A. Mamas

The role of metabolites and metabolomics in clinically applicable biomarkers of disease.

Metabolomics allows the simultaneous and relative quantification of thousands of different metabolites within a given sample using sensitive and specific methodologies such as gas or liquid chromatography coupled to mass spectrometry, typically in discovery phases of studies. Biomarkers are biological characteristics that are objectively measured and evaluated as indicators of normal biological processes, pathological processes or pharmacologic responses to a therapeutic intervention. Biomarkers are widely used in clinical practice for the diagnosis, assessment of severity and response to therapy in a number of clinical disease states. In human studies, metabolomics has been applied to define biomarkers related to prognosis or diagnosis of a disease or drug toxicity/efficacy and in doing so hopes to provide greater pathophysiological understanding of disease or therapeutic toxicity/efficacy. This review discusses the application of metabolomics in the discovery and subsequent application of biomarkers in the diagnosis and management of inborn errors of metabolism, cardiovascular disease and cancer. We critically appraise how novel biomarkers discovered through metabolomic analysis may be utilized in future clinical practice by addressing the following three fundamental questions: (1) Can the clinician measure them? (2) Do they add new information? (3) Do they help the clinician to manage patients? Although a number of novel biomarkers have been discovered through metabolomic studies of human diseases in the last decade, none have currently made the transition to routine use in clinical practice. Metabolites identified from these early studies will need to form the basis of larger, prospective, externally validated studies in clinical cohorts for their future use as biomarkers. At this stage, the absolute quantification of these biomarkers will need to be assessed epidemiologically, as will the ultimate deployment in the clinic via routine biochemistry, dip stick or similar rapid at- or near-patient care technologies.

A meta‐analysis of the prognostic significance of atrial fibrillation in chronic heart failure

Atrial fibrillation (AF) is one of the commonest sustained arrhythmias in chronic heart failure (CHF), although the prognostic implications of the presence of AF in CHF remain controversial. We have therefore performed this meta‐analysis to study the effects of the presence of AF on mortality in CHF patients.

Cardiovascular manifestations associated with influenza virus infection

Influenza accounts for 3 to 5 million cases of severe illness and up to 300,000 deaths annually. Cardiovascular involvement in acute influenza infection can occur through direct effects of the virus on the myocardium or through exacerbation of existing cardiovascular disease. Epidemiological studies have demonstrated an association between influenza epidemics and cardiovascular mortality and a decrease in cardiovascular mortality in high risk patients has been demonstrated following vaccination with influenza vaccine. Influenza is a recognised cause of myocarditis which can lead to significant impairment of cardiac function and mortality. With recent concerns regarding another potential global pandemic of influenza the huge potential for cardiovascular morbidity and mortality is discussed.

Influence of access site selection on PCI-related adverse events in patients with STEMI: meta-analysis of randomised controlled trials

Objective A meta-analysis of all randomised controlled studies that compare outcomes of transradial versus the transfemoral route to better define best practice in patients with ST elevation myocardial infarction (STEMI). Design A Medline and Embase search was conducted using the search terms ‘transradial,’ ‘radial’, ‘STEMI’, ‘myocardial’ and ‘infarction’. Setting Randomised controlled studies that compare outcomes of transradial versus the transfemoral route. Patients A total of nine studies were identified that consisted of 2977 patients with STEMI. Interventions Studies that compare outcomes of transradial versus the transfemoral route. Main outcome measures The primary clinical outcomes of interest were (1) mortality; (2) major adverse cardiac events (MACE); (3) major bleeding and (4) access site complications. Results Transradial PCI was associated with a reduction in mortality (OR 0.53, 95% CI 0.33 to 0.84; p=0.008), MACE (OR 0.62, 95% CI 0.43 to 0.90; p=0.012), major bleeding events (OR 0.63, 95% CI 0.35-1.12; p=0.12) and access site complications (OR 0.30, 95% CI 0.19 to 0.48; p<0.0001) compared with procedures performed through the femoral route. Conclusions This meta-analysis demonstrates a significant reduction in mortality, MACE and major access site complications associated with the transradial access site in STEMI. The meta-analysis supports the preferential use of radial access for STEMI PCI.

