General B1 stuff Flashcards
Statins (MOA)
- HMG CoA Reductase Inhibitors
- Structural similarity of all statins to HMG CoA substrate
-Act as reversible competitive inhibitors for the active site on HMG CoA reductase, the initial rate-limiting step in cholesterol biosynthesis;
have a higher affinity for the enzyme than natural substrate, HMG-CoA.
-Inhibition of an early and rate-limiting step in cholesterol synthesis, particularly in the hepatocyte, results in an increased need for exogenous (extracellular) cholesterol; this need is met by increased uptake of LDL particles which are rich in cholesterol
-Increase in LDL receptor gene.
o mechanism: In response to the reduced free cholesterol content within hepatocytes, membrane-bound Sterol Regulatory Element- Binding Proteins (SREBPs) are cleaved by a protease and translocated to the nucleus. The transcription factors then bind the sterol-responsive element of the LDL receptor gene, enhancing transcription and increasing the synthesis of LDL receptors (see fig 3)
-up-regulation of LDL receptor results in increased catabolism of LDL. Plasma concentration of LDL falls and less LDL is available to react with cellular elements in blood and blood vessel walls
Statins (pharmacokinetics)
- first-pass hepatic uptake of all statins, mediated primarily by the organic anion transporter OATP1B1
- limits systemic exposure to active compound
- all HMG CoA reductase inhibitors seem to preferentially effect the
liver - lovastatin (and simvastatin) administered as inactive lactone
- on uptake by liver cells, lactone prodrug is hydrolyzed to the beta-
hydroxy acid (which is the active form and principal metabolite) - atorvastatin administered in active, open-ring form
- highly bound to plasma proteins
- plasma concentrations peak at 1-4 hours;
o t1/2 of simvastatin is 12 hours o t1/2 of atorvastatin is 20 hours
all other statins have t 1/2 of 1 to 4 hours; clinical implications of this unclear - liver biotransforms all statins; about 70% of statin metabolites excreted by liver
atorvastatin, simvastatin, lovastatin metabolized by CYP3A4
Intercalated discs (transverse part)
Transmits force
- a modified Z-band (z-line)
- consists of fascia adeherens (N-cadherins) & desmosomes
Intercalated discs (lateral part)
CM-CM signaling
-gap junctions (nexi) & a few desmosomes
Excitation-contraction coupling (electrical)
Excitation (electrical)
- AP: depolarization —> T-tubules
- phase 2 of AP: L-type Cav1.2 —> Ca++ influx (highly enriched in cardiomyocytes
- ryanodine receptors in SR: —>—>—> Ca+++ (CICR….calcium induced calcium release
Monckeberg Arteriolosclerosis
- calcific deposits in media (& internal elastic lamina) of medium-sized muscular arteries (typically radial and ulnar arteries)
- > 50 years of age
- no obstruction to the blood flow
- usually not clinically significant
- unrelated to atherosclerosis
- its cause is not completely understood
Chronology of Heart Attack
1) immediate: myocyte death —> MB-CK and cTnl
2) +15 hours: inflammation
3) +2-3 days: wound healing via cardiac fibroblasts….collagen deposition (fibrosis)
4) +204 days: angiogenesis (clinical enhancement via VEGF, FGF)
5) Scar deposition (due to collagen cross-linking)
can pre-existing myocytes mobilize to fix damaged myocardium?
maybe
proliferation can be induced by…
1) inhibiting p38 MAP kinase
2) pro-proliferative agent
Can adult stem cells in the heart fix damaged heart?
- no, but maybe mobilize
- stem cells ID’s by expression of c-Kit
- treat heart with drugs/growth factors to mobilize and expand c-Kit+ cells within their niches
can c-kit+ adult stem cells be transplanted to fix injured myocardium?
- maybe….phase 1 trial SCIPIO
- some function is resotred and infarcted area is reduced, while no harm is done
can transplanted bone marrow cells fix the heart?
maybe. …
- paracrine effect…functional benefit, but little or no re-muscularization
Transplantation of CM derived from iPSCs
-best bet to re-muscularize
-
Continuous capillary
Where?
- CNS
- heart
- skeletal muscle
- lung
Item transported?
-oxygen
fenestrated capillary
where?
- endocrine glands
- GI tract
- kidneys
item transported?
- hormones
- nutrients
- ions
sinusoidal capillary
where?
- BM
- spleen
- liver
item transported?
