<0.01). The discrimination of the score was internally assessed with apparent validation and cross-validation. The score was externally validated in 4578 patients from the MASTER DAPT trial and 5970 patients from the STOPDAPT-2 total cohort. RESULTS: The PRECISE-HBR score (age, estimated glomerular filtration rate, hemoglobin, white-blood-cell count, previous bleeding, oral anticoagulation, and ARC-HBR criteria) showed an area under the curve (AUC) for 1-year BARC 3 or 5 bleeding of 0.73 (95% CI, 0.71-0.74) at apparent validation, 0.72 (95% CI, 0.70-0.73) at cross-validation, 0.74 (95% CI, 0.68-0.80) in the MASTER DAPT, and 0.73 (95% CI, 0.66-0.79) in the STOPDAPT-2, with superior discrimination than the PRECISE-DAPT (cross-validation: Δ AUC, 0.01; p=0.02; MASTER DAPT: Δ AUC, 0.05; p=0.004; STOPDAPT-2: Δ AUC, 0.02; p=0.20) and other risk scores. In the derivation cohort, a cut-off of 23 points identified 11,414 patients (39.1%) with a 1-year BARC 3 or 5 bleeding risk ≥4%. An alternative version of the score, including acute myocardial infarction on admission instead of white-blood-cell count, showed similar predictive ability. CONCLUSIONS: The PRECISE-HBR score is a contemporary, simple 7-item risk score to predict bleeding after PCI, offering a moderate improvement in discrimination over multiple existing scores. Further evaluation is required to assess its impact on clinical practice.

De-escalation to ticagrelor monotherapy versus 12 months of dual antiplatelet therapy in patients with and without acute coronary syndromes: a systematic review and individual patient-level meta-analysis of randomised trials.

BACKGROUND: Dual antiplatelet therapy (DAPT) for 12 months is the standard of care after coronary stenting in patients with acute coronary syndrome (ACS). The aim of this individual patient-level meta-analysis was to summarise the evidence comparing DAPT de-escalation to ticagrelor monotherapy versus continuing DAPT for 12 months after coronary drug-eluting stent implantation. METHODS: A systematic review and individual patient data (IPD)-level meta-analysis of randomised trials with centrally adjudicated endpoints was performed to evaluate the comparative efficacy and safety of ticagrelor monotherapy (90 mg twice a day) after short-term DAPT (from 2 weeks to 3 months) versus 12-month DAPT in patients undergoing percutaneous coronary intervention with a coronary drug-eluting stent. Randomised trials comparing P2Y12 inhibitor monotherapy with DAPT after coronary revascularisation were searched in Ovid MEDLINE, Embase, and two websites (www.tctmd.com and www.escardio.org) from database inception up to May 20, 2024. Trials that included patients with an indication for long-term oral anticoagulants were excluded. The risk of bias was assessed using the revised Cochrane risk-of-bias tool. The principal investigators of the eligible trials provided IPD by means of an anonymised electronic dataset. The three ranked coprimary endpoints were major adverse cardiovascular or cerebrovascular events (MACCE; a composite of all-cause death, myocardial infarction, or stroke) tested for non-inferiority in the per-protocol population; and Bleeding Academic Research Consortium (BARC) 3 or 5 bleeding and all-cause death tested for superiority in the intention-to-treat population. All outcomes are reported as Kaplan-Meier estimates. The non-inferiority was tested using a one-sided α of 0·025 with the prespecified non-inferiority margin of 1·15 (hazard ratio [HR] scale), followed by the ranked superiority testing at a two-sided α of 0·05. This study is registered with PROSPERO (CRD42024506083). FINDINGS: A total of 8361 unique citations were screened, of which 610 records were considered potentially eligible during the screening of titles and abstracts. Of these, six trials that randomly assigned patients to ticagrelor monotherapy or DAPT were identified. De-escalation took place a median of 78 days (IQR 31-92) after intervention, with a median duration of treatment of 334 days (329-365). Among 23 256 patients in the per-protocol population, MACCE occurred in 297 (Kaplan-Meier estimate 2·8%) with ticagrelor monotherapy and 332 (Kaplan-Meier estimate 3·2%) with DAPT (HR 0·91 [95% CI 0·78-1·07]; p=0·0039 for non-inferiority; τ2<0·0001). Among 24 407 patients in the intention-to-treat population, the risks of BARC 3 or 5 bleeding (Kaplan-Meier estimate 0·9% vs 2·1%; HR 0·43 [95% CI 0·34-0·54]; p<0·0001 for superiority; τ2=0·079) and all-cause death (Kaplan-Meier estimate 0·9% vs 1·2%; 0·76 [0·59-0·98]; p=0·034 for superiority; τ2<0·0001) were lower with ticagrelor monotherapy. Trial sequential analysis showed strong evidence of non-inferiority for MACCE and superiority for bleeding among the overall and ACS populations (the z-curve crossed the monitoring boundaries or the required information size without crossing the futility boundaries or approaching the null). The treatment effects were heterogeneous by sex for MACCE (p interaction=0·041) and all-cause death (p interaction=0·050), indicating a possible benefit in women with ticagrelor monotherapy, and by clinical presentation for bleeding (p interaction=0·022), indicating a benefit in ACS with ticagrelor monotherapy. INTERPRETATION: Our study found robust evidence that, compared with 12 months of DAPT, de-escalation to ticagrelor monotherapy does not increase ischaemic risk and reduces the risk of major bleeding, especially in patients with ACS. Ticagrelor monotherapy might also be associated with a mortality benefit, particularly among women, which warrants further investigation. FUNDING: Cardiocentro Ticino Institute, Ente Ospedaliero Cantonale.

