Clinical approach to the inflammatory etiology of cardiovascular diseases

Inflammation is an obligatory marker of arterial disease, both stemming from the inflammatory activity of cholesterol itself and from well-established molecular mechanisms. Raised progenitor cell recruitment after major events and clonal hematopoiesis related mechanisms have provided an improved understanding of factors regulating inflammatory phenomena. Trials with inflammation antagonists have led to an extensive evaluation of biomarkers such as the high sensitivity C reactive protein (hsCRP), not exerting a causative role, but frequently indicative of the individual cardiovascular (CV) risk. Aim of this review is to provide indication on the anti-inflammatory profile of agents of general use in CV prevention, i.e. affecting lipids, blood pressure, diabetes as well nutraceuticals such as n-3 fatty acids. A crucial issue in the evaluation of the benefit of the anti-inflammatory activity is the frequent discordance between a beneficial activity on a major risk factor and associated changes of hsCRP, as in the case of statins vs PCSK9 antagonists. In hypertension, angiotensin converting enzyme inhibitors exert an optimal anti-inflammatory activity, vs the case of sartans. The remarkable preventive activity of SLGT-2 inhibitors in heart failure is not associated with a clear anti-inflammatory mechanism. Finally, icosapent ethyl has been shown to reduce the CV risk in hypertriglyceridemia, with a 27 % reduction of hsCRP. The inflammation-based approach to arterial disease has considerably gained from an improved understanding of the clinical diagnostic strategy and from a better knowledge on the mode of action of numerous agents, including nutraceuticals

Pharmacological aspects of ANGPTL3 and ANGPTL4 inhibitors: new therapeutic approaches for the treatment of atherogenic dyslipidemia

Among the determinants of atherosclerotic cardiovascular disease (ASCVD), genetic and experimental evidence has provided data on a major role of angiopoietin-like proteins 3 and 4 (ANGPTL3 and ANGPTL4) in regulating the activity of lipoprotein lipase (LPL), antagonizing the hydrolysis of triglycerides (TG). Indeed, beyond low-density lipoprotein cholesterol (LDL-C), ASCVD risk is also dependent on a cluster of metabolic abnormalities characterized by elevated fasting and post-prandial levels of TG-rich lipoproteins and their remnants. In a head-to-head comparison between murine models for ANGPTL3 and ANGPTL4, the former was found to be a better pharmacological target for the treatment of hypertriglyceridemia. In humans, loss-of-function mutations of ANGPTL3 are associated with a marked reduction of plasma levels of VLDL, low-density lipoprotein (LDL) and high-density lipoprotein (HDL). Carriers of loss-of-function mutations of ANGPTL4 show instead lower TG-rich lipoproteins and a modest but significant increase of HDL. The relevance of ANGPTL3 and ANGPTL4 as new therapeutic targets is proven by the development of monoclonal antibodies or antisense oligonucleotides. Studies in animal models, including non-human primates, have demonstrated that short-term treatment with monoclonal antibodies against ANGPTL3 and ANGPTL4 induces activation of LPL and a marked reduction of plasma TG-rich-lipoproteins, apparently without any major side effects. Inhibition of both targets also partially reduces LDL-C, independent of the LDL receptor. Similar evidence has been observed with the antisense oligonucleotide ANGPTL3-LRX. The genetic studies have paved the way for the development of new ANGPTL3 and 4 antagonists for the treatment of atherogenic dyslipidemias. Conclusive data of phase 2 and 3 clinical trials are still needed in order to define their safety and efficacy profile

Cardiovascular risk changes after lipid lowering medications: are they predictable?

