Clinical, behavioral and biomarker predictors of PCSK9 levels in HIV-infected patients naïve of statin therapy: A cross-sectional analysis from the Swiss HIV cohort.

BACKGROUND AND AIMS: Better characterization of Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) profile is currently needed to tailor appropriate lipid-lowering strategies in HIV patients. METHODS: HIV-infected individuals aged ≥ 40 years and naive of statin therapy included in the Swiss HIV cohort study were screened for PCSK9 levels with a routine blood sample collection in 2014 at the Geneva University Hospitals. An exploratory linear regression model was built including clinical (age, sex, ethnicity, cardiovascular risk factors, body mass index, low CD4 defined as ≤200 cells/µl, leucocytes, lymphocytes, platelet, antiretroviral therapy), behavioral (tobacco and marijuana smoking, alcohol use and physical activity) and biomarker (CRP, TNF-α, IL-8, Il-10 and MCP-1) to investigate association with continuous PCSK9 levels. RESULTS: We studied 239 HIV-infected individuals who met inclusion criteria and available PCSK9 levels with a mean age of 49 years. 35 subjects (14.6%) reported marijuana consumption, of whom 20 (57.1%) reported daily consumption and 15 (6.3%) occasional use. PCSK9 levels were correlated with low-density lipoprotein-cholesterol (LDL-C). Our exploratory model identified marijuana consumption (p=0.023) and low CD4 values (p=0.020) as significantly associated factors with higher PCSK9 levels. No association was found with Framingham risk score. Patients with marijuana consumption had significantly higher levels of PCSK9 with a dose-response effect (p < 0.001); the association persisted after adjustment for the calculated Framingham risk score (p=0.003) and additional adjustment for clinical variables (p=0.027). CONCLUSIONS: In HIV-infected individuals naïve of statin treatment, marijuana consumption and low CD4 values are associated with higher PCSK9 levels independently of clinically relevant confounding factors.

Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management.

Statin-associated muscle symptoms (SAMS) are one of the principal reasons for statin non-adherence and/or discontinuation, contributing to adverse cardiovascular outcomes. This European Atherosclerosis Society (EAS) Consensus Panel overviews current understanding of the pathophysiology of statin-associated myopathy, and provides guidance for diagnosis and management of SAMS. Statin-associated myopathy, with significant elevation of serum creatine kinase (CK), is a rare but serious side effect of statins, affecting 1 per 1000 to 1 per 10 000 people on standard statin doses. Statin-associated muscle symptoms cover a broader range of clinical presentations, usually with normal or minimally elevated CK levels, with a prevalence of 7-29% in registries and observational studies. Preclinical studies show that statins decrease mitochondrial function, attenuate energy production, and alter muscle protein degradation, thereby providing a potential link between statins and muscle symptoms; controlled mechanistic and genetic studies in humans are necessary to further understanding. The Panel proposes to identify SAMS by symptoms typical of statin myalgia (i.e. muscle pain or aching) and their temporal association with discontinuation and response to repetitive statin re-challenge. In people with SAMS, the Panel recommends the use of a maximally tolerated statin dose combined with non-statin lipid-lowering therapies to attain recommended low-density lipoprotein cholesterol targets. The Panel recommends a structured work-up to identify individuals with clinically relevant SAMS generally to at least three different statins, so that they can be offered therapeutic regimens to satisfactorily address their cardiovascular risk. Further research into the underlying pathophysiological mechanisms may offer future therapeutic potential.

Update on selective treatments targeting neutrophilic inflammation in atherogenesis and atherothrombosis.

Atherosclerosis is the most common pathological process underlying cardiovascular diseases. Current therapies are largely focused on alleviating hyperlipidaemia and preventing thrombotic complications, but do not completely eliminate risk of suffering recurrent acute ischaemic events. Specifically targeting the inflammatory processes may help to reduce this residual risk of major adverse cardiovascular events in atherosclerotic patients. The involvement of neutrophils in the pathophysiology of atherosclerosis is an emerging field, where evidence for their causal contribution during various stages of atherosclerosis is accumulating. Therefore, the identification of neutrophils as a potential therapeutic target may offer new therapeutic perspective to reduce the current atherosclerotic burden. This narrative review highlights the expanding role of neutrophils in atherogenesis and discusses on the potential treatment targeting neutrophil-related inflammation and associated atherosclerotic plaque vulnerability.

