wk 9, lec 1 Flashcards
how common is hypertension
Affects > 1 billion people, prevalence in those older
than 60 is > 60%
risk factors for hypertension
▪ Ischemic heart disease and congestive heart failure ▪ Peripheral arterial disease
▪ Dementia, stroke, and chronic kidney disease
effects of medications on hypertesnion
antihypertensive therapy reduces the risk of the above complications
▪ However, it is estimated that over half are not treated at all or are inadequately treated
what organ systems are involved in hypertension
▪ Central and peripheral nervous system
▪ Endocrine system
▪ Kidney
▪ Vascular system
▪ Digestive system, microbiome, and DIET
▪ Immune system
common factors in primary hypertension
▪ Arteriolar vasoconstriction and altered endothelial function
▪ Increased sodium retention & increased renin secretion
▪ Increased activation of the sympathetic nervous system
hypertension ____ resistance and ____ lumen size and ____ average resting muscle tone
increase, decrease, increase
increase in vessel wall thickness increases the resistance
what is the major site where total peripheral resistance is regualted
arterioles
what is vascular tone under the control of
hormonal, neural and local endothelial factors
what remodelling happens to the arteriole wall in hypertension
arteriosclerosis;;
▪ Hypertrophy and sometimes hyperplasia of smooth muscle cells
▪ Increased deposition of extracellular matrix
in hypertension the vascular endothelium releases ___ vasodilator susbtances (i.e. Nitric oxide)
less
remodelling of larger vessels in hypertension
become more stiff
arteriosclerosis
what organs can vascular changes to arterioles and arteries be seen in a lot
kidneys (regulate blood pressure)
initial vs chronic hypertesnion changes
initial: hypertrophy of smooth muscle cells –> hypererreactive to vascoactivite stimuli
chronic: arteriosclerosis; fibromuscular intimal thickening by new layers of elastin, reduplication of intimal elastic lamina, increased connective tissue, accumulate plasma proteins and basement membrane deposition
what happens with sodium intake increases beyond usual ability of kidney to excrete sodium
increased sodium –> increased blood volume –> increased mean arterial pressure
▪ Most arterioles will constrict in response to this increased pressure (remember autoregulation) to reduce flow to capillary beds
▪ Increased pressure at the kidney –> increased salt and water loss… however, it is thought that in hypertensive patients over time it takes higher and higher pressures to attain the same level of salt loss
what happens to the nervous system in hypertension? why?
increase SNS outflow; baroreceptors in brainstem reset to new higher normal
what do baroreceptor dysfunction causes
decrease afferent inhibitory signals
increase SNS
decrease limb blood flow
increase vasopressin, renin, angiotensin II
decrease renal blood flow
increase aldosterone secretion, sodium reabsorption, water reabsorption
Increased activation of the sympathetic nervous system leads to:
- Vasoconstriction of systemic arterioles (alpha-1 receptors)
- Increased ADH (vasopressin) release (increased water retention)
- Increased release of renin and AT2 (angiotensin II)
which receptor in RAAS is implicated in hypertension
the aldosterone receptor has been found in blood vessels outside the kidney and has been implicated in abnormal vascular function
where do leukocytes/WBC migrate into in hypertension
▪ The kidneys – well-known
▪ Vascular walls – knowledge is developing
what activates leukocytes (Th17 and ILC3) in hypertension and what are they implicated in
activated by increased extracellular sodium
mplicated and are likely involved in remodeling the vasculature both within and outside the kidney
how do insulin resistance and obesity link to hypertension
mpaired vasodilatory function of the vascular endothelium
▪ Weight loss and improved insulin sensitivity are associated with improved blood pressure, but there are many factors here to consider (i.e. improvements in diet)
▪ Interestingly, renal sodium-glucose cotransporters are closely integrated with sodium handling in the kidney
hypertension and atherosclerosis of renal arteries
Hypertension is one of the major risk factors for development of atherosclerosis, and atherosclerosis of the renal arteries can cause hypertension
▪ Reduced blood flow to the kidney –> increased secretion of renin –>vasoconstriction and sodium retention
primary vs secondary hypertension %
primary 90%
secondary 10%
causes of secondary hypertesnion impact which systems
kidneys and SNS mostly
SLIDE 16 chart
secondary causes of hypertesion
renal: chronic kidney disease (Na+ retention)
