Cardios

Question 1

Signs of Hemodynamic INstablity

Answer 1

1. Ischemic chest pain - Heart

2. Hypotension, ALOC - Forward flow

3. Left heart failure/wet lungs - Reverse flow

Question 2

ACS

Answer 2

Angina – typically described as squeezing, pressure, heaviness, tightness or pain in your chest.

1. STEMI (Tronponins and ECG)
2. NSTEMI (Troponins)
3. UA (Clinical Diagnosis)

• *STEMI**
• *Positive troponins.**
• *ST Elevations >1mm in two contiguous leads.**
• *NSTEMI**
• *Positive troponins.**
• *Downsloping ST depression** in two contigious leads is suggestive of cardiac ischemia. ST depression >1mm is highly specific and conveys worse prognosis, >2mm in >2 leads gives a high probability of NSTEMI and and predicts significant mortality (35% in 30 days). T wave inverstions can be considered evidence of myocardial ischemia if >1mm, present in >1 lead with dominant R waves, and/or are not seen on previous EKG or changing.

Unstable Angina (Clinical Diagnosis)
Non-diagnostic troponins.
With or without ECG changes.
One of the following:
1. New onset (within one month) and severe (CCS grading III, occurs with minimal exertion)
2. Occurs at rest (or minimal exertion) usually lasing more than 20 min.
3. More frequent, with longer duration, and with less exertion.

ID]
Age > 65, Male

HPI]
Radiation to right shoulder/both shoulders/left arm, worse with exertion,
N/V/Diaphoresis, similar to previous MI, pressure-like

PMHx]
DM
HTN
DL

FMHx]
1st degree relative with early age MI

SHx]
Smoking

O/E] Unstable vitals
Cardios – S34 or M

CODE STEMI/NSTEMI
NP/A,B] O2 (if SpO2<94%)
NP/C] PIV, Art-line
NP/Mon] ambulatory heart monitoring, BP, O2 sat

P/Poin] Morphine 2-4mg (2-8mg increments) IV q5-15min (pain, only use if severe as it may decrease cardiac output so use with caution in hypotension and inferior MI and can also decrease the effect Plavix)
P/Naus] {Zofran} Ondansetron 4mg IV
P/Haim] ASA 325mg chewed (anti-platlet, irreversible COX1 inibitior), {Plavix} Clopidogrel 300-600mg (anti-platelet, irreversible ADP receptor inhibitor), {Lovenox} Enoxaparin (LMWH) 1mg/kg SC (anticoagulant)
P/Meta] {Lipitor} Atorvastatin 80mg PO (antilipid)
P/Org(Cardios)] Metoprolol 50mg PO (initated in 24 hours for protection except in heart failure, hypotension, bradycardia or heart block)

Note: In colcaine related ACS DO NOT give betablockers, treat with
lorazepam 2-4mg IV q15min

P/Org(Vasculos)] NTG 0.4mg SPRAY/SL x2 q5min x3 (reduce pre/after load)

Note: Hold NTG if SBP<90 (RV infarction and preload dependant) , if no more pain, contraindicated in PGE inhibitors
Note: If no relief from sublingual NTG then start NTG 5-10mcg/min IV
DO NOT use NTG when infarct is preload dependant due to right ventricle infarct. Hypotension will worsen ischemia. Suspected when STE in V1, STE in III > II. Confirmed when STE in V3R-V6R.

Surg]
Cath Lab within 90minutes for STEMI, door to baloon time. Fibrinolytics if time to treatment is <6 to 12 hours from symptom onset.

Note: ACS Risk Stratification – HEART score for separating high, medium, low risk and how to triage patients for follow up. TIMI score.

• *1.** Low risk - Exercise Treadmill Test (ETT)
• *2.** Intermediate risk – Exercise/Pharmacologic ECHO looks for worsening of wall motion abnormalities. Can also look at the valves and for effusion.
• *Exercise/Pharmacologic MPI (Myocardial Perfusion Imaging)** looks for the perfusion (via tracer) at rest and under stress. When there is less under stress this indicates ischemia, less both under stress and at rest indicates infarction. Can alos detect wall motion and ejection fraction.
• *3.** High risk – Angiogram with catheterization.

Question 3

CHF

Answer 3

HPI]
Dyspnea (SOB), orthopnea, PND, nocturia, fatigue, new cough

O/E] TC, HTN/HypoTN, DP, Low SpO2, T, Wt
Cardios – raised JVP, S3/S4, new murmur
Pulmos – crackles
PV – pitting edema

INVESTIGATIO]
L(H)/Haim] CBC
L(H)/Meta] K+
L(H)/Org(Cardios)] Troponins, BNP
(BNP <100 rules out, BNP >400 rules in)
Note: BNP released with ventricles
too dilated for the kidneys to get rid of volume.

