CV Week 1b Flashcards
What is the primary mechanism of EC coupling? What are the 3 main steps?
CALCIUM cytosolic fluctuations
1) Ca2+ enters cell via DHPR (L-type Ca2+ channel) → activates RyR2 in SR → flux of Ca2+ into myoplasm
2) Ca2+ binds troponin → myosin binds actin → contraction
3) Ca2+ removed from myoplasm by → relaxation
3 mechanisms by which Ca2+ is removed from the cytoplasm
In order of most contribution:
1) SERCA2 pump
2) NCX Na+/Ca2+ exchanger
3) ATP Ca2+ pump (PMCA) - minimal contribution
SERCA2 pump
- pumps Ca2+ into SR, on longitudinal SR
- Ca2+ binds calsequestrin (low affinity, high capacity) in SR
- Dominant mechanism of removal of Ca2+ because longitudinal SR surrounds each myofibril (requires less energy)
- Inhibited by PLB
NCX located in _________
junctional domains of plasma membrane and t-tubules
______ muscle REQUIRES entry of external Ca2+ where as _______ muscle does not
Cardiac
Skeletal
Explain the bidirectional qualities of NCX
3 Na for 1 Ca
At beginning of AP (phase 0) Na+ out/Ca2+ in (depolarization)
At end of AP (phase 3/4) Na+ in/Ca2+out (repolarization, steady-state)
Maintains balance of Ca2+ entry during steady-state
How is NCX arrhythmogenic?
If Ca2+ released from SR when cardiac myocyte at REST (diastole) → causes 3Na+ in/1Ca2+ out → depolarization
→ delayed afterdepolarizations and arrhythmias
2 mechanisms of calcium homeostasis
1) NCX exchanger
2) L-type Ca2+ channel and CDI
Calcium Dependent inactivation (CDI)
-L-type Ca2+ channel undergoes inactivation dependent on [Ca2+] near cytoplasmic side of channel
-maintains constant SR Ca2+ content
If amount of Ca2+ in SR increases, greater CDI causes less Ca2+ to enter via L-type channel.
-If amount of Ca2+ in SR decreases, less CDI causes more Ca2+ to enter via L-type channel.
Sympathetic Activation → (4)
1) Positive Lusitropy: increase rate of relaxation
2) Positive Inotropy: increase contractile force
3) Positive Chronotropy: increased HR by raising pacemaker firing rate in SA node
4) Alter propagation through conduction pathways
Targets of PKA
1) L-type Ca2+ channel
2) RyR2
3) Phosphoalmban (PLB)
4) Troponin
PKA effect on L-type Ca2+ channel
Phosphorylation → increases amplitude of L-type Ca2+ current → increases size of RyR2 activation
Increase Ca2+ entry → increase quantity of Ca2+ stored in SR
→ Contributes to POSITIVE INOTROPY
PKA effect on RyR2 channel
phosphorylation of RyR2 → Ryr sensitized to activation by Ca2+
→ POSITIVE INOTROPY
PKA effect on PLB
- Association of PLB with SERCA2 inhibits Ca2+ pumping activity
- Phosphorylation → PLB dissociates from SERCA2 → relieves inhibition and increases Ca2+ pumping into SR
→ Speeds relaxation, increases the quantity of Ca2+ stored in SR
→ Both POSITIVE INOTROPY and POSITIVE LUSITROPY
PKA effect on Troponin
phosphorylation → speed rate of Ca2+ dissociation from actin
→ POSITIVE LUSITROPY
Timothy Syndrome
Other associated abnormalities?
Associated mutations?
Impact of mutations?
Outcomes?
syncope, cardiac arrhythmias, sudden death
Associated with intermittent hypoglycemia, immune deficiency, and cognitive abnormalities (autism)
De novo mutations in Cav1.2 (L-type Ca2+ channel)
→ profound suppression of voltage-dependent inactivation of Ca2+ channel → prolonged AP
→ AV block, prolonged QT intervals, polymorphic ventricular tachycardia
Brugada syndrome (aka sudden unexplained death syndrome)
Associated with a number of ECG alterations (revealed by administration of Class IC antiarrhythmics - Na+ channel blockers)
Mutation in cardiac Na+ channel (Nav 1.5), Transiently outward K+ channel, and L-type Ca2+ channel
→ large reduction in magnitude of L-type Ca2+ current as consequence of impaired membrane trafficking current
→ shortened AP
→ Significantly shortened Q-T intervals.
Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)
No ECG abnormalities at rest, but abnormalities with exercise or infusion of catecholamines
Mutations in RyR2 (AD inheritance)
Mutation in calsequestrin 2 (CasQ2) (AR inheritance)
CPVT mutations + increased SR Ca2+ release (due to increased ___________) → ?
increased B-adrenergic receptor activation
–> Ca2+ release NOT directly triggered by L-Ca2+ current during AP plateau
–> Ca2+ release occurs after repolarization
Extrusion of Ca2+ via NCX → depolarizations that can trigger ectopic APs and initiate arrhythmias
Treatment of CPVT
B-blockers are not effective
- Must block aberrant Ca2+ release from RyR2
- Flecainide (class IC antiarrhythmic) possible therapy
Mutations in RyR2 in CPVT causes…
Increase resting “leak” of Ca2+ out of SR and/or render RyR2 more sensitive to activation by Ca2+
Mutations in calsequestrin2 (CasQ2) in CPVT causes…
Homozygous CasQ2 mutations → dramatic loss of luminal Ca2+ buffering, some result in no effect.
CasQ2 has role in regulation of RyR2 function
-This regulation may be altered in CPVT CasQ2 mutations
cAMP dependent protein kinase
PKA
G protein associated with alpha 1 adrenergic receptor
Gq
Signaling pathway associated with alpha 1 adrenergic receptor activation
PLC, PKC-> increase intracellular Ca2+
Effect of alpha 1 adrenergic receptor activation
vasoconstriction
G protein associated with beta adrenergic receptor
Gs
Signaling pathway associated with beta adrenergic receptor activation
stimulates adenylate cyclase, increases cAMP, PKA activation
Effect of beta adrenergic receptor activation
heart: increase chronotropy, luisotropy, inotropy, dromotropy
G protein associated with muscarinic Ach receptor
Gi/o
Signaling pathway associated with muscarinic Ach receptor activation
inhibits adenylate cyclase, decreases cAMP
- releases beta gamma subunits
Effect of muscarinic Ach receptor activation
Decrease chronotropy
Channels that produce If (funny current)
Hyperpolarization-Activated Cyclic Nucleotide-Gated channels (HCNs)
Sympathetic stimulation to SA node cells → increase cAMP → cAMP binds HCN channels → ?
make channels easier to open (shift voltage dependence activation)
→ speeds rate of diastolic depolarization
B-adrenergic (sympathetic) stimulation → increased L-type Ca2+ current →
Increase heart rate
Sympathetic stimulation → increased SR Ca2+ load via PKA phosphorylation via LTCC, RyR, and PLB→
increase spontaneous Ca2+ release rate → more diastolic depolarization by activating inward current through sodium-calcium exchanger (NCX) → faster firing rate
Molecular targets for sympathetic control of chronotropy (3)
- Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels (HCNs)
- L-Type Ca2+ channels and RyR
- RyR and Sodium-Calcium Exchanger (NCX)
Parasympathetic control of chronotropy occurs through activation of _____ receptors by _____
M2 muscarinic receptors
Ach
M2 receptors coupled to ____ G protein → activation → ____ and ___ subunits released as signals →
Gi/o
Gai/0 and GBy
inhibit AC → reduce cAMP
Molecular targets for parasympathetic inhibition of chronotropy
- GIRKs
2. HCNs, L-type Ca2+ channels, and ryanodine receptors
G-Protein Coupled Inwardly Rectifying K+ (GIRKs)
GBy subunit → binds GIRK channel → increase K+ current in → stabilize membrane potential near Ek → dampens excitation, slows firing frequency
Parasympathetic effect on HCNs, LTCC, and RyR
Gai/o subunit → inhibit adenylate cyclase → reduce cAMP levels → Reduce inward current via HCN channel, LTCC, and RyR-NCX
6 properties of vascular smooth muscle cells (VSMCs) that differentiate them from cardiac myocytes
i. Small, mononucleated cells, electrically coupled via gap junctions
ii. Not striated, NO SARCOMERES
iii. NO TROPONIN OR TROPOMYOSIN
iv. Ca2+ release from SR not essential for contraction in VSMCs
- Ca2+ regulation of smooth muscle contraction via myosin
v. Rate of contraction slower and contractions are sustained and tonic in VSMCs
vi. DIFFERENT CONTRACTILE MECHANISM: Contraction initiated by mechanical, electrical or chemical stimuli
3 types of contractile mechanisms in VSMCs
- Mechanical stretching → contraction via myogenic response
- Electrical depolarization → contraction via LTCC activation (graded potential sufficient, AP not required)
- Chemical stimuli (neuronal/hormonal regulators) → directly activate contraction
Ca2+ regulation of VSM contraction (5)
- Ca2+ enters cytoplasm from SR (mainly) and voltage-gated Ca2+ channels on surface membrane
2) Ca2+ binds to calmodulin (CaM), intracellular Ca2+ binding protein
3) Ca2+-CAM binds to myosin light chain kinase (MLCK), activating it
4) Activated MLCK phosphorylates light chain of myosin (myosin head), → permits cross bridge cycling to occur
5) Contraction halted by dephosphorylation of myosin light chain by myosin light chain phosphatase (MLCP)
cAMP causes _____ of VSMCs via:
relaxation
via inhibition of MLCK
Autonomic regulation of vasculature is primarily ___
sympathetic
leading to vasoconstriction
Sympathetic stimulation in VSMCs occurs through ____ receptors
alpha 1 adrenergic
A1 adrenergic receptors
GPCRs coupled to Gq G protein
→ Ga1 subunit → activates PLC → produces DAG and IP3
IP3 → activates IP3 receptors on SR of VSMCs → IP3R channel releases Ca2+ into cytoplasm from SR → VSMC contraction
PKC furthers VSMC contraction by activating inward current via LTCCs → CICR
Sympathetic innervation of vascular beds _____ in skin and kidneys but ____ in cerebral and coronary circulations
abundant
sparse
Arterial baroreceptor reflex
acute, short-term neural mechanism for control of BP
i. Pressure-sensitive NEURONS in aortic arch and carotid sinus.
