Expression of sterol regulatory element-binding transcription factor (SREBF) 2 and SREBF cleavage-activating protein (SCAP) in human atheroma and the association of their allelic variants with sudden cardiac death

<p>Abstract</p> <p>Background</p> <p>Disturbed cellular cholesterol homeostasis may lead to accumulation of cholesterol in human atheroma plaques. Cellular cholesterol homeostasis is controlled by the sterol regulatory element-binding transcription factor 2 (SREBF-2) and the SREBF cleavage-activating protein (SCAP). We investigated whole genome expression in a series of human atherosclerotic samples from different vascular territories and studied whether the non-synonymous coding variants in the interacting domains of two genes, <it>SREBF-2 </it>1784G>C (rs2228314) and <it>SCAP </it>2386A>G, are related to the progression of coronary atherosclerosis and the risk of pre-hospital sudden cardiac death (SCD).</p> <p>Methods</p> <p>Whole genome expression profiling was completed in twenty vascular samples from carotid, aortic and femoral atherosclerotic plaques and six control samples from internal mammary arteries. Three hundred sudden pre-hospital deaths of middle-aged (33–69 years) Caucasian Finnish men were subjected to detailed autopsy in the Helsinki Sudden Death Study. Coronary narrowing and areas of coronary wall covered with fatty streaks or fibrotic, calcified or complicated lesions were measured and related to the <it>SREBF-2 </it>and <it>SCAP </it>genotypes.</p> <p>Results</p> <p>Whole genome expression profiling showed a significant (p = 0.02) down-regulation of <it>SREBF-2 </it>in atherosclerotic carotid plaques (types IV-V), but not in the aorta or femoral arteries (p = NS for both), as compared with the histologically confirmed non-atherosclerotic tissues. In logistic regression analysis, a significant interaction between the <it>SREBF-2 </it>1784G>C and the <it>SCAP </it>2386A>G genotype was observed on the risk of SCD (p = 0.046). Men with the <it>SREBF-2 </it>C allele and the <it>SCAP </it>G allele had a significantly increased risk of SCD (OR 2.68, 95% CI 1.07–6.71), compared to <it>SCAP </it>AA homologous subjects carrying the <it>SREBF-2 </it>C allele. Furthermore, similar trends for having complicated lesions and for the occurrence of thrombosis were found, although the results were not statistically significant.</p> <p>Conclusion</p> <p>The results suggest that the allelic variants (<it>SREBF-2 </it>1784G>C and <it>SCAP </it>2386A>G) in the cholesterol homeostasis regulating SREBF-SCAP pathway may contribute to SCD in early middle-aged men.</p

Percutaneous coronary angioplasty versus coronary artery bypass grafting in treatment of unprotected left main stenosis (NOBLE) : a prospective, randomised, open-label, non-inferiority trial

Background Coronary artery bypass grafting (CABG) is the standard treatment for revascularisation in patients with left main coronary artery disease, but use of percutaneous coronary intervention (PCI) for this indication is increasing. We aimed to compare PCI and CABG for treatment of left main coronary artery disease. Methods In this prospective, randomised, open-label, non-inferiority trial, patients with left main coronary artery disease were enrolled in 36 centres in northern Europe and randomised 1: 1 to treatment with PCI or CABG. Eligible patients had stable angina pectoris, unstable angina pectoris, or non-ST-elevation myocardial infarction. Exclusion criteria were ST-elevation myocardial infarction within 24 h, being considered too high risk for CABG or PCI, or expected survival of less than 1 year. The primary endpoint was major adverse cardiac or cerebrovascular events (MACCE), a composite of all-cause mortality, non-procedural myocardial infarction, any repeat coronary revascularisation, and stroke. Non-inferiority of PCI to CABG required the lower end of the 95% CI not to exceed a hazard ratio (HR) of 1 . 35 after up to 5 years of follow-up. The intention-to-treat principle was used in the analysis if not specified otherwise. This trial is registered with ClinicalTrials.gov identifier, number NCT01496651. Findings Between Dec 9, 2008, and Jan 21, 2015, 1201 patients were randomly assigned, 598 to PCI and 603 to CABG, and 592 in each group entered analysis by intention to treat. Kaplan-Meier 5 year estimates of MACCE were 29% for PCI (121 events) and 19% for CABG (81 events), HR 1 . 48 (95% CI 1 . 11-1 . 96), exceeding the limit for non-inferiority, and CABG was significantly better than PCI (p=0 . 0066). As-treated estimates were 28% versus 19% (1 . 55, 1 . 18-2 . 04, p= 0 . 0015). Comparing PCI with CABG, 5 year estimates were 12% versus 9% (1 . 07, 0 . 67-1 . 72, p= 0 . 77) for all-cause mortality, 7% versus 2% (2 . 88, 1 . 40-5 . 90, p= 0 . 0040) for non-procedural myocardial infarction, 16% versus 10% (1 . 50, 1 . 04-2 . 17, p= 0 . 032) for any revascularisation, and 5% versus 2% (2 . 25, 0 . 93-5 . 48, p= 0 . 073) for stroke. Interpretation The findings of this study suggest that CABG might be better than PCI for treatment of left main stem coronary artery disease.Peer reviewe

