Inflammation in Metabolic Cardiomyopathy

Overlapping pandemics of lifestyle-related diseases pose a substantial threat to cardiovascular health. Apart from coronary artery disease, metabolic disturbances linked to obesity, insulin resistance and diabetes directly compromise myocardial structure and function through independent and shared mechanisms heavily involving inflammatory signals. Accumulating evidence indicates that metabolic dysregulation causes systemic inflammation, which in turn aggravates cardiovascular disease. Indeed, elevated systemic levels of pro-inflammatory cytokines and metabolic substrates induce an inflammatory state in different cardiac cells and lead to subcellular alterations thereby promoting maladaptive myocardial remodeling. At the cellular level, inflammation-induced oxidative stress, mitochondrial dysfunction, impaired calcium handling, and lipotoxicity contribute to cardiomyocyte hypertrophy and dysfunction, extracellular matrix accumulation and microvascular disease. In cardiometabolic patients, myocardial inflammation is maintained by innate immune cell activation mediated by pattern recognition receptors such as Toll-like receptor 4 (TLR4) and downstream activation of the NLRP3 inflammasome and NF-κB-dependent pathways. Chronic low-grade inflammation progressively alters metabolic processes in the heart, leading to a metabolic cardiomyopathy (MC) phenotype and eventually to heart failure with preserved ejection fraction (HFpEF). In accordance with preclinical data, observational studies consistently showed increased inflammatory markers and cardiometabolic features in patients with HFpEF. Future treatment approaches of MC may target inflammatory mediators as they are closely intertwined with cardiac nutrient metabolism. Here, we review current evidence on inflammatory processes involved in the development of MC and provide an overview of nutrient and cytokine-driven pro-inflammatory effects stratified by cell type

Right and left ventricles: as inseparable as the twin brothers ‘Castor and Pollux’

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Genetic deletion of the adaptor protein p66Shc increases susceptibility to short-term ischaemic myocardial injury via intracellular salvage pathways

Genetic deletion of p66Shc, as shown in the present study, leads to increased myocardial infarction in response to short-term ischaemia and reperfusion. Therefore, heart-specific activation of p66Shc protein may represent a promising novel strategy to prevent ischaemic and reperfusion myocardial injury. In particular, pharmacological modulation of apoptosis via myocardial salvage pathways involving p66Shc might be a promising approach to limit short-term ischaemic injury, for instance in patients with acute coronary syndrome (ACS) from the time of symptom onset to percutaneous coronary intervention. However, the present study also adds complexity to the use of this pathway as a therapeutic target. Indeed, given the different effects of activation and silencing of p66Shc in different cells, tissues and organs, tissue selective inhibition would be required. Indeed, while short-term activation might be protective in the context of an ACS, long-term inhibition may prevent endothelial dysfunction, atherosclerosis, and diabetic vascular disease. Obviously, this complexity also raises safety concerns for the potential use of p66Shc in acute myocardial infarction that need to be clarified by additional researc

Targeting prolyl-isomerase Pin1 prevents mitochondrial oxidative stress and vascular dysfunction: insights in patients with diabetes

The present study demonstrates that Pin1 is a common activator of key pathways involved in diabetic vascular disease in different experimental settings including primary human endothelial cells, knockout mice, and diabetic patients. Gene silencing and genetic disruption of Pin1 prevent hyperglycaemia-induced mitochondrial oxidative stress, endothelial dysfunction, and vascular inflammation. Moreover, we have translated our findings to diabetic patients. In line with our experimental observations, Pin1 up-regulation is associated with impaired flow-mediated dilation, increased oxidative stress, and plasma levels of adhesion molecules. In perspective, these findings may provide the rationale for mechanism-based therapeutic strategies in patients with diabete

Deletion of the ageing gene p66Shc reduces early stroke size following ischaemia/reperfusion brain injury

Aims Stroke is a leading cause of morbidity and mortality, and its incidence increases with age. Both in animals and in humans, oxidative stress appears to play an important role in ischaemic stroke, with or without reperfusion. The adaptor protein p66Shc is a key regulator of reactive oxygen species (ROS) production and a mediator of ischaemia/reperfusion damage in ex vivo hearts. Hence, we hypothesized that p66Shc may be involved in ischaemia/reperfusion brain damage. To this end, we investigated whether genetic deletion of p66Shc protects from ischaemia/reperfusion brain injury. Methods and results Transient middle cerebral artery occlusion (MCAO) was performed to induce ischaemia/reperfusion brain injury in wild-type (Wt) and p66Shc knockout mice (p66Shc−/−), followed by 24 h of reperfusion. Cerebral blood flow and blood pressure measurements revealed comparable haemodynamics in both experimental groups. Neuronal nuclear antigen immunohistochemical staining showed a significantly reduced stroke size in p66Shc−/− when compared with Wt mice (P < 0.05, n = 7-8). In line with this, p66Shc−/− mice exhibited a less impaired neurological function and a decreased production of free radicals locally and systemically (P < 0.05, n = 4-5). Following MCAO, protein levels of gp91phox nicotinamide adenine dinucleotide phosphate oxidase subunit were increased in brain homogenates of Wt (P < 0.05, n = 4), but not of p66Shc−/− mice. Further, reperfusion injury in Wt mice induced p66Shc protein in the basilar and middle cerebral artery, but not in brain tissue, suggesting a predominant involvement of vascular p66Shc. Conclusion In the present study, we show that the deletion of the ageing gene p66Shc protects mice from ischaemia/reperfusion brain injury through a blunted production of free radicals. The ROS mediator p66Shc may represent a novel therapeutical target for the treatment of ischaemic strok

Epigenetics in the primary and secondary prevention of cardiovascular disease: influence of exercise and nutrition