Atherosclerotic Plaque Erosion: Mechanisms, Clinical Implications, and Potential Therapeutic Strategies-A Review.

ABSTRACT: Atherosclerosis is an insidious and progressive inflammatory disease characterized by the formation of lipid-laden plaques within the intima of arterial walls with potentially devastating consequences. While rupture of vulnerable plaques has been extensively studied, a distinct mechanism known as plaque erosion (PE) has gained recognition and attention in recent years. PE, characterized by the loss of endothelial cell lining in the presence of intact fibrous cap, contributes to a significant and growing proportion of acute coronary events. However, despite a heterogeneous substrate underlying coronary thrombosis, treatment remains identical. This article provides an overview of atherosclerotic PE characteristics and its underlying mechanisms, highlights its clinical implications, and discusses potential therapeutic strategies.

Antithrombotic Treatment for Chronic Coronary Syndrome: Evidence and Future Perspectives.

BACKGROUND: The clinical presentation of coronary artery disease can range from asymptomatic, through stable disease in the form of chronic coronary syndrome, to acute coronary syndrome. Chronic coronary syndrome is a frequent condition, and secondary prevention of ischaemic events is essential. SUMMARY: Antithrombotic therapy is a key component of secondary prevention strategies, and it may vary in type and intensity depending on patient characteristics, comorbidities, and revascularisation modalities. Dual antiplatelet therapy is the default strategy in patients with chronic coronary syndrome and recent coronary stent implantation, while antiplatelet monotherapy is commonly prescribed for long-term prevention of cardiovascular events. Oral anticoagulation, in combination with antiplatelet therapy or alone, is used in patients with, e.g., concomitant atrial fibrillation or venous thromboembolism. KEY MESSAGES: This review provides an overview of antithrombotic treatment strategies in patients with chronic coronary syndrome. Key messages from current guidelines are conveyed, and we provide future perspectives on long-term antithrombotic strategies.

Understanding the role of coronary artery revascularization in patients with left ventricular dysfunction and multivessel disease.

