Browsing by Subject "Atherosclerosis"

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  • Theelen, Thomas L.; Lappalainen, Jari P.; Sluimer, Judith C.; Gurzeler, Erika; Cleutjens, Jack P.; Gijbels, Marion J.; Biessen, Erik A. L.; Daemen, Mat J. A. P.; Alitalo, Kari; Yla-Herttuala, Seppo (2015)
    Objective: Angiopoietin-2 (Ang-2) blocking agents are currently undergoing clinical trials for use in cancer treatment. Ang-2 has also been associated with rupture-prone atherosclerotic plaques in humans, suggesting a role for Ang-2 in plaque stability. Despite the availability of Ang-2 blocking agents, their clinical use is still lacking. Our aim was to establish if Ang-2 has a role in atheroma development and in the transition of subclinical to clinically relevant atherosclerosis. We investigated the effect of antibody-mediated Ang-2 blockage on atherogenesis after in a mouse model of atherosclerosis. Methods: Hypercholesterolemic (low-density lipoprotein receptor(-/-) apolipoprotein B-100/100) mice were subjected to high-cholesterol diet for eight weeks, one group with and one group without Ang-2 blocking antibody treatment during weeks 4-8. To enhance plaque development, a peri-adventitial collar was placed around the carotid arteries at the start of antibody treatment. Aortic root, carotid arteries and brachiocephalic arteries were analyzed to evaluate the effect of Ang-2 blockage on atherosclerotic plaque size and stable plaque characteristics. Results: Anti-Ang-2 treatment reduced the size of fatty streaks in the brachiocephalic artery (-72%, p <0.05). In addition, antibody-mediated Ang-2 blockage reduced plasma triglycerides (-27%, p <0.05). In contrast, Ang-2 blockage did not have any effect on the size or composition (collagen content, macrophage percentage, adventitial microvessel density) of pre-existing plaques in the aortic root or collar-induced plaques in the carotid artery. Conclusions: Ang-2 blockage was beneficial as it decreased fatty streak formation and plasma triglyceride levels, but had no adverse effect on pre-existing atherosclerosis in hypercholesterolemic mice. (C) 2015 The Authors. Published by Elsevier Ireland Ltd.
  • Koskinen, Juhani S.; Kytö, Ville; Juonala, Markus; Viikari, Jorma S. A.; Nevalainen, Jaakko; Kähönen, Mika; Lehtimäki, Terho; Hutri-Kähönen, Nina; Laitinen, Tomi; Tossavainen, Päivi; Jokinen, Eero; Magnussen, Costan G.; Raitakari, Olli T. (2020)
    Background and aims: Carotid plaque is a specific sign of atherosclerosis and adults with carotid plaque are at increased risk for cardiovascular outcomes. Atherosclerosis has roots in childhood and pediatric guidelines provide cut-off values for cardiovascular risk factors. However, it is unknown whether these cut-offs predict adulthood advanced atherosclerosis. Methods: The Cardiovascular Risk in Young Finns Study is a follow-up of children that begun in 1980 when 2653 participants with data for the present analyses were aged 3-18 years. In 2001 and 2007 follow-ups, in addition to adulthood cardiovascular risk factors, carotid ultrasound data was collected. Long-term burden, as the area under the curve, was evaluated for childhood (6-18 years) risk factors. To study the associations of guideline-based cut-offs with carotid plaque, both childhood and adult risk factors were classified according to clinical practice guidelines. Results: Carotid plaque, defined as a focal structure of the arterial wall protruding into lumen > 50% compared to adjacent intima-media thickness, was present in 88 (3.3%) participants. Relative risk for carotid plaque, when adjusted for age and sex, was 3.03 (95% CI, 1.76-5.21) for childhood dyslipidemia, 1.51 (95% CI, 0.99-2.32) for childhood elevated systolic blood pressure, and 1.93 (95% CI, 1.26-2.94) for childhood smoking. Childhood dyslipidemia and smoking remained independent predictors of carotid plaque in models additionally adjusted for adult risk factors and family history of coronary heart disease. Carotid plaque was present in less than 1% of adults with no childhood risk factors. Conclusions: Findings reinforce childhood prevention efforts and demonstrate the utility of guideline-based cutoffs in identifying children at increased risk for adulthood atherosclerosis.
