Lipoprotein(a) in Atherosclerotic Diseases: From Pathophysiology to Diagnosis and Treatment.

Lipoprotein(a) (Lp(a)) is a low-density lipoprotein (LDL) cholesterol-like particle bound to apolipoprotein(a). Increased Lp(a) levels are an independent, heritable causal risk factor for atherosclerotic cardiovascular disease (ASCVD) as they are largely determined by variations in the Lp(a) gene (LPA) locus encoding apo(a). Lp(a) is the preferential lipoprotein carrier for oxidized phospholipids (OxPL), and its role adversely affects vascular inflammation, atherosclerotic lesions, endothelial function and thrombogenicity, which pathophysiologically leads to cardiovascular (CV) events. Despite this crucial role of Lp(a), its measurement lacks a globally unified method, and, between different laboratories, results need standardization. Standard antilipidemic therapies, such as statins, fibrates and ezetimibe, have a mediocre effect on Lp(a) levels, although it is not yet clear whether such treatments can affect CV events and prognosis. This narrative review aims to summarize knowledge regarding the mechanisms mediating the effect of Lp(a) on inflammation, atherosclerosis and thrombosis and discuss current diagnostic and therapeutic potentials.

Negative interaction between nitrates and remote ischemic preconditioning in patients undergoing cardiac surgery: the ERIC-GTN and ERICCA studies.

Remote ischaemic preconditioning (RIPC) using transient limb ischaemia failed to improve clinical outcomes following cardiac surgery and the reasons for this remain unclear. In the ERIC-GTN study, we evaluated whether concomitant nitrate therapy abrogated RIPC cardioprotection. We also undertook a post-hoc analysis of the ERICCA study, to investigate a potential negative interaction between RIPC and nitrates on clinical outcomes following cardiac surgery. In ERIC-GTN, 185 patients undergoing cardiac surgery were randomized to: (1) Control (no RIPC or nitrates); (2) RIPC alone; (3); Nitrates alone; and (4) RIPC + Nitrates. An intravenous infusion of nitrates (glyceryl trinitrate 1 mg/mL solution) was commenced on arrival at the operating theatre at a rate of 2-5 mL/h to maintain a mean arterial pressure between 60 and 70 mmHg and was stopped when the patient was taken off cardiopulmonary bypass. The primary endpoint was peri-operative myocardial injury (PMI) quantified by a 48-h area-under-the-curve high-sensitivity Troponin-T (48 h-AUC-hs-cTnT). In ERICCA, we analysed data for 1502 patients undergoing cardiac surgery to investigate for a potential negative interaction between RIPC and nitrates on clinical outcomes at 12-months. In ERIC-GTN, RIPC alone reduced 48 h-AUC-hs-cTnT by 37.1%, when compared to control (ratio of AUC 0.629 [95% CI 0.413-0.957], p = 0.031), and this cardioprotective effect was abrogated in the presence of nitrates. Treatment with nitrates alone did not reduce 48 h-AUC-hs-cTnT, when compared to control. In ERICCA there was a negative interaction between nitrate use and RIPC for all-cause and cardiovascular mortality at 12-months, and for risk of peri-operative myocardial infarction. RIPC alone reduced the risk of peri-operative myocardial infarction, compared to control, but no significant effect of RIPC was demonstrated for the other outcomes. When RIPC and nitrates were used together they had an adverse impact in patients undergoing cardiac surgery with the presence of nitrates abrogating RIPC-induced cardioprotection and increasing the risk of mortality at 12-months post-cardiac surgery in patients receiving RIPC.

Remote Ischemic Preconditioning and Outcomes of Cardiac Surgery.

BACKGROUND: Whether remote ischemic preconditioning (transient ischemia and reperfusion of the arm) can improve clinical outcomes in patients undergoing coronary-artery bypass graft (CABG) surgery is not known. We investigated this question in a randomized trial. METHODS: We conducted a multicenter, sham-controlled trial involving adults at increased surgical risk who were undergoing on-pump CABG (with or without valve surgery) with blood cardioplegia. After anesthesia induction and before surgical incision, patients were randomly assigned to remote ischemic preconditioning (four 5-minute inflations and deflations of a standard blood-pressure cuff on the upper arm) or sham conditioning (control group). Anesthetic management and perioperative care were not standardized. The combined primary end point was death from cardiovascular causes, nonfatal myocardial infarction, coronary revascularization, or stroke, assessed 12 months after randomization. RESULTS: We enrolled a total of 1612 patients (811 in the control group and 801 in the ischemic-preconditioning group) at 30 cardiac surgery centers in the United Kingdom. There was no significant difference in the cumulative incidence of the primary end point at 12 months between the patients in the remote ischemic preconditioning group and those in the control group (212 patients [26.5%] and 225 patients [27.7%], respectively; hazard ratio with ischemic preconditioning, 0.95; 95% confidence interval, 0.79 to 1.15; P=0.58). Furthermore, there were no significant between-group differences in either adverse events or the secondary end points of perioperative myocardial injury (assessed on the basis of the area under the curve for the high-sensitivity assay of serum troponin T at 72 hours), inotrope score (calculated from the maximum dose of the individual inotropic agents administered in the first 3 days after surgery), acute kidney injury, duration of stay in the intensive care unit and hospital, distance on the 6-minute walk test, and quality of life. CONCLUSIONS: Remote ischemic preconditioning did not improve clinical outcomes in patients undergoing elective on-pump CABG with or without valve surgery. (Funded by the Efficacy and Mechanism Evaluation Program [a Medical Research Council and National Institute of Health Research partnership] and the British Heart Foundation; ERICCA ClinicalTrials.gov number, NCT01247545.).

