The official journal of the Japan Atherosclerosis Society and the Asian Pacific Society of Atherosclerosis and Vascular Diseases Review Atherosclerosis is initiated by functional changes in the endothelium accompanied by accumulation, oxidation, and glycation of LDL-cholesterol in the inner layer of the arterial wall and continues with the expression of adhesion molecules and release of chemoattractants. PCSK9 is a proprotein convertase that increases circulating LDL levels by directing hepatic LDL receptors into lysosomes for degradation. The effects of PCSK9 on hepatic LDL receptors and contribution to atherosclerosis via the induction of hyperlipidemia are well defined. Monoclonal PCSK9 antibodies that block the effects of PCSK9 on LDL receptors demonstrated beneficial results in cardiovascular outcome trials. In recent years, extrahepatic functions of PCSK9, particularly its direct effects on atherosclerotic plaques have received increasing attention. Experimental trials have revealed that PCSK9 plays a significant role in every step of atherosclerotic plaque formation. It contributes to foam cell formation by increasing the uptake of LDL by macrophages via scavenger receptors and inhibiting cholesterol efflux from macrophages. It induces the expression of inflammatory cytokines, adhesion molecules, and chemoattractants, thereby increasing monocyte recruitment, inflammatory cell adhesion, and inflammation at the atherosclerotic vascular wall. Moreover, low shear stress is associated with increased PCSK9 expression. PCSK9 may induce endothelial cell apoptosis and autophagy and stimulate the differentiation of smooth muscle cells from the contractile phenotype to synthetic phenotype. Increasing evidence indicates that PCSK9 is a molecular target in the development of novel approaches toward the prevention and treatment of atherosclerosis. This review focuses on the molecular roles of PCSK9 in atherosclerotic plaque formation.
Background: Narrow fragmented QRS (fQRS) has recently been recognized as a significant predictor of prognosis in various cardiovascular diseases. Hypothesis: We hypothesized that the presence of narrow fQRS on admission electrocardiogram (ECG) in patients with decompensated systolic heart failure (HF) of any cause would be associated with long-term prognosis. Methods: Patients hospitalized for decompensated HF due to ischemic or nonischemic dilated cardiomyopathy (left ventricular ejection fraction <35%) were retrospectively analyzed. The primary clinical end points were cardiovascular mortality, sudden cardiac death, and rehospitalization for HF. Results: The mean duration of follow-up was 3.73 ± 1.41 years. Patients were classified as fQRS(+) group (n = 114; mean age, 63.49 ± 12.04 years) and fQRS(−) group (n = 113 patients; mean age, 65.04 ± 11.95 years). fQRS on ECG was significantly correlated with New York Heart Association (NYHA) functional class (P = 0.001). In multivariate Cox proportional hazard analysis, narrow fQRS (odds ratio [OR]: 3.130, 95% confidence interval [CI]: 1.560-2.848, P = 0.001), chronic renal failure (OR: 2.455, 95% CI: 1.120-5.381, P = 0.025), NYHA class (OR: 8.305, 95% CI: 2.568-26.855, P < 0.0001), and hypoalbuminemia (OR: 2.099, 95% CI: 1.122-3.926, P = 0.020) were independent predictors of cardiovascular mortality. In Kaplan-Meier survival analysis, narrow fQRS on admission ECG predicted worse survival rate at 84 months; survival probability significantly decreased in the fQRS(+) group compared with fQRS(−) group (P < 0.0001). Conclusions: Presence of narrow fQRS is associated with worse NYHA functional class in patients hospitalized for decompensated HF. Narrow fQRS predicts cardiovascular mortality in a specific subgroup of systolic HF patients, namely those hospitalized for decompensated HF of both ischemic and nonischemic causes.
Background
Although previous studies reported frequent premature atrial contractions(fPACs) increased the risk of adverse cardiovascular outcomes, especially atrial fibrillation(AF), there is a substantial inconsistency between reports concerning the definition of fPAC. In this study, we aimed to investigate the relationship between fPAC and cardiovascular outcomes, especially AF. We further searched for a cutoff value of fPAC for prediction of AF.
