Week 1 Pathology HTN PAD ischemic heart disease Flashcards
What is the importance and equation for MAP? what is the usual cause for an increase in MAP
All physiology in body goes toward maintaining MAP.
MAP= COxSVR
or estimated as MAP is about equal to DP+ .33 Pulse Pressure (SBP-DBP)
Usually an increase in MAP is by increased SVR but CO can also cause it
LO: define HTN, define shock
MAP below 60 is shock, above 105= HTN
**HTN is = to 140/90mmHg (if either number is equal to or greater)
LO: When is SBP and DBP measured in relation to the cardiac cycle?
SBP measures the maximum pressure of cardiac cycle at end of systole
DBP is minimum pressure right before systole begins
LO: Recognize and describe the molecular, cellular, and tissue pathology of HTN
Molecular- HTN induces changes in endothelial walls, turns on MLCK etc to get proliferation of smooth muscle
In essential HTN get hyaline arteriolosclerosis- glassy pink scar think wall with thin artery lumen
In malignant HTN get hyperplastic arterosclerosis- more layers than hyaline, and little area for blood to flow through
Also fibrinoid necrosis- damage arterial wall and endothelium and leaks plasma that congeals and clots
LO: List the clinical outcomes associated with chronic HTN
There are two major complication from HTN: increased after load, arterial damage
What are the consequences of increased after load from HTN?
Increased after load (end load against which the heart contracts to eject blood): heart must generate more pump, more contractility leading to systolic dysfunction, if over time the heart can’t keep up increased contractility and systolic dysfunction with LVH and diastolic dysfunction (can’t fill or relax properly) lead to heart failure.
Also the myocardium needs more O2 to keep up and can lead to myocardial ischemia or MI
What are the consequences of arterial damage from HTN? what are the effects in coronary, cerebral, aorta vessels (larger vessels)
HTN increases pressure in endothelium to increase smooth muscle activity and creates damage- atheroscelosis: deposits in the vessels, can’t get as much blood into the vessels but need more
In coronary vessels this decreases myocardial O2 leading to myocardial ischemia and infarction
In cerebral vessels it can lead to ischemic stroke (clogging of vessels)
In aorta can lead to aneurysm and dissection
Large vessels clog up
What are the effects HTN has in the smaller vessels?
what is effect in cerebral, renal, ophthalmic vessels
In smaller vessels HTN leads to weakened vessel walls
could affect aorta, small vessels break
in cerebral vessels in causes a hemmorhagic stroke (breaking of vessels)
in renal vessles in can lead to nephrosclerosis and renal failure
in opthalamic vessels it can lead to retionopathy
What are examples of things that can raise BP other than increasing SVR
hyperthyoidism, secondary polycythemia, beriberi
What are some symptoms of HTN?
headache, physical exam cardiac findings, vision changes, frothy urine
if left untreated HTN can reduce 15 years of life
What are examples of things that can raise BP other than increasing SVR
hyperthyoidism, secondary polycythemia, beriberi, obstructive sleep apnea (baroreceptor sensitivity changes, RAA system effects endothelial dysfunction)
What is the difference in primary and secondary HTN
Primary- don’t know what is causing it, genetics or something we don’t know yet
Secondary- something else in body is causing it and we know about it
What are the signs, symptoms and effects of coarctation of aorta? What is a typical patient presenting with this look like?
A pinched aorta near aortic arch, occurs in younger patients M>F
Signs: Aterial HTN in UE with low BP in LE!!
Sign of 3 on CXR- literally looks like a 3 in aorta. creates resistance to flow
A cause of secondary HTN
What are the effects and signs of salt hypersenstativty? who is more like to be effected?
salt sensativity is a common cause of secondary HTN in lots of people but blacks are more likely to have it
thought to be a MLCK or rho kinase mediated
kidneys can’t control fluids properly
What is renal artery stenosis and its effects on HTN? What is the cause behind it?
