Maria Camacho-Encina

Maria Camacho-Encina, Laura K Booth, Rachael Redgrave, Minna Honkanen-Scott, William E Scott, III, Carmen Martin-Ruiz, Guy MacGowan, Sarah Richardson, John

Cardiovascular diseases (CVDs), a group of disorders affecting the heart or blood vessels, are the primary cause of death worldwide, with an immense impact on patient quality of life and disability. According to the World Health Organization, CVD takes an estimated 17.9 million lives each year, where more than four out of five CVD deaths are due to heart attacks and strokes. In the decades to come, an increased prevalence of age-related CVD, such as atherosclerosis, coronary artery stenosis, myocardial infarction (MI), valvular heart disease, and heart failure (HF) will contribute to an even greater health and economic burden as the global average life expectancy increases and consequently the world’s population continues to age. Considering this, it is important to focus our research efforts on understanding the fundamental mechanisms underlying CVD. In this review, we focus on cellular senescence and mitochondrial dysfunction, which have long been established to contribute to CVD. We also assess the recent advances in targeting mitochondrial dysfunction including energy starvation and oxidative stress, mitochondria dynamics imbalance, cell apoptosis, mitophagy, and senescence with a focus on therapies that influence both and therefore perhaps represent strategies with the most clinical potential, range, and utility.

Cardiovascular disease (CVD), a group of disorders affecting the heart or blood vessels, are the primary cause of death worldwide, with an immense impact on patient quality of life and disa-bility. According to the World Health Organization, CVD takes an estimated 17.9 million lives each year, where more than four out of five CVD deaths are due to heart attacks and strokes. In the decades to come, increased prevalence of age-related CVD, such as atherosclerosis, coronary artery stenosis, myocardial infarction (MI), valvular heart disease, and heart failure (HF) will contribute to even greater health and economic burden as the global average life expectancy increases and consequently the world’s population continues to age. Considering this, it is important to focus our research efforts on understanding the fundamental mechanisms underlying CVD. In this review, we focus on cellular senescence and mitochondrial dysfunction, which have long been established to contribute to CVD. We also assess the recent advances in targeting mitochondrial dysfunction and senescence with a focus on therapies that influence both and therefore perhaps represent strategies with the most clinical potential, range, and utility.

Radiofrequency ablation commonly requires the creation of a contiguous line of ablation lesions, with even small gaps potentially leading to breakthrough conduction.¹ Lesion spacing is dependent on lesion size, which is influenced by factors including power delivery, tissue contact and application duration, but also lesion shape as this determines the degree of lesion overlap required to achieve contiguity. Irrigated catheters are the standard tool for radiofrequency ablation in the left heart. However, lesions created by irrigated catheters demonstrate a ‘tear-drop’ shape due to endocardial sparing.² Manufacturer-recommended flow rates of 17 mL/min for ≤30 W and 30 mL/min for >30 W appear to be relatively arbitrary and there are scant data to support these figures or this dichotomy. Equally, a low flow rate of 2 mL/min may be insufficient to provide adequate lesion depth in thicker tissue.³ We, therefore, assessed if varying the irrigation flow rate during ablation could optimise lesion shape by minimising endocardial sparing while maintaining lesion depth, in turn improving the efficiency of ablation line delivery (see Supplementary material online , Figure S1).

