cardiology3 Flashcards
atherosclerosis
a specific form of arteriosclerosis in which an artery wall thickens as a result of invasion and accumulation of white blood cells (WBCs). Atherosclerosis is therefore a syndrome affecting arterial blood vessels due to a chronic inflammatory response of WBCs in the walls of arteries. This is promoted by low-density lipoproteins (LDL, plasma proteins that carry cholesterol and triglycerides) without adequate removal of fats and cholesterol from the macrophages by functional high-density lipoproteins (HDL). It is commonly referred to as a “hardening” or furring of the arteries. It is caused by the formation of multiple atheromatous plaques within the arteries.
Process of atherosclerosis
endothelial injury causes lipid deposition and macrophage and T cell recruitment leading to formation of a fatty streak. Acitvated macrophages (foam cells); smooth muscle proliferation forms a fibrous cap; which leads to a progressive lipid accumulation in core of plaque. Now, the atherosclerotic plaque is no long clinically silent and is potentially occlusive leading to effort angina or claudication. Acutely, the plaque could rupture or fissure due to disruption causing thrombus formation and vessel occlusion. This could lead to unstable angina, myocardial infarction, stroke, or critical leg ischemia.
Fatty streaks
The accumulation of the WBCs is termed “fatty streaks” early on because of appearance being similar to that of marbled steak. These accumulations contain both living, active WBCs (producing inflammation) and remnants of dead cells, including cholesterol and triglycerides. The remnants eventually include calcium and other crystallized materials, within the outermost and oldest plaque. The “fatty streaks” reduce the elasticity of the artery walls. However, they do not affect blood flow for decades, because the artery muscular wall enlarges at the locations of plaque. The wall stiffening may eventually increase pulse pressure; widened pulse pressure is one possible result of advanced disease within the major arteries.
The plaque is divided into three distinct components
The atheroma (“lump of gruel”, meaning “gruel”), which is the nodular accumulation of a soft, flaky, yellowish material at the center of large plaques, composed of macrophages nearest the lumen of the artery. Underlying areas of cholesterol crystals. Calcification at the outer base of older or more advanced lesions.
Pathobiology of atherosclerotic lesions
The pathobiology of atherosclerotic lesions is very complicated but generally, stable atherosclerotic plaques, which tend to be asymptomatic, are rich in extracellular matrix and smooth muscle cells, while, unstable plaques are rich in macrophages and foam cells and the extracellular matrix separating the lesion from the arterial lumen (also known as the fibrous cap) is usually weak and prone to rupture. Ruptures of the fibrous cap expose thrombogenic material, such as collagen, to the circulation and eventually induce thrombus formation in the lumen. Upon formation, intraluminal thrombi can occlude arteries outright (e.g. coronary occlusion), but more often they detach, move into the circulation and eventually occluding smaller downstream branches causing thromboembolism. Apart from thromboembolism, chronically expanding atherosclerotic lesions can cause complete closure of the lumen. Chronically expanding lesions are often asymptomatic until lumen stenosis is so severe (usually over 80%) that blood supply to downstream tissue(s) is insufficient, resulting in ischemia.
Risk factors for coronary artery disease
risk reducing treatable factors include smoking, hypertension, and dyslipidemia. Treatable factors with unclear risk include diabetes/ insulin resistance, obesity, inflammation, psychological stress, and sedentary lifestyle. Untreatable risk factors include male gender, age, and majority of the genetic factors.
Smoking risk for atherosclerosis
has a 50% increase in CAD risk. Mechanisms of risks include thrombogenic tendency, platelet activation, increased fibrinogen, Aryl hydrocarbon compounds promote atherosclerosis, endothelial dysfunction, vasospasm, CO decreases myocardial oxygen delivery and Adverse effect on lipoproteins (decreased HDL). Cessation can normalize risk
Atherosclerotic risk due to hypertension
Graded risk depending on blood pressure. Mechanisms of risk: Increased shear stress on arterial wall causes direct endothelial cell injury, Increased arterial wall stress initiates pathologic cell signaling program causing oxidant stress, cellular proliferation, Circulating hormones increased in HTN (angiotensin, aldosterone, norepinephrine) exert adverse effects on arterial wall, and A chronic increase in heart work causes left ventricular hypertrophy which may be an independent risk factor. Treatment of hypertension reduces cardiovascular risk
Diabetes and insulin resistance
are associated with inflammation, oxidative stress, dyslipidemia that predispose to atherosclerosis.
Dyslipidemia and risk of CHD
The dyslipidemic triad includes high low-density lipoprotein cholesterol (LDL), low high-density lipoprotein cholesterol (HDL), and high triglycerides. Each may be an independent risk factor and respond to different forms of therapy.
Deleterious effects of LDL cholesterol
when oxidized, LDL cholesterol becomes pro-inflammatory and atherogenic. Injured vascular endothelium impairs endothelial function. Deposited in arterial and taken up by macrophages causes progressive increase in plaque volume. This activates inflammatory cells that play a role in progression and instability of lesions. It also activates platelets and pro thrombotic events.