  • Simonen, Piia; Lehtonen, Jukka; Gylling, Helena; Kupari, Markku (2016)
    Background and aims: Patients with cardiac sarcoidosis (CS) suffer from myocardial inflammation, but atherosclerosis is not infrequent in these patients. However, the classical atherosclerotic risk factors, such as perturbed serum lipids and whole-body cholesterol metabolism, remain unravelled in CS. Methods: We assessed serum non-cholesterol sterols, biomarkers of whole-body cholesterol synthesis and cholesterol absorption efficiency, with gas-liquid chromatography in 39 patients with histologically verified CS and in an age-adjusted random population sample (n = 124). Results: CS was inactive or responding to treatment in all patients. Concentrations of serum, LDL, and HDL cholesterol and serum triglycerides were similar in CS patients and in control subjects. Cholesterol absorption markers were higher in CS patients than in controls (eg serum campesterol to cholesterol ratio in CS 246 +/- 18 vs in controls 190 +/- 8 10(2) x mu mol/mmol of cholesterol, p = 0.001). Cholesterol synthesis markers were lower in CS patients than in controls (eg serum lathosterol to cholesterol ratio in CS 102 +/- 8 vs in controls 195 +/- 5 10(2) x mu mol/mmol of cholesterol, p = 0.000). In CS patients, cholesterol absorption markers significantly correlated with plasma prohormone brain natriuretic peptide (proBNP), a marker of hemodynamic load. Conclusion: High cholesterol absorption efficiency, which is suggested to be atherogenic, characterized the metabolic profile of cholesterol in CS patients. The association between cholesterol absorption efficiency and plasma proBNP concentration, which suggests a link between inflammation, cholesterol homeostasis, and hemodynamic load, warrants further studies in order to confirm this finding and to reveal the underlying mechanisms. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
  • Uusitalo, Valtteri; Kamperidis, Vasileios; de Graaf, Michiel A.; Maaniitty, Teemu; Stenstrom, Iida; Broersen, Alexander; Dijkstra, Jouke; Scholte, Arthur J.; Saraste, Antti; Bax, Jeroen J.; Knuuti, Juhani (2017)
    Background: We evaluated the prognostic value of an integrated atherosclerosis risk score combining the markers of coronary plaque burden, location and composition as assessed by computed tomography angiography (CTA). Methods: 922 consecutive patients underwent CTA for suspected coronary artery disease (CAD). Patients without atherosclerosis (n = 261) and in whom quantitative CTA analysis was not feasible due to image quality, step-artefacts or technical factors related to image acquisition or data storage (n = 153) were excluded. Thus, final study group consisted of 508 patients aged 63 9 years. Coronary plaque location, severity and composition for each coronary segment were identified using automated CTA quantification software and integrated in a single CTA score (0-42). Adverse events (AE) including death, myocardial infarction (MI) and unstable angina (UA) were obtained from the national healthcare statistics. Results: There were a total of 20 (4%) AE during a median follow-up of 3.6 years (9 deaths, 5 MI and 6 UA). The CTA risk score was divided into tertiles: 0-6.7, 6.8-14.8 and > 14.8, respectively. All MI (n = 5) and most of the other AE occurred in the highest risk score tertile (3 vs. 3 vs. 14, p = 0.002). After correction for age and gender, the CTA risk score remained independently associated with AE. Conclusions: Comprehensive CIA risk score integrating the location, burden and composition of coronary atherosclerosis predicts future cardiac events in patients with suspected CAD. (C) 2017 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.
  • Wickstrom, Jan-Erik; Jalkanen, Juho M.; Venermo, Maarit; Hakovirta, Harri H. (2017)
    Background and aims: Limited data exist on the association of the anatomical distribution of atherosclerotic lesions and the extent of atherosclerosis at defined arterial segments with life expectancy. We recently presented a new classification of the extent of atherosclerosis in crural vessels and showed that Crural Index (CIx) was associated with mid-term survival of symptomatic peripheral artery disease (PAD) patients. This study evaluates the significance of the extent of crural atherosclerosis on long-term cardiovascular mortality. Methods: 887 consecutive patients with PAD, admitted for digital subtraction angiography (DSA) at Turku University Hospital Department of Vascular Surgery (Turku, Finland) between January 1st, 2009 and July 30th, 2011, were retrospectively analysed. Each crural angiographic image was graded according to CIx criteria. Aorto-iliac and femoro-popliteal arterial segments were similarly graded according to modified TASC II criteria. CIx was used as the categorical variable for the extent of atherosclerosis in crural vessels for survival analysis. Survival was also evaluated with respect to which arterial segment was most severely affected. Causes of death were provided by the Cause of Death Registry of Statistics Finland, updated on January 23rd, 2017. Results: Altogether, 408 (46%) patients died during follow-up. The majority of deaths were due to cardiovascular causes (n = 246, 60%). Cardiovascular mortality was strongly associated with a high CIx (CIx III (Hazard ratio (HR) 2.16, Confidence interval (CI) 95% 1.23-3.80, p = 0.007)) and CIx IV (HR 3.513, 95% CI 1.93-4.565, p <0.001), as compared to CIx 0. In patients having the crural segment as the most severely affected arterial segment, cardiovascular mortality was significantly increased (HR 2.321, 95% CI 1.45-3.73, p <0.001), as was overall mortality (HR 2.177, 95% CI 1.53-3.10, p <0.001). Conclusions: High Crural Index and extensive crural vessel atherosclerosis are associated with long-term cardiovascular mortality, and both may serve as useful indicators of survival among patients with symptomatic PAD. (c) 2017 Elsevier B.V. All rights reserved.
