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We here describe the case of an 84-year-old woman with a history of ischemic heart disease, paroxysmal atrial fibrillation, and severe aortic stenosis, admitted to the coronary care unit of our hospital for an ST-elevation myocardial infarction secondary to in-stent thrombosis and treated with primary percutaneous coronary intervention. On admission, the patient was on chronic therapy with apixaban for atrial fibrillation, and reported no history of bleeding. However, the day after the administration of the loading doses of aspirin and clopidogrel, the patient developed multiple episodes of rectal bleeding and melena, requiring blood transfusions. The endoscopic work-up was negative for bleeding lesions in the upper gastrointestinal tract and in the colon, but with a blood leakage from the ileocecal valve, prompting the diagnostic suspicion of an ileal bleeding secondary to angiodysplasia. Considering the well-known link between severe aortic stenosis and ileal angiodysplasia (i.e. Heyde's syndrome), the patient, already in the waiting list for elective transcatheter aortic valve implantation, underwent the procedure during the index hospitalization. The procedure was performed in the absence of complications and the patient was discharged with a personalized antithrombotic therapy. In the following weeks, no further episodes of bleeding were reported.

Inflammation plays an important role in cardiovascular disease. Growing evidence suggests a profound involvement of the inflammatory response in the development and progression of atherosclerosis and its complications. In patients with atherosclerotic cardiovascular disease (ASCVD), residual cardiovascular risk often remains high despite optimal medical therapy and the achievement of the therapeutic targets recommended by current guidelines. Among the multiple components of residual risk, residual inflammatory risk, assessed by plasma levels of high-sensitivity C-reactive protein, has shown a strong association with the incidence of cardiovascular events. Recent studies suggest that therapeutic modulation of inflammation, particularly the interleukin (IL)-1/IL-6 pathway, is a promising strategy for the prevention and treatment of cardiovascular and kidney diseases. This review aims to discuss pragmatically the interaction between inflammation and ASCVD, describe current evidence on anti-inflammatory therapies in patients with cardiovascular and renal diseases, and outline the potential implications of these new therapeutic approaches in contemporary and future practice.

In the context of secondary prevention, the efficacy of aspirin in reducing cardiovascular events is widely acknowledged. However, its use for primary prevention is still debated because of uncertain data regarding the risk-benefit ratio. Despite the reduction in atherothrombotic events, almost all randomized clinical trials and meta-analyses have failed to demonstrate a net clinical benefit, as cardiovascular outcome improvement was counterbalanced by increased bleeding. We have, however, to acknowledge that, within the population eligible for primary prevention, cardiovascular risk distribution is extremely heterogeneous. Using data obtained from the most recent trials, we performed a meta-regression of benefits and risks associated with aspirin related to 10-year risk of major adverse cardiovascular events (MACEs). We are thus proposing a tailored approach to find the proper patient category to treat with aspirin in primary prevention. In patients <70 years old with an optimal control of cardiovascular risk factors, physicians should carefully evaluate individual MACE risk and make a therapeutic decision accordingly, also considering bleeding risk and patient preference. The results of net clinical benefit analysis of aspirin therapy suggest that patients with intermediate-high cardiovascular risk (10-year MACE risk >10%) without a prohibitive bleeding risk may represent the target population, since in these patients the reduction in atherothrombotic events overcomes the induced excess of bleeding. Antiplatelet therapy benefits also appear to be amplified by the simultaneous administration of gastroprotective agents and treatment of other cardiovascular risk factors, such as dyslipidemia and hypertension.

Acute coronary syndromes have heterogeneous clinical presentations, features and prognosis. They can also occur without angiographic evidence of significant coronary artery stenosis, based on multiple causes. We report on the diagnostic and therapeutic management of a 56-year-old man with an acute coronary syndrome and angiographic evidence of non-obstructive coronary artery disease. In addition to the basic angiographic evaluation, intracoronary imaging was here helpful to understand the underlying mechanism, prompting a tailored therapeutic strategy and avoiding inappropriate treatment with percutaneous coronary intervention and stenting. This clinical case here described offers the opportunity to briefly recapitulate the most meaningful milestones in the progress in the pathophysiology of acute coronary syndromes, also focusing on myocardial infarction non-obstructive coronary artery, and to appreciate the occurrence of rare cases and consequent lessons.

