BACKGROUND AND AIM: The involvement of cholesterol in cancer development remains a topic of debate, and its association with breast cancer has yet to be consistently demonstrated. Considering that circulating cholesterol levels depend on several concomitant processes, we tested the liability of plasma levels of proprotein convertase subtilisin/kexin type 9 (PCSK9), one of the key regulators of cholesterol levels, as a prognostic biomarker in the context of breast neoplastic events. METHODS: Within a prospective randomized breast cancer prevention trial we measured baseline plasma levels of PCSK9. A total of 235 at-risk premenopausal women were randomized and followed up for 17 years. Participants enrolled in this placebo-controlled, phase II, double-blind trial were randomly assigned to receive either tamoxifen 5 mg/d or fenretinide 200 mg/d, both agents, or placebo for 2 years. The associations with breast cancer events were evaluated through competing risk and Cox regression survival models, adjusted for randomization strata (5-year Gail risk ≥ 1.3% vs. intraepithelial neoplasia or small invasive breast cancer of favorable prognosis), age, and treatment allocation. PCSK9 associations with biomarkers linked to breast cancer risk were assessed on blood samples collected at baseline. RESULTS: The plasmatic PCSK9 median and interquartile range were 207 ng/mL and 170-252 ng/mL, respectively. Over a median follow-up period of 17 years and 89 breast neoplastic events, disease-free survival curves showed a hazard ratio of 1.002 (95% CI: 0.999-1.005, p = 0.22) for women with PCSK9 plasma levels ≥ 207 ng/mL compared to women with levels below 207 ng/mL. No differences between randomization strata were observed. We found a negative correlation between PCSK9 and estradiol (r = -0.305), maintained even after partial adjustment for BMI and age (r = -0.287). Cholesterol (r = 0.266), LDL-C (r = 0.207), non-HDL-C (r = 0.246), remnant cholesterol (r = 0.233), and triglycerides (r = 0.233) also correlated with PCSK9. CONCLUSIONS: In premenopausal women at risk of early-stage breast cancer, PCSK9 did not appear to have a role as a prognostic biomarker of breast neoplastic events. Larger studies are warranted investigating patients in different settings.
Epicardial adipose tissue (EAT) is a fat depot located between the myocardium and the visceral layer of the epicardium, which, owing to its location, can influence surrounding tissues and can act as a local transducer of systemic inflammation. The mechanisms upon which such influence depends on are however unclear. Given the role EAT undoubtedly has in the scheme of cardiovascular diseases (CVDs), understanding the impact of its cellular components is of upmost importance. Extracellular vesicles (EVs) constitute promising candidates to fill the gap in the knowledge concerning the unexplored mechanisms through which EAT promotes onset and progression of CVDs. Owing to their ability of transporting active biomolecules, EAT-derived EVs have been reported to be actively involved in the pathogenesis of ischemia/reperfusion injury, coronary atherosclerosis, heart failure, and atrial fibrillation. Exploring the precise functions EVs exert in this context may aid in connecting the dots between EAT and CVDs.
The modern history of cholesterol-lowering drugs started in 1972 when Dr. Akira Endo identified an active compound (compactin) that inhibited cholesterol biosynthesis from the culture broth of blue-green mold (Penicillium citrinum Pen-51). Since 1987, statins have represented the milestone for the treatment of atherosclerotic cardiovascular disease. A new therapy for the treatment of hypercholesterolemia since the discovery of statins is ezetimibe, the first and only agent inhibiting intestinal cholesterol absorption. Ezetimibe was approved by the FDA in October 2002. A year later, the association between gain-of-function PCSK9 genetic mutations and hypercholesterolemia was reported, and this discovery opened a new era in lipid-lowering therapies. Monoclonal antibodies and small-interfering RNA approaches to reduce PCSK9 were developed and approved for clinical use in 2015 and 2022, respectively. Finally, the newly approved bempedoic acid, an oral adenosine triphosphate citrate lyase inhibitor that lowers LDL-C, is able to reduce major adverse cardiovascular events in both primary and secondary prevention. In the present narrative review, we summarize the pharmacological properties and the clinical efficacy of all these agents currently used for a tailored therapy of hypercholesterolemia in patients with atherosclerotic cardiovascular disease.
