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Aims: Low-density lipoprotein (LDL) particles cause atherosclerotic cardiovascular disease (ASCVD) through their retention, modification, and accumulation within the arterial intima. High plasma concentrations of LDL drive this disease, but LDL quality may also contribute. Here, we focused on the intrinsic propensity of LDL to aggregate upon modification. We examined whether inter-individual differences in this quality are linked with LDL lipid composition and coronary artery disease (CAD) death, and basic mechanisms for plaque growth and destabilization. Methods and results: We developed a novel, reproducible method to assess the susceptibility of LDL particles to aggregate during lipolysis induced ex vivo by human recombinant secretory sphingomyelinase. Among patients with an established CAD, we found that the presence of aggregation-prone LDL was predictive of future cardiovascular deaths, independently of conventional risk factors. Aggregation-prone LDL contained more sphingolipids and less phosphatidylcholines than did aggregation-resistant LDL. Three interventions in animal models to rationally alter LDL composition lowered its susceptibility to aggregate and slowed atherosclerosis. Similar compositional changes induced in humans by PCSK9 inhibition or healthy diet also lowered LDL aggregation susceptibility. Aggregated LDL in vitro activated macrophages and T cells, two key cell types involved in plaque progression and rupture. Conclusion: Our results identify the susceptibility of LDL to aggregate as a novel measurable and modifiable factor in the progression of human ASCVD.

Introduction Concentric left ventricular hypertrophy (LVH) and diastolic dysfunction develops as an adaptive response to pressure overload. Eventually this may lead to decompensated hypertrophy characterised by interstitial fibrosis, contractile dysfunction as well as changes in metabolism and electrophysiology, consequentially triggering heart failure. The molecular mechanisms involved in cardiac remodelling are not fully understood but maladaptive angiogenesis could promote the transition from adaptive LVH to decompensated heart failure. Angiogenesis is mediated by vascular endothelial growth factors but their role in LVH has remained unresolved. Purpose In this study, we wanted to investigate whether vascular endothelial growth factor receptor 1 (VEGFR-1) signaling has a role in the progression of LVH and development of heart failure. Methods We used wild type littermate controls and domain specific knock out mouse lacking the intracellular VEGFR-1 tyrosine kinase domain (VEGFR-1 TK−/−) and induced pathological hypertrophy with subcutaneous angiotensin II infusion. We examined the cardiac function with echocardiography and acquired surface ECG signal during the development of LVH. Mice were followed up for 14 days before sacrification and sample collection. Cross-sectional cardiac samples were stained with Masson's trichrome to assess the level of fibrosis and immunostained for lectin to determine capillary area. Additionally, we performed a CD31 whole mount staining to visualise capillary 3D network. To analyse changes in gene expression levels, we performed RT qPCR measurements. Results VEGFR-1 TK deficiency led to increased mortality (33.3%) and lack of adaptive LVH. Whereas wild type mice responded to angiotensin II infusion with a significant increase in ejection fraction (55.5% to 69.9%) within the first 6 days, VEGFR-1 TK−/− mice displayed a 5.2% decrease and without adaptive thickening of the LV anterior wall. The most striking difference was seen in LV volume, where wild type mice displayed a 63.3% reduction but in VEGFR-1 TK−/− mice it remained unaltered after angiotensin II infusion. Histological analyses showed that VEGFR-1 TK−/− mice displayed significant cardiomyocyte hypertrophy combined with ventricular dilatation but without changes in fibrosis or angiogenesis. ECG analysis revealed that VEGFR-1 TK−/− mice exhibited widening of the QRS complex, similar to human LVH, and this was accompanied by increased ANP/BNP levels. Conclusions In this study, we show that the ablation of VEGFR-1 TK signaling has an unexpected role in pressure overload inducing mortality. VEGFR-1 TK−/− mice displayed dilated LVH and a protracted response to angiotensin II infusion, suggesting that VEGFR-1 signaling is required for the adaptive response and concentric hypertrophy of the myocardium.