Current Vascular Pharmacology

In Part 1 of this Thematic Issue entitled “Systemic Autoimmune Rheumatic Diseases and Cardiology”, a panel of specialists and experts in cardiology, rheumatology, immunology and related fields discussed the cardiovascular complications of spondyloarthritides, rheumatoid arthritis, Sjogren’s syndrome and vasculitides, as well as relevant cardiovascular issues related to non-biologic and biologic disease-modifying anti-rheumatic drugs (DMARDs), and provided their recommendations for prevention and management of these complications. In part 2 of this Thematic Issue, experts discuss the enhanced cardiovascular risk conferred by additional autoimmune rheumatic diseases (ARDs), including systemic lupus erythematosus, the antiphospholipid syndrome, psoriasis and psoriatic arthritis and juvenile idiopathic arthritis. These, and the previous articles, place inflammation as the key common link to explain the enhanced risk of cardiovascular complications in patients with ARDs. It follows that treatment should probably target inflammation. From all these contemporary reviews, the conclusion that is derived further supports the notion of the emerging field of Cardio- Rheumatology where physicians and experts from these two disciplines collaborate in risk stratification and optimization of preventive strategies and drug therapies in patients with ARDs.

Systemic Autoimmune Rheumatic Diseases and Cardiology - Part 1

Aging is a universal biological process that leads to progressive and deleterious changes in organisms. Slowing aging is always a popular research area. Nowadays, the meaning of slowing aging has changed from simply prolonging lifespan to an emphasis on quality of life. The concept of healthy aging and prevention of pathological aging, which is associated with diseases, including cardiovascular diseases (CVDs), is responsible for a large number of deaths worldwide. CVDs can be associated with a number of aging-associated conditions, which contribute to increased cardiovascular risk, such as hypertension, dyslipidaemia, obesity and type 2 diabetes, insomnia or cognitive disorder in aging populations [1, 2]. Herbal medicine (HM) has a long history in Asian countries. It is believed that many HMs, such as ginseng, radix astragali, ganoderma or gingko and herbal medicinal compounds have anti-aging properties. Recent studies have shown that some medicinal herbs are effective in intervention or prevention of aging-associated cardiovascular risk or cognitive disorder, but the mechanisms and safety remain unclear [3, 4]. This special issue entitled “Herbal Medicine for Slowing Aging and Cardiovascular Risk: Mechanisms and Safety”, consists of 7 articles describing the use of HM and the mechanisms or safety involved for aging-associated cardiovascular risk or cognitive disorder. Cheng et al. [5] reports the potential role of HM and non-pharmacological therapies in the treatment of insomnia and summarizes the scientific evidence reported from 2008 to 2018. Based on this evidence, HM may be applicable in clinical settings. The combination of acupuncture and herbs should also be emphasized in clinical practice, in order to prevent adverse reactions and drug-dependence as observed with some Western medications in the treatment of insomnia. Kim and Kang [6] summarize the clinical evidence on the benefits of herbal drugs and proposes an evidence map outlining their effects on vascular dementia (VaD) based on systematic reviews. HMs used individually or in combination with Western medicine might lead to benefits for VaD patients. However, there is still room for further evaluation of the evidence and the mechanisms of the action involved. Zhang et al. [7] systemically summarizes the effects and potential mechanism of Chinese Medicines on inhibiting advanced glycation end products (AGEs)-related aging diseases. Five classes of components from Chinese Medicines have been found to be effective in reducing AGEs-mediated damage (e.g. flavonoids, saponins, polysaccharides, alkaloids and polyphenols). Anti- AGEs action might be one reason why Chinese Medicine may have anti-aging diseases effects. Li et al. [8] discuss the pathophysiological alterations in aged vasculature and the underlying mechanisms of Ginkgo biloba extract (GBE) in vascular aging inhibition. The main effects of GBE in aged vasculature might be associated with longevity signaling pathways. GBE also attenuates the progression of vascular aging in diabetes mellitus via regulation of glucose and lipid metabolism. Yang et al. [9] systematically summarize the pharmacological activities of U. rhynchophylla (UR, a common Chinese HM known as Gou-teng in Chinese) and its major components on central nervous system (CNS). UR and its major components, such as alkaloids, flavonoids and terpenoids, have beneficial effects on CNS diseases via acting on various risk factors and biochemical pathways involved in CNS disease pathogenesis. Wang et al. [10] reviewed the mechanisms of the active ingredients of Rhizoma coptidis and Rhizoma coptidis-containing Chinese herbal compounds in the treatment of Alzheimer’s disease (AD) and VaD. The “One-Molecule, One-Target” paradigm has suffered heavy setbacks, but a “multitarget-directed ligands” strategy may be viable. Rhizoma coptidis active ingredients and Rhizoma Coptidis-containing Chinese herbal compounds have potential multi-aspect therapeutic effects for AD and VaD. Phu et al. [11] focused on the efficacy, mechanisms, and safety of some of the most recognized HMs (e.g. Ginseng, Radix astragali, Ganoderma lucidum, Ginkgo biloba and Gynostemma pentaphyllum), describing and critically analysing their effect in slowing aging and aging-associated diseases such as cognitive impairment and cardiovascular risk. These 7 articles highlight the latest evidence regarding the use of HM and the mechanisms or safety involved for agingassociated cardiovascular risk or cognitive disorder.