Beneficial effects of HDL cholesterol
It inhibits oxidation of LDLs, inhibits tissue factor, enhances reverse cholesterol transport, stimulates endothelial NO production and inhibits endothelial adhesion molecules. All of these actions oppose atherothrombosis
Inflammation and CHD
Inflammation plays a key role in initiation and progression of atherosclerosis. Lipid-laden macrophages in arterial wall plaque are highly pro-inflammatory. Extravascular inflammation (dental, respiratory, immunologic diseases) may also increase the risk of atherosclerotic cardiovascular events. Circulating markers of inflammation (e.g., C-reactive protein) provide information about future CV risk. Both lipids and inflammatory markers predict risk of a first cardiovascular event in healthy subjects
C-reactive protein (CRP)
is an annular (ring-shaped), pentameric protein found in the blood plasma, the levels of which rise in response to inflammation (i.e., C-reactive protein is an acute-phase protein of hepatic origin that increases following interleukin-6 secretion from macrophages and T cells). Its physiological role is to bind to lysophosphatidylcholine expressed on the surface of dead or dying cells (and some types of bacteria) in order to activate the complement system via the C1Q complex. CRP is synthesized by the liver in response to factors released by macrophages and fat cells (adipocytes). It is a member of the pentraxin family of proteins. CRP is used mainly as a marker of inflammation. Apart from liver failure, there are few known factors that interfere with CRP production.
Stable Coronary Artery Disease
Pathophysiology: Obstructive coronary lesion limits coronary flow and causes myocardial ischemia (tissue blood flow insufficient to meet oxygen requirements), particularly when cardiac work and oxygen demand increase. Myocardial ischemia = imbalance between coronary oxygen delivery and myocardial oxygen demand. Cardinal symptom of myocardial ischemia: chest pain (angina pectoris)
What’s different about the coronary circulation?
Unlike skeletal muscle, the myocardium depends on aerobic metabolism for energy supply. Under resting conditions, a near-maximal amount of oxygen is extracted from coronary arterial blood; therefore, the only effective means of increasing myocardial O2 supply is to increase blood flow rate. The left ventricle is perfused in diastole only
Determinants of myocardial O2 supply
Coronary flood flow rate ( due to perfusion pressure, perfusion time (1/HR), and vascular resistance), oxygen content of blood, oxygen delivery (mmol/min) = CBF rate (ml/min), and x oxygen content (mmol/ml).
Perfusion pressure
it is autoregulation of blood flow. In the normal coronary circulation, autoregulation provides protection from moderate changes in perfusion pressure. Autoregulation occurs at the level of small arterioles. In coronary heart disease, autoregulation may be exhausted when pressure drops across an epicardial coronary stenosis. As epicardial coronar stenosis causes a drop in perfusion pressure. The pressure across lesion is proportional to stenosis length (L0 and diameter (d)^-4. Dilation of resistance vessels can compensate for pressure drop across stenosis (autoregulation). An epicardial coronary stenosis may cause autpregulation to be exhausted and lead to ischemia. Increasing stenosis severity exhausts autoregulation so that coronay flow cannot increase further.
Diastolic perfusion time
LV perfusion predominantly diastolic because of compression of intramural coronary vessels in systole. Increased heart rate shortens the cardiac cycle, predominantly by shortening diastole. Tachycardia can therefore compromise coronary flow. Coronary stenosis may be dynamic due to the effect of vasomotor tone.
Myocardial O2 supply
it is equal to oxygen content of arterial blood. Oxygen delivery (mol/min) = coronary flow rate (ml/min) x arterial oxygen content (mol O2/ml blood). Oxygen supply may be compromised by anemia(less hemoglobin per ml blood) or hypoxemia (incomplete saturation of hemoglobin)
Treatment of chronic stable angina
treatment aims at increasing O2 supply. Factor effecting O2 supply include perfusion pressure (preventing hypotension), diastolic time (due to rate-slowing drugs), coronary resistance (changeable with vasodilator drugs (nitrates, calcium channel blockers), coronary angioplasty or bypass surgery), and oxygen content (can treat anemia and hypoxemia). Other factors (and treatments) includes controlling systolic pressure (antihypertensive drugs), heart rate (rate-slowing drugs (e.g. beta blockers calcium channel blockers)), wall tension (limit V cavity size by limiting excessive preload with diuretics and nitrates), and inotropic state (negative inotropes to attenuate contractile state such as beta blockers and calcium channel blockers).
Determinants of myocardial O2 demand
heart rate, wall tension, and inotropic state.
Factors that increase myocardial oxygen demand
Heart rate and Wall tension. Determinants are systolic blood pressure and cardiac chamber dimension, according to Law of LaPlace: Wall tension proportional to cavity pressure (P), cavity dimension (r), and 1/wall thickness). Inotropic state (contractility). Higher tension means higher oxygen demand for arteries.