• *I]**
• *ECG** – r/o infarction, arrythmias, LVH
• *CXR** – pulmonary edmea, cardiomegaly, Kerly B lines, cephalization (pulmonary vessels in upper chest due to venous hypertension from the left atrium), interstitial edema, alveolar edema.
• *POCUS** – Plural sliding and B Lines

RECIPERE]
NP/A,B] NP, NRB, NPPV (Non invasive Postivie Pressure Ventiation), Intubation – SpO2 to 95%
NP/C] PIV
NP/Mon] SpO2

P/ Org(Vasculos)] NTG 0.4mg SPRAY/SL x2 q5min x3
P/ Org(Nephros)] Furosemide 20-100mg IV (equal to and up to 2x maintainence dose)

IF BP>150/100:
NTG 10mcg/kg/min IV titrated to 250mcg/hour (consider adding beta blocker)
IF HTN not responding to NTG
Nitroprusside 10mcg/min titrated up every 5 min to 5-300mcg/min
Note: Caution of the use of Nitro for PDE-5 inhibitors such as Viagra or Cialis

Cardiogenic Shock
SBP<90 OR drop in MAP>30 with HR>60
Dobutamine 2.5mg/kg/min (sympathomimetic/inotrope)
IF no response
Dopamine 5-10 mcg/kg/min to SBP 90-100 (vasopressor)

Question 4

Atrial Fibrillation

Answer 4

Is patient stable? Yes or No

• *No**
• *Ischemic pain** – heart not perfusing itself
• *Hypotension, ALOC** – weak forward pressure
• *Pulmonary edema** – backup flow into lungs

RECIPERE]
NP/Pro]
Electrical Cardioversion
P/Haim]
Immediate OAC in ED for >or= 4 weeks

Yes
What is the immediate risk of stroke?

• *High**
  1. Onset >48hours or unknown
  2. CVA/TIA <6months
  3. Mechanical/Rheumatic valve disease

RECIPERE]
P/Org(Cardios)]
Rate Control (or TEE Guided Cardioversion)
Metoprolol 2.5-5mg IV bolus over 3min, x3 if needed
Metoprolol 25-100mg PO BID
OR
Diltiazem 0.25mg/kg IV bolus over 2min, 5-15mg/h
Diltiazem 120-360mg PO OD
P/Haim]
Therapeutic OAC x 3 weeks before cardioversion.

Low
Clear onset <48hours
Therapeutic OAC >or= 3weeks

RECIPERE]
NP/Pro]
Electrical Cardioversion (150-200J)
OR
P/Org(Cardios)]
Flecainide 2mg/kg IV over 10 min
Flecainide 200-300mg PO
P/Haim]
No OAC needed before cardioversion. After cardiovesion, OAC by CHADS65.

Note: Flecainide blocks Nav1.5 sodium channel in the heart, slowing the upstroke of the cardiac action potential. The effect of flecainide on the sodium channels of the heart increases as the heart rate increases, known as use-dependence. Use dependence is why flecainide is useful to break a tachyarrhythmia.

Question 5

Chest Pain

Answer 5

DDx
Haim]
STEMI (ACS) – visceral pain described as pressure-like, heaviness, and aching, tighness, squeezing, radiates to right arm or shoulder/both shoulders/left arm, diaphoresis, nausea, vomiting, worse with exertion
PE–persistent tachycardia,dyspnea(SOB)/tachypnea, pleuritic chest pain, syncope, hemoptysis

Org(Cardios)]
Tamponade – dyspnea (SOB), decreased exercise tolerace, Becks triad (HypoTN, JVD, muffled heard sounds), pulses paradoxus, shock

Org(Pulmos)]
Tension pneumothorax – Becks Lung Triad (HypoTN, JVD, deviated trachea), dyspnea(SOB)/tachypnea, tachycardia

Org(Vasculos)]
TAD (Thoracic Aortic Dissection) – HTN, “tearing” or “ripping” pain radiating to the back, diaphoresis, syncope, 1/3 have neurological complaints

Org (Gastrointestino)]

• *Boerhaave’s syndrome** – crepitus, septic, febrile, alcohol consumption
• *Incarcerated diaphragmatic hernia**

Infla]
Pericarditis – pleuritic pain, worse with inspiration and supine,improved with leaning forward, retrosternal or left precordial, not affected by exertion

HPI]
STEMI (ACS) – pressure-like, heaviness, pain radiates to the right/both shoulders/left, nausea, diaphoresis, worse with exertion
PE–persistent tachycardia, dyspnea (SOB)/tachypnea,pleuritic chest pain,syncope, hemoptysis
Note: PERC, Wells
Tamponade – dyspnea (SOB), decreased exercise tolerance
Tension pneumothorax – tachycardia, dyspnea (SOB)/tachypnea
TAD – sudden “tearing” or “ripping” pain that radiates to the back, diaphoresis, syncope
Boerhaave’s – crepitus, EtOH
Incarcerated diaphragmatic hernia
Percarditis – pleuritic pain, worse with inspiration and supine, improved pain with leaning forward

PMHx]
History of DVT, PE (PE)
Immobilization (>3d) or surgery in the last 4 weeks (PE)
DM, DL, HTN (ACS, TAD), Uremia/ESRD (Tamponade)
Marfans (TAD)
Lung disease – infectous, interstitial (Tension pneumo)
Cardiac disease – coarctation, bicuspid aortic valve (TAD)
Inflammatory – SLE, RA (Pericarditis/Tamponade)
Malignancy, treatment in the last 6 months (Tamponade, PE)
Infectous – Viral, bacterial, TB (Pericarditis/Tamponade)
Iatrogenic – Central lines (Tension pneumo)

Meds]
Anti-coagulants (Tamponade)

