The pleiotropic effects of statins on endothelial function, vascular inflammation, immunomodulation and thrombogenesis

doi:10.1016/j.atherosclerosis.2008.08.022

Atherosclerosis

Volume 203, Issue 2, April 2009, Pages 325-330

https://doi.org/10.1016/j.atherosclerosis.2008.08.022 Get rights and content

Abstract

Statins have been demonstrated to significantly affect the prognosis and outcome of patients with risk factors to atherosclerosis (in primary and secondary prevention trials). Several clinical and recently basic studies have suggested an extra-beneficial effect of the statins in the prevention of atherosclerosis and coronary artery disease. These studies showed that statins may affect the cardiovascular system beyond their effect on the lipid profile, and it was suggested that they affect the immunological system and vascular inflammation. Many of the beneficial pleiotropic effects of statins occur as a result of modulated endothelial function and reduced inflammatory processes. Attempting to understand these properties of statins is an exciting field of research that will also improve our understanding of vascular biology in health and disease, and thus enable the better use of this drug class in clinical practice.

Section snippets

Statin use and cardiovascular prevention

Five large randomized clinical trials showed the benefits of lipid lowering with statins on cardiac morbidity and mortality. Three of these were secondary prevention trials—the long term intervention with pravastatin in ischemic disease (LIPID) study, cholesterol and recurrent events (CARE), and Scandinavian simvastatin survival study (4S). The CARE and LIPID studies comprise populations that are representative of the majority of patients with coronary artery disease in that they included

The ASAP trial

The effect of aggressive versus conventional lipid lowering in atherosclerosis progression in familial hypercholesterolemia trial randomized 325 patients with familial hypercholesterolemia to atorvastatin 80 mg daily or simvastatin 40 mg daily. The primary endpoint was change of carotid intima media thickness (IMT) measured by quantitative B-mode ultrasound over 2 years. LDL-cholesterol lowering was significantly greater with atorvastatin (from 8.00 to 3.88 mmol/L) than simvastatin (from 8.33 to

Primary prevention studies

All randomized trials of at least 1 year duration that examined drug treatment for patients with no known coronary heart disease, cerebrovascular disease, or peripheral vascular disease and that measured clinical end points (all cause mortality, coronary heart disease mortality, non-fatal myocardial infarctions) were included in a meta analysis. The objective of the study was to summarize the effect of primary prevention with lipid lowering drugs on coronary heart disease events, coronary heart

Acute coronary syndromes and acute myocardial infarction

Until recently, it was unclear whether early treatment with statins following acute myocardial infarction (AMI) influences survival. In order to evaluate the association between statin treatment initiated before or at the time of hospital discharge and 1 year mortality after AMI, a prospective cohort study was established, using data from the Swedish Register of Cardiac Intensive Care on patients admitted to the coronary care units of 58 Swedish hospitals from 1995 to 1998. The mortality data

Statins and restenosis

The regression growth evaluation statin study (REGRESS) was designed as a placebo-controlled multicenter study that assessed the effects of 2-year treatment with pravastatin on the progression and regression of angiographically documented coronary artery disease. One of the secondary endpoints was the occurrence of 2-year restenosis in the percutaneous transluminal coronary angioplasty (PTCA) block. Patients were randomly assigned to receive pravastatin 40 mg daily or placebo. The endpoint was

Vascular inflammation

In the last 2 years several studies demonstrated that beneficial effects of statins might occur beyond the lipid lowering effect alone. Pravastatin treatment that was given to heart transplant patients reduced the lipid profile but also reduced plasma markers of inflammation and improved peripheral endothelial function. These effects on the endothelium and on markers of inflammation may explain the improved survival of heart transplant patients treated with statins [12]. The hypothesis that

Summary

Primary and secondary prevention clinical human trials have shown that statin use is beneficial and reduces cardiovascular morbidity and mortality. No harmful side effects were found with short and long term use of statins, including cancer prevalence and all cause mortality. Increasing evidence suggests that there are mechanisms beyond the lipid lowering effect that contribute to the antiatherogenic properties of statins.