Renin-angiotensin system blockade and contrast-induced renal toxicity.

BACKGROUND: The influence of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) on contrast-induced renal toxicity has been poorly studied. Nevertheless, it is a common practice in many centers to stop these drugs before coronarography. Our goal was to study whether renal function was affected in patients taking ACEIs or ARBs and undergoing a coronary angiogram. METHODS: Patients on ACEIs or ARBs (n=17) and those not on ACEIs or ARBs (n=18) admitted for a coronary angiogram underwent glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) assessment either by isotopic clearances (51Cr-EDTA and MAG3) or inulin and paraimmuno-hippurate clearances 24 hours prior to and immediately after coronary angiogram. RESULTS: Median percentage GFR changes induced by the injection of contrast medium during coronary angiogram were -9% (interquartile range -19% to +3%) in the control group and -1% (interquartile range -9% to +39%) in the ACEI/ARB group. Mean ERPF remained stable after coronarography in the control group (median change -8%; interquartile range -18% to +6%) and increased slightly in the ACEI/ARB group (median change +9%; interquartile range -17% to +60%). The median percentage difference in EPRF change was not statistically significant between the 2 groups (p=0.18). CONCLUSIONS: Inhibition of the renin-angiotensin system is not associated with a decline in renal function in patients receiving contrast media, and there is no need to interrupt this treatment prior to coronary angiogram.

New anti-inflammatory agents to reduce atherosclerosis.

The concept that inflammation plays a major role in atherogenesis has become accepted in recent years (Hansson 2005). As a result, anti-inflammatory agents may become increasingly important in the treatment of atherogenesis, atherosclerosis, and possibly even acute coronary or ischemic syndromes. This presentation reviews two types of molecules associated with the diagnosis, development, or treatment of atherosclerosis: C-reactive protein (CRP), and cannabis.

Towards a therapeutic use of selective CB2 cannabinoid receptor ligands for atherosclerosis.

Atherosclerosis remains the primary cause of heart disease and stroke, causing approximately 50% of all deaths in Western countries. The identification of promising novel anti-atherosclerotic therapies is therefore of great interest and represents a continued challenge to the medical community. Cannabinoids, such as Delta9-tetrahydrocannabinol (THC), which is the major psychoactive compound of marijuana, modulate immune functions and might therefore be of therapeutic use for the treatment of inflammatory diseases. The authors have demonstrated recently that oral treatment with low dose THC inhibits atherosclerosis progression in mice through pleiotropic immunomodulatory effects on inflammatory cells. All these effects were mediated via the cannabinoid receptor CB(2), the main cannabinoid receptor expressed on immune cells. However, these promising results are in conflict with the known health risks of smoking marijuana, as THC binds to and activates both cannabinoid receptors, CB(1) and CB(2). The identification and characterization of cannabinoid derivative that selectively activate CB(2) receptors and are devoid of adverse effects might offer a novel therapeutic strategy for the treatment of atherosclerosis.

Toward a role for statins in immunomodulation.

The family of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors, collectively known as statins, is used clinically to reduce cholesterol levels in patients. Recent reports suggest that not only would statin therapy be beneficial for at-risk (genetically predisposed) people without symptoms of hypercholesterolemia, but that statins may have beneficial, pleiotropic effects in the treatment of autoimmune diseases. Youssef et al. have described how an HMG-CoA inhibitor, atorvastatin, might ameliorate experimental autoimmune encephalomyelitis (EAE), the mouse model for human multiple sclerosis. The possible clinical use of statins as anti-inflammatory drugs has also been demonstrated in other published reports. These provocative results suggest a role for statins in relieving autoimmune diseases such as multiple sclerosis.