Background: The ongoing prospective, single-arm, observational, phase 4 ETNA-AF Europe study is collecting real-world data about the safety and, secondarily, the effectiveness and therapeutic adherence of newly prescribed edoxaban for non-valvular atrial fibrillation in Europe., Methods: At the end of enrollment in 2018, 13 980 subjects were included, of whom 3509 were Italian. Of them, 3341 (95.2%) had follow-up data available at 1 year., Results: Their mean age was 75 ± 9.3 years, with 56.9% being ≥75 years old. The CHA2DS2-VASc score was ≥4 in 1380 (41.3%) patients. Overall, 662 patients (19.7%) were judged as "frail" by the investigators. Edoxaban 30 mg/day was given to 1048 (31.4%) subjects, who were older with more comorbidities and a lower estimated creatinine clearance than those prescribed the 60 mg/day dose. Overall, the rates of bleeding and thromboembolic events were low: major bleeding was 1.63%/year, intracranial hemorrhage 0.16%/year, stroke or systemic embolism 0.50%/year and all-cause mortality 3.72%/year. Rates were higher in subjects ≥75 years or with a CHA2DS2-VASc score ≥4 and in frail individuals. Remarkably, there was a trend for no increase in intracranial bleeding with more advanced age., Conclusions: These findings confirm the favorable safety and effectiveness profile of edoxaban in atrial fibrillation patients in routine clinical care in Italy.

Clinical guidelines, while representing an objective reference to perform appropriate treatment choices, contain grey zones, where recommendations are not supported by solid evidence. In a conference held in Bergamo in October 2018, an attempt was made to highlight some of the main gray zones in Cardiology and, through a comparison between experts, to draw shared conclusions that can illuminate our clinical practice. This manuscript contains the statements of the symposium concerning the controversies regarding dual antiplatelet therapy (DAPT). The manuscript represents the organization of the meeting, with an initial review of current guidelines on this topic, followed by an expert presentation of pros (white) and cons (black) related to the identified "gaps of evidence". For every issue is then reported the response derived from the votes of the experts and the public, the discussion and, finally, the highlights, which are intended as practical "take home messages" to be used in everyday clinical practice. The first topic concerns the utility of scores to shorten the duration of DAPT in patients at high bleeding risk. The second issue examines the appropriateness of the level of evidence to prolong DAPT beyond 1 year in patients at high ischemic risk. The last "gap in evidence" concerns the possibility of adopting the single antiplatelet therapy plus an anticoagulant vs the triple therapy in patients with atrial fibrillation and acute coronary syndrome. The work has also been implemented with evidences deriving from important randomized studies published after the date of the Conference.

The introduction of direct oral anticoagulants (DOACs) has been the main therapeutic revolution in the last 20 years. Four molecules have been approved for the thromboembolic prophylaxis in patients with non-valvular atrial fibrillation (AF). After the publication of phase 3 clinical trials, many studies evaluating DOAC safety and efficacy in daily clinical practice have been published. Edoxaban is the latest DOAC available on the market, based on the results of the ENGAGE AF-TIMI 48 trial. The phase 4 ETNA-AF (Edoxaban Treatment in Routine Clinical Practice for Patients With Non-Valvular Atrial Fibrillation) observational study was designed with the aim to confirm the results of the pivotal clinical trial in routine care in unselected patients with AF. This registry involved several sites and enrolled a large population in Europe and in Italy (13 980 and 3512 patients, respectively). The broad spectrum of patients will allow to have an overview of the characteristics of the AF population and to make a comparison with previous national registries and between different European realities.