Pathophysiology of unstable coronary syndromes
Inflammation in arterial wall. Weakening of fibromuscular cap. Abrupt plaque fissure or rupture. Thrombogenic components (lipids, tissue factor) exposed to blood. Thrombosis with partial or complete vessel occlusion. Myocardial injury and/or necrosis (serum markers). Cardiac dysfunction, risk of arrhythmias, death. Inflammation can cause stable, mature plaques into unstable, ruptured plaque.
The characteristic features of ruptured plaques
a thin fibrous cap; a higher ratio of macrophages to vascular smooth muscle cells (VSMCs) in the cap; less collagen, the main strength-giving component, in the cap; and a large, lipid-rich, collagen-poor necrotic core
Inflammation and plaque instability
Plaques vulnerable to rupture have thin fibrous caps, an excess of macrophages over vascular smooth muscle cells, large lipid cores, and depletion of collagen and other matrix proteins form the cap and lipid core. Production of matrix metalloproteinases from macrophages is prominent in human plaques, and studies in genetically modified mice imply a causative role for metalloproteinases in plaque vulnerability. Loss of collagen and other extracellular matrix (ECM) components occurs in the highly-inflamed regions of plaque cap thereby reducing tensile strength; it also occurs in the lipid core, which promotes transfer of hydrodynamic forces during the cardiac cycle to the high-strain, shoulder regions of the plaque. Apart from scavenging cholesterol to form foam cells, plaque macrophages participate in an arterial immune-inflammatory reaction most likely initiated by oxidised phospholipids and cholesterol derivatives derived from low-density lipoprotein (LDL). Enzymic and oxidative modification of LDL triggers both innate and acquired immunity. Among the lymphocytes, CD4+ T-helper (Th) cells predominate in plaques. Initially present in a Th0 ground state, Th cells can differentiate to Th1 cells, which secrete and respond to interferon (IFN-γ) or to Th2 cells, which secrete and respond to interleukin (IL)-4. Not surprisingly, therefore, IFN-γ promotes atherosclerosis formation.
Unstable coronary disease
Unstable angina. Near-complete occlusion of vessel with thrombus. “Threatened” heart attack. Biomarkers (e.g., troponin) usually negative. May not result in permanent myocardial damage if treated successfully. High risk of recurrent events in first year. Persistent and severe coronary flow reduction. Thrombus usually with complete vessel occlusion. Wavefront of myocardial necrosis; leads to cardiac dysfunction and failure; biomarkers (troponin) elevated. Cardinal symptom: severe and unremitting chest discomfort at rest (although 30% of MI’s are “silent”). Early reperfusion is key to treatment, but may also provoke additional injury (reperfusion injury). High early mortality: 1/3 of patients don’t get to hospital. Late mortality related to extent of LV dysfunction
Markers of vascular inflammation and myocardial injury in unstable CAD
inflamed arterial atheroma have inflammatory markers (e.g. CRP). Down stream myocardial injury have cardiac markers such as troponin and creatine kinase.
Impact of HTN on the CV system
Increased Resistance to blood flow accelerates atherosclerosis, leads to LV hypertrophy – more muscle and thicker heart. LVH ultimately leads to LV dilation & heart failure. Hypertension is the No. 1 risk factor for Heart Failure. LV mass greater in pre hypertensives than in normotensive. CRP as a marker of inflammation may be increased. BP and lipid control account for the 40% decline in CVD mortality in the last decade.
CVD myths debunked
Raising HDL with drugs reduces CVD. Tight glycemic control reduces CVD events in Type II DM. Aspirin reduces CVD events in Type II DM. Smoke-free policy definitively reduces the risk of acute myocardial infarction
Acute coronary syndrome (ACS)
any array of clinical symptoms resulting from underlying acute myocardial ischemia
Causes of ACS
Atherosclerotic plaque rupture with thrombus, Coronary embolism, Congenital anomalies
Coronary trauma or aneurysm,
Severe coronary artery spasm (e.g. cocaine), Increased blood viscosity,
Spontaneous coronary dissection, and
Markedly increased myocardial 02 demand
Pathophysiology of ACS
Inflammation + risk factors promote atherosclerosis Primary risk factors include: Diabetes, hypertension, hyperlipidemia, tobacco Other possible risk factors: poor diet, inactivity, obesity, kidney disease, family history. Atherosclerosis promotes a dysfunctional endothelium Dysfunctional endothelium has decreased vasodilator effect and decreased antithrombotic effect compared to normal endothelium. Inflammatory mediators weaken the atherosclerotic fibrous cap; if cap bursts, thrombogenic tissue factor is released, activating the coagulation cascade and creating platelet aggregation. Dysfunctional endothelium + coagulation + platelet aggregation = Coronary thrombosis
Troponin (I and T)
Regulatory proteins involved in actin-myosin interaction. Felt specific to heart. Released into bloodstream with myocyte necrosis. Myocardial necrosis leads to release of Troponin into blood within 3-12 hours, peaking in 18-24 hours. Troponin felt to be more specific, remains elevated longer. Look for rise and fall in appropriate time frame (prolonged in renal failure)
Distinctions of ACS Spectrum Caused by Coronary Thrombosis
Complete coronary vessel occlusion: ST elevation myocardial infarction (STEMI).