-whole cells
Atherosclerosis: clinical syndromes
Elastic arteries
- aorta: aneurysm with rupture
- carotid arteries: occlusion causing stroke*
- iliac arteries: occlusion causing gangrene*
Large/medium sized muscular arteries
- coronary arteries: occlusion causing MI*
- popliteal arteries: occlusion causing gangrene*
- renal artery: narrowing/occlusion causing secondary hypertension*
- mesenteric arteries: narrowing/occlusion causing bowel infarction*
*possibly associated with thrombosis
Advanced/vulnerable plaque
At risk for:
1) Rupture, ulceration, erosion, and hemorrhage
- lead to thrombosis, embolism
- progressive luminal narrowing (leading to critical stenosis)
2) Atheroembolism
3) aneurysm formation
- wall weakening leading to aneurysm and rupture
Atherosclerosis pathogenesis
Hypothesis:chronicinflammatoryresponseof arterial wall to endothelial injury
• Components of process:
– Endothelial injury
– Hemodynamic disturbances – Lipid accumulation
– Inflammation
– Infection
– Smooth muscle proliferation
Chronic endothelial injury/dysfunction: ↑permeability, enhanced leukocyte adhesion – Specific cause unknown – Strongly suspected causes: • Hemodynamic disturbances: plaques occur in areas of disturbed flow patterns (at ostia and vessel branch points) • Hypercholesterolemia • Other possible contributors: – Hypertension – Cigarette smoke toxins – Homocysteine – Infectious agents
• Inflammation:
– Adhesion molecules (from endothelial cells) attract leukocytes
– Monocyte adhesion, migration & transformation to macrophages
• Initially protective response, but ultimately cause lesion
progression
– T lymphs: secretion of cytokines & fibrogenic mediators
Infection: Importance is unclear at present
– Herpes virus
– CMV
– Chlamydia pneumoniae
• Smooth muscle cells: Proliferation and migration into intima with production of matrix proteins
ApoA-I
HDL
-activates LCAT; interacts with ABC transporter
ApoB-48
Chylomicrons
-cholesterol transport/clearance
ApoB-100
VLDL, LDL
-binds to LDL receptor
ApoC-II
Chylomicrons, VLDL, HDL
-activates lipoprotein lipase
ApoC-III
Chylomicrons, VLDL, HDL
-inhibits lipoprotein lipase
ApoE
Chylomicrons, VLDL, HDL
-triggers clearance of VLDL and chylomicron remnants
NPC1L1 (Niemann-Pick C1-Like 1 protein)
- intestinal cholesterol and plant sterol absorption is mediated by this
- TARGET OF ezetimibe, a cholesterol absorption inhibitor
ABCG5/G8
-export plant sterols back into the intestinal lumen
Sitosterolemia
- autosomal recessive disorder have mutations in either ABCG5 or ABCG8
- absorb unusually large amounts of plant sterols
- fail to excrete dietary sterols into the bile
- accumulate plant sterols in the blood and tissues
- accumulation is associated with TENDON AND SUBCUTANEOUS XANTHOMAS and a markedly increased risk of PREMATURE CHD
Type III hyperlipoproteinemia
- inherited absence of a functional apoE
- inhibition of remnant clearance by the LDL receptor and LRP
- increased TG and cholesterol-rich remnant lipoproteins in the plasma
MTP
- helps transfer TG to the VLDL core
- also required for TG transfer to chylomicrons in the intestine
abetalipoproteinemia
- mutations of MTP
- vitamin deficiency
- fat in stool
- developmental delays
ACAT
Acyl-CoA:cholesterol acyltransferase
-esterifies cholesterol to form cholesteryl esters (CE)
- dietary or endogenous cholesterol in excess of need for membrane synthesis is metabolized to CE by ACAT for storage
- important physiological role in control of cellular FC pool that serves as substrate for bile acid and steroid hormone formation
PCSK9
-A serine protease that decreases the steady-state level of expression of the LDL receptor on the hepatocyte cell membrane (binds to the EGF-A domain of LDLR)
• Promotes intracellular degradation of the LDL receptor
• LDLr/PCSK9 complex gets internalized and targeted to the lysosomal compartment for degradation
– Prevents LDLR recycling to the cell surface
– Reduces LDLR population on cell surface
– Reduces clearance of LDL from the circulation, hence increased plasma LDL levels
Lp(a)
An LDL-like particle where apoB-100 is covalently bound to apolipoprotein(a) [apo(a)]
• Apo(a) proteins vary in size due to a variable number of so-called kringle IV repeats in the LPA gene (highly homologous to plasminogen).
• There is a general inverse correlation between the size of the apo(a) isoform and the Lp(a) plasma concentration
• Apo(a) is expressed by human or non-human primate liver cells (hepatocytes), also the site of Lp(a) assembly
• The half-life of Lp(a) in the circulation is about 3 to 4 days
• Lp(a) is a risk factor for cardiovascular disease
ABCA1
ATP binding cassette transporter (ABCA1) helps release free cholesterol to apoA-I to make discoidal HDL
Membrane transporter expressed abundantly in the liver, intestine, macrophages, brain and other tissues
• Promotes efflux of cellular phospholipid and cholesterol to lipid-free apoA-I (primarily secreted from liver and intestines), but NOT to spherical HDL
• Mutations in ABCA1 result in:
– Severely reduced cholesterol efflux to apoA-I
– Markedly reduced HDL levels as poorly-lipidated nascent HDL are metabolized rapidly
apoA-I
- Primary protein component of HDL
- Synthesized in liver and intestine and is required for normal production of HDL
- Mutations in the apoA-I gene that cause HDL deficiency are variable in their clinical expression and often are associated with accelerated atherogenesis.
- Conversely, overexpression of apoA-I in transgenic mice protects against experimentally induced atherogenesis.
- ApoA-I mutations are also known to reduce the capacity of apoA-I to activate LCAT
The ABCA1-mediated transfer of phospholipid and FC to apoA-I results in the formation of nascent or discoidal HDL (pre-HDL)
• Majority of pre-HDL formation occurs at the liver and intestine (also sites of apoA-I synthesis and ABCA1 expression)
• Discoidal pre-HDL can then acquire free unesterified cholesterol from the cell membranes of tissues, such as arterial wall macrophages.
Tangier Disease
Tangier Disease results from mutations in ABCA1
Loss-of-function mutations of ABCA1 cause the defect observed in Tangier disease, a genetic disorder characterized by extremely low levels of HDL and cholesterol (CE) accumulation in the liver, spleen, tonsils, and neurons of peripheral nerves.
• Extremely rare, affecting ~ 100 people world- wide
• Near-absence of normal HDL particles since patients fail to form discoidal OR spherical HDL
• Enlarged spleens and tonsils (orange in color due to accumulation of carotenoids)
• Very low total plasma cholesterol
• ABCA1 mutations account for ~ 10% of subjects with low HDL levels
Lecithin-Cholesterol Acyl Transferase (LCAT)
Lecithin-Cholesterol Acyl Transferase (LCAT) helps form the CE core of HDL
- Secreted by liver and circulates in blood, at times, by physically associating with HDL
- After free cholesterol is acquired by the preHDL, it is esterified by LCAT
- The newly esterified and nonpolar cholesterol moves into the core of the discoidal HDL
- As the CE content increases, the HDL particle becomes spherical.