1. Adapt to prolonged changes in BP
2. Sensitivity ↓ in hypertension and aging
Baroreceptors respond to stretch in arterial walls by
Increasing firing RATE
1.MECHANOsensitive epithelial Na+ channels (eNaC) open in response to stretch induced by high BP → Na+ current depolarizes baroreceptor neurons → fire APs
Baroreceptor neurons fire APs that project into the ____
“Cardiovascular Control Center”
- CV control center integrates signals from baroreceptors and other brain brain regions
- Output projections of sympathetic and parasympathetic fibers to heart and sympathetic fibers to vasculature
Arterial baroreceptor reflex arc:
↑BP→↑baroreceptor firing rate
→ CV control center → ↓sympathetic output and ↑parasympathetic output from CV center
- → ↓heart rate, ↓inotropy and ↓vascular tone (vasodilation)
- → ↓blood pressure
Primary mechanism of blood flow matched to metabolic demand of tissue
Vasoactive metabolites
Vasoactive metabolites (4)
all act to cause vasodilation
- ↓ PO2
- ↑PCO2/pH
- ↑ extracellular K+: in active skeletal muscle, Na+ enters cell and K+ leaves during APs
a. High level of activity → Na+/K+-ATPase can’t keep up → K+ accumulates in interstitial space - ↑Adenosine: produced by hydrolysis of ATP
a. In VSMCs, binds A2 purinergic receptors (GPCR) coupled to Gs
b. ↑ Adenosine = ↑cAMP levels in VSMCs → vasodilation by inhibition of MLCK
Myogenic response
Feedback mechanism that maintains constant flow despite changes in pressure
1.Independent of metabolic demand
EX) postural change
Mechanism of myogenic response
Intrinsic to VSMCs - occurs in denervated vessels
Stretch → open stretch-activated Trp ion channels → inward Ca2+ current → VMSC contraction → vasoconstriction and depolarization of VSMC → further increase in intracellular Ca2+ via LTCC
Myogenic response can be overcome by vasoactive metabolites
Nitric oxide (NO) regulation of VSM tone
VASODILATOR produced in vascular endothelium by nitric oxide synthase
- Short half life → local response
- Basal release of NO sets resting vascular tone (↓ NO = ↑ increase BP)
- Agonist stimulated release = MAJOR mechanism for vasodilation
NO and disease: (4)
- Susceptible to CV disease risk factors (smoking, oxidative stress, etc.)
- NO is anti-atherosclerotic, inhibits development of plaques
- ↓NO is associated with greatly increased risk for atherosclerosis
- Pts with HTN often have ↓NO, which worsens their condition
NO pathway
i. Vascular endothelial cells → produce NO via NO synthase (NOS)
- Humoral regulators (ACh, bradykinin) stimulates activity of NOS
ii.VSM cells → site of NO action
iii. NO → activate guanylate cyclase → produce cGMP → cGMP activate Protein Kinase G (PKG)
→ reduce intracellular Ca2+ via activation of SERCA and inhibition of LTCC
→ Relaxation of VSMC → vasodilation
Endothelin regulation of VSM tone
i. VASOCONSTRICTOR produced by vascular endothelium with Endothelin Converting Enzyme (ECE)
- Endothelin binds ET receptors (GPCRs on VSMCs)
- ET receptors coupled to Gq → increase intracellular Ca2+ in VSMC → Vasoconstriction
ii.Has both a transient (a-adrenergic effect) and a longer lasting effect
Primary system for long term control of BP
Renin-angiotensin-aldosterone system
Renin
proteolytic enzyme released by juxtaglomerular (JG) cells in renal glomerulus
Renin release stimulated by (3)
1) Sympathetic stimulation of JG cells
2) Decreased BP in renal artery
3) Decreased Na+ resorption in kidney
What does renin do?