SHx]
EtOH (Boerhaave)
Smoking (ACS)
Cocaine/Meth (TAD)
Pregnancy (TAD)

FHx]
Early CAD

• *O/E] TC** (persistent in PE, Tension pneumo), HypoTN (Tamponade, Tension pneumo, PE when severe), HTN (TAD), Dyspnea (SOB)/Tachypnea (PE, Tension pneumo, Tamponade), SpO2 <94% (PE), febrile (Boerhaave)
• *Pulses paradoxus/pulse deficit** (Tamponade) – dropped radial pulse upon inspiration
• *General** – LOC (alert, confused, lethargic, obtunded, stuporous, comatose), orientation, creptius (Boerhaave)
• *Neuros** – focal deficits, motor or sensory (TAD)
• *Cardios** – new murmur (STEMI), aortic regurg (TAD), JVD (Tamponade, Tension pneumo, PE), pulse deficit/pulsus paradoxus (Tamponade), muffled heart shounds (Tamponade), unequal pulses (TAD)
• *Pulmos** – crackles, wheeze or pleural rub (PE), decreased air entry (Tension pneumo)
• *PV** – edema (pitting CHF vs non-pitting DVT), unilaterial leg swelling (PE)

INVESTIGATIO]
L(H)/Haim] CBC, Hb (Anemia), WBC (Pneumoniae/Pericarditis), D-Dimer (PE), INR, PTT
L(H)/Meta] SMA7 (Lytes)
L(H)/Org(Cardios)] Troponins
L(H)/Org(Nephros) Cr (Imaging, Pericarditis, Tamponade)
L(H)/Infla] ESR (Pericarditis,Tamponade), CRP
Note: Repeat troponin and ECG q3h if high sensitivity troponin, q6h if low sensitivity troponin. Troponin elevation following cardiac cell necrosis starts within 2–3 hours, peaks in approx. 24 hours, and persists for 1–2 weeks

I]
ECG – Rate, Rhythm (sinus or nonsinus), Axis, Intervals (P-R, QRS, QT), Signs of Ischemia (STE, STD, new LBBB, flipped T waves)
I, aVL (lateral, LCx)
II, III, aVF (inferior, RCA or LCx, order right heart leads)

Note: 30% of inferior MIs involve the right ventricle, order right heart leads, STE V4R is highly suggestive of RV infarction.
Note: Inferior and lateral have recipricol changes.

V1-V3 (anteroseptal, LAD)
STE V1 (right heart, RCA, order right heart leads)
V4-V6 (lateral,LCx)
STD V1-V4 (posterior, LCA or RCA, order posterior leads)

Note: PE signs of right heart strain – **most specific finding is T wave inversions in the inferior leads II, III, aVF, and precordial leads V1-V4 (90% specific), sinus tachycardia (44% of patients), SIQIIITIII, dominant R wave in V1, non-specific ST segment and T wave changes, cor pulmonale – peaked p-waves in inferior leads II, III, aVF >2.5mm (9% of patients)

Note: Pericarditis
Stage 1 – (acute pain) diffuse STE except aVR and VI, PR depression
Stage 2 – (days later) ST return to baseline with flattening T waves
Stage 3 – inverted T waves
Stage 4 – (weeks to months) EKG returns to baseline with +/- persistent
T wave inversions (chronic pericarditis)

CXR – widened mediastinum (TAD, Boerhaave, Tension pneumo, Tamponade)
CTPA w contrast (PE)
V/Q (PE) if cant take radiation (pregnancy) or contrast (ESRD)
Leg Doppler – PE to look for DVT
CTAorta w contrast (TAD)
TEE or cardiac MRI – (TAD) if cant have contrast
POCUS – A lines, NO lung sliding or B lines (Tension pneumo), pericardial effusion (Tamponade, Pericarditis), Aortic flap (TAD)

RECIPERE]
CODE STEMI/NSTEMI
NP/A,B] O2 (if SpO2<94%)
NP/C] PIV, Art-line
NP/Mon] cardiac monitoring, BP, O2 sat

P/Poin] Morphine 2-4mg (2-8mg increments) IV q5-15min (pain, only use if severe as it may decrease cardiac output so use with caution in hypotension and inferior MI and right ventricle MI)
P/Naus] {Zofran} Ondansetron 4mg IV
P/Haim] ASA 325mg chewed (anti-platlet, irreversible COX1 inibitior), {Plavix} Clopidogrel 300-600mg (anti-platelet, irreversible ADP receptor inhibitor), {Lovenox} Enoxaparin (LMWH) 1mg/kg SC (anticoagulant)
P/Meta] {Lipitor} Atorvastatin 80mg PO (antilipid)
P/Org(Cardios)] Metoprolol 50mg PO (initated in 24 hours for protection except in hypotension or bradycardia)
Note: In colcaine related ACS DO NOT give betablockers, treat with
lorazepam 2-4mg IV q15min.

P/Org(Vasculos)] NTG 0.4mg SPRAY/SL x2 q5min x3 (reduce pre/after load)
Note: HOLD if SBP<90 (inferior/right ventricle MI and preload dependant) or if no more pain
Note: NTG contraindicated in PGE inhibitors
Note: If no relief from sublingual NTG then start NTG 5-10mcg/min IV
DO NOT use NTG when infarct is preload dependant due to right ventricle infarct. Hypotension will worsen ischemia. Suspected when STE in V1, STE in III > II. Confirmed when STE in right leads V3R-V6R.