Novel Approaches to the Management of Diabetes Mellitus in Patients with Coronary Artery Disease.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in individuals with diabetes mellitus (DM). Although benefit has been attributed to the strict control of hyperglycemia with traditional antidiabetic treatments, novel antidiabetic medications have demonstrated cardiovascular (CV) safety and benefits by reducing major adverse cardiac events, improving heart failure (HF), and decreasing CVD-related mortality. Emerging data underline the interrelation between diabetes, as a metabolic disorder, and inflammation, endothelial dysfunction, and oxidative stress in the pathogenesis of microvascular and macrovascular complications. Conventional glucose-lowering medications demonstrate controversial CV effects. Dipeptidyl peptidase- 4 inhibitors have not only failed to prove to be beneficial in patients with coronary artery disease, but also their safety is questionable for the treatment of patients with CVD. However, metformin, as the first-line option for type 2 DM (T2DM), shows CVD protective properties for DM-induced atherosclerotic and macrovascular complications. Thiazolidinedione and sulfonylureas have questionable effects, as evidence from large studies shows a reduction in the risk of CV events and deaths, but with an increased rate of hospitalization for HF. Moreover, several studies have revealed that insulin monotherapy for T2DM treatment increases the risk of major CV events and deaths from HF, when compared to metformin, although it may reduce the risk of myocardial infarction. Finally, this review aimed to summarize the mechanisms of action of novel antidiabetic drugs acting as glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors that show favorable effects on blood pressure, lipid levels, and inflammation, leading to reduced CVD risk in T2DM patients.

Diabetes Mellitus in Acute Coronary Syndrome.

The global prevalence of diabetes mellitus (DM) has led to a pandemic, with significant microvascular and macrovascular complications including coronary artery disease (CAD), which worsen clinical outcomes and cardiovascular prognosis. Patients with both acute coronary syndrome (ACS) and DM have worse prognosis and several pathophysiologic mechanisms have been implicated including, insulin resistance, hyperglycemia, endothelial dysfunction, platelet activation and aggregations as well as plaque characteristics and extent of coronary lesions. Therefore, regarding reperfusion strategies in the more complex anatomies coronary artery bypass surgery may be the preferred therapeutic strategy over percutaneous coronary intervention while both hyperglycemia and hypoglycemia should be avoided with closed monitoring of glycemic status during the acute phase of myocardial infraction. However, the best treatment strategy remains undefined. Non-insulin therapies, due to the low risk of hypoglycemia concurrently with the multifactorial CV protective effects, may be proved to be the best treatment option in the future. Nevertheless, evidence for the beneficial effects of glucagon like peptide-1 receptor agonists, dipeptidyl-peptidase 4 inhibitors and sodium glycose cotransporter 2 inhibitors, despite accumulating, is not robust and future randomized control trials may provide more definitive data.

Diabetic ketoacidosis as first presentation of latent autoimmune diabetes in adults in a patient with hashitoxicosis as first presentation of Hashimoto's thyroiditis: a case report.

