Koristi zdravljenja s statini odtehtajo njihove stranske učinke

Zdravila iz skupine statinov so v zadnjih več kot 20 letih ena najpogosteje predpisovanih zdravil. Poleg znižanja koncentracije holesterola LDL namreč zelo pomembno znižajo srčnožilno obolevnost in umrljivost. Statini kompetitivno zavirajo aktivno mesto reduktaze HMG-CoA prvega in ključnega hitrost omejujočega encima v mevalonatni poti. Ta mehanizem je poleg zmanjšanja vrednosti holesterola LDL najverjetneje odgovoren tudi za večino stranskih učinkov, čeprav za to ni zanesljivih dokazov. Najpogostejši stranski učinki, ki so tudi vzrok za prekinitev zdravljenja, so povezani z mišičnimi bolečinami, čeprav natančne razširjenosti ne poznamo, saj ni enotne definicije teh stranskih učinkov. Drugi stranski učinki so še novo nastala sladkorna bolezen tipa 2, hepatotoksičnost, hemoragična možganska kap in nevrološke motnje. Vsem tem stranskim učinkom navkljub je korist zdravljenja s statini mnogo večja od navedenih stranskih učinkov. Kljub novim terapijam za znižanje holesterola LDL in zato zmanjšani srčnožilni umrljivosti bo terapija s statini še naslednjih nekaj let ostala prva izbira tako pri primarni kot tudi sekundarni preventivi, saj še ni dovolj podatkov o dolgoročni učinkovitosti in predvsem varnosti novih zdravil. Nikakor pa ne smemo zanemariti niti ekonomskega vidika, saj je stroškovna učinkovitost statinov v primerjavi z novimi zdravili zaenkrat še mnogo večja

Dolgoročni rezultati po anatomski korekciji D-transpozicije velikih arterij – izkušnja enega centra

Izhodišča: Anatomska korekcija (ASO) je zdravljenje izbire za D-transpozicijo velikih arterij (D-TGA). Namen raziskave je bil oceniti dolgoročno uspešnost anatomske kirurške korekcije. Metode: Delno retrospektivno smo pregledali dokumentacijo ali ponovno ocenili zdravstveno stanje 38 bolnikov (30 moških, 8 žensk) v času tranzicije mladostnikov v odraslo dobo (starost ob zadnjem kliničnem pregledu 17,1 ± 1,4 let), ki so bili rojeni od leta 2000 do leta 2005 z D-TGA in so imeli ASO. Ocenili smo: funkcijski razred po NYHA, spremembe, ki so ostale, na neoaorti in neoaortni zaklopki, neopulmonalni zaklopki in pljučnih arterijah, funkcijo desnega in levega prekata, telesno zmogljivost in znake ishemije miokarda. Rezultati: Nihče v skupini ni umrl (interval zaupanja (0,00-0,09). 32 bolnikov (84,2 %) je bilo v NYHA I, 6 bolnikov (15,7 %) je bilo v NYHA II. Pri 83,3 % bolnikov se je bulbus aorte razširil (20,9 ± 2,8 mm/m2, max. 27,7 mm/m2). Pri 27 bolnikih (90 %) je bila prisotna regurgitacija neoaortne zaklopke. Med skupinami brez, z blago ali zmerno neoaortno regurgitacijo ni bilo razlik v širini bulbusa, normaliziranih na telesno površino (p = 0,6). Regurgitacija neopulmonalne zaklopke je bila prisotna pri 58,1 % bolnikov. Zaradi obstrukcije v iztoku iz desnega prekata je bila potrebna ponovna operacija v enem primeru in perkutana dilatacija neopulmonalne zaklopke v enem primeru. Zaradi zapletov na koronarnih arterijah je bil potreben le en kirurški poseg zaradi miokardnega infarkta med naporom. Zaključek: Pozni rezultati po anatomski korekciji D-TGA so dobri in primerljivi z večjimi centri. Nihče ni umrl, večina bolnikov je bila brez simptomov, z normalno sistolično funkcijo obeh prekatov in z normalno telesno zmogljivostjo. Ponovne operacije in perkutani posegi so bili dokaj redki, toda dolgoročno uspešni