Background: Oxidative stress induced by the excessive production of reactive oxygen species is one of the primary mechanisms implicated in anthracycline (ANT)-induced cardiotoxicity. There is a strong clinical need for a molecule capable of effectively preventing and reducing the oxidative damage caused by ANT. In vitro and in vivo studies conducted in mice have shown that melatonin stimulates the expression of antioxidative agents and reduces lipid peroxidation induced by ANT. Methods: We investigated this issue through a meta-analysis of murine model studies. The outcome of the meta-analysis was to compare oxidative damage, estimated by products of lipid peroxidation (MDA = Malondialdehyde) and markers of oxidative stress (SOD = Superoxide Dismutase, GSH = Glutathione), along with a marker of cardiac damage (CK-MB = creatine kinase-myocardial band), assessed by measurements in heart and/or blood samples in mice undergoing ANT chemotherapy and assuming melatonin vs. controls. The PubMed, OVID-MEDLINE and Cochrane library databases were analysed to search English-language review papers published from the inception up to August 1st, 2023. Studies were identified by using Me-SH terms and crossing the following terms: "melatonin", "oxidative stress", "lipid peroxidation", "anthracycline", "cardiotoxicity". Results: The metanalysis included 153 mice administered melatonin before, during or immediately after ANT and 153 controls from 13 studies. Compared with controls, the levels of all oxidative stress markers were significantly better in the pooled melatonin group, with standardized mean differences (SMD) for MDA, GSH and SOD being -8.03 ± 1.2 (CI: -10.43/-5.64, p < 0.001), 7.95 ± 1.8 (CI: 4.41/11.5, p < 0.001) and 3.94 ± 1.6 (CI: 0.77/7.12, p = 0.015) respectively. Similarly, compared with controls, CK-MB levels reflecting myocardial damage were significantly lower in the pooled melatonin group, with an SMD of -4.90 ± 0.5 (CI: -5.82/-3.98, p < 0.001). Conclusion: Melatonin mitigates the oxidative damage induced by ANT in mouse model. High-quality human clinical studies are needed to further evaluate the use of melatonin as a preventative/treatment strategy for ANT-induced cardiotoxicity.
BACKGROUND AND AIM: Nitric oxide inhibits platelet aggregation by increasing the second messenger cyclic guanosine-3',5'-monophosphate (cGMP) through the activation of soluble guanylyl cyclase in target cells. Within this context, the oxidative stress associated with the aldosterone excess impairs the nitric oxide availability. Thus, the aim of the present study was to assess the impact of chronic aldosterone excess on the platelet nitric oxide/cGMP pathway in humans. METHODS: The levels of cGMP were evaluated in platelets of male patients, 12 with primary aldosteronism (PA) and 32 with uncomplicated essential hypertension (EH), matched for age and blood pressure (BP) values. RESULTS: PA and EH patients were 52.8 ± 3 years old and 51.6 ± 1.6 years old, respectively. Systolic and diastolic BP were 158 ± 5.0 mmHg and 105.9 ± 2.3 mmHg in PA and did not differ compared to EH patients (156.6 ± 2.4 mmHg and 104.7 ± 1.2 mmHg). Mean aldosterone levels were significantly higher in PA (25.5 ± 8.8 ng/dL) compared toEH (8.11 ± 0.73 ng/dL), whereas potassium was significantly lower in PA (3.52 ± 0.18 mEq/L) compared to EH (4.08 ± 0.04 mEq/L). Aldosterone and potassium were inversely related (r = -0.49, p = 0.0006) in the whole study population (n = 44). Platelet cGMP was significantly lower in PA (5.1 ± 0.36 pM/109 cells) than in EH (7.1 ± 0.53 pM/109 cells), and in the entire study cohort, it was directly related to plasma potassium (r = 0.43, p = 0.0321). CONCLUSIONS: These results show an impairment of nitric oxide/cGMP signaling in platelets of PA patients. This effect is likely related to the potassium-depleting effect of chronic aldosterone excess. Future studies are needed to understand whether the platelet nitric oxide/cGMP system is involved in the atherothrombotic events in these patients.