- Spherical HDL particles further enlarge by accepting more free cholesterol, which is in turn esterified by LCAT
- apoA-I activates LCAT
LCAT deficiency
-fish eye disease
Homozygotes
- corneal clouding
- nephropathy
- hemolytic anemia
- HDL deficiency
Heterozygotes
-half-normal HDL-C levels (frequently
ABCG1
ABCG1 transfers cholesterol to spherical HDL
- Expressed in spleen, thymus, lung and brain, liver and macrophages
- Promotes cholesterol efflux to HDL, and not lipid-free apoA-I
- Contributes to HDL remodeling
- Alters distribution of cholesterol on the cell membranes and allows its removal by HDL
CETP
Cholesteryl ester transfer protein (CETP) exchanges lipids between LDL and HDL
• Promotes transfer of CE from HDL to VLDL, IDL and LDL, in exchange for TG
• In humans, CETP accounts for the removal of about two-thirds of the CE associated with HDL (via LDLR-mediated endocytosis)
• Deficiency in humans is associated with increased HDL levels
– CETP deficiency in a Japanese population is associated with reduced risk for CAD
• Recent therapies have focused on inhibiting CETP to keep HDL levels high
-study: inhibiting CETP to keep HDL high….thought to target it…doubles HDL…however clinical trials had DYING patients….
HL
Hepatic lipase (HL)
• Hydrolyzes TG and PL to generate smaller, spherical HDL particles that recirculate and acquire additional free cholesterol from tissues
• Both androgens and estrogens affect HL gene expression, but with opposite effects.
– Androgens increase HL activity, which accounts for the lower HDL-C values observed in men than in women.
– Estrogens reduce HL activity, but their impact on HDL-C levels in women is substantially less than that of androgens on HDL-C levels in men.
• HL appears to have a pivotal role in regulating HDL-C levels, as HL activity is increased in many patients with low HDL-C levels.
SR-BI
Scavenger receptor BI (SR-BI) is the HDL receptor
• Expressed in liver, ovaries, testes, adrenal glands
• Overexpression of SR-BI in mice:
– HDL-CE uptake, HDL-cholesterol
– biliary cholesterol excretion
• Disruption of SR-BI in mice:
– plasma HDL-cholesterol levels
• Transgenic and knock-out mouse models confirm an athero-protective role for SR-BI
• Recently identified mutations in human SR-BI have confirmed the importance of SR-BI in maintaining plasma cholesterol levels and support a protective role of SR-BI against atherosclerosis
• The CE core is transferred to cells via SR-BI by “selective uptake”
– Only lipid is transferred to cells
– Entire HDL particle is NOT internalized
• The lipid-depleted particle can circulate back to peripheral tissues to pick up more cholesterol
• ApoA-IandApoA-IIareremovedfromplasma synchronously and that a portion of the degradation occurs in liver and in kidney.
Regulation of Cholesterol Synthesis and Transport (4)
1) Covalent modification of HMG-CoA reductase
2) Transcriptional regulation of HMG-CoA gene
3) Activation of ACAT, which increases esterification for storage
4) Transcriptional regulation of the LDL receptor
Regulation of Cholesterol Metabolism (3)
1) AMP-dependent protein kinase
- when AMP rises, kinase
phosphorylates HMG-CoA reductase –> decreased activity , decreased cholesterol synthesis
2) Glucagon, epinephrine - cascades lead to phosphorylation, decrease activity
3) Insulin
- cascades lead to dephosphorylation, increased activity
Covalent modification provides short-term regulation.
Longer-term Regulation of HMG-CoA Reductase through Transcriptional Control
• Sterol regulatory element-binding proteins (SREBPs)
– When cellular sterol levels are high, SREBP is in ER membrane with other proteins
– When cellular sterol levels decrease, complex is cleaved, moves to the nucleus
– Activates transcription of HMG-CoA reductase and LDL receptor as well as other genes
The metabolic syndrome criteria
• Criteria – requires > 3 of the 5
- Waist > 40” in male or > 35” in female
- Fasting blood sugar > 100
- BP > 135/85 or on treatment
- Triglycerides > 150
- HDL
Why do we measure and treat lipids when it’s the lipoproteins that actually cross the endothelium?
• Since 1960, medicine has studied cholesterol and triglycerides, not lipoproteins
• Huge epidemiological data and pathology show that serum level of cholesterol is causally linked to atherosclerosis
• Numerous outcome studies that show the benefit of treatment to lower cholesterol have been based on lipid values
• No outcome studies on lipoproteins
-“proxy”
Lipid panel (calculations)
• Total cholesterol and HDL cholesterol and triglycerides are measured values
• LDL and non-HDL are calculated
• LDL is calculated by the Friedewald equation
• LDL-C= TC – (HDL-C + TG/5)
• LDL-C= TC – (HDL-C + VLDL-C) (can’t measure this)
• ____= 215 – (45 + 150/5)
• Calculation is invalid when trigs > 400
• Non-HDL = TC – HDL
= sum of all potentially atherogenic cholesterol
will probably become leading marker of treatment
= cholesterol in all VLDL + VLDL remnants + LDL
Lipid panel (risks)
- LDL-C > 100 risk for ASCVD
* HDL 1000 risk for pancreatitis
Genetic lipid disorders (intro)
• All genetic disorders can be made worse by a poor lifestyle or environment and better by a good lifestyle
•
• Types I and IIA are predominantly genetic with minimal lifestyle
influence
• Types IIB, III, IV, and V are often dormant until lifestyle (diabesity) or other diseases (diabetes) unmask or promote them
Fredrickson Genetic Hyperlipidemia I
I
Severe hypertriglyceridemia
Childhood with trigs > 2000
Excess:
Chylomicron
Primary Defect:
LPL or apo C2 or C3
Very rare
main abnormal lipid:
TG > 2000
Fredrickson Genetic Hyperlipidemia IIa
IIa
Familial Hypercholesterolemia
CAD 275, LDL-C > 190
Fredrickson Genetic Hyperlipidemia IIb
IIb
Familial Combined Hyperlipidemia or with Metabolic Syndrome (dyslipidemia slide)
CAD risk 2X normal despite borderline lipid numbers
Excess:
LDL, VLDL
Primary Defect:
Overproduction of apoB100
Common
main abnormal lipid:
LDL 100, trigs 200 – 500, HDL