Surg]
Cath Lab within 90minutes for STEMI, door to baloon time. Fibrinolytics if time to treatment is <6 to 12 hours from symptom onset.

Note: ACS Risk Stratification – HEART score for separating high, medium, low risk and how to triage patients for follow up. TIMI score.

• *1. Low risk** - Exercise Treadmill Test (ETT)
• *2. Intermediate risk** – Exercise/Pharmacologic ECHO looks for worsening of wall motion abnormalities. Can also look at the valves and for effusion.
• *Exercise/Pharmacologic MPI** (Myocardial Perfusion Imaging) looks for the perfusion (via tracer) at rest and under stress. When there is less under stress this indicates ischemia, less both under stress and at rest indicates infarction. Can alos detect wall motion and ejection fraction.
• *3. High risk** – Angiogram with catheterization.

Tamponade
NP/C] PIV, 500mL to 1000mL fluid Bolus
NP/Proc] Pericardiocentesis

Pericarditis
Need two of:
1. Chest pain - typical
2. Pericardial friction rub
3. ECG changes
4. Pericardial effusion
Myocarditis – Pericarditis and one of:
1. Increase in troponins
2. New LV dysfunction
Treat based on underlying cause:
Viral/Idiopathic
P/Infla]
Indomethacin 50mg PO q8h (COX1 and COX2) x 2 weeks OR
Ibuprofen 400-800mg PO q6-8h max 3200mg (COX1 and COX2) x 2 weeks
Colchicine 0.5mg PO BID (OD if <70kg) x 3 months

PE
NP/A,B] O2>90%
P/Haim]
{Lovenox} Enoxaparin (LMWH) 1mg/kg SQ OD x 5 days AND
Warfarin 10mg PO for first 2 days then adjusted to INR 2-3
OR
{Xarelto} Rivaroxaban 15mg PO BID x21days THEN
Xarelto 20mg PO OD for the remainder (3 months or more)
OR
{Eliquis} Apixaban 10mg PO BID x7days THEN
Eliquis 5mg PO BID for the remainder (3 months or more)
OR if active cancer
{Lovenox} 1mg/kg SQ OD for the remainder

Note: Anticoagulation should be for a minimum of 3 months in
provoked PE, and may be indefinite in unprovoked PE.

Note: If severe renal insuffiency (CrCl<30mL/min) use UFH
(Unfractionated Heparin) – where LMWH and DOAC should
be avoided, or if rapid reversal is needed, or patients receiving
thromobolytic therapy. aPTT is 2-3x baseline
UFN stared with bolus 80U/kg followed by 18-20U/kg/hr

If signs of shock SBP<90 or 40mmHg drop from baseline, refractory to fluid challange, right heart faulure and do not have a contraindiction to thrombolytics,
rt-PA 100mg over 2 hours
OR 0.6mg/kg bolus THEN UFN

Tension Pneumothorax
NP/A,B] O2 3-10L NP
NP/Proc] Needle thoracostomy followed by tube thoracostomy

TAD
P/Poin] Morphine 4-6mg IV q5-15min OR Fentanyl 0.35-0.5 IV q30-60min
PNaus] Zofran 4mg IV
P/Org(Cardios)]
Labetalol 20mg IV push over 2 min, additional 40-80mg at 10min intervals, up to a maximum of 300mg (stop tachycardia and shearing forces)
Note: Goal of HR<60, if BP is still 120/80 then start vasodilators. DO NOT use vasodilators without first beta blockers as it can cause reflex tachycardia.
P/Org(Vasculo)]
Nitroprusside 0.3-0.5 mcg/kg/min, can be titrated to 0.5mcg/kg/min to a maximum of 10mcg/kg/min (reduce afterload)
Note: Goal of HR<60 and BP<120/80
Surg/Consult] Type A – Cardiothoracic Surgery

TAD – pain and blood pressure control, fentanyl for pain, beta blockers first to stop tachycardia and shearing forces of heart each time it pumps (esmolol – can titrate), after load decrease such as nitroprusside.
Note: Get BPs in both arms and tirate to the higher BP.
Note: Type A dissection involves the ascending arch of the aorta where it can rip into the pericardium, also causing an MI and aortic valve deficiency – mostly operative repair. Type B involves the descending aorta and typically can be handled with medical management.

Boerhaave
NP/C] PIV, Art-line
NP/Nut] NPO
P/Poin] Morphine 4-6mg IV q5-15min
P/Org(Gastro)] {Pantoloc} Pantoprazole 80mg loading dose, 8mg/hour infusion/72 hrs
P/Infect] Broad Sectrum – Imipenam/cilastatin, Pip-tazo
Surg/Consult] Cardiothoracic surgeon

Question 6

Cardiac Electrical System

and Drugs

Answer 6

**Conduction system works on f-channel, and If (influx Na+/K+) and T-type Ca2+ channel and L-Type Ca2+ channel, and slow Ca2+ currents. There are NO fast Na+ currents like in nerve cells and muscle cells.