BACKGROUND: Latent autoimmune diabetes in adults is an infrequent form of autoimmune diabetes mellitus, while Hashimoto's thyroiditis, the most common thyroid disease in adults, rarely manifests as thyrotoxicosis. The concurrent initial presentation of these two autoimmune disorders is extremely rare. CASE PRESENTATION: A 29-year-old male of Albanian descent presented after being hospitalized owing to diabetic ketoacidosis. The diagnosis of type 1 diabetes mellitus was placed, and intensified insulin therapy was initiated. Medical history was not of significance except a 5 kg weight loss within 2 months. The patient presented with recurrent episodes of hypoglycemia, and the doses of preprandial and basal insulin were reduced. The differential diagnosis included type 1 diabetes mellitus "honeymoon" period or another type of diabetes mellitus. His serological tests only revealed positive autoantibodies against glutamic acid decarboxylase 65 and C-peptide. The diagnosis leaned toward latent autoimmune diabetes in adults, and the therapeutic approach involved cessation of preprandial insulin therapy, regulation, and subsequent discontinuation of basal insulin and introduction of metformin. Two years later, basal insulin was reintroduced along with a glucagon-like peptide-receptor agonist and metformin. Further physical examination during the initial visit disclosed upper limb tremor, lid lag, excessive sweating, increased sensitivity to heat, and tachycardia. Laboratory tests were indicative of hashitoxicosis (suppressed level of thyroid-stimulating hormone, high levels of total and free thyroid hormones, positive anti-thyroglobulin and anti-thyroid peroxidase, and negative anti-thyroid-stimulating hormone receptor). Thyroid-stimulating hormone level was spontaneously restored, but an increase was observed during follow-up. Levothyroxine was administrated for 2 years until the patient had normal thyroid function. CONCLUSIONS: The prevalence of thyroid autoantibodies in patients with latent autoimmune diabetes in adults ranges from 20% to 30%. This correlation can be attributed to genetic involvement as well as disorders of immune tolerance to autoantigens. Hence, this report gives prominence to the holistic approach and consideration of comorbidities in patients with diabetes mellitus.

Interleukin-1 in Coronary Artery Disease.

Cardiovascular disease is the leading cause of mortality worldwide. Inflammation has long been established as a key component in the pathophysiology of coronary artery disease. The interleukin-1 family consists of 11 members that regulate the inflammatory response through both pro- and anti-inflammatory properties with the Nod-like receptor (NLR) family pyrin domain containing 3 inflammasome having a pivotal role in the process of converting interleukin-1 beta and interleukin- 18, two key inflammatory mediators, into their mature forms. Interleukin-1 affects various cell types that participate in the pathogenesis of atherosclerosis as it enhances the expression of leukocyte adhesion molecules on the surface of endothelial cells and augments the permeability of the endothelial cell barrier, attracting monocytes and macrophages into the vessel wall and aids the migration of smooth muscle cells toward atheroma. It also enhances the aggregation of low-density lipoprotein particles in endothelium and smooth muscle cells and exhibits procoagulant activity by inducing synthesis, cell-surface expression and release of tissue factor in endothelial cells, promoting platelet adhesion. The value of interleukin-1 as a diagnostic biomarker is currently limited, but interleukin-1 beta, interleukin-18 and interleukin-37 have shown promising data regarding their prognostic value in coronary artery disease. Importantly, target anti-inflammatory treatments have shown promising results regarding atherosclerosis progression and cardiovascular events. In this review article, we focus on the immense role of interleukin-1 in atherosclerosis progression, inflammation cascade and in the clinical application of target anti-inflammatory treatments.

Dietary Patterns and Polycystic Ovary Syndrome: a Systematic Review.

Background: Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders affecting women of reproductive age. The goal of this study was to present the suitable diet recommended by the international literature for women with polycystic ovary syndrome to alleviate their symptoms. Methods: A systematic search of electronic databases containing medical topics was conducted. Results: A total number of 123 articles were retrieved and seven of them were relevant to our chosen topic concerning the diet-related polycystic ovary syndrome. According to research, it seems that diet plays a very important role on the clinical picture and laboratory findings of PCOS. According to the included studies, the change in the diet of women brought positive results in terms of clinical appearance of the syndrome. Ôhis review presents the type of diet that is deemed helpful in the clinical and laboratory picture of the syndrome. Conclusion: In the future, more research should be conducted on a larger population with PCOS and for a longer period of time, during which subjects would be given a specific diet. It would also be important to compare diet to mild exercise and dietary supplementation.

Scenario-based design for a hospital setting: An exploratory study of opportunities and barriers for personal health records usage.

Personal health records (PHRs) offer patients the opportunity to be more actively involved in their own care. There is limited research into the application during hospital admissions for elective or emergency presentations. We used techniques from scenario-based design to test the opportunities and boundaries of a commercially available PHR in a simulated environment. Scenarios included a patient in his 80s admitted for hip surgery with his son, and a younger patient admitted with pneumonia. A catastrophic deterioration was demonstrated with a mannequin in a high-fidelity simulation. Workflows were summarised in swim-lane diagrams. The PHR allowed patients to file information prior to the interaction with the clinical team. This led to shorter time requirements for acquisition of data. The elderly patient required assistance from a relative but this aided verification of history prior to the encounter with the clinical team. Ward rounds could be prepared by the patient with specific 'what matters' questions. Documentation in the PHR environment during a simulated life-threatening emergency did not result in information that was unintelligible or useful for the 'patient'. Usage of a commercially available PHR during hospital admission is feasible and might aid workflow. Documentation of emergencies might require different documentation formats.