Patients with chronic kidney disease (CKD) have a high prevalence of atrial fibrillation (AF). Stroke in patients with CKD and AF is frequent, and is usually more severe than in the absence of CKD. Current European Society of Cardiology guidelines recommend oral anticoagulant therapy in order to reduce thromboembolic risk in AF patients in general, and also in the presence of CKD, excluding however stage 4 and dialysis (stage 5) patients. Warfarin and other vitamin K antagonists are still the most frequently used drugs in these settings, despite the high bleeding risk. In the United States, the non-vitamin K antagonist oral anticoagulants, especially apixaban, are here used off-label, despite the absence of strong evidences of efficacy and safety. Several clinical trials are ongoing, and further evidence is needed before non-vitamin K antagonists can be recommended in these patients.

Iron is an essential element for cardiomyocyte viability and contractility. Systemic iron deficiency, even without anemia, is reflected by iron deficiency in cardiomyocytes. As in other cells, there is here a complex, local and autonomous regulation of iron metabolism, based on two molecular systems: the hepcidin/ferroportin/transferrin receptor-1 axis; and the iron regulatory proteins-1,2 system. These molecular pathways allow cardiomyocytes to react to changes in serum iron availability. In mice, dietary manipulations of serum iron availability or cardio-specific deletions and mutations of regulatory genes for intracellular iron metabolism have clarified some aspects of the causal relationship between cardiomyocyte iron deficiency and the development of severe heart failure, prevented by intravenous iron treatment even without the occurrence of iron deficiency (sideropenic) anemia. The deleterious effects of iron deficiency and hypoxia on gene expression of the main regulators of intracellular iron and oxygen metabolism and on cardiac function are very similar in heart failure and in chronic stable ischemic heart disease, and conjure towards cardiomyocyte injury. We here hypothesize that in non-anemic patients with stable ischemic heart disease a chronic or acute serum iron deficiency can amplify the chronic activation of the cardiomyocyte hypoxia-inducible factor-1α. As a consequence, cardiac adaptative responses to chronic hypoxia/ischemia are significantly impaired, and cardiac dysfunction exacerbated. We hypothesize that, in such patients, iron replacement through forced iron supplementation may replete cardiomyocyte iron deficiency and improve ischemic heart disease. This hypothesis requires further experimental studies, but also, and already now, specific clinical trials.

Atrial fibrillation (AF) is the most frequent sustained cardiac arrhythmia, and its prevalence is increasing, partly due to the progressive aging of the population. AF predisposes to thrombus formation in the atria and the atrial appendage through a complex interaction among local, systemic and hemodynamic factors, significantly increasing the risk for cerebral and systemic thromboembolic events. These complications have a major impact in terms of morbidity and mortality, and numerous therapeutic strategies have been proposed to reduce such risk. Systemic anticoagulation is the main strategy in the prevention of atrial and left atrial appendage thrombosis, and the advent of non-vitamin K antagonist oral anticoagulants (NOACs) has been a significant step forward, especially for safety, compared to warfarin. While prevention of atrial appendage thrombosis with NOACs has been widely explored, their role in the resolution of thrombi is less clear. The use of NOACs in this setting is largely unexplored, and some studies are underway to clarify their effectiveness. The objective of this paper is to review the literature on atrial and left atrial appendage thrombosis, describing pathophysiological mechanisms and current treatment strategies using NOACs.

Myocardial revascularization in patients with stable ischemic heart disease aims at eliminating myocardial ischemia, in order to (i) relieve anginal symptoms; (ii) improve functional capacity; and, possibly, (iii) improve prognosis. Given that ischemic recurrences are relatively common in patients undergoing myocardial revascularization, an appropriate follow-up is needed as part of a secondary prevention program. Stress testing can be here useful to: (i) detect residual or recurrent ischemia/angina; (ii) define functional capacity in order to establish physical aerobic training individualized programs; (iii) stratify prognosis. These goals can in large part be achieved by the ECG stress test, by far the cheapest, the easiest to perform and the most accessible test among those proposed so far, particularly compared with other imaging stress test modalities. There is, however, considerable discrepancy among scientific society recommendations on the use, timing and methods of ECG stress testing and of stress testing in general after revascularization. In addition to the diversity of recommendations, the use of stress tests in general is extremely variable in current clinical practice.This review aims therefore at revisiting principles, advantages and limitations of the ECG stress test and of stress tests in general in revascularized patients, highlighting recent developments of the ECG stress technique. This should also aim at issuing new recommendations to avoid the inappropriate prescription of expensive and more cumbersome techniques, to be reserved only to a second-tier diagnostic level and in a minority of cases.

