Cardiovascular & Hematological Disorders-Drug Targets

Cardiovascular and hematological disorders are the most common diseases afflicting humans. The aim of this mini thematic issue entitled “Recent Advancements in Identification of Novel Drug Targets and Drug Delivery for Cardiovascular and Hematological Disorders” is to summarize the recent advancements regarding the identification of novel drug targets and drug delivery techniques in cardiovascular and hematological disorders. It presents a compilation of updated articles written by the researchers with the comprehensive understanding in this field. Diabetes is treatable, but even when glucose levels are under control it greatly increases the risk of cardiovascular disease and stroke. This predisposition is because people with diabetes, particularly type 2 diabetes, may have hypertension, obesity or abnormal cholesterol conditions that contribute to their risk of developing cardiovascular disease. Cardiovascular Disorders (CVD) are the foremost reasons for morbidity and mortality amongst diabetic populations. Kumar et al. [1] have discussed the interplay role of diabetes in cardiovascular disease. They have highlighted the mechanisms of diabetic associated cardiovascular disease and the role of Adenosine Monophosphate Activated Protein Kinase (AMPK) enzyme as a potential target in cardiac hypertrophy, atherosclerosis or heart failure with regards to its cardioprotective potential. Sarkar and Rafiq [2] have discussed the role of cellular or humoral immune system and its association with CVD. This article discusses that the immune cell infiltration to adipose tissue contributes to the production and secretion of the proinflammatory mediators. This infiltration also promotes both the local and systemic pro-inflammatory that triggers various inflammatory pathways within cardiac tissue and ultimately leads to cardiac dysfunction. They have specifically highlighted the role of B-cells and its pathogenesis in heart failure. The study stressed upon identifying novel therapeutic targets along with the development of newer/better therapeutic strategies to combat the complex problem of CVD. Another challenge in CVD is Infective Endocarditis (IE). The IE emergence of new antimicrobial agents has shifted the pattern of pathogens that cause IE. Pseudomonas aeruginosa is one of the emerging pathogens that has been associated with IE. However, the interaction of P. aeruginosa with Human Aortic Endothelial Cells (HAECs) is not known. The binding and subsequent invasion of HAECs is one of the most crucial hallmarks of IE. In this issue, Mittal et al. [3] have demonstrated that P. aeruginosa can invade HAECs in a dose and time-dependent manner using gentamicin protection assay. It was also observed by the authors that P. aeruginosa induces cytokine production and cell damage as observed in human clinical conditions. This model can be of immense importance for high throughput screening of drugs that will prevent P. aeruginosa invasion of HAECs, cytokine production, and cell damage. The availability of these new drugs will provide novel avenues for the treatment of IE. Although CVD is a leading cause of morbidity and mortality worldwide, there are still drug delivery challenges for the effective treatment of these disorders. Mittal et al. [4] reviewed the pathogenesis of atherosclerosis, first-line medical treatment for CVD, and key obstacles inefficient drug delivery. A better understanding of the molecular mechanisms underlying the pathogenesis of CVDs will help in developing novel efficacious treatment modalities beyond conventional therapies for heart diseases. Despite advances in medical technology, the conventional therapies for CVD still lack efficacy and site specificity. To address these concerns there has been an increased interest in the cardiovascular community to develop newer techniques such as nanocarrier systems that possess the potential to revolutionize the treatment of CVDs. Nanocarrier systems modify the physicochemical properties of the therapeutic drug and are specific to the targeted delivery site. Further, nanocarrier based delivery systems can overcome the biological challenges of conventional therapies by a combinatory approach such as drug delivery along with the added advantage of image-guided therapy for targeted/ personalized treatment known as the nanotheranostics approach. Gupta et al. [5] have discussed the role of nanotechnology in the development of novel nanocarrierbased approaches to improve existing research concerning such nanoparticulate drug delivery systems, their reported effectiveness and the challenges facing their translation into pervasive clinical use. In summary, we believe that mini thematic issue will provide the latest information to the researchers and clinicians working in the field of cardiovascular and hematological disorders. The issue is well within the scope of ‘Cardiovascular & Hematological Disorders-Drug Targets’ and will be appealing to the audience of this journal. Finally, a special word of appreciation is due to all the contributors that embraced our challenge and made the present issue possible.