Reperfusion therapy for ST elevation acute myocardial infarction 2010/2011: current status in 37 ESC countries

Aims Primary percutaneous coronary intervention (PPCI) is the preferred reperfusion therapy in ST-elevation myocardial infarction (STEMI). We conducted this study to evaluate the contemporary status on the use and type of reperfusion therapy in patients admitted with STEMI in the European Society of Cardiology (ESC) member countries. Methods and results A cross-sectional descriptive study based on aggregated country-level data on the use of reperfusion therapy in patients admitted with STEMI during 2010 or 2011. Thirty-seven ESC countries were able to provide data from existing national or regional registries. In countries where no such registries exist, data were based on best expert estimates. Data were collected on the use of STEMI reperfusion treatment and mortality, the numbers of cardiologists, and the availability of PPCI facilities in each country. Our survey provides a brief data summary of the degree of variation in reperfusion therapy across Europe. The number of PPCI procedures varied between countries, ranging from 23 to 884 per million inhabitants. Primary percutaneous coronary intervention and thrombolysis were the dominant reperfusion strategy in 33 and 4 countries, respectively. The mean population served by a single PPCI centre with a 24-h service 7 days a week ranged from 31 300 inhabitants per centre to 6 533 000 inhabitants per centre. Twenty-seven of the total 37 countries participated in a former survey from 2007, and major increases in PPCI utilization were observed in 13 of these countries. Conclusion Large variations in reperfusion treatment are still present across Europe. Countries in Eastern and Southern Europe reported that a substantial number of STEMI patients are not receiving any reperfusion therapy. Implementation of the best reperfusion therapy as recommended in the guidelines should be encourage