The correct management of acute heart failure continues to pose diagnostic and therapeutic challenges. In particular, administering the right type and dose of fluids and drugs, thus avoiding fluid overload while establishing organ perfusion, is of key importance in stabilizing critical patients and improving prognosis. A correct estimate of the fluid volume status, however, may be difficult, as the invasive evaluation of cardiac filling pressures by cardiac catheterization is limited in routine medical practice, and there is no universal consensus on the best tools for its non-invasive evaluation. Here we review current evidence about diagnosis and treatment of fluid volume abnormalities in acute heart failure according to the most recent guidelines.

The incidental finding of a cardiac or paracardiac mass constitutes for cardiologists a relevant diagnostic and therapeutic problem. In fact, although primary cardiac tumors are infrequently, metastases, as well as non-neoplastic masses and pseudomasses, are much more frequent. A key role is played by echocardiography, but the latter is not always nullifying. Sometimes even the currently used imaging techniques may be limited in oncology. Cardiac magnetic resonance (CMR) is a multi-parametric technique of imaging considered nowadays the gold standard for non-invasive soft tissue characterization. CMR allows (i) to better evaluate the relationship between the tumor and adjacent structures, (ii) to detect the degree of infiltration or the expansion of the mass in the pericardium, and (iii) to predict the possible malignancy of a mass with a higher accuracy than other methods. In addition, CMR can favor the choice of the technique for surgical resection by providing information regarding cardiac function and the possible hemodynamic impairment. In this regard, we here present a narrative review on the most frequent cardiac manifestations of tumors, masses and pseudomasses, as well as the currently used CMR techniques in this setting.

Cardiovascular disease remains the leading cause of death worldwide, and this underscores the importance of primary prevention before the occurrence of its clinical manifestations. Actually, there is an important need for new ways to improve upon traditional risk assessment. Efforts to address the problem of better identifying persons at risk of developing a first cardiovascular event have largely focused on the use of new measurements - biomarkers - which could add to traditional risk scores to improve prediction. Hundreds of candidate biomarkers, mostly deriving from measurement of plasma levels of certain substances, have been proposed, and some of them have shown solid statistical associations with the incidence of future events in addition to traditional markers. However, in general they offer only a modest increase in the predictive value of current scores. On the contrary, assessment of subclinical atherosclerosis by multiple means clearly shows a substantial incremental return. Here we critically review the available literature for studies assessing the added value of new biomarkers, especially in multiple combinations, with a particular focus on non-invasive imaging markers of subclinical atherosclerosis, on top of traditional risk algorithms in primary prevention of cardiovascular disease.

The intravascular administration of contrast media is an important tool in cardiovascular imaging, especially in percutaneous coronary interventions (PCI). Owing to the widespread use of these procedures, contrast-induced acute kidney injury (CI-AKI) has become one of the most common types of acute renal failures. CI-AKI is mainly mediated by mechanisms of oxidative damage, and its onset is associated with prolonged hospitalization and significant morbidity and mortality. Preexisting chronic kidney disease, diabetes, age, heart failure, and characteristics related to the procedure (primary or elective PCI, type and amount of contrast medium) are the most important risk factors for the development of post-PCI CI-AKI.For this serious complication, prevention is more important than treatment, and various preventive measures have been widely tested in recent years. However, none of the strategies so far evaluated, with the exception of pre-procedural hydration with isotonic saline, has been shown to effectively prevent CI-AKI in randomized trials in large populations. In this review, we discuss the incidence, risk factors, main pathogenetic mechanisms and current strategies for the prevention of CI-AKI.

After more than 3 years from the appearance in Italy of the non-vitamin K antagonist oral anticoagulants (NOACs), their use for the prevention of thromboembolism in atrial fibrillation is still limited, with wide differences in prescriptions across regions. When NOACs became available for clinical practice, several doubts arose about their practical management in the "real world". This article analyses the 10 more frequent questions asked by clinicians dealing with NOACs in their daily activity with atrial fibrillation patients. The answers are synthetic and schematic with pragmatic suggestions that could help clinicians in their doubts.