Abstract Changes in cardiovascular risk after lipid lowering medications are generally expressed as relative risk reduction (RRR). Comparison of the eight major studies published in this last decade indicates that the RRRs ranged from a minimum (19%) for the LRC Study with cholestyramine, to maximal values of 34 -37% for studies such as the HHS, 4S and AFCAPS/TexCAPS. These RRRs were barely related to the drugs' effects on major lipid parameters, e.g. LDL cholesterol. Instead, by using the absolute risk reduction (ARRs), easily calculated by subtracting the percentage end points for the drug treated from these values of the placebo group in all studies, a wide range of values was found, also adding to the series a non pharmacological study such as the Program on the Surgical Control of the Hyperlipidemias (POSCH) trial. Calculated ARRs were directly correlated to the baseline cardiovascular (CV) risk in all studies, thus allowing an easy prediction of a drug's effect in the selected population. Drugs with different mechanisms (statins, fibrates and resins) all fitted into this correlation nomogram. These findings clearly indicate that the CV effects of lipid changes, such as LDL cholesterol and triglyceride reduction or HDL rises, are in the same direction, and can be well predicted. The similar, almost identical behavior of drugs affecting LDL cholesterolemia to a different degree or not at all, indicates that novel approaches should be sought to improve risk reduction and that individual therapy should be ideally pursued, rather than a 'one drug' approach

Limited proteolysis of a disulfide-linked apoA-I dimer in reconstituted HDL.

The apolipoprotein A-I Milano (apoA-I M ) is a mo- lecular variant of apoA-I characterized by the Arg 173 → Cys substitution, leading to the formation of homodimers A-I M / A-I M. Upon interaction with palmitoyloleoylphosphatidyl- choline, A-I M /A-I M forms only two species of reconstituted HDL (rHDL) particles, with diameters of 7.8 and 12.5 nm. We used limited proteolysis to analyze the conformation of A-I M /A-I M in the two rHDL particles, in comparison with that of apoA-I in rHDL of similar size. ApoA-I in the small, 7.8-nm rHDL is degraded to a greater extent (50% after 6 h) than in the large rHDL ( � 10% degraded after 6 h). The pro- tease susceptibility of A-I M /A-I M in small and large rHDL is instead remarkably the same, with A-I M /A-I M being much more sensitive to proteolytic digestion (50% degraded after 10 min) than apoA-I. The identification of the proteolytic fragments by immunoblotting, N-terminal sequencing, and molecular mass determination, shows that the N-terminus of both proteins is resistant to proteolysis, with six cleavage sites located in the central and carboxy-terminal portions of the molecules. Cleavage in the middle of apoA-I occurs at dis- tinct sites in 7.8-nm (Lys 118 ) and 12.7-nm (Arg 123 ) rHDL, in- dicating a different conformation in small and large rHDL particles. The A-I M /A-I M instead adopts a unique and identi- cal conformation in small and large rHDL, with the carboxy- terminal portion of the molecule being remarkably more ac- cessible to the proteases than in apoA-I. This suggests the presence of a novel carboxy-terminal domain in A-I M /A-I M , not organized in a compact structure and not shared by wild-type apoA-I, which may account for the unique functional proper- ties of A-I M /A-I M. —Calabresi, L., G. Tedeschi, C. Treu, S. Ron- chi, D. Galbiati, S. Airoldi, C. R. Sirtori, Y. Marcel, and G. Franceschini. Limited proteolysis of a disulfide-linked apoA-I dimer in reconstituted HDL. J. Lipid Res. 2001. 42: 935-942

Nutraceutical approach for the management of cardiovascular risk \u2013 a combination containing the probiotic Bifidobacterium longum BB536 and red yeast rice extract: results from a randomized, double-blind, placebo-controlled study