Genetic and environmental factors in alcoholic heart muscle disease

Runsaan alkoholin kulutuksen tiedetään olevan yhteydessä sydänlihasmuutoksiin, mutta annos-vasteriippuvuudesta on saatu ristiriitaisia tuloksia. Yleinen olettamus on ollut, että pitkäaikainen runsas alkoholin kulutus aiheuttaa laajentavaa sydänlihassairautta, jota on kutsuttu alkoholikardiomyopatiaksi. Kuitenkin kliinisissä tutkimuksissa on alkoholisteilla todettu vasemman kammion hypertrofiaa eli koon kasvua sekä lievää sydämen vajaatoimintaa, mutta laajentava sydänlihassairaus on ollut harvinainen. Useimmiten nämä muutokset ovat oireettomia, mutta toisaalta niiden epäillään aiheuttavan lisääntynyttä rytmihäiriöherkkyyttä ja sydänäkkikuoleman riskiä. Tutkimuksessa selvitettiin alkoholikardiomyopatian esiintymistä sekä siihen vaikuttavia geneettisiä ja ympäristötekijöitä. Materiaalina käytettiin kahta ruumiinavaussarjaa, jotka koostuivat 700 äkkillisesti keski-ikäisenä kuolleesta suomalaisesta miehestä. Ruumiinavauksessa rutiiniprotokollan lisäksi mitattiin sydämen kammioiden koko ja seinämäpaksuudet sekä sepelvaltimoiden ahtautumisaste erityismenetelmin. Elintapatekijöitä ja aikaisempia sairauksia kartoitettiin laajalla henkilökohtaisella omaishaastattelulla. Alkoholinkäyttöä selvitettiin erityisesti 14 kysymyksen avulla, joiden perusteella laskettiin kuolemaa edeltänyt keskimäärainen päivittäinen kulutus grammoina. Mitokondriaalisen DNA:n (mtDNA) muutoksia analysoitiin molekyyligeneettisiä menetelmiä käyttäen sydänlihaksesta sekä myös muista kudoksista. Sydämen vasemman kammion koko riippui alkoholin kulutuksesta U-käyrän muotoisesti, eli vasen kammio oli pienempi kohtuullisesti- ja runsaasti kuluttavilla kuin niukasti tai hyvin runsaasti kuluttavilla. Oikean kammion koko puolestaan kasvoi hyvin runsaasti kuluttavilla. Alkoholin lisäksi sepelvaltimoiden ahtautumisaste vaikutti ratkaisevasti sydämen vasemman kammion rakenteen muutoksiin. mtDNA:n muutokset eivät olleet yhteydessä ruumiinavauksessa diagnosoituun alkoholikardiomyopatiaan. Vähäisinä määrinä terveessä sydänlihaksessa esiintyviä mtDNA:n muutoksia tutkittin tarkemmin. mtDNA-varianttien havaittiin esiintyvän runsaimmin uusiutumattomissa kudoksissa kuten sydän- ja luurankolihaksessa ja aivoissa. Osa varianteista oli spesifisiä kyseiselle kudokselle. Näiden mtDNA:n muotojen rakenteen havaittiin läheisesti muistuttavan patologisissa tiloissa esiintyviä muutoksia, ja niiden monistuminen tietyissä tilanteissa tarjoaa uuden potentiaalisen tautimekanismin. mtDNA-varianttien synty- ja ylläpitomekanismit ovat vielä kuitenkin pääosin tuntemattomia. Ruumiinavausaineistossa tiettyjen mtDNA-varianttien havaittiin korreloivan positiivisesti ikään ja tupakointiin, mutta ei mihinkään sydämen patologiseen muutokseen.Excessive alcohol use per se is known to be damaging to the myocardium, but the dose-dependence of different pathological alterations is not commonly agreed. It is commonly believed that heavy alcohol consumption may result in a form of dilated cardiomyopathy, called alcoholic cardiomyopathy (ACM). However, among alcoholics, the most common clinical cardiac findings have been left ventricular (LV) hypertrophy and mild systolic/diastolic dysfunction, rarely accompanied by ventricular dilatation resembling dilated cardiomyopathy. Although mostly asymptomatic, the myocardial abnormalities have been suspected to contribute to the greatly increased risk of arrhythmias and sudden cardiac death among heavy alcohol users. To clarify the entity earlier termed alcoholic heart muscle disease (AHMD) or ACM, a large prospective series of middle-aged men, who died out-of-hospital, was studied via recourse to a medicolegal autopsy. Cardiac examinations for research purposes were added to a routine autopsy protocol to obtain detailed data on ventricular weights and dimensions and coronary artery anatomy. The calculated average daily alcohol dose was found independently to predict heart weight and right ventricular (RV) cavity size, but not LV size, among all men. In the subgroup of men free of coronary artery disease (CAD), LV cavity area showed with increasing alcohol doses a U-shaped response without change in weight (concentric remodeling), whereas RV cavity dilated with very heavy drinking. The LV concentric remodeling was modulated by CAD in a dose-dependent fashion, so that men with no or mild coronary narrowings presented a concentric change, while the opposite (eccentric remodeling) was seen in men with severe CAD. In all, the present results question the idea of progressive LV dilatation with increasing alcohol consumption among middle-aged men. In heart, mtDNA rearrangements did not differ in any systematic manner between controls and cases with alcoholic cardiomyopathy diagnosed at autopsy. These low-abundance rearranged mtDNA molecules, found also in control myocardium, were termed sublimons, by analogy with plant mitochondria. Sublimons were in general most abundant in post-mitotic tissues, and certain sets of sublimons were specific to a given tissue. The structure of sublimons in heart was found closely to resemble pathological mtDNA rearrangements, introducing sublimon amplification as a potential new pathogenic mechanism in mitochondrial disease. In control heart, sublimons were detectable also by non-PCR methods, and like the pathological re-arrangements, sublimons were present in partially duplicated forms and also as deletion mono- and multimers. Rearrangement break-point hotspots were adjacent to known sites of protein binding in the 16S rRNA/tRNA(LeuUUR) gene boundary (by the mitochondrial transcription termination factor, mTERF), and near the end of the D-loop. This suggests the possibility of the involvement of protein-protein interactions in the generation of sublimons. In hearts of healthy individuals, sublimon abundance was found to vary over as much as three orders of magnitude, and in an autopsy series the most prevalent class of sublimons correlated independently with age and intensity of lifetime smoking. There was no correlation with any myocardial pathological finding, and thus it was proposed that sublimons, instead of being a causal factor in cardiac aging, may co-exist with wild-type mtDNA in an equilibrium which is regulated during aging by as yet unknown mechanisms