Lower extremity artery disease (LEAD) is a leading cause of atherosclerotic vascular morbidity in Europe, being even more prevalent that coronary artery disease (CAD) [1]. Importantly, LEAD is an established independent risk factor for cardiovascular (CV) mortality and morbidity [2-4], particularly in its advanced stages, i.e. in patients requiring lower limb revascularisation [5, 6], and in patients suffering from chronic limb-threatening ischaemia (CLTI) [7]. The strong association between LEAD and CAD, with at least one-third of LEAD patients having history and/or electrocardiographic signs of associated CAD, and with up to 70% showing significant disease at coronary angiography [8, 9], has led to the identification of LEAD as a high-risk subgroup in all randomised trials focussed on CAD [4, 10-14]. Given the great advances in the treatment of CAD over the last decades, clinical research in this field is currently focussed on addressing “residual risk” in patients suffering from CAD. Therefore, being a marker of worse prognosis in CAD patients, LEAD has attained a growing interest from the community of Cardiologists, leading to the issue of guidelines on the management of peripheral arterial diseases from the European Society of Cardiology (ESC), firstly in 2011 [15] and again in 2017 [16]. Most recently, LEAD attained the same “dignity” as CAD in the large randomised COMPASS (Cardiovascular Outcomes for People Using Anti-coagulation Strategies) trial, where patients suffering from LEAD (or from carotid artery disease) were enrolled independent of the presence of coexisting CAD, i.e. LEAD was not a subgroup of CAD but a distinct disease category [17]. In COMPASS, rivaroxaban 2.5 mg twice daily on top of aspirin was more effective in reducing the risk of major CV events in the peripheral artery disease population compared with the CAD population, and was also associated with an impressive 46% reduction in major adverse limb events (acute and chronic limb ischaemia including major amputation) [18]. On the other hand, the risk of major bleeding was also increased with the dual antithrombotic regimen, highlighting the need for a careful estimation of the bleeding risk of individual patients before embarking in more potent antithrombotic treatments. Based on COMPASS results, low-dose rivaroxaban may soon be proposed as standard of care in patients with stable LEAD who are not at high risk for bleeding. This may have a potentially huge impact on public healthcare costs, considering the current pricing of the drug and the prevalence of LEAD in an ageing population. In this setting, cost-effectiveness analysis should be regarded as a powerful tool in the hands of the clinicians when dealing with public health stakeholders and decisions bodies, because it enables us to assess whether a new treatment is cost-effective - and thus affordable - for the community, on top of being clinically effective [19]. As a matter of fact, two recent cost-effectiveness analyses of the COMPASS trial performed from an Australian perspective showed that low-dose rivaroxaban is cost-effective in the vast majority of the scenarios explored, and even more so in patients with LEAD [20] compared with patients with CAD [21]. A further source of interest for LEAD in recent years was represented by the rapid development of endovascular revascularisation techniques, leading to an exponential increase in the number of patients undergoing lower limb revascularisation (currently 80% of cases undergo endovascular procedures) [22]. Such growth in the interventional treatment of LEAD was accompanied by a large number of clinical studies, including randomised trials, enrolling patients with LEAD; however, the vast majority of these trials are focussed on the evaluation of short-term outcomes of endovascular devices and techniques, leaving wide gaps in evidence to be filled by future studies. In particular, very little evidence is available on the best antithrombotic treatment following lower extremity revascularization. In this context, it is my belief that it is now prime time for LEAD on the stages of both clinical research and clinical practice in the field of atherothrombotic vascular diseases. A sign of these times is the quick growth of the Working Group on Aorta and Peripheral Vascular Diseases of the ESC, which I had the honour to chair [23]. It was within this scientific community that the idea of the present special issue of Current