Partial coronary vessel occlusion with myocardial necrosis: non ST elevation MI (NSTEMI).
Partial coronary vessel occlusion, escalating symptoms without myocardial necrosis: Unstable angina.
CK-MB isoforms
time to initial elevation is 4-6 hous. Time to peak elevation is 18 hours. Time to return to normal 2-4 days.
cTnI
time to initial elevation is 4-6 hours. Time to peak elevation is 12 hours. Time to return to normal is 3-10 days.
cTnT
time to initial elevation is 4-6 hours. Time to peak elevation 12-48 hours. Time to return to normal is 7-10 days.
Serum Markers of Myocardial Necrosis
Necrosis of myocardial tissue causes intracellular leak of molecules into the bloodstream. Detection of these molecules, especially cardiac troponin is important to diagnose MI. Cardiac troponin is very sensitive and specific for myocardium.
Angina
discomfort due to myocardial ischemia classically experienced as substernal chest pain or tightness, but may be less classicàleft arm pain, shortness of breath, nausea, weakness
Stable angina
present when there is increased demand for myocardial oxygen in a reproducible fashion
Unstable angina
discomfort which is new in onset or is increased in duration, frequency or intensity with less exertion or at rest compared to previous episodes of discomfort
Goals of treatment of ACS
relief of ischemia by reducing myocardial oxygen demand and opening the artery or prevent further arterial occlusion. And prevent adverse outcomes.
Treatment of STEMI
Artery is occluded so need to open it. If artery can be opened within 90 minutes, go to cardiac cath lab to open mechanically (cardiac catheterization). If cannot be opened within 90 minutes, consider fibrinolytics. If hemodynamically stable, consider oral beta blockers or nitrates to decrease myocardial oxygen demand
Treatment of NSTEMI / Unstable Angina
Artery is partially occluded need to halt the thrombotic process from completely occluding the artery by giving anticoagulant and antiplatelet agents. Anticoagulants: unfractionated heparin, low-molecular weight heparin, fondaparinux Antiplatelets: P2Y12 inhibitors (clopidogrel, prasugrel, ticagrelor), GIIb/IIIa inhibitors PLUS Aspirin
If hemodynamically stable, consider oral beta blockers or nitrates to decrease myocardial oxygen.
Diagnosis of stable coronary artery disease
History: chest pain, dyspnea, risk factors. Physical examination: May be normal, or reveal evidence of cardiac dysfunction from prior myocardial damage (congestive heart failure), evidence of atherosclerosis in other vascular beds. Electrocardiogram at rest or with exercise (stress test). Non-invasive imaging: echocardiography, nuclear medicine (perfusion imaging), ultrafast CT. Coronary angiography
Diagnosis of Coronary Artery Disease from ECG
Resting ECG: ST segment changes (usually depression), T wave inversion, and Q-waves (indicate prior infarction). Exercise ECG (stress testing): dynamic ST segment changes
Problems with ECG diagnosis
Resting ECG is insensitive. Exercise ECG: Sensitivity and specificity still suboptimal (~70% and 75%, respectively)
Stress ECG
Ischemic response: horizontal or downsloping ST depression with exercise, reflecting subendocardial ischemia. Functional information (exercise time and intensity) and accompanying symptoms help to interpret the results. Concurrent imaging of myocardial perfusion (radiopharmaceuticals) or wall motion (echocardiography) improves sensitivity and specificity of stress ECG
Diagnosis of Coronary Artery Disease by CT or direct angiography
Picture of the vessel lumen – but does not tell us about the vessel wall. Good for diagnosis of coronary obstruction causing anginal symptoms; not as good for predicting future events. Guides therapeutic intervention (angioplasty, bypass surgery)
Treatment of Coronary Artery Disease
Risk factor modification (for prevention AND treatment of overt disease) such as diet, exercise, smoking cessation. Drugs to treat angina, blood pressure, lipids, platelets. Revascularization with coronary angioplasty or coronary artery bypass surgery
Classes of drugs useful in treatment of Coronary heart disease
Lipid-modifying: Statins. Anti-platelet: Aspirin, clopidogrel. Anti-anginal: Nitrates, beta blockers, calcium channel blockers. LV dysfunction: ACE inhibitors or angiotensin receptor blocker
Acute treatment of Unstable Angina
Hospitalization, Intravenous nitroglycerin, Beta blockers, Aspirin and other anti-platelet agents, Anticoagulation (heparin), and Usually early catheterization and coronary intervention
Problems with balloon angioplasty
Problem: acute occlusion. Solution: stents and antiplatelet drugs. Problem: Restenosis. Solution: Stents, particularly those that elute antiproliferative drugs
Treatment of acute myocardial infarction with ST elevation
Treatment may be initiated in the field. Immediate aspirin, nitroglycerin, ± beta blocker. Reperfusion therapy ASAP: Usually coronary angioplasty, if unavailable thrombolytic therapy.