Cleaves circulating inactive protein angiotensinogen → angiotensin I
Angiotensin I cleaved by Angiotensin Converting Enzyme (ACE) to Angiotensin II
Angiotensin II (5)
ACTIVE FORM, potent vasoconstrictor
- Systemic vasoconstriction via binding to GPCRs on VSMCs
- Stimulates sympathetic activity (thus more vasoconstriction)
- Stimulates aldosterone release from adrenal cortex
- Stimulates release of endothelin from vascular endothelium
- Stimulates release of ADH from pituitary
Aldosterone
produced in adrenal cortex
i. Hormone, acts on receptors in kidney collecting ducts
ii. Promotes resorption of Na+ and water → increase blood volume → increase BP
Antidiuretic hormone
formed in hypothalamus, released from pituitary in response to hypovolemia, hypotension, high osmolarity, angiotensin II and sympathetic stimulation
i. Binds kidney receptors, increases water reabsorption
ii. Binds vasculature receptors, causes vasoconstriction
Atrial natriuretic peptide (ANP)
i. VASODILATOR peptide
ii. Released by atria following mechanical stretch → endocrine function of heart
iii. Long-term sodium regulator, water balance, blood volume, and arterial pressure
- ANP acts on ANPRs throughout the body
- ANPRs are receptor guanylate cyclases (NOT GPCRs)
- Produce cGMP → activates SERCA to stimulate Ca2+ uptake
ANP affects (3)
i. Kidney: ↑glomerular filtration rate and ↑secretion of sodium and water.
ii. Vasculature: ↑ vasodilation
iii. Adrenal gland: inhibits release of aldosterone and renin release.
Heart failure in the United States
Prevalence: approx 5,000,000
Annual incidence: 550,000
Mortality: 250,000
Cost: $37.5 billion
Compliance
relaxation
Worse compliance = same filling pressure (preload) of LV produces less filling → reduce SV
Compliance allows for greater diastolic filling at same pressure
Definition of heart failure:
forward vs. backward failure
Inability of heart to pump blood forward at a sufficient rate to meet metabolic demands of the body (forward failure)
OR ability to do so only if cardiac filling pressures are abnormally high (backward failure)
Two components of HF syndrome
1) Poor forward blood flow
- Low flow → ↓CO
2) Backward buildup of pressure
- Congestion → ↑filling pressure
- Typically a response to low flow
Systolic dysfunction two major hallmarks
1) Decreased ejection fraction
- Heart failure with reduced ejection fraction = HFrEF
- Left ventricular systolic dysfunction = LVSD
2) Ventricular enlargement
- Dilated cardiomyopathy = DCM (heart tends to get bigger and bigger)
Systolic vs. diastolic dysfunction
Systolic = problem with squeeze → ↓contraction (↓inotropy)
Diastolic = problem with filling → ↓lusitropy/decrease in relaxation
Primary causes of systolic dysfunction (3)
1) Direct destruction of heart muscle cells (myocardial infarction, viral myocarditis, peripartum cardiomyopathy, idiopathic dilated cardiomyopathy, alcohol)
2) Overstressed heart muscle (tachycardia-mediated HF, meth abuse, catecholamine mediated)
3) Volume overloaded heart muscle (mitral regurgitation, high CO)
2 Hallmarks of Diastolic dysfunction
1) Normal ejection fraction:
- HF with preserved ejection fraction = HFpEF
- Preserved systolic function = PSF
2) Ventricular wall thickening:
- Left ventricular hypertrophy = LVH
- Hypertrophic cardiomyopathy = HCM→genetic
Primary causes of diastolic dysfunction (3)
1) High afterload/pressure afterload (HTN, aortic stenosis, dialysis/inadequate volume removal)
2) Myocardial thickening/fibrosis (HCM, primary restrictive cardiomyopathy)
3) External compression (may not be HF since it doesn’t involve heart itself)
Pericardial fibrosis/constrictive pericarditis, pericardial effusion
2 main features of Right-Sided Heart Failure
stress to RV causes inadequate blood pumped through lungs
1) Decrease circulating blood flow (forward RV HF)
2) Increased venous pressures (backward RV HF)
Primary causes of right-sided heart failure (4)
1) Left heart failure → increase pulmonary venous pressure
2) Lung disease → pulmonary HTN
3) RV volume overload
4) Damage to RV myocardium
4 main compensatory mechanisms for low CO
1) Sodium/fluid retention –> increase preload
2) hypertrophy –> increase contractility
3) dilation –> increase contractility
4) Tachycardia –> increase HR
Compensatory responses to decreased CO (3)
1) Neurohormonal activation –> vasoconstriction, Na+ retention, increase HR
2) Frank-Starling increase in preload –> increase end diastolic filling/pressure
3) Ventricular hypertrophy and dilation –> increase contractility
Juxtaglomular apparatus response to low CO
Juxtaglomerular apparatus in kidney senses lower flow → renin-angiotensin-aldosterone (RAAS) activation
- ↑Sodium retention
- Vasoconstriction
Carotid sinus/aortic baroreceptors response to low CO
sense lower pressure → autonomic nervous system/adrenergic activation
- ↑HR (tachycardia)
- Vasoconstriction
Chornic neurohormonal activation in response to low CO causes what?