Fredrickson Genetic Hyperlipidemia III
III
Dysbetalipoproteinemia
Premature CAD
Excess:
VLDL, IDL
Primary Defect:
Apo E2 + overproduction
Rare
main abnormal lipid:
TC and trigs both 200 to 500
Fredrickson Genetic Hyperlipidemia IV
IV
Hypertriglyceridemia
Pancreatitis
Excess:
VLDL
Primary Defect:
LPL or apoC3
Common
main abnormal lipid:
Trigs 500 - 1000
Fredrickson Genetic Hyperlipidemia V
V
Hypertriglyceridemia
Pancreatitis, usually diabetic
Excess:
VLDL, chylo
Primary Defect:
LPL or apoC3
Uncommon
main abnormal lipid:
Trigs > 1000
Major Triglyceride Disorders (Summary)
Type I Hyper-chylomicronemia
• Children with trigs > 2000
• Inherited loss of LPL or defective apoC2 or C3
• Chylomicrons fill with trigs (at enterocyte) but cannot offload trigs to peripheral cells
Type IIB (Familial Combined Hyperlipidemia)
• Trigs 200 to 500
• Over-production of VLDL May be inherited, but most commonly is seen with insulin resistance, metabolic syndrome, inflammation of visceral adiposity
Type IV
• Trigs 500 to 1000
• Large VLDL (LPL not function well)
• Combination of genetics and environment
Type V
• Trigs > 1000
• Trigs + chylomicrons
Lipid disorders that cause ASCVD
Elevated total cholesterol or LDL levels
Elevated non-HDL
• Excess numbers of non-HDL apoB lipoproteins
• Often seen in patients with metabolic syndrome or Familial Hypercholesterolemia
Depressed HDL levels
Elevated Lp(a)
But most ASCVD happens in people with “normal” cholesterol
Lipid disorders that increase risk of ASCVD
Type IIA Familial Hypercholesterolemia
Type IIB • If inherited: • Familial combined hyperlipidemia • If environmental: •Insulin resistance (metabolic syndrome or excess VLDL remnants and increased LDL-P, which are atherogenic)
Type III
• Excess of both VLDL and LDL Due to apoE2/2
Familial hypercholesterolemia
The most common potentially lethal inherited disease in the world • Heterozygote 1 in 500 • Homozygote 1 in 1,000,000 • Autosomal dominant • (Very rarely autosomal recessive) Founder effect in some populations risk 1 in 100 • French Canadians • SouthAfrikaners • Ashkenazi Jews
Familial Hypercholesterolemia—
One phenotype, several different mutations
Genetic mutations 1)LDL-R mutation (decreased number or function) • 90% of FH • 1600 known mutations 2) apoB mutation (can’t bind to LDL-R) 3) PCSK9 gain of function mutation
Therapeutic goals for FH
• Make diagnosis as young as possible
• Treat with statins by age 12 or 18 for sure
• Once make diagnosis, need to test all first-degree family members
• Treatment with statins is lifetime (except when pregnant)
- And soon PCSK9 inhibitors
• If treatment started when young, ASCVD risk approaches that of normal population
Hyperchylomicronemia
- Rare disease of childhood (Type I) (1 in 1,000,000) or seen with Type V in adults
- Genetically absent or reduced LPL or apoC2 or apoC3, which is also on VLDL
- Triglycerides 2,000 to 25,000
- Chylomicrons carry mainly triglycerides from gut to liver
- Long-term treatment is near total fat restriction or use of medium chain fatty acids (bypass pathways of the more common long chain fatty acids)
Pathogenesis of Aneurysms
Factors affecting collagen structure or function:
1) Inadequate or abnormal syntheses of collagen
- Marfan syndrome
• Defective synthesis of fibrillin
• Fibrillin is “scaffolding” for deposition of elastic tissue
• Results in cystic medial necrosis of aorta
media starts dying from the pressure on it
• Leads to aneurysm formation & aortic dissection
- Ehlers-Danlos syndrome
• One variant has defective synthesis of Type III collagen • Leads to aneurysm formation
2) Excessive connective tissue degradation
• Occurs with increased matrix metalloproteinase (MMP) or
decreased tissue inhibitors of metalloproteinase (TIMP)
• In the setting of inflammation (atherosclerosis) polymorphisms of MMP &/or TIMP genes may predispose to aneurysm formation
Loss of smooth muscle cells
1)Thickening of intima (due to atherosclerosis)
• Leads to ischemia of inner media
2) Systemic hypertension
• Narrows vasa vasorum, leading to ischemia of outer media
3) Morphologic results is cystic medial degeneration
Specific Underlying Causes of Aneurysms
Common
1) Atherosclerosis – abdominal aorta
2) Hypertension – ascending aorta
Uncommon
1)Congenital defects
• Berry aneurysm: bifurcation of cerebral arteries, subarachnoid hemorrhage
2) Infections (bacteria, fungi)
• Mycotic aneurysm: septic emboli, direct extension, direct infection by circulating organisms
• Syphilis (Treponema pallidum)
3) Trauma – AV (fistula) aneurysm
4) Vasculitis inflammation…alters enzymes of MMP and
inhibitors
5) Genetic defects in collagen (Marfan’s & Ehlers-Danlos)
Thoracic Aortic Aneurysms
Causes: ▫ Hypertension ▫ Marfan’s syndrome ▫ Syphilis (tertiary) ClinicalFeatures: 1)Mediastinum encroachment ▫ Trachealcompression ▫ Esophagealcompression ▫ Bone erosion ▫ Cough due to irritation of recurrent laryngeal nerve 2)Cardiac Symptoms ▫ Heart failure due to aortic valve insufficiency 3) Aortic rupture
Pathogenesis of Immune-mediated Vasculitis
1) Immune complex mediated
• SLE (Systemic Lupus Erythematosis): DNA – anti-DNA complexes
• Hypersensitivity to drugs
• Viral infections (not the infection, but the deposition of immune complexes)
-HBsAg – anti-HBSsAg
2) Anti Neutrophil Cytoplasmic Antibodies (ANCA) associated
• Autoantibodies against enzymes in granules of neutrophils
• Ab titers mirror clinical severity
• Two main patterns:
**I. Antiproteinase-3 (PR3-ANCA) – Wegener Granulomatosis
-Target antigen is PR3 (neutrophil granule constituent)
****II. Anti-myeloperoxidase(MPO-ANCA) – Microscopic polyangiitis and Churg- Strauss syndrome
-Target antigen is myeloperoxidase
3)Other mechanisms
• Antibodies to endothelial cells - Kawasaki disease
Vasculitis of infectious origin & unknown origin
Infectious 1)Direct invasion • Classic example is syphilis • Aspergillus & mucormycosis 2)Indirect via immune mechanisms triggering cross-reactivity (hep B...)
