ATHEROSCLEROSIS
A To Formation of atherosclerosis play very most risk factors:
1.Dyslipidemia
2.Hypertention
3.Smoke
4.Diabetes Mellitus TYPE II
Its(atherosclerosis) make easy formation Backgraund factors:
1.Obesity BMI > 30kg/m2 (B=Body,M=Mass,I=Index)
2.Sedantary Life
3.Fat and from cholesterol rich diet
4.Genetic
5. Bad socio-economic event.
Helper risk factors:
1.Hypertriglyceridemia
2.Increased small Dense LDL-C
3.High lipoprotein(a) level
4.Hyperhomocysteinemia
5.Prothrombotic states (eg, hyperfibrinogenemia, high plasminogen activator inhibitor level)
Risk Factors for Atherosclerosis Nonmodifiable
1.Age
2.Sex
3.Genetic
4.Psycosocial factors.
New risk factors inside for atherosclerosis
1. Homocysteinemia
2. Lipoprotein
3. Fibrinogen
4. Fibrinolitic fonction markers(t-PA,PAI-1)
5. inflamation markers(CRP).We are look over this risk factors
DYSLIPOPROTEINEMIA
They are main two kind Lipids(Triglycerid,cholesterol).They dont melt at water.Lipids combine whit apolipoproteins so they melt at water.This alternativeies look over in rows
CHOLESTEROL
balmumu niteliğinde, yağ benzeri bir maddedir. (Lipidtir.) Hücre zarında sinirlerin yalıtımında; çeşitli hormonların (siteroidlerin) yapısında ve safra asitlerinin yapımında rol oynar. Kolesterolün % 20’si besinlerden; % 80’i karaciğerden sağlanır. Kolesterol hydroxymethylglutaryl coenzym A(HMG COA) aracılığı ile endoplazmik retikulumdan sentez edilir. Kanda kolesterol esteri halinde dolaşır. Açlık kolesterolün çoğunu düşük yoğunluklu kolesterol (LDL-C) oluşturur. Lipid türleri içinde LDL-C’ün primer aterojenik özellikte olduğu kanıtlanmıştır.Bu nedenle Ulusal Kolesterol Eğitim programı(NCEP) ilk hedefte LDL-C’üdüşürmeyi amaçlamaktadır.LDL-C yüksekliği aşağıdakiözellikleri ile erken ateroskleroza yol açar:
High level LDL-C did constitute the pathology
1.Intima layer of vessel wall lipid ac(plax oluşumu)
2. Endotel disfonksiyonu(NO, salınımı bozulur)
3. Kararsız plak, plak yırtılması, tromboz
4. Proinflamatuvar yanıt
5. Güçlü mitojenik etkiLDL-C’ün oksidasyonu aterojenik özellik kazandırır.
Framingham incelemelerine göre: %1 kolesterol yüksekliği; %2 ateroskleroz artışı ile birliktedir.Tototal ve LDL-C düzeyi düşük olan insanlarda, diğer önemli risklerin(örneğin sigara, hipertansiyon ve diabetes)KKH riski düşmektedir.LDL-C düşürmekle aterosklerozun ilerlemesi önlenmekte; büyük ölçüde duraklama sağlanmakla beraber; regresyon(gerileme)dahi görülmektedir.
