Integrating platelet reactivity in the age, creatinine and ejection fraction score to predict clinical outcomes following percutaneous coronary intervention in patients with chronic coronary syndrome: the PR-ACEF score.

To evaluate if integrating platelet reactivity (PR) evaluation in the original age, creatinine and ejection fraction (ACEF) score could improve the diagnostic accuracy of the model in patients with stable coronary artery disease (CAD). We enrolled patients treated with percutaneous coronary intervention between 2010 and 2011. High PR was included in the model (PR-ACEF). Co-primary end points were a composite of death/myocardial infarction (MI) and major adverse cardiovascular events (MACE). Overall, 471 patients were enrolled. Compared to the ACEF score, the PR-ACEF showed an improved diagnostic accuracy for death/MI (AUC 0.610 vs 0.670, p < 0.001) and MACE (AUC 0.572 vs 0.634, p < 0.001). These findings were confirmed using internal validation with bootstrap resampling. At 5 years, the PR-ACEF value > 1.75 was independently associated with death/MI [HR 3.51, 95% CI (1.97-6.23)] and MACE [HR 2.77, 95% CI (1.69-4.53)]. The PR-ACEF score was effective in improving the diagnostic performance of the ACEF score at the long-term follow-up.

Coronary Chronic Total Occlusion Revascularization: When, Who and How?

Coronary chronic total occlusions (CTO) are an increasingly frequent entity in clinical practice and represent a challenging percutaneous coronary intervention (PCI) scenario. Despite data from randomized trials that have not yet demonstrated a clear benefit of CTO recanalization, the widespread of CTO-PCI has substantially increased. The improvement in operators' techniques, equipment, and training programs has led to an improvement in the success rate and safety of these procedures, which will represent an important field of future development of PCI. The present review will summarize clinical outcomes and technical and safety issues of CTO revascularization with the aim to guide clinical daily cath-lab practice.

Takotsubo Syndrome and Coronary Artery Disease: Which Came First-The Chicken or the Egg?

Takotsubo syndrome (TTS) is a clinical condition characterized by temporary regional wall motion anomalies and dysfunction that extend beyond a single epicardial vascular distribution. Various pathophysiological mechanisms, including inflammation, microvascular dysfunction, direct catecholamine toxicity, metabolic changes, sympathetic overdrive-mediated multi-vessel epicardial spasms, and transitory ischemia may cause the observed reversible myocardial stunning. Despite the fact that TTS usually has an acute coronary syndrome-like pattern of presentation, the absence of culprit atherosclerotic coronary artery disease is often reported at coronary angiography. However, the idea that coronary artery disease (CAD) and TTS conditions are mutually exclusive has been cast into doubt by numerous recent studies suggesting that CAD may coexist in many TTS patients, with significant clinical and prognostic repercussions. Whether the relationship between CAD and TTS is a mere coincidence or a bidirectional cause-and-effect is still up for debate, and misdiagnosis of the two disorders could lead to improper patient treatment with unfavourable outcomes. Therefore, this review seeks to provide a profound understanding of the relationship between CAD and TTS by analyzing potential common underlying pathways, addressing challenges in differential diagnosis, and discussing medical and procedural techniques to treat these conditions appropriately.

Leptin as predictor of cardiovascular events and high platelet reactivity in patients undergoing percutaneous coronary intervention.