Renal artery stenosis is the narrowing of one of the renal arteries, most often caused by atherosclerosis or fibromuscular dysplasia. This narrowing of the renal artery can impede blood flow to the target kidney, resulting in renovascular hypertension – a secondary type of high blood pressure. Possible complications of renal artery stenosis are chronic kidney disease and coronary artery disease.[1]
What types of renal artery stenosis are there and who is effected
Renal artery stenosis is most often caused by atherosclerosis which causes the renal arteries to harden and narrow due to the build-up of plaque. This accounts for about 90% of cases with most of the rest due to fibromuscular dysplasia.[4]Fibromuscular dysplasia is the predominant cause in young patients, usually females under 40 years of age.[5]
In fibromuscular dysplasia see beads on a string appearance on angiogram
What types of renal artery stenosis are there and who is effected
Renal artery stenosis is most often caused by atherosclerosis which causes the renal arteries to harden and narrow due to the build-up of plaque. This accounts for about 90% of cases with most of the rest due to fibromuscular dysplasia.[4]Fibromuscular dysplasia is the predominant cause in young patients, usually females under 40 years of age.[5]
In fibromuscular dysplasia see beads on a string appearance on angiogram. It is a increase in endothelial and smooth muscle growth of renal artery, kidney problems, kidney can’t measure blood properly after it
what is glomerulonephritis and what is its effect?
It is an inflammation of the glomerulus- the filtering mechanism of the kidney, can’t excrete salt so excess water is retained and blood volume is expanded- SVR increases increasing BP
cause of secondary HTN
How can a shift in the RAAS axis after BP and lead to HTN
RAAS= renin angiotensin aldosterone system
angiotensinogen made by liver, increased with estrogen so in 1% of girls on OC pills can increase BP
and some people just make more angiotensinogen leading to secondary HTN
Increased aldosterone increases salt retention, increase SVR increase BP
Increased Angiotensin II vasoconstricts to increase BP
What are the 3 types of mineralocorticoid excess and how do they lead to HTN?
Mineralocorticoids are secreted from adrenal medulla glomerulosa and regulate salt in body
1) Conn syndrome- tumor in zona glomerulosa that releases excess aldosterone, sodium retention, SVR increases and increase BP
2) DOC hypersecretion- increased ACTH for any reason, hyper secrete deoxycortisone, retain sodium, SVR increase
3) glucocorticoid remediable aldosteronism- genes encoding aldosterone synthase and 11beta hydroxylase are linked in embryogenesis. ACTH causes hyper secretion of glucocorticoids and aldosterone, seen with severe HTN early in life, treated with glucocorticoids to suppress ACTH release - need to do properly or Cushings syndrome could occur with tx
What are two classic examples of DOC hyper secretion in pediatric patients
17 alpha hydroxylase deficiency, congential adrenal hyperplasia
What is another way to get mineralocorticoid excess via diet
many herbal supplements like licorice increase aldosterone when metabolized leading to secondary HTN
What are three main effects of excess glucocorticoids?
Glucocorticoids are made in zona fasiculta of adrenal medulla, regulate blood sugar
3 effects of excess glucocorticoids are:
cushings syndrome, vascular effects of glucocorticoids, overwhelming of mineralocorticoid receptors
Describe cause, effects, signs of Cushing’s syndrome
Cushing’s syndrome is due to excess glucocorticoids for any reason, most common reason is oral corticosteroids
From pituitary= Cushing disease
Glucocorticoids increase angiotensingoen release and increase HTN (from cortisol)
Presentation: moon face, high BP, red straie, central adiposity, thin arms and legs, red cheeks, buffalo hump, bruising, thin skin
How can excess catecholamines increase BP? what are symptoms and what is a tumor causing this called?