TRIGLYCERIDEMIA
Trigliseridler, düşük yoğunlukta lipitlerdir.Yağlı yemek sonu, alınan serum bekletilirse, üstte kaymak tabakası(chylomicron) birikir.Bu tabaka trigliseridden çok zengindir.Lipoproteinlerle birleştiğinde, trigliseridler çok düşük yoğunluklu lipoprotein(VLDL)yapısını alırlar.Chylomicronlar barsaktan portal ven yolu ile karaciğere taşınır.Oradanda duktus torasikus yolu ile dolaşıma geçer.Kas ve yağ dokusuna geçerek enerjiye dönüşürler.Trigliseridin fazla aterojenik olmadığı kanısı vardı.Fakat trigliseridin (VLDL’in) fazla artışı sonucu VLDL kalıntılarının orta dansiteli lipoproteine(LDL)dönüştüğü; daha yoğun, küçük ve düşük dansiteli LDL’in ortaya çıktığı anlaşılmıştır.Bu değişim, önemli derece aterojenik (hatta LDL-C’den daha etkin) özellik kazandırmaktadır.Bu nedenle trigliserid düzeyini 100-150 mg/dl sınırında tutmak yerinde olur.Genellikle yüksek VLDL’i olanlarda HDL-C düşük olur.VLDL uretimi K.C. gerceklestikten sonra Vasculer Damar yatagina heparan sulfat la baglı endotel hucrelerine yapısmis LPL enzimi VLDL yi tirtiklar total VLDL nin 2/3 reminant IDL ye donusurken 1/3 LDL-C donusurHDL-C,Karaciğer ve barsakta üretilir.HDL-C, kolesterol transportunu tersine çevirir (kolesterolü atardamardan karaciğere taşır); LDL’nin damardaki tortularını temizler. HDL kan kolesterolünün 1/3’ü veya 1/4’ünü taşır. Lipoprotein oksidasyonunu sınırlar. HDL-C aterogenezi önleyici özelliktedir. Düşük olması aterogenezi hızlandırır.Total-C/HDL-C<5,framingham ii="Atherosclerosis">30 kg/m2Şişmanlık, zararlı yağları (LDL-C’ü) artırır; yararlı yağları (HDL-C’ü) düşürür. Şişmanlar tansiyon yükselmesine elverişlidir. Şişmanlarda geç gelişen diabet görülebilmektedir. Şişmanlık KKH gelişimine zemin hazırlar. Şişmanlarda kalbin yükü artar (diastolik disfonksiyon gelişir) Vücut kitle indeksi BMI<25 ii="Atherosclerosis">30 kg/m2Şişmanlık, zararlı yağları (LDL-C’ü) artırır; yararlı yağları (HDL-C’ü) düşürür. Şişmanlar tansiyon yükselmesine elverişlidir. Şişmanlarda geç gelişen diabet görülebilmektedir. Şişmanlık KKH gelişimine zemin hazırlar. Şişmanlarda kalbin yükü artar (diastolik disfonksiyon gelişir) Vücut kitle indeksi BMI<25 bmi="25-29.9">
Risk Factors for Atherosclerosis Nonmodifiable
1.Age
2.Sex
3.Genetic
4.Psycosocial factors.
Yaş ile CAD arasında sıkı bir ilişki vardır. Erkeklerin %52’si, kadınların %47’si CAD’dan olur. Erkeklerde 45 yaş üstü, kadınlarda 55 yaş üzeri ateroskleroz yaşıdır. 2-4 misli erkeklerde fazladır.Cinsiyet ele alınırsa, menapoza kadar kadınlarda KKH ölümü azdır. Menapoz sonu eşitlenir. Genetik yatkınlık için erkeklerde 65 yaş altında ebeveyn veya kardeşlerden birinde; hanımlarda 55 yaş altında aynı bireylerde CAD gelişmesidir. CAD genç yaşa kaydıkça genetik (aile öyküsü) ön plana çıkmaktadır. Risk tedavi sonunda devam eder. Bunlarda primer korunmaya çok önem verilmelidir.Psikososyal Faktörler:Sosyoekonomik durumu bozuk olan toplumlarda depresyon ve asrımızın bir hastalığı olan stres koroner, kalp hastalığı üzerine olumsuz etki yapmaktadır. Stresler (sinir sistemi gerginliği, öfke, sinirsel çatışma, depresyon) katekolamin salgısını artırarak koroner damarları daraltmakta ve ani kalp krizi; ani kardiyak ölüme yol açabilmektedir.Temelde aterosklerozu olanlarda bu etkiler daha belirgin olur. Kişilik ve davranış tipleri ile CAD arasında ilişki olduğunu savunanlar vardır.A tipi(snirli, aceleci,sabırsız, kısa sürede amacına ulaşmak isteyen aşırı ihtiraslı)kişilerde CAD riski daha fazladır.Hiperinsulinemi (insulin direnci) androjen şişmanlık (bel çevresinde şişmanlık), hipertansiyon, periferal insulin direnci; LDL-C, genellikle trigliserid artışı(küçük, yoğun LDL artışı) ve HDL-C düşüşü ile karakterize bir klinik, sendromdur.Ayrıca fibrinogen ve PAI-1 artışı da olur İnsülin güçlü bir trofik hormondur.Katekolaminleri artırır.Ayrıca renal sodyum emilimini artırır.