  • Nuotio, Joel; Vahamurto, Lauri; Pahkala, Katja; Magnussen, Costan G.; Hutri-Kahonen, Nina; Kahonen, Mika; Laitinen, Tomi; Taittonen, Leena; Tossavainen, Paivi; Lehtimaki, Terho; Jokinen, Eero; Viikari, Jorma S. A.; Raitakari, Olli; Juonala, Markus (2019)
    Aims: Disparity in cardiovascular disease (CVD) mortality and risk factor levels between urban and rural regions has been confirmed worldwide. The aim of this study was to examine how living in different community types (urban-rural) in childhood and adulthood are related to cardiovascular risk factors and surrogate markers of CVD such as carotid intima-media thickness (IMT) and left ventricular mass (LVM). Methods: The study population comprised 2903 participants (54.1% female, mean age 10.5 years in 1980) of the Cardiovascular Risk in Young Finns Study who had been clinically examined in 1980 (age 3-18 years) and had participated in at least one adult follow-up (2001-2011). Results: In adulthood, urban residents had lower systolic blood pressure (-1 mmHg), LDL-cholesterol (-0.05 mmol/l), lower body mass index (-1.0 kg/m(2)) and glycosylated haemoglobin levels (-0.05 mmol/mol), and lower prevalence of metabolic syndrome (19.9 v. 23.7%) than their rural counterparts. In addition, participants continuously living in urban areas had significantly lower IMT (-0.01 mm), LVM (1.59 g/m(2.7)) and pulse wave velocity (-0.22 m/s) and higher carotid artery compliance (0.07%/10 mmHg) compared to persistently rural residents. The differences in surrogate markers of CVD were only partially attenuated when adjusted for cardiovascular risk factors. Conclusions: Participants living in urban communities had a more favourable cardiovascular risk factor profile than rural residents. Furthermore, participants continuously living in urban areas had less subclinical markers related to CVD compared with participants living in rural areas. Urban-rural differences in cardiovascular health might provide important opportunities for optimizing prevention by targeting areas of highest need.
  • Vahamurto, Lauri; Pahkala, Katja; Magnussen, Costan G.; Mikkilä, Vera; Hutri-Kahonen, Nina; Kahonen, Mika; Laitinen, Tomi; Taittonen, Leena; Tosavainen, Paivi; Lehtimaki, Terho; Jokinen, Eero; Telama, Risto; Ronnemaa, Tapio; Viikari, Jorma; Juonala, Markus; Raitakari, Olli (2016)
    Background: Coronary heart disease mortality has been internationally high in eastern Finland. The excessive mortality risk in Eastern compared with western Finns is explained by differences in cardiometabolic risk profile. Current risk profile differences and association with migration have not been reported. We examined the association of place of residence (east west) and specifically migration with cardiometabolic risk markers and carotid intima media thickness (IMT). Methods: The study population included 2204 participants with data available from childhood/youth in 1980 and follow-up examination in 2007. Results: Participants residing in eastern Finland in adulthood had 0.022 +/- 0.004mm higher IMT than Western participants. Those who migrated east-to-west had lower IMT than those staying in the east (0.027 +/- 0.006mm, p
  • Luetjohann, Dieter; Björkhem, Ingemar; Friedrichs, Silvia; Kerksiek, Anja; Lovgren-Sandblom, Anita; Geilenkeuser, Wolf-Jochen; Ahrends, Robert; Andrade, Isabel; Ansorena, Diana; Astiasaran, Iciar; Baila-Rueda, Lucia; Barriuso, Bianca; Becker, Susen; Bretillon, Lionel; Browne, Richard W.; Caccia, Claudio; Ceglarek, Uta; Cenarro, Ana; Crick, Peter J.; Fauler, Günter; Garcia-Llatas, Guadalupe; Gray, Robert; Griffiths, William J.; Gylling, Helena; Harding, Scott; Helmschrodt, Christin; Iuliano, Luigi; Janssen, Hans-Gerd; Jones, Peter; Kaipiainen, Leena; Kannenberg, Frank; Jesus Lagarda, Maria; Leoni, Valerio; Lottenberg, Ana Maria; MacKay, Dylan S.; Matysik, Silke; McDonald, Jeff; Menendez-Carreno, Maria; Myrie, Semone B.; Nunes, Valeria Sutti; Ostlund, Richard E.; Polisecki, Eliana; Ramos, Fernando; Rideout, Todd C.; Schaefer, Ernst J.; Schmitz, Gerd; Wang, Yuqin; Zerbinati, Chiara; Diczfalusy, Ulf; Schött, Hans-Frieder (2019)