Increase in NE from adrenal medulla chromafin cells increases SBP and DBP
usually causes sustaine HTN but 15% of cases are episodic
Symptoms inculde palpitations, headache, glycosuria (glycogen in urine) and extreme SBP
Tumors causing excess catecholamines is called pheochromocytoma- too much NE released from medulla chromaffin cells
What is the most common mechanisms behind essential (primary) HTN? what are the main thoughts on how it is causes
Primary HTN- no identifiable cause
Natriuretic hormones- normally dump sodium into urine, there is a NP in blood called ouabain that causes Na to be lost in urine but Ca accumulates causing vascular smooth muscle contraction- digitalis like NP
Neurologic disorders- interruption of afferent input raises BP, evidence that chronic pressure on RVLM (pressor center of medulla) can cause HTN
NO- inhibit NO synthase will decrease NO and raise BP, can’t relax endothelium as well
Metabolic syndrome- most important-
What is the most common mechanisms behind essential (primary) HTN? what are the main thoughts on how it is causes
Primary HTN- no identifiable cause
Natriuretic hormones- normally dump sodium into urine, there is a NP in blood called ouabain that causes Na to be lost in urine but Ca accumulates causing vascular smooth muscle contraction- digitalis like NP
Neurologic disorders- interruption of afferent input raises BP, evidence that chronic pressure on RVLM (pressor center of medulla) can cause HTN
NO- inhibit NO synthase will decrease NO and raise BP, can’t relax endothelium as well
Metabolic syndrome- most important- distict entity of insulin resistance, hyper insulinemia, HLD, and obesity the characteristics. Tends to be in patients with essential HTN. Too much insulin and can’t do anything with it but it may increases SNS activity, insulin may vasodilate
- Outline the risk factors and clinical presentation of PAD
Risk factorsSmoking- twice as likely to develop PAD as CAD
DM
HTN
Dyslipidemia
Atherosclerosis is a systemic illness, if have it one bed then good chance it is in lots of beds
Presentation
- Many are asymptomatic
- Many people get claudication, muscle cramp or pain with exertion bc can’t match O2 demand with supply bc stenosis, relieved with rest and reproducible
- Critical limb ischemia- pain at rest, ulcers, gangrene from worse stenosis
- Understand the principles of ABI and Non-Invasive Flow Studies in diagnosing PAD
ABI= ankle-brachial index
Put BP cuffs on arms and ankles, BP should be about same in both beds, PAD affects LE more so get ration, if lower in ankles then lower ratio and decrease in blood flow to LE= PAD, very specific and sensitive
Segmental Pressures- measure brachial, thigh, calf, ankle pressures side to side and compare. A drop in 20mmHg going down or side to side is suggestive of PAD in that bed
or barely covered but can look at PVR- pulse volume recording in same spots. Plethysmography
- Describe evidence-based therapy for PAD
Three prong approach to PAD tx
1) risk factor modification- smoking cessation, manage HTN and DM, high intensity statin
2) anti-platelet therapy- prevents MI CAD or strokes, no need to add clopidogrel with ASA, just ASA is fine
3) exercise program- promotes angiogenesis to make by pass circuits, significantly reduces claudication from PAD
- Define acute aortic syndromes
Aortic dissection- tear in intima of aorta allowing access of blood into the media and formation of true and false lumens
Intramural hematoma- collection of blood in wall of aorta btn intima and media without an entry tear, “like a bruise”
Penetrating aortic ulcer- inflamed atherosclerotic plaque growth leading to a crater like outputting of aortic wall
Rapid aneurysm expansion- accelerated dilation of aorta that is associated with weakening of the vessel wall and impending rupture, if grows over 0.5cm per year is indication for fix
Aortic rupture- tear through entire wall of aorta causing hemorrhage into extravascular space, emergency or die
- Identify risk factors for aortic dissection and rupture
“What are the genetic vs acquired risk factors for acute aortic syndromes”
Acquired- HTN, cocaine/amphetamines, syphillis
Genetic- marfans (FBN1), EDS(type IIIcollagen), BAV (bicuspid aortic valve) is most common, aortic coarctation, LDS (TGFBR)
- Describe the approach to diagnosis of acute aortic syndromes
Hx, CTA or MRI, look at each card for the diseases
PAD dx with NIFS
What is the main difference btn TAA and AAA besides location?
Most AAA are atherosclerotic in nature. Most TAA are degenerative- with time and athersclerotic risk factors you can develop it but other factors lead to degeneration.
Degeneration is due to breakdown of ECM proteins and mechanical forces leading to cystic medial necrosis.
What is the main difference btn TAA and AAA besides location?
Most AAA are atherosclerotic in nature. Most TAA are degenerative- with time and atherosclerotic risk factors you can develop it but other factors lead to degeneration.
Degeneration is due to breakdown of ECM proteins and mechanical forces leading to cystic medial necrosis.
What are the types, causes, and risk factors for TAA?
Two types: descending (distal to lig arteriosum), most related to atherosclerosis
Ascending- proximal to lig arteriosum, related to bicuspid aortic valve (aortopathy- a genetic issue), connective tissue diseases (marfan, EDS, LDS), tertiary syphillis- causes inflammation leading to dilation
What are the genetic risk factors leading to TAA? What genes should we know
proximal/ascending TAA or more related to genetics.