Coronary artery disease (CAD) is the most common cause of heart failure with reduced ejection fraction (HFrEF). Advances and innovations in medical therapy have been shown to play a crucial role in improving the prognosis of patients with CAD and HFrEF; however, mortality rate in these patients remains high, and the role of surgical and/or percutaneous revascularization strategy is still debated. The Surgical Treatment for Ischemic Heart Failure (STICH) trial and the Revascularization for Ischemic Ventricular Dysfunction (REVIVED) trial have attempted to provide an answer to this issue. Nevertheless, the results of these two trials have generated further uncertainties. Their findings do not provide a definitive answer about the ideal clinical phenotype for surgical or percutaneous coronary revascularization and dispute the historical dogma on myocardial viability and the theory of myocardial hibernation, raising new questions about the proper selection of patients who are candidates for coronary revascularization. The aim of this review is to provide an overview on the actual available evidence of coronary artery revascularization in patients with CAD and left ventricular dysfunction and to suggest new insights on the proper selection and management strategies in this high-risk clinical setting.

Pathophysiology and Treatment of the No-Reflow Phenomenon in ST-Segment Elevation Myocardial Infarction: Focus on Low-Dose Fibrinolysis during Primary Percutaneous Intervention.

Primary percutaneous coronary intervention (PCI) is the current class I therapeutic approach to treat acute ST-elevation myocardial infarction (STEMI). While primary PCI can restore adequate flow in the infarcted artery in the majority of cases, some patients experience the 'no-reflow' phenomenon, i.e., an abnormal myocardial reperfusion occurring even after the occluded coronary artery has been opened. No-reflow occurs when microvascular obstruction arises from embolization of thrombus or components of the atheromatous plaques. These embolic materials travel downstream within the infarct-related artery at time of primary PCI, leading to compromised blood flow. Currently, no expert consensus documents exist to outline an optimal strategy to prevent or treat no-reflow. Interventional cardiologists frequently employ intracoronary adenosine, calcium channel blockers, nicorandil, nitroprusside or glycoprotein IIb/IIIa inhibitors. However, evidence suggests that these interventions consistently enhance myocardial blood flow in only a specific subset of patients experiencing no-reflow. A recent and innovative therapeutic approach gaining attention is low-dose fibrinolysis during primary PCI, which offers the potential to augment coronary flow post-myocardial revascularization.

Outcomes in diabetic patients treated with SGLT2-Inhibitors with acute myocardial infarction undergoing PCI: The SGLT2-I AMI PROTECT Registry.

AIMS: To investigate in-hospital and long-term prognosis in T2DM patients presenting with acute myocardial infarction (AMI) treated with SGLT2-I versus other oral anti-diabetic agents (non-SGLT2-I users). METHODS: In this multicenter international registry all consecutive diabetic AMI patients undergoing percutaneous coronary intervention between 2018 and 2021 were enrolled and, based on the admission anti-diabetic therapy, divided into SGLT-I users versus non-SGLT2-I users. The primary endpoint was defined as a composite of cardiovascular death, recurrent AMI, and hospitalization for HF (MACE). Secondary outcomes included i) in-hospital cardiovascular death, recurrent AMI, occurrence of arrhythmias, and contrast-induced acute kidney injury (CI-AKI); ii) long-term cardiovascular mortality, recurrent AMI, heart failure (HF) hospitalization. RESULTS: The study population consisted of 646 AMI patients (with or without ST-segment elevation): 111 SGLT2-I users and 535 non-SGLT-I users. The use of SGLT2-I was associated with a significantly lower in-hospital cardiovascular death, arrhythmic burden, and occurrence of CI-AKI (all p < 0.05). During a median follow-up of 24 ± 13 months, the primary composite endpoint, as well as cardiovascular mortality and HF hospitalization were lower for SGLT2-I users compared to non-SGLT2-I patients (p < 0.04 for all). After adjusting for confounding factors, the use of SGLT2-I was identified as independent predictor of reduced MACE occurrence (HR=0.57; 95%CI:0.33-0.99; p = 0.039) and HF hospitalization (HR=0.46; 95%CI:0.21-0.98; p = 0.041). CONCLUSIONS: In T2DM AMI patients, the use of SGLT2-I was associated with a lower risk of adverse cardiovascular outcomes during index hospitalization and long-term follow-up. Our findings provide new insights into the cardioprotective effects of SGLT2-I in the setting of AMI. REGISTRATION: Data are part of the observational international registry: SGLT2-I AMI PROTECT. CLINICALTRIALS: gov Identifier: NCT05261867.