BACKGROUND AND AIMS: Leptin is a hormone involved in the regulation of food intake. Previous studies suggested an interplay between leptin, platelet aggregation, and cardiovascular outcome but this issue was not investigated in vivo in patients treated with percutaneous coronary intervention (PCI). We designed a study to evaluate the possible relation between leptin, cardiovascular outcome, and platelet reactivity (PR) in patients undergoing PCI. METHODS: 155 PCI patients had preprocedural measurements of PR and leptin plasma levels. The latter were assessed by ELISA. Hyperleptinemia was defined as leptin levels ≥14 ng/ml. PR was evaluated by the VerifyNowP2Y12 assay and expressed as P2Y12 reaction units (PRU). Patients were divided into three groups based on PR values and defined as low (LPR), normal (NPR), and high (HPR). Patients were followed for up 8 years. The primary endpoint was the incidence of Major Acute Cardiac Events (MACE) at long-term follow-up according to leptin groups. Secondary endpoints were the evaluation of leptin levels according to PR groups and the incidence of periprocedural myocardial infarction (PMI) according to leptin groups. RESULTS: Long-term follow-up was completed in 140 patients. Patients with hyperleptinemia experienced a higher MACE rate than the normoleptinemic group (HR 2.3; CI 95% 1.14-4.6, P = 0.02). These results remained unchanged after adjusting for Body Mass Index, hypertension, and gender. Leptin levels were significantly different among groups of PR (P = 0.047). Leptin levels were higher in the HPR group (12.61 ± 16.58 ng/ml) compared to the LPR group (7.83 ± 8.87 ng/ml, P = 0.044) and NPR group (7.04 ± 7.03 ng/ml, P = 0.01). The rate of PMI was higher in hyperleptinemia patients (15.1% vs. 6.5%, P = 0.22). CONCLUSIONS: This study suggests that high leptin levels are associated with a worse clinical outcome in patients undergoing PCI and with HPR. Further studies are needed to define better the pathophysiological pathways underlying this association.

Incretins-Based Therapies and Their Cardiovascular Effects: New Game-Changers for the Management of Patients with Diabetes and Cardiovascular Disease.

Atherosclerosis is the leading cause of death worldwide, especially in patients with type 2 diabetes mellitus (T2D). GLP-1 receptor agonists and DPP-4 inhibitors were demonstrated to play a markedly protective role for the cardiovascular system beyond their glycemic control. Several cardiovascular outcome trials (CVOT) reported the association between using these agents and a significant reduction in cardiovascular events in patients with T2D and a high cardiovascular risk profile. Moreover, recent evidence highlights a favorable benefit/risk profile in myocardial infarction and percutaneous coronary revascularization settings. These clinical effects result from their actions on multiple molecular mechanisms involving the immune system, platelets, and endothelial and vascular smooth muscle cells. This comprehensive review specifically concentrates on these cellular and molecular processes mediating the cardiovascular effects of incretins-like molecules, aiming to improve clinicians' knowledge and stimulate a more extensive use of these drugs in clinical practice as helpful cardiovascular preventive strategies.

Relationship Between the Completeness of Revascularization and Myocardial Injury in Patients Treated With Percutaneous Coronary Intervention.

BACKGROUND: Clinical outcomes of patients suffering periprocedural myocardial injury and undergoing incomplete revascularization (IR) following percutaneous coronary intervention (PCI) has never been investigated. OBJECTIVE: To investigate the relationship between different thresholds of post-PCI cardiac troponin (cTn) elevation and revascularization completeness in determining long-term clinical outcomes. METHODS: Patients were stratified in tertiles according to preprocedural SYNTAX score (SS) (low: 0-6; medium: >6-11; high: >11) and residual SS (low: 0-4; medium: >4-8; high: >8). IR was defined by a rSS value >4. Three thresholds of myocardial injury were pre-specified: 5×, 35× and 70× 99th percentile upper reference limit (URL) increase of baseline cTn. Primary outcome was a composite of major adverse cardiac events (MACE) at two years of follow-up. RESULTS: 1061 patients undergoing PCI for stable coronary artery disease were enrolled. IR occurred in 249 (23.4 %) and major myocardial injury in 540 (50.9 %). Patients belonging to the highest tertile of SS showed an increased risk of experiencing IR and periprocedural myocardial injury. Two-year follow-up was available in 869. At multi-variate Cox's regression analysis, patients undergoing IR + cTn > 35 × URL and IR + cTn > 70 × URL showed an increased risk of MACE [HR 2.30 (1.19-4.41) and HR 3.20 (1.38-7.41); respectively]. CONCLUSIONS: Periprocedural myocardial injury is critically associated with MACE at two-year follow-up in patient treated with PCI who achieve IR. Despite conflicting evidence exists regarding the influence of periprocedural myocardial injury on clinical outcomes, patients undergoing IR seem to represent a high-risk subgroup.