1) ↑sodium retention + vasoconstriction + ↑HR →↑volume
2) →↑LV filling → supranormal filling pressures (cause congestion)
Low CO output → fluid retention to maintain SV/CO → congestion in CHF
Chronic neurohormonal activation begets worsening HF
Adverse cardiac remodeling includes:
1) Ventricular hypertrophy/dilation
2) Myocardial damage/apoptosis and fibrosis
Result of long term increase in cardiac workload and increased metabolic demands
Overtime remodeling causes (3)
1) Decreased contractile force
2) Decreased dynamic function
3) Increased diastolic stiffness (decreases preload)
Neurotransmitters of ANS
Preganglionic sympathetic and parasympathetic = ACh
Post ganglionic sympathetic = NE
Post ganglionic parasympathetic = ACh
Receptor subtypes for ACh (2)
Nicotinic
Muscarinic
Nicotinic Receptors
in cell body of postganglionic neurons of autonomic ganglia
Ligand gated, non-selective cation channel (Na+ and K+) → depolarization and excitation
Muscarinic receptors
in effector cells of cardiac and smooth muscle, and glands
G-Protein Coupled Receptor - 5 subtypes of M receptors
ACh binds → conformational change in receptor → activation of G protein → stimulates or inhibits other intracellular effectors
Receptor subtype for NE?
Adrenergic receptors (alpha or beta)
Sympathetic nervous system:
Preganglions located in _______ and ______
Postganglions located where?
myelinated? NT?
Fight or Flight
Preganglions located in thoracic and lumbar spinal cord
Postganglionic neurons in ganglia of sympathetic trunk (NEAR SPINAL CORD)
-Project to target organs → innervate smooth muscle, cardiac muscle, or glands
Preganglionic = myelinated (ACh) Postganglionic = unmyelinated (NE)
Adrenal medulla
neuroendocrine gland of sympathetic nervous system
Secretes epinephrine and NE → bind adrenergic receptors in bloodstream (act as HORMONES)
Sympathetic nervous system main actions on CV system (3)
1) Primary control of vasodilation (decreased sympathetic input) and vasoconstriction (increased sympathetic input)
2) Increases HR
3) Increase force of contraction
Parasympathetic nervous system:
Preganglions located in _______ and ______
Postganglions located where?
long or short axons? NT?
Preganglions located in brainstem nuclei and sacral spinal cord
- long axons
- ACh
Postganglions located in ganglia NEAR OR IN target organ
- short axons
- ACh
Parasympathetic nervous system main actions on CV system (3)
1) decrease HR
2) decrease force of contraction
3) small amount of vasodilation
How does sympathetic NS increase HR and force of contraction?
Sympathetic stimulation (increased NE) → increase BP (increased HR and contractile force)
NE → B1-adrenergic → increase cAMP → PKA → Ca2+ channels, HCN channels
1) Steeper AP depolarization → time between AP decreased = increased HR
2) Increased AP amplitude = increased contractility
How does parasympathetic NS decrease HR and force of contraction
Parasympathetic stimulation (increased ACh) → decreases BP (decreases HR and contractility)
ACh → M2 muscarinic receptors → decrease cAMP → activates K+ channels
1) Shallower slope of AP → decreased HR
2) Decreased AP amplitude → decreased contractility
ANS maintenance of homeostasis to control BP via what mechanisms?
1) Sympathetic stimulation to increase HR and force of contraction (NE –> B1 adrenergic receptors –> increase cAMP)
2) Parasympathetic stimulation to decrease HR and force of contraction (ACh –> M2 receptors –> decrease cAMP)
3) Baroreceptor Reflex:
- Low BP → increase in sympathetic output
- High BP → increase in parasympathetic output
Hypothalamic regulation of CV system
Controls Humoral Response to Low BP: controls release of hormones via pituitary
Head Ganglion of ANS - Integrates information from several brain regions to convey needs of of body to preganglionic autonomic centers in brainstem and spinal cord
Hypothalamic humoral response to low BP
Low BP detected by hypothalamus → release of ADH (vasopressin) from posterior pituitary → vasoconstriction
→ kidneys increase water retention
Low BP detected by kidneys → renin released → angiotensin II → constrict blood vessels, increase water retention → activate neurons in hypothalamus
What happens when you stand up? (postural accommodation - lying down to sitting/standing)
4 steps
1) More blood pools in LE but skeletal musculature acts as venous pump with movement
2) → Increase venous return
3) → Increased End Diastolic Volume (stretching heart more)
4) → increased force of contraction and thus SV
What happens during isotonic exercise? (4 things)
biking, jogging, swimming
1) Decrease peripheral vascular resistance → decrease afterload
2) → Increased venous return (Frank-Starling) → increased EDV –> increased inotropy
3) Increase HR
4) Increased preload AND decreased afterload
What happens during isometric exercise?