    Serum concentrations of lathosterol, the plant sterols campesterol and sitosterol and the cholesterol metabolite 5 alpha-cholestanol are widely used as surrogate markers of cholesterol synthesis and absorption, respectively. Increasing numbers of laboratories utilize a broad spectrum of well-established and recently developed methods for the determination of cholesterol and non-cholesterol sterols (NCS). In order to evaluate the quality of these measurements and to identify possible sources of analytical errors our group initiated the first international survey for cholesterol and NCS. The cholesterol and NCS survey was structured as a two-part survey which took place in the years 2013 and 2014. The first survey part was designed as descriptive, providing information about the variation of reported results from different laboratories. A set of two lyophilized pooled sera (A and B) was sent to twenty laboratories specialized in chromatographic lipid analysis. The different sterols were quantified either by gas chromatography-flame ionization detection, gas chromatography- or liquid chromatography-mass selective detection. The participants were requested to determine cholesterol and NCS concentrations in the provided samples as part of their normal laboratory routine. The second part was designed as interventional survey. Twenty-two laboratories agreed to participate and received again two different lyophilized pooled sera (C and D). In contrast to the first international survey, each participant received standard stock solutions with defined concentrations of cholesterol and NCS. The participants were requested to use diluted calibration solutions from the provided standard stock solutions for quantification of cholesterol and NCS. In both surveys, each laboratory used its own internal standard (5 alpha-cholestane, epicoprostanol or deuterium labelled sterols). Main outcome of the survey was, that unacceptably high interlaboratory variations for cholesterol and NCS concentrations are reported, even when the individual laboratories used the same calibration material. We discuss different sources of errors and recommend all laboratories analysing cholesterol and NCS to participate in regular quality control programs.
  • Vähämurto, L.; Juonala, M.; Ruohonen, S.; Hutri-Kähönen, N.; Kähönen, M.; Laitinen, T.; Tossavainen, P.; Jokinen, E.; Viikari, J.; Raitakari, O. T.; Pahkala, K. (2018)
    Aims: Eastern Finns have higher risk of coronary heart disease (CHD) and carotid intima-media thickness than western Finns although current differences in CHD risk factors are minimal. Left ventricular (LV) mass and diastolic function predict future cardiovascular events but their east-west differences are unknown. We examined the association of eastern/western baseline origin with LV mass and diastolic function. Methods : The study population included 2045 subjects of the Cardiovascular Risk in Young Finns Study with data from the baseline survey (1980) and the latest follow-up (2011) when echocardiography was performed at the age of 34-49 years. Results: Subjects with eastern baseline origin had in 2011 higher LV mass (139 +/- 1.0 vs. 135 +/- 1.0 g, p=0.006) and E/e-ratio indicating weaker LV diastolic function (4.86 +/- 0.03 vs. 4.74 +/- 0.03, p=0.02) than western subjects. Results were independent of age, sex, area of examination and CHD risk factors such as blood pressure and BMI (LV mass indexed with height: p