Increasing evidence links changes in epigenetic systems, such as DNA methylation, histone modification, and non-coding RNA expression, to the occurrence of cardiovascular disease (CVD). These epigenetic modifications can change genetic function under influence of exogenous stimuli and can be transferred to next generations, providing a potential mechanism for inheritance of behavioural intervention effects. The benefits of exercise and nutritional interventions in the primary and secondary prevention of CVD are well established, but the mechanisms are not completely understood. In this review, we describe the acute and chronic epigenetic effects of physical activity and dietary changes. We propose exercise and nutrition as potential triggers of epigenetic signals, promoting the reshaping of transcriptional programmes with effects on CVD phenotypes. Finally, we highlight recent developments in epigenetic therapeutics with implications for primary and secondary CVD prevention

Interleukin-1\u3b2 Mediates Arterial Thrombus Formation via NET-Associated Tissue Factor

CANTOS reported reduced secondary atherothrombotic events in patients with residual inflammatory risk treated with the inhibitory anti-IL-1\u3b2 antibody, Canakinumab. Yet, mechanisms that underlie this benefit remain elusive. Recent work has implicated formation of neutrophil extracellular traps (NETosis) in arterial thrombosis. Hence, the present study explored the potential link between IL-1\u3b2, NETs, and tissue factor (TF)-the key trigger of the coagulation cascade-in atherothrombosis. To this end, ST-elevation myocardial infarction (STEMI) patients from the Swiss multicenter trial SPUM-ACS were retrospectively and randomly selected based on their CRP levels. In particular, 33 patients with STEMI and high C-reactive protein (CRP) levels ( 65 10 mg/L) and, 33 with STEMI and low CRP levels ( 64 4 mg/L) were investigated. High CRP patients displayed elevated circulating IL-1\u3b2, NETosis, and NET-associated TF plasma levels compared with low CRP ones. Additionally, analysis of patients stratified by circulating IL-1\u3b2 levels yielded similar results. Moreover, NETosis and NET-associated TF plasma levels correlated positively in the whole population. In addition to the above, translational research experiments provided mechanistic confirmation for the clinical data identifying IL-1\u3b2 as the initial trigger for the release of the pro-coagulant, NET-associated TF. In conclusion, blunted TF presentation by activated neutrophils undergoing NETosis may provide a mechanistic explanation to reduced secondary atherothrombotic events as observed in canakinumab-treated patients in CANTOS

Endothelial overexpression of LOX-1 increases plaque formation and promotes atherosclerosis in vivo

Aims Lectin-like oxLDL receptor-1 (LOX-1) mediates the uptake of oxidized low-density lipoprotein (oxLDL) in endothelial cells and macrophages. However, the different atherogenic potential of LOX-1-mediated endothelial and macrophage oxLDL uptake remains unclear. The present study was designed to investigate the in vivo role of endothelial LOX-1 in atherogenesis. Methods and results Endothelial-specific LOX-1 transgenic mice were generated using the Tie2 promoter (LOX-1TG). Oxidized low-density lipoprotein uptake was enhanced in cultured endothelial cells, but not in macrophages of LOX-1TG mice. Six-week-old male LOX-1TG and wild-type (WT) mice were fed a high-cholesterol diet (HCD) for 30 weeks. Increased reactive oxygen species production, impaired endothelial nitric oxide synthase activity and endothelial dysfunction were observed in LOX-1TG mice as compared with WT littermates. LOX-1 overexpression led to p38 phosphorylation, increased nuclear factor κB activity and subsequent up-regulation of vascular cell adhesion molecule-1, thereby favouring macrophage accumulation and aortic fatty streaks. Consistently, HCD-fed double-mutant LOX-1TG/ApoE−/− displayed oxidative stress and vascular inflammation with higher aortic plaques than ApoE−/− controls. Finally, bone marrow transplantation experiments showed that endothelial LOX-1 was sufficient for atherosclerosis development in vivo. Conclusions Endothelial-specific LOX-1 overexpression enhanced aortic oxLDL levels, thereby favouring endothelial dysfunction, vascular inflammation and plaque formation. Thus, LOX-1 may serve as a novel therapeutic target for atherosclerosi

Personalised Management of Dyslipidaemias in patients with diabetes - It is time for a new approach.

Dyslipidemia in patients with type 2 diabetes (DMT2) is one of the worst controlled worldwide, with only about 1/4 of patients being on the low-density lipoprotein cholesterol (LDL-C) target. There are many reasons of this, including physicians’ inertia, including diabetologists and cardiologists, therapy nonadherence, but also underusage and underdosing of lipid lowering drugs due to unsuitable cardiovascular (CV) risk stratification. In the last several years there is a big debate on the risk stratification of DMT2 patients, with the strong indications that all patients with diabetes should be at least at high cardiovascular disease (CVD) risk. Moreover, we have finally lipid lowering drugs, that not only allow for the effective reduction of LDL-C and do not increase the risk of new onset diabetes (NOD), and/or glucose impairment; in the opposite, some of them might effectively improve glucose control. One of the most interesting is pitavastatin, which is now available in Europe, with the best metabolic profile within statins (no risk of NOD, improvement of fasting blood glucose, HOMA-IR, HbA1c), bempedoic acid (with the potential for the reduction of NOD risk), innovative therapies - PCSK9 inhibitors and inclisiran with no DMT2 risk increase, and new forthcoming therapies, including apabetalone and obicetrapib – for the latter one with the possibility of even decreasing the number of patients diagnosed with prediabetes and DMT2. Altogether, nowadays we have possibility to individualize lipid lowering therapy in DMT2 patients and increase the number of patients on LDL-C goal without any risk of new onset diabetes and/or diabetes control worsening, and in consequence to reduce the risk of CVD complications due to progression of atherosclerosis in this patients’ group