Vascular Pharmacology was conceived. This issue, dedicated to antithrombotic therapy in patients with LEAD, represents a vehicle for the dissemination of knowledge in the field of LEAD, hopefully contributing to a better understanding and management of LEAD patients in clinical practice. To increase the awareness and knowledge of LEAD is actually the mission of the Working Group on Aorta and Peripheral Vascular Diseases of the ESC. The need for an awareness campaign on LEAD is proven by recent epidemiologic studies, showing that a large proportion of patients with LEAD does not yet receive guideline-recommended secondary prevention therapy, with antiplatelets and angiotensin- converting enzyme inhibitors or angiotensin-receptor blockers being prescribed to <50% of the patients and statins to only two thirds [24]. The mainstays of guideline-recommended pharmacological treatment of LEAD include antiplatelets (with clopidogrel as first choice), statins, and angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers [16]. Antithrombotic therapy was chosen as the topic of this special issue because of its prominent role in the prevention of CV events and of limb events in patients suffering from LEAD, which is not associated with exhaustive evidence regarding the choice of drug(s) and treatment duration in the numerous clinical settings that make up the wide spectrum of LEAD. In this issue of Current Vascular Pharmacology we will cover all aspects of antithrombotic therapy in patients with LEAD, from the pathophysiology of thrombosis to the assessment of the bleeding risk. Habib, et al., provide a comprehensive description of the pathophysiology of vascular athero-thrombosis in LEAD, including an in-depth analysis of the interplay between pro- and anti-thrombotic vascular receptors, and of the contribution of platelets and circulating coagulation factors in triggering the pro-thrombotic response [25]. In particular, the role of nitric oxide, prostanoids and endogenous purines is described with a translational approach, along with the consequences of the disruption of the protective pathways and with the mechanisms of action of the numerous pharmacological agents that are active along these pathways. Vrsalovic and Aboyans review the available clinical evidence on antithrombotic therapy in patients with LEAD [26]. This review covers the full spectrum of clinical scenarios of LEAD, from asymptomatic to chronic limb-threatening ischaemia. In particular, the role of single and dual antiplatelet treatment is discussed, as well as the role of oral anticoagulants, with a specific focus on the results of the COMPASS trial with low-dose rivaroxaban. The authors also address the clinically relevant issue of LEAD patients requiring antithrombotic regimens for concomitant CV diseases, such as atrial fibrillation and CAD, offering a balanced point of view on the management of these patients. The third paper, which I authored together with Angelillis and Liga, offers an updated overview of antithrombotic therapy in patients undergoing peripheral revascularisation, both endovascular and surgical. We start with a description of the indications and techniques of lower extremity revascularisation, and proceed with in-depth analysis of the available evidence regarding type and duration of antiplatelet and anticoagulant treatment following endovascular and surgical revascularisation [27]. A specific focus is dedicated to endovascular revascularisation, whose growth in numbers has not been accompanied by a parallel growth in high-quality scientific evidence, particularly regarding antithrombotic therapy, which is substantially extrapolated from the coronary field. Given the lack of randomised trials comparing different antithrombotic regimens and durations across the wide range of indication, location and modality of peripheral revascularisation, we pragmatically analyse and compare the antithrombotic strategies chosen by the experts leading the randomised trials dedicated to endovascular devices and techniques. Lastly, Alatri and Mazzolai provide an in-depth review of how to assess the bleeding risk of our patients, in the era of precision medicine [28]. In fact, while we strive to reduce local and systemic thrombotic events in patients with LEAD by using new antithrombotic regimens, we should avoid exposing them to an excess in bleeding risk, tailoring antithrombotic regimen on the individual patient’s clinical setting. It is therefore of the utmost importance to understand the numerous scores for the prediction of inhospital and long-term bleeding events that have been developed in various clinical settings. In particular, the authors describe the bleeding risk scores for patients receiving oral anticoagulants, single antiplatelet therapy and dual antiplatelet therapy. In summary, I believe that the present special issue of Current Vascular Pharmacology may be useful as an ensemble, providing a comprehensive outlook on all the aspects of antithrombotic therapy in patients with LEAD. On the other hand, each review may be also regarded as a stand-alone expert advice on the specific topic covered, providing insights and guidance for both researchers and clinicians.