Epidemiologic, genetic, and clinical intervention studies have indisputably shown that low-density lipoprotein cholesterol (LDL-C) is causal in the development of atherosclerotic cardiovascular disease (ASCVD). However, LDL-C variability could be related to increased ASCVD risk in patients already treated with statins. The aim of the present retrospective real-life study was to assess the prognostic impact of LDL-C variability on all-cause mortality and cardiovascular hospitalizations in patients with stable cardiovascular artery disease. A total of 3398 patients were enrolled and followed up for a median of 56 months. Considering LDL-C < 70 mg/dL as the therapeutical target, during follow-up, the percentage of patients who achieved this goal raised from 20.7% to 31.9%. In total, 1988 events were recorded, of which 428 were all-cause deaths and 1560 were cardiovascular hospitalizations. At the last medical examination, each increase in LDL-C levels of 20 mg/dL corresponded to a 6% raise in the risk of any event (HR 1.06; 95%CI, 1.03 to 1.09). In conclusion, our real-world study supports the hypothesis that a continuous and progressive downward trend in LDL-C levels is needed to achieve and maintain a cardiovascular benefit, at least in secondary prevention.
BACKGROUND: Several closure devices are routinely used for percutaneous arterial access, while a relatively low number is available for the management of large bore venous accesses. The Woggle technique is a modification of the purse-string suture which was introduced several years ago in patients undergoing hemodialysis. METHODS: A population of 45 patients who underwent transvenous femoral structural heart interventions was retrospectively evaluated. The Woggle technique consists of a purge string suture with a collar to maintain the tension as stable over time and a suture lock to tighten the suture. RESULTS: Sheaths magnitude ranged from 8 French (F) to 14 F. A rapid post-procedural hemostasis was achieved in the whole population, and in 95% of cases, definite hemostasis was obtained after the first single release; the mean time of release was 302 ± 83 min. Although no relevant bleedings were reported, a significant reduction in hemoglobin levels was found in the whole population. This decrement was statistically significant only in the group with sheaths higher than 12 F. A single mild local hematoma was recorded in the group in which smaller sheaths were used. Seventy-two percent of patients were pre-treated with a dual antiplatelet therapy. CONCLUSIONS: The Woggle technique has shown to be a simple, effective, and safe approach for the management of large bore venous in percutaneous structural heart interventions.
PURPOSE OF REVIEW: It is clear from epidemiological studies that patients at high and very-high risk of atherosclerotic cardiovascular diseases (ASCVD) risk do not reach lipid guideline-recommended targets. Thus, fixed-dose combinations of statins/ezetimibe, bempedoic acid/ezetimibe and statins/fibrates may represent a further armamentarium in the field of lipid-lowering approaches in these individuals. RECENT FINDINGS: The combination therapy of moderate-intensity statin with ezetimibe is not inferior to high-intensity statin monotherapy in reducing cardiovascular outcomes. Drug discontinuation or dose reduction is inferior with fixed-dose combination. The fixed-dose combination of bempedoic acid with ezetimibe is superior to bempedoic acid in monotherapy in lowering LDL-C and in reducing high-sensitivity C-reactive protein concentrations. The combination fenofibrate with atorvastatin is superior to monotherapies in lowering triglycerides. Lipid-lowering fixed-dose combinations may guarantee a higher therapy adherence, representing a better approach to control plasma lipids and thus ameliorate ASCVD burden. Additional studies will define the advantages on cardiovascular outcomes in high and very high-risk patients.