  • Strawbridge, Rona J.; Silveira, Angela; den Hoed, Marcel; Gustafsson, Stefan; Luan, Jian'an; Rybin, Denis; Dupuis, Josee; Li-Gao, Ruifang; Kavousi, Maryam; Dehghan, Abbas; Haljas, Kadri; Lahti, Jari; Gadin, Jesper R.; Backlund, Alexandra; de Faire, Ulf; Gertow, Karl; Giral, Phillipe; Goel, Anuj; Humphries, Steve E.; Kurl, Sudhir; Langenberg, Claudia; Lannfelt, Lars L.; Lind, Lars; Lindgren, Cecilia C. M.; Mannarino, Elmo; Mook-Kanamori, Dennis O.; Morris, Andrew P.; de Mutsert, Renee; Rauramaa, Rainer; Saliba-Gustafsson, Peter; Sennblad, Bengt; Smit, Andries J.; Syvanen, Ann-Christine; Tremoli, Elena; Veglia, Fabrizio; Zethelius, Bjorn; Bjorck, Hanna M.; Eriksson, Johan G.; Hofman, Albert; Franco, Oscar H.; Watkins, Hugh; Jukema, J. Wouter; Florez, Jose C.; Wareham, Nicholas J.; Meigs, James B.; Ingelsson, Erik; Baldassarre, Damiano; Hamsten, Anders; IMPROVE Study Grp (2017)
    Background and aims: Increased proinsulin relative to insulin levels have been associated with subclinical atherosclerosis (measured by carotid intima-media thickness (cIMT)) and are predictive of future cardiovascular disease (CVD), independently of established risk factors. The mechanisms linking proinsulin to atherosclerosis and CVD are unclear. A genome-wide meta-analysis has identified nine loci associated with circulating proinsulin levels. Using proinsulin-associated SNPs, we set out to use a Mendelian randomisation approach to test the hypothesis that proinsulin plays a causal role in subclinical vascular remodelling. Methods: We studied the high CVD-risk IMPROVE cohort (n = 3345), which has detailed biochemical phenotyping and repeated, state-of-the-art, high-resolution carotid ultrasound examinations. Genotyping was performed using Illumina Cardio-Metabo and Immuno arrays, which include reported proinsulin-associated loci. Participants with type 2 diabetes (n = 904) were omitted from the analysis. Linear regression was used to identify proinsulin-associated genetic variants. Results: We identified a proinsulin locus on chromosome 15 (rs8029765) and replicated it in data from 20,003 additional individuals. An 11-SNP score, including the previously identified and the chromosome 15 proinsulin-associated loci, was significantly and negatively associated with baseline IMTmean and IMTmax (the primary cIMT phenotypes) but not with progression measures. However, MR-Eggers refuted any significant effect of the proinsulin-associated 11-SNP score, and a non-pleiotropic SNP score of three variants (including rs8029765) demonstrated no effect on baseline or progression cIMT measures. Conclusions: We identified a novel proinsulin-associated locus and demonstrated that whilst proinsulin levels are associated with cIMT measures, proinsulin per se is unlikely to have a causative effect on cIMT. (C) 2017 The Authors. Published by Elsevier Ireland Ltd.
  • Kaye, Sanna; Heinonen, Sini; Pietiläinen, Kirsi (2020)
    Vertailemalla harvinaisia identtisiä mutta eripainoisia kaksosia voidaan selvittää lihavuuden vaikutusta aineenvaihduntaan DNA-sekvenssin samankaltaisuudesta riippumatta. Hankinnainen lihavuus vaikuttaa epäedullisesti veren rasvoihin, hyytymistekijöiden pitoisuuksiin ja tulehdusvälittäjäaineisiin sekä huonontaa endoteelitoimintaa ja altistaa ateroskleroosille. Tutkimusten perusteella rasvakudos on keskeisessä asemassa siinä, miten lihavuuden havaitut haitalliset aineenvaihdunnan muutokset syntyvät. Hankinnainen lihavuus liittyy rasvakudoksessa mitokondriotoiminnan heikentymiseen ja lievään tulehdukseen sekä insuliiniresistenssiin. Nämä muutokset heikentävät rasvakudoksen laajenemiskapasiteettia, jolloin ylimääräinen rasva alkaa varastoitua muihin kudoksiin, kuten maksaan, haimaan ja lihakseen, ja aiheuttaa aineenvaihdunnan laaja-alaisen häiriötilan. Erityisesti maksaan kertyvä rasva näyttää määrittävän lihavuuden haitallista metaboliaa.