Glycaemic Control in Patients Undergoing Percutaneous Coronary Intervention: What Is the Role for the Novel Antidiabetic Agents? A Comprehensive Review of Basic Science and Clinical Data.

Coronary artery disease (CAD) remains one of the most important causes of morbidity and mortality worldwide, and revascularization through percutaneous coronary interventions (PCI) significantly improves survival. In this setting, poor glycaemic control, regardless of diabetes, has been associated with increased incidence of peri-procedural and long-term complications and worse prognosis. Novel antidiabetic agents have represented a paradigm shift in managing patients with diabetes and cardiovascular diseases. However, limited data are reported so far in patients undergoing coronary stenting. This review intends to provide an overview of the biological mechanisms underlying hyperglycaemia-induced vascular damage and the contrasting actions of new antidiabetic drugs. We summarize existing evidence on the effects of these drugs in the setting of PCI, addressing pre-clinical and clinical studies and drug-drug interactions with antiplatelet agents, thus highlighting new opportunities for optimal long-term management of these patients.

Contrast-induced Acute Kidney Injury in Diabetic Patients and SGLT-2 Inhibitors: A Preventive Opportunity or Promoting Element?

ABSTRACT: Contrast-induced acute kidney injury (CI-AKI) is a serious complication in patients undergoing diagnostic or therapeutic procedures that require contrast use and negatively affects the long-term outcomes. Patients with type 2 diabetes mellitus (DM), particularly those who have already developed diabetic nephropathy (DN), are more susceptible to contrast-induced renal damage. Indeed, contrast media amplify some pathological molecular and cellular pathways already in place in the DN setting. In recent years, sodium-glucose cotransporter-2 inhibitors (SGLT2i) have triggered a paradigm shift in managing patients with type 2 DM, reducing cardiovascular and renal adverse events, and slowing DN development. Some evidence also suggests favorable effects of SGLT2i on acute kidney injury despite the initial alarm; however, little data exist regarding CI-AKI. The present review provides an updated overview of the most recent experimental and clinical studies investigating the beneficial effects of SGLT2i on chronic and acute renal injury, focusing on their potential role in the development of CI-AKI. Thus, we aimed to expand the clinicians' understanding by underscoring new opportunities to prevent this complication in the setting of DM, where effective preventive strategies are still lacking.

Antithrombotic treatment for valve prostheses: Which drug, which dose, and when?

Despite the significant reduction of the overall burden of cardiovascular diseases (CVD), valvular heart disease (VHD) still represents an important cause of CVD morbidity and mortality. While the number of patients with prosthetic heart valves (PHV) is increasing, management of antithrombotic therapy in this setting remains particularly challenge. This happens also because the scientific guidelines and consensus documents rely on limited evidences. Nevertheless, the evolution in prostheses' materials, the spread of transcatheter interventions, and the introduction of direct oral anticoagulants (DOACs), altogether led to a scientific renaissance of this field. Our purpose is to examine and discuss the available evidences on the use of antithrombotic treatments in patients with mechanical and biological PHV, with the aim to provide a practical tool for decision making in every day clinical practice.

Circadian variations of platelet reactivity on clopidogrel in patients treated with elective percutaneous coronary intervention.

Evidence assessing potential diurnal variations of platelet reactivity in patients on clopidogrel treated with elective percutaneous coronary intervention (PCI) for chronic coronary syndrome (CCS) are currently lacking. We prospectively enrolled 15 patients affected by stable coronary artery disease (CAD) previously treated with elective PCI and on clopidogrel for at least 8 days (administered at 8 a.m.). A significant heterogeneity in diurnal levels of ADP-dependent platelet aggregation was found (p = 0.0004), with a peak of platelet reactivity occurring at the 6 a.m. assessment, which resulted significantly increased compared to the afternoon (6 p.m.) evaluation (255 ± 66 vs 184 ± 67, p = 0.002). In addition, at the early-morning evaluation a considerably high proportion of patients with high platelet reactivity (53.3%) were observed. In conclusion, clopidogrel-induced platelet inhibition in patients with CCS after elective PCI follows a circadian rhythm, thus suggesting that a consistent and durable antiplatelet inhibition is often failed with standard clopidogrel administration at morning.

