Exam 2 Concepts Flashcards
BMI
body weight in kilograms over (height in meters)^2
crude measure determine relative healthy body weight
obesity BMI
>25>29.9 = overweight >40 = morbid obesity >50 = super morbid obesity
age to start BMI
36 months
greater predisposition to obesity
Native Americans
Pacific Islanders
African Americans
Latinos (Mexico and Puerto Rico)
more women than men
prevalence of obesity increases with age and declines after 60
location of obesity in U.S.
southern and midwestern states
genetics of obesity
leptin deficiency
Prader-Willi syndrome
environmental factors of obesity
increase in sugar, fat, salt (corn syrup)
increased portion sizes
fast food outlets
psychology manipulation by fast food industry
the “there-ness” of food - there and hard to say no
social factors of obesity
food deserts in inner cities
sedentary lifestyles
adipocyte definition
cells that store fat in the form of triglycerides. release triglycerides for energy/fuel purposes
adipocytes under conditions of energy excess
proliferate (hyperplasia)
hypertrophy: maladaptive response to energy excess
triglycerides definition
main storage form of fat
adiposopathy
hypertrophy of adipocytes in combination with visceral (organ) fat accumulation
aka “sick fat”
main patterns of fat deposition
central obesity - apple shape
peripheral obesity - pear shape
visceral fat definition
internal abdominal fat, located inside peritoneal cavity, packed between internal organs
subcutaneous fat definition
found under the skin
visceral fat pathology
fat deposited in and on organs, including heart, liver, and muscles, when capacity of adipocytes to store fat is exceeded
more hormonally active and more inflammation-promoting that subcutaneous fat
adipose tissue
organ cushioning
endocrine fxns
produces hormones and cytokines that contribute to inflammation, atherosclerosis, thrombosis, create conditions that develop and maintain obesity
leptin definition
increases satiety and energy expenditure
increases insulin sensitivity
leptin pathology
under conditions of increased/hypertrophied adipocytes, too much leptin is produced (“leptin resistance”)
adiponectin definition
hormone released from adipocytes
increases nitric oxide in vasculature, thereby increasing anti-atherogenic activities of vascular endothelium (prevents atherogenesis)
adiponectin pathology
as fat mass increases, amount of adiponectin decreases, promoting atherogenesis
atherogenesis definition
formation of subintimal lipid-containing plaques (atheromas) in lining of arteries
resistin definition
hormone release from adipocytes
increases insulin resistance
macrophage and monocyte chemoattractant protein-1 (MMCP-1)
hormone released from adipocytes
promotes inflammation by activating macrophages. increases insulin resistance.
TNF-alpha
hormone released from adipocytes
promotes inflammation and increases insulin resistance
plasminogen activator inhibitor-1
hormone released from adipocytes
inhibits breakdown of fibrin clots (pro thrombotic - pro clot-forming)
IL-6
hormone released from adipocytes
promotes inflammation
increases insulin resistance
increases hepatic lipid and glucose production
angiotensin II and aldosterone
hormones released from adipocytes
identified in adipose tissue –> hypertension
FFAs
free fatty acids
accumulate in obese people (intracellular)
toxic intermediates from the middle of the metabolic pathway hang around and overwhelm normal insulin signaling and muscle glucose transporter (GLUT4) fxns. excess FFAs contribute to insulin resistance
resulting pathologies of increased fat/adipocyte/adipose tissue
inflammation hypertension atherosclerosis thrombosis atherogenic dyslipidemia insulin-resistance Type-2 diabetes
clinical manifestations and sequlae of obesity
central and/or peripheral obesity
dyslipidemia
cardiovascular disease
stroke
insulin resistance or frank diabetes
hypertension
cancer
sleep apnea
gallbladder disease
joint stress/osteoarthritis
NAFLD
dyslipidemia
includes hypertriglyceridemia accompanied by low HDL and smaller, denser LDL that are more pro-atherogenic (can get into arteries easier –> MI)
cardiovascular disease pathology in obesity
prothrombotic and atherogenic
stroke pathology in obesity
prothrombotic and atherogenic
frank diabetes
all the following markers of diabetes present, not just insulin resistance:
multiple hormones and cytokines released by adipocytes
excess FFAs
hypertension pathology in obesity
increased angiotensin II and aldosterone (vasoconstrictors)
decreaed NO
cancer pathology in obesity
breast endometrial colon kidney esophageal liver pancreatic
cancer researchers call fat a carcinogen
sleep apnea pathology in obesity
increased upper airway pressure, reduced chest compliance related to truncal fat deposition
causes sleep deficit which decreases leptin and increases grehlin
grehlin definition
hormone produced by stomach that stimulates appetite
gallbladder disease pathology in obesity
accumulation of cholesterol
NAFLD definition
Nonalcoholic Fatty Liver Disease aka hepatic steatosis
triglycerides accumulate in liver cells, swelling and damaging the liver
NAFLD pathology in obesity
diseased liver cells resemble adipocytes
first hint of NAFLD: high levels of AST and LFTs (necrosis of liver cells)
obesity-related liver disease
liver disease progression. possible to move from 2 back to 1
- NAFLD
- NASH
- fibrosis progressing to cirrhosis
- hepatocellular carcinoma
NASH
non-alcoholic steatohepatitis
steatosis (fat accumulation) + inflammation (increased cytokine signaling)
genetic influences in NAFLD
Latinos particularly vulnerable
carry a variant of gene PNPLA3 that results in high liver fat content
pathology of BMI over 35
quick rise in mortality compared to lower end of BMI spectrum
obese children
- high risk of diabetes
- high risk of becoming obese adults
- develop NAFLD (#1 cause of chronic liver disease in children)
- early evidence of atherosclerosis
- metabolic syndrome
metabolic syndrome definition
(MetS): constellation of symptoms that increases risk of cardiovascular disease. closely related to obesity but not the same thing. 3 of 5 characteristics
5 characteristics of MetS
large waist size high TGs low good cholesterol high BP high fasting serum glucose
symptoms related to MetS
central obesity
dyslipidemia (w/ decreased HDL)
increased BP
hyperglycemia
why care about MetS?