Diabetes mellitus (DM) is a very prevalent disease worldwide [1-3]. It holds an outstanding position among non commutable diseases with an increasing prevalence trend and mortality [1-3]. In particular: • 1 in 11 adults has diabetes (425 million). • 1 in 2 adults with diabetes is undiagnosed (212 million). • 1 in 6 births is affected by hyperglycaemia in pregnancy. • Over 1 million children and adolescents have type 1 diabetes. • Two-thirds of people with diabetes live in urban areas (279 million). • Two-thirds of people with diabetes are of working age (327 million). • In 2012 alone diabetes caused 1.5 million deaths. • 3/4 of people with diabetes live in low and middle income countries. • 12% of global health expenditure is spent on diabetes ($727 billion) [1-3]. Diabetes is associated with micro- and macrovascular complication. Microvascular complications include diabetic nephropathy, neuropathy, and retinopathy [4]. Macrovascular complications of DM include peripheral vascular disease, myocardial infarction, stroke, and congestive heart failure [5, 6]. The epidemic of DM, its complications, and their impact on morbidity and mortality have become a massive global problem and need effective control [4-7]. There is a significant deficit in understanding the risk of DM‐related complications, both by a lot of patients and by some physicians [8]. Patients with DM, mainly those from ethnic minorities, were often unaware of the risks of complications, especially for macrovascular events [8]. In a large study, nearly 70% of people with T2DM did not know that they were at increased risk for developing CVD more than the general population [9]. The aim of this special issue of Current Vascular Pharmacology is to provide an up-to-date overview about the risks of DM complications and the effect of newer antidiabetic dugs, the new kids on the block, to avoid them, improving the quality of life at the same time. These drugs range from selective PPAR modulators [SPPARMs] and dual PPAR agonists to the available glucagon like peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose co-transporter-2 inhibitors (SGLT2i). Thiazolidinediones (TZDs) are useful, especially the novel selective PPAR-γ modulators, which increase adiponectin without significant weight gain [10]. SPPARMs and dual PPAR agonists may play an important role in the treatment of CVD disorders due to lipid-modifying, anti-inflammatory and insulin-sensitizing effects [11]. INT131, a SPPARM-γ with predominantly insulin-sensitizing actions, may also have favourable lipid-modifying effects [12]. INT131 achieved a high level of antidiabetic action by an increase in insulin sensitivity that led to reduction in substantial glucose and insulin levels, without noteworthy adverse effects [12]. Besides SPPARMs, there are dual PPAR agonists too. Elafibranor is a PPAR-α/δ agonist, which was investigated in a phase 2 trial in 274 (107 with T2DM) patients with biopsy-proven non-alcoholic steatohepatitis (NASH) [13]. Elafibranor and lobeglitazone [14], resolved NASH in a significant percentage of patients without fibrosis and improved the hepatic and metabolic profile, glucose and lipids levels [15]. Microvascular complications are common and are mainly related to glycemic control [16]. The new antidiabetic drugs contribute to glycemic control and have their share in preventing or treating microvascular complications [17]. In regard to macrovascular complications the new antidiabetics GLP-1 RA, commercially available, include liraglutide, exenatide, lixisenatide, and dulaglutide, which are used for the treatment of T2DM [18]. In the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial, liraglutide reduced the composite endpoint of all CVD events (mainly myocardial infarction and stroke) and CVD death as well as all-cause mortality in comparison with placebo [19]. Patients with a GFR < 60 ml/min/1.73 m2 benefited the most. Since NAFLD was not evaluated in this study, a posthoc analysis would be important [19]. In animal models, administration of the GLP-1 Exendin-4 reduced systemic hypertension and albuminuria as well as