BACKGROUND: Probiotics incorporated into dairy products have been shown to reduce total (TC) and LDL cholesterolemia (LDL-C) in subjects with moderate hypercholesterolemia. More specifically, probiotics with high biliary salt hydrolase activity, e.g. Bifidobacterium longum BB536, may decrease TC and LDL-C by lowering intestinal cholesterol reabsorption and, combined with other nutraceuticals, may be useful to manage hypercholesterolemia in subjects with low cardiovascular (CV) risk. This study was conducted to evaluate the efficacy and safety of a nutraceutical combination containing Bifidobacterium longum BB536, red yeast rice (RYR) extract (10\u2009mg/day monacolin K), niacin, coenzyme Q10 (Lactoflorene Colesterolo\uae). The end-points were changes of lipid CV risk markers (LDL-C, TC, non-HDL-cholesterol (HDL-C), triglycerides (TG), apolipoprotein B (ApoB), HDL-C, apolipoprotein AI (ApoAI), lipoprotein(a) (Lp(a), proprotein convertase subtilisin/kexin type 9 (PCSK9)), and of markers of cholesterol synthesis/absorption. METHODS: A 12-week randomized, parallel, double-blind, placebo-controlled study. Thirty-three subjects (18-70\u2009years) in primary CV prevention and low CV risk (SCORE: 0-1% in 24 and 2-4% in 9 subjects; LDL-C: 130-200\u2009mg/dL) were randomly allocated to either nutraceutical (N\u2009=\u200916) or placebo (N\u2009=\u200917). RESULTS: Twelve-week treatment with the nutraceutical combination, compared to placebo, significantly reduced TC (-\u200916.7%), LDL-C (-\u200925.7%), non-HDL-C (-\u200924%) (all p\u2009<\u20090.0001), apoB (-\u200917%, p\u2009=\u20090.003). TG, HDL-C, apoAI, Lp(a), PCSK9 were unchanged. Lathosterol:TC ratio was significantly reduced by the nutraceutical combination, while campesterol:TC ratio and sitosterol:TC ratio did not change, suggesting reduction of synthesis without increased absorption of cholesterol. No adverse effects and a 97% compliance were observed. CONCLUSIONS: A 12-week treatment with a nutraceutical combination containing the probiotic Bifidobacterium longum BB536 and RYR extract significantly improved the atherogenic lipid profile and was well tolerated by low CV risk subjects. TRIAL REGISTRATION: NCT02689934

Dose-Related Effects of Repeated ETC-216 (Recombinant Apolipoprotein A-IMilano/1-Palmitoyl-2-Oleoyl Phosphatidylcholine Complexes) Administrations on Rabbit Lipid-Rich Soft Plaques In Vivo Assessment by Intravascular Ultrasound and Magnetic Resonance Imaging

ObjectivesThis study sought to evaluate in vivo the minimal dose of apolipoprotein (apo) A-IMilano phospholipid complex (recombinant apoA-IMilano and 1-palmitoyl-2-oleoyl phosphatidylcholine complexes [ETC-216]) able to induce atherosclerosis regression in a rabbit model of lipid-rich plaques.BackgroundA single high dose of recombinant apoA-IMilano has promoted atherosclerosis regression in animal models. More recently, regression of atherosclerosis was achieved in coronary patients by repeated infusions of ETC-216.MethodsThirty-six rabbits underwent perivascular injury at both carotid arteries, followed by a 1.5% cholesterol diet. After 90 days, rabbits were randomly divided into 6 groups and treated 5 times with vehicle or ETC-216 at 5, 10, 20, 40, or 150 mg/kg dose every 4 days. Carotid plaque changes were evaluated in vivo by intravascular ultrasound (IVUS) and magnetic resonance imaging (MRI), performed before and at the end of treatments. Magnetic resonance imaging scans were also recorded after administration of the second dose for rabbits infused with vehicle 40 or 150 mg/kg.ResultsAtheroma volume in vehicle-treated rabbits increased dramatically between the first and the second IVUS analyses (+26.53%), whereas in ETC-216–treated animals, a reduced progression at the lower doses and a significant regression at the higher doses, up to −6.83%, was detected. Results obtained by MRI analysis correlated significantly with those at IVUS (r = 0.706; p < 0.0001). The MRI evaluations after the second infusion established that a significant regression was achieved with only 2 administrations of the highest dose.ConclusionsThese results confirm the efficacy of ETC-216 for atherosclerosis treatment and provide guidance for dose selection and frequency to obtain a significant reduction of plaque volume

Impact of nutraceuticals on markers of systemic inflammation: Potential relevance to cardiovascular diseases – A position paper from the International Lipid Expert Panel (ILEP)