red-warning flag
continuum from preventing to managing to managing comorbidities to death
lipogenesis
formation of new lipid (usually via metabolism of glucose by acetyl CoA)
intake > output
excess ingested glucose used for lipogenesis
excess ingested fat directly deposited in adipocytes
insulin in obesity
main anabolic hormone of body. promotes cellular uptake of glucose, storage of TGs in adipose tissue, and other processes
without insulin
glucose cannot enter cells and fat deposition in adipose tissue is impaired
glycogen
storage form of glucose in liver
stored by liver
where fat comes from
glucose not used/stored by liver metabolized by acetyl CoA to synthesize triglyceride and cholesterol
liver packages TFs and fatty acids into VLDL
adipose cells take up glucose via GLUT 4 receptor for energy needs and to synthesize fatty acids and TGs
end result of glucose
lipids (cholesterol and TGs)
fructose
part of disaccharide sucrose
more likely to be converted to fat than glucose
its biochemical metabolic pathway preferentially leads to the production of fat
chylomicrons
lipoproteins made outside of the liver (in the small intestine) from absorbed dietary fats that travel to the thoracic duct to enter the bloodstream
travel in circulation to deliver fat (mostly TGs) to tissues
- fats broken down by lipoprotein lipase
- fatty acids diffuse into adipocytes to reform TGs
lipoprotein lipase
enzyme found on vascular endothelial cells throughout the body (particularly in adipose tissue) that breaks down TGs from VLDLs and chylomicrons into fatty acids that can diffuse into adipocyte
once in the adipocyte, the TGs are reformed and stored
insulin promotes activity of lipoprotein lipase - insulin is hormone that promotes fat storage
hormone-sensitive lipase
enzyme that promotes the breakdown of stored TGs so the adipocyte can release free fatty acids and glycerol
lipoprotein definition
any of a number of complex molecules that consist of a protein membrane surrounding a core of lipids
carry cholesterol and other lipids from digestive tract to liver and other tissues
VLDL
(very low density lipoprotein)
primarily delivers TGs to tissues
LDL
(low density lipoprotein)
primarily delivers cholesterol to tissues
plays major role in atherogenesis in blood vessels
-which is why it’s called “bad cholesterol”
HDL
(high density lipoprotein)
carries out out reverse cholesterol transport and brings cholesterol back to liver
-which is why it’s called “good cholesterol”
lipoprotein structure
generalized structure of a non-polar (hydrophobic) core of TGs and cholesterol esters surrounded by hydrophilic shell of phospholipids (most abundant constituent part), non-esterfied cholesterol and apoproteins
hydrophilic shell allows lipoproteins to travel in plasma
dyslipidemia
abnormal blood lipid panel
high TGs and/or high VLDL or LDL and/or low HDL
used interchangeably with hyperlipidemia (most focused on)
excess fatty acids can contribute to insulin resistance
insulin resistance
may activate adipose tissue hormone-sensitive lipase and inhibit lipoprotein lipase
-increase VLDL levels
hormone-sensitive lipase sends more fatty acids to liver to be packaged into VLDLs
lipoprotein lipase can no longer break down TGs from VLDLs and chylomicrons for diffusion in adipocytes
fate of fatty acids and glycerol in liver
liver synthesizes new lipids from products of lipolysis
glycerol can be used to form new glucose
atherosclerosis definition
complex process by which arteries become progressively narrowed, impairing supply of oxygen and nutrients to tissues
involves deposition of lipoproteins (particularly LDL-C), macrophages, inflammatory mediators and smooth muscle cells in tunica intima layer of arteries; formation of plaques
atherosclerosis pathology
impaired blood flow can result in ischemia and cause angina or intermittent claudication
atherosclerotic plaques can rupture, triggering acute formation of clot, and abrupt loss of blood supply to tissues - resulting in MI
intermittent claudication
walking and legs start to hurt because muscles aren’t getting enough oxygen (especially lower legs)
statins
HMG-CoA-reductase inhibitors
decrease LDL
decrease TGs
increase HDL
stabilize atherosclerotic plaques
most effective for lowering LDL and total cholesterol. only medication for managing cardiovascular risk
somewhat controversial
PCSK9 inhibitors
proprotein convertase subtilisin-kexin type 9
monoclonal antibodies that block PCSK9 that normally binds to LDL receptor and prevents it from returning to surface to take in more LDL from the blood
-med allows constant recycling of LDL which drastically lowers serum cholestrol levels
glucose
polar and hydrophilic
glucose diffusion
facilitated diffusion down concentration gradient (e>i)
sometimes against concentration gradient via secondary active transport (SGLT) with sodium (occurs in renal tubes)
GLUT 2 on liver cells
after eating:
glucose is high in liver blood supply and low in intracellular fluid, so GLUT 2 moves glucose into liver cell
while fasting:
liver cells make glucose via glycogenolysis and gluconeogenesis which raises glucose levels inside liver cell, so GLUT 2 moves glucose to extracellular fluid of liver cell and ultimately to bloodstream
GLUT 4
sensitive to insulin
found mostly on muscle and fat cells - translocation to cell membrane stimulated by insulin-receptor interaction
translocation also enhanced by muscle contraction during exercise (i.e. exercise can improve insulin sensitivity)
GLUT 4 on muscle cells
after eating:
glucose and insulin levels increase, so GLUT 4 translocate to muscle cell membrane to move glucose into cell (moves because of signal created by insulin)
glucosuria
glucose in the urine
occurs when hyperglycemia levels in DM overwhelm transporters in renal tubes, leading to persistent urinary glucose
glucose as energy source
converted to glucose-6-phosphate (G6P) by hexokinase or glucokinase when it enters cells
G6P undergoes glycolysis, producing pyruvate
pyruvate enters mito
w/ oxxygen, pyruvate converted to acetyl CoA, which enters Krebs cycle
electron transport produces most ATP
liver processes during fed state (w. insulin present)
- glucose uptake and glycogenesis (glycogen synthesis)
- glycolysis, forming acetyl CoA
Acetyl CoA used to synthesize:
- triglyceride (lipogenesis) forming VLDLs
- cholesterol
adipose processes during fed state (w. insulin present)
glucose uptake via GLUT 4
triglyceride uptake via lipoprotein lipase and storage
muscle processes during fed state (w. insulin present)
glucose uptake via GLUT 4 and amino acids (facilitated by insulin)
protein and glycogen synthesis
processes during fasting
hepatic glucose production depends on ability to produce G6P and ability to remove phosphate, releasing free glucose
glucose entry into ALL cells is followed by phosphorylation, trapping G6P inside cell
-in liver cells, this is reversible because of G6-phosphatase enzyme
glucose phosphorylation and dephosphorylation
All cells:
glucose + phosphate
–> glucose-6-phosphate
(G6P trapped in cell)
Liver and kidney cells:
glucose-6-phosphate
–> glucose + phosphate
(free glucose that can be transported outside cell)