1) Increased peripheral vascular resistance (maintain blood flow to exercising muscle group) → increased afterload → decreased SV
2) Increase HR
3) No increase (or decrease) in CO
what happens during the acute pahse of a myocardial infarction (3 main things)
1) Loss of functional myocardium
2) Increased catecholamine surge (Sweating, tachycardia, +/- HTN)
→ Increased inotropy to maintain CO despite increased BP (afterload)
3) Heterogenous cellular environment
- Local/regional changes in pH, membrane potential and secondary effect on cytosolic calcium
Physiologic hypertrophy
due to: chronic exercise, pregnancy
1) Increase myocyte length > increase myocyte width
2) Increase in ATPase and in aa dimer of myosin heavy chain
Pathologic hypertrophy
due to: chronic HTN (diastolic HF), fibrosis
1) Increase myocyte width > myocyte length
2) Decrease in ATPase activity and increase in BB dimer of myosin heavy chain
Cardiac dilation occurs due to _______ or ______ and results in what changes to the myocyte
MI or DCM (systolic HF)
Increase myocyte length»_space; increase in myocyte width
Contemporary view of the heart’s ability to adapt
1) cardiac adaptation is dynamic, involving structural and architectural changes
2) In response to environment, both quantity and quality of contractile elements altered
3) programmatic alterations in gene and protein expression occur in response to pathologic or physiologic triggers –> both phenotypic and genotypic plasticity
Left Ventricular Hypertrophy is often due to _______.
Mechanism?
longstanding HTN (increased afterload = decreased SV)
Mechanism:
- Increase in Ca2+ via LTCC
- Reduced SERCA2 function (due to increased PLB)
–> impaired relaxation and increased cytosolic Ca2+ (new steady state)
LVH can lead to ______
CHF
SERCA2 Gene transfer study
SERCA2 gene transfer sufficient to correct mechanical defects in cardiocytes from animals with HF
-Increasing SERCA2 –> increase lusitropy BUT also increases inotropy
Altered NFAT transcriptional regulation study
Increased Ca2+ steady state present in LVH –> Ca2+ activates calcineurin –> calcinueirn cleaves phosphate from NFAT
–> Activates NFAT
–> NFAT affects cardiac growth and remodeling genes
–> NFAT upregulation drastically increases muscle mass and decreases inotropy
Positive feedback of CHF and worsening cardiac function
1) Primary muscle damage → pump dysfunction → decreased CO
2) Decreased CO → hypertrophy, myocyte remodeling, dilation, adrenergic stimulation, neurohormonal stimulation
a) Neurohumoral activation
→ apoptosis and further muscle damage
→ RAS and sympathetic activation → Edema, tachycardia, congestion
b) Ventricular remodeling
- Left ventricular hypertrophy and myocyte remodeling → edema, tachycardia, congestion
Symptoms of HF are due to (3)
1) Decreased CO –> decreased perfusion of organs
2) Increased pulmonary venous pressure –> dyspnea
3) Increased central venous pressure (increased R-sided filling pressures) –> peripheral edema, hepatic congestion, ascites
Orthopnea
immediate SOB when lying flat (blood pooling in legs now poolling in abdomen/thorax)
Paroxysmal nocturnal dyspnea (PND)
delayed SOB, waking patients from sleep → mobilization of edema from tissue through lymphatics back into bloodstream and into lungs
Acute pulmonary edema
acute, intense SOB
- Occurs once fluid retention/left atrial pressure overwhelms compensatory mechanisms → fluid spills from pulmonary vasculature into interstitial space and then into alveoli→hypoxia
- “fluffy” infiltrates on CXR
NY heart association functional class system
I: asymptomatic
II: symptomatic with moderate exertion
III: symptomatic with minimal exertion
IV: symptomatic at rest
ACC/AHA HF Stages
A: At high risk for HF but without structural heart disease or symptoms of HF
B: Structural heart disease but without symptoms of heart failure.
C: Structural heart disease with prior or current symptoms of heart failure.
D: refractory heart failure requiring specialized interventions.
Common precipitants of worsening HF (6)
1) Increased circulating volume (preload)
2) Increased pressure (afterload)
3) Worsened contractility (due to MI, intotrope, B-blocker, etc.)
4) Arrhythmia
5) Increased metabolic demands
6) non-adherence with HF meds
Physical signs of low flow include…(3)
1) Cool extremities—peripheral vasoconstriction to redirect what existing blood flow there is to vital organs.
2) Tachycardia—compensate for low stroke volume
3) Low pulse pressure—reflection of low output.
Signs of elevated LEFT-sided filling pressures (6)
1) Dyspnea, orthopne, paroxysmal nocturnal dyspnea, hypoxia, rales
2) Tachypnea, Tachycardia
3) Diaphoresis
4) Fatigue
5) S3 gallop –> systolic dysfunction
6) S4 gallop –> diastolic dysfunction
Signs of elevated RIGHT-sided filling pressures (3)
1) Peripheral edema
2) RUQ discomfort due to hepatic congestion/enlargement
3) JVD (increased central venous pressure)
JVP = ?