Anticholesteremic Agents , Atherosclerosis , Dyslipidemias , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Cholesterol, LDL , Ezetimibe/therapeutic use , Dyslipidemias/drug therapy , Drug Therapy, Combination , Atherosclerosis/drug therapy , Anticholesteremic Agents/therapeutic use , Treatment Outcome
BACKGROUND: Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of morbidity and mortality, being twofold to fourfold more common in patients with type 2 diabetes mellitus (T2DM) than in individuals without diabetes. However, despite this decade-old knowledge, the identification of a specific prognostic risk biomarker remains particularly challenging. METHODS: Taking advantage of a large sample of Caucasian patients (n = 529) with a diagnosis of T2DM followed for a median of 16.8 years, the present study was aimed at testing the hypothesis that fasting serum proprotein convertase subtilisin/kexin type 9 (PCSK9) levels could be prognostic for major adverse cardiovascular events (MACE) and all-cause mortality. RESULTS: Median levels of PCSK9 were 259.8 ng/mL, being higher in women compared to men and increasing even more in the presence of a complication (e.g., diabetic kidney disease). PCSK9 positively correlated with markers of blood glucose homeostasis (e.g., HbA1c, fasting insulin and HOMA-IR) and the atherogenic lipid profile (e.g., non-HDL-C, apoB and remnant cholesterol). Serum PCSK9 predicted new-onset of MACE, either fatal or non-fatal, only in women (Odds Ratio: 2.26, 95% CI 1.12-4.58) and all-cause mortality only in men (Hazard Ratio: 1.79, 95% CI 1.13-2.82). CONCLUSIONS: Considering that up to two-thirds of individuals with T2DM develop ASCVD in their lifetime, the assessment of circulating PCSK9 levels can be envisioned within the context of a biomarker-based strategy of risk stratification. However, the sex difference found highlights an urgent need to develop sex-specific risk assessment strategies. TRIAL REGISTRATION: It is a retrospective study.
Atherosclerosis , Diabetes Mellitus, Type 2 , Humans , Female , Male , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/epidemiology , Follow-Up Studies , Proprotein Convertase 9 , Prognosis , Retrospective Studies
Frailty is a geriatric syndrome that results from multisystem impairment caused by age-associated accumulation of deficits. The frailty index is used to define the level of frailty. Several studies have searched for molecular biomarkers associated with frailty, to meet the needs for personalized care. Cyclase-associated protein 2 (CAP2) is a multifunctional actin-binding protein involved in various physiological and pathological processes, that might reflect frailty's intrinsic complexity. This study aimed to investigate the association between frailty index and circulating CAP2 concentration in 467 community-dwelling older adults (median age: 79; range: 65-92 years) from Milan, Italy. The selected robust regression model showed that circulating CAP2 concentration was not associated with chronological age, as well as sex and education. However, circulating CAP2 concentration was significantly and inversely associated with the frailty index: a 0.1-unit increase in frailty index leads to ~0.5-point mean decrease in CAP2 concentration. Furthermore, mean CAP2 concentration was significantly lower in frail participants (i.e., frailty index ≥0.25) than in non-frail participants. This study shows the association between serum CAP2 concentration and frailty status for the first time, highlighting the potential of CAP2 as a biomarker for age-associated accumulation of deficits.
Adaptor Proteins, Signal Transducing , Frailty , Membrane Proteins , Aged , Humans , Biomarkers/blood , Cross-Sectional Studies , Frail Elderly , Frailty/blood , Geriatric Assessment/methods , Independent Living , Membrane Proteins/blood , Adaptor Proteins, Signal Transducing/blood
Antecubital access for right heart catheterization (RHC) is a widespread technique, even though there is a need to clarify if there are differences and significant advantages compared to proximal vein access. To pursue this issue, we retrospectively identified patients who underwent RHC in our clinic over a 7 year period (between January 2015 and December 2022). We revised demographic, anthropometric, and procedural data, including the fluoroscopy time, the radiation exposure, and the use of guidewires. The presence of any complications was also assessed. In patients with antecubital access, the fluoroscopy time and the radiation exposure were lower compared to proximal vein access (6 vs. 3 min, mean difference of 2 min, CI 95% 1-4 min, p < 0.001 and 61 vs. 30 cGy/m2, mean difference 64 cGy/m2, CI 95% 50-77, p < 0.001). The number of patients requiring the use of at least one guidewire was lower in the group undergoing RHC through antecubital access compared to proximal vein access (55% vs. 43%, p = 0.01). The feasibility was optimal, as just 0.9% of procedures switched from antecubital to femoral access, with a negligible rate of complications. The choice of the antecubital site exhibits advantages, e.g., a shorter fluoroscopy time, a reduced radiation dose, and a lower average number of guidewires used compared to proximal vein access.