pathways of hepatic glucose production
glycogenolysis
gluconeogenesis (also in kidney)
glycogenolysis in liver
breakdown of glycogen to produce G6P. G6-phosphatase removes phosphate, generating free glucose that can be transported into blood stream
gluconeogenesis in liver
substrates generated by liver, muscle, fat can enter pathway to synthesize new glucose
precursors include: lactate and amino acids from muscle, glycerol from fat
precursors for hepatic gluconeogenesis
amino acids - from muscle proteolysis
lactate - from muscle glycogenolysis
glycerol - from adipose lipolysis
catabolic pathways in muscle
glycogenolysis
proteolysis
glycogenolysis in muscle
breakdown of muscle glycogen to G6P
G6P not dephosphorylated - undergoes glycolysis and converted to lactate
lactate travels through bloodstream to liver as precursor to gluconeogenesis
proteolysis in muscle
protein breakdown releases amino acids to be used as precursor for gluconeogenesis
precursors released by muscle for liver gluconeogenesis
lactate (glycogenolysis)
amino acids (proteolysis)
lipolysis in adipose tissue
decreased insulin, increase epi, increased cortisol
–> activates fat breakdown via hormone-sensitive lipase (HSL)
- TG broken down to glycerol + 3 fatty acids
- glycerol travels to liver for gluconeogenesis
- fatty acids travel via circulation to
- muscle for fuel
- liver for fuel and production of ketone bodies
ketogenesis
a liver catabolic pathway that depends on adipose lipolysis
fatty acids released by adipose lipolysis become oxidized by liver at high rate to produce ketone bodies
liver ketogenesis is favored by
prolonged fasting
absence of insulin
low carb diet
high levels of glucagon and stress hormones
ketone bodies
acetoacetate
beta-hydroxybutyrate
can be used by brain and many tissues for fuel, but create metabolic acidosis
conditions favoring ketone body formation
hormone balance:
- increased glucagon/counter-insulin hormones
- decrease/absent insulin
adipose tissue:
accelerated lipolysis
liver:
- fatty acid oxidation increases Acetyl CoA
- Acetyl CoA synthesizes ketone bodies
prolonged fasting and/or low carb intake
counter-insulin hormones =
stress hormones
hormonal regulation of glucose metabolism
insulin synthesized in pancreas by B-cells of islets of Langerhans
B-cells produce proinsulin, which is stored in granules and cleaved into insulin and c-peptide
a-cells produce glucagon
islet of Langerhans
cluster of pancreatic endocrine cells
insulin molecule
protein hormone with A chain and B chain joined by disulfide bonds
connecting peptide has two a.a. cleaved from each end by peptidase enzyme to create C peptide (secreted with insulin)
c-peptide assay used to measure endogenous insulin production (no C-peptide = no insulin)
insulin secretion overview
increased plasma glucose is primary stimulus for insulin release
glucose enters B cells passively through GLUT 2
glucose triggers chain of events that results in exocytosis of insulin
insulin binds to receptor on insulin-sensitive cells and triggers glucose uptake via GLUT 4
first phase of insulin secretion
glucose in food causes brief rise in insulin release/secretion (short term)
second phase of insulin secretion
continued glucose presence causes insulin production (long term)
incretin effect
ingestion of nutrient stimulates release of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) from cells in gut
GIP and GLP-1 stimulate production of insulin and GLP-1 also inhibits glucagon
steps involved in insulin secretion
- glucose enters cell via GLUT2 - phosphate added by glucokinase
- G6P oxidized, producing ATP
- ATP closes ATP-sensitive potassium channel (sulfonylurea-sensitive)
- cell depolarizes, activating voltage-gated calcium channels
- calcium entry = signal for insulin secretion via exocytosis
insulin actions on liver
increases glycogen storage and glycolysis
increases TG synthesis and release (VLDL)
inhibits gluconeogenesis and ketone production
insulin actions on muscle
increases uptake, storage and use of glucose. storage form = glycogen
increases uptake of a.a. and protein synthesis
insulin actions on fat
stimulates lipoprotein lipase and TG synthesis and storage
strongly inhibits hormone-sensitive lipase (which would cause lipolysis)
increases uptake and use of glucose
intraislet paracrine action
inhibits glucagon secretion
glucagon during fasting state
dominant hormone
responsible for most glucose production during fasting state
source: alpha cells
inhibited by insulin (paracrine effect), GLP-1, glucose at sufficient levels
“counter-regulatory” or “counter-insulin” hormone
glucagon actions on liver
increases glycogenolysis: glycogen breakdown
increases gluconeogenesis: new glucose
increases ketone body formation: ketogenesis
cortisol
counter-insulin hormone
- released during stress
- increases hepatic gluconeogenesis
- promotes muscle proteolysis, increasing amino acid pool for glucose production
- at high levels, promotes lipolysis, increasing free fatty acids and glycerol
- overall effect is to promote glucose production and release
note the hyperglycemic effects of glucocorticoid medications
metabolic actions of epinephrine
stress/anti-insulin hormone
liver: intracellular MOA to increase glycogenolysis, gluconeogenesis, ketogenesis, inhibit glycogenesis
adipose: decrease TG synthesis, stimulates lipolysis
(–> ketone production)
muscle: suppress glucose uptake, stimulates glycolysis with release of lactate into circulation
anti-insulin hormones complicate blood glucose regulation in hospitalized patients
- stress hormones can increase blood glucose levels
- glucocorticoids can exacerbate situation
- increased blood glucose can delay healing time
- insulin-dependent diabetics may require more insulin than usual
- non-insulin-dependent diabetics may require insulin
- even some non-diabetics may temporarily require insulin
growth hormone
anti-insulin hormone
released during hypoglycemia
GH excess (acromegaly) results in diabetes
chorionic somatomammotropin
(pregnancy - anti-insulin hormone)
gestational diabetes
genetics of DM
some heritable tendency in T1DM but greater in T2DM
- still some work to determine genetic variations that make people more susceptible to T1DM
- hard to tease out “pure” genetic factors from environmental factors in T2DM
genome-wide association studies
majority of genes implicated in immune response (autoimmunity - T1DM) are HLA genes
–most associations are weak
in T2DM, more complex mixture of potential pathways are being studied
timeline of T1DM
peak onset between 11 and 13
possible precipitating event: viral infection (occurs a lot in autoimmune disorders)
classic DM presentation
polyuria - excessive urinary output polydipsia - excessive thirst polyphagia - excessive eating weight loss hyperglycemia and hyperlipidemia
DUE TO;
absence of insulin (T1) OR
lack of effective insulin coupled with insulin deficiency (T2)
clinical presentation of T1DM
- patients often extremely ill and may be in diabetic ketoacidosis
- 3 “polys”
- ketone formation due to unopposed glucagon action
- contributes to osmotic diuresis, and metabolic acidosis
- weight loss, fatigue
What causes the 3 “polys”?