Sodium-Glucose Cotransporter 2 Inhibitors in Patients with Diabetes and Coronary Artery Disease: Translating the Benefits of the Molecular Mechanisms of Gliflozins into Clinical Practice.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were initially developed for the treatment of diabetes due to their antihyperglycemic activity. However, in the light of the most recent clinical studies, they are revolutionizing the approach to cardiovascular disease in patients with and without diabetes. We aimed to generate real-world data about the use of SGLT2i in patients with T2DM and coronary artery disease (CAD), focusing on their effectiveness in glycemic control, adherence, long-term efficacy, and safety outcomes. On the basis of the inclusion and exclusion criteria, 143 patients were enrolled. Patients were treated with canagliflozin (n = 33 patients; 23%), dapagliflozin (n = 52 patients, 36.4%), empagliflozin (n = 48 patients; 33.6%), or ertugliflozin (n = 10 patients; 7%) as monotherapy or in combination with other antidiabetic drugs. All patients performed a clinical visit, and their medical history, blood sampling, and anthropometric parameters were measured at discharge and at 1-year follow-up. The reduction in HbA1c % value at 12 months was significant (8.2 vs. 7.4; p < 0.001). Trends in body weight and body mass index also confirmed the positive effect of the treatment (p < 0.0001), as did the reduction in abdominal adiposity (expressed via waist circumference). At 1-year follow-up, 74.1% of patients were adherent to the treatment, and 81.1% were persistent to the treatment. A total of 27 patients (18.8%) had to discontinue treatment early due to drug intolerance caused by genitourinary infections (11.9%), the drub being permanently ineffective (HbA1c not at target or decreasing: 4.9%), or because of expressing. a desire not to continue (2%). No major drug-related adverse events (diabetic ketoacidosis, Fournier's gangrene, lower-limb amputations) occurred at follow-up, while MACE events occurred in 14 patients (9.8%). In real-world patients with T2DM and CAD, SGLT2i have been effective in long-term glycemic control and the improvement in anthropometric indices with good tolerance, high adherence, persistence to treatment, and no major adverse events at 1-year follow-up.

Antithrombotic Therapy in Patients Undergoing Transcatheter Interventions for Structural Heart Disease.

Contemporary evidence supports device-based transcatheter interventions for the management of patients with structural heart disease. These procedures, which include aortic valve implantation, mitral or tricuspid valve repair/implantation, left atrial appendage occlusion, and patent foramen ovale closure, profoundly differ with respect to clinical indications and procedural aspects. Yet, patients undergoing transcatheter cardiac interventions require antithrombotic therapy before, during, or after the procedure to prevent thromboembolic events. However, these therapies are associated with an increased risk of bleeding complications. To date, challenges and controversies exist regarding balancing the risk of thrombotic and bleeding complications in these patients such that the optimal antithrombotic regimens to adopt in each specific procedure is still unclear. In this review, we summarize current evidence on antithrombotic therapies for device-based transcatheter interventions targeting structural heart disease and emphasize the importance of a tailored approach in these patients.

Infarct size, inflammatory burden, and admission hyperglycemia in diabetic patients with acute myocardial infarction treated with SGLT2-inhibitors: a multicenter international registry.