BACKGROUND: Coronary artery disease (CAD) is associated with perioperative liver transplantation (LT) mortality. In absence of a defined risk algorithm, we aimed to test whether stress echocardiography and coronary computed tomography angiography (CCTA) could detect CAD in end-stage liver disease (ESLD) patients without previous evidence of heart disease. METHODS: LT candidates ≥30 years underwent a cardiovascular (CV) assessment through stress echocardiography. CCTA was performed in patients ≥50 years with two or more CV risk factors (e.g. diabetes, CAD family history, dyslipidaemia). Coronary angiography (CAG) was scheduled when stress echocardiography and/or CCTA were positive. Sensibility, specificity, positive and negative predictive values of stress echocardiography and CCTA were assessed by numbers of coronary revascularization (true positives) and lack of acute coronary events over a mean follow-up of 3 years (true negatives). RESULTS: Stress echocardiography was performed in 273 patients, CCTA in 34 and CAG in 41. Eight patients had critical coronary lesions, and 19 not-critical lesions. Sensitivity, specificity, positive and negative predictive values were 50.0%, 90.2%, 13.3% and 98.4% for stress echocardiography and 100%, 76.7%, 36.4% and 100% for CCTA. Among 163 patients who underwent LT (57.6%), 16 died and 5 had major adverse CV events over a mean follow-up of 3 years. CONCLUSIONS: A very low prevalence of CAD in a selected population of ESLD at intermediate to high CV risk was found. A screening based on stress echocardiography and CCTA resulted in low incidence of post-LT acute coronary events in ELSD patients. CAD has no impact on mid-term survival.
Coronary Artery Disease , Liver Transplantation , Myocardial Ischemia , Humans , Coronary Artery Disease/complications , Liver Transplantation/adverse effects , Myocardial Ischemia/surgery , Coronary Angiography , Tomography, X-Ray Computed , Predictive Value of Tests
Proprotein convertase subtilisin/kexin type 9 (PCSK9), one of the key regulators of the low-density lipoprotein receptor (LDLR), can play a direct role in atheroma development. Although advances in the understandings of genetic PCSK9 polymorphisms have enabled to reveal the role of PCSK9 in the complex pathophysiology of cardiovascular diseases (CVDs), increasing lines of evidence support non-cholesterol-related processes mediated by PCSK9. Owing to major improvements in mass spectrometry-based technologies, multimarker proteomic and lipidomic panels hold the promise to identify novel lipids and proteins potentially related to PCSK9. Within this context, this narrative review aims to provide an overview of the most significant proteomics and lipidomics studies related to PCSK9 effects beyond cholesterol lowering. These approaches have enabled to unveil non-common targets of PCSK9, potentially leading to the development of novel statistical models for CVD risk prediction. Finally, in the era of precision medicine, we have reported the impact of PCSK9 on extracellular vesicles (EVs) composition, an effect that could contribute to an increased prothrombotic status in CVD patients. The possibility to modulate EVs release and cargo could help counteract the development and progression of the atherosclerotic process.