A wave = ?
C wave = ?
V wave = ?
Right atrial pressure
A wave = atrial contraction (absent in AFIB)
C wave = closing of tricuspid valve early in systole
V wave: movement of RV annulus and tricuspid valve backward at very end of systole (before valve opens)
S3 gallop
Symptom of systolic HF
rapid expansion of ventricular walls in early diastole
HFrEF/dilated heart
Ken-tuc-ky (S1-S2-S3)
Implies high LA filling pressure
S4 gallop
Symptom of diastolic HF
atria contracting forcefully in an effort to overcome abnormally stiff or hypertrophic LV
Ten-ne-ssee (S4-S1-S2)
Absent in AFIB
B-type natriuretic protein (BNP)
BNP secreted by myocardium in response to:
- Ventricular stretch
- Hyperadrenergic state, RAAS activation, ischemia
BNP/NT-proBNP assays used to rule out HF (unlikely you have HF with a low BNP)
Right heart catheterization
- measures pressure and flow and thus can calculate resistance as well
1) Catheter placed into major vein, floated through R heart into pulmonary artery
2) Balloon on end helps blood flow carry it to lungs
3) Balloon occludes branch of pulmonary artery so downstream pressure can be measured = LA pressure / left sided filling pressure
Echocardiocraphy
Provides: LVEF, chamber size (dilation), LV wall thickness (hypertrophy), measures of relaxation (diastology), valvular anatomy and function, filling pressures, pulmonary pressures.
Advantages: real time, non-invasive, no radiation, inexpensive
Specific goals of HF treatment (5)
1) Correct underlying cause of HF (ex-revascularization for ischemia)
2) Eliminate precipitating factors (acute infection, arrhythmias, salt)
3) Reduce pulmonary and systemic congestion (salt restriction, diuretics)
4) Improve forward CO (flow) (vasodilators and positive inotropic drugs)
5) Modulate neurohormonal action (prevent negative remodeling)
Diuretics
promote elimination of Na+ and H2O → reduce intravascular volume and venous return to heart = VOLUME CONTROL
-DECREASE ventricular end-diastolic pressure by increasing salt and water excretion → decrease venous congestion → decrease dyspnea and edema
Arterial Vasodilators
↓ systemic vascular resistance → ↓ LV afterload, ↓ cardiac work, ↓ mitral regurgitation
Venous vasodilators
increase venous capacitance → ↓ venous return → ↓ preload and LV diastolic pressure
–> decreased oxygen demand by cardiac myocytes (useful during ischemic event - use of NTG with CP)
Pulmonary vasodilators
↓ RV afterload
ACE inhibitors
“pril”
1) Inhibit conversion of ATI –> ATII
- prevent vasoconstriction (decrease afterload)
- prevent release of ADH
- prevent absorption of Na+ and H2O
2) Inhibit breakdown of Bradykinin
- promote vasodilation (via NO)
- reduce sympathetic activity
Angiotensin receptor blockers (ARBs)
“artan”
Selective inhibition of AT1 Receptor (Ang II receptor)
Similar effects as ACE inhibitors
Advantages over ACEI:
- no cough/angioedema from kinin –> use ARB if pt has cough on ACE inhibitor
- blocks non-ACE pathways also
Disadvantages:
- no kinin vasodilation, blocks just AT1 (no AT2)
- more expensive
Aldosterone receptor blockers
- Block aldosterone in collecting tubules → increase sodium excretion → diuretic
- Also antifibrotic
B-blockers
“olol”
Antagonize effects of Sympathetic nervous system → ↓chronotropy ↓inotropy (short term loss for long term gain)
Side effects of ACE inhibitors
hypotension, worsening renal failure, hyperkalemia, **cough (kinin production), angioedema
Inotropes
administered via IV agents short term in ICU to reverse shock (cold and wet)
Long term = worsen remodeling ↑mortality
OVERALL TREATMENT of Chronic (stable) HFrEF patients
1) ACE inhibitors / ARBs
+ 2) B-blockers
+ 3) diuretics
→ Anti-remodeling + Decreased hypertrophy, fibrosis, and apoptosis
–> decreased volume (reduce congestion, edema, etc.)