hyperglycemia overwhelms the kidneys’ ability to reabsorb glucose
leads to osmotic diuresis (water follows glucose into urine) and excessive urination (polyuria) which leads to dehydration which leads to thirst reaction (polydipsia)
loss of satiety signals, primarily insulin, leads to polyphagia. body also perceives starvation because glucose cannot get into cells
diabetic ketoacidosis (DKA)
- precipitating event
- severe hyperglycemia but perceived by the body as starving for glucose, so liver continues to make glucose (stimulated by glucagon not insulin)
- adipose tissue only sees glucagon, epi, and cortisol, which activates hormone-sensitive lipase and metabolizes TGs into FFA and glycerol into blood stream
- liver takes up glycerol for glucose and FFA for ketone bodies
- muscle releases lactate and a.a. for liver gluconeogenesis
- stress hormones worsen hyperglycemia
- kidneys overwhelmed by hyperglycemia, which spills glucose into urine, followed by water –> dehydration
hospital management of DKA
isotonic fluids
insulin
K+
glucose later
without management, patient will become comatose and die
hypoglycemia in T1DM
- reduced counterregulatory responses (no glucagon response, decreased epi and cortisol responses)
- hypoglycemia unawareness
- worse after exercise and during sleep (coma and seizures)
T2DM overview
- incidence increases with age; familial connection; obesity closely linked
- decreased insulin secretion accompanied by insulin resistance and eventual B-cell dysfunction
- glucagon secreted at high levels, increasing hepatic glucose production
- often preceded by prediabetes, indicated by impaired glucose tolerance (IGT) and impaired fasting glucose (IFG)
double whammy of T2DM
insulin resistance: hyperglycemia and dysregulation of liver glucose production
high glucagon levels: insulin not exerting paracrine effect on Islets of Langerhans (excessive glucagon tells liver to produce excess glucose)
pancreatic cells in T2DM
initially respond to insulin resistance with hyperplasia and hypersecretion of insulin - maintains euglycemia for some time
B-cells are worked to death, leading to frank insulin deficiency. patients may require more and more insulin as disease progresses
hemoglobin A1c
formed when N-terminal valine of beta chains of hemoglobin A is modified by addition of glucose
resulting molecule is stable and can be measured
algorithm convers percentage of A1c in serum to an average blood glucose over ~last 3 months (blood glucose is attached to erythrocytes, which have a lifespan of ~3 months)
monitoring A1c
ADA recommends A1c less than 7%
AACE recommends 6.5% or less
healthy older adults: 7.5
complex/intermediate older adults: 8.0
older adults in poor health: 8.5
worried about hypoglycemia and falls in older adults
hyperosmolar hyperglycemic state (HHS)
precipitating event (usually infection - 60%) that decreases fluid intake and increases insensible loss, leading to increased stress hormone secretion
hyperglycemia is extreme, but lack of metabolic acidosis does not make patients sick enough to seek help
greater fluid loss than DKA
hyperosmolar state with severe intracellular dehydration
low level of insulin preventse ketosis
DKA vs HHS
in HHS: higher blood glucose higher bicarb (more ketone bodies so body is trying to normalize pH with bicarb) higher pH low insulin (vs. absent) greater fluid loss
T2DM acute complications
long-term T2DM can develop DKA, but less common than in T1
hypoglycemia less common, but can occur with insulin, secretagogues, older adults
nonpharmacologic management of T2DM
diet and weight loss increase physical activity reduce stress increase sleep assess/treat depression
chronic DM complicatons
microvascular:
retinopathy
nephropathy
macrovascular:
dyslipidemia
neuropathy:
polyneuropathy (distal pain)
autonomic neuropathy (orthostatic hypotension, tachycardia, silent MI, sexual dysfxn)
foot ulcers (neuropathy + vessel disease + poor wound healing)
infections
diabetic retinopathy
thickening of retinal capillaries
microinfarcts
microaneurysms
comorbid hypertension
hypoglycemia risk factors
mismatch of insulin timing, amount, or type for carb intake
oral secretagogues w/o sufficient carb intake
reduction in nutrient intake
- NPO
- not finishing meal/snack
- IV carb discontinued/decreased
- interruption of enteral feeding
nausea/vomiting
geriatric patieqnts at higher risk
Somogyi Effect
undetected hypoglycemia early in the morning )(2/2 PM intermediate NPH dose peak) followed by hyperglycemia later in the morning
confirm with 3am BG or 3-day continuous glucose monitoring system
Dawn Phenomenon
rise in BG between 4-8am 2/2 counterregulatory hormones that are normally released
hyperglycemia in morning
check 3am BG
- hypoglycemia = Somogyi
- hyperglycemia = Dawn
- euglycemia = more checks
patient/family teaching about insulin
store unopened vials or pens in refrigerator; do not freeze
current vial/pen can be stored at room temp for 1 mo
suspension forms (NPH) should be rolled gently between palms; do not shake
cloudy insulin should be discarded
swab top of vial with alcohol prior to syringe
clear skin before injection and allow alcohol to dry
inject in subQ fat of abdomen, upper arm or upper/lateral thigh
rotate injection sites
do not reuse syringes/pens
teach S/Sx of hypoglycemia and how to manage (carry quick source of glucose)
pts must eat if using rapid- or short-acting insulin
glucometer, especially when sick
calculate carbs and adjust bolus
medical alert bracelet
peripheral circulation highlights
- parallel circuits
- variation in regional flow
- increased flow in active tissues
- decreased flow in inactive tissues
- maintained flow to vital organs
- limit change to systemic flow on minute-to-minute basis
stroke volume
SV
amount of blood ejected from the ventricle with each contraction (LV or RV, usually LV)
systemic vascular resistance
SVR (also TPR)
resistance to blood flow offered by all of the systemic vasculature, excluding pulmonary vasculature
vasoconstriction on SVR
increases SVR
vasodilation on SVR
decreases SVR
what determines blood pressure?
mean arterial pressure =
CO * SVR
CO = HR * SV
mean pulmonary artery pressure =
CO * pulmonary vascular resistance
how is systemic mean arterial pressure estimated clinically from SBP and DBP?
DP + (SP-DP)/3
diastole takes 2X as much time to occur than systole
SA node innervated by…
right vagus nerve
AV node innervated by…
left vagus nerve
autonomic nervous system in HR regulation
parasympathetic (vagus nerve, acetylcholine):
- slow heart
- acetylcholine acts at muscarinic receptors
- resting state under control of vagus nerve (vagal tone)
sympathetic:
- speeds up heart
- norepinephrine acts at B1 adrenergic receptors (dominated by B1 over B2)
training/conditioning in regulation of HR
slower resting HR
maintaining CO
determinants of stroke volume
preload
afterload
contractility
preload
amount of blood filling heart right before it starts to contract (EDV)
determining factors of preload
blood volume and body volume: decrease volume, decrease preload (vice versa)
ability of ventricle to relax normally during diastole
venoconstriction via symp. nervous system: squeezes blood toward heart
muscular pump in calf returning blood to heart
increased preload lead to increased stretch of cardiac sarcomeres leads to stronger contraction leads to increased SV
increase/decrease preload, increase/decrease SV
amount of blood in venous system at any one time
3/4
afterload
pressure that the ventricle sees after it starts to contract. force that has to be overcome to pump blood into systemic circulation
in LV, working to open aortic valve and working against diastolic presure in aorta
determining factors of afterload
systemic vascular resistance and aortic pressure
valve integrity
increase afterload, decrease SV
decrease afterload, increase SV
contractility
intrinsic strength of cardiac contraction. force with which the ventricle contracts
determining factors of contractility
sympathetic control of ventricle (norepinephrine, B1)
activation of B1 receptors leads to increased contractility
conditioning/training improves performance
increase/decrease contractility, increase/decrease SV
determinants of SVR
vessel radius, length, and blood viscosity
-mostly radius (1/r^4)
arterioles (radius): controlled by
- symp. nervous system (a1-adrenergic mediated constrxn (prevents orthostatic hypotension)
- voltage gated calcium channels on smooth muscle: increased calcium flow to cause vasoconstriction
- receptors for hormones and loacl mediators
which tunica is composed of primarily smooth muscle?