Cells within the sinoatrial (SA) node are the primary pacemaker site within the heart. These cells are characterized as having no true resting potential, but instead generate regular, spontaneous action potentials. Unlike non-pacemaker action potentials in the heart, and most other cells that elicit action potentials (e.g., nerve cells, muscle cells), the depolarizing current is carried into the cell primarily by Na+/K+ inward currents and relatively slow Ca2+ currents, instead of by fast Na+ currents. There are NO fast Na+ channels and currents operating in sinoatrial (SA) nodal cells. This results in slower action potentials in terms of how rapidly they depolarize. Therefore, these pacemaker action potentials are sometimes referred to as “slow response” action potentials.

Action potentials described for SA nodal cells are very similar to those found in the atrioventrcular (AV) node. Therefore, action potentials in the AV node, like the SA node, are determined primarily by changes in inward Na+/K+ currents and slow Ca2+ currents, and do not involve fast Na+ currents. AV nodal action potentials also have intrinsic pacemaker activity produced by the same ion currents as described above for SA nodal cells.

Parasympathetic (PS) CNX and Sympathetic (S) T1-4 innervate SAN, AVN and atrium. Only S innervates the ventricles. PS with release of Ach binds to M2 activating Gi which inhibits adenyl cyclase decreasing cAMP. Gi also opens KAch channels. Together the decreased cAMP and K+ efflux results in hyperpolarization and a decreased slope in phase 4, decreased heartrate (negative chronotropy), and decreased conduction through AVN (negative dromotropy), with no effect on ventricle contraction (no PS innervation to ventricles). S with release of NE binds to beta1R which activates Gs and adenyl cyclase increasing cAMP resulting in an increaserd slope in phase 4 and increased heartrate (positive chronotropy), and increased conduction through AVN (positive dromotropy).

In the myocytes Beta1R are coupled to Gs-proteins, which activate adenyl cyclase to form cAMP. Increased cAMP activates a cAMP-dependent protein kinase A (PK-A) that phosphorylates L-type Ca2+ channels, which causes increased calcium entry into the cells. Increased calcium entry during action potentials leads to enhanced release of calcium by the sarcoplasmic reticulum in the heart; these actions increase inotropy. PK-A phosphorylates sites on the sarcoplasmic reticulum, which enhances the release of calcium through the ryanodine receptors (ryanodine-sensitive, calcium-release channels) associated with the sarcoplasmic reticulum. This provides more calcium for binding the troponin-C (Troponin complex – C, I, T) which enhances inotropy. Finally, PK-A can phosphorylate myosin light chains, which may also contribute to the positive inotropic effect of beta1R stimulation. Together this causes more foceful contraction (positive inotropy).

f (funny) channel, If (funny current) from Na+/K+ INWARD current
f-channel has a duel feature of activation by:
i) Voltage – hyperpolarization
Mixed Na+/K+ INWARD current– If (funny current) –activated on hyperpolarization (-60mV, with threshold at -40mV). Without the membrane voltage becoming very negative at the end of phase 3, f-channels remain inactivated, which suppresses If currents and decreases the slope of phase 4.This is one reason why cellular hypoxia, which depolarizes the cell and alters phase 3 hyperpolarization, leads to a reduction in pacemaker rate (i.e., produces bradycardia).
ii) Cyclic nucleotides (cAMP)
cAMP binds directly to f-channels intracellularly and increases the open probablility.

• *SAN and AVN – as described above**
• *Spontaneuos tissue of the heart – SAN, AVN, Purjinkie fibers – exhibit** If (funny current) Na+/K+ INWARD current through the f- channel (HCN channel – Hyperpolarization-activated Cyclic Nucleotide-gated). Resting potential -60mV to -70mv is maintained by a continuous ouflow of K+ through K+ “leak” channels. SA node also innervated by parasympathetic CN X (Vagus nerve) and sympathetic T1-T4 with M2 receptors and beta1 receptors respectively.

ICaT (Transient)
T-type Ca2+ channel – Transient volage gated ion channel, activated around -55mV.

ICaL (Long lasting)
L-type Ca2+ channel – Long lasting voltage gated ion channel, activated by more postive voltages in phase 0-2.

• *Sympathetic – as described above**
• *Sympathic stimulation (T1-4)** by the relase of norepinephrine binds to beta1 receptors (GPCR) of the SAN which activates Gs and adenyl cyclase which raises intracellular cAMP and causes Na+/K+ to enter the cell. The increased Na+/K+ and If increases the slope of phase 4 toward an earlier depolarization causing increased heartrate (positive chromotropy) and increased conduction velocity through AVN (positive dromotropy).