Bariatric surgery and its impact on cardiovascular disease and mortality: a systematic review and meta-analysis.

BACKGROUND Bariatric surgery has been shown to improve cardiovascular risk factors but long term benefits for survival and cardiovascular events are still uncertain. METHODS We searched MEDLINE and EMBASE for parallel group studies that evaluated the clinical outcomes associated with bariatric surgery as compared to non-surgical treatment. Relevant studies were pooled using random effects meta-analysis for risk of myocardial infarction, stroke, cardiovascular events and mortality. RESULTS 14 studies met the inclusion criteria, which included 29,208 patients who underwent bariatric surgery and 166,200 nonsurgical controls (mean age 48 years, 30% male, follow up period ranged from 2 years to 14.7 years). Four studies were considered at moderate-high risk of bias, whilst ten studies were at moderate or lower risk of bias. Compared to nonsurgical controls there was more than 50% reduction in mortality amongst patients who had bariatric surgery (OR 0.48 95% CI 0.35-0.64, I2=86%, 14 studies). In pooled analysis of four studies with adjusted data, bariatric surgery was associated with a significantly reduced risk of composite cardiovascular adverse events (OR 0.54 95% CI 0.41-0.70, I2=58%). Bariatric surgery was also associated with significant reduction in specific endpoints of myocardial infarction (OR 0.46 95% CI 0.30-0.69, I2=79%, 4 studies) and stroke (OR 0.49 95% CI 0.32-0.75, I2=59%, 4 studies). CONCLUSIONS Data from observational studies indicates that patients undergoing bariatric surgery have a reduced risk of myocardial infarction, stroke, cardiovascular events and mortality compared to non-surgical controls. Future randomized studies should investigate whether these observations are reproduced in a clinical trials setting.

Longitudinal stent deformation: a retrospective analysis of frequency and mechanisms.

AIMS Modern drug-eluting stents are constructed with thin struts and are easy to deliver and highly conformable. However, although innovative designs have enabled maintenance of radial strength, longitudinal strength may be lower with these stents and there have been recent reports of longitudinal stent compression of ostially deployed stents. We report the experience in our centre on longitudinal stent deformation and explore mechanisms of this complication and its frequency with various drug-eluting stent platforms. METHODS AND RESULTS Nine cases of longitudinal stent deformation were identified over a four year period representing 0.2% of cases and affected 0.097% of stents deployed. There were several mechanisms for this complication including compression by post-dilatation balloons, guide catheter extensions and proximal embolic protection devices. The rate of stent deformation varied from 0% in several stent types to 0.86% in the case of the Promus Element stent. There was one case of late stent thrombosis attributable to longitudinal stent deformation. CONCLUSIONS Longitudinal stent deformation can occur secondary to a variety of mechanisms and identification is important as, left untreated, it may be associated with a risk of stent thrombosis. Although seen with several different stents, in our series it was more commonly observed with the Promus Element stent.

Role of advanced glycation end products in cardiovascular disease

Advanced glycation end products (AGEs) are produced through the non enzymatic glycation and oxidation of proteins, lipids and nucleic acids. Enhanced formation of AGEs occurs particularly in conditions associated with hyperglycaemia such as diabetes mellitus (DM). AGEs are believed to have a key role in the development and progression of cardiovascular disease in patients with DM through the modification of the structure, function and mechanical properties of tissues through crosslinking intracellular as well as extracellular matrix proteins and through modulating cellular processes through binding to cell surface receptors [receptor for AGEs (RAGE)]. A number of studies have shown a correlation between serum AGE levels and the development and severity of heart failure (HF). Moreover, some studies have suggested that therapies targeted against AGEs may have therapeutic potential in patients with HF. The purpose of this review is to discuss the role of AGEs in cardiovascular disease and in particular in heart failure, focussing on both cellular mechanisms of action as well as highlighting how targeting AGEs may represent a novel therapeutic strategy in the treatment of HF.