tunica media
tunica of arterioles
tunica interna
tunica media
tunica externa
why are arterioles major blood vessel type that influences SVR?
blood flow becomes steady, not pulsing
hormonal determinants of SVR
constrictors:
- angiotensin II (RAAS - kidney) -increases aldosterone which conserves sodium and blood volume
- vasopressin/ADH (posterior pituitary) - kidneys conserve water and blood volume, vasoconstriction of smooth muscle
- endothelin (endothelium) - locally constricts blood vessels
dilators:
- nitric oxide (endothelium) - locally dilates blood vessels
- ANP, BNP (when heart is stretched) - sense heart stretch, increase natriuresis in kidney (Na excretion), vasodilation in smooth muscle
- B-adrenergic receptors in some vascular beds
short-term control of BP
largely controlled by baroreceptors
vasomotor center
in medulla
directly activated by various stimuli or indirectly via baroreceptors which monitor MAP variations on a moment-by-moment basis
baroreceptors
arch of aorta
carotid artery sinuses
baroreceptor reflex
changes in MAP initiated by baroreceptors
can be downregulated after even a relatively short hospital stay
decrease in MAP results in:
activation of:
- a1-receptors in smooth muscle of arterioles (vasoconstriction)
- B1 receptors in heart (increase HR)
normotension
BP
hypertension
BP > 140/90
essential hypertension
common, correlated with prevalence of obesity and diet high in fats and sodium
most idiopathic
managed with lifestyle and pharmacological approaches
prehypertension
systolic 120-139, diastolic 80-89
potentially treatable causes of hypertension
(~10% of cases)
- chronic kidney disease
- renovascular
- endocrine
- aldosterone excess
- pheochromocytoma (tumor produces epi)
- cortisol excess (Cushing’s disease)
pulmonary hypertension
one cause of right heart failure
more common in women
primary PH - poorly understood
idiopathic
secondary to chronic lung disease
systemic arterial hypertension risk factors
- family history
- older age
- obesity
- increased dietary sodium and decreased calcium, potassium, magnesium
- smoking (nicotine = vasoconstrictor)
- African American
- excessive alcohol consumption
- social determinants of health
clinical manifestations of hypertension
- may be asymptomatic for years
- may have headaches but nonspecific
- organ damage w.o treatment
- white coat hypertension
cellular dysfxn in essential hypertension
two hypotheses:
- defect of vascular smooth muscle with abnormal reactivity, possibly also made worse by stress –> vascular resistance increases
- defect of renal sodium excretion –> body fluid vol. increases, BP increases
lifestyle approaches to managing hypertension
- Na restriction
- DASH diet
- alcohol reduction
- exercise
- stop smoking
- K+ Ca++ intake
- recognize barriers to adherence and principles of behavior change
hypertension: end-organ effects
heart and circulation (arteries) kidneys brain eyes reproductive system (i.e. erectile dysfxn)
arteriosclerosis
hardening and stenosis of arteries where they become less flexible due to collagen deposition (general)
increased pulse pressure: SBP-DBP
atheroclerosis
development of a plaque in focal areas via cholesterol deposition
hypertension on renal arterioles
hypertrophy, constriction
hypertension on brain
hemorrhage
hypertension on eyes
retinopathy:
- hemorrhage
- cotton wool spots
- hard exudates
Starling’s Law of the Heart
increased preload –> increased SV
contractility influences position of Frank-Starling Curve
- SNS activity increases contractility, shifting curve up: greater SV at any given ventricular end-diastolic volume
- HF shifts curve down. Higher and higher levels of preload do not lead to normal stroke volumes, but do increae workoad of heart
determinants of blood volume
part of extracellular fluid compartment
sodium intake
hormonal regulation of Na and water retention or excretion by kidneys allows fine-tuning
- aldosterone regulates Na (increases retention, increases water retention/volume)
- vasopressin/ADH: regulates water
- natriuretic peptides (ANP, BNP): regulate sodium (increase excretion, decrease water retention, decrease volume
heart failure concepts
not a single disease - syndrome with common findings regardless of etiology
defined as inability of heart to produce enough CO to meet needs of body
left HF more common, most common cause of R HF
isolated right HF often 2/2 lung disease
late stages, most patients biventricular failure
ejection fraction
SV/LVEDV
fraction of blood volume from the ventricle at end of diastole that is actually ejected into systemic circulation
systolic heart failure
impaired ability of the ventricle to contract, reducing SV and EF to ,40% (normally 55-70%)
generally occurs due to weakened heart wall
remodeling
best described in systolic failure
wall of ventricle thins, chamber gets larger (increase in volume, but decrease in pressure). myocytes die and replaced with stiff, fibrotic tissue, ventricle dilates
no longer has good shape for contracting/pumping
generally occurs due to chronically increased preload
ventricular wall thinning due to
chronically increased preload
ventricular wall thickening due to
chronically increased afterload
etiology of systolic HF
- coronary artery disease/MI
- hypertension
- valve disorders
- familial/genetic - dilated cardiomyopathy
- toxic damage
- idiopathic
diastolic remodeling
increase wall tension
increase preload/afterload
systolic remodeling
death of myocardial cells
dilated cardiomyopathy
not the same as systolic HF
condition where heart becomes enormous and can’t pump
diastolic heart failure
impaired relaxation of the ventricle decreases the amount of filling and end-diastolic volume. ventricle wall is too stiff. ventricular hypertrophy is a common cause of diastolic failure.