**_Parasympathetic -- as described above_
Parasympathetic stimulation (CNX, Vagus)**releases**acetylcholine**which binds to**M2**(Muscarinic receptors, GPCR) at the**SAN**causing Gi to be activated which inhibits adenyl cyclase leading to a**decrease of intracellular cAMP,**and an opening of**KAch**channels (and closing of Ca2+ channels). The decreased Na+/K+ influx and K+ efflux**decreases If and the slope of phase 4**and**lowers heartrate**(**negative chronotropy),**and at the**AVN****reduced conduction velocity**(**negative dromotropy)**. 
Note: M2 receptor antagonists, **atropine**, causes **chronotropy and dromotropy but does not influence inotropy, as there is no PS innervation to ventricles ie. no M2 receptors.**

Drugs

Atropine
Anticholinergic. Antagonist of the M receptors. Antagonism of M2 receptors at SAN and AVN causes more S stimulation, a rise in cAMP, f-channel activation, Na+/K+ influx, increases the slope of phase 4 and a rise in heartrate (positive chronotropy), and faster conduction through AVN (positive dromotropy), and decreased atrial contraction. (**But no positive inotropy because no PS innervation to ventricles.) Antagonism of M3 receptors in the bronchus reduces secretions.
Some uses of Atropine are the following:
1. Bradycardia and AV block due to excessive vagal tone.
2. Reduce respiratory secretions.
3. Antidote to overdose of cholergic drugs or cholinesterase inhibitors such as in organophosphate poisoning.
4. Antidote to mushroom poisoning when alkoloid muscarine is involved.

Dobutamine
Sympathomimetic. Agonist of beta1R and slight agonist of beta2R. Agonism of beta1R at the SAN and AVN causes a rise in cAMP, which binds to f-channel, Na+/K+ influx, steeper phase 4 slope, and a rise in heartrate (positive chronotropy), faster conduction through AVN (positive dromotropy). Positive inotrophy on beta1R activation on myocytes through activation of Gs and adenyl cyclase, rise in cAMP and PKA causing more Ca2+ to enter the cell and consequent release of Ca2+ from sarcoplastic reticulum. Ca2+ binds to tronponin C.
Some uses of dobutamine are the following based on the positive chronotropic, dromotropic AND inotropic action:
1. Heart failure
2. Cardiogenic shock
3. Septic shock

Adenosine – nucloside
Purinergic receptors A1/A2 (found on pacemaker cells, and vascular smooth muscle cells).
On the SAN and AVN node, adenosine binds to the A1R activating Gi protein which opens K+ channels hyperpolarizing the cell, and the Gi protein also inhibits adenyl cyclase reducing cAMP. The reduction in cAMP causes less binding to f-channel, reduction in Na+/K+ influx, less steep phase 4 slope, and a drop in heartrate (negative chronotropy), slower conduction through AVN (negative dromotropy),

The reduction of cAMP also inhibits the L-type Ca2+ channel and Ca2+ into the cell. Inhibition of L-type Ca2+ channels also decreases conduction velocity (negative dromotropic effect) particularly at the atrioventricular (AV) nodes.

Finally, adenosine by acting on presynaptic purinergic receptors located on sympathetic nerve terminals inhibits the release of norepinephrine.

In coronary vascular smooth muscle, adenosine binds to adenosine type A2R, which are coupled to the Gs protein. Activation of Gs stimulates adenyl cyclase, increases cAMP and causes protein kinase activation. This stimulates KATP channels, which hyperpolarizes the smooth muscle, causing relaxation. Increased cAMP also causes smooth muscle relaxation by inhibiting myosin light chain kinase, which leads to decreased myosin phosphorylation and a decrease in contractile force.

Some uses of adenosine are the following:
Used to slow the electrical conduction of the heart or stablizie the heart rhythm.
1. SVT – causes momentary AV node heart block. Used in AVNRT but contraindicated in AVRT WPW because the blocked AV node encourages the accessory pathway in WPW (bundle of Kent) leading to ventricular fibrillation.
2. Stress tests – Endothelial-dependent relaxation of smooth muscle in arteries.

Question 7

Postural Hypotension

Answer 7

DDx]
Haim]
Hemorrhage
Dehydration(vomiting, diarrhea)

Meta]

• *Diabetes (neuropathy)**
• *Drugs –** diuretics, beta blockers, alpha blockers (Terazosin), vasodilators (CCBs, Hydralazine, Nitroglycerine).
• *Synucleinopathies** – Parkinsons, Lewy Body Dementia, Multiple System Atrophy (MSA). Alpha synuclein collecting in cell bodies and glial cells of the central and peripheral autonomic nerves.
• *Amyloidosis**

Hor]
Primary adrenal insufficiency (Addisons)

Org/(Neuros)]
Autonomic failure

Org/(Cardios)]
CHF

Immun]
nAChR autoantibodies

Oncos]
Paraneoplastic autoantibodies
(anti-Hu from small cell lung cancer)

Cong]
Familial dysautonomia (Riley Day Syndrome)

Etiology]
Delayed constriction of lower blood vessels when changing positions. Blood pools in lower legs and is not returned to the heart.

Blood pressure control is through chemoreceptors and baroreceptors found in the aortic arch and carotid bifurcation.

CNX Vagus in the aortic arch responds to increase and decrease in arterial BP transmitted TO nucleus tractus solitarus in medulla. CNIX Glossopharyngeal in the carotid bifurcation responds to increase in BP trasmitted TO nucleus tractus solitarus in medulla.

Arteries and veins have ONLY sympathetic innervation to the tunica media – thick smooth muscle in artery, thin smooth msucle in vein.

SAN and AVN have sympathetic (beta1) AND parasympathic innervation (M2). Ventricles have sympathetic innervation (beta1), atrium have slight parasympathetic innervation (M2).