Genetic factors: bicuspid aortic valve (aortopathy)= a genetic issue disrupting TAA and ECM proteins
Connetive tissue disorders: Marfan (FBN1 gene), Ehlers Danlos syndrome (type III collagen), Loeys-Dietz syndrome (autosomal dominant TGFBR mutation)
would want to check family members for genes too
Describe cystic medial necrosis. What is it associated with?
Cystic medial necrosis- mucoid material accumulation in media of aorta
associated with TAA (not AAA)
What are the types, causes, and risk factors for TAA?
Two types: descending (distal to lig arteriosum), most related to atherosclerosis
Ascending- proximal to lig arteriosum, related to bicuspid aortic valve (aortopathy- a genetic issue), connective tissue diseases (marfan, EDS, LDS), tertiary syphillis- causes inflammation leading to dilation
What size of aortic aneurysm is associated with increased risk of rupture? when do you try to treat?
Aortic size above 6cm is massive rise in risk for rupture or complicaitons. Try to catch at 5cm and fix.
Describe Marfan syndrome causes, inheritance, and presenation and related diseases
Marfans is a FBN1 mutation (fibrilin deficiency), accumulation of TGFb, AD inheritance
Presentation: Tall, long wingspan, ectopic lens, joint hyper mobility, Pecuts, scoliosis, spontaneous pneumothorax
Related to EDS (col3A) and LDS (TGFBR1/2)
What is an aortic dissection? and its pathophysiology
A tear in aortic intima from wall stress or degeneration of aortic media (non traumatic aortic dissection)
Blood passes into the aortic media separating it from media to create false lumen, propogates distal and proximal to tear, multiple tears possible
What are the types of aortic dissection? Where do they occur? Which is more serious? what arteries are involved?
Type A- usually occurs in right lateral wall of ascending aorta a few cm from aortic valve, usually spirals, can go in either direction, can involve RCA which could lead to R heart ischemia or into aortic annulus to get regurg
So Type A is more serious
Type B- beyond ligament arteriosum in descending aorta
How does aortic dissections present and what is diagnostic techniques
Presents with abrupt onset of severe chest pain radiating to the back, tearing sensation in chest, unequal b/l BP not a reliable dx tool
Negative D dimer rules out dissection
Rapid dx is with imaging and critical: CTA or TEE or MRI (slower)
What is an aortic intramural hematoma? What is possible mechanism? And how is it best dx?
Collection of blood in the aortic media without obvious dissection flap or entry tear
Could be from spontaneous hemmorhage from vaso versorum but not sure
Best dx with CTA with non contrast and contrast for comparison
Fresh hematoma suggests IMH (hemorrhage)
Tx: observe, don’t usually dissect or rupture
What is the common approach to acute aortic dissections and then how do you treat the different types of dissections specifically? What do you give and what do you avoid
First want to decrease stress by decrease BP and HR (Iabetalol, nitroprusside) to prevent propagation of dissection- goal to get SBP 100-120 and HR<60bpm.
And then avoid vasodilators in dissections (hydralzine and nitroglycerin) bc don’t want blood to pool on venous side
Type A: ascending, surgical emergency d/t risk of complications (stroke, MI, tamponade- bleeding into pericardium, aortic insufficiency)
Type B: in descending aorta, treat risk factors and prevent propagation medically, surgery considered with persistent pain from ongoing dissection, involvement of end organ vessels (ie. renal arteries), and extent of dissection, rupture, expansion, malperfusion, or marfans
How do you treat chronic dissections in both types? When to send to sx?
Type A: in acute all patients go but with chronic with dimension greater than 5.5cm, Marfan with greater than 4cm, increase in dimension > 1cm/year, severe aortic regard, symptoms of expansion or compression
Type B: max dimension 6cm or greater, increase in 1cm/year or greater, symptoms of expansion or compression
How can you get an aortic rupture? What is prognosis
From trauma, aneursym or dissection can predispose
Usually fatal
What are effects of HTN on the heart pathologically?
HTN can lead to cardiac hypertrophy- a compensatory increase in mass of LV.
- Know the effect of systemic HTN on the heart including gross and microscopic findings.
HTN leads to cardiac hypertrophy via increased afterload on ventricle- typically concentric hypertrophy, a thick wall and small chamber volume. When limits of compensation are reached then may get cardiac decompensation with cardiac dilation. hypertrophy can lead to ventricular arythrmias and sudden cardiac death. An increase in preload leads to eccentric LVH.