BACKGROUND: The inflammatory response occurring in acute myocardial infarction (AMI) has been proposed as a potential pharmacological target. Sodium-glucose co-transporter 2 inhibitors (SGLT2-I) currently receive intense clinical interest in patients with and without diabetes mellitus (DM) for their pleiotropic beneficial effects. We tested the hypothesis that SGLT2-I have anti-inflammatory effects along with glucose-lowering properties. Therefore, we investigated the link between stress hyperglycemia, inflammatory burden, and infarct size in a cohort of type 2 diabetic patients presenting with AMI treated with SGLT2-I versus other oral anti-diabetic (OAD) agents. METHODS: In this multicenter international observational registry, consecutive diabetic AMI patients undergoing percutaneous coronary intervention (PCI) between 2018 and 2021 were enrolled. Based on the presence of anti-diabetic therapy at the admission, patients were divided into those receiving SGLT2-I (SGLT-I users) versus other OAD agents (non-SGLT2-I users). The following inflammatory markers were evaluated at different time points: white-blood-cell count, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), neutrophil-to-platelet ratio (NPR), and C-reactive protein. Infarct size was assessed by echocardiography and by peak troponin levels. RESULTS: The study population consisted of 583 AMI patients (with or without ST-segment elevation): 98 SGLT2-I users and 485 non-SGLT-I users. Hyperglycemia at admission was less prevalent in the SGLT2-I group. Smaller infarct size was observed in patients treated with SGLT2-I compared to non-SGLT2-I group. On admission and at 24 h, inflammatory indices were significantly higher in non-SGLT2-I users compared to SGLT2-I patients, with a significant increase in neutrophil levels at 24 h. At multivariable analysis, the use of SGLT2-I was a significant predictor of reduced inflammatory response (OR 0.457, 95% CI 0.275-0.758, p = 0.002), independently of age, admission creatinine values, and admission glycemia. Conversely, peak troponin values and NSTEMI occurrence were independent predictors of a higher inflammatory status. CONCLUSIONS: Type 2 diabetic AMI patients receiving SGLT2-I exhibited significantly reduced inflammatory response and smaller infarct size compared to those receiving other OAD agents, independently of glucose-metabolic control. Our findings are hypothesis generating and provide new insights on the cardioprotective effects of SGLT2-I in the setting of coronary artery disease. TRIAL REGISTRATION: Data are part of the ongoing observational registry: SGLT2-I AMI PROTECT. CLINICALTRIALS: gov Identifier: NCT05261867.

Cardiorenal Impact of SGLT-2 Inhibitors: A Conceptual Revolution in The Management of Type 2 Diabetes, Heart Failure and Chronic Kidney Disease.

Type 2 Diabetes Mellitus (T2DM) is associated with an elevated incidence of cardiovascular and renal diseases, responsible for mortality rates significantly higher than in the general population. The management of both cardiovascular risk and progression of kidney disease thus seem crucial in the treatment of the diabetic patient. The availability of new classes of drugs which positively affect both cardiovascular and renal risk, regardless of the glycemic control, represents a revolution in the treatment of T2DM and shifts the attention from the intensive glycemic control to a holistic management of the diabetic patient. Among these, sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been associated with a remarkable reduction of cardiovascular and renal mortality, lower hospitalization rates for heart failure and lower progression of renal damage and albuminuria. Thus, their use in selected subpopulations seems mandatory. Aim of this review was the assessment of the current evidence on SGLT2i and their related impact on the cardiovascular and renal profiles.

Gender-related differences in changes of estimated bleeding risk in patients on dual antiplatelet therapy: the RE-SCORE multicenter prospective registry.

The risk of bleeding as predicted by the PRECISE-DAPT score can vary over time after percutaneous coronary intervention (PCI). We sought to compare the predictive ability of the PRECISE-DAPT score calculated at baseline and reassessed during follow-up in male and female patients undergoing PCI. The RE-SCORE was a multicenter, prospective registry including patients undergoing PCI treated with dual antiplatelet therapy (DAPT) for 1 year. The primary endpoint was Bleeding Academic Research Consortium (BARC) type 2, 3 or 5 bleeding. The PRECISE-DAPT score was determined for each patient at the time of PCI and at 1, 4 and 8-month follow-up visits or before the occurrence of an endpoint event. A total of 480 patients undergoing PCI were included. At baseline, median PRECISE-DAPT score was similar in males (23.2 [IQR 20.1-24.2]) and females (23.4 [IQR 20.2-25.3]; p = .22). During follow-up, an increase in the PRECISE-DAPT occurred significantly more often in females (44%) than in males (23%; p < .001). The discrimination of the PRECISE-DAPT score calculated at baseline was marginal in both males (c-index = 0.59, 95% CI: 0.51-0.65) and females (c-index = 0.55, 95% CI: 0.49-0.60). The discriminative ability of the score reassessed at follow-up was excellent in females (c-index = 0.84; 95% CI: 0.77-0.91) but remained modest in males (c-index = 0.61; 95% CI: 0.55-0.70). The bleeding predictive ability of the PRECISE-DAPT score can vary over time, more commonly in females than males. The discrimination of the score calculated during follow-up appeared improved in females but remained modest in males.Clinical Trial Registration - ClinicalTrials.gov Identifier: NCT03526614.