ameliorated biopsy-proven renal damage [20]. In the EMPA REG study, the primary composite endpoint (death from CVD causes, myocardial infarction, or stroke) was reduced by 15% with empagliflozin, p=0.04 for superiority [21]. The hospitalization for heart failure had a 35% and death from all causes a 32% risk reduction [21]. In the EMPA-REG Renal study, renal function (diabetic nephropathy, a microvascular complication of DM) was substantially improved (less nephropathy worsening, less doubling of the serum creatinine level and less renal kidney replacement therapy) [22]. The above suggest that there are indeed new kids on the block that might substantially control glycemic control, micro-, and macrovascular complications, leading to a considerable reduction in morbidity and (for the first time) mortality. These drugs are commercially available to be used and all we need is a better education of patients and physicians. Towards this direction, this issue of Current Vascular Pharmacology covers several topics in the fields of prevalence, identification, scouting, and mainly treatment of diabetes mellitus complications. Lovic et al. [23] describe the growing epidemic of diabetes mellitus according to its types, discuss the contributors for the continuous increase in its prevalence, and critically evaluate existing epidemiological data. Viigimaa and colleagues [24] report the macrovascular complications of type 2 diabetes mellitus (T2DM), including the heart and brain consequences of long-term hyperglycemia. Faselis et al. reviewed the microvascular complications of T2DM [25], including the traditional ones (diabetic nephropathy, neuropathy, and retinopathy) and critically discussing sexual dysfunction as an emerging multifactorial microvascular complication of diabetes mellitus. Patoulias and colleagues [26] report the current status and the future perspectives on the treatment of pharmacological management of cardiac disease in diabetic patients. They provide a really fresh look of this topic, since they initially discuss the effects of intensive versus standard therapy of its cardiovascular risk factor, and then they critically evaluate the cardiac effects of each class of therapeutic agents. Papademetriou and colleagues [27] report recent data on pharmacological management of diabetic nephropathy, the most prominent microvascular complication of diabetes mellitus, critically evaluating all available evidence in this field and providing their own expert opinion on the advantages and disadvantages of relevant trials. Didangellos, Kantartzis [28] review whether insulin for the treatment of diabetes in patients with heart failure is an enemy or a friend? They provide available experimental and clinical evidence on the effects of hyperglycemia and hyperinsulinemia on heart failure, and they conclude that hyperglycemia seems to be the main contributor for heart failure, while insulin does not seem to be the main contributor. Didangelos, Veves [29] report the recent data on the treatment of diabetic neuropathy, and they provide their expert opinion on available and future therapeutic options for this devastating microvascular complication of diabetes mellitus. Alvaro-Afonso and colleagues [30] report the existing data on the advances in dermoepidermal skin substitutes for diabetic foot ulcers. They systematically reviewed 28 randomized controlled trials comparing the effects of dermal substitutes (either cellular or acellular) on the course of diabetic foot ulcers. Athyros and colleagues [31] analyzed the recent developments on pharmacological management of non-alcoholic fatty liver disease in T2DM, a frequently overlooked comorbidity in patients with type 2 diabetes mellitus. They discuss the effects of traditional and new antidiabetic drugs on steatohepatitis, and they critically evaluate available evidence on emerging drugs such as SPPARMs. We hope that this special issue if CVP will contribute to the improvement of physicians approach for the management of diabetes to offer a proper and evidence-based treatment that will ameliorate the CV profile of the diabetic patient.