even though contractility and ejection fraction are normal, SV is decreased due to poor filling
etiology of diastolic HF
- secondary hypertrophy (hypertension)
- aging
- ischemic fibrosis
- hypertrophic caridiomyopathy
hypertrophic cardiomyopathy
- genetic disease
- second decade of life or later
- abnormal thickening or enlargement of ventricular walls, obstruction of blood flow at the left ventricular outflow tract, sarcomere disarray
- HCM clinical presentation: heart failure, syncope, arrhythmia
- leading cause of sudden death in young athletes
high output HF
when the needs of the body are increased
ex: hyperthyroidism in older person, severe anemia, some kidney failure
need to treat precipitating cause
Classification Scheme - NYHA
patients may go back and forth in stages, depending on symptoms
Class I HF
no incapacity
although patient has heart disease, fxnal capacity is not sufficiently impaired to produce symptoms
Class II HF
slight limitation
patient is comfortable at rest and with mild exertion. symptoms occur only with more strenuous activity
Class III HF
incapacity w. slight exertion
patient is comfortable at rest by dyspnea, fatigue, palpitation, or angina appears with slight exertion
Class IV HF
incapacity with rest
slightest exertion invariably produces symptoms, symptoms frequenly occur at rest
Classification Scheme ACC/AHA
based on history, risk factors, and structural changes, emphasizes progression among stages (not necessarily true for symptoms)
Stage A
patients at high risk for heart failure but without structural heart disease or symptoms of heart failure
Stage B
patients with structural heart disease but without signs or symptoms of heart failure
Stage C
patients with structural heart disease with prior or current symptoms of heart disease
Stage D
patients with refractory heart failure (symptoms at rest despite maximal medical therapy) requiring specialized intervention
heart failure pathophysiology
three main adaptive/injury response mechanisms
- Frank Starling mechanism: increased preload via fluid retention “should” increase contractile force
- Neurohumoral adaptation (RAAS activation, SNS stimulation):
-Dilation/hypertrophy/structural alterations:
-remodeling
-cardiac overload leads to ventricular hypertrophy leads to ischemic vulnerability leads to cell death by apoptosis
OR
-cardiac weakening leads to dilation and wall thinning leads to cell death by apoptosis leads to replacement with fibrotic tissue
problem with compensatory mechanisms in HF
constant bombardment of sympathetic stimulation plus increased preload, afterload further stress the already weakened heart
fluid retention in HF leads to
increased ventricular filling and ventricular dilation
increased cardiac sympathetic (B-adrenergic) activity in HF leads to
increased oxygen demand and remodeling
increased vascular sympathetic (a-adrenergic) activity in HF leads to
afterload increases
RAAS activation in HF leads to
constriction, fluid retention, increased afterload and preload and remodeling
vasopressin activation in HF leads to
constriction, fluid retention, increased afterload and preload
ANP and BNP in HF leads to
early compensation that may fail later
vasodilation and decreased renin
injury process to myocardium in HF leads to
inflammation and fibrosis
compensatory responses in HF
- cardiac dilation
- activation of the sympathetic nervous system
- activation of the RAAS system
- retention of water and increased blood volume
clinical manifestations of increased left ventricular pressure
higher L atrial pressure backing into pulmonary veins and capillaries (really bad - normally low pressure)
S/Sx: SOB, DOE, orthopnea, paroxysmal nocturnal dyspnea, cyanosis, basilar crackles
inadequate systemic perfusion S/Sx
hypoxia, decreased capillary refill, fatigue, activation of RAAS, peripheral cyanosis/coolness
forward effects of LV failure
systemic perfusion (in direction of blood flow
fatigue oliguria increased HR faint pulses restlessness confusion anxiety
backward effects of LV failure
opposite of blood flow (increasing pressure backwards)
towards the right side of the heart
LV failure most common cause of RV failure because R side of heart not built to deal with high pressure
clinical manifestations of increased RV pressure
increased pressure in R atrium, IVC/SVC
S/Sx: peripheral edema, venous congestion (enlarged liver), jugular venous distension
backward effects of RV failure
hepatomegaly ascites: fluid in periotoneal cavity splenomegaly anorexia subcutaneous edema jugular vein distension
clinical manifestations of HF
fatigue, exercise intolerance due to lack of adequate SV/CO
SOB: pulmonary congestions (lungs stretch and fill with greater volume/pressure to provide adequate pressure to fill heart)
systemic circulation congestions: dependent edema and JVD (liver distention later and GI discomfort increase)
severe decompensation and pulmonary edema
alveolar capillaries have higher and higher pressures - leak into interstitium
eventually leak into alveolar lumen (sense of drowning because inadequate gas exchange)
hypoxia: patient cannot lie down at all
HF sequelae
A.Fib and other arrhythmias
inflammation, fibrosis of myocardial cells
liver/kidney disease
lung disease/pulmonary hypertension
hemostasis
arrest of bleeding: explosive, positive-feedback interaction of:
platelets
clotting factors
endothelial cells: lining all blood vessels (normally inhibits clotting)
under normal, healthy conditions, clotting is a localized phenomenon
stages of clot formation and resolution
- vasoconstriction: reducing blood flow and limiting site of clot formation
- primary hemostasis: release substances to call other substances to site of injury (platelets can secrete and receive substances - recruitment and aggregation)
- secondary hemostasis: release of tissue factor, fibrin net formation - hold clot together
- antithrombotic conterregulation: resolution of clot where fibrinolysis causes stoppage of clot formation
platelets
from megakaryocytes of bone marrow
5-10 day lifespan
platelet adhesion normally inhibited by prostacyclin (PGI2 from arachidonic acid) produced by intact endothelial cells
activation occurs rapidly on exposure to collagen via von Willebrand factor, ADP, thrombin
activated platelets release granules containing mediators that promote and amplify platelet aggregation
platelet conformation change on activation enhances aggregation: round to spiky (for more attachment sites)
platelet receptors
ADP VWF TxA2 Fibrinogen Collagen Epi Thrombin
platelet pro-clotting substances
Factor V and VIII VWF ADP TxA2 Thrombospondin Fibrinogen Fibronectin
implication for platelet not having nucleus
no transcripxn
can’t make proteins (why aspirin is irreversible inhibitor of COX-1 because platelet can’t make new COX proteins
VWF
von Willebrand Factor
connects/links platelet to subendothelial collagen that is exposed on damaged endothelium
GpIb
Glycoprotein Ib
platelet surface membrane glycoprotein that acts as receptor for VWF. Without GpIb (and VWF), platelets cannot adhere to exposed collagen
Fibrinogen
permits connecting/linking of adjoining platelets (and formation of stable clot)
GPIIb/IIIa
Glycoprotein IIb/IIIa
integrin complex found on platelets. receptor for fibrinogen. without GpIIb/IIIa, platelet aggregation is inhibited
Thromboxane A2 and ADP
potent promoters of platelet aggregation. TXA2 also stimulates expression of GpIIb/IIIa receptors
serotonin in platelets
taken up from plasma by SERT (SERotonin Transport) and stored
released when platelets activated
role not completely understood: contributes to reflex vasoconstriction and enhances platelet ability to aggregate
controversial whether SSRIs used for depression increase bleeding risk
platelet activation and aggregation steps
- endothelial cells normally prevent platelet aggregation by releasing NO and PGI2
- Injury to vessel wall exposes collagen and VWF which adhere and become activated
- activated platelets release chemical mediators to bind to and stimulate other platelets. aggregate by binding fibrinogen to GpIIb/IIIa receptors
COX in platelet aggregation
activates prostacyclin from endothelium and thromboxane from platelets
intrinsic pathway
less common
activated when factor XII contacts subendothelial substances exposed by vasular injury
extrinsic pathway
most common
activated when tissue factor (TF - Factor III) released by damaged endothelial and tissue cells.