Background: Baseline data of the PREFER in AF (PREvention oF thromboembolic events - European Registry in Atrial Fibrillation) Registry have shown undertreatment of patients with atrial fibrillation (AF), particularly in Italy, where greater difficulties in the management of antithrombotic drugs compared with other European countries were also observed. The aim of the follow-up evaluation was to verify the trends of examined variables after 1 year., Methods: Clinical features, patterns of prescriptions and patient adherence to guidelines, quality-of-life and treatment satisfaction variables were evaluated at follow-up, similarly to baseline., Results: In Italy, 88% of patients originally enrolled completed the 1-year follow-up. The incidence of major cardiovascular events was lower than at baseline (12.6 vs 30.8%, p<0.0001), but was higher compared with the European mean (12.6 vs 10.4%, p=0.0006). In particular, the incidence of heart failure (5.1 vs 3.6%, p=0.0003) and transient ischemic attacks (1.4 vs 0.7%, p<0.0001) were more frequent in Italy; on the other hand, the incidence of major bleeding was lower in Italy compared with the European mean (1.6 vs 2.4, p=0.0168). Patients with a high thromboembolic risk (CHA 2DS2-VASc ≥2) were >80%, similarly to baseline, with a mean CHA2DS2-VASc score of 3.3. However, about one fourth of high-risk patients continued not to be treated with anticoagulant drugs, and treated patients at follow-up were fewer than at baseline (65.1 vs 72.6%, p<0.0001). The percentage of patients treated with non-vitamin K antagonist oral anticoagulants (NOACs) was increased at follow-up compared with baseline (3.3 vs 0.3%, p<0.0001), although lower than the European mean (12.6 vs 6.1%, p<0.0001). The number of INR measurements was higher and related to a higher time in therapeutic range (TTR), compared with baseline, and exceeded the European mean TTR. However, similarly to baseline, a higher difficulty in managing anticoagulant therapy and a lower level of satisfaction for treatment was reported in Italian patients compared with the rest of Europe., Conclusions: The Italian data of the PREFER in AF Registry at 1-year follow-up continue to demonstrate undertreatment of patients with AF at increased risk of stroke and a high grade of unsatisfaction for anticoagulant treatment. The low percentage of patients treated with NOACs did not allow the evaluation of their impact on clinical events and acceptance of therapy.

The severity of side effects that may occur with vitamin K antagonists due to their narrow therapeutic window requires great attention in finding out the most appropriate dose for these drugs. Pharmacogenetic research has now considerably helped clarifying the relationships between genetic variants and sensitivity to such therapy, paving the ground to predictive algorithms that include clinical and genetic variables to establish the best doses to start and maintain an adequate anticoagulation. Pharmacogenetic algorithms indeed aim at identifying tailored regimens, reducing adverse drug reactions and subsequent hospitalizations, optimizing therapeutic efficacy and containing costs. Here we describe the results so far achieved in pharmacogenetic research with vitamin K antagonists, analyzing studies that have assessed the usefulness of such algorithms.

The narrow therapeutic index, the large interindividual variability, and the severity of adverse drug reactions connected with vitamin K antagonists, together with their ample use in medical therapy, have prompted the search for strategies to better assist doctors in the choice of the safest and most effective dose of these drugs. The molecular mechanism by which oral anticoagulants exert their effect is an interference with the bioactivation of vitamin K. This mechanism is therefore the subject of numerous pharmacogenetic studies, aimed at finding the relationship between genetic variants influencing the metabolism or action of the drug and therapeutic outcomes. However, genes involved in the metabolism or action of vitamin K antagonists are many, and the role of some of them has not yet been fully understood. In this review we present and discuss current knowledge about the relationship between genotypes and the development of adverse drug reactions, focusing on gene variants that appear to influence dosing and clinical endpoints, and aiming at clarifying the usefulness of pharmacogenetic approaches as applied to this treatment.

