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Cardiovascular disease is the leading cause of mortality worldwide. Observational data indicate that low-density lipoprotein cholesterol levels are strongly positively associated with the risk of coronary heart disease, whilst the level of high-density lipoprotein cholesterol is strongly inversely associated, with additional associations being observed for other lipid parameters such as triglycerides, apolipoproteins and lipoprotein(a). This has led to an interest in the development of novel lipid intervention therapies.
Statins remain the cornerstone of lipid management for cardiovascular risk reduction, but even with intensive statin therapy, some groups of patients remain at significant residual cardiovascular risk. In addition, some people are intolerant to statin therapy. Additional risk reduction can be achieved by concomitant use of other lipid-lowering therapies. Ezetimibe is the drug most commonly added to statins for cardiovascular risk reduction. New drugs such as PCSK9 inhibitors provide additional LDL-lowering and may prove valuable as a therapeutic tool.
Short-term dietary nitrate or nitrite supplementation has nitric oxide (NO)-mediated beneficial effects on blood pressure and inflammation, and reduces mitochondrial oxygen consumption, possibly preventing hypoxia. As these processes are implicated in atherogenesis, dietary nitrate has been hypothesized to prevent plaque initiation, hypoxia and inflammation.
In their paper published in the February issue of Atherosclerosis, Marsch et al. studied the impact of long-term dietary nitrate supplementation on atherogenesis, hypoxia, and inflammation, in low density lipoprotein receptor knockout mice (LDLr−/−).
They observed that plasma nitrate levels were elevated after 14 weeks of nitrate supplementation. However, prolonged dietary nitrate did not affect systemic inflammation, hematopoiesis, erythropoiesis and plasma cholesterol levels, suggesting no severe side effects. Surprisingly, neither blood pressure, nor atherogenesis was altered.
The authors also showed that plasma nitrate and nitrite were high after two weeks, but decreased over time, with plasma nitrite reaching baseline levels at 14 weeks. Moreover, hemoglobin-bound NO levels were unaltered after 14 weeks. This compensation was not due to altered endothelial nitric oxide synthase (eNOS) activity or conversion into peroxynitrite and other reactive nitrogen intermediates (RNI), suggesting reduced nitrite formation or enhanced nitrate/nitrite clearance.
In conclusion, the authors showed that prolonged dietary nitrate supplementation results in compensation of nitrite and nitric oxide levels and does not affect atherogenesis or exerts systemic side effects.
In their invited commentary, Ramms and Gordts point out that results from this study urge for a more sophisticated treatment strategy to address whether dietary nitrite supplementation will attenuate or reverse atherosclerosis development. They also underline the importance of rigorously and frequently monitor nitrite and NO levels over the entire treatment period and the need to understand the process responsible for the inability to maintain elevated nitrite and NO levels during long-term dietary nitrate supplementation.
Very encouragingly, no evidence was found for increased tumor formation or cancer incidence in the nitrate supplemented group. However, it remains to be evaluated how these preclinical observations translate to human patients.
Longer duration of statin therapy is associated with decreased carotid plaque vascularity by magnetic resonance imaging
Plaque neovasculature is a major route for lipoprotein and leukocyte ingress into plaques, and has been identified as a risk factor for carotid plaque disruption. Carotid plaque fractional plasma volume (Vp) is an imaging-based marker of neovasculature density, previously validated using histology. Since lipid-lowering therapy has been associated with regression of neovasculature in animal models, O’Brien and colleagues aimed at determining clinical correlates of carotid plaque neovasculature (as assessed by Vp measurement) in 98 subjects on statin therapy for established cardiovascular disease.
The authors showed that in univariate analyses, shorter duration of statin therapy, the presence of metabolic syndrome, and higher body mass index and lipoprotein(a) were all significantly associated with higher baseline Vp values. In multivariate analyses, significant associations remained between shorter duration of statin therapy and lipoprotein(a).
These first in vivo findings in humans suggest a relationship between duration of statin therapy and regression of carotid plaque neovasculature. Future longitudinal studies are warranted both to confirm this finding and to address whether changes in neovasculature may translate into changes in risk for plaque disruption.
In their invited commentary, Shah and Murthy highlight that this study provides provocative, translational evidence of a link between non-invasive cardiac magnetic resonance (CMR)-based markers of plaque vascularity and use of statin therapy in humans, in line with previous investigations suggesting the pleotropic effect of statin therapy on plaque vascularity.
This translational study extends not only the horizons of CMR imaging to phenotype tissue-level carotid plaque characteristics, but also adds to the mounting evidence that statin therapies exert pleotropic, quantifiable effects on human vascular tissue. The authors also point out that with larger longitudinal studies in the context of novel therapeutics and improved, more generalizable CMR acquisitions, advanced imaging may unlock pathogenic mechanisms and therapeutic response in human atherosclerosis.
Announcement: “Atherosclerosis: Open Access (OMICS Group)”
The Atherosclerosis Editorial Board has been recently informed by Elsevier about their ongoing dispute with the OMICS Group.