exposure of TF allows TF to form complex with factor VII in presence of calcium
factor VII activated to factor VIIa
proteases in clotting cascade
active enzymes
XII, XI, IX (intrinsic), VIII (extrinsic)
X (common pathway - thrombin activator), II (thrombin)
IX, X, VIII and II require Vitamin K-dependent modification for full activity
cofactors in clotting cascade
accelerators of proteases
V, VIII
regulatory proteins in clotting cascade
Protein C, S, others
activated C splits/inactivates V and VIII, slowing clotting
what is clot made of?
fibrin
product of fibrinogen after cleavage by thrombin (IIa)
clotting fxn doesn’t work well in liver disease
prothrombin converting complex
Xa + Va + calcium + phospholipids
key roles of thrombin in clotting
- catalyzes conversion of fibrinogen into fibrin
- activates XIII, which cause fibrin threads to crosslink
- catalyzes conversion of V to Va
- catalyzes VIII to VIIIa
-platelet activation
conversion of fibrinogen into fibrin
fibrinogen = large soluble protein
fibrin = insoluble molecules that adhere to each other and assemble long fibrin threads (fibrils)
fibrils: entangle platelets and build up a spongy mass that gradually hardens
antithrombin III
blocks thrombin and Xa
protein C activation
protein C inactivates V and VIII, which accelerate protease activity
inactivation of V more physiologically important because V activates thrombin
fibrinolysis
plasmin system breaks down clots when they are no longer needed
XII, HMWK, kallikrein, thrombin release plasminogen activators which cleave plasminogen to form plasmin
plasmin digests fibrin and fibrinogen and inactives V and VIII
HMWK
high molecular weight kininogen
fibrin split products
result of cleaved fibrin proteins (can be measured in lab tests)
lab assessment of clotting fxn
- platelet count
- prothrombin time (PT) - international normalized ratio (INR)
- activated partial thromboplastin time (aPPT)
- d-dimer (fibrin degradation product created by breakdown of cross-linked fibrin due to plasmin activity)
prothrombin time
PT
evaluates extrinsic pathway
partial thromboplastin time
aPTT
evaluates intrinsic pathway
balance of hemostasis
between:
pro-clotting forces (exposed collagen, VWF, platelets, clotting cascade proteins)
anti-clotting forces (intact endothelium, NO and prostacyclin, protein C to inactivate factor V, plasmin to break down clots, other proteins)
principles of clotting and bleeding disorders
- clotting needs to be limited to sites of injury, not disseminated thru body
- clotting needs to be freely available and efficient at all times, to prevent blood loss in event of trauma
- there needs to be a mechanism to STOP clotting when it is no longer needed
- pathophysiology can lead to hypocoagulable or hypercoagulable states
hypocoagulable states (bleeding disorders)
- platelet deficiencies
- deficiencies of clotting factors or cofactors
- anti-clotting factor excesses
examples:
- Von Willebrand disease (abnormal platelet adhesion and decreased VIII)
- hemophilia (decreased VIII or IX)
- heparin-induced thrombocytopenia (HIT): antibodies form to complexes of platelet factor IV and heparin
- late DIC
thromboytopenia
platelet deficiency
ecchymoses
blotchy areas of hemorrhage (medium-sized)
petechia
small blotchy areas of hemorrhage
purpura
large blotchy areas of hemorrhage
hypercoagulable states (clotting disorders)
- deficient or abnormal anti-clotting factors
- excessive pro-clotting factors
most common disorders:
- factor V Leiden (genetic): AKA activated protein C resistance
- prothrombin excess
- early DIC: excess tissue factor-like substances promote disseminated clot formation in small vessels throughout body
Disseminated Intravascular Coagulation (DIC)
tiny cloths (microthrombi and microemboli) form so clotting factors are used up and the person then has excessive bleeding and hemorrhagic shock
where do clots come from in the absence of trauma/tissue injury with bleeding?
intrinsic pathway
Virchow’s Triad
Virchow’s Triad
blood stasis - absence of normal flow along endothelium
damaged endothelium
hypercoagulability
thrombus
clot
embolus
traveling clot
most common site of venous thromboembolism
deep veins of calf
risk factors of venous thromboembolism
immobility/inflammation; decreased bloodflow
- fracture
- hip/knee replacement
- major trauma
- spinal cord injury
- major general surgery
- cancer
- oral contraceptives and smoking
- pregnancy
- chemo
- stroke w/ paralysis
- arthroscopic knee surgery
- central venous lines
- CHF or RF
- previous VTE
- prolonged sitting
DVT
clinical manifestation of thromboses
- asymptomatic OR
- leg pain, tenderness, swelling
- discolored, cyanotic, venous distension distal
PE
clinical manifestation of thromboses
- tachypnea, dyspnea, pleuritic chest pain
- may have cough, hemoptysis, leg pain
- if massive, rapid death
- up to 2/3 diagnosed at autopsy
organ dysfxn w/ thrombus/embolism
depends on location
lung dysfxn with thrombus
PE, lack of blood flow to all or part of one lungs leads to rapid loss of oxygen saturation.