Unknown
• Giant cell arteritis
• Takayasu arteritis
• Polyarteritis nodosa
Giant Cell (Temporal) Arteritis
• Most common form of systemic vasculitis in adults
• Affects aorta and its major branches, especially temporal artery,
ophthalmic, and vertebral arteries
• Pathogenesis: uncertain
—-? T-cell mediated, driven by antigen (? Elastin)
Clinical:
• > 50 y, often with painful superficial temporal artery, diplopia, visual loss, headache
• Increased ESR (Erythrocyte Sedimentation Rate)
• Diagnosis: biopsy
• Treatment: steroids
Temporal (giant cells) arteritis
Gross morphology
-Nodular thickenings of artery with narrowed lumen
-Patchy (discontinuous) segments affected
- Biopsy requires 2-3 cm
◦ Multiple levels examined
Temporal (giant cell) arteritis Histology
- Granulomatous inflammation of inner half of media around internal elastic lamina
- Destruction of internal elastic lamina
- Multinucleated giant cells (but not always!)
Takayasu Arteritis
- Pulseless disease (upper extremities), ocular disturbances
- Japanese women younger than 40 yrs
- Granulomatous inflammation of aortic arch and its branches
- Pulmonary arterties are involved 50%; coronary and renal arteries may be involved
- Pathogenesis: autoimmune etiology
- Histology: lymphocytes, giant cells, collagenous fibrosis
Polyarteritis Nodosa (Classic)
- Systemic segmental transmural necrotizing inflammation of small or medium-sized muscular arteries
- Renal and visceral arteries affected, spares lung
- Focal, random, episodic
- All stages of inflammation and fibrosis co-exist
- Aneurysms
- Young adults (30% Hep B antigen), no ANCA
- Acute, chronic, subacute, or remittent course
- 90% remission or cure - corticosteroids, cyclophosphamide
Classic presentation:
• Rapidly accelerating hypertension (renal artery involvement)
• Abdominal pain & bloody stools
• Peripheral neuritis
Kawasaki Syndrome
• Endemic in Japan
• Rare, but increasing in the US
• Large, medium and small arteries, often coronaries with aneurysm formation
• With mucocutaneous lymph node syndrome
—-Mucous membrane inflammation
—-Enlarged lymph nodes
• 80% are
Microscopic Polyangiitis (Leukocytoclastic Vasculitis)
• Arterioles,capillaries,venules
• Skin, mucous membranes, lungs, brain, heart, GIT, kidneys, muscles
▫ Necrotizing glomerulonephritis (90%) and pulmonary capillaritis
——(not many things have more vessels than kidney…)
• MPO-ANCA + in 70%
• Immunologic reaction to antigens- drug, Strep, tumor proteins
• Histology: fibrinoid necrosis, neutrophils, nuclear dust (karyorrhexis)
Major clinical features are dependent on vascular bed involved:
• Hemoptysis, hematuria, proteinuria, abdominal pain or bleeding, muscle pain or bleeding, & cutaneous purpura
Wegener Granulomatosis
Necrotizing vasculitis
• Granulomas of lung &/or upper respiratory tract (ear, nose, sinuses, throat)
• Vasculitis of small to medium sized vassels in lungs & upper respiratory tract
• Glomerulonephritis
PR3-ANCAs present in >95%
• Likely cell-mediated hypersensitivity response against inhaled infections or environmental antigen
M > F, ~40 years of age • Without treatment: 1 yr – 80% mortality • Symptoms 1)Pneumonitis (95%) 2)Sinusitis (90%) 3)Nasopharyngeal ulcerations (75%) 4)Renal disease (80%)
Churg-Strauss Syndrome (allergic granulomatosis and angiitis)
Small vessel vasculitis associated with:
• Asthma
• Allergic rhinitis
• Lung infiltrates
• Peripheral eosinophilia & infiltration of vessels by eosinophils
• Extravascular necrotizing granulomas
Clinical symptoms • Palpable purpura • GI bleeding • Renal impairment • Cardiomyopathy
- Possible hyper-responsiveness to allergic stimulus
- MPO-ANCAs – present in minority
Thromboangiitis Obliterans (Buerger disease)
Inflammation and thrombosis of medium to small sized muscular arteries and secondarily the veins and nerves
• Tibial and radial arteries
• Smokers*,
Raynaud Phenomenon
• Paroxysmal pallor or cyanosis of fingers, toes, nose or ears
Primary:
• Recurrent vasospasm of unknown cause (exaggerated response to cold)
• Young, healthy women
• No structural changes in the arterial walls (until late in disease)
Secondary:
• Arterial insufficiency due to narrowing and can be due to SLE, SS (Systemic sclerosis – Scleroderma), atherosclerosis, Buerger disease
Intermittent claudication
Claudicatio = to limp
Cramping, tightness, fatigue
Involves buttock, hip, thigh, calf, foot
Exercised-induced
Distance to claudication is unchanged
Does not occur with standing
Relieved by rest (Usually within 5 minutes)
Only ~ 1/3 of the PAD patients experience classic IC and the remaining have either atypical symptoms or are asymptomatic
Cigarette Smoking (PAD)
Two to fivefold increased risk of PAD
Approximately 84%-90% of patients with claudication are
current or ex-smokers
Smoking increases the risk of PAD»CAD
Diagnosis of PVD is made 10 years earlier among smokers
The amount and duration of tobacco use correlate directly with the development of PAD
Patients that continue to smoke experience More common progression to CLI and limb loss Decreased the LE arterial bypass patency rates
Diabetes Mellitus (PAD)
Two to fourfold increased risk of PAD
Different anatomic characteristics:
- Extensive disease
- Greater propensity for vascular calcification
- Infrapopliteal disease more common
Among patients with PAD diabetics more likely to have an amputation
UK prospective diabetes study (UKPDS): Risk reduction per 1% reduction in HgA1c: -Risk for amputation 37% -Death from PAD 43% -Myocardial infarction 14% -Stroke 12% -Heart failure 16% (P
GPA
Granulomatosis with polyangiitis
Clinical features of GPA
1)Constitutional symptoms
2)ENT
-Chronic sinusitis, rhinitis, epistaxis, saddle nose deformity, conductive and sensorineural hearing loss, tracheal or subglottic granulomatous masses
-Conjunctivitis, episcleritis, uveitis, optic nerve vasculitis, retinal artery occlusion, proptosis
3)Nervous system
-Mononeuritis multiplex, sensorimotor PN, and cranial nerve palsies, vasculitis of brain or spinal cord with granulomatous masses affecting different areas
4) Derm
-Most commonly leukocytoclastic vasculitis, palpable purpura or skin ulcers
5)MSK
• Arthralgias more than arthritis
6)Cardiac
• Rarely detected ante mortem but pericarditis and coronary arteritis seen in 10-20% of cases which can lead to MI or sudden death
7) Heme
• Hypercoaguable state leading to PEs, etc.
