Current Vascular Pharmacology

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.