Sympathetic stimulation of arteries and arterioles (resistance vessels) causes increased vascular resistance, increased arterial pressure and decreased distal blood flow. Sympathetic stimulation of veins (capacitance vessels) causes increased venous pressure and blood return to the heart. Alpha 1 and beta 2 receptors on the smooth muscle cells of the arteries, arterioles and veins respond to sympathetic stimulation (norepinphrine and epinephrine).

Standing causes pooling of blood in the lower extremities and splanchnic system (SMV, IMV) –> decreased venous return to the heart –> decreased CO (EF) and BP –> decreased stretch at aortic arch baroreceptors –> decreased afferent parasympathetic baroreceptor firing CNIX, CNX –> nucelus tractus soltaris prompts compensatory reflex (baroreceptor reflex) by increasing sympathetic outflow and decreasing parasympathetic outflow.

Orthostatic hypotension:

1. Cardiac
2. Fluid volume
3. ANS response

HPI]
Generalized weakness, sensations of dizziness or lightheadedness, visual blurring or less commonly syncope.

O/E] Orthostatic vitals
20mmHg fall in systolic or 10mmHg fall in diastolic upon standing.

Question 8

Aortic Stenosis

Answer 8

Etiology]
Infect]
Rheumatic aortic stenosis
Cong]
Congenital valvular aortic stenosis with bicuspid valves
Struct]
Degenerative calcified aortic stenosis

HPI]

• *SOBOE**
  1. Exertional shortness of breath or decreased exercise tolerance – less blood going to the muscles and more blood backed up in the lungs on exertion will cause sensation of shortness of breath.
• *Syncope**
  2. Exertional dizziness, presyncope or syncope – less blood going to the head on exertion will cause lightheadedness.
• *Angina or exertion**
  3. Exertional angina – left and right main coronary arteries come off the aortic bulb above the leaflets. Less blood going to heart on exertion will cause angina like pain.

O/E]
Cardios – midsystolic ejection murmur, crescendo and decrescendo, radiation to right carotid,
pulses parvus et tardus at radial pulse

INVESTIGATIO]
I]
ECG - LVH, tall R waves in many leads
ECHO - thickened leaflets and calcified, possible bicusped valve, pressure gradiant >40mmHg, Aortic Valve Area <1cm2, LVEF <50%, for severe

P/Surg] Aortic Valve Replacement

Question 9

Afib Anticoagulation and Risk

Valvular vs Nonvalvular

Answer 9

Double CHADS2 score to get an approximation of risk of stroke per year. CHADS2-VASC >= 2 gives a STRONG recommendation for oral anti-coagulation.

Note: Relative risk reduction of stroke by 2/3 with anti-coagulant and 20% with ASA. Although the effect of ASA to reduce the risk of stroke was not significant and one trail showed an increase in stroke.

Nonvalvular atrial fibrillation
Rivaroxaban {Xarelto} – factor Xa inhibitor
CrCl ≥50 mL/minute – 20mg PO OD
CrCl 30 to 49 mL/minute – 15 mg PO OD
CrCl <30 mL/minute – Avoid

• *Apixaban {Eliquis}** – factor Xa inhibitor
• *5mg PO BID**
• *2.5mg PO BID if any two of the following:**
  1. Age >or= 80
  2. Weight <or></or>3. Cr >or= 132umol/L, CrCl <15 mL/minute – Avoid

Valvular atrial fibrillation – Rheumatic heart disease/Mitral Stenosis or Mechanical Valve
Warfarin.

Question 10

Afib Thrombus

Answer 10

• *Virchow Triad**
• *1. Stasis**
• *2. Endothelial damage**
• *3. Hypercoaguability**
• *Stasis**
• *Dilated left atrium and left atrial appendage leads to more chance of stasis** in the left atrial appendage.Left ventricular dysfunction. SAVE trial showed 5% decrease in EF correlated with 18% increase in stroke.Poorly contracting left ventricle contributes to stasis.

Endothelial Damage
HTNdamages arising fromshear stress or hypertension. Contact with procoagulant surfaces. Bacteria,biomaterials,membranes of activated platelets, andmembranes of monocytes in chronic inflammation.

• *Hypercoaguability**
• *Hyperviscosity (high hematocrit), factor V Leiden mutation, factor II (prothrombin) G20210A mutation, antithrombin III deficiency, protein C or S deficiency, nephrotic syndrome, changes after severe trauma or burn, cancer, late pregnancy and delivery, cigarette smoking, hormonal contraceptives, and obesity.** All of these risk factors can cause the situation called hypercoagulability (excessively easy clotting of blood).

Note: factor V Leiden mutation is an autosomal dominant genetic condition with incomplete penetrance. The factor V Leiden variant is resistant to aPC (activated Protein C) degredation which leads to inappropriate clotting.

Note: factor II G20210A mutation produce an overabundance of factor II leading to a higher chance of clotting.

Note: Estrogen containing oral contraceptives increase the plasma concentrations of clotting factors II, VII, X, XII, factor VIII, fibrinogen, and thrombin activatable fibrinolysis inhibitor (TAFI). Not all of the increases in clotting factors are of the same magnitude. Factor VII appears to have the greatest magnitude of increase and factor VIII the least magnitude of increase, comparatively. Estrogen, like many lipophilic hormones, affects the gene transcription of various proteins. Thus, estrogen increases plasma concentrations of these clotting factors by increasing gene transcription.