  • Ruuth, Maija; Janssen, Laura G. M.; Aikas, Lauri; Tigistu-Sahle, Feven; Nahon, Kimberly J.; Ritvos, Olli; Ruhanen, Hanna; Käkelä, Reijo; Boon, Marlette R.; Öörni, Katariina; Rensen, Patrick C. N. (2019)
    BACKGROUND: South Asians are more prone to develop atherosclerotic cardiovascular disease (ASCVD) compared with white Caucasians, which is not fully explained by classical risk factors. We recently reported that the presence of aggregation-prone low-density lipoprotein (LDL) in the circulation is associated with increased ASCVD mortality. OBJECTIVE: We hypothesized that LDL of South Asians is more prone to aggregate, which may be explained by differences in their LDL lipid composition. METHODS: In this cross-sectional hypothesis-generating study, LDL was isolated from plasma of healthy South Asians (n = 12) and age- and BMI-matched white Caucasians (n = 12), and its aggregation susceptibility and lipid composition were analyzed. RESULTS: LDL from South Asians was markedly more prone to aggregate compared with white Caucasians. Among all measured lipids, sphingomyelin 24:0 and triacylglycerol 56:8 showed the highest positive correlation with LDL aggregation. In addition, LDL from South Asians was enriched in arachidonic acid containing phosphatidylcholine 38:4 and had less phosphatidylcholines and cholesteryl esters containing monounsaturated fatty acids. Interestingly, body fat percentage, which was higher in South Asians (+26%), positively correlated with LDL aggregation and highly positively correlated with triacylglycerol 56:8, sphingomyelin 24:0, and total sphingomyelin. CONCLUSIONS: LDL aggregation susceptibility is higher in healthy young South Asians compared with white Caucasians. This may be partly explained by the higher body fat percentage of South Asians, leading to sphingomyelin enrichment of LDL. We anticipate that the presence of sphingomyelin-rich, aggregation -prone LDL particles in young South Asians may increase LDL accumulation in the arterial wall and thereby contribute to their increased risk of developing ASCVD later in life. (C) 2019 National Lipid Association. Published by Elsevier Inc.
  • Vuorio, Alpo; Jauhiainen, Matti; Kovanen, Petri T. (2020)
    Lipoproteiini (a) [Lp(a)] on LDL:n kaltainen kolesterolia kuljettava aterotromboottinen seerumin lipoproteiini ja ateroskleroottisen valtimotaudin itsenäinen riskitekijä. Ihmisten Lp(a)-pitoisuudet vaihtelevat suuresti ja määräytyvät pääosin perinnöllisesti. Suurentunut Lp(a)-pitoisuus liittyy sepelvaltimotautiin, sydän- ja aivoinfarktiin, perifeeriseen valtimotautiin ja aorttaläpän ahtaumaan. Seerumin Lp(a)-pitoisuuden mittaamista suositellaan erityisesti familiaalisen hyperkolesterolemian (FH) yhteydessä sekä silloin, kun potilaan suvussa on varhaisia valtimotautitapauksia tai potilaan valtimotautien kokonaisriski on suuri tai erittäin suuri. Statiinilääkitys ei pienennä Lp(a)-pitoisuutta. Sen sijaan LDL-kolesterolipitoisuutta voimakkaasti pienentävät PCSK9:n estäjät pienentävät Lp(a)-pitoisuutta noin 30 % ja näyttävät pienentävän valtimotautiriskiä myös tätä kautta. Lähivuosina markkinoille on tulossa seerumin Lp(a)-pitoisuutta erittäin tehokkaasti pienentäviä RNA:han kohdentuvia täsmälääkkeitä.
  • Vuorio, Alpo; Watts, Gerald F.; Kovanen, Petri T. (2019)
    A large number of epidemiological studies in ethnically diverse populations show that lipoprotein(a) [Lp(a)] levels above 30-50 mg/dL are significantly associated with calcific aortic valve stenosis, although less so in African Americans. Patients with heterozygous familial hypercholesterolemia (he-FH) have a marked lifelong elevation of serum low-density lipoprotein cholesterol (LDL-C) level, and the prevalence of aortic valve calcification (AVC) is at least two-fold higher among adult he-FH patients compared with healthy controls. Additionally, Lp(a) levels above 50 mg/dL were recently found to be an independent risk factor for AVC among asymptomatic statin-treated he-FH patients. Given that worldwide an estimated 1.4 billion people have an Lp(a) level over 50 mg/dL, and that one out of 250 individuals has he-FH, then globally about 5 million he-FH patients should have an Lp(a) level higher than 50 mg/dL. However, because Lp(a) levels are, on average, significantly higher in he-FH patients than the general population, the actual number of he-FH patients with such high Lp(a) levels must be even higher. We proposed recently that Lp(a) life-years is a useful metric of cumulative burden of risk for atherosclerotic cardiovascular disease (ASCVD), and now posit that this metric may be extended to the development of AVC. The Lp(a) life-years illustrates the age-dependent exposure to a given Lp(a) level (years x mg/dL). Effective novel pharmacotherapies using apo(a) antisense oligonucleotides (ASOs) or small interfering RNA (siRNA)-based therapies targeting the hepatic expression of apo(a) offer unprecedented potential for significant reduction in the cumulative exposure of the aortic valves to Lp(a), and need to be tested in controlled clinical trials on the progression of AVC.