Hypertrophic cells have an increased diameter with enlarged hyperchromatic and rectangular boxcar nuclei
- Know the effects of HTN on small arteries (hyaline and hyperplastic arteriolosclerosis) and their associations and clinical consequences.
In small arterioles HTN causes arteriosclerosis, hardening of small arteries. This leads to hyaline arteriosclerosis first- hyaline thickening with lumen narrowing from plasma protein leakage across injured endothelial cells and increased smooth muscle cell matrix synthesis in response to chronic hemodynamic stress. Hyaline= glassy, scarred appearence. In kidney lose renal parenchyma and is called benign nephrosclerosis. Hyaline changes also in elderly and diabetic microangopathy
2nd is hyperplastic arteriosclerosis- in malignant HTN, onion skin leasion, with concentric laminated thickening of walls and lumen narrowing. Laminations= smooth muscle cells with reduplicated thick basement membranes. Sometimes accompanied with fibrinoid deposits and vessel wall necrosis (necrotizing arteriolitis) esp in kidney
- Know the gross and microscopic appearance of benign and malignant nephrosclerosis, and their associations with hypertension
Benign nephrosclerosis- HTN leads to vascular changes, hyaline arteriosclerosis, medial and intimal thickening- leads to ISCHEMIC damage- glomerulosclerosis and chronic tubulointerstitial injury leads to cortical scarring and shrinking of kidney grossly, kideny with surface granulations (grain leather) with subscapular microscopic scars with sclerosed glomeruli and tubular drop outs
Malignant nephrosclerosis- malignant or accelorated HTN leads to VASCULAR DAMAGE (fibrinoid necrosis of arterioles and small arteries, hyperplastic arterioscelerosis)- ischemic kidneys with rupture of arterioles/capillaries- small pinpoint petechiae hemorrhages on kidney= flea bitten appearance on kidney
- Know the effects of HTN on the CNS and be able to recognize and describe gross and microscopic findings (Lacunar infarcts, Slit hemorrhages, intracerebral hemorrhage, hypertensive encephalopathy)
Lacunar infarcts- lake like spaces less than 15mm. Cerebral vessels develop arteriolar sclerosis and may become occluded leading to small cavity infarcts known as lacunae. Microscopically: see tissue loss, lipid laden macrophage (swallow debris from necrosis), surrounding gliosis (glial cells react and proliferate)
Slit hemmorhages- d/t rupture of small-caliber penetrating vessels and the development of small slit hemorrhages, with time they resorb and leave behind a slit cavity surrounded by brownish discoloration. Mic: focal tissue destruction, pigment laden macrophages, gliosis
brain parechymal hemorrhage- HTN is the most common underlying cause of primary brain parenchymal hemorrhage, arteriolar walls are weakened and vulnerable to rupture. HTN can lead to minute aneursyms (Charcot–Bouchard microaneursyms) which may rupture
Hypertensive encephalopathy- acute syndrome arising in pt with malignant HTN, characterized by: diffuse cerebral dysfunction -headaches, confusion, vomitting, convulsions, coma. Need to reduce the increased intracranial pressue. Autopsy show edematous brain with or without herniation. Petehiae and fibrinoid necrosis of arterioles in gray and white matter
- Know the effects of hypertension on the retina and be able to recognize and describe the findings.
Hypertensive retinopathy from HTN. Commonly associated with arteriosclerosis affects retinal microvasculature, light reflected from thickened walls has silver (total occlusion) or copper (some bloodflow) wire appearance. See cotton wool spots d/t axonal ischemic damage. Hemorrhages are common in retina and exudates frequently form a star around the macula (macular star). See AV nicking where arterioles cross veins. Optic head is edematous= blurry
- Define aortic dissection and know the pathogenesis with underlying risk factors
Aortic dissection- separation of aortic media by blood entering aortic media through an intimal tear
HTN is the major risk factor for aortic dissection. HTN leads to degen changes of aortic wall- weakened media- dissection.
Also occurs in CT disorders= Marfan, EDS, etc
Most frequent preexisting histo lesion is cystic medial degeneration. Inflammation is characteristically absent
Once a tear has occurred, blood flow under systemic pressure dissects through the media leading to progression of hematoma
Compare and contrast retina outcomes in malignant vs chronic HTN.