Note: A hypercoagulable or prothrombotic state of malignancy occurs due to the ability of tumor cells to activate the coagulation system. Tumor cells to produce and secrete procoagulant/fibrinolytic substances and inflammatory cytokines. The physical interaction between tumor cell and blood (monocytes, platelets, neutrophils) or vascular cells can lead to endothelial damage.

Other mechanisms of thrombus promotion in malignancy include nonspecific factors such as the generation of acute phase reactants and necrosis (i.e., inflammation), abnormal protein metabolism (i.e., paraproteinemia), and hemodynamic compromise (i.e., stasis). Anticancer therapy (i.e., surgery/chemotherapy/hormone therapy) may significantly increase the risk of thromboembolic events by similar mechanisms, e.g., procoagulant release, endothelial damage, or stimulation of tissue factor production by host cells.

Question 11

NOAC and Afib

Non-vitamen K antagonist Oral Anti-coagulants

Answer 11

Dabigatran {Pradaxa} - prothrombin (IIa) inhibitor, and thrombin bound to fibrin.
CrCl>50 mL/minute – 150mg PO BID
CrCl 30-50 mL/minute – generall no issues except if > 75, then 110mg PO BID
CrCl<30 mL/minute – Avoid

Xarelto {Rivaroxaban} – factor Xa inhibitor
CrCl ≥50 mL/minute – 20mg PO OD
CrCl 30 to 49 mL/minute – 15 mg PO OD
CrCl <30 mL/minute – Avoid

Apixaban {Eliquis} – factor Xa inhibitor.
5mg PO BID
2.5mg PO BID if any two of the following:
1. Age >or= 80
2. Weight
3. Cr >or= 132umol/L
CrCl <15 mL/minute – Avoid

Question 12

HASBLED

Anticoag Bleeding Risk

Answer 12

Age]
Elderly > 65 (1)

PMHx]

• *S**troke (1)
• *H**TN - systolic > 160 (1)
• *B**lood - bleeding history or anemia (1)

Medications]
Drugs - antiplatet or NSAIDS (1)

SHx]
Drugs - alcohol > 8 drinks per week (1)

INVESTIGATIO]
L(H)/Haim | Org(Hepatos | Nephros)]
Labile INR - time in therapeutic range < 60% (1) Abnormal hepatos - cirrhosis, billirubin > 2xUNL OR ASL/ALT/AP > 3xUNL (1)
Abnormal nephros - dialysis, transplant, Cr > 200 (1)

Question 13

Hyperkalemia

Answer 13

Hyperkalemia

SAN
The higher concentration of K+ outside the cell, causes less K+ to leak out of the K+ leak channels, and increased intracellular voltage. The cell is now closer to threshold potential with increased RMP and steeper phase 4 – If channels and T-type Ca2+ channel open sooner, causing a increased heartrate.

• *Myocytes**
  1. More K+ outside the cell causes less driving force for “leaky” K+ to leave the cell shifting the resting membrane potential (RMP) toward depolarization (more positive). Early on in hyperkalemia the cells are more excitable.

2. The shifted RMP causes “some” fast Na+ channels to open and shut at the myocytes. The fast Na+ channels once activated have a mechanism to stop them from being reactivated (ball and chain), not allowing Na+ ions through.
3. There are “fewer” fast Na+ channels left that can respond raising the threshold potential. At this stage in hyperkalemia, the cells are LESS excitable. Due to the fewer fast Na+ channels available the phase 0 depolarization of the myocyte is slowed causing widened QRS complex.
4. In phase 2 and 3, K+ leaves the cell. IKr currents are sensitive to external K+ levels (a K+ ion holds the K+ channel open). As the external K+ concentration increaes, IKr increases out of the myocyte. Due to the increased IKr, phase 2 and 3 are shortened represented as ST-T depression, shortened QT interval, and peaked T waves.

Question 14

Hypokalemia

Answer 14

Hypokalemia

SAN
The lower concentration of K+ outside the cell, causes more K+ to leak out of the K+ leak channels, and decreased intracellular voltage. The cell is now farther from threshold potential with increased RMP and less steep phase 4 – If channels and T-type Ca2+ channel open later, causing a decreased heartrate.

• *Myocytes**
  1. Less K+ outside the cell causes more driving force for “leaky” K+ to leave the cell shifting the resting membrane potential (RMP) toward hyperpolarization (less positive).

2. Hyperpolarization causes “more” fast Na+ channels to be available at the myocytes. The fast Na+ channels once activated have a mechanism to stop them from being reactivated (ball and chain), not allowing Na+ ions through. Since the cell is hyperpolarized less fast Na+ channels are blocked by the ball and chain.
3. “More” fast Na+ channels can respond. At this stage in hypokalemia, the cells are MORE excitable. Due to having more fast Na+ channels available, the phase 0 depolarization of the myocyte is steep causing normal/narrow QRS complex.
4. In phase 2 and 3, K+ leaves the cell. IKr currents are sensitive to external K+ levels (a K+ ion holds the K+ channel open). As the external K+ concentration decreases, IKr decreases out of the myocyte as there are less K+ ions holding the K+ channels open. Due to the decreased IKr, phase 2 and 3 are legthened represented as lengthened QT interval, ST-T depression, and flat T waves with U waves.