Reducing infarct size during a cardiac ischaemic‐reperfusion episode is still of paramount importance, because the extension of myocardial necrosis is an important risk factor for developing heart failure. Cardiac ischaemia‐reperfusion injury (IRI) is in principle a metabolic pathology as it is caused by abruptly halted metabolism during the ischaemic episode and exacerbated by sudden restart of specific metabolic pathways at reperfusion. It should therefore not come as a surprise that therapy directed at metabolic pathways can modulate IRI. Here, we summarize the current knowledge of important metabolic pathways as therapeutic targets to combat cardiac IRI. Activating metabolic pathways such as glycolysis (eg AMPK activators), glucose oxidation (activating pyruvate dehydrogenase complex), ketone oxidation (increasing ketone plasma levels), hexosamine biosynthesis pathway (O‐GlcNAcylation; administration of glucosamine/glutamine) and deacetylation (activating sirtuins 1 or 3; administration of NAD+‐boosting compounds) all seem to hold promise to reduce acute IRI. In contrast, some metabolic pathways may offer protection through diminished activity. These pathways comprise the malate‐aspartate shuttle (in need of novel specific reversible inhibitors), mitochondrial oxygen consumption, fatty acid oxidation (CD36 inhibitors, malonyl‐CoA decarboxylase inhibitors) and mitochondrial succinate metabolism (malonate). Additionally, protecting the cristae structure of the mitochondria during IR, by maintaining the association of hexokinase II or creatine kinase with mitochondria, or inhibiting destabilization of FOF1‐ATPase dimers, prevents mitochondrial damage and thereby reduces cardiac IRI. Currently, the most promising and druggable metabolic therapy against cardiac IRI seems to be the singular or combined targeting of glycolysis, O‐GlcNAcylation and metabolism of ketones, fatty acids and succinate.

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Background Until 2021, the strongest guidelines on surgical correction of severe aortic regurgitation (AR) focused on the left ventricular systolic function (LVEF) and the presence of symptoms. However, those situations lead to an outcome penalty, even after surgical correction. Left ventricle end-systolic diameter (LVESD) gained in strength in 2021 European guidelines. Moreover, more inclusive cut-off values are now recommended (class IIb) in patients at low surgical risk, reflecting the will to recommend surgery before developing heart failure and its consequences on post-operative outcome. Purpose We sought to evaluate the impact of guidelines triggers and their recent changes on postoperative survival of patients with severe AR from a large multicentric international registry. Method and results Postoperative overall survival of 1899 patients operated for severe and chronic AR (mean age 49±15 years, 85% male) in the international multicenter surgery registry for aortic valve surgery, AVIATOR, was evaluated over a median of 37 months. Twelve patients (0.6%) died postoperatively, and 68 within 10 years. By multivariable Cox analysis, presence of heart failure symptoms (HR 2.60; 95% CI [1.20–5.66]; p=0; 016), and either LVESD >50 mm or >25 mm/m2 (HR 1.64; 95% CI [1.05–2.55]; p=0.029) predicted survival independently over and above age (HR 2.25 per SD, 95% CI [1.67–3.03], p<0.001), female gender and bicuspid phenotype. Therefore, patients operated on when meeting either old or new 2021 class I triggers had worse adjusted survival (respectively 86±2% and 87±2%) than patients operated on without meeting triggers (97±2%, p<0.01). However asymptomatic patients operated on while meeting new 2021 ESC class IIb triggers (ie LVESD >20 mm/m2 or LVEF between 50–55%, 10-year survival 97±3%). Moreover, the sub-group of patients having a dilated LVESD >50 mm or >25 mm/m2 but a preserved LVEF >50% had excellent survival (10-year survival 95±3%). Conclusions In severe AR, patients operated on when meeting any class I trigger have postoperative survival penalty. Asymptomatic patients operated on earlier have better survival. This supports early surgery in AR as encouraged by the recent ESC/EACTS guidelines. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Fondation Nationale de la Recherche Scientifique of the Belgian Government

Background Inflammation and oxidative stress are thought to play an important role in the pathophysiology of HFpEF through the development of endothelial dysfunction. Myeloperoxidase (MPO), a leukocyte-derived enzyme, functions as a link between oxidative stress and inflammation and is an interesting therapeutic target. Purpose To compare MPO levels between HFpEF and old controls and to define clinical characteristics associated with high levels of MPO. Methods Patients with HFpEF (N=55) and controls >60 years (N=18) were prospectively included. All subjects underwent complete echocardiography and standard biology. MPO levels were dosed by ELISA assay. Endothelial function was assessed by peripheral arterial tonometry through the reactive hyperemia index (RHI). Characteristics were compared using independent samples t-test or chi square test. Results Patients with HFpEF (80±8.5 years, 65% female) had higher levels of myeloperoxidase compared to controls (74±6.2 years, 72% female) (34.7 ng/mL [22.7; 43.9] versus 22.5 [18.1; 31.9], p=0.026) (Figure 1). HFpEF patients with levels of MPO above the median were more often men and diabetic and had higher levels of NTproBNP and CRP. However, MPO levels were not associated with endothelial function measured by RHI (Table 1). Conclusion(s) HFpEF patients have higher levels of myeloperoxidase than control subjects, reflecting leukocyte activation and oxidative stress. Myeloperoxidase levels are associated with inflammation and disease severity. Myeloperoxidase inhibitors could be useful for the treatment of HFpEF patients, especially in the subgroup of patients with diabetes. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Fondation Damman