New Frontiers in the Treatment of Homozygous Familial Hypercholesterolemia.

Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder. The most common cause is a mutation in both alleles of the gene encoding for the low-density lipoprotein (LDL) receptor, although other causative mutations have been identified. Complications of atherosclerotic cardiovascular disease are common in these patients; therefore, reducing the elevated LDL-cholesterol burden is critical in their management. Conventionally, this is achieved by patients initiating lipid-lowering therapy, but this can present challenges in clinical practice. Fortunately, novel therapeutic strategies have enabled promising innovations in HoFH treatment. This review highlights recent and ongoing studies examining new therapeutic options for patients with HoFH.

Cangrelor, Tirofiban, and Chewed or Standard Prasugrel Regimens in Patients With ST-Segment-Elevation Myocardial Infarction: Primary Results of the FABOLUS-FASTER Trial.

BACKGROUND: Standard administration of newer oral P2Y12 inhibitors, including prasugrel or ticagrelor, provides suboptimal early inhibition of platelet aggregation (IPA) in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention. We aimed to investigate the effects of cangrelor, tirofiban, and prasugrel, administered as chewed or integral loading dose, on IPA in patients undergoing primary percutaneous coronary intervention. METHODS: The FABOLUS-FASTER trial (Facilitation Through Aggrastat or Cangrelor Bolus and Infusion Over Prasugrel: A Multicenter Randomized Open-Label Trial in Patients with ST-Elevation Myocardial Infarction Referred for Primary Percutaneous Intervention) is an investigator-initiated, multicenter, open-label, randomized study. A total of 122 P2Y12-naive patients with ST-segment-elevation myocardial infarction were randomly allocated (1:1:1) to cangrelor (n=40), tirofiban (n=40) (both administered as bolus and 2-hour infusion followed by 60 mg of prasugrel), or 60-mg loading dose of prasugrel (n=42). The latter group underwent an immediate 1:1 subrandomization to chewed (n=21) or integral (n=21) tablets administration. The trial was powered to test 3 hypotheses (noninferiority of cangrelor compared with tirofiban using a noninferiority margin of 9%, superiority of both tirofiban and cangrelor compared with chewed prasugrel, and superiority of chewed prasugrel as compared with integral prasugrel, each with α=0.016 for the primary end point, which was 30-minute IPA at light transmittance aggregometry in response to 20 µmol/L adenosine diphosphate. RESULTS: At 30 minutes, cangrelor did not satisfy noninferiority compared with tirofiban, which yielded superior IPA over cangrelor (95.0±8.9 versus 34.1±22.5; P<0.001). Cangrelor or tirofiban were both superior to chewed prasugrel (IPA, 10.5±11.0; P<0.001 for both comparisons), which did not provide higher IPA over integral prasugrel (6.3±11.4; P=0.47), despite yielding higher prasugrel active metabolite concentration (ng/mL; 62.3±82.6 versus 17.1±43.5; P=0.016). CONCLUSIONS: Cangrelor provided inferior IPA compared with tirofiban; both treatments yielded greater IPA compared with chewed prasugrel, which led to higher active metabolite concentration but not greater IPA compared with integral prasugrel. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02978040; URL: https://www.clinicaltrialsregister.eu; EudraCT 2017-001065-24.

Pathophysiological mechanisms and clinical evidence of relationship between Nonalcoholic fatty liver disease (NAFLD) and cardiovascular disease.