8) Less commonly can involve GI, lower GU tract, parotid glands, thyroid, liver, or breast
**EULER CLASSIFICATION
Diagnosis -Based on clinical symptoms -ANCAs can aid diagnosis -Biopsy: necrotizing granulomas 1)Lung 2)Kidney 3)Sinus
Atrial Flutter (general description)
- AV conduction is variable, can be 1:1 but more commonly more flutter waves than QRS complexes.
- Drugs that slow atrial flutter circuit (e.g. flecainide) may promote 1:1 AV conduction, paradoxically increasing ventricular rate.
- May be asymptomatic or associated with palpitations, dyspnea, weakness, and stroke from atrial thrombus (loss atrial contractility d/t rapid A rates).
- Predisposing factors: prior heart surgery, coronary disease, cardiomyopathy.
Atrial Flutter: Treatment
• Rate control: beta blockers, calcium channel blockers, digoxin
Rhythm control:
• Duration > 48 hours necessitates transesophageal echo to rule out left atrial thrombus or 3 weeks anticoagulation prior to conversion. Anticoagulation continued post cardioversion at least 4 weeks (delay recovery mechanical atrial function).
• Electrical cardioversion
• Pace termination
• Catheter ablation of tricuspid caval isthmus, curative 95%, thus preferred
• Antiarrhythmic drug therapy (class I, III agents) for sinus rhythm maintenance, occasional chemically convert, modestly effective.
Atrial Fibrillation (AF)
- Chaotic rapid rhythm with atrial rates > 400 discharges/min).
- No distinct P waves.
- Most of P waves find AV node refractory, only some of the depolarizations are conducted to ventricle, resulting in “irregularly irregular” rhythm.
- Mechanisms: triggered by rapid firing from atrial foci often localized to atrial muscle extending into pulmonary veins.
- AF is sustained by multiple wandering reentrant circuits within the atria; minimum number of circuits required for AF, thus AF promoted by enlarged atrium.
- Predisposing factors: ETOH, CHF, valvular disease, enlarged atria, hypertension, coronary disease, pulmonary disease, sleep apnea, hyperthyroidism, cardiothoracic surgery.
Mechanisms of A-fib
- Multiple-wavelet hypothesis1
* Focal mechanism with fibrillatory conduction
Clinical Consequences of A-fib
- Ventricular response rates may be rapid and lead to symptoms, hypotension or heart failure.
- Rapid atrial activation results in absence of organized atrial contraction, blood stasis in atrium and risk of thrombus formation, especially in left atrial appendage, with risk of embolization and stroke.
Treatment of A-fib
- Anticoagulation:
- Acute: time of cardioversion • Chronic: CHADSVasc score
- Rate control : AV nodal blockade (Beta blocker, calcium channel blocker, digoxin)
Restoration Sinus Rhythm:
• Cardioversion (>48 hours, preceded by 3 weeks anticoagulation or TEE)
• Antiarrhythmic Drugs
• Catheter ablation
CHA2DS2-VASc Score
C -----CHF----- 1pt H -----hypertension-----1pt A2-----Age >=72-----2pts D-----Diabetes-----1pt S2-----Stroke-----2pts V-----Vascular disease-----1pt A-----Age >= 65-----1pt Sc-----Sex category, female-----1pt
Max total score: 9
0 —–> no therapy
1 —–> aspirin or oral anticoagulation
>=2—–> oral anticoagulation
Management of AF Stroke Prevention Anticoagulation
Antiplatelet
Aspirin
Oral Anticoagulant Coumadin (Warfarin) [Vit K] Dabigatran (Pradaxa) [Thrombin] Rivaroxiban (Xarelto) [Xa] Apixaban (Eliquis) [Xa]
AV Nodal Reentrant Tachycardia (AVNRT) (summary)
• Most common form paroxysmal SVT
• Reentry utilizing two AV nodal pathways, fast (rapid conduction and long
refractory period) and slow (slow conduction and short refractory period).
• Relies on transient unidirectional block in one pathway and relatively slow conduction in the other.
• Typically conduction antegrade from A to V occurs over slow pathway and retrograde limb of reentrant circuit is over fast pathway.
• Presents in young adults
• Symptoms include palpitations, dizziness, chest pain, dyspnea.
AV Nodal Reentrant Tachycardia (AVNRT) (acute and chronic treatment)
- Acute treatment aimed at termination: valsalva maneuvers, adenosinebolded*, beta blockers, calcium channel blockers.
- Chronic treatment: observation, AV nodal blockade, catheter ablation targeting “slow” pathway of AV node and infrequently Class I, III antiarrhythmic drugs.
Atrioventricular Reentrant Tachycardias (AVRT)
• Reentry utilizing bypass tract or accessory pathway
• Accessory pathway is an abnormal band of muscle cells
crossing the AV groove to connect atrium and ventricle.
• Prevalence: 1 in 1500 people
• May conduct antegrade (atrium to ventricle), retrograde (ventricle to atrium) or bidirectionally.