Diabetes mellitus is a major public health disorder that affects more than 400 million subjects, with a prevalence ranging from 7.2 to 11.4% in the general population, worldwide [1, 2]. Diabetes is associated with various metabolic disorders and vascular damage of great extent [3] and thus, the management of the diabetic patient should aim in the attenuation of hyperglycemia and other concomitant cardiovascular conditions [4-7]. Current antidiabetic treatment options were unable to offer consistent cardiovascular benefits. Apart from metformin and glucagon-like peptide 1 analogues, the rest of the available hypoglycemic agents have not provided consistent benefits from the cardiovascular standpoint. Furthermore, the impact of these drugs on other cardiovascular risk factors is either neutral or beneficial, and in some cases even harmful [8-15]. Sodium-glucose co-transporters (SGLT) 2 inhibitors are a novel antidiabetic class of drugs that offer a different approach for the amelioration of hyperglycemia than the other antidiabetic drug classes. SGLT-2 inhibitors block the reabsorption of glucose in the renal proximal tubule, resulting in decreased glucose reabsorption, increased urine excretion of glucose and attenuation of glycemic parameters [16, 17]. Through their unique mechanism of action, SGLT- 2 inhibitors seem to offer several beneficial effects on a cluster of other cardiovascular risk factors. These drugs are associated with a mild increase in sodium urine excretion; this combined with the osmotic effect of the excreted glucose, results in a mild diuretic effect that leads to hemodynamic improvements. A mild decrease in blood pressure accompanied with a mild reduction in body weight is noted with SGLT-2 inhibition. In addition, beneficial effects with these drugs are observed in serum acid levels, triglycerides and high-density lipoprotein cholesterol levels. Ameliorating effects are also noted in other established cardiovascular risk factors such as diabetic nephropathy, non-alcoholic fatty liver disease and arterial stiffness [18, 19]. The pleiotropic effect of SGLT-2 inhibitors on the aforementioned abundance of cardiovascular risk factors has raised several expectations for their cardiovascular profile. As of this issue, two cardiovascular studies on these novel drugs exist and have provided encouraging results. Empagliflozin in the EMPA-REG study and (to a lesser extent) canaglifllozin in CANVAS study have shown remarkable benefits in cardiovascular morbidity and mortality [20, 21]. Furthermore, SGLT-2 inhibitors seem to attenuate heart failure and renal outcomes [20-23]. In this special issue of Cardiovascular and Hematological Diseases-Drug Targets, we aim to present current data on the multidimensional profile of SGLT-2 inhibitors and discuss the benefits and potential contradictory findings with this class of drugs. Manolis et al. discuss in detail the mechanism of action of SGLT-2 inhibitors and comprehensively explain the SGLT-2 inhibitors-induced increased excretion of glucose, sodium, water and of other substances that might result in important outcome benefits. They further describe the effect of SGLT-2 inhibition on other organs and systems, as well [24]. The antidiabetic profile of the drugs is presented by Kihm et al. in the following review. The authors report the results from studies of several SGLT-2 inhibitors used as monotherapy or as add-on treatment to preexisting antidiabetic drugs. They noted a significant reduction in fasting plasma glucose and glycated hemoglobin of approximately 0.5 to 1% (in absolutes values). Importantly, it is stated that SGLT-2 inhibitors are not inferior to other hypoglycemic drugs in terms of glycemic control, with insignificant differences in glycated hemoglobin between SGLT-2 inhibitors-treated patients and other actively treated groups [25]. Subsequently, Tsioufis et al. in their review present the blood pressure-lowering effect of SGLT-2 inhibitors (mostly due to increased diuresis) from studies with office and ambulatory blood pressure measurements that range from 3 to 5 mmHg in systolic and 1 to 2 mmHg of diastolic blood pressure. Furthermore, it is stated that with their use, a mild body weight reduction of 2 to 3 kg is achieved, that is sustained with long-term treatment [26]. The significant cardiovascular and mortality risk reductions are reported by Lovic et al. who discussed the data obtained from the two aforementioned cardiovascular trials and from one large observational study in detail. Among the favorable data presented, the authors report the concerning higher amputation risk observed with Doumas et al. and Papademetriou et al. comprehensively present data and potential underlying mechanisms of the attenuating impact of SGLT-2 inhibitors on renal and heart failure outcomes, respectively [28, 29]. In the article by Doumas et al. it is stated that SGLT-2 inhibitors are associated with a significant delay in the progression of diabetic kidney disease, with empagliflozin and canagliflozin achieving a remarkable deceleration of estimated glomerular filtration rate decline (0.9 ml/min/year) and amelioration of albuminuria status, respectively [28]. Papademetriou et al. present the benefits of SGLT-2 inhibition in heart failure outcomes and support that these findings could potentially be attributed to the ameliorating effect of SGLT-2 inhibitors on blood pressure, visceral obesity, arterial stiffness, diastolic dysfunction and importantly to the SGLT-2 inhibitorsinduced increase in ketones bioavailability [29]. Tziomalos et al. report in detail the impact of these drugs on stroke risk factors and the contradictory neutral impact of SGLT-2 inhibitors on stroke risk, implying that other factors may be in play that need to be unveiled [30]. Last, Karagiannis et al. discuss the concerns of a potential increase in the risk of euglycemic diabetic ketoacidosis with this novel class of drugs. The authors present randomized controlled trials, meta-analyses, case series and case reports and note that most ketoacidosis cases were observed in patients with type 1 diabetes, due to off-label use of SGLT-2 inhibitors, or in patients previously misdiagnosed as having type 2 diabetes, who in fact suffered from late autoimmune diabetes of adults [31]. The recent CANVAS study provided similar results with the EMPA-REG trial and suggests a class effect of SGLT-2 inhibitors on morbidity and mortality outcomes. These remarkable findings could establish this class of drugs as an optimal second-line treatment option after metformin monotherapy. The concerning findings in terms of stroke and amputations risk will place at the epicenter of the scientific interest, the identification of patients’ groups that might be more prone to these events, such as patients with increased hematocrit levels or severe peripheral artery disease. Ongoing cardiovascular and renal trials will potentially provide further credence for this novel and very promising class of drugs.