PCSK9 as an Atherothrombotic Risk Factor

Disturbances in lipid metabolism are among the most important risk factors for atherosclerotic cardiovascular disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key protein in lipid metabolism that is also involved in the production of inflammatory cytokines, endothelial dysfunction and aherosclerotic plaque development. Studies have shown a connection between PCSK9 and various indicators of inflammation. Signalling pathways that include PCSK9 play important role in the initiation and development of atherosclerotic lesions by inducing vascular inflammation. Studies so far have suggested that PCSK9 is associated with procoagulation, enhancing the development of atherosclerosis. Experimentally, it was also found that an increased concentration of PCSK9 significantly accelerated the apoptosis of endothelial cells and reduced endothelial function, which created conditions for the development of atherosclerosis. PCSK9 inhibitors can therefore improve clinical outcomes not only in a lipid-dependent manner, but also through lipid-independent pathways. The aim of our review was to shed light on the impact of PCSK9 on these factors, which are not directly related to low-density lipoprotein (LDL) cholesterol metabolism

PCSK9 as an Atherothrombotic Risk Factor

Disturbances in lipid metabolism are among the most important risk factors for atherosclerotic cardiovascular disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key protein in lipid metabolism that is also involved in the production of inflammatory cytokines, endothelial dysfunction and aherosclerotic plaque development. Studies have shown a connection between PCSK9 and various indicators of inflammation. Signalling pathways that include PCSK9 play important role in the initiation and development of atherosclerotic lesions by inducing vascular inflammation. Studies so far have suggested that PCSK9 is associated with procoagulation, enhancing the development of atherosclerosis. Experimentally, it was also found that an increased concentration of PCSK9 significantly accelerated the apoptosis of endothelial cells and reduced endothelial function, which created conditions for the development of atherosclerosis. PCSK9 inhibitors can therefore improve clinical outcomes not only in a lipid-dependent manner, but also through lipid-independent pathways. The aim of our review was to shed light on the impact of PCSK9 on these factors, which are not directly related to low-density lipoprotein (LDL) cholesterol metabolism

Lipoprotein(a)—the crossroads of atherosclerosis, atherothrombosis and inflammation

Increased lipoprotein(a) (Lp(a)) levels are an independent predictor of coronary artery disease (CAD), degenerative aortic stenosis (DAS), and heart failure independent of CAD and DAS. Lp(a) levels are genetically determinated in an autosomal dominant mode, with great intra- and inter-ethnic diversity. Most variations in Lp(a) levels arise from genetic variations of the gene that encodes the apolipoprotein(a) component of Lp(a), the LPA gene. LPA is located on the long arm of chromosome 6, within region 6q2.6–2.7. Lp(a) levels increase cardiovascular risk through several unrelated mechanisms. Lp(a) quantitatively carries all of the atherogenic risk of low-density lipoprotein cholesterol, although it is even more prone to oxidation and penetration through endothelia to promote the production of foam cells. The thrombogenic properties of Lp(a) result from the homology between apolipoprotein(a) and plasminogen, which compete for the same binding sites on endothelial cells to inhibit fibrinolysis and promote intravascular thrombosis. LPA has up to 70% homology with the human plasminogen gene. Oxidized phospholipids promote differentiation of pro-inflammatory macrophages that secrete pro-inflammatory cytokines (e. g., interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor-α). The aim of this review is to define which of these mechanisms of Lp(a) is predominant in different groups of patients

Predictors of functional and morphological arterial wall properties in coronary artery disease patients with increased lipoprotein (a) levels before and after treatment with proprotein convertase subtilisin-kexin type 9 inhibitors

Abstract Background In addition to proatherogenic properties, lipoprotein (a) (Lp(a)) has also pro-inflammatory, antifibrinolytic and prothrombogenic features. The aim of the current study was to identify the predictors of functional and morphological properties of the arterial wall in patients after myocardial infarction and increased Lp(a) levels at the beginning and after treatment with proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors. Methods Seventy-six post-myocardial infarction patients with high Lp(a) levels were included in the study. Ultrasound measurements of flow-mediated dilation of brachial artery (FMD), carotid intima-media thickness (c-IMT) and pulse wave velocity (PWV) were performed initially and after 6 months of treatment. At the same time points lipids, Lp(a), inflammatory and hemostasis markers were measured in blood samples. Results In linear regression model FMD significantly correlated with age at first myocardial infarction (β = 0.689; p = 0.022), high-sensitivity C-reactive protein (β = -1.200; p = 0.009), vascular cell adhesion protein 1 (VCAM-1) (β = -0.992; p = 0.006), overall coagulation potential (β = 1.428; p = 0.014) and overall hemostasis potential (β = -1.473; p = 0.008). c-IMT significantly correlated with age at first myocardial infarction (β = 0.574; p = 0.033) and Lp(a) (β = 0.524; p = 0.040). PWV significantly correlated with systolic blood pressure (β = 0.332; p = 0.002), tumor necrosis factor alpha (β = 0.406; p = 0.002), interleukin-8 (β = -0.315; p = 0.015) and plasminogen activator inhibitor 1 (β = 0.229; p = 0.031). After treatment FMD reached statistical significance only in univariant analysis with systolic blood pressure (r = -0.286; p = 0.004) and VCAM-1 (r = -0.229; p = 0.024). PWV and c-IMT correlated with age (r = 0.334; p = 0.001 and r = 0.486; p < 0.0001, respectively) and systolic blood pressure (r = 0.556; p < 0.0001 and r = 0.233; p = 0.021, respectively). Conclusions Our results suggest that age, systolic blood pressure, Lp(a) levels and other biochemical markers associated with Lp(a) are predictors of functional and morphological properties of the arterial vessel wall in post-myocardial patients with high Lp(a) levels initially. However, after 6 months of treatment with PCSK9 inhibitors only age and systolic blood pressure seem to be predictors of these properties. Trial registration The protocol for this study was registered with clinicaltrials.gov on November, 3 2020 under registration number NCT04613167. Graphical Abstrac