renovascular: atherosclerosis (increase renin)
obstructive sleep apnea (increase SNS)
endocrine: hypo/hyperthyroid, cushings etc (increase SNS or aldosterone)
congenital : aorta (hypoperfused renal)
medications/substances: decongestants, amphetamine, cocaine, TCAs, NSAIDs (impair vasodilation and icnrease SNS)
which BP (systolic or diastolic) does hyper and hypothryoid increase
Hyperthyroidism – increases SBP
Hypothyroidism – increases DBP
diagram on slide 17
shows secondary hypertension and mechanisms; i.e. Na+ retention, SNS< –> peripheral resistance and vasoconstriction
what gives an immediate diagnosis of hypertension
> 180/110 mm Hg
▪ Need multiple visits to diagnose hypertension, unless the
hypertension is severe
what factors to consider in BP measurement
- Home measurements are superior to medical office
measurements – less white coat HTN - automated measurements are superior to those done by a healthcare professional
- 24-hour measurements are very useful – BP that remains relatively high during sleep entails a higher risk of complications
hypertension value in diabetes vs non diabetic using automated BP
▪ In general, if mean awake automated systolic BP is 135 mm Hg or diastolic BP is 85 mm Hg –>
hypertension
* If measuring throughout a 24 hour period, average should be less than 130/80 mm Hg
▪ If diabetes, BP ≥ 130/80 mm Hg
office measurement BP value for hypertesnion
office measurements, takes 4-5 visits and average is 140 mm Hg systolic or 90 mm Hg diastolic
office vs automated BP for hypertension vs
office 140/90
auto 135/85
hypertesnion urgency vs hypertension emergency
Hypertensive urgency = greatly elevated blood pressure that should be treated urgently to minimize the likelihood of end-organ damage
Hypertensive emergency = hypertension with symptoms/signs that suggest end-organ damage is occurring due to high blood pressure
hypertesnion urgency
greatly elevated blood pressure that should be treated urgently to minimize the likelihood of end-organ damage
▪ i.e. stroke, IHD/heart attack, development of heart failure, acute kidney injury
▪ Usual definition is a systolic pressure > 180 mm Hg or a diastolic pressure > 120 mm Hg
hypertesnion emergency
hypertension with symptoms/signs that suggest end-organ damage is occurring due to high blood pressure
▪ Typical symptoms/signs: blurry/impaired vision, intractable headaches, stroke, worsening angina, polyuria or anuria
▪ No exact BP criteria – defined by hypertension in a setting of end-organ damage
malignant hypertesnion
▪ Rapid development of severe increases in blood pressure (> 180/120 mm Hg)
▪ Usually have signs of end-organ damage, and is often the cause of a hypertensive emergency
▪ Causes are not always clear, but may be linked to an insult (i.e. renal disease, discontinuation of antihypertensives)
- Pathological finding – severe remodeling of arterioles – known as hyperplastic or malignant arteriolosclerosis
4 antihypertensive medications
- alpha receptor blockers
- ace inhibitors
- angiotensin II receptor (ARB) blockers
4.calcium channel blockers
calcium channel blockers do what
▪ Block influx of calcium by inhibiting calcium channels in heart and in smooth muscle cells of coronary and peripheral arteriolar vessels
- Vascular smooth muscle relaxation and dilation
- Some blockers also inhibit calcium influx into heart’s conduction fibers and/or pacemakers resulting in negative dromotropy and negative chronotropy respectively
calcium channel blockers
block ca2+ influx to stop contraction
undesired effects of calcium channel blockers
Negative dromotropic and chronotropy may aggravate heart block and heart failure
(decrease conduction speed and heart rate)
ACE inhibitors do what
▪ Block conversion of angiotensin into angiotensin II, thus block its vasoconstrictive impact leading to reduced peripheral vascular resistance
* Less aldosterone and thus less Na+ retention
▪ Block ACE from destroying bradykinin, which promotes
nitric oxide production (vasodilation)
ACE inhibitors act on
enzyme that converts angiotensin into angiotensin 2 = less aldosterone and Na+ retention and block vasoconstriction
also cant destroy bradykinin = NO produced and vasodilate
angiotensin II receptor ARB blockers vs ACE inhibitors differnce
ACE inhibitors effect bradykinin (stop its destruction; thus the subsequent nitric oxide) and ARB do not
angiotensin II receptors ARB blockers
▪ Block AT1 receptors resulting in arteriolar and venous dilation (reduced BP) and block of aldosterone secretion (reduced ventricular preload due to reduced Na+ retention)
▪ Do not offer the benefit of increasing bradykinin (and subsequent nitric oxide)
what Angiotensin II Receptors (ARB) Blockers block?