The indications for the use of aspirin in primary cardiovascular prevention continue to be a source of intense debate, with major international guidelines providing conflicting advices. This document, written by delegates of the main Italian scientific societies dealing with cardiovascular prevention and modeled on a similar document by the European Society of Cardiology Working Group on Thrombosis, reviews the evidence in favor and against the use of aspirin therapy in primary prevention based on data cumulated so far, including recent data linking aspirin with cancer protection. While awaiting the results of several ongoing studies, this document argues for a pragmatic approach to the use of low-dose aspirin in primary cardiovascular prevention, and suggests its use in patients at high cardiovascular risk, defined as ≥2 major cardiovascular events (death, myocardial infarction, or stroke) projected per 100 person-years, who are not at increased risk of bleeding.

Background: Atrial fibrillation (AF) is a common heart rhythm disorder associated with an increased risk of stroke, heart failure and death. Although available evidence supports the administration of oral anticoagulants with respect to other treatment options to prevent thromboembolism, the use of oral anticoagulation therapy remains suboptimal. The PREFER in AF registry was conducted to evaluate patterns of prescriptions and patient adherence to guidelines, clinical features, quality of life and treatment satisfaction., Methods: The PREFER in AF registry enrolled consecutive patients with AF recruited in high-volume cardiology centers, with AF documented during the previous 12 months. Patients were assessed at baseline and at 1-year follow-up. The present report provides Italian baseline data compared with data from other European countries participating in the registry., Results: The registry enrolled 1888 Italian patients (out of 7243 in Europe), with an average age of 70.9 years. Main comorbidities included hypertension (73.5%), dyslipidemia (38.7%) and obesity (21.9%). The risk of thromboembolism was assessed using the CHA2DS2-VASc score, according to which only 4.7% of Italian patients scored 0, whereas 11.3% scored 1 and 84% scored ≥2. Italy is the Western European country with the lowest use of vitamin K antagonists (71.6%; average rate in Europe: 78.3%) and the highest average INR measurements, whereas time in therapeutic range is 72.2%, lower than in any other Western European country with the exception of Spain. Most Italian patients are unsatisfied with treatment, and only 36% report no difficulties in taking anticoagulation therapy compared with 70.3% of patients in other Western European countries., Conclusions: Among Western European countries included in the registry, Italy has the lowest prescription rate of vitamin K antagonists and the highest rate of INR measurements. Italian patients also report lower levels of satisfaction with treatment and a higher subjective difficulty in managing anticoagulation therapy. The new oral anticoagulants may favor treatment management, thus having the potential of improving medication adherence and persistence as well as quality of life.

Anthracyclines rank among the most effective anticancer drugs. They may however cause a dose-dependent and cumulative cardiotoxicity, eventually leading to heart failure. The antitumoral cytotoxicity of anthracyclines and their cardiotoxicity are believed to be due to different mechanisms, and there is therefore an active search for developing drugs able to protect the heart without impairing their chemotherapeutic efficacy. The foremost hypothesis explaining cardiotoxicity is the anthracycline-dependent production of reactive oxygen species (ROS). A ROS-induced calcium (Ca 2+)-calmodulin-dependent protein kinase II (CaMKII) hyperactivity can cause diastolic Ca2+ overload secondary to the activation of the late sodium (Na+) current (INaL). Furthermore, INaL hyperactivation can initiate a vicious cycle leading to sustained oxidative stress and energetic stress, with serious ATP depletion, similar to that occurring after the exposure of hearts or isolated cardiomyocytes exposed to anthracyclines. We hypothesize that anthracyclines may cause, through a ROS-dependent CaMKII hyperactivation, increased INaL, leading to a vicious cycle that worsens the redox imbalance with resulting mechanical and electrophysiological dysfunction and heart failure. In this light, we here review the molecular and clinical characteristics of ranolazine, the most powerful and selective clinical inhibitor of INaL, and speculate on the possibility that it may be used as an effective drug protecting against anthracycline-related cardiotoxicity.