large embolism can lead to death
heart dysfxn w. thrombrus
acute coronary syndrome
myocardial infarction
brain dysfxn w/ thrombus
stroke or transient ischemic attack (TIA)
limb dyxfxn w/ thrombus
ischemia, gangrene
kidney dysfxn w/ thrombrus
acute renal failure
A. fib as major cause of stroke
disorganized rhythm causes blood stasis which sets up conditions for formation of thrombus
if it embolizes, it can enter systemic circulation and cause a stroke
coronary blood flow overview
heart muscle uses abundant ATP for contraxn and ionic balance (Na/K); constantly generating action potentials
heart is .3% body weight but 7% oxygen utilization
90% coronary blood flow occurs during diastole
part of the myocardium most vulnerable to ischemia
innermost, closest to endocardium
myocardial arterial oxygen extraction
75% at rest
myocardium extracts 3 of 4 oxygen molecules from hemoglobin
exercise increases oxygen demand
can only be met by increasing blood flow via vasodilation
stiff, narrowed vessels such as in CAD can’t respond to increased demand which leads to imbalance in cardiac oxygen supply and demand
coronary occlusion
blockage of coronary artery almost always due to thrombus formation at site of an atherosclerotic plaque causing hypoxia and ischemia
angina pectoris
chest pain
- dull pressure pain at center of chest or substernal
- may radiate to jaw, neck or arm
- often brought on by exertion
- atypical presentations common:
- SOB, dizziness, pressure in upper back, fatigue, nausea (women)
stable angina
effort-associated, usually relieved with rest and/or nitroglycerin
unstable angina
unpredictable, can occur at rest or during sleep, may last longer than stable form
prinzmetal’s variant angina
unpredictable, caused by coronary artery vasospasm
Non-ST elevation myocardial infarction (NSTEMI)
partial thickness cardiac muscle infarct. usually occurs by developing a partial occlusion of a major coronary artery or a complete occlusion or a minor coronary artery
ST elevation myocardial infarction (STEMI)
full thickness cardiac muscle infarct (transmural infarct). occurs because of total occlusion of major coronary artery
myocardial infarction
disruption of flow in coronary vessel for >20 min resulting in permanent cell death
may have ST segment elevation (STEMI) or not (NSTEMI). both types will have elevated cardiac biomarkers due to necrosis of cells (troponins, CK-MB, myoglobin)
stable and unstable angina will NOT have biomarkers
acute coronary syndrome
STEMI + biomarkers
NSTEMI + biomarkers
unstable angina (-biomarkers)
STEMI
indicated by changes in ECG due to inability of cardiomyocytes to maintain their normal resting membrane potential and action potential activity. indicates full thickness infarct
typical ECG findings:
ST-segment elevation with pathological Q-wave formation. T-wave inversion possible but less-specific
ST segment elevation indicates
full thickness cardiac muscle injury
pathological Q-wave indicates
muscle necrosis
T-wave inversion indicates
muscle ischemia
normal ECG
isoelectric line before P wave: all atrial and ventricular cells at RMP
P-R segment: atrial cells in plateau phase; ventricular cells are at RMP
S-T segment: all ventricular cells in plateau phase, RMP approximately zero
ST segment elevation in STEMI
as MI evolves, some cells become infarcted w. no electrical activity. ischemic cells still generate some.
ischemic cells have limited ATP to power membrane pumps and leak ions across cell membranes, which causes current flow even when heart is at rest
variation in electrical activity manifests as elevated ST
usually resolves over time
clinical manifestations of MI
chest pain crushing pain radiating indigestion/heartburn nausea severe fatigue diaphoresis blood pressure alterations, hypertension, hypotension nerve dysfxn in diabetes silent MI in diabetes varied symptoms in women loss of consciousness
organ and cellular dysfxn in MI
disruption of large atherosclertoci plague within vessel sometimes associated with systemic inflammation
exposure of subendothelial plaque allows rapid platelet adhesion and activation, thromboplastin-like substances converting prothrombin to thrombin to accelerate coagulation
clot forms, rapidly expands, completely/partially occludes vessel
development of atherosclerosis
- chronic endothelial injury leads to…
- endothelial dysfxn, permeability, and inflammation
- activated monocytes infiltrate arterial wall and smooth muscle proliferates
- macrophages engulf lipid to become foam cells
- lipid core forms in arterial wall and fibrous cap evolves
endothelial injury
endothelium damaged by smoking, hypertension, hyperlipidemia, toxins, other damage. arterial bifurcations are particularly vulnerable to damage
lipoprotein deposition
when endothelium is injured or disrupted, LDL molecules can migrate into arterial intima, where they are then modified by oxidation. modified LDL is proinflammatory and ingested by macrophages, creating foam cells causing a fatty streak in arterial wall
inflammatory reaction
modified LDL, plus endothelial injury, attracts more inflammatory cells into arterial intima
lipid core formation
lipids and cellular debris accumulate in vessel wall
smooth muscle cell cap formation
smooth muscle cells stimulated by activated macrophages and foam cells, proliferate and migrate to surface of the plaque creating a fibrous cap over lipid core
when cap is thick, plaque stable. when cap is thin, more prone to thrombosis
unstable plaque characteristics
large lipid core thin fibrous cap inflammatory cells macrophages few smooth muscle cells
percutaneous coronary intervention
mechanical revascularization, angioplasty
plain or drug-eluting stent placed to maintain vessel patency
CABG
internal mammary artery graft bypasses occlusion and resupplies myocardium with blood flow
pump function in MI
systolic dysfxn and diastolic dysfxn
leads to: varying degrees of acute impairment of cardiac output
sympathetic stimulation increases myocardial oxygen demand, creating a vicious cycle
structural complications of MI
ventricular septal rupture
mitral regurgitation
aneurysm
cardiogenic shock
invasive hemodynamic monitoring needed
increased risk of second MI until scar forms
electrical complications of MI
ventricular arrhythmia
areas of myocardial ischemia and death
eleated sympathetic tone
initially all cells still electrically coupled
-increased intracellular Ca closes some gap jxns which stops spread of depolarization but predispose to reentry arrhythmias and ventricular fibrillation (ultimately scarring takes over reducing ventricular ectopy)
ectopy
irregular heart beat NOT coming from SA node (pretty much anywhere else)
functional complications of MI
myocardial stunning - persistent systolic dysfxn for several weeks after MI revascularization
myocardial hibernation - prolonged reduction in systolic fxn due to coronary artery insufficiency
MI is risk factor for HF: acute or gradual
anti-ischemic therapy in NSTEMI/unstable angina
oxygen
vasodilators
B-blockers
morphine PRN
anti-platelet therapy in NSTEMI/unstable angina
antiplatelet agents
anticoagulants
STEMI: acute management therapeutic approach
restore blood flow
reduce cardiac oxygen demand/increase oxygen supply
reduce workload of heart
reduce pain (reduce sympathetic nervous system response)
limit ventricular remodeling
restoring blood flow in STEMI
PCI (+ aspiring + clopidogrel)
lyse existing clot (TPA + aspirin + clopidogrel)
reducing cardiac oxygen demand/increase oxygen supply in STEMI
B-blockers
oxygen
morphine
nitroglycerin
reducing pain in STEMI
morphine (also venodilates to reduce preload and modest arterial dilation, to reduce afterload)
limiting ventricular remodeling in STEMI
ACE inhibitor
drug eluting stents
restenosis after stenting can occur because smooth muscle cell proliferation and migration that re-occludes vessel
prevented with stent that elutes anti-proliferative drug over weeks/months
re-endothelialization is reduced and can increase risk of late thrombosis (concurrent use of aspirin and clopidogrel)
why is PCI preferred to fibrinolysis?
better at reducing overall short-term death, non-fatal reinfarction, stroke, and combined endpoint of death, non-fatal reinfarction, and stroke
better followup
nitroglycerin in acute STEMI
does not reduce mortality
sublingually every 5 min x 3 doses
can be given IV, slow and continuous
glass bottle, special tubing
NOT given with PDE5 inhibitors
early initiation of maintenance therapy to prevent reoccurrence
treatment of hyperlipidemia, HTN, diabetes
clopidogrel, aspirin
beta-blockers
ACEI/ARBs