AT1 receptors
what do alpha receptors block
alpha 1 adenoreceptors
alpha receptor blockers
▪ Block Alpha-1 adrenoreceptor resulting in reduced peripheral vascular resistance and lower blood pressure
▪ Minimal impact on cardiac output
adverse events from alpha receptor blockers
Reflex tachycardia and postural hypotension (initially)
vasculitis is
inflammation & necrosis of blood vessels
primary vasculitis vs secondary vasculitis
Primary vasculitis = the vasculitis is not caused by an
underlying disorder
▪ Secondary vasculitis = Vasculitis that is caused by other disorders
* Medications
* Infections - Hepatitis B and C in particular
* Autoimmunedisease–lupusandRAinparticular
causes of secondary vasculitis
- Medications
- Infections - Hepatitis B and C in particular
- Autoimmunedisease–lupusandRAinparticular
large arteries involve in vasculitis
temporal arteritis, Takayasu arteritis
small and medium sized arteries involved in vasculitis
- Polyarteritis nodosa
- Thromboangiitis obliterans
small and medium size arteries and veins involved in vasculitis
- Granulomatosis with polyangiitis, Churg-Strauss Syndrome
- Behcet disease
3 things occurring in vascultitis
- t-lymphocyte activation
- formation of granulomas
- type 3 hypersensitivity (immune complex)
which T cells are activated in vasculitis
Th1/Th17 helper T cells
immune complex/ type 3 hypersensitivity in seen in what type of vasculitis
autoimmune vasculitis due to rheumatoid arthritis or lupus
polyarteritis nodosa and Hep B infection?
what happens in immune complex formation in vasculitis
▪ Immune complexes deposit in the walls of a variety of small vessels –> complement activation and fibrinoid necrosis
immune complexes/type 3 hypersensitivity cause
vascultisi, glomerulonephritis (with PMN) and complement activation
why does vasculitis happen?
Anti-neutrophil cytoplasmic antibodies (ANCAs)
what are Anti-neutrophil cytoplasmic antibodies (ANCAs)? where are they found?
Antibodies against neutrophil proteins found in the
cytoplasm
2 types of ANCAs
p-ANCA and c-ANCA
p-ANCA vs c-ANCA? where are they found what do they bind?
- p-ANCA – found close to the neutrophil nucleus, usually p-ANCA antibodies bind to myeloperoxidase
- C-ANCA – found distributed throughout the cytoplasm, these antibodies bind to proteinase-3
c-ANCA? found? bind?
cytoplasm
bind proteinase 3
p-ANCA? found? bind?
close to neutrophil nucleus
bind myeloperoxidase
mechanism of vasculitis via ACNAs
neutrophil activation –> expression of myeloperoxidase/proteinase-3 on the cytoplasm –> antibody binding and increased neutrophil release of neutrophil cytokines –> increased leukocyte recruitment and damage to endothelial cells
where are ANCA antigens normally found? what happens in inflammation and infection?
ANCA antigens are normally in neutrophil cytoplasm
in infection/inflam - increased cell surface of ANCA antigens on neutrophils
circulating ANCA binds ANCA antigens on surface –> neutrophil activation and interact with endothelial cells –>
Neutrophil degranulation releases toxic factors including reactive oxygen species, proteinase 3 (PR3), and myeloperoxidase, and other granule enzymes leading to endothelial damage
what does neutrophils release during degranulation when activated by ANCA in inflammation and infection? what does it damage?