Atherosclerotic Cardiovascular Disease: Risk Assessment, Prevention and Treatment Strategies

Despite enormous advances in both surgical and pharmacological treatment, cardiovascular diseases are still the most common cause of morbidity and disability in the western world [...

LPA genotypes and haplotypes are associated with lipoprotein(a) levels but not arterial wall properties in stable post-coronary event patients with very high lipoprotein(a) levels

Lipoprotein(a) [Lp(a)] levels are an independent risk factor for coronary artery disease (CAD). Two single-nucleotide polymorphisms (rs10455872, rs3798220) and number of KIV-2 repeats in the gene encoding Lp(a) (LPA) are associated with Lp(a) and CAD. Our aim was to investigate whether in patients with stable CAD and high Lp(a) levels these genetic variants are associated with increased Lp(a) and arterial wall properties. Blood samples underwent biochemical and genetic analyses. Ultrasound measurements for the functional and morphological properties of arterial wall were performed. Genotypes of rs10455872 and haplotypes AT and GT showed significant association with Lp(a) levels. Patients with GG showed significantly higher Lp(a) levels compared with those with AG genotype (2180 vs. 1391 mg/L, p = 0.045). Patients with no AT haplotype had significantly higher Lp(a) compared to carriers of one AT haplotype (2158 vs. 1478 mg/L, p = 0.023) or two AT haplotypes (2158 vs. 1487 mg/L, p = 0.044). There were no significant associations with the properties of the arterial wall. Lp(a) levels significantly correlated also with number of KIV-2 repeats (r = −0.601p < 0.0001). In our patients, these two LPA polymorphisms and number of KIV-2 repeats are associated with Lp(a), but not arterial wall properties

The Influence of Treatment with PCSK9 Inhibitors and Variants in the CRP (rs1800947), TNFA (rs1800629), and IL6 (rs1800795) Genes on the Corresponding Inflammatory Markers in Patients with Very High Lipoprotein(a) Levels

Chronic inflammation contributes significantly to the development and progression of atherosclerosis. However, the factors that lead to an inflammatory imbalance towards a proinflammatory state are not yet fully understood. The CRP rs1800947, TNFA rs1800629, and IL6 rs1800795 polymorphisms may play a role in the pathogenesis of atherosclerosis and were therefore selected to investigate the influence of genetic variability on the corresponding plasma levels after treatment with a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. A group of 69 patients with stable coronary artery disease after myocardial infarction before the age of 50 years and very high lipoprotein(a) levels were enrolled in the study. All patients received a PCSK9 inhibitor (evolocumab or alirocumab). Genotyping was performed using TaqMan assays (CRP rs1800947, TNFA rs1800629, and IL6 rs1800795). Consistent with previous studies, no significant change in levels of inflammatory biomarkers was observed after 6 months of treatment with PCSK9 inhibitors. We also did not detect any significant association between single nucleotide polymorphisms CRP rs1800947, TNFA rs1800629, and IL6 rs1800795 and plasma levels of high-sensitivity C-reactive protein (hsCRP), tumor necrosis factor-&alpha; (TNF-&alpha;), or interleukin 6 (IL6), respectively, at enrollment. However, the difference in IL6 levels after treatment with PCSK9 inhibitors was statistically significant (p = 0.050) in patients with IL6-74CC genotype, indicating the possible role of the IL6 rs1800795 polymorphism in modulating inflammation