Evidence suggests a close connection between Nonalcoholic Fatty Liver Disease (NAFLD) and increased cardiovascular (CV) risk. Several cross-sectional studies report that NAFLD is related to preclinical atherosclerotic damage, and to coronary, cerebral and peripheral vascular events. Similar results have been showed by prospective studies and also by meta-analyzes on observational studies. The pathophysiological mechanisms of NAFLD are related to insulin resistance, which causes a dysfunction in adipokine production, especially adiponectin, from adipose tissue. A proinflammatory state and an increase in oxidative stress, due to increased reacting oxygen species (ROS) formation with consequent oxidation of free fatty acids and increased de novo lipogenesis with accumulation of triglycerides, are observed. These mechanisms may have an impact on atherosclerotic plaque formation and progression, and they can lead to increased cardiovascular risk in subjects with NAFLD. This review extensively discusses and comments current and developing NAFLD therapies and their possible impact on cardiovascular outcome.

Impact of Regular Physical Activity on Aortic Diameter Progression in Paediatric Patients with Bicuspid Aortic Valve.

Patients with bicuspid aortic valve (BAV) have an increased risk of aortic dilation and aortic dissection or rupture. The impact of physical training on the natural course of aortopathy in BAV patients remains unclear. The aim of this study was to evaluate the impact of regular physical activity on aortic diameters in a consecutive cohort of paediatric patients with BAV. Consecutive paediatric BAV patients were evaluated and categorized into two groups: physically active and sedentary subjects. Only the subjects with a complete 2-year follow-up were included in the study. To evaluate the potential impact of physical activity on aortic size, aortic diameters were measured at the sinus of Valsalva and mid-ascending aorta using echocardiography. We defined aortic diameter progression the increase of aortic diameter ≥ 10% from baseline. Among 90 BAV patients (11.5 ± 3.4 years of age, 77% males), 53 (59%) were physically active subjects. Compared to sedentary, physically active subjects were not significantly more likely to have > 10% increase in sinus of Valsalva (13% vs. 8%, p-value = 0.45) or mid-ascending aorta diameter (9% vs. 13%, p-value = 0.55) at 2 years follow-up, both in subjects with sinus of Valsalva diameter progression (3.7 ± 1.0 mm vs. 3.5 ± 0.8 mm, p-value = 0.67) and in those with ascending aorta diameter progression (3.0 ± 0.8 mm vs. 3.2 ± 1.3 mm, p-value = 0.83). In our paediatric cohort of BAV patients, the prevalence and the degree of aortic diameter progression was not significantly different between physically active and sedentary subjects, suggesting that aortic dilation is unrelated to regular physical activity over a 2-year period.

Validation of high bleeding risk criteria and definition as proposed by the academic research consortium for high bleeding risk.

AIMS: To validate the set of clinical and biochemical criteria proposed by consensus by the Academic Research Consortium (ARC) for High Bleeding Risk (HBR) for the identification of HBR patients. These criteria were categorized into major and minor, if expected to carry in isolation, respectively, ≥4% and <4% Bleeding Academic Research Consortium (BARC) 3 or 5 bleeding risk within 1-year after percutaneous coronary intervention (PCI). High bleeding risk patients are those meeting at least 1 major or 2 minor criteria. METHODS AND RESULTS: All patients undergoing PCI at Bern University Hospital, between February 2009 and September 2018 were prospectively entered into the Bern PCI Registry (NCT02241291). Age, haemoglobin, platelet count, creatinine, and use of oral anticoagulation were prospectively collected, while the remaining HBR criteria except for planned surgery were retrospectively adjudicated. A total of 16 580 participants with complete ARC-HBR criteria were included. After assigning 1 point to each major and 0.5 point to each minor criterion, we observed for every 0.5 score increase a step-wise augmentation of BARC 3 or 5 bleeding rates at 1 year ranging from 1.90% among patients fulfilling no criterion, through 4.01%, 5.98%, 7.42%, 8.60%, 12.21%, 12.29%, and 17.64%. All major and five out of six minor criteria, conferred in isolation a risk for BARC 3 or 5 bleeding at 1 year exceeding 4% at the upper limit of the 95% confidence intervals. CONCLUSION: All major and the majority of minor ARC-HBR criteria identify in isolation patients at HBR.

Impact of SGLT2 Inhibitors on Heart Failure: From Pathophysiology to Clinical Effects.