• If tract conducts only retrograde can promote supraventricular tachycardia but is termed “concealed”.
• Tract that conducts antegrade produces finding on EKG termed Wolff-Parkinson-White or ventricular pre- excitation syndrome.
Wolff-Parkinson-White (WPW) Syndrome
Delta Wave:
• conduction over AP beats AVN, short PR
• Slurred QRS due to slow ventricular
activation by pathway other than HPS and fusion activation of ventricle by
2 wavefronts, proceeding over AP and HPS.
• No delta wave in orthodromic tachycardia (narrow QRS) as antegrade depolarization of ventricles occurs exclusively over AV node.
WPW: Treatment
- Because digoxin, beta blockers and calcium channel blockers may actually shorten the refractory period of accessory pathways, effectively speeding conduction, these drugs should not be used in WPW patients presenting with wide complex or pre-excited tachycardias.
- Intravenous amiodarone or procainamide may be used, slow accessory pathway conduction.
- Acute therapy may require cardioversion if hemodynamically unstable.
- Definitive therapy with catheter ablation of accessory pathway is preferred in symptomatic and high risk patients.
Ventricular Premature Beats or Contractions (PVCs)
- Common and often benign
- Produced by firing of ectopic ventricular focus
- Produces a widened QRS because impulse originates from ectopic ventricular site and depolarizes ventricles not through the normal rapidly conducting His Purkinje system but via slow cell-to-cell connections.
- Due to ventricular origin there is either no relationship to P wave or retrograde V-A conduction with retrograde P wave inverted in II, III, aVF.
- May occur in repeating patterns or consecutively.
- May signal underlying cardiac disorder but can be seen in normal hearts.
- High density PVCs ( > 20% of QRS complexes) may produce left ventricular systolic dysfunction which may be reversible with suppression of PVCs, medically or with ablation.
- Primary therapy is observation and at times, beta blockers.
Ventricular Tachycardia
- Series of 3 or more PVCs
- Sustained VT: > 30 seconds
- Non-sustained VT: 120 ms), rate > 100 bpm.
Monomorphic VT
- QRS complexes are identical from beat to beat and rate is regular.
- Sustained monomorphic VT typically results from reentry and indicates underlying structural heart disease or myocardial scar.
- Occasionally occurs as a triggered arrhythmia originating from an ectopic focus in a patient without structural heart disease.
Polymorphic VT
- QRS complex continually changes shape and rate varies from beat to beat.
- Mechanism is either multiple ectopic foci or changing reentrant circuit.
- Causes include long QT with Torsades de pointes, acute ischemia or infarction, other rare inherited abnormalities of cardiac ion channels or calcium handling (Brugada, catecholaminergic polymorphic VT).
- If sustained, may cause syncope or cardiac arrest.
Torsades de Pointes (Twisting of Points)
- Specific form polymorphic VT presenting with varying amplitudes of QRS as though complexes were “twisting” about the baseline.
- Mechanism is triggered activity, early after depolarizations.
- Observed in patients with QT prolongation (prolonged action potential duration), either due to drugs, bradycardia, electrolyte/metabolic disturbances or hereditary abnormality of ion channels (congenital long QT).
- Symptoms include lightheadedness, syncope and sudden cardiac death.
- Acute treatment: cardiovert sustained VT to restore sinus rhythm, IV magnesium, correct underlying abnormalities (stop offending drugs), elevate heart rate and thus shorten QT either with beta agonists (isoproterenol) or pacing.
- Chronic treatment: correct underlying triggers. If congenital long QT consider beta blocker and ICD.
Management of VT
• Sustained VT is potentially life-threatening and may degenerate to ventricular fibrillation or be associated with hemodynamic collapse.
• Acute therapy in unstable patient: electrical cardioversion.
• Acute therapy stable patient: antiarrhythmic drugs (amiodarone,
lidocaine) or sedate/cardiovert.
• After sinus rhythm restored look for structural heart disease and correct aggravating factors.
• Long term consider need for implantable cardioverter defibrillator (ICD) for secondary prevention and potentially need for antiarrhythmic drugs or VT ablation.
Ventricular Fibrillation
- Immediately life-threatening
- Disordered rapid activation of ventricles
- Does not produce coordinated ventricular contraction
- Occurs typically in setting of severe underlying heart disease or acute ischemia
- Untreated leads to death
- Rx: immediate electrical defibrillation, then look for cause, consider IV amiodarone.
- Survivors usually receive ICD unless reversible cause identified (such as acute myocardial infarctions).