These mechanisms of action are complex and involve nitric oxide

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In the progression of cardiovascular disease (CVD), myocardial inflammation and vascular endothelial inflammation are prevalent pathological phenomena. However, the development of drug delivery platform with high specificity against these inflammatory injury sites remains a challenge. To overcome this, we fused RAW264.7 macrophage membranes with human umbilical vein endothelial cell (HUVEC) membranes to prepare hybrid extracellular vesicles (RAW-HEVs) consisted of both types of cell membrane proteins. This hybrid EVs exhibited high uptake ratio towards LPS-induced inflammatory HUVECs and H9C2 cells. By leveraging the stealth properties of HUVEC membranes in the bloodstream and the innate inflammation-targeting ability of RAW264.7 macrophage membranes, RAW-HEVs actively accumulated at inflammatory sites of the heart and thoracic aorta in vivo. By loading curcumin (Cur) with anti-inflammatory activity to prepare Cur-loaded hybrid extracellular vesicles (RAW-H/Cur). RAW-H/Cur significantly reduced the expression of pro-inflammatory cytokines in cell supernatants and mice serum as compared to free Cur, as determined by ELISA. In addition, a significant reduction in LPS-induced organ damage in the heart and thoracic aorta was observed with RAW-H/Cur treatment, determined by Hematoxylin-eosin staining and immunohistochemistry. In conclusion, RAW-H/Cur, as a promising bionic delivery system for cardiovascular inflammatory diseases, is expected to help deliver Cur to inflamed regions of the heart and blood vessels and alleviate inflammatory symptoms.
Chronic PCSK9 inhibitor therapy leads to sustained improvements in endothelial function, arterial stiffness, and microvascular function
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Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) effectively decrease low-density lipoprotein cholesterol (LDL-C) and reduce cardiovascular events in patients at very high cardiovascular risk. Recent short-term studies suggest a partially LDL-C independent beneficial effect of PCSK9 inhibitor (PCSK9i) therapy on endothelial function and arterial stiffness, whereas it is unknown if this effect persists and what the effect is on microcirculation.
To investigate the effects of PCSK9i therapy on vascular parameters beyond its lipid lowering effect.
In this prospective trial, 32 patients at very high cardiovascular risk and indication for PCSK9i therapy were included. Measurements were performed at baseline and after 6 months of PCSK9i treatment. Endothelial function was assessed as flow-mediated dilation (FMD). Arterial stiffness was measured as pulse wave velocity (PWV) and aortic augmentation index (AIx). Peripheral tissue oxygenation (StO₂) as a marker of microvascular function was assessed at the distal extremities using near-infrared spectroscopy camera.
Six months of PCSK9i therapy decreased LDL-C levels from 141 ± 54 to 60 ± 30 mg/dl (−56 ± 21 %, p < 0.001), FMD significantly increased from 5.4 ± 1.7 % to 6.4 ± 1.9 % (+19 ± 10 %, p < 0.001), PWV decreased in male patients significantly from 8.9 ± 2.1 to 7.9 ± 1.5 m/s (−12 ± 9 %, p = 0.025). AIx decreased from 27.1 ± 10.4 % to 23.0 ± 9.7 % (−16 ± 14 %, p < 0.001), StO₂ significantly increased from 67 ± 12 % to 71 ± 11 % (+7 ± 6 %, p = 0.012). Brachial and aortic blood pressure showed no significant changes after six months. There was no correlation between LDL-C reduction and changes in vascular parameters.
Chronic PCSK9i therapy is associated with sustained improvements in endothelial function, arterial stiffness, and microvascular function independent from lipid lowering.
Anti-inflammatory effect of rosuvastatin in patients with HIV infection: An FDG-PET pilot study
2022, Journal of Nuclear Cardiology
This study aimed to evaluate markers of systemic as well as imaging markers of inflammation in the ascending aorta, bone marrow, and spleen measured by 18F-FDG PET/CT, in HIV+ patients at baseline and following therapy with rosuvastatin.
Of the 35 HIV+ patients enrolled, 17 were randomized to treatment with 10 mg/day rosuvastatin and 18 to usual care for 6 months. An HIV− control cohort was selected for baseline comparison of serum inflammatory markers and monocyte markers of inflammation. 18F-FDG-PET/CT imaging of bone marrow, spleen, and thoracic aorta was performed in the HIV+ cohort at baseline and 6 months. While CD14++CD16− and CCR2 expressions were reduced, serum levels of IL-7, IL-8, and MCP-1 were elevated in the HIV+ population compared to the controls. There was a significant drop in FDG uptake in the bone marrow (TBR_max), spleen (SUV_max) and thoracic aortic (TBR_max) in the statin-treated group compared to the control group (bone marrow: − 10.3 ± 16.9% versus 5.0 ± 18.9%, p = .0262; spleen: − 9.8 ± 20.3% versus 11.3 ± 28.8%, p = .0497; thoracic aorta: − 19.1 ± 24.2% versus 4.3 ± 15.4%, p = .003).
HIV+ patients had significantly markers of systemic inflammation including monocyte activation. Treatment with low-dose rosuvastatin in the HIV+ cohort significantly reduced bone marrow, spleen and thoracic aortic FDG uptake.
The effect of pitavastatin in an ischemic skin flap model in rats
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Distinct effects of rosuvastatin and rosuvastatin/ezetimibe on senescence markers of CD8+ T cells in patients with type 2 diabetes mellitus: a randomized controlled trial
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Simvastatin Significantly Reduced Alcohol-Induced Cardiac Damage in Adolescent Mice
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ReviewThe pleiotropic effects of statins on endothelial function, vascular inflammation, immunomodulation and thrombogenesis

Abstract

Section snippets

Statin use and cardiovascular prevention

The ASAP trial

Primary prevention studies

Acute coronary syndromes and acute myocardial infarction

Statins and restenosis

Vascular inflammation

Summary

Am J Cardiol

Am J Cardiol

Am J Cardiol

Int J Cardiol

Clinical relevance of statins: their role in secondary prevention

Atheroscler Suppl

Early time to benefit with intensive statin treatment: could it be the pleiotropic effects?

Am J Cardiol

Treating to new targets (TNT) investigators intensive lipid lowering with atorvastatin in patients with stable coronary disease

N Engl J Med

Use of lipid lowering drugs for primary prevention of coronary heart disease: meta-analysis of randomized trials

BMJ

Primary prevention of cardiovascular diseases with statin therapy

Arch Intern Med

Swedish register of cardiac intensive care (RIKSHIA) early statin treatment following acute myocardial infarction and 1-year survival

JAMA

Effective strategies for long-term statin use

Am J Cardiol

Circulation

Review
The pleiotropic effects of statins on endothelial function, vascular inflammation, immunomodulation and thrombogenesis