Heart failure (HF) affects up to over 20% of patients with type 2 diabetes (T2DM), even more in the elderly. Although, in T2DM, both hyperglycemia and the proinflammatory status induced by insulin resistance are crucial in cardiac function impairment, SGLT2i cardioprotective mechanisms against HF are several. In particular, these beneficial effects seem attributable to the significant reduction of intracellular sodium levels, well-known to exert a cardioprotective role in the prevention of oxidative stress and consequent cardiomyocyte death. From a molecular perspective, patients' exposure to gliflozins' treatment mimics nutrient and oxygen deprivation, with consequent autophagy stimulation. This allows to maintain the cellular homeostasis through different degradative pathways. Thus, since their introduction in the clinical practice, the hypotheses on SGLT2i mechanisms of action have changed: from simple glycosuric drugs, with consequent glucose lowering, erythropoiesis enhancing and ketogenesis stimulating, to intracellular sodium-lowering molecules. This provides their consequent cardioprotective effect, which justifies its significant reduction in CV events, especially in populations at higher risk. Finally, the updated clinical evidence of SGLT2i benefits on HF was summarized. Thus, this review aimed to analyze the cardioprotective mechanisms of sodium glucose transporter 2 inhibitors (SGLT2i) in patients with HF, as well as their clinical impact on cardiovascular events.

MicroRNA-33 and SIRT1 influence the coronary thrombus burden in hyperglycemic STEMI patients.

Primary percutaneous coronary intervention (PPCI) is a pivotal treatment in ST-segment elevation myocardial infarction (STEMI) patients. However, in hyperglycemic-STEMI patients, the incidence of death is still significant. Here, the involvement of sirtuin 1 (SIRT1) and miR33 on the pro-inflammatory/pro-coagulable state of the coronary thrombus was investigated. Moreover, 1-year outcomes in hyperglycemic STEMI in patients subjected to thrombus aspiration before PPCI were evaluated. Results showed that hyperglycemic thrombi displayed higher size and increased miR33, reactive oxygen species, and pro-inflammatory/pro-coagulable markers. Conversely, the hyperglycemic thrombi showed a lower endothelial SIRT1 expression. Moreover, in vitro experiments on endothelial cells showed a causal effect of SIRT1 modulation on the pro-inflammatory/pro-coagulative state via hyperglycemia-induced miR33 expression. Finally, SIRT1 expression negatively correlated with STEMI outcomes. These observations demonstrate the involvement of the miR33/SIRT1 pathway in the increased pro-inflammatory and pro-coagulable state of coronary thrombi in hyperglycemic STEMI patients.

Low-Dose Ticagrelor in Patients With High Ischemic Risk and Previous Myocardial Infarction: A Multicenter Prospective Real-World Observational Study.

Prolonged dual antiplatelet therapy after 12 months in patients with previous myocardial infarction (MI) is attractive to reduce long-term ischemic complications. In the PEGASUS-TIMI 54, the use of low-dose ticagrelor (60 mg b.i.d.) plus aspirin after 12 months from MI reduced the risk of ischemic events, at the price of limited increase on bleeding complications. However, data on the use of low-dose ticagrelor in real-world practice lack. We aim at providing data on prescription/eligibility criteria and outcomes in patients receiving low-dose ticagrelor in the real-world setting. We enrolled consecutive patients eligible for ticagrelor 60 mg according to Italian national regulation in 3 high-volume centers and collected 1-year outcomes. The primary objective of the study is to generate real-world data about clinical characteristics, eligibility criteria, major adverse cardiovascular events, bleeding, and adverse event in patients receiving low-dose ticagrelor from our cohort. One hundred eighty-one patients were consecutively enrolled with a median follow-up of 18 months. The most used and the least used prescription criteria were multivessel coronary disease (72.4%) and chronic kidney disease (15.5%), respectively. At 1-year follow-up, the rate of major adverse cardiovascular events was 4.97%; of these, 3.86% of patients had a MI, and 1.1% had a stroke/transient ischemic attack, whereas no major bleeding occurred. In conclusion, in a real-world study, including patients with previous MI, low-dose ticagrelor for prolonged dual antiplatelet therapy showed to be effective and safe, with no major bleeding occurring at follow-up.