This issue aims to provide a comprehensive overview and current knowledge regarding the association between menopause and cardiovascular risk, with special report on menopausal hormone therapy (MHT, risks and benefits). This issue also covers special topics, such as premature ovarian insufficiency, peri-menopause, calcium and vitamin D supplementation, non-MHT refimen and non-alcoholic fatty liver disease.

Insulin is a key hormone involved in the modulation of vascular tone. Several diseases with altered response to this hormone show with dysregulation of vascular tone, hypertension, and abnormal regulation of substrates transport and membrane receptors signaling. Insulin therapy, insulin resistance and vascular dysfunction in pregnancy diseases and other disorders such as hyperglycaemia, obesity, metabolic syndrome, kidney diseases, lipid disorders, cancer, angiogenesis, lipid metabolism, oxidative stress, has not been well summarized in the literature. This special issue covers the cellular alterations and metabolism of vascular cells in a context of insulin resistance.

Cardiovascular diseases are the primary cause of early death and disability in Western countries. The control of blood cholesterol levels (total and low-density lipoprotein cholesterol) within the limits recommended by the current guidelines, is one of the cornerstones of the ischemic heart disease therapy. Statins are among the most widely used drugs in the fight against cardiovascular diseases, as they can reduce blood cholesterol levels. Furthermore, the ancillary effects of statins, the so-called pleiotropic effects, extend the range of therapeutic indications to other conditions different from the ischemic heart disease. There are several statins available to the physician. Although they share the same principle of action, differences in the chemical composition and in pharmacokinetics (absorption, distribution, excretion and drug-drug interaction) influence therapeutic and adverse effects. Moreover, cost/benefit analysis limits the use of some molecules only to certain categories of patients. The aim of this mini-thematic issue is to give a full overview of statins available on the market, analyzing their main features, with strengths and weaknesses, in order to provide the clinician with a useful tool in daily practice.

Aims & Scope: Cardiovascular (CV) disease is a leading cause of morbidity and mortality in both the developing and developed world. Beside traditional risk factors, several genetic and epigenetic factors are also involved in the development of atherosclerosis. Dyslipidaemias are the most studied risk factor for CV diseases. Beside familial hypercholesterolaemia, one of the most prevalent forms of inherited disorders of lipid metabolism, rare variants of dyslipidaemias have also an important impact on the prevalence of CV diseases. Additionally, genetic variants have also impact on the action of the drugs (pharmacogenetics). Management of atherosclerosis should be focused directly on the arterial wall. Additionally, novel anticoagulants are expected to have an important role in the treatment of atherosclerosis. A personalized approach using different “omic” technologies may optimize the efficacy of drug treatment, and pharmacogenetics are expected to play an important role in this regard. Keywords: atherosclerosis; diabetes mellitus; genetics; genetic variability; screening; rare genetic variants; direct anticoagulants; P2Y12 receptor blockers; drugs, Caveolin-1; personalized medicine

Strong inhibition of platelets and thrombin generation at the time of Percutaneous Coronary Intervention (PCI) is essential to reducing the risk of acute stent thrombosis and may also reduce the risk of restenosis. In this thematic issue, reviews take us from the pre-PCI scenario, through the peri-operative PCI setting, to short- and long-term out-patient antithrombotic pharmacotherapeutic options. Arguably the most challenging and high-risk patients presenting to the cath lab are those with severe aortic stenosis or cardiogenic shock and enhanced bleeding and thrombotic risk requiring individual antithrombotic regimens. This thematic issue also addresses the challenges faced in the management of these high-risk patients and discusses available therapeutic options. There is no situation where this is more important than in the setting of primary PCI (PPCI) for ST-elevation myocardial infarction. Yet it would appear that administration of opiate-analgesia for pain relief in patients with STEMI delays gastric emptying and may impair absorption of orally administered P2Y12 receptor antagonists. A thorough review of the literature in this issue reveals pharmacokinetic data showing both reduced platelet inhibition and delayed effect of