Prevention of atrial fibrillation (AF)-related stroke and thromboembolism is an important part of AF management. However, stroke risk varies considerably with associated morbidities and risk factors. Several stroke risk stratification schemes have been developed, and categorize patients' stroke risk into categories based on the presence and combination of risk factors. Based on the perceived level of risk, current guidelines recommend that patients with AF receive some form of antithrombotic therapy. Despite guideline recommendations, however, many patients with AF do not receive adequate thromboprophylaxis. This review will discuss some of the reasons why guidelines are not adhered to in clinical practice and current gaps in knowledge. Low adherence to guidelines is in part related to the drawbacks associated with vitamin K antagonist therapy and to the imperfection of current schemes for stratification of both thromboembolic and bleeding risks. Such drawbacks have highlighted the need for new anticoagulants for the prevention of stroke in patients with AF. The novel oral anticoagulants in development, four of which - dabigatran, rivaroxaban, apixaban and edoxaban - have completed or are completing phase III testing, may overcome some of the limitations of vitamin K antagonist therapy and address the underuse and safety concerns associated with current antithrombotic therapies in patients with AF.

Dual antiplatelet therapy with aspirin and clopidogrel reduces cardiovascular events following an acute coronary syndrome or stent implantation, but the associated increased risk of gastrointestinal bleeding often leads clinicians to the co-administration of proton pump inhibitors (PPIs). PPIs have been shown to decrease antiplatelet effects of clopidogrel ex vivo, raising doubts on the safety of this drug combination. Clinical trials investigating PPI-clopidogrel interaction have provided conflicting results and have been often criticized. Moreover, a prospective, double-bind, randomized, placebo-controlled study conducted with adequate follow-up and sample size has not yet been performed. Indeed, the COGENT trial, which would have had such characteristics, has been stopped prematurely. The question is therefore still unresolved, and clinical effects of PPI-clopidogrel interaction cannot be excluded. As a practical consequence, this combination therapy is recommended only for patients at high risk of bleeding (prior upper gastrointestinal bleeding, advanced age, concomitant use of warfarin, steroidal or non-steroidal anti-inflammatory drugs and Helicobacter pylori infection), avoiding in any case PPIs with greater affinity for CYP2C19, such as omeprazole and esomeprazole.

Atrial fibrillation (AF) is an independent major risk factor for stroke, and antithrombotic therapy is here recommended according to stratification of the patient's thromboembolic and hemorrhagic risks. Recent evidence is leading to the replacement of vitamin K antagonists, the efficacy of which in preventing stroke in AF is well established, with better tolerated and more manageable new anticoagulant drugs, with a lower risk of intracranial bleeding, no clear interactions with food, fewer interactions with medications, and no need for frequent laboratory monitoring and dose adjustments. Among new anticoagulants, dabigatran etexilate is a direct, competitive inhibitor of thrombin. It was evaluated for patients with AF in the RE-LY trial, showing lower rates of stroke and systemic embolism at a dose of 150 mg twice daily with similar rates of major hemorrhage compared with warfarin; and non-inferiority compared with warfarin for the prevention of stroke and systemic embolism at a dose of 110 mg twice daily, with lower rates of major bleeding. Beside dabigatran, oral factor Xa inhibitors are also emerging for the prevention of thromboembolic events in AF. Despite the obvious advantages of these new oral anticoagulants over vitamin K antagonists, further information is still needed on how to prioritize the patients deriving the greatest benefit from these novel agents on the basis of patient characteristics or drug pharmacokinetics. There is also a need for assessing their long-term efficacy and safety over decades in the real-world setting.

The angiographic evidence of normal coronary arteries or moderate coronary artery disease is a relatively common finding in patients with a history of angina, with a higher prevalence in females. This condition is not a single pathological entity, but comprises several different presentations, such as cardiac syndrome X, vasospastic angina, myocardial bridges, as well as coronary alterations with more doubtful clinical implications, such as serial moderate coronary artery lesions or focal coronary dilations. These pathological conditions are different in pathophysiology, management, and prognosis, and for this reason their correct diagnostic definition, beyond the angiographic evidence of normal coronary arteries, appears mandatory. This review aims at providing an update in the conundrum of entities comprising angina with normal coronary arteries, and at explaining different diagnostic and therapeutic approaches.