  • Ference, Brian A.; Ginsberg, Henry N.; Graham, Ian; Ray, Kausik K.; Packard, Chris J.; Bruckert, Eric; Hegele, Robert A.; Krauss, Ronald M.; Raal, Frederick J.; Schunkert, Heribert; Watts, Gerald F.; Boren, Jan; Fazio, Sergio; Horton, Jay D.; Masana, Luis; Nicholls, Stephen J.; Nordestgaard, Borge G.; van de Sluis, Bart; Taskinen, Marja-Riitta; Tokgözoglu, Lale; Landmesser, Ulf; Laufs, Ulrich; Wiklund, Olov; Stock, Jane K.; Chapman, M. John; Catapano, Alberico L. (2017)
    Aims To appraise the clinical and genetic evidence that low-density lipoproteins (LDLs) cause atherosclerotic cardiovascular disease (ASCVD). Methods and results We assessed whether the association between LDL and ASCVD fulfils the criteria for causality by evaluating the totality of evidence from genetic studies, prospective epidemiologic cohort studies, Mendelian randomization studies, and randomized trials of LDL-lowering therapies. In clinical studies, plasma LDL burden is usually estimated by determination of plasma LDL cholesterol level (LDL-C). Rare genetic mutations that cause reduced LDL receptor function lead to markedly higher LDL-C and a dose-dependent increase in the risk of ASCVD, whereas rare variants leading to lower LDL-C are associated with a correspondingly lower risk of ASCVD. Separate meta-analyses of over 200 prospective cohort studies, Mendelian randomization studies, and randomized trials including more than 2 million participants with over 20 million person-years of follow-up and over 150 000 cardiovascular events demonstrate a remarkably consistent dose-dependent log-linear association between the absolute magnitude of exposure of the vasculature to LDL-C and the risk of ASCVD; and this effect appears to increase with increasing duration of exposure to LDL-C. Both the naturally randomized genetic studies and the randomized intervention trials consistently demonstrate that any mechanism of lowering plasma LDL particle concentration should reduce the risk of ASCVD events proportional to the absolute reduction in LDL-C and the cumulative duration of exposure to lower LDL-C, provided that the achieved reduction in LDL-C is concordant with the reduction in LDL particle number and that there are no competing deleterious off-target effects. Conclusion Consistent evidence from numerous and multiple different types of clinical and genetic studies unequivocally establishes that LDL causes ASCVD.
  • Kinnunen, K.; Piippo, N.; Loukovaara, S.; Hytti, M.; Kaarniranta, K.; Kauppinen, A. (2017)
    Inflammation is a crucial component in the pathogenesis of many vascular diseases, such as atherosclerosis and diabetes. Inflammasomes are intracellular signalling complexes whose activation promotes inflammation. Nucleotide-binding domain and Leucine-rich repeat Receptor containing a Pyrin domain 3 (NLRP3) is a pattern recognition receptor (PRR) forming the best-known inflammasome. Disturbances in NLRP3 have been associated with multiple diseases. The purpose of this study was to explore the lysosomal destabilizationrelated NLRP3 inflammasome signaling pathway in human endothelial cells. In order to prime and activate NLRP3, human umbilical vein cells (HUVECs) were exposed to TNF-alpha and the lysosomal destructive agent Leusine-Leusine-OMethylesther (Leu-Leu-OMe), respectively. A caspase-1 inhibitor was used to block caspase-1' s enzymatic function and an interleukin 1 receptor antagonist (IL-1RA) to prevent any possible secondary effects of IL-1 beta. Leu-Leu-OMe increased the expression of NLRP3, IL-1 beta, and IL-18 in HUVECs. Exposure to Leu-Leu-OMe significantly promoted the production of IL-6 and IL-8 in primed HUVECs; this effect was prevented by the pre-treatment of cells with an IL-1RA. Our results suggest that lysosomal destabilization activates the NLRP3 inflammasome pathway that promotes the production of IL-6 and IL-8 in an autocrine manner in HUVEC cells.