Long extension PCR to detect deleted mitochondrial DNA molecules is compromized by technical artefacts.

Syventävä työ ei kirjastoss

Long extension PCR to detect deleted mitochondrial DNA molecules is compromized by technical artefacts.

Syventävä työ ei kirjastoss

Genetic and environmental factors in alcoholic heart muscle disease

Runsaan alkoholin kulutuksen tiedetään olevan yhteydessä sydänlihasmuutoksiin, mutta annos-vasteriippuvuudesta on saatu ristiriitaisia tuloksia. Yleinen olettamus on ollut, että pitkäaikainen runsas alkoholin kulutus aiheuttaa laajentavaa sydänlihassairautta, jota on kutsuttu alkoholikardiomyopatiaksi. Kuitenkin kliinisissä tutkimuksissa on alkoholisteilla todettu vasemman kammion hypertrofiaa eli koon kasvua sekä lievää sydämen vajaatoimintaa, mutta laajentava sydänlihassairaus on ollut harvinainen. Useimmiten nämä muutokset ovat oireettomia, mutta toisaalta niiden epäillään aiheuttavan lisääntynyttä rytmihäiriöherkkyyttä ja sydänäkkikuoleman riskiä. Tutkimuksessa selvitettiin alkoholikardiomyopatian esiintymistä sekä siihen vaikuttavia geneettisiä ja ympäristötekijöitä. Materiaalina käytettiin kahta ruumiinavaussarjaa, jotka koostuivat 700 äkkillisesti keski-ikäisenä kuolleesta suomalaisesta miehestä. Ruumiinavauksessa rutiiniprotokollan lisäksi mitattiin sydämen kammioiden koko ja seinämäpaksuudet sekä sepelvaltimoiden ahtautumisaste erityismenetelmin. Elintapatekijöitä ja aikaisempia sairauksia kartoitettiin laajalla henkilökohtaisella omaishaastattelulla. Alkoholinkäyttöä selvitettiin erityisesti 14 kysymyksen avulla, joiden perusteella laskettiin kuolemaa edeltänyt keskimäärainen päivittäinen kulutus grammoina. Mitokondriaalisen DNA:n (mtDNA) muutoksia analysoitiin molekyyligeneettisiä menetelmiä käyttäen sydänlihaksesta sekä myös muista kudoksista. Sydämen vasemman kammion koko riippui alkoholin kulutuksesta U-käyrän muotoisesti, eli vasen kammio oli pienempi kohtuullisesti- ja runsaasti kuluttavilla kuin niukasti tai hyvin runsaasti kuluttavilla. Oikean kammion koko puolestaan kasvoi hyvin runsaasti kuluttavilla. Alkoholin lisäksi sepelvaltimoiden ahtautumisaste vaikutti ratkaisevasti sydämen vasemman kammion rakenteen muutoksiin. mtDNA:n muutokset eivät olleet yhteydessä ruumiinavauksessa diagnosoituun alkoholikardiomyopatiaan. Vähäisinä määrinä terveessä sydänlihaksessa esiintyviä mtDNA:n muutoksia tutkittin tarkemmin. mtDNA-varianttien havaittiin esiintyvän runsaimmin uusiutumattomissa kudoksissa kuten sydän- ja luurankolihaksessa ja aivoissa. Osa varianteista oli spesifisiä kyseiselle kudokselle. Näiden mtDNA:n muotojen rakenteen havaittiin läheisesti muistuttavan patologisissa tiloissa esiintyviä muutoksia, ja niiden monistuminen tietyissä tilanteissa tarjoaa uuden potentiaalisen tautimekanismin. mtDNA-varianttien synty- ja ylläpitomekanismit ovat vielä kuitenkin pääosin tuntemattomia. Ruumiinavausaineistossa tiettyjen mtDNA-varianttien havaittiin korreloivan positiivisesti ikään ja tupakointiin, mutta ei mihinkään sydämen patologiseen muutokseen.Excessive alcohol use per se is known to be damaging to the myocardium, but the dose-dependence of different pathological alterations is not commonly agreed. It is commonly believed that heavy alcohol consumption may result in a form of dilated cardiomyopathy, called alcoholic cardiomyopathy (ACM). However, among alcoholics, the most common clinical cardiac