Long-term Glycemic Variability and Risk of Adverse Outcomes: A Systematic Review and Meta-analysis

OBJECTIVE Glycemic variability is emerging as a measure of glycemic control, which may be a reliable predictor of complications. This systematic review and meta-analysis evaluates the association between HbA1c variability and micro- and macrovascular complications and mortality in type 1 and type 2 diabetes. RESEARCH DESIGN AND METHODS Medline and Embase were searched (2004–2015) for studies describing associations between HbA1c variability and adverse outcomes in patients with type 1 and type 2 diabetes. Data extraction was performed independently by two reviewers. Random-effects meta-analysis was performed with stratification according to the measure of HbA1c variability, method of analysis, and diabetes type. RESULTS Seven studies evaluated HbA1c variability among patients with type 1 diabetes and showed an association of HbA1c variability with renal disease (risk ratio 1.56 [95% CI 1.08–2.25], two studies), cardiovascular events (1.98 [1.39–2.82]), and retinopathy (2.11 [1.54–2.89]). Thirteen studies evaluated HbA1c variability among patients with type 2 diabetes. Higher HbA1c variability was associated with higher risk of renal disease (1.34 [1.15–1.57], two studies), macrovascular events (1.21 [1.06–1.38]), ulceration/gangrene (1.50 [1.06–2.12]), cardiovascular disease (1.27 [1.15–1.40]), and mortality (1.34 [1.18–1.53]). Most studies were retrospective with lack of adjustment for potential confounders, and inconsistency existed in the definition of HbA1c variability. CONCLUSIONS HbA1c variability was positively associated with micro- and macrovascular complications and mortality independently of the HbA1c level and might play a future role in clinical risk assessment.

Longitudinal stent deformation: insights on mechanisms, treatments and outcomes from the Food and Drug Administration Manufacturer and User Facility Device Experience database.

AIMS Longitudinal stent deformation (LSD) is a recently described complication of PCI, but mechanisms contributing to its occurrence and associated clinical outcomes remain unclear. The FDA Manufacturer and User Facility Device Experience (MAUDE) database was searched to identify cases of LSD to gain insight into procedural and anatomical factors that predispose to this complication and associated clinical outcomes. METHODS AND RESULTS The MAUDE database is a voluntary international electronic reporting system whose aim is to capture major adverse events involving medical devices. Using defined search terms, we identified 57 unique cases of LSD ranging from 2004-2011. A significant increase in the reporting of LSD in the last two years was observed with most reported cases in stents based on the Element platform (90%). The lesions in which LSD was reported were complex (vessel calcification 26%; tortuosity 25%; long 28%; ostial disease 21%) and most frequently occurred following attempts to pass or withdraw secondary devices through a previously deployed stent (89% cases where mechanism identified). Adverse clinical outcomes including emergent cardiac surgery and acute and sub-acute stent thrombosis occurred in eight cases. CONCLUSIONS LSD can occur secondary to a variety of mechanisms; identification and treatment is important since adverse incidents such as emergent CABG and stent thrombosis may occur. A novel classification system is proposed to facilitate future reporting of this complication.

Use of the sheathless guide catheter during routine transradial percutaneous coronary intervention: a feasibility study.

Objective: The aim of this study is to investigate the feasibility of using a 6.5 Fr sheathless guide catheter as a default system in transradial (TRA) percutaneous coronary intervention (PCI). Background: TRA PCI has been shown to reduce mortality rates through a reduction in access site related bleeding complications compared with procedures performed though a femoral approach. Complications associated with the TRA route increase with the size of sheath used. These complications may be reduced by the use of a sheathless guide catheter system (Asahi Intecc, Japan) that is 1–2 Fr sizes smaller in diameter than the corresponding introducer sheath. Methods: We performed PCI in 100 consecutive cases using 6.5 Fr sheathless guides to determine the procedural success, rates of symptomatic radial spasm and radial occlusion. Results: Procedural success using the 6.5 Fr sheathless guide catheter system was 100% with no cases requiring conversion to a conventional guide and catheter system. There were no procedural complications recorded associated with the use of the catheter. Adjunctive devices used in this cohort included IVUS, stent delivery catheters, distal protection devices, and simple thrombectomy catheters. The rate of radial spasm was 5% and the rate of radial occlusion at 2 months was 2%. Conclusion: Use of the 6.5 Fr sheathless guide catheter system, which has an outer diameter <5 Fr sheath, as the default system in routine PCI is feasible with a high rate of procedural success via the radial artery.