The prevalence of cardiovascular and metabolic disease in China has been rapidly increased during last 20 years in parallel with the rapid industrialization of the country [1, 2]. Hypertension, obesity, unhealthy diet and inactivity lifestyle appear to play important roles in the boost of heart disease, stroke and diabetes in China [3, 4]. Heart disease is the number 2 cause of death in Canada [5]. One out 3 of Canadians is diagnosed as diabetes or pre-diabetes [6]. Since 2011, Chinese Atherosclerosis Society (CAS) and Canadian Society of Atherosclerosis , Thrombosis and Vascular Biology (CSATVB) have organized 5 joint symposiums which were held in Beijing (2011), Vancouver (2013), Nanjing (2014), Calgary (2016) and Hengyang (2017). More than 1,000 of researchers, clinicians and trainees from China and Canada presented their research results. The CASCSATVB joint symposiums become an important platform to develop scientific collaborations between institutes and researchers in the two countries. The Cardiovascular and Hematologic Disorders-Drug Target journal published two hot topic issues as the proceeding of those joint symposiums [7, 8]. This special issue selected 4 mini-reviews presented by Canadian or Chinese researchers and their colleagues on recent joint symposiums. Dr. Michael Walsh in University of Calgary reported in his plenary lecture on the regulation of smooth muscle myosin light chain phosphatase by multi-site phosphorylation of the myosin targeting subunit, Myosin phosphatase targeting subunit 1 (MYPT1). Their findings provided deep insight for the phoshphorylation of MYPT1, which may be important therapeutic target for a number of cardiovascular disorders including chronic heart failure, intestinal inflammation, pulmonary hypertension, asthma or diabetic vasculopathy [9]. Dr. Lemin Zheng and his colleagues in Beijing University School of Medicine reported their findings of the involvement of Connexin 43 and myocardial ischemia-reperfusion injury [10]. Connexin 43 is the major component of cardiomyocyte Gap Junctions and plays an important role in cardioprotection. Myocardial connexin 43 is upregulated in acute myocardial ischemic injury and it becomes an emerging therapeutic target for ischemic/perfusion injury of heart. Dr. Paolo Raggi and his colleague in University of Alberta reported the findings of his group on role of epicardial adipose tissue in atherosclerosis. Their studies suggest that adipose tissue is an important source for inflammatory mediators, which play critical roles in the initiation of inflammation on endothelial surface and atherogenesis [11]. Dr. Huiyong Yin and his colleagues in Shanghai Institute of Life Sciences demonstrated their research progress in the field of Cholesterol Homeostasis and Liver X Receptor (LXR) in Atherosclerosis. The activation of LXR in liver inhibits cholesterol uptake and enhances cholesterol efflux. LXR has become a therapeutic target for the treatment of atherosclerosis. Natural LXR agonists are mostly oxysterol or cytochrome P450. Synthesized LXR agonists have been developed (T0901317 and GW3965). In contrast, polyunsaturated fatty acids and geranylgeranylpyrophosphate inhibited LXR activity [12]. Since the reviews have been written between 2016 and 2017, many related studies have been done by now. The studies described in the thematic issue reflect the rapid progresses in atherosclerosis researches among researchers in Canada and China. Multiple researchers reported the findings generated from the collaborative studies between the two countries resulted from previous joint symposiums of CSATVB and CAS. We are looking forward to see more of collaborative researches to be developed between the researchers and trainees between the two countries and societies.