The infiltration of activated T cells, such as CD8+ effector, in metabolic tissues plays a crucial role for the initiation and propagation of obesity-induced inflammation. Given the pivotal role of lactate transporter monocarboxylate transporter 1 (MCT1) in immune cell activation, we present a protocol for the isolation and activation of CD8+ T lymphocytes selectively lacking MCT1. We describe steps for the induction of adipocyte differentiation, CD8+ T isolation and activation, and adipocyte-CD8+ T cell co-culture. We then detail qPCR analysis on differentiated adipocytes. For complete details on the use and execution of this protocol, please refer to Macchi et al.1.
The knowledge that roughly 20% of survivors from an acute coronary syndrome (ACS) event experience a subsequent ischaemic cardiovascular event within 24 months with a 5-year mortality range between 19 and 22% highlights the importance of the lipid-lowering strategies in the secondary prevention after ACS. In this framework, statin treatment significantly improves clinical outcome after ACS. Within this remit, in the present review we critically discuss the use of statin and non-statin lipid-lowering approaches (ezetimibe, evolocumab, alirocumab, inclisiran, and bempedoic acid) in the early management of ACS patients. Relative to this latter aspect, the knowledge that circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) levels are raised during ACS could be a generating hypothesis justifying the use of PCSK9 inhibitors in ACS. Thus, in a field fraught of uncertainty, the main barrier to the widespread prescription of non-statin agents (e.g. PCSK9 inhibitors) relates to their costs when compared with other lipid-lowering agents (e.g. statins and ezetimibe).
According to the WHO, the entire global population is exposed to air pollution levels higher than recommended for health preservation. Air pollution is a complex mixture of nano- to micro-sized particles and gaseous components that poses a major global threat to public health. Among the most important air pollutants, causal associations have been established between particulate matter (PM), mainly < 2.5 µm, and cardiovascular diseases (CVD), i.e., hypertension, coronary artery disease, ischemic stroke, congestive heart failure, arrhythmias as well as total cardiovascular mortality. Aim of this narrative review is to describe and critically discuss the proatherogenic effects of PM2.5 that have been attributed to many direct or indirect effects comprising endothelial dysfunction, a chronic low-grade inflammatory state, increased production of reactive oxygen species, mitochondrial dysfunction and activation of metalloproteases, all leading to unstable arterial plaques. Higher concentrations of air pollutants are associated with the presence of vulnerable plaques and plaque ruptures witnessing coronary artery instability. Air pollution is often disregarded as a CVD risk factor, in spite of the fact that it is one of the main modifiable factors relevant for prevention and management of CVD. Thus, not only structural actions should be taken in order to mitigate emissions, but health professionals should also take care to counsel patients on the risks of air pollution.
Air Pollutants , Air Pollution , Atherosclerosis , Cardiovascular Diseases , Humans , Particulate Matter/adverse effects , Environmental Exposure/adverse effects , Air Pollutants/adverse effects , Air Pollutants/analysis , Air Pollution/adverse effects , Atherosclerosis/etiology , Atherosclerosis/chemically induced , Cardiovascular Diseases/etiology , Cardiovascular Diseases/chemically induced
Introduction: Inflammatory bowel diseases (IBD) are chronic inflammatory conditions that typically involve diarrhea, abdominal pain, fatigue, and weight loss, with a dramatic impact on patients' quality of life. Standard medications are often associated with adverse side effects. Thus, alternative treatments such as probiotics are of great interest. The purpose of the present study was to evaluate the effects of oral administration of Lentilactobacillus kefiri (basonym: Lactobacillus kefiri) SGL 13 and Andrographis paniculata, namely, Paniculin 13™, on dextran sodium sulfate (DSS)- treated C57BL/6J mice. Methods: Colitis was induced by administering 1.5% DSS in drinking water for 9 days. Forty male mice were divided into four groups, receiving PBS (control), 1.5% DSS, Paniculin 13™ and 1.5% DSS + Paniculin 13™. Results: The results showed that body weight loss and Disease Activity Index (DAI) score were improved by Paniculin 13™. Moreover, Paniculin 13™ ameliorated DSS-induced dysbiosis, by modulating the gut microbiota composition. The gene expression of MPO, TNFα and iNOS in colon tissue was reduced and these data matched with the histological results, supporting the efficacy of Paniculin 13™ in reducing the inflammatory response. No adverse effects were associated to Paniculin 13™ administration. Discussion: In conclusion, Paniculin 13™ could be an effective add-on approach to conventional therapies for IBD.