Inflammation is a marker of arterial disease stemming from cholesterol-dependent to -independent molecular mechanisms. In recent years, the role of inflammation in atherogenesis has been underpinned by pharmacological approaches targeting systemic inflammation that have led to a significant reduction in cardiovascular disease (CVD) risk. Although the use of nutraceuticals to prevent CVD has largely focused on lipid-lowering (e.g, red-yeast rice and omega-3 fatty acids), there is growing interest and need, especially now in the time of coronavirus pandemic, in the use of nutraceuticals to reduce inflammatory markers, and potentially the inflammatory CVD burden, however, there is still not enough evidence to confirm this. Indeed, diet is an important lifestyle determinant of health and can influence both systemic and vascular inflammation, to varying extents, according to the individual nutraceutical constituents. Thus, the aim of this Position Paper is to provide the first attempt at recommendations on the use of nutraceuticals with effective anti-inflammatory properties

Automatic identification of variables in epidemiological datasets using logic regression

textabstractBackground: For an individual participant data (IPD) meta-analysis, multiple datasets must be transformed in a consistent format, e.g. using uniform variable names. When large numbers of datasets have to be processed, this can be a time-consuming and error-prone task. Automated or semi-automated identification of variables can help to reduce the workload and improve the data quality. For semi-automation high sensitivity in the recognition of matching variables is particularly important, because it allows creating software which for a target variable presents a choice of source variables, from which a user can choose the matching one, with only low risk of having missed a correct source variable. Methods: For each variable in a set of target variables, a number of simple rules were manually created. With logic regression, an optimal Boolean combination of these rules was searched for every target variable, using a random subset of a large database of epidemiological and clinical cohort data (construction subset). In a second subset of this database (validation subset), this optimal combination rules were validated. Results: In the construction sample, 41 target variables were allocated on average with a positive predictive value (PPV) of 34%, and a negative predictive value (NPV) of 95%. In the validation sample, PPV was 33%, whereas NPV remained at 94%. In the construction sample, PPV was 50% or less in 63% of all variables, in the validation sample in 71% of all variables. Conclusions: We demonstrated that the application of logic regression in a complex data management task in large epidemiological IPD meta-analyses is feasible. However, the performance of the algorithm is poor, which may require backup strategies

Predictive value for cardiovascular events of common carotid intima media thickness and its rate of change in individuals at high cardiovascular risk - Results from the PROG-IMT collaboration.

AIMS: Carotid intima media thickness (CIMT) predicts cardiovascular (CVD) events, but the predictive value of CIMT change is debated. We assessed the relation between CIMT change and events in individuals at high cardiovascular risk. METHODS AND RESULTS: From 31 cohorts with two CIMT scans (total n = 89070) on average 3.6 years apart and clinical follow-up, subcohorts were drawn: (A) individuals with at least 3 cardiovascular risk factors without previous CVD events, (B) individuals with carotid plaques without previous CVD events, and (C) individuals with previous CVD events. Cox regression models were fit to estimate the hazard ratio (HR) of the combined endpoint (myocardial infarction, stroke or vascular death) per standard deviation (SD) of CIMT change, adjusted for CVD risk factors. These HRs were pooled across studies. In groups A, B and C we observed 3483, 2845 and 1165 endpoint events, respectively. Average common CIMT was 0.79mm (SD 0.16mm), and annual common CIMT change was 0.01mm (SD 0.07mm), both in group A. The pooled HR per SD of annual common CIMT change (0.02 to 0.43mm) was 0.99 (95% confidence interval: 0.95-1.02) in group A, 0.98 (0.93-1.04) in group B, and 0.95 (0.89-1.04) in group C. The HR per SD of common CIMT (average of the first and the second CIMT scan, 0.09 to 0.75mm) was 1.15 (1.07-1.23) in group A, 1.13 (1.05-1.22) in group B, and 1.12 (1.05-1.20) in group C. CONCLUSIONS: We confirm that common CIMT is associated with future CVD events in individuals at high risk. CIMT change does not relate to future event risk in high-risk individuals