Severe malignant HTN with acute onset- burst small retinal vessels-
hemorrhages!, exudation of plasma lipids, areas of local infarction.
Papillidema!- swelling of optic disc with blurring of its margins, from high intracranial pressure when BP reaches malignant levels and regulation fails
Chronic HTN: VASOCONSTRICTION- results in arterial narrowing and medial hypertrophy thickens the vessel wall- AV nicks
With more severe chronic HTN arterial sclerosis is evident as an increased reflection of light through scope- copper or silver wire
NO PAPILLEDEMA
- Lipoprotein classes and their atherogenic properties
Pro-atherogenic= Chylomicrons, VLDL, Remnant lipoproteins (over 30nm) and LDL (20-22nm). ApoB is pro atherogenic- 90% of ApoB is LDL. ApoB is more indicative of risk than just measuring cholesterol.
Anti-atherogenic- ApoA=HDL (9-15nm)
- Primary and secondary causes of dyslipidemia
Primary= genetic
Two ones he wants us to know:
Type II familia hypercholsterolemia (defect in LDL receptor apoB100 or PCSK9), majority of genetic lipid defects are with LDL-R, consider if LDL greater than 190. Heterozygotes will have LDL above 190 and half have CV events before 50. Homozygotes have LDL 500-600 and very rare. CV events in twenties
Type IV familial hypertriglyceridemia- If triglycerides over 900 it is a genetic defect, can lead to pacreatitis which can be fatal
PE: xanthomas (cholesterol) or arcus senilus ( lipids) are deposits
Secondary= diet, lifestyle, medical conditions. is more common by far
Important one: drugs (corticosteroids, protease inhibitors for HIV, immunosuppresants)
Others: diet, inactivity, obesity, DM, metabolic syndrome, hypothyroidism, cholestatic liver disease, nephrotic syndrome
How does the body regulate cholesterol stores?
The liver makes cholesterol (VLDL) to bloodstream or gets rid or excess as bile to intestine to poop out. Intenstines can reabsorb bile in form of chylomicrons back to liver
- Describe the classes of lipid-lowering therapies, their mechanisms of action, and their impact on lipid profile
1st line to lower cholesterol= statins
Statins- block HMG CoA reductase, a key enzyme in liver production of cholesterol, this makes liver produce more receptors to suck more LDL out of blood to increase its LDL levels and decrease blood levels, reduce LDL-C about 30-50%, less apoB=less CHD disease, NNT=25, provide benefit in pts with elevates CRP levels
Bile acid sequestrants- body can’t resorb bile, decreases LDL-C, increase BA excretion and increase LDL receptors increase VLDL and LDL removal
Ezetimibe- blocks receptor that reputes BA back into circulation, decrease LDL by 10%
Nicotinic acid- niacin- reduces the amount of free FA out of adipose tissue and VLDL your liver is making, decreased FFA release with niacin, more HDL, less LDL, much less TG
Fibrates- lower triglycerides, same MOA as niacin, turn on PPAR, increase HDL, decrease TG and LDL
PCSK9 inhibitors- new, effective in lowering LDL, THEY WERE EMPHASIZED-
- Toxicities/side-effects of common lipid-lowering therapies
Statins- small number get elevated transaminase but not causing liver failure and reversible. increased myositis. REAL problem is with rhabdomyolysis- breakdown of muscle, low incidence but can be fatal
Drug interactions: broken down by CYP450-3A4 so grapefruit can increase simvastatin and lovastatin. Protease inhibitors can increase rosuvastatin (use atorvastatin), use pravastatin or rosuvastatin in all transplant patients, Interactions with fibrates
BA sequestrants- GI upset, decreased absorption fat soluble vitamins or rx
Ezetimibe- diarrhea
Niacin- flushing (better with NSAIDs or ASA), hyperglycemia, hyperuricemia (avoid in gout)
Fibrates- myopathy (increased with statin use), cholesterol gallstones, rhabdo with statins
PCSK9 inhibitors- PCSK9 is a cofactor for LDL receptor , when binds to LDLR it marks it for degradation, if inhibit with MAB that bind up all PCSK9, get more LDLR and less circulating LDL, reduces LDL by 60% on top of statin reduction, injections twice a month, very expensive now