Implanted cardioverter defibrillator is used in patients with _______ or _____ and acts to…
LVEF less than 35% or with prior dangerous rhythms
Abort sudden cardiac death from ventricular tachycardia/fibrillation
Cardiac Resynchronization Therapy
- Fixes dyssynchrony caused by LBBB
- LV lead placed from RA through coronary sinus over epicardium of LV (3 leads: RA, RV coronary sinus/LV)
- For patients with QRS > 120 msec (bundle branch block)
Cause lateral wall and septal wall to contract together, which produces:
- More efficient contraction→ ↑ stroke volume
- May also improve mitral valve function→ ↓ regurgitation
Advanced cardiac therapies include (3)
1) Transplantation
2) Mechanical support devices (LVAD)
3) Hospice
Treatment of HFpEF
Neurohormonal antagonists, ARB, and ACE inhibitors NOT successful in improving outcomes for HFpEF
1) Treat underlying disorder: HTN, diabetes, kidney dysfunction, aortic stenosis
2) Diuretics: keep volume normal (sodium retention common)
3) Vasodilators: maintain normal BP
Drug-drug interactions of ACE inhibitors (2)
- lithium
- NSAIDs
Both ACE inhibitors and ARBs are contraindicated in…
pregnancy
Hydrochlorothiazide (thiazide diuretics) mechanism of action
Block NaC; reabsorption in distal tubule by inhibiting Na/Cl cotransporter
-increases reabsorption of Ca2+
Side effects of Hydrochlorothiazide
1) secretion competes with uric acid secretion (may cause gout attack)
2) Hypokalemia
Loop diuretics mechanism of action
- preferred class of diuretics for CHF
- inhibits Na/K/2Cl cotransporter and thus Na+ reabsorption in kidney tubules
Neprilysin inhibitors
Used in combination with Valsartan (ARB)
-Neprilysin: acts to break down BNP
We don’t want BNP to be broken down because it:
→ vasodilation, decrease BP, decrease sympathetic tone, decrease ADH, decrease fibrosis/hypertrophy, natriuresis/diuresis
**Use recommended for patients with HFrEF, in conjunction with other HF therapies in place of an ACE inhibitor or ARB
DO NOT use Neprilysin inhibitors with contaminant use of ________
ACE inhibitor
Ivabridine
new drug on market
- Effects HR NOT force of contraction
- Blocks funny current channel
- For pts with chronic HFrEF
Increased CNS sympathetic outflow results in…
_______ act to prevent this
1) Increase cardiac activity → Myocyte death, increased arrhythmias, B1-receptor downregulation, increased HR
Cardiac myocyte growth
Positive inotropy
2) Increased sympathetic activity to kidney and blood vessels
→ vasoconstriction, sodium retention
B-BLOCKERS
B-Blockers prevent (4) and act to IMPROVE _________
1) Downregulation of B1-receptors
2) Apoptosis/Oxidative stress and cell death
3) Increased arrhythmic potential
4) Hypertrophy/Fibrosis
will eventually IMPROVE contractility, but can make patients feel worse in short term (must titrate dose up)
DO NOT use B-blockers in patients with:
1) Lung disease
2) taking inotropes or vasodilators
Use B-blockers in combination with _____ and _____ for patients with _____________
ACE inhibitor and diuretic
HFrEF with current or prior symptoms
Digoxin mechanism of action
1) Blocks Na/K+ ATPase exchanger → dec. Na extrusion → inc. Ca influx via NCX→ Ca-induced Ca release → increases inotropy
2) Decrease sympathetic (NE) action in AV node –> slow HR
Digoxin reduces _____ but not ________ in terms of patient outcomes and used for what patients?
patient hospitalizations
NOT mortality
HFrEF, NOT for HFpEF
- HF due to reduced contractility
- HF with AFIB
Pharmacokinetics of Digoxin
Effects are dose-dependent (use LOW doses b/c of narrow therapeutic index)
Oral or parenteral
T ½ = 38hrs (slow onset= don’t use in acute situations)
RENAL excretion with some P-glycoprotein metabolism
For severe overdoses of digoxin…
can adminster Digibind (anti-dig Ab)
Side effects of digoxin (5)
1) GI = nausea, vomiting, abdominal pain
2) Neuro = weakness, confusion
3) Electrolyte = hyperkalemia
4) Cardiac = bradycardia, heart block, arrhythmias
5) Visual = light sensitivity, blurred vision, yellow halo around lights
Drug-drug interactions with digoxin
beware of use with drugs that inhibit P-glycoprotein (involved in digoxin metabolism)
Anti-arrhythmics Antifungals Ca2+ channel blocker Macrolides Quinine
Dobutamine mechanism of action
B1 receptor agonist (Gs→ cAMP→ PKA → increase Ca) → increase contractility
Slight peripheral vasodilation
-rapid onset (T 1/2 = 2 min)
ONLY use intoropes when?
ONLY use in acute HF (hypoperfusion with/without congestion)
Use only for acute HF because it’s like “beating a dead horse” – Telling failing heart to pump faster and harder by increasing Ca2+ influx and sympathetic tone
Milrinone mechanism of action
PDE inhibitor → inhibit breakdown of cAMP → augment myocyte Ca2+ utilization
Dopamine mechanism of action
B-adrenergic agonist
Endogenous precursor of NE → stimulate adrenergic receptors and increase release of NE from nerve terminals
Dose-dependent effects
Continuous infusion via infusion pump
Acute toxicity associated with digoxin
Second or third degree heart block
- Progressive bradycardia
- Severe ventricular arrhythmias
Elevated serum potassium levels > 5.5 mEq/L