IHD - Pathogenesis
• Diminished coronary blood flow relative to myocardial demand ISCHEMIA
Cause of IHD:
▫ >90%: reduced coronary blood flow due to atherosclerotic
narrowing
▫ Other causes: lowered systolic blood pressure, vasculitis, structural anomaly, severe hypertension, diminished oxygenation or diminished oxygen-carrying capacity
Causes of decreased blood flow:
- Fixed atherosclerotic narrowing
- Acute plaque change
- Thrombosis overlying ruptured plaque
- Vasospasm
Causes of decreased blood flow: 1. Fixed obstruction
• Anatomicnarrowing/occlusion
– Narrowing of > 70% causes symptomatic ischemia with
exercise
– > 90% stenosis causes ischemia at rest
• Often multiple arteries are affected
– Most commonly: first several cm of left anterior descending (LAD), left circumflex (LCX), entire length of right coronary artery (RCA)
• Effects modified by collaterals
Causes of decreased blood flow: 2. Acute plaque change
• Unpredictable, abrupt conversion of stable plaque to an unstable atherothrombotic lesion that results in myocardial ischemia
– Rupture/fissures/ulcerations
• Exposes underlying thrombogenic substances
– Hemorrhage into atheroma
• Expands plaque & further narrows lumen
• Results in: Acute coronary syndromes
– AcuteMI
– Unstableangina
– Suddencardiacdeath
Influences contributing to acute plaque change
• Intrinsic factors: – Structure and composition of plaque • Large areas of foam cells/lipid • Thin fibrous cap • Most dangerous lesions are the moderately stenotic (50-75%), lipid rich atheromas (soft-core) • Abundant inflammation • Few smooth muscle cells – Mechanical stress (at the junction of fibrous cap and adjacent normal wall)
• Extrinsic factors:
– Adrenergic stimulation
• Upon awakening
• Emotional
Causes of decreased blood flow: 3. Coronary Thrombosis
- Partial or total, superimposed on a partially stenotic plaque
- Critical to the pathogenesis of acute coronary syndromes
- Total occlusion → acute transmural MI or sudden death
• Incomplete occlusion (mural thrombus)
– Unstable angina, acute subendocardial infarction,
sudden death
– Emboli (into more distal coronary artery)
Causes of decreased blood flow 4. Vasoconstriction
- Compromises lumen size and increases mechanical forces that contribute to plaque rupture
- Leads to severe but transient reduction in coronary blood flow
• Stimulated by: – adrenergic agonists in circulation – locally released platelet contents – endothelial dysfunction leading to impaired secretion of endothelial relaxing factors – mediators released from mast cells
Angina Pectoris
• Paroxysmal & recurrent attacks of chest pain caused by transient myocardial ischemia, 15 seconds to 15 minutes
– No cellular necrosis
• Three patterns:
– Stable - produced by physical activity or emotional excitement, attributed to chronic stenosing coronary AS
– Prinzmetal - due to coronary artery spasm, at rest
– Unstable - occurs with progressively increasing frequency and progressively less effort, often at rest and of prolonged duration
•—–Induced by disruption of plaque with superimposed partial thrombosis
•—–Often prodrome of acute MI
Myocardial Infarction (MI)
• Death of cardiac muscle due to ischemia
• M>F (premenopausal)
• Risk factors: increasing age & predisposition to atherosclerosis
• HTN, cigarettes, DM, increased cholesterol &/or lipids • Pathogenesis:
—–In 90%: acute plaque change resulting in thrombosis & occlusion of coronary artery
—–In 10%: vasospasm, emboli or unexplained
Myocardial Response
• Loss of contractility - 60 sec of ischemia
– May precipitate acute heart failure
- Loss of blood supply reversible damage in early stages
- 20-40 minutes irreversible damage (coagulative necrosis)
- Early thrombolytic therapy (3-4 hrs) reperfusion and limit size of infarct
- Arrhythmias (induced by myocardial irritability secondary to ischemia/infarction – ventricular fibrillation) sudden death
• Frequencies of involvement of three main coronary arteries:
– LAD: most often (40-50%)
– RCA: next most often (30-40%)
– LCA: least common (15-20%)
Myocardial infarction: Gross morphology
• 2 weeks
– Gray-white scar begins to form
Myocardial infarction: histology
• 4-12 hrs; wavy fibers
• 12 hrs–7 days; coagulative necrosis becomes well-established & ongoing
– Initially pyknotic nuclei, hyper-eosinophilic myocytes.
– Followed by neutrophils (max 1-3 days), loss of nuclei & striations. By 7 days, macrophages at border
- 7-14 days: granulation tissue well-established; collagen begins to deposit
- > 14 days; progressively more collagen deposition, eventually dense fibrous scar
Acute Myocardial Infarction: Reperfusion Injury
• Usually occurs after: – Thrombolysis, balloon angioplasty, or bypass grafts • Reperfusion prevents necrosis if occurs within 20 minutes • Pathology associated with reperfusion: – Gross: hemorrhage into infarcted tissue
• Micro: necrosis with contraction bands – Due to influx of calcium • May result from: – Oxygen free radicals released from leukocytes – Microvascular injury causes hemorrhage and endothelial swelling that occludes capillaries (no flow) – Platelet & complement activation
MI – Clinical Features and Diagnostic Evaluation
• Chest pain – Severe,crushing,substernal – Radiation into left arm, neck, jaw, epigastrium – Last several minutes to hours – No relief by nitroglycerin or rest
- Rapid weak pulse, diaphoresis, dyspnea due to pulmonary edema
- Approx. 10-15% without symptoms
- ECG patterns
- Lab evaluation: cardiac enzymes, C-reactive protein (See Dr. Koethe’s lecture)
Complications of MI
• Contractile dysfunction – in proportion to amount of damage
• Cardiogenic shock (pump failure)- (10-15%); associated with damage to 40% or more of LV
– Correlates with size of the infarct
• Arrhythmia (early in the course) - sudden death
• Myocardial rupture (3 – 7 days)
– Freewall- hemopericardium, tamponade, aneurysm
– Ventricular septum – LtRt shunt
– Papillarymuscle–mitral regurgitation
• Pericarditis (2 – 3 days)
others: • Mural thrombus & thromboembolism • Ventricular aneurysm(late) • Papillary muscle dysfunction – Secondary to scarring/fibrosis • Progressive heart failure (late)
Acute MI - Prognosis
- Depends on infarct size, site and transmural extent
* Long-term prognosis depends on quality of left ventricular function and the extent of vascular obstruction
Chronic Ischemic Heart Disease
Elderly patients with progressive heart failure due to ischemic myocardial damage
– Post-infarction cardiac decompensation (rest of fibers become hypertrophic and get “burned out”)
•—- “Exhaustion” of remaining hypertrophic fibers
– Severe coronary artery disease without infarction but with
myocardial dysfunction
Morphology:
– Enlarged heavy heart with left ventricular hypertrophy and dilation, coronary AS, scars, subendocardial myocyte vacuolization
Sudden Cardiac Death (SCD)
• Unexpected death from cardiac causes, early after or without onset of symptoms
– Death due to lethal arrhythmia (asystole or ventricular fibrillation)
• Most often due to IHD and is its first manifestation (80-90% of SCD)
• Non-atherosclerotic causes: – Hypertrophy – Cardiac conduction system abnormalities – Mitral valve prolapse – Congenital abnormalities – Myocarditis – Cardiomyopathy – Pulmonary HTN
• Morphology: coronary atherosclerosis, acute plaque change, MI, scars from old MIs or pathology associated with non- atherosclerotic causes (above)
ECG inferior wall
II, III, aVF
ECG lateral wall
V5, V6, I, aVL
ECG anterior wall
V2, V3, V4