Coronary artery bypass grafting
Not all coronary obstructions can be treated percutaneously (angioplasty); some require bypass surgery (CABG). In randomized clinical trials, bypass surgery has been shown to reduce mortality in selected patients, compared to medical therapy, and may be better than angioplasty when there are multiple blockages. Principal types of grafts: Internal mammary artery, Saphenous vein, and Prosthetic materials have not proven successful as coronary grafts
Normal vs. abnormal vascular endothelial cell function
normal: impermeable to large molecules, anti-inflammatory, resist leukocyte adhesion, promote vasodilation, and resist thrombosis. Activated/abnormal: increased permeability, increased inflammatory cytokines, increased leukocyte adhesion molecules, decreased vasodilatory molecules, decreased antithrombotic molecules.
Normal vs. abnormal vascular smooth muscle cell function
normal: normal contractile function, maintain extracellular matrix, and contained in medial layer. Activated/abnormal smooth muscle cell: increased inflammatory cytokines, increased extracellular matrix synthesis, and increased migration and proliferation into subintima.
Nitric Oxide Synthase
Expressed on luminal side of endothelium. Responds to multiple stimuli. NO from Arginine. Multiple cofactors. NO diffuses to smooth muscle in media. cGMP-mediated vasodilatation.
Nitric Oxide and Healthy Endothelium
triggers such as acetylcholine, serotonin, thrombin, bradykinin, and shear stress. Nitric oxide, known as the ‘endothelium-derived relaxing factor’, or ‘EDRF’, is biosynthesized endogenously from L-arginine, oxygen, and NADPH by various nitric oxide synthase (NOS) enzymes. Reduction of inorganic nitrate may also serve to make nitric oxide. The endothelium (inner lining) of blood vessels uses nitric oxide to signal the surrounding smooth muscle to relax, thus resulting in vasodilation and increasing blood flow. Nitric oxide is highly reactive (having a lifetime of a few seconds), yet diffuses freely across membranes. These attributes make nitric oxide ideal for a transient paracrine (between adjacent cells) and autocrine (within a single cell) signaling molecule.
Mechanism of action of NO
There are several mechanisms by which NO has been demonstrated to affect the biology of living cells. These include oxidation of iron-containing proteins such as ribonucleotide reductase and aconitase, activation of the soluble guanylate cyclase, ADP ribosylation of proteins, protein sulfhydryl group nitrosylation, and iron regulatory factor activation. NO has been demonstrated to activate NF-κB in peripheral blood mononuclear cells, an important transcription factor in iNOS gene expression in response to inflammation. It was found that NO acts through the stimulation of the soluble guanylate cyclase, which is a heterodimeric enzyme with subsequent formation of cyclic-GMP. Cyclic-GMP activates protein kinase G, which causes reuptake of Ca2+ and the opening of calcium-activated potassium channels. The fall in concentration of Ca2+ ensures that the myosin light-chain kinase (MLCK) can no longer phosphorylate the myosin molecule, thereby stopping the crossbridge cycle and leading to relaxation of the smooth muscle cell.
Generation of inflammatory state in endothelial cell
decreased NO and oxidative stress causes signals at the endothelial cell leading to transcription and translation of pro-inflammatory proteins. Such molecules include selectins, cell adhesion molecules for monocyte, and cytokines. Initial damage to the endothelium results in an inflammatory response. Monocytes enter the artery wall from the bloodstream, with platelets adhering to the area of insult. This may be promoted by redox signaling induction of factors such as VCAM-1, which recruit circulating monocytes, and M-CSF, which is selectively required for the differentiation of monocytes to macrophages. The monocytes differentiate into macrophages, which ingest oxidized LDL, slowly turning into large “foam cells” – so-called because of their changed appearance resulting from the numerous internal cytoplasmic vesicles and resulting high lipid content. Under the microscope, the lesion now appears as a fatty streak. Foam cells eventually die, and further propagate the inflammatory process. There is also smooth muscle proliferation and migration from the tunica media into the intima responding to cytokines secreted by damaged endothelial cells. This causes the formation of a fibrous capsule covering the fatty streak. Intact endothelium could prevent the proliferation by releasing nitric oxide.