Non-Alcoholic Fatty Liver Disease (NAFLD) is a common condition affecting around 10-25% of the general adult population, 15% of children, and even > 50% of individuals who have type 2 diabetes mellitus. It is a major cause of liver-related morbidity, and cardiovascular (CV) mortality is a common cause of death. In addition to being the initial step of irreversible alterations of the liver parenchyma causing cirrhosis, about 1/6 of those who develop NASH are at risk also developing CV disease (CVD). More recently the acronym MAFLD (Metabolic Associated Fatty Liver Disease) has been preferred by many European and US specialists, providing a clearer message on the metabolic etiology of the disease. The suggestions for the management of NAFLD are like those recommended by guidelines for CVD prevention. In this context, the general approach is to prescribe physical activity and dietary changes the effect weight loss. Lifestyle change in the NAFLD patient has been supplemented in some by the use of nutraceuticals, but the evidence based for these remains uncertain. The aim of this Position Paper was to summarize the clinical evidence relating to the effect of nutraceuticals on NAFLD-related parameters. Our reading of the data is that whilst many nutraceuticals have been studied in relation to NAFLD, none have sufficient evidence to recommend their routine use; robust trials are required to appropriately address efficacy and safety.
Cardiovascular Diseases , Diabetes Mellitus, Type 2 , Non-alcoholic Fatty Liver Disease , Adult , Child , Humans , Non-alcoholic Fatty Liver Disease/drug therapy , Diabetes Mellitus, Type 2/complications , Dietary Supplements , Liver Cirrhosis/complications , Cardiovascular Diseases/prevention & control , Lipids/therapeutic use
Treatment with statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, has proven beneficial preventive effects on cardiovascular events. However, discontinuation due to intolerance and non-adherence remain two of the major gaps in both primary and secondary prevention. This leads many patients with high-risk of atherosclerotic cardiovascular disease (ASCVD) to be inadequately treated or not to achieve target lipid level goals, and as consequence they undergo an increased risk of cardiovascular events. The aim of this review is thus to give an overview of the reasons for discontinuation and on the possible mechanisms behind them. Although statins, as a class, are generally safe, they are associated with an increased risk of diabetes mellitus and hepatic transaminase elevations. Incidence of cataracts or cognitive dysfunction and others presented in the literature (e.g. proteinuria and haematuria) have been never confirmed to have a causal link. Conversely, debated remains the effect on myalgia. Muscle side effects are the most commonly reported, although myalgia is still believed by some to be the result of a nocebo/drucebo effect. Concerning mechanisms behind muscular side effects, no clear conclusions have been reached. Thus, if on one side it is important to identify individuals either at higher risk to develop a side effect, or with confirmed risk factors and conditions of statin intolerance, on the other side alternative strategies should be identified to avoid an increased ASCVD risk.
Cardiovascular Diseases , Diabetes Mellitus , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Myalgia/chemically induced , Myalgia/drug therapy , Risk Factors , Diabetes Mellitus/drug therapy , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/prevention & control
Pathophysiological, epidemiological and genetic studies convincingly showed lipoprotein(a) (Lp(a)) to be a causal mediator of atherosclerotic cardiovascular disease (ASCVD). This happens through a myriad of mechanisms including activation of innate immune cells, endothelial cells as well as platelets. Although these certainties whether or not Lp(a) is ready for prime-time clinical use remain debated. Thus, remit of the present review is to provide an overview of different methods that have been employed for the measurement of Lp(a). The methods include dynamic light scattering, multi-angle light scattering analysis, near-field imaging, sedimentation, gel filtration, and electron microscopy. The development of multiple Lp(a) detection methods is vital for improved prediction of ASCVD risk.