  • Bhalke, Monika (Helsingin yliopisto, 2020)
    Lipoproteins are biochemical carriers of the insoluble lipids. They are complexes combining lipids and proteins for the transport of lipids. Amongst the type of lipoproteins are low-density lipoproteins (LDL) which are prevalent in various diseases such as obesity, diabetes, atherosclerosis, and other cardiovascular diseases (CVD). Omega-3 fatty acids are polyunsaturated fatty acids (PUFA) that are essential components of lipid metabolism and play a significant role in the human diet. Omega-3 PUFAs such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are derived from fish and are necessary for proper cardiovascular functioning. Because the human body is unable to produce enough quantities of some omega-3, diet is an important source for its availability. When a diet is rich in saturated fats, the above-mentioned diseases transpire. This study investigated how consumption of two fish diets, Lean fish and Fatty fish, influence the lipid species of human LDL particles. The lipid species analysed in this study are phospholipids such as phosphatidylcholine (PC), sphingomyelin (SM), and lysophosphatidylcholine (LPC), and cholesteryl esters (CE), and triacylglycerols (TAG). A total of 42 volunteers with a history of impaired fasting glucose had randomly been divided into two groups: fatty fish (4 fish meals/week) and lean fish (4 fish meals/week) for 12 weeks. Blood samples had been collected from the volunteers before and after consumption of the fish meals and LDL particles had been isolated from the blood samples by ultracentrifugation. In this study, the lipids were extracted by Folch method, and the extracted lipids were analysed using Triple quadrupole mass spectrometry. The lipid class profile did not change due to the two fish type diets. However, the consumption of fatty fish diet increased the levels of lipid species of PC, LPC, and CE containing EPA and DHA acyl chains, while decreasing levels of several TAG species. Lean fish induced minor changes in the lipid composition of LDL particles. Based on these results, fatty fish diet alters the plasma LDL lipidome profile with changes induced to both the surface and the core composition of the LDL particles in a positive way regarding cardiovascular health.
  • Nuotio, Krista; Ijäs, Petra; Heikkilä, Hanna M.; Koskinen, Suvi M.; Saksi, Jani; Vikatmaa, Pirkka; Sorto, Pia; Mäkitie, Laura; Eriksson, Henrietta; Kasari, Sonja; Silvennoinen, Heli; Valanne, Leena; Mäyränpää, Mikko I.; Kovanen, Petri T.; Soinne, Lauri; Lindsberg, Perttu J. (2018)
    Introduction: Every fifth ischemic stroke is caused by thromboembolism originating from an atherosclerotic carotid artery plaque. While prevention is the most cost-effective stroke therapy, antiplatelet and cholesterol-lowering drugs have a ceiling effect in their efficacy. Therefore, discovery of novel pathophysiologic targets are needed to improve the primary and secondary prevention of stroke. This article provides a detailed study design and protocol of HeCES2, an observational prospective cohort study with the objective to investigate the pathophysiology of carotid atherosclerosis.Materials and Methods: Recruitment and carotid endarterectomies of the study patients with carotid atherosclerosis were performed from October 2012 to September 2015. After brain and carotid artery imaging, endarterectomised carotid plaques (CPs) and blood samples were collected from 500 patients for detailed biochemical and molecular analyses.Findings to date: We developed a morphological grading for macroscopic characteristics within CPs. The dominant macroscopic CP characteristics were: smoothness 62%, ulceration 61%, intraplaque hemorrhage 60%, atheromatous gruel 59%, luminal coral-type calcification 34%, abundant (44%) and moderate (39%) intramural calcification, and symptom-causing hot spot area 53%.Future plans: By combining clinically oriented and basic biomedical research, this large-scale study attempts to untangle the pathophysiological perplexities of human carotid atherosclerosis.Key MessagesThis article is a rationale and design of the HeCES2 study that is an observational prospective cohort study with the objective to investigate the pathophysiology of carotid atherosclerosis.The HeCES2 study strives to develop diagnostic algorithms including radiologic imaging to identify carotid atherosclerosis patients who warrant surgical treatment.In addition, the study aims at finding out new tools for clinical risk stratification as well as novel molecular targets for drug development.