Progression of Atherosclerotic plaque
first, a fatty streak develops leading to endothelial dysfunction, lipoprotein entry and modification, leukocyte recruitment, and foam cell formation. Next, plaque progression occurs leading to smooth muscle cell migration and altered matrix synthesis and degradation. Disruption of the plaque integrity leads to thrombus formation.
fibrous cap
a layer of fibrous connective tissue, which is thicker and less cellular than the normal intima, found in atherosclerotic plaques. The fibrous cap contains macrophages and smooth muscle cells. The fibrous cap of an atheroma is composed of bundles of muscle cells, macrophages, foam cells, lymphocytes, collagen and elastin. The fibrous cap is prone to rupture and ulceration which can lead to thrombosis. In advanced lesions further complications may arise including calcification of the fibrous cap. Foam cells release MMPs, causing degradation of the fibrous cap.
Stable vs. vulnerable plaques
Atherosclerotic lesions, or atherosclerotic plaques, are separated into two broad categories: Stable and unstable (also called vulnerable).[4] The pathobiology of atherosclerotic lesions is very complicated but generally, stable atherosclerotic plaques, which tend to be asymptomatic, are rich in extracellular matrix and smooth muscle cells, while, unstable plaques are rich in macrophages and foam cells and the extracellular matrix separating the lesion from the arterial lumen (also known as the fibrous cap) is usually weak and prone to rupture. Stable plaques are rich in fibrous tissue, calcified, and have less lipid content, inflammation, and apoptosis. Vulnerable plaques have less fibrous tissue and calcification and more lipid content, inflammation, apoptosis. A rupture of a plaque can lead thrombus formation. Much of thrombosis is regulated by molecules expressed on surface of or secreted by endothelium. Such molecules include heparin sulfate, thrombin, NO, platelet activation, and prostacyclin.
Common mechanisms of stroke
Atheroembolization from carotid bifurcation lesion. Source lesion does not need to be obstructive (<70% diameter reduction). Often lodged in the ophthalmic artery. Thromboembolization from left atrial appendage in setting of atrial fibrillation.
Common mechanism of coronary artery disease
Myocardial infarction and chronic stable angina are both manifestations of CAD. However, vascular pathology is different. MI – ruptured plaque, in-situ thrombosis, not necessarily obstructive prior to rupture. Angina – stable, obstructive (>70% diameter reduction) lesion
Myocardial infarction
Not all the same severity. Plaque rupture à non-occlusive thrombosis à some flow but intermittent occlusion or embolization à stabilize with anticoagulation / vasodilators. Plaque rupture à occlusive thrombus à no flow à clinical emergency à recanalize
Clinical sequence of ruptured coronary plaque
Coronary thrombus can be small (non-flow limiting), partially occlusive, or completely occlusive. Small thrombus have no ECG changes and can lead to either healing and/or plaque enlargement. Partially occlusive thrombus have ST segment depression and/or T wave inversion with or without serum markers. When serum biomarkers are present, it is a non-ST-segment elevation MI. When it is not present, there may be an unstable angina. Occlusive thrombus may be transient (similar presentation as partially occlusive thrombus) or prolonged presenting as ST elevation (Q waves later). Serum biomarkers are also present here for ST segment elevation MI
Mechanism of peripheral arterial disease
Claudication and acute limb ischemia are manifestations of PAD. However, underlying endothelial pathology differs. Claudication: obstructive (>70% diameter reduction), stable plaque. Acute limb ischemia: acute event obstructs blood flow without prior development of collaterals, could be atheroembolization or thromboembolization, rarely in-situ thrombosis.
Stable plaques
less biologically active. Cause angina and claudication (exertional ischemia) if obstructive (>70% diameter reduction). less likely to cause thrombotic and embolic events
Unstable / Vulnerable plaques
more biologically active, cause MI and stroke, and more likely via thrombotic and embolic mechanisms
Mechanism of venous thromboembolic disease
Includes deep venous thrombosis and pulmonary embolism. Venous thrombosis different than arterial thrombosis
Venous vs Arterial Thrombosis
Venous Thrombosis is Fibrin rich, RBC, Areas of stasis, Genetic predisposition, Environmental predisposition, Treated with anticoagulation. Arterial Thrombosis is Platelet rich, Plaque rupture, Areas of high flow, Atherosclerosis, trauma, APLA. Focus more on antiplatelet therapy.
Vasospastic Disorders
Raynaud’s (primary vs secondary), Pernio, Erythromyalgia, Acrocyanosis. Dysfunctional endothelium involved but not necessarily thrombosis or atherosclerosis
Micro-bubbles
Red blood cells ~ 6 - 8 µm in diameter. Micro-bubbles < 10 µm pass through pulmonary capillaries. Agitated saline: Creates micro-bubbles ~ 16 µm in diameter. Do not pass through pulmonary capillaries. Do not show up in left heart unless right to left communication and flow. If they do show up it is a sign of either intra-cardiac shunt or Intra-pulmonary shunt
Types of Coronary Artery Disease (CAD)
Asymptomatic, non-obstructive CAD, Ischemia (Stable exertional angina or Unstable angina), Myocardial infarction (MI), cellular necrosis
General concepts of stress testing
Precipitate ischemia by increasing myocardial oxygen demand (stress). Identify ischemia by changes in: blood pressure, ECG, symptoms, blood flow (perfusion) imaging, and wall motion (echocardiography) imaging.