findings have been left ventricular (LV) hypertrophy and mild systolic/diastolic dysfunction, rarely accompanied by ventricular dilatation resembling dilated cardiomyopathy. Although mostly asymptomatic, the myocardial abnormalities have been suspected to contribute to the greatly increased risk of arrhythmias and sudden cardiac death among heavy alcohol users. To clarify the entity earlier termed alcoholic heart muscle disease (AHMD) or ACM, a large prospective series of middle-aged men, who died out-of-hospital, was studied via recourse to a medicolegal autopsy. Cardiac examinations for research purposes were added to a routine autopsy protocol to obtain detailed data on ventricular weights and dimensions and coronary artery anatomy. The calculated average daily alcohol dose was found independently to predict heart weight and right ventricular (RV) cavity size, but not LV size, among all men. In the subgroup of men free of coronary artery disease (CAD), LV cavity area showed with increasing alcohol doses a U-shaped response without change in weight (concentric remodeling), whereas RV cavity dilated with very heavy drinking. The LV concentric remodeling was modulated by CAD in a dose-dependent fashion, so that men with no or mild coronary narrowings presented a concentric change, while the opposite (eccentric remodeling) was seen in men with severe CAD. In all, the present results question the idea of progressive LV dilatation with increasing alcohol consumption among middle-aged men. In heart, mtDNA rearrangements did not differ in any systematic manner between controls and cases with alcoholic cardiomyopathy diagnosed at autopsy. These low-abundance rearranged mtDNA molecules, found also in control myocardium, were termed sublimons, by analogy with plant mitochondria. Sublimons were in general most abundant in post-mitotic tissues, and certain sets of sublimons were specific to a given tissue. The structure of sublimons in heart was found closely to resemble pathological mtDNA rearrangements, introducing sublimon amplification as a potential new pathogenic mechanism in mitochondrial disease. In control heart, sublimons were detectable also by non-PCR methods, and like the pathological re-arrangements, sublimons were present in partially duplicated forms and also as deletion mono- and multimers. Rearrangement break-point hotspots were adjacent to known sites of protein binding in the 16S rRNA/tRNA(LeuUUR) gene boundary (by the mitochondrial transcription termination factor, mTERF), and near the end of the D-loop. This suggests the possibility of the involvement of protein-protein interactions in the generation of sublimons. In hearts of healthy individuals, sublimon abundance was found to vary over as much as three orders of magnitude, and in an autopsy series the most prevalent class of sublimons correlated independently with age and intensity of lifetime smoking. There was no correlation with any myocardial pathological finding, and thus it was proposed that sublimons, instead of being a causal factor in cardiac aging, may co-exist with wild-type mtDNA in an equilibrium which is regulated during aging by as yet unknown mechanisms

Mediaatio : mitä se on?

Mediaatio on merkitysten välittämistä ja rakentavaa vuorovaikutusta. Mediaatiotaitoja on harjoiteltu kieltenopetuksessa jo pitkään - nyt ne on koottu yhden käsitteen alle.nonPeerReviewe