Clinical Safety and Feasibility of the Advanced Bolus Calculator for Type 1 Diabetes Based on Case-Based Reasoning: A 6-Week Nonrandomized Single-Arm Pilot Study.

BACKGROUND: The Advanced Bolus Calculator for Diabetes (ABC4D) is an insulin bolus dose decision support system based on case-based reasoning (CBR). The system is implemented in a smartphone application to provide personalized and adaptive insulin bolus advice for people with type 1 diabetes. We aimed to assess proof of concept, safety, and feasibility of ABC4D in a free-living environment over 6 weeks. METHODS: Prospective nonrandomized single-arm pilot study. Participants used the ABC4D smartphone application for 6 weeks in their home environment, attending the clinical research facility weekly for data upload, revision, and adaptation of the CBR case base. The primary outcome was postprandial hypoglycemia. RESULTS: Ten adults with type 1 diabetes, on multiple daily injections of insulin, mean (standard deviation) age 47 (17), diabetes duration 25 (16), and HbA1c 68 (16) mmol/mol (8.4 (1.5) %) participated. A total of 182 and 150 meals, in week 1 and week 6, respectively, were included in the analysis of postprandial outcomes. The median (interquartile range) number of postprandial hypoglycemia episodes within 6-h after the meal was 4.5 (2.0-8.2) in week 1 versus 2.0 (0.5-6.5) in week 6 (P = 0.1). No episodes of severe hypoglycemia occurred during the study. CONCLUSION: The ABC4D is safe for use as a decision support tool for insulin bolus dosing in self-management of type 1 diabetes. A trend suggesting a reduction in postprandial hypoglycemia was observed in the final week compared with week 1.

An Advanced Bolus Calculator for Type 1 Diabetes: System Architecture and Usability Results.

This paper presents the architecture and initial usability results of an advanced insulin bolus calculator for diabetes (ABC4D), which provides personalized insulin recommendations for people with diabetes by differentiating between various diabetes scenarios and automatically adjusting its parameters over time. The proposed platform comprises two main components: a smartphone-based patient platform allowing manual input of glucose and variables affecting blood glucose levels (e.g., meal carbohydrate content and exercise) and providing real-time insulin bolus recommendations; and a clinical revision platform to supervise the automatic adaptations of the bolus calculator parameters. The system implements a previously in silico validated bolus calculator algorithm based on case-based reasoning, which uses information from similar past events (i.e., cases) to suggest improved personalized insulin bolus recommendations and automatically learns from new events. Usability of ABC4D was assessed by analyzing the system usage at the end of a six-week pilot study (n = 10). Further feedback on the use of ABC4D has been obtained from each participant at the end of the study from a usability questionnaire. On average, each participant requested 115 ± 21 insulin recommendations, of which 103 ± 28 (90%) were accepted. The clinical revision software proposed a total of 754 case revisions, where 723 (96%) adaptations were approved by a clinical expert and updated in the patient platform.

The Effect of Remote Ischemic Conditioning and Glyceryl Trinitrate on Perioperative Myocardial Injury in Cardiac Bypass Surgery Patients: Rationale and Design of the ERIC-GTN Study.

Remote ischemic conditioning (RIC) using transient limb ischemia/reperfusion has been reported to reduce perioperative myocardial injury in patients undergoing coronary artery bypass grafting and/or valve surgery. The role of intravenous glyceryl trinitrate (GTN) therapy administered during cardiac surgery as a cardioprotective agent and whether it interferes with RIC cardioprotection is not clear and is investigated in the ERIC-GTN trial ( http://www.clinicaltrials.gov: NCT01864252). The ERIC-GTN trial is a single-site, double-blind, randomized, placebo-controlled study. Consenting adult patients (age > 18 years) undergoing elective coronary artery bypass grafting ± valve surgery with blood cardioplegia will be eligible for inclusion. Two hundred sixty patients will be randomized to 1 of 4 treatment groups following anesthetic induction: (1) RIC alone, a RIC protocol comprising three 5-minute cycles of simultaneous upper-arm and thigh cuff inflation/deflation followed by an intravenous (IV) placebo infusion; (2) GTN alone, a simulated sham RIC protocol followed by an IV GTN infusion; (3) RIC + GTN, a RIC protocol followed by an IV GTN infusion; and (4) neither RIC nor GTN, a sham RIC protocol followed by IV placebo infusion. The primary endpoint will be perioperative myocardial injury as quantified by the 72-hour area-under-the-curve serum high-sensitivity troponin T. The ERIC-GTN trial will determine whether intraoperative GTN therapy is cardioprotective during cardiac surgery and whether it affects RIC cardioprotection.