Indications for exercise treadmill test
Screening for coronary artery disease (CAD), Evaluate chest pain, Exercise capacity, Prognosis, and Evaluation after revascularization
Contraindications of an Exercise treadmill test
Unstable angina, Untreated life-threatening arrhythmias, Uncompensated heart failure, Advanced AV block, Acute myocarditis, pericarditis, Critical aortic stenosis, Significant HOCM, Uncontrolled HTN, and Acute systemic illness
Imaging Stress Tests
Radionuclide or Echocardiography. Exercise with either Treadmill or Bicycle. Pharmacologic Vasodilator (Dipyridamole (Persantine), Adenosine (Adenocard), and Regadenoson (Lexiscan)) and Dobutamine. Patient preparation: Nothing to eat or drink ³ 4 hrs, Dipyridamole, adenosine, regadenoson (if No significant reactive airways dz and No caffeine, theophylline for at least 24 hrs)
Indications for Imaging Stress Tests
Abnormal baseline ECG, digoxin, Wolf-Parkinson-White, Increase sensitivity, Localization, Preoperative cardiac risk assessment, and Myocardial viability
Contraindications for Imaging Stress Tests
Unstable angina, Untreated life-threatening arrhythmias, Uncompensated heart failure, Advanced AV block, Acute myocarditis, pericarditis, Critical aortic stenosis, Significant HOCM, Uncontrolled HTN, and Acute systemic illness.
Radionuclide Perfusion Imaging
Tracer deposited based on blood flow. Imbalance between supply and demand results in relative decreased perfusion. Compare perfusion during increased demand (stress) and decreased demand (rest). Reversible perfusion defects indicate reversible ischemia. Fixed perfusion defects indicate infarction, scar
Radionuclide Perfusion Imaging Agents
Thallium-201: Potassium analog, Initial accumulation µ blood flow, Continuous exchange across cell membrane. Technetium-99m-Sestamibi (Cardiolite): Lipophilic monovalent cation, Initial accumulation µ blood flow, Rapid hepatic accumulation,Biliary clearance, One pass, Gating – LV ejection fraction and wall motion
Stress Echocardiography
Imbalance between supply and demand results in wall motion abnormality. Compare increased demand (stress) wall motion to decreased demand (rest) wall motion. Normally left ventricle should beat faster and thicken more with exercise or dobutamine
Magnetic Resonance Imaging (MRI)
Strong magnetic field, 3D, tomographic images, No ionizing radiation, Contraindications: Metallic implants and Kidney dysfunction for Gadolinium contrast. Anatomic imaging (spin echo). Functional imaging (cine CMRI)
Cardiac Catheterization and Coronary Angiography
Catheter inserted into artery or vein, advanced to heart or coronary arteries. Measurements of: pressure, gradients, saturation, intracardiac shunt. Inject contrast for angiography
B-Type Natriuretic Peptide (BNP)
Found only in the cardiac ventricles. Released in response to stretch, increase in volume in the ventricle. BNP levels correlate with: Left ventricular end-diastolic pressure, New York Heart Association (NYHA) classification, and Objective heart failure diagnosis in patients 55 or older. BNP levels tend to be higher in women, elderly. BNP levels elevated in renal insufficiency. BNP < 100 pg/ml 90% sensitivity, 76% specificity, 83% accuracy for non-HF cause
Echocardiogram
Ultrasound sent into body, strikes objects and returns to transducer. Returned ultrasound can be transformed into: 2-Dimensional motion picture, M-Mode, Color Doppler map of blood flow, Echocardiogram and Spectral Doppler map of blood or tissue velocity
Targets of atherosclerosis
coronary arteries leading to ischemic heart disease. When complicated by thrombosis, it can lead to MI. cerebral arteries, leading to brain infarcts (strokes), neurologic disease. Aorta, leading to abdominal aortic aneurysms. Critical ischemia of intestines. Ischemia of lower extremities.
Aortic aneurysm
most occur in abdominal aorta, below renal arteries. Atherosclerosis weakens wall. Mass effect can simulate tumors causing compression and erosion of adjacent structures. Risk of rupture is related to size of aneurysm.