INSULIN RESISTANCE UND HYPERINSULINEMIA
The clinical associations of insulin resistance
1-Metabolic syndrome
National Cholesterol Education Program Adult Treatment Panel (ATP III),
a-Abdominal obesity: a waist circumference over 102 cm (40 in) in men and over 88 cm (35 inches) in women.
b- Serum triglycerides 150 mg/dl or above.
c- HDL cholesterol 40mg/dl or lower in men and 50mg/dl or lower in women.
d- Blood pressure of 130/85 or more.
e- Fasting blood glucose of 110 mg/dl or above. (Some groups say 100mg/dl)
Any three of the following traits in the same individual meet the criteria for the metabolic syndrome:
Metabolic syndrome is quite common. Approximately 20%-30% of the population in USA industrialized countries have metabolic syndrome.
2-Polycystic ovarian syndrome
3-Non-alcoholic steatohepatitis(Liver Oiled)
4-Secondary to other disease eg pancreatitis, acromegaly
5-Secondary to drug use eg corticosteroids, ant-HIV drugs, diuretics and β-blockers
6-Pre-diabetic states eg impaired glucose tolerance
7-Type 2 diabetes mellitus
Insülin trofik etkisi ile protein sentezi ile arterlerde hipertrofi yapar.NO, salgısını azaltır. Yeni Aterosklerotik Risk Faktörleri -HomosisteinAmino asit türevi olan plasma homosistein artışı vasküler endotele direk toksik etki yapar.EDRF etkisini bozar; LDL oksidasyonunu hızlandırır. Homosistein belirleyicileri folat ile B6 ve B12 vitaminliridir.Homosistein artışı %10 ateroskleroza yol açar denmektedir.
-Fibrinogen yükselmesi trombosit agregasyonuna; kanın vizkozitesinin artışına neden olur.Fibrinogen,yaş, obesite, sigara, şeker hastalığı ve LDL-C ile pozitif ilişkidedir.Az miktarda alkol alınması, fizik aktivite, egsersiz(fizik aktivite) ve HDL-C ile negatif korelasyonu vardır.Tedavide fibrale kullanılır.(%9 fibrinogeni düşürür.) -Fibrinoletik fonksiyon (PAI-1,t-PA, D-Dimer)Endojen fibrinolitik aktivite, doku tipi plasminojen aktivatörü (t-PA)ile bunun inhibitörü (PAI-1)arasındaki denge ile sağlanır.PAI-1 artışı dengeyi bozar.Sabahın erken saatlerinde t-PA düzeyi düşer,PAI-1 yükselir(MI riski artar). Şişmanlarda PAI-1 yükselir.D-Dimer artışıda fibrinolitik işlevi bozar.İnflamasyon İşaretleri (Markerları) -C-Reaktif protein(CRP), inflamasyon göstergesi olan, dolaşımdaki sitokin fonksiyonlarını yansıtan bir proteindir.Aterosklerozun her aşamasında inflamasyon vardır.Önce lokositler, endotele hücum eder; trigliseridler toplanır. Tümör nekroz faktör (TNF) interlokin… gibi sitokinler harekete geçer. Yaşlılarda ve sigara içenlerde yüksek düzeyde C-RP bulunması, ileride inme, myokard infarktüsü (MI) ve periferik damar hastalığı habercisi kabul edilmektedir. İnflamasyon (CRP artışı) MI oluşumunda yeni bir hipotezdir.Lipit düşürülmesi inflamasyonu geriletmektedir
-Lipoprotein (a)
[Lp(a)]Lp(a), apolipoproteine bağlı, LDL’den oluşur. Bağımsız aterojenik olduğu sanılmaktadır. PAI-1 salgısını artırır. Gençlerde ve genetik alanda daha baskındır
Histopathology of atherosclerotic lesion
Stary I lesion: The endothelium also expresses surface adhesion molecules E selectin and P selectin, attracting more polymorphonuclear cells and monocytes in the subendothelial space.