While the use of aspirin in the secondary prevention of cardiovascular atherothrombotic disease is well established, many aspects of primary prevention are still unclear. Uncertainties mostly depend on a doubtful risk-benefit ratio, because of the low atherothrombotic risk of populations involved on the one hand, and the non-negligible bleeding risk of treatment on the other. Areas of specific doubt are those of diabetes and asymptomatic peripheral arterial disease, where neither single trials nor meta-analyses allow issuing high-grade specific recommendations at the moment. The present review aims at giving an account on this topic, highlighting areas for further studies, but also attempting at providing a rationale for what to do practically now, while awaiting more conclusive evidence. Based on the results of a number of clinical trials and meta-analyses, and especially considering the absolute figures of the benefit (major cardiovascular events avoided) and of the harm (major bleeding events occurred related to aspirin), the authors recommend to limit primary cardiovascular prevention with aspirin (in apparently healthy subjects with no previous cardiovascular events) to subjects with an estimated global cardiovascular risk ≥2 major cardiovascular events per 100 patients-year, as assessed by the risk score assessments proposed in the Italian "Progetto Cuore" (www.progettocuore.it). This cut-off should also be adopted for primary prevention in patients with type 2 diabetes and/or asymptomatic peripheral arterial disease.

Nitrates have been commonly used in the therapy of cardiovascular disease for more than 150 years. In spite of this longevity and the popularity of their use, it appears somewhat paradoxical that their use is not consistent among cardiologists, both as to their indications and as to their mode of administration. In part this results from their contradictory pharmacodynamics: when given acutely, their effectiveness is indisputable; however, their long-term efficacy is substantially limited by the development of tolerance and the induction of endothelial dysfunction, which may have negative prognostic implications. This review, reporting the most recent biochemical and pathophysiological acquisitions, re-examines the role of nitrates in cardiovascular medicine, reporting, comparing and commenting international guidelines.

Type 2 diabetes and acute coronary syndromes are widely interconnected. Individuals with type 2 diabetes are more likely than non-diabetic subjects to experience silent or manifest episodes of myocardial ischemia as the first presentation of coronary artery disease. Insulin resistance, inflammation, microvascular disease and a tendency to thrombosis are common in these patients. Intensive blood glucose control with intravenous insulin infusion has been demonstrated to significantly reduce morbidity and mortality in critically ill hyperglycemic patients admitted to an intensive care unit. Direct glucose toxicity likely plays a crucial role in explaining the clinical benefits of intensive insulin therapy in such critical patients. However, the difficult implementation of nurse-driven protocols for insulin infusion, able to achieve more rapid and effective blood glucose control without significant episodes of hypoglycemia, has led physicians to consider alternative drugs for this purpose. New intravenous or oral agents include the incretin glucagon-like peptide-1, its analogs, and dipeptidyl peptidase-4 inhibitors, which potentiate the activity of glucagon-like peptide-1 and thus enhance glucose-dependent insulin secretion. Improved glycemic control with protective effects on myocardial and vascular tissue, with lesser side effects and a better therapeutic compliance may represent an important therapeutic potential for this class of drugs in acutely ill patients in general, and in patients with acute coronary syndromes in particular. Such drugs should be known by practicing cardiologists for their possible use in intensive care units in the years to come.

Myocardial infarction with angiographically normal coronary arteries was recognized more than 30 years ago. Since then, various series of patients with such condition have been described, but the etiology and pathogenesis still remain a matter of debate. Evidence exists for a role of coronary vasospasm, thrombosis, embolization and inflammation, per se or combined, in determining the occurrence of myocardial infarction with angiographically normal coronary arteries. Endothelial dysfunction, possibly superimposed to non-angiographically evident atherosclerosis, may be an underlying common feature predisposing to the acute event. Additionally, myocarditis may explain some of these occurrences. Myocardial infarction with normal coronary arteries is therefore likely to be the result of multiple pathogenetic mechanisms. Although most reports emphasize the good prognosis of this condition, in general much better than myocardial infarction with coronary artery disease, prognosis is likely variable according to the underlying mechanism. This review summarizes current knowledge on this condition and examines areas of recent progress.