toxic factors –> damage endothelial
Neutrophil degranulation releases toxic factors including reactive oxygen species, proteinase 3 (PR3), and myeloperoxidase, and other granule enzymes leading to endothelial damage
what areas does temporal arteritis involve
carotid artery branches – in
particular the temporal arteries and ophthalmic arteries
what is temporal arteritis
Patchy granulomatous inflammation of larger arteries
most common form of vasculitis
temporal arteritis
esp if 70 yrs old
temporal arthritis pathogeneisis
giant cells and T cells in patchy granulomas
lumen compressed from inflammation –> thrombosis
ethology of temporal arteritis
HLA-DR4 gene and 1st degree relatives
clinical features of temporal arteritis
-temopral headache and scalp tender
-vision loss or double vision
-fever and fatigue and polymyalgia rheumatica
diagnose temporal arteritis
ESR and CRP
ultrsound temporal artery
treatment of temporal arteritiis
glucocorticoids
prevalence of polyarteritis nodosa
rare
what organs does polyarteritis nodosa effect
- Wide range of organs involved – but very rarely affects the lung
▪ GI tract, liver, spleen
▪ Heart
▪ Kidneys, testes/ovaries
▪ Peripheral & central nervous system ▪ Skin, joints, and muscle
ethology of polyarteritis nodosa
hepatitis B infection
pathological findings in polyarteritis nodosa
neutrophil invade walls –> fibrinoid necrosis and degenerate intima and media
later: neutrophils, plasma cells, other lymphocytes, macrophages invade and are found in all layers
–> thrombosis –> infarct or aneurysm
clinical features in polyarteritis nodosa
- Kidneys – renal failure, hypertension
- MSK – arthritis, arthralgias, myalgias
- Peripheral neuropathies – often “weird” patterns (mononeuritis multiplex)
RARELY
- Infarcts in the bowel/pancreas/liver, cholecystitis –
abdominal pain and nausea are common - Infarcts or aneurysms in the coronary arteries ! myocardial infarction, pericarditis, heart failure
- Infarcts or bleeds in the CNS ! stroke, seizures
skin findings in polyarteritis nodosa
▪ Wide range of skin findings – purpura, nodules, infarcts, Raynaud’s phenomenon
diagnosis for polyarteritis nodosa
no diagnostic test but can use angiogram (imaging)
▪ Labs: CRP elevations, hypergammaglobulinemia, elevated neutrophils
thromboangitis obliterates
- Inflammatory involvement of medium and small arteries in distal arms and legs ! occlusion and ischemia
who is thromboangitis obliterates common in
men and smokers
symptoms of thromboangitis obliterates
▪ Claudication symptoms
▪ Painful ischemic ulcerations of toes and hands
▪ Large arteries are not impacted, only more distal arteries
smoking and thromboangitis obliterans
inflammation –. abnormal endothelial vasodilation
pathogenesis of thromboangitis obliterates
neutrophil invade with micro abscesses –> thrombus
Granulomatosis with Polyangiitis
- Necrotizing vasculitis of small arteries and veins with either intravascular or extravascular granuloma formation
common sites for Granulomatosis with Polyangiitis
upper and lower respiratory tract and kidneys
▪ Upper respiratory tract – sinusitis, damage to nasal
mucosa or bones, otitis media
▪ Lower respiratory tract – pulmonary infiltrates & nodules, pleuritis
▪ Kidney – glomerulonephritis
highest mortality site of invoelvement in Granulomatosis with Polyangiitis
▪ Kidney – glomerulonephritis
* Renal involvement entails a high morbidity and
mortality
Granulomatosis with Polyangiitis
-flares (ie.. fatigue, weak)
if upper and lower respiratory: Sinus pain, bloody nasal discharge, nasal ulcerations, cough, dyspnea, hemoptysis
renal failure
diagnosis of Granulomatosis with Polyangiitis
c-ANCA positivity and biopsy
raynauds phenomenon
Intermittent bilateral but patchy/asymmetric ischemia of the fingers and toes caused by transient vasospasm
Often accompanied by paresthesias and pain
what precipitates raynauds
cold or stress
what is rare in raynauds
ulceration or gangreen
if raynauds phenomenon occurs in isolation with no underlying disease then its called
raynauds disease/disorder
what immunologic disorders can raynauds phenomenon be present in
lupus, systemic scleorisi
symptoms in raynauds –progression (colours)
▪ Digits first turn white (vasoconstriction), then blue (cyanosis), then bright red (hyperemia) when blood flow is restored