P2Y12 receptor antagonists with co-administration of morphine. Although randomised controlled trials are lacking, small nonrandomised studies suggest this combination therapy results in larger infarct size. This concern raises the need for additional anti-platelet pharmacotherapy, over and above oral P2Y12 receptor antagonists in patients presenting with STEMI who require opiate analgesia. Whilst awaiting the results of definitive trials, the use of intravenous platelet inhibitors, in high risk patients such as those undergoing PPCI, should be considered early. In this regard, cangrelor, a relatively novel intravenous P2Y12-receptor inhibitor with immediate on-and offset of platelet inhibition appears very attractive. The cost of cangrelor is prohibitive of routine peri-PCI use, and in a detailed review of the potential pharmacokinetic effect and the clinical trials using cangrelor, it would appear to have a clear role in urgent revascularisation settings, where oral P2Y12 receptor antagonist may not be adequate such as in PPCI or cardiogenic shock, or similarly in patients undergoing high-risk intervention such as those with multi-vessel PCI, bifurcation lesion or left main PCI, or those with early stent thrombosis. The authors however caution that direct head-to-head comparison with newer oral P2Y12 receptor antagonists (prasugrel and ticagrelor) are lacking, so tailored use to the clinical situation is advised. In addition to Dual Antiplatelet Therapy (DAPT), use of glycoprotein IIb/IIIa inhibitors, significantly reduced ischemic complications in patients undergoing PCI, particularly in ACS, but was offset by increased bleeding. In a detailed review of clinical trials to date, taking into account the availability of the newer P2Y12-receptor inhibitors and increasing use of the radial approach, Rubboli and Patti propose a very useful algorithm for selective GPI use in a number of settings including stable angina, ACS and STEMI, as well as for bailout in the event of no-reflow during complicated PCI. Beyond the initial ACS, there remains an increased risk of recurrent cardiovascular events over the subsequent 30 days, despite DAPT. A comprehensive review in this issue evaluates trials of additional antithrombotic therapy over-and-above DAPT. Whilst additional agents such as anticoagulants or PAR-1 antagonists generally significantly increase bleeding, vorapaxar or low-dose rivaroxaban may reduce ischemic events in high-risk ACS patients and could be considered on a case-bycase basis. Aradi and co-workers then focus on the timeframe beyond the guideline-recommended 1-year treatment period for DAPT and explore trials of more prolonged or alternative antiplatelet agents. They conclude that whilst not for allcomers, some patients with prior MI may benefit from prolonged DAPT, with low-dose ticagrelor, although the increased bleeding risk highlights the need for risk stratification and individualised treatment. Since the refinement of PCI techniques, transvascular aortic valve replacement is the most exciting addition to the armamentarium of treatments offered in the cath lab. In this setting, where peri-operative stroke is a major concern and absence of guidelines on adjunctive pharmacotherapy, the authors provide a very thorough and balanced overview of available clinical data including, importantly, the lack of evidence for currently employed DAPT regimens. The review highlights the need to screen for atrial fibrillation, ongoing clinical trials and possible use of non-vitamin K oral anticoagulants. Controversy also surrounds the optimal management of the sickest cohort of patients in the cardiac cath lab, namely those with cardiogenic shock. These patients have a very high short-term mortality and the optimal haemodynamic support remains an issue of contention. Although trials of intra-aortic balloon counter-pulsation have produced neutral results, newer percutaneous mechanical devices including the Impella device may have an important role. Options for and evidence supporting such mechanical support devices in these patients are discussed by Bonello and colleagues. Finally, there appears to be ethnic variation not only in thrombotic risk, but also in response to antithrombotic medications. In a detailed and comprehensive review, Jeong and colleagues review the data on the efficacy and safety of antithrombotic medications in East Asian patients with ACS or undergoing PCI. This ethnic group, while relatively under-represented in clinical trials, appears to have lower risk of thrombosis but greater susceptibility to bleeding, with different pharmacokinetic and pharmacodynamic response to P2Y12 inhibitors compared to Westerners. The authors propose the concept of future “racetailored antithrombotic treatment”.