Methods
We retrospectively analyzed the ambulatory 24‐hr Holter monitoring records and 392 patients included. Frequent PAC was defined as more than 720 PAC/24 hr as used for frequent ventricular premature beats. Patients’ baseline characteristics, echocardiographic variables and medical history were recorded.
Results
There were 189 patients with fPAC and 203 patients without fPAC. Patients with fPAC had more comorbidities in terms of hypertension, diabetes mellitus, coronary artery disease and congestive heart failure. CHA2DS2‐VaSc was higher in patients with fPAC. Mean follow‐up duration was 31 months, and the number of patients with new‐onset AF during follow‐up was significantly higher in fPAC group (22% vs. 5%, p < .001). fPAC was significantly and independently associated with new‐onset AF and predicted AF with a cutoff value of 3,459 PAC/24 hr, and the risk of AF was 11‐fold higher than those with <3,000 PAC/24 hr. In addition, an increased CHA2DS2‐VaSc score was also associated with new‐onset atrial fibrillation.
Conclusion
In our study, we have demonstrated that fPAC is significantly associated with new‐onset AF, and this association is the strongest among those patients who have more than 3,000 PAC in 24 hr.
Amaç: Ateroskleroz dünyada görülen en sık ölüm sebebidir. Ateroskleroz inflamatuar bir hastalık olup, damar duvarı
hücrelerinde belirgin şekil ve fonksiyon değişikliklerine neden
olur. Damar duvarındaki ana hücreler olan endotel hücreleri
ile düz kas hücrelerinin ateroskleroz sırasında iletişim halinde
oldukları bilinen bir gerçek olmakla beraber, bu iletişimin mekanizmaları net değildir. PCSK9 ise hiperlipidemi etyolojisinde
yer alan bir molekül olmakla birlikte, damar duvar hücrelerinde ateroksleroz sırasında artar ve damar duvar hücrelerine
direk aterosklerotik etkileri vardır. Çalışmamızda aterojenik
etkenlere maruz kalan endotel hücrelerinin, düz kas hücrelerinde yaptığı değişiklikleri ve inflamasyonun en önemli molekülü olan NF-kB ve direct aterosklerotik etkileri son zamanlarda keşfedilmiş olan PCSK9 protein ekspresyonlarına olan
etkilerini araştırdık.
Metod: İnsan umblikal veninden izole edilen hücreler (HUVEC) ayrı ayrı 24 saat boyunca 300 µM hidrojen peroksit
(H2O2), 40 µg/ml okside LDL (Ox-LDL) %5 sigara duman
ekstraktı (SDE) ile inkübe edildi, 24 saat sonra aterojenik etkenlere maruz kalan endotel hücrelerinin süpernatantları
uygun işlemlerden sonra insan aortic düz kas hücrelerinin
(HAVSMC) inkübe edilmesi için kullanıldı. Düz kas hücrelerinden 48 saat sonra protein ekstraksiyonu yapılarak Western
Blot yöntemiyle analiz edildi.
Bulgular: Aterojenik maddelere maruz kalan HUVEC’lerde
canlılığın korunduğu saptandı. Bu maddelere maruz kalan
endotel hücre süpernatantları ile inkübe edilen HASMC’de belirgin bir morfolojik değişiklik saptandı. %5 SDE ve 300 µM
H2O2’ye maruz kalan endotel hücre süpernatantları ile inkübe edilen HASMC’lerde NF-kB (sırasıyla p=0.024,p=0.043)ve PCSK9 protein (p=0.034, p=0.0137) ekspresyonları artmış
bulundu. Ox-LDL’ye maruz kalan endotel hücre süpernatantı
ile inkübe edilen HASMC’lerde ise PCSK9 ekspresyonu artmış
olup (p=0.037), NF-kB ekspresyonunda anlamlı bir artış izlenmemiştir. (p=0.89)
Sonuç: Çalışmamızın sonucunda aterojenik etkenlere maruz
kalan endotel hücrelerinin, damar düz kas üzerinde değişikliklere neden olduğu,damar düz kas hücrelerindeki PCSK9 ve
NF-kB ekspresyonunu arttırdığı gözlenmiştir.
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