Background: The improvement of the existing diagnostic methods to detect pre-radiographic knee OA (KOA) may facilitate the development of preventive strategies. It has been postulated that combining biochemical with clinical markers, may increase the prognostic power to detect who is at high risk for developing KOA. Objectives: To validate and qualify the ability of 6 proteins with biomarker potential to generate a prognostic model of knee OA prediction through the combination of validated OA biomarkers and clinical markers. Methods: In the validation phase (Figure 1), 749 sera at the baseline visit belonging to participants from the Osteoarthritis Initiative (OAI) Cohort were randomly selected to blindly quantify 6 biomarkers using in-house custom sandwich microarrays built using the xMAP technology. Among these, only 540 participants have a Kellgren and Lawrence (KL) grade = 0-1 at the beginning of the OAI study in at least one knee. After a follow-up period of 96 months, 209 participants developed KOA in at least one knee (KL ≥ 2) and were classified as incident group, whereas 331 did not developed the disease (KL = 0-1) and were classified as not-incident group. Statistical differences between the outcome groups were assessed by non-parametric Mann-Whitney U tests. In the qualification phase (n=540), univariate regression analyses were carried out to investigate whether the individual biomarkers were associated with the risk of KOA development. A clinical prognostic model was defined by stepwise regression analysis using clinical non-radiographic variables significantly associated with the OA incidence. The utility of the potential biomarkers, alone or in combination, was evaluated by comparing the Area Under the Curve (AUC) of the clinical prognostic model with the biomarkers plus clinical prognostic models. In addition, sen Study desing Results: The incident group showed significant higher serum concentrations at the baseline visit (p < 0.05) for all the potential biomarkers analyzed in this study. Moreover, 5 of them were also significantly associated with the future appearance of radiographic KOA, yielding Odds Ratios (OR) ≥ 10 per 10 µg/ml increase. Among all the possible combinations, the inclusion of 2 biomarkers to the clinical prognostic model showed a significant improvement of the predictive capacity (AUCs = 0.78 vs 0.82, p= 0,044) with 65% (95% Confidence Interval (95%CI): 60-70%) specificity and 88% (95%CI: 81-91%) sensitivity. Variables included in the regression model and all metrics comparing the biomarkers plus clinical prognostic model with the clinical prognostic model are shown in Figure 2A. The ROC curves of the biomarkers-only model, clinical prognostic model and biomarkers plus clinical prognostic model are represented in Figure 2B. (A) Multivariate regression analysis (B) ROC curves of the models Conclusion: We have generated a prognostic model for the prediction of KOA by combining biomarkers and clinical variables, which showed a putative utility in the clinical setting by improving the predictive capacity of a clinical prognostic model to identify patients at a higher risk to develop radiographic KOA. Disclosure of Interests: Maria Camacho Encina: None declared, Vanesa Balboa-Barreiro: None declared, Ignacio Rego-Perez: None declared, Rocío Paz González: None declared, Valentina Calamia: None declared, Lucía Lourido: None declared, Cristina Ruiz-Romero: None declared, Francisco J. Blanco Grant/research support from: Sanofi-Aventis, Lilly, Bristol MS, Amgen, Pfizer, Abbvie, TRB Chemedica International, Glaxo SmithKline, Archigen Biotech Limited, Novartis, Nichi-iko pharmaceutical Co, Genentech, Jannsen Research & Development, UCB Biopharma, Centrexion Theurapeutics, Celgene, Roche, Regeneron Pharmaceuticals Inc, Biohope, Corbus Pharmaceutical, Tedec Meiji Pharma, Kiniksa Pharmaceuticals, Ltd, Gilead Sciences Inc, Consultant of: Lilly, Bristol MS, Pfizer

Background Two different phenotypes of hand osteoarthritis (HOA) have been defined: nodal hand osteoarthritis (NHOA) and erosive hand osteoarthritis (EHOA). NHOA involve bone enlargement of the underlying interphalangeal joints, which may typically give rise to Heberden’s nodes, synovitis and swelling. EHOA is a particularly aggressive form characterised by an abrupt onset, as well as signs of inflammation and subchondral erosions. In the absence of efficient diagnostic methods, searching for specific biomarkers for each subtype may help to characterise them. Objectives To define a panel of specific protein markers for the characterisation of EHOA and NHOA and its potential use in clinic. Methods A proteomic approach based on peptide labelling with Isobaric tags for relative and absolute quantitation (iTRAQ) was performed using two different sets of sera (n=55). Samples were classified in 4 groups of study (EHOA, n=10; non-EHOA, n=10; NHOA n=10; non-NHOA, n=5) and 2 control groups (rheumatoid arthritis (RA), n=10 and psoriatic arthritis (PSA), n=10). Serum proteins were digested and peptides from each condition to be compared were differentially labelled with iTRAQ reagents (Sciex). Then, samples were combined and analysed by two-dimensional liquid chromatography coupled to mass spectrometry in a TripleTOF 5600 Mass Spectrometer System (Sciex). Protein identification and quantitation was carried out using ProteinPilot software v.5.0.1. Results A total of 257 different proteins were identify with more than two peptides and a total score ≥2 at 95% confidence. In order to identify specific biomarkers for the characterisation of NHOA and EHOA phenotypes, each group was compared with the non-NHOA or non-EHOA respectively, and also with the control groups. After all the comparisons were made, 26 unique different proteins were found specific of the nodular phenotype. Vasorin (VAS) showed elevated levels in patients diagnosed with NHOA when compared to non-NHOA, RA and PSA groups. On the other hand, 36 unique proteins were identified in those patients with EHOA. Extracellular matrix protein 1 (ECM1) was found with higher concentrations in EHOA than in non-EHOA, RA and PSA patients. In addition, both HOA phenotypes were compared to the control groups and a panel of 30 different proteins were defined. Among these proteins, vascular cell adhesion molecule-1 (VCAM1) was found increased in HOA compared to RA and PSA groups. Conclusions A specific protein profile for the characterisation of EHOA and NHOA disorders has been established. VAS showed elevated levels in patients with NHOA, whereas ECM1 was increased in patients diagnosed with the erosive form of the disease. As none of them were identify in the other phenotype, they might be phenotype-specific biomarkers. In addition, VCAM1 was found with higher levels in both phenotypes of HOA when compared with RA and PSA and might be used to differentiate hand osteoarthritis from other rheumatic diseases. Acknowledgements Financial support (IN606A-2016/012) from the Xunta de Galicia and the European Union (European Social Fund – ESF), is gratefully acknowledged. Disclosure of Interest None declared