Cardiac surgery is no doubt a challenge for the surgeon, anesthesiologist and intensivist when trying to minimize the damage that occurs during its performance by the required ischemia and reperfusion. Both mechanisms have been described as cardiac preconditioning or postconditioning, in order to to diminish the damage of ischemic injury and reperfusion. There is an initial evidence, at least in cardiac surgery, that total intra-venous anesthesia (usually a propofol-based total intra- venous anesthesia) is associated to an increased mortality when compared to an anesthetic plan including an halogenated anesthetics [1]. In our issue, we will try to deepen into the effector mechanisms of this benefit and will also discover mechanism that could assist in extracorporeal circulation [2]. The preoperative right ventricular dysfunction has an influence at the postoperative outcome in patients undergoing valve surgery. Patients with impaired contractility or altered morphology of the right ventricle are exposed to a high perioperative risk, mainly to changes in ventricle function detected at echocardiographic findings such as TAPSE or right ventricular dilatation. The studies evaluating the preoperative administration of levosimendan in patients with ventricular dysfunction demonstrated cardiac benefits, including; [1] cardiac index (CI), [2] stroke volume index (SI), and [3] left ventricular ejection fraction (LVEF). Levosimendan is a drug that showed improved cardiac function in the immediate postoperative period. Levosimendan is beneficial if its use was started prior to the start of the surgery and anesthesia, and was more effective than delayed administration. The opening of KATP channels in the mitochondria has a predominant role in the protection of the myocardium from ischaemia and reperfusion injury. The opening of the KATP channel offers a reduction in myocardial cell necrosis and apoptosis induced by ischaemia–reperfusion injury by attenuation of calcium accumulation in the mitochondria and stabilisation of the mitochondrial inner membrane permeability. It means a treatment with the KATP channel opener levosimendan prior to myocardial ischaemia will mimic ischaemic preconditioning. Our intention is to assess whether there is an evidence on the effects of levosimendan in patients who are undergoing cardiovascular surgery at pre and postconditioning cardiac level [3]. Neurological dysfunction and various measures of cerebral protection in carotid surgery, or in situations of total circulatory arrest in cardiac surgery, neurological monitoring and different therapeutic strategies that could reduce their perioperative dysfunction, as well as handling it in the immediate postoperative period become increasingly important. Neurological complications associated with cardiovascular surgery are relatively common, and generate a large increase in morbidity and mortality. The main function of the medical team which evaluates and treats patients who require cardiac surgery is therefore, the proper assessment and prevention of these complications. The genesis of postsurgical neurological deficits are a functional or morphological suffering of neurons, by factors related to surgery (embolism or hypoperfusion), on a sometimes already committed suffering chronic cerebral atherosclerosis. In this area and in the perioperative suffering are added brain enhancers such as hyperthermia, hyperglycemia, and systemic inflammatory response. Impact will be focal, multifocal or diffuse depending on the extent of anatomical damage in relation to the magnitude and duration of noxa, and according to this will also be the clinical characteristics of neurological manifestations. They range from cerebral infarction, prolonged coma, stupor, convulsions, or a variety of neuropsychiatric disorders manifested by waking late and psychomotor excitement (encephalopathy), or subtle changes in intellectual function, memory, and behavior (cognitive impairment). Drugs such as corticosteroids, lignocaine, statins, sodium pentothal, ketamine, sedatives or hypnotics, or maneuvers such as hypothermia have been proposed as possible neurological protectors. We are trying to determine what is the scientific evidence for each one of therapeutic strategies [4]. Our intention is to review the following four points so that this can serve as a guide to physicians involved in treating the patients. [1] Mechanisms of Cardioprotection of Halogenated Agents during Extracorporeal Circulation in Cardiac Surgery. [2] Halogenated and Cardiovascular Surgery: Has Mortality Really Decreased? [3] Calcium Sensitizers in Cardiac Surgery (Who, When, How and Why). [4] Neurological Protection in Cardiovascular Surgery.

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