Stary II lesion: Macrophages begin to take up large amounts of LDL (fatty streak).
Stary III lesion: As the process continues, macrophages eventually become foam cells.
Stary IV lesion: Lipid exudes into the extracellular space and begins to coalesce to form the lipid core.
Stary V lesion: SMCs and fibroblasts move in, forming fibroatheromas with soft inner lipid cores and outer fibrous caps.
Stary VI lesion: Rupture of the fibrous cap with resultant thrombosis causes ACS.
Stary VII and VIII lesions: As lesions stabilize, they become fibrocalcific (Stary VII lesion) and, ultimately, fibrotic with extensive collagen content (Stary VIII lesion).
ATHEROSCLEROSIS Part II
BMI="25-29.9"> 50% and may produce predictable exercise-induced stable angina. Clinical consequences of plaque rupture in coronary arteries depend not only on plaque anatomy but also on relative balance of procoagulant and anticoagulant activity in the blood and on the vulnerability of the myocardium to arrhythmias. A link between infection and atherosclerosis has been observed, specifically an association between serologic evidence of certain infections (eg, Chlamydia pneumoniae, cytomegalovirus) and coronary artery disease (CAD). Putative mechanisms include indirect effects of chronic inflammation in the bloodstream, cross-reactive antibodies, and inflammatory effects of infectious pathogens on the arterial wall. Risk Factors There are numerous risk factors
Arteriosclerosis: Risk Factors for Atherosclerosis.
Certain factors tend to cluster as the metabolic syndrome, which is becoming increasingly pr***ent. This syndrome includes abdominal obesity, atherogenic dyslipidemia, hypertension, insulin resistance, a prothrombotic state, and a proinflammatory state in sedentary patients Insulin resistance is not synonymous with the metabolic syndrome but may be key in its etiology.
Risk Factors for Atherosclerosis Nonmodifiable
-Age
-Family history of premature atherosclerosis*
-Male sex
Risk Factor for Atherosclerosis Modifiable
-Established Certain dyslipidemias (high total or LDL level, low HDL level, increased total to HDL cholesterol ratio)
-Cigarette smoking
-Diabetes mellitus
Acute comlications
Chronic comlications
Microvascular Complications
*Eye disease
-Retinopathy (nonproliferative/proliferative)
-Macular edema
*Neuropathy
-Sensory and motor (mono- and polyneuropathy)
-Autonomic
*Nephropathy
Macrovascular Complications
*Coronary artery disease
*Peripheral vascular disease
*Cerebrovascular disease
Other
*Gastrointestinal (gastroparesis, diarrhea)
*Genitourinary (uropathy/sexual dysfunction)
*Dermatologic
*Infectious
*Cataracts
*Glaucoma
-Hypertension Modifiable, under study
-Alcohol intake (other than moderate) Chlamydia pneumoniae infection
-High CRP level
-High level of small, dense LDL
-High lipoprotein(a) level
-Hyperhomocysteinemia
-Hyperinsulinemia
-Hypertriglyceridemia
-5-Lipoxygenase polymorphisms
-Low intake of fruits and vegetables Obesity or metabolic syndrome Prothrombotic states (eg, hyperfibrinogenemia, high plasminogen activator inhibitor level)
-Psychosocial factors (eg, type A personality, depression, anxiety, work characteristics, socioeconomic status)
-Renal insufficiency Sedentary lifestyle† CRP = C-reactive protein, HDL = high density lipoprotein, LDL = low density lipoprotein. *Disease in a first-degree relative before age 55 for men and before age 65 for women. †How much these factors contribute independent of other frequently-associated risk factors (eg, diabetes, dyslipidemia) is unclear.
Dyslipidemia (high total, high LDL, or low high density lipoprotein [HDL] cholesterol), hypertension, and diabetes promote atherosclerosis by amplifying or augmenting endothelial dys**** and inflammatory pathways in vascular endothelium. In dyslipidemia, subendothelial uptake and oxidation of LDL increases; oxidized lipids stimulate production of adhesion molecules and inflammatory cytokines and may be antigenic,
inciting
a T cell–mediated immune response and inflammation in the arterial wall. HDL protects against atherosclerosis via reverse cholesterol transport it may also protect by transporting antioxidant enzymes, which can break down and neutralize oxidized lipids.
The role of hypertriglyceridemia in atherogenesis is complex, although it may have a small independent effect. Hypertension may lead to vascular inflammation via angiotensin II–mediated mechanisms. Angiotensin II stimulates endothelial cells,
vascular smooth muscle cells, and macrophages to produce proatherogenic mediators, including proinflammatory cytokines; superoxide anions; prothrombotic factors; growth factors; and lectin-like oxidized LDL receptors.
Diabetes leads to the formation of advanced glycation end products, which increase the production of proinflammatory cytokines from endothelial cells. Oxidative stress and reactive oxygen radicals, generated in diabetes, directly injure the endothelium and promote atherogenesis.
Tobacco smoke contains nicotine and other chemicals that are toxic to vascular endothelium. Smoking, including passive smoking, increases platelet reactivity (possibly promoting platelet thrombosis) and plasma fibrinogen levels and Hct (increasing blood viscosity). Smoking increases LDL and decreases HDL; it also promotes vasoconstriction, which is particularly dangerous in arteries already narrowed by atherosclerosis. HDL increases by about 6 to 8 mg/dL (0.16 to 0.21 mmol/L) within 1 mo of smoking cessation.
Hyperhomocysteinemia increases risk of atherosclerosis, although not as much as the above risk factors. It may result from folate deficiency or a genetic metabolic defect. The pathophysiologic mechanism is unknown but may involve direct endothelial injury,
stimulation of monocyte and T-cell recruitment, LDL uptake by macrophages, and smooth muscle cell proliferation.
Lipoprotein(a) is a modified form of LDL that has a cysteine-rich region homologous with the fibrin-binding domain of plasminogen. High levels of lipoprotein(a) may compete with fibrin to bind with plasminogen and thus interfere with thrombolysis, predisposing to atherothrombosis. A high level of small, dense LDL, characteristic of diabetes, is highly atherogenic.
Mechanisms may include increased susceptibility to oxidation and nonspecific endothelial binding
A high C-reactive protein (CRP) level does not reliably predict extent of atherosclerosis but can predict increased likelihood of ischemic events. In the absence of other inflammatory disorders, it may indicate increased risk of atherosclerotic plaque rupture, ongoing ulceration or thrombosis,
or increased activity of lymphocytes and macrophages. CRP may have a direct role in atherogenesis through multiple mechanisms, including downregulation of nitric oxide synthesis and upregulation of angiotensin type 1 receptors, chemoattractant proteins, and adhesion molecules. C. pneumoniae infection or other infections (eg, viral, Helicobacter pylori) may cause endothelial dys**** through direct infection, exposure to endotoxin, or stimulation of systemic or subendothelial inflammation.
Renal insufficiency promotes development of atherosclerosis via several pathways, including worsening hypertension and insulin resistance, decreased apolipoprotein A-I levels, and increased lipoprotein(a), homocysteine, fibrinogen, and CRP levels. Prothrombotic states increase likelihood of atherothrombosis.
5-Lipoxygenase polymorphisms (deletion or addition of alleles) may promote atherosclerosis by increasing leukotriene production within plaques, which causes vascular permeability and monocyte-macrophage migration, thus increasing subendothelial inflammation and dys****. Documented vascular disease: The presence of atherosclerotic disease in one vascular territory increases the likelihood of disease in other vascular territories. Patients with noncoronary atherosclerotic vascular disease have cardiac event rates comparable to those of patients with known CAD, and they are now considered to have a CAD risk equivalent and should be treated as aggressively. Symptoms and Signs Atherosclerosis is initially asymptomatic, often for decades. Symptoms and signs develop when lesions impede blood flow.
Transient ischemic symptoms (eg, stable exertional angina, transient ischemic attacks, intermittent claudication) may develop when stable plaques grow and reduce the arterial lumen by > 70%. Symptoms of unstable angina or infarction, ischemic stroke, or rest pain in the limbs may develop when unstable plaques rupture and acutely occlude a major artery, with superimposition of thrombosis or embolism.
Atherosclerosis may also cause sudden death without preceding stable or unstable angina pectoris. Atherosclerotic involvement of the arterial wall can lead to aneurysms and arterial dissection, which can manifest as pain, a pulsatile mass, absent pulses, or sudden death. Diagnosis Approach depends on the presence or absence of symptoms. Symptomatic patients: Patients with symptoms and signs of ischemia are *uated for the amount and location of vascular occlusion by various invasive and noninvasive tests, depending on the organ involved (see elsewhere in The Manual). Such patients also should be *uated for atherosclerosis risk factors by using History and physical examination Fasting lipid profile Plasma glucose and glycosylated hemoglobin (HbA1c) levels Patients with documented disease at one site (eg, peripheral arteries) should be ***uated for disease at other sites (eg, coronary and carotid arteries). Because not all atherosclerotic plaques have similar risk, various imaging technologies are being studied as a way to identify plaques especially vulnerable to rupture.
Most technologies are catheter-based; they include intravascular ultrasonography (which uses an ultrasound transducer on the tip of a catheter to produce images of the arterial lumen and wall), angioscopy, plaque thermography (to detect the increased temperature in plaques with active inflammation), optical coherence tomography (which uses infrared laser light for imaging), and elastography (to identify soft, lipid-rich plaques). Immunoscintigraphy is a noninvasive alternative using radioactive tracers that localize in vulnerable plaque. Some clinicians measure serum markers of inflammation.
CRP levels > 3 mg/dL (> 3000 μg/L) are highly predictive of cardiovascular events. High levels of lipoprotein-associated phospholipase A2 appear to predict cardiovascular events in patients with a normal or low LDL level. Asymptomatic patients (screening): In patients with risk factors for atherosclerosis but no symptoms or signs of ischemia, the role of additional testing beyond the fasting lipid profile is unclear. Although imaging studies such as electron beam or multidetector row CT, MRI, and ultrasound (see Principles of Radiologic Imaging) can detect atherosclerotic plaque,
they probably do not improve prediction of ischemic events over assessment of risk factors or established prediction tools Urinary microalbuminuria (> 30 mg albumin/24 h) is a marker for renal disorders and their progression, as well as a strong predictor of cardiovascular and noncardiovascular morbidity and mortality; however, the direct relationship between microalbuminuria and atherosclerosis has not been established. Treatment Lifestyle changes (diet, smoking, physical activity) Drug treatment of diagnosed risk factors Antiplatelet drugs Possibly statins, ACE inhibitors, β-blockers Treatment involves aggressive modification of risk factors to slow progression and induce regression of existing plaques. Recent evidence suggests that LDL should be
HUMBOLDT Universität Medizinischen Fakultät HERZ-ADER CHIROGI GERHARD Alexander,MD(Assistent Artz)