Association Between Platelet Reactivity and Long-Term Bleeding Complications After Percutaneous Coronary Intervention According to Diabetes Status.

The relation between diabetes mellitus (DM) and bleeding complications after percutaneous coronary intervention (PCI) is controversial. This study investigates the role of low platelet reactivity (LPR) in the bleeding risk stratification of patients who underwent PCI according to DM status. A total of 472 patients who underwent PCI on aspirin and clopidogrel were included retrospectively. Platelet reactivity was assessed using the VerifyNow P2Y(12) assay. LPR was defined as platelet reactivity unit ≤178. The primary end point was the occurrence of any bleeding at 5 years stratified by DM status and LPR. DM was present in 30.5% of patients. LPR was less frequent in patients with DM (p = 0.077). Overall, 11.9% of patients experienced a bleeding complication at 5 years. The incidence of bleeding did not differ in subjects with and without DM (p = 0.24). LPR had a similar value for stratifying the increased bleeding risk in patients with and without DM (interaction p between DM and LPR 0.69). A stepwise increase in the crude rates of bleeding complications was observed across patients with and without LPR and DM (log-rank p = 0.004), with those affected by both conditions having the highest crude incidence rate. In conclusion, on top of aspirin, approximately 1/3 of patients who underwent PCI on clopidogrel have LPR. Assessment of LPR provides a significant incremental value for predicting bleeding irrespective of DM status. Although the presence of DM per se does not increase the incidence of hemorrhagic complications, the coexistence of DM and LPR identifies the subgroup with the highest bleeding risk.

Prediction of type 4a myocardial infarction with the angiography-derived hemodynamic (ADDED) index.

Percutaneous coronary intervention (PCI) is frequently complicated by type 4a myocardial infarction (MI), which is associated with an increased risk of mortality. We assessed the usefulness of the angiography-derived hemodynamic index (ADDED), which is based on the extent of myocardium at risk and on the anatomical lesion severity, in predicting type 4a MI in patients with chronic coronary syndrome (CCS) undergoing PCI. We enrolled 442 patients treated with single-vessel PCI. The ADDED index was calculated as the ratio of the Duke Jeopardy Score to the minimum lumen diameter assessed with quantitative angiography analysis. Type 4a MI was defined according to the 4th Universal Definition of MI. The overall population was divided into tertiles of ADDED index. Type 4a MI occurred in 5 patients (3.3%) in the ADDED-low tertile, 8 (5.5%) in the ADDED-mid tertile, and 26 (17.7%) in the ADDED-high tertile (p < 0.0001). At ROC curve analysis, the ADDED index could significantly discriminate between patients with and without type 4a MI (area under the curve 0.745). At multivariate analysis, an ADDED index value > 5.25 was the strongest independent predictor type 4a MI. Our results support the role of the ADDED index as a predictor of type 4a MI in patients with CCS treated with elective PCI of a single vessel. Whether a selective use of additional preventive measures in patients considered at high risk based on ADDED index values may improve peri-procedural and long-term outcomes remains to be tested in dedicated investigations.

Platelet reactivity and clinical outcomes following percutaneous coronary intervention in complex higher-risk patients.

AIMS: To investigate the levels of platelet reactivity and the impact of high platelet reactivity (HPR) on long-term clinical outcomes of complex higher-risk and indicated patients (CHIP) with stable coronary artery disease (CAD) treated with elective percutaneous coronary intervention (PCI). METHODS: We enrolled 500 patients undergoing elective PCI for stable CAD and treated with aspirin and clopidogrel. Patients were divided into four groups based on the presence of CHIP features and HPR. Primary endpoint was the occurrence of major adverse clinical events (MACE) at 5 years. RESULTS: The prevalence of HPR was significantly greater in the CHIP population rather than non-CHIP patients (39.9% vs 29.8%, P = 0.021). Patients with both CHIP features and HPR showed the highest estimates of MACE (22.1%, log-rank P = 0.047). At Cox proportional hazard analysis, the combination of CHIP features and HPR was an independent predictor of MACE (hazard ratio 2.57, 95% confidence interval 1.30-5.05, P = 0.006). CONCLUSION: Among patients with stable CAD undergoing elective PCI and treated with aspirin and clopidogrel, the combination of CHIP features and HPR identifies a cohort of patients with the highest risk of MACE at 5 years, who might benefit from more potent antiplatelet strategies.

Usefulness of Adding Pre-procedural Glycemia to the Mehran Score to Enhance Its Ability to Predict Contrast-induced Kidney Injury in Patients Undergoing Percutaneous Coronary Intervention Development and Validation of a Predictive Model.

The Mehran score is the most widely accepted tool for predicting contrast-induced acute kidney injury (CI-AKI), a major complication of percutaneous coronary intervention (PCI). Similarly, abnormal fasting pre-procedural glycemia (FPG) represents a modifiable risk factor for CI-AKI, but it is not included in current risk models for CI-AKI prediction. We sought to analyze whether adding FPG to the Mehran score improves its ability to predict CI-AKI following PCI. We analyzed 671 consecutive patients undergoing PCI (age 69 [63,75] years, 23% females), regardless of their diabetic status, to derive a revised Mehran score obtained by including FPG in the original Mehran score (Derivation Cohort). The new risk model (GlyMehr) was externally validated in 673 consecutive patients (Validation Cohort) (age 69 [62,76] years, 21% females). In the Derivation Cohort, both FPG and the original Mehran score predicted CI-AKI (AUC 0.703 and 0.673, respectively). The GlyMehr score showed a better predictive ability when compared with the Mehran score both in the Derivation Cohort (AUC 0.749, 95%CI 0.662 to 0.836; p = 0.0016) and the Validation Cohort (AUC 0.848, 95%CI, 0.792 to 0.903; p = 0.0008). In the overall population (n = 1344), the GlyMehr score confirmed its independent and incremental predictive ability regardless of diabetic status (p ≤0.0034) or unstable/stable coronary syndromes (p ≤0.0272). In conclusion, adding FPG to the Mehran score significantly enhances our ability to predict CI-AKI. The GlyMehr score may contribute to improve the clinical management of patients undergoing PCI by identifying those at high risk of CI-AKI and potentially detecting modifiable risk factors.

Impact of Chronic Kidney Disease and Platelet Reactivity on Clinical Outcomes Following Percutaneous Coronary Intervention.

We investigated the interaction between chronic kidney disease (CKD) and high platelet reactivity (HPR) in determining long-term clinical outcomes following elective PCI for stable coronary artery disease (CAD). A total of 500 patients treated with aspirin and clopidogrel were divided based on the presence of CKD (defined as glomerular filtration rate of < 60 ml/min/1.73 m2) and HPR (defined as a P2Y12 reaction unit value ≥ 240 at VerifyNow assay). Primary endpoint was the occurrence of major adverse clinical events (MACE) at 5 years. Patients with both CKD and HPR showed the highest estimates of MACE (25.6%, p = 0.005), all-cause death (17.9%, p = 0.004), and cardiac death (7.7%, p = 0.004). The combination of CKD and HPR was an independent predictor of MACE (HR 3.12, 95% CI 1.46-6.68, p = 0.003). In conclusion, the combination of CKD and HPR identifies a cohort of patients with the highest risk of MACE at 5 years.

Prediction of 5-Year Mortality in Patients with Chronic Coronary Syndrome Treated with Elective Percutaneous Coronary Intervention: Role of the ACEF Score.

We evaluated the predictive power of age, creatinine, and ejection fraction (ACEF) score on mortality at 5-year follow-up in a population of 471 patients with chronic coronary syndrome (CCS) treated with percutaneous coronary intervention (PCI). Patients in the ACEF-High tertile showed the highest incidence of death at 5 years (15.7% vs. 2.6% in ACEF-Low and 4.3% in ACEF-Mid; log rank p<0.001). The ACEF score could significantly discriminate between patients who died and those who were still alive at 5 years (AUC 0.741, 95% CI 0.654-0.828), and an ACEF score >1.32 was identified as the optimal cutoff point to predict 5-year mortality (sensitivity 74%, specificity 68%). An ACEF score >1.32 was an independent predictor of 5-year mortality (HR 5.77, 95% CI 2.70-12.31; p<0.001). Our study shows that the ACEF score can predict mortality at 5-year follow-up in patients with CCS treated with PCI.