cystic medial necrosis of aorta
is an autosomal dominant disorder of large arteries. A degenerative breakdown of collagen, elastin, and smooth muscle caused by aging contributes to weakening of the wall of the artery. In the aorta, this can result in the formation of a fusiform aneurysm. There is also increased risk of aortic dissection. Can be seen in marfan syndrome
aortic dissection
Aortic dissection occurs when a tear in the inner wall of the aorta causes blood to flow between the layers of the wall of the aorta, forcing the layers apart. In most cases this is associated with severe characteristic chest or abdominal pain described as “tearing” in character and radiating pain to the back, and often with other symptoms that result from decreased blood supply to other organs. Aortic dissection is a medical emergency and can quickly lead to death, even with optimal treatment, as a result of decreased blood supply to other organs, heart failure, and sometimes rupture of the aorta. Aortic dissection is more common in those with a history of high blood pressure, a known thoracic aortic aneurysm, and in a number of connective tissue diseases that affect blood vessel wall integrity such as Marfan syndrome and the vascular subtype of Ehlers–Danlos syndrome. The diagnosis is made with medical imaging (computed tomography, magnetic resonance imaging or echocardiography). In an aortic dissection, blood penetrates the intima and enters the media layer. The high pressure rips the tissue of the media apart along the laminated plane splitting the inner 2/3 and the outer 1/3 of the media apart. This can propagate along the length of the aorta for a variable distance forward or backwards. Dissections that propagate towards the iliac bifurcation (with the flow of blood) are called anterograde dissections and those that propagate towards the aortic root (opposite of the flow of blood) are called retrograde dissections.
double-barreled aorta
Anterograde dissections may propagate all the way to the iliac bifurcation of the aorta, rupture the aortic wall, or recanalize into the intravascular lumen leading to a double barrel aorta. The double barrel aorta relieves the pressure of blood flow and reduces the risk of rupture. Rupture leads to hemorrhaging into a body cavity and prognosis depends on the area of rupture. Retroperitoneal and pericardial ruptures are both possible.
Debakey Type I
Originates in ascending aorta, propagates at least to the aortic arch and often beyond it distally. It is most often seen in patients less than 65 years of age and is the most lethal form of the disease.
DeBakey Type II
Originates in ascending aorta and is confined to the ascending aorta.
DeBakey Type III
Originates in descending aorta, rarely extends proximally but will extend distally. It most often occurs in elderly patients with atherosclerosis and hypertension.
Vasculitis
a group of disorders that destroy blood vessels by inflammation, which can lead to fibrinoid necrosis, vessel wall inflammation and damage. One or few vessels may be affected due to localized infection, irradiation, trauma, or Arthus reaction. Viruses have been localized in lesions. DNA-anti-DNA immune complexes and complement is seen in SLE. Systemic vasculitis classification depends on:
– size of the blood vessels,
anatomic site,
microscopic characteristics of the lesion, and clinical manifestations
Polyarteritis nodosa
Medium to small arteries
– All stages of activity may coexist
Microscopic polyarteritis
Arterioles, capillaries, venules
– All lesions tend to be at same stage
Temporal arteritis (giant cell arteritis)
effects arteries of the head including temporal arteries, ophthalmic branches. May lead to blindness. Granulomatous inflammation is present. Effects mostly elderly people above the age of 50.
Wegener’s granulomatosis
this is vasculitis plus granulomas. Can involve both lungs and kidneys. Can involve both lungs and kidneys. If untreated, there is over a 90% mortality in 2 years.
Takayasu’s arteritis (pulseless disease)
affects aorta, main branches and pulmonary arteries. Causes narrow orifices of great vessels leading to pulseless. Coldness and numbness of fingers and legs also present. Younger people (under the age of 40), females more than males, and asains are more likely to be effected.
Kawasaki’s disease
Infancy and early childhood. Fever, erythema of palms and soles, rash. In most cases, coronary arteries are affected. Many cases are self limited; 0.5-1% develop MI.
Buerger’s disease
Male cigarette smokers. Femal incidence also increases with smoking. Leads to thrombosis of medium-sized vessels, tibial and radial arteries. Can lead to gangrene and severe pain, even at rest, due to nerve involvement.
Thrombophlebitis
is a venous disorders. Clots forming within deep leg veins leading to death from pulmonary emboli (saddle embolus). Can be due to prolonged bed rest, immobilization, or cancer (hypercoagulability).
Trousseau sign of malignancy or Trousseau’s Syndrome
a medical sign involving episodes of vessel inflammation due to blood clot (thrombophlebitis) which are recurrent or appearing in different locations over time (thrombophlebitis migrans or migratory thrombophlebitis). The location of the clot is tender and the clot can be felt as a nodule under the skin. Trousseau’s sign can be an early sign of gastric or pancreatic cancer, typically appearing months to years before the tumor would be otherwise detected. Heparin therapy is recommended to prevent future clots. The Trousseau sign of malignancy should not be confused with the Trousseau sign of latent tetany caused by hypocalcemia.
Arthus reaction
a type of local type III hypersensitivity reaction. Type III hypersensitivity reactions are immune complex-mediated, and involve the deposition of antigen/antibody complexes mainly in the vascular walls, serosa (pleura, pericardium, synovium), and glomeruli.
Fibrinoid necrosis
a form of necrosis, or tissue death, in which there is accumulation of amorphous, basic, proteinaceous material in the tissue matrix with a staining pattern reminiscent of fibrin. It is associated with conditions such as immune vasculitis (e.g. Polyarteritis nodosa), malignant hypertension, preeclampsia, or hyperacute transplant rejection.