Gender Issues in Italian Catheterization Laboratories: The Gender-CATH Study.

Background Women represent an increasing percentage of interventional cardiologists in Italy compared with other countries. However, gaps exist in understanding and adapting to the impact of these changing demographics. Methods and Results We performed a national survey to analyze demographics, gender-based professional difference, needs in terms of catheterization laboratory (Cath-Lab) abstention, and radiation safety issues in Italian Cath-Lab settings. A survey supported by the Italian Society of Interventional Cardiology (Società Italiana di Cardiologia Interventistica-Gruppo Italiano di Studi Emodinamici SICI-GISE) was mailed to all SICI-GISE members. Categorical data were compared using the χ2 test. P<0.05 was considered significant. There were 326 respondents: 20.2% were <35 years old, and 64.4% had >10 years of Cath-Lab experience. Notably, 26.4% were women. Workload was not gender-influenced (women performed "on-call" duty 69.8% versus men 68.3%; P=0.97). Women were more frequently unmarried (22.1% women versus 8.7% men; P=0.002) and childless (43.9% versus 56.1%; P<0.001). Interestingly, 69.8% of women versus 44.6% of men (P<0.001) argued that pregnancy/breastfeeding negatively impacts professional skill development and career advancement. For Cath-Lab abstention, 38.9% and 69.6% of respondents considered it useful to perform percutaneous coronary intervention robotic simulations and "refresh-skill" sessions while they were absent or on return to work, respectively, without gender differences. Overall, 80% of respondents described current radioprotection counseling efforts as inadequate and not gender specific. Finally, 26.7% faced some type of job discrimination, a significantly higher proportion of whom were women. Conclusions Several gender-based differences exist or are perceived to exist among interventional cardiologists in Italian Cath-Labs. Joint strategies addressing Cath-Lab abstention and radiation exposure education should be developed to promote gender equity in interventional cardiologists.

Ranolazine Improves Glycemic Variability and Endothelial Function in Patients with Diabetes and Chronic Coronary Syndromes: Results from an Experimental Study.

BACKGROUND: Ranolazine is a second-line drug for the management of chronic coronary syndromes (CCS). Glucose-lowering and endothelial effects have also been reported with this agent. However, whether ranolazine may improve short-term glycemic variability (GV), strictly related to the prognosis of patients with type 2 diabetes (T2D), is unknown. Thus, we aimed to explore the effects of adding ranolazine to standard anti-ischemic and glucose-lowering therapy on long- and short-term GV as well as on endothelial function and oxidative stress in patients with T2D and CCS. METHODS: Patients starting ranolazine (n = 16) were evaluated for short-term GV, haemoglobin 1Ac (Hb1Ac) levels, endothelial-dependent flow-mediated vasodilation (FMD), and oxidative stress levels at enrolment and after 3-month follow-up. The same measurements were collected from 16 patients with CCS and T2D that did not receive ranolazine, matched for age, gender, and body mass index. RESULTS: A significant decline in Hb1Ac levels was reported after 3-month ranolazine treatment (mean change -0.60%; 2-way ANOVA p = 0.025). Moreover, among patients receiving ranolazine, short-term GV indexes were significantly improved over time compared with baseline (p = 0.001 for time in range; 2-way ANOVA p = 0.010). Conversely, no significant changes were reported in patients without ranolazine. Finally, greater FMD and lower oxidative stress levels were observed in patients on ranolazine at 3 months. CONCLUSIONS: Ranolazine added to standard anti-ischemic and glucose-lowering therapy demonstrated benefit in improving the glycemic status of patients with T2D and CCS. How this improvement contributes